Affiliations
Department of Infectious Diseases, Medicine Institute, Cleveland Clinic, Cleveland, Ohio
Given name(s)
Susan J.
Family name
Rehm
Degrees
MD

The pneumococcal gauntlet has been thrown: Can we pick it up?

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The pneumococcal gauntlet has been thrown: Can we pick it up?

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices has presented physicians with a challenge by adding the 13-valent pneumococcal conjugate vaccine to its protective roster for a subset of high-risk adults.

It’s wonderful that we have a new prevention tool. The question is how to ensure that it’s implemented when we are still far from perfect in fulfilling longstanding adult vaccination recommendations for the 23-valent pneumococcal polysaccharide vaccine (PPSV23). There are strategies and resources that can help us meet the pneumococcal vaccination needs of our patients, whether they require one or both vaccines.

The new recommendations call for one dose of 13-valent pneumococcal conjugate vaccine (PCV13), in addition to PPSV23, for adults with immunocompromising conditions (including HIV infection), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants (MMWR 2012;61:816-19). The Advisory Committee on Immunization Practices did not change recommendations for other adults. Adults who are at least 65 years old who smoke or have chronic conditions such as alcoholism, asthma, diabetes, or heart disease should receive PPSV23 only.

These recommendations are in place for good reason. Case fatality rates for pneumococcal bacteremia and meningitis are as high as 20%-30%. Pneumococcal pneumonia is less dangerous, with mortality of 5%-7%, but it is much more prevalent, leading to 175,000 hospitalizations in the United States annually.

Adults with chronic conditions such as diabetes and heart disease have up to ten times as great a risk for invasive pneumococcal disease (IPD), compared with healthy individuals. For immunocompromised patients, such as those with HIV or cancer, the risk is 173 and 186 times greater, respectively (J. Infect. Dis. 2005;192:377-86). Every effort should be made to protect these adults from pneumococcal infection.

Dr. Susan J. Rehm

Vaccination provides the best chance of protection against invasive disease, yet compliance is low. According to the most recent National Health Interview Survey data, 64.7% of adults who are at least 65 years old have received a pneumococcal vaccination, up from 59.7% in 2010. We are still a long way from reaching Healthy People 2020 objectives. Rates among younger adults are even more disappointing. Only 18.5% of working-age adults with a pneumococcal vaccine indication have received it (MMWR 2012;61:66-72).

Another reason for pneumococcal vaccination is that secondary bacteremic pneumococcal pneumonia can be a major complication of flu. Pneumococcal vaccine, which can be administered at the same time as flu vaccine, may have an impact on this life-threatening complication.

There are many strategies that health care professionals can implement to address this public health problem (Postgrad. Med. 2012;124:71-79). A good place to start is to become familiar with the recommendations, educate caregivers, and engage clinical and ancillary staff in screening and vaccinating patients as appropriate (National Foundation for Infectious Diseases, Pneumococcal Vaccination Is Everyone’s Responsibility, April 2012).

The vaccination approach, including potential sequencing of PCV13 and PPSV23, varies depending on a patient’s risk condition and history. Vaccine-naive adults with an indication for PPSV23 should receive only a first dose immediately, with a second dose at age 65 years (or later if less than 5 years has elapsed). Dosing for those with a PCV13 indication is more complicated, but the sequence is outlined in several resources, including an Adult Pneumococcal Vaccination Guide.

Dr. Thomas M. File

Further, every pneumococcal discussion opens the door for identifying other vaccination needs such as influenza, Tdap, and hepatitis B, which is now indicated for adults aged 19-59 years with diabetes (MMWR 2011;60:1709-11). Tools to support these efforts are available at the NFID, the CDC, and the Immunization Action Coalition.

Dr. Rehm is medical director of the National Foundation for Infectious Diseases and vice chair of the department of infectious diseases at the Cleveland Clinic. She is a member of advisory boards for Becton Dickenson, Merck, and Pfizer.

Dr. File is president of NFID and chair of the division of infectious disease at Summa Health System in Akron, Ohio. He is a consultant and/or a member of advisory boards for Astellas, Bayer, Cerexa/Forest, DaiichiSankyo, Durata, GSK, Merck, Pfizer, and Tetraphase.

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The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices has presented physicians with a challenge by adding the 13-valent pneumococcal conjugate vaccine to its protective roster for a subset of high-risk adults.

It’s wonderful that we have a new prevention tool. The question is how to ensure that it’s implemented when we are still far from perfect in fulfilling longstanding adult vaccination recommendations for the 23-valent pneumococcal polysaccharide vaccine (PPSV23). There are strategies and resources that can help us meet the pneumococcal vaccination needs of our patients, whether they require one or both vaccines.

The new recommendations call for one dose of 13-valent pneumococcal conjugate vaccine (PCV13), in addition to PPSV23, for adults with immunocompromising conditions (including HIV infection), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants (MMWR 2012;61:816-19). The Advisory Committee on Immunization Practices did not change recommendations for other adults. Adults who are at least 65 years old who smoke or have chronic conditions such as alcoholism, asthma, diabetes, or heart disease should receive PPSV23 only.

These recommendations are in place for good reason. Case fatality rates for pneumococcal bacteremia and meningitis are as high as 20%-30%. Pneumococcal pneumonia is less dangerous, with mortality of 5%-7%, but it is much more prevalent, leading to 175,000 hospitalizations in the United States annually.

Adults with chronic conditions such as diabetes and heart disease have up to ten times as great a risk for invasive pneumococcal disease (IPD), compared with healthy individuals. For immunocompromised patients, such as those with HIV or cancer, the risk is 173 and 186 times greater, respectively (J. Infect. Dis. 2005;192:377-86). Every effort should be made to protect these adults from pneumococcal infection.

Dr. Susan J. Rehm

Vaccination provides the best chance of protection against invasive disease, yet compliance is low. According to the most recent National Health Interview Survey data, 64.7% of adults who are at least 65 years old have received a pneumococcal vaccination, up from 59.7% in 2010. We are still a long way from reaching Healthy People 2020 objectives. Rates among younger adults are even more disappointing. Only 18.5% of working-age adults with a pneumococcal vaccine indication have received it (MMWR 2012;61:66-72).

Another reason for pneumococcal vaccination is that secondary bacteremic pneumococcal pneumonia can be a major complication of flu. Pneumococcal vaccine, which can be administered at the same time as flu vaccine, may have an impact on this life-threatening complication.

There are many strategies that health care professionals can implement to address this public health problem (Postgrad. Med. 2012;124:71-79). A good place to start is to become familiar with the recommendations, educate caregivers, and engage clinical and ancillary staff in screening and vaccinating patients as appropriate (National Foundation for Infectious Diseases, Pneumococcal Vaccination Is Everyone’s Responsibility, April 2012).

The vaccination approach, including potential sequencing of PCV13 and PPSV23, varies depending on a patient’s risk condition and history. Vaccine-naive adults with an indication for PPSV23 should receive only a first dose immediately, with a second dose at age 65 years (or later if less than 5 years has elapsed). Dosing for those with a PCV13 indication is more complicated, but the sequence is outlined in several resources, including an Adult Pneumococcal Vaccination Guide.

Dr. Thomas M. File

Further, every pneumococcal discussion opens the door for identifying other vaccination needs such as influenza, Tdap, and hepatitis B, which is now indicated for adults aged 19-59 years with diabetes (MMWR 2011;60:1709-11). Tools to support these efforts are available at the NFID, the CDC, and the Immunization Action Coalition.

Dr. Rehm is medical director of the National Foundation for Infectious Diseases and vice chair of the department of infectious diseases at the Cleveland Clinic. She is a member of advisory boards for Becton Dickenson, Merck, and Pfizer.

Dr. File is president of NFID and chair of the division of infectious disease at Summa Health System in Akron, Ohio. He is a consultant and/or a member of advisory boards for Astellas, Bayer, Cerexa/Forest, DaiichiSankyo, Durata, GSK, Merck, Pfizer, and Tetraphase.

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices has presented physicians with a challenge by adding the 13-valent pneumococcal conjugate vaccine to its protective roster for a subset of high-risk adults.

It’s wonderful that we have a new prevention tool. The question is how to ensure that it’s implemented when we are still far from perfect in fulfilling longstanding adult vaccination recommendations for the 23-valent pneumococcal polysaccharide vaccine (PPSV23). There are strategies and resources that can help us meet the pneumococcal vaccination needs of our patients, whether they require one or both vaccines.

The new recommendations call for one dose of 13-valent pneumococcal conjugate vaccine (PCV13), in addition to PPSV23, for adults with immunocompromising conditions (including HIV infection), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants (MMWR 2012;61:816-19). The Advisory Committee on Immunization Practices did not change recommendations for other adults. Adults who are at least 65 years old who smoke or have chronic conditions such as alcoholism, asthma, diabetes, or heart disease should receive PPSV23 only.

These recommendations are in place for good reason. Case fatality rates for pneumococcal bacteremia and meningitis are as high as 20%-30%. Pneumococcal pneumonia is less dangerous, with mortality of 5%-7%, but it is much more prevalent, leading to 175,000 hospitalizations in the United States annually.

Adults with chronic conditions such as diabetes and heart disease have up to ten times as great a risk for invasive pneumococcal disease (IPD), compared with healthy individuals. For immunocompromised patients, such as those with HIV or cancer, the risk is 173 and 186 times greater, respectively (J. Infect. Dis. 2005;192:377-86). Every effort should be made to protect these adults from pneumococcal infection.

Dr. Susan J. Rehm

Vaccination provides the best chance of protection against invasive disease, yet compliance is low. According to the most recent National Health Interview Survey data, 64.7% of adults who are at least 65 years old have received a pneumococcal vaccination, up from 59.7% in 2010. We are still a long way from reaching Healthy People 2020 objectives. Rates among younger adults are even more disappointing. Only 18.5% of working-age adults with a pneumococcal vaccine indication have received it (MMWR 2012;61:66-72).

Another reason for pneumococcal vaccination is that secondary bacteremic pneumococcal pneumonia can be a major complication of flu. Pneumococcal vaccine, which can be administered at the same time as flu vaccine, may have an impact on this life-threatening complication.

There are many strategies that health care professionals can implement to address this public health problem (Postgrad. Med. 2012;124:71-79). A good place to start is to become familiar with the recommendations, educate caregivers, and engage clinical and ancillary staff in screening and vaccinating patients as appropriate (National Foundation for Infectious Diseases, Pneumococcal Vaccination Is Everyone’s Responsibility, April 2012).

The vaccination approach, including potential sequencing of PCV13 and PPSV23, varies depending on a patient’s risk condition and history. Vaccine-naive adults with an indication for PPSV23 should receive only a first dose immediately, with a second dose at age 65 years (or later if less than 5 years has elapsed). Dosing for those with a PCV13 indication is more complicated, but the sequence is outlined in several resources, including an Adult Pneumococcal Vaccination Guide.

Dr. Thomas M. File

Further, every pneumococcal discussion opens the door for identifying other vaccination needs such as influenza, Tdap, and hepatitis B, which is now indicated for adults aged 19-59 years with diabetes (MMWR 2011;60:1709-11). Tools to support these efforts are available at the NFID, the CDC, and the Immunization Action Coalition.

Dr. Rehm is medical director of the National Foundation for Infectious Diseases and vice chair of the department of infectious diseases at the Cleveland Clinic. She is a member of advisory boards for Becton Dickenson, Merck, and Pfizer.

Dr. File is president of NFID and chair of the division of infectious disease at Summa Health System in Akron, Ohio. He is a consultant and/or a member of advisory boards for Astellas, Bayer, Cerexa/Forest, DaiichiSankyo, Durata, GSK, Merck, Pfizer, and Tetraphase.

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The pneumococcal gauntlet has been thrown: Can we pick it up?
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Contribution of Predischarge ID Consult

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Contribution of infectious disease consultation toward the care of inpatients being considered for community‐based parenteral anti‐infective therapy

With dramatically increasing costs of healthcare, it has become increasingly necessary for healthcare providers to demonstrate value in the delivery of care. Porter and Teisberg have strongly advocated that healthcare reform efforts should focus on improving value rather than limiting cost, with value being defined as quality per unit cost.1 However, it has been pointed out that value means different things to different people.2 The biggest challenge in defining value stems mainly from the difficulty in defining quality, because it, too, means vastly different things to different people. Modern medicine is increasingly characterized by multidisciplinary care. With limited or shrinking resources, it will become necessary for individual specialists to describe and articulate, in quantitative terms, their specific contributions to the overall outcome of individual patients.

Previous publications have provided broad descriptions of the value provided by infectious disease (ID) specialists in the domains of sepsis, infection control, outpatient antibiotic therapy, antimicrobial stewardship, and directive care and teaching.3, 4 Studies have also shown the value of ID physicians in specific disease conditions. ID consultation is associated with lower mortality5, 6 and lower relapse rates7 in hospitalized patients with Staphylococcus aureus bacteremia. In another study evaluating the impact of ID consultants, patients seen by ID consultants had longer lengths of hospital stay, longer intensive care unit lengths of stay, and higher antibiotic costs than matched controls not seen by ID consultants.8 It can be argued that a major limitation of the study was that controls were not matched for the ID diagnosis, nor for the causative microorganisms, but it is clear that ID physicians are challenged to demonstrate their contribution to the care of patients.

A unique activity of ID physicians is the management of community‐based parenteral anti‐infective therapy (CoPAT). At Baystate Medical Center, a policy of mandatory ID consultation was instituted for patients leaving hospital on parenteral antibiotics. A study was conducted on the impact of predischarge ID consultation for 44 patients who were not already being followed by the ID service. The study documented change from intravenous (IV) to oral formulation, change of antibiotic choice, and change of dose/duration of treatment in a substantial proportion of patients.9 These are significant changes, but ID consultation contributes more than the themes explored in the study.

The purpose of this study was to evaluate the contribution of ID consultation when consulted for CoPAT, an activity specific to ID practice, in a different institution, and using an expanded definition of medical contribution.

METHODS

The Cleveland Clinic's Department of Infectious Disease has 24 staff physicians and 11 inpatient ID consultative services. These include: 2 solid organ transplant services; a bone marrow transplant and oncologic service; 2 infective endocarditis/cardiac device infection services; an intensive care unit (ICU) service; a bone and joint infection service; a neuroinfection service; and 3 general ID consult services. Consultative services are provided 7 days a week. At the Cleveland Clinic, ID consultation is required prior to discharge on parenteral antibiotic therapy.10, 11 ID consultation for CoPAT usually occurs when the primary service deems the patient is close to being discharged from hospital. This circumstance allows for assessing the specific contribution of ID physicians beyond that of the primary service and other consulting services.

Case Ascertainment

The study was approved by the institutional review board. In February 2010, an electronic form for requesting ID consultations had been introduced into the computerized provider order entry (CPOE) system at the Cleveland Clinic. One of the required questions on the form was whether the consultation was regarding CoPAT, with options of Yes, No, or Not sure. These electronic ID consultation requests were screened to identify consultation requests for this study.

Inclusion and Exclusion Criteria

All adult ID consultations between February 11, 2010 and May 15, 2010 for which the CoPAT consult? field was marked Yes were included in the study. All other consultations, including not sure for CoPAT, were excluded.

Definitions

The first ID consultation during a hospitalization was considered an initial consultation. ID consultations for patients whom an ID service had previously seen during the same hospitalization were deemed reconsultations. Value provided was defined as contribution of the ID consultation team in the following domains: 1) optimization of antimicrobial therapy, 2) significant change in patient assessment, 3) additional medical care contribution. Specific contributions included in each domain are outlined in Table 1.

Definitions of ID Contributions in the Identified Domains
  • Abbreviation: ID, infectious disease.

Domain 1: Optimization of antibiotic therapy
Alteration of an antibiotic (change of antibiotic or route of administration)
Defining duration of therapy
Identification of psychosocial factors (eg, injection drug use) that influence treatment
Domain 2: Significant change in patient assessment
Diagnosis of an infectious process
Better appreciation of extent of disease
Refutation of a false infectious disease diagnosis
Recognition of a noninfectious process needing urgent attention
Identification of a positive culture as contaminant/colonization
Recognition of a need for additional testing (testing needed to arrive at a diagnosis or clarify a treatment plan before a patient could be safely discharged from hospital)
Recognition of need for surgery/emnvasive intervention
Refutation of antibiotic allergy by history or allergy testing
Domain 3: Additional medical care contribution
Administration of vaccines
Identification of an unrecognized medical problem that needed to be addressed after discharge from hospital
Provision of effective transition of care (ensuring that the same ID physician who saw the patient in hospital followed the patient after discharge from hospital)

Data Collected

For each ID consultation episode, clinicians' notes were reviewed from the day of the ID consultation to the day the patient was discharged from hospital or the day the ID service signed off, whichever happened sooner. Results of recommended tests were followed up to determine if results led to a change in patient assessment. Data elements collected for each consultation episode included patient age, gender, race, date of hospitalization, date of discharge, date of ID consultation or reconsultation, primary service, and documentation of ID service contributions. Data were collected and entered in a Microsoft Access relational database. To minimize bias, the data collection was performed by physicians who had not participated in the care of the patient.

Analysis

The proportion of ID consultations in which the ID team contributed in the defined domains were enumerated, and described for the group overall and also separately for initial consultations and reconsultations.

RESULTS

In the time period studied, there were 1326 CPOE requests for ID consultation. The response to the question, CoPAT consult? was Yes for 304, No for 507, and Not sure for 515 requests. Of the 304 consultation requests marked Yes, 41 were excluded. Reasons for exclusion were: no ID consultation note (21), wrong service consulted (8), consultation request placed while the ID service was already following the patient (7), and duplicate consultation request (5). The remaining 263 consultation requests corresponded to 1 or more CoPAT consultation requests for 249 patients (across different hospitalizations). Of the 263 consultation requests, 172 were initial consultations, while the remaining 91 were reconsultations (patients not actively being followed by the ID service, but previously seen during the same hospitalization).

Consultation characteristics are outlined in Table 2. The most common group of infections for which CoPAT was sought was bone and joint infections, accounting for over 20% of the consultation requests. CoPAT consultations were requested a median of 4 days after hospitalization. Patients were discharged from hospital a median of 3 days after they were seen by the ID service. ID consultation did not delay discharge. The ID service usually saw the patient the same day, and followed the patient in hospital for a median of 1 day. There was no difference in hospital days after consult for patients who did not need antibiotics versus those who did.

Consultation Characteristics
Characteristic Initial Consultation [172] n (%)* Reconsultation [91] n (%)* Overall [263] n (%)*
  • Abbreviations: ID, infectious disease; IQR, interquartile range; IV, intravenous; SD, standard deviation.

  • Unless otherwise specified.

Patient age in years, mean (SD) 58 (14) 62 (13) 59 (14)
Male gender 98 (60) 91 (56) 149 (57)
Caucasian race 126 (73) 74 (81) 200 (76)
Services requesting consults (5 most common overall)
Medicine 41 (17) 14 (15) 55 (21)
Orthopedics 34 (14) 0 (0) 34 (13)
Hematology/Oncology 16 (7) 10 (11) 26 (10)
Cardiology 9 (4) 15 (16) 24 (9)
Gastroenterology 14 (6) 5 (5) 19 (7)
Consult diagnosis (5 most common overall)
Bone and joint infection 45 (26) 9 (10) 54 (21)
Skin or soft tissue infection or rash 21 (12) 8 (9) 29 (11)
Endocarditis or cardiac device infection 7 (4) 15 (16) 22 (8)
IV catheter or other endovascular infection 9 (5) 8 (9) 17 (6)
Urinary tract infection 12 (7) 5 (5) 17 (6)
Days from admission to ID consult, median (IQR) 4 (1‐11) 7 (2‐19) 4 (1‐14)
Days to respond to consult request, median (IQR) 0 (0‐1) 0 (0‐0) 0 (0‐0)
Days from ID consult to discharge, median (IQR) 3 (2‐7) 2 (1‐4.5) 3 (1‐6)

ID consultation provided value in at least 1 domain in 260 of the 263 consultations. This included optimization of antimicrobial treatment in 84%, significant alteration of patient assessment in 52%, and additional medical care contribution in 71% of consultations. Substantial contributions were made in all domains in both initial consultations and in reconsultations. Specific ID contributions within each of the domains are shown in Figure 1. There was wide overlap of contributions across the 3 domains for individual consultations (Figure 2), with contributions in all domains occurring in 34% of consultations. CoPAT was deemed not to be necessary in 27% of consultations. Among patients who did not require CoPAT, 60% received oral antibiotics and 40% were deemed not to need any antibiotics at hospital discharge. Among the patients discharged on CoPAT, a follow‐up appointment with a Cleveland Clinic ID physician familiar with the patient was set up 86% of the time; the rest either followed up with another physician or it was deemed that a scheduled follow‐up ID visit was not necessary.0

Figure 1
Specific infectious disease (ID) contributions with numbers of consultations in which they were made (total of 263 consultations).
Figure 2
Venn diagram showing overlap of contributions in the different domains for individual consultations.

DISCUSSION

Physicians practicing in the specialty of infectious diseases face challenges and opportunities, as they adapt to changing demands within hospital practice in regard to reimbursement in an Accountable Care environment. Other challenges include emerging infections, antimicrobial resistance, need for antimicrobial stewardship, and increasing numbers of immunocompromised patients.12 From a health systems perspective, the overall value of care provided by the entire organization, and overall outcomes, are ultimately what matter. However, healthcare administrators need an appreciation of contributions of individual providers and specialties to fairly allocate resources and compensation for care provided. Articulating unique contributions is particularly challenging for individuals or services that provide purely cognitive input. Shrinking healthcare resources makes it critically important for cognitive specialists to be able to define their unique role in the care of patients with complex problems.

Our study found that a major contribution of ID consultation for CoPAT is that the process identifies a large number of patients who do not need CoPAT, thus effecting a powerful antimicrobial stewardship function. In our study, CoPAT was deemed unnecessary 27% of the time. The Infectious Diseases Society of America practice guidelines on outpatient parenteral antimicrobial therapy emphasize the importance of careful evaluation of patients considered for parenteral antibiotics outside the hospital setting.13 The focus on careful selection of appropriate patients for CoPAT has been a cornerstone of the Cleveland Clinic model of care. Nearly 30 years ago, we found that outpatient parenteral antibiotic therapy was unnecessary or not feasible in 40% of the patients referred for evaluation.10 If we adjust the numbers with the assumption that reimbursement issues present at that time are now less of an issue, the proportion of patients who were referred for CoPAT but not discharged on it was 29%, a figure remarkably similar to that found in the current study.

Another major contribution of ID consultation is the provision of effective transition of care from the inpatient to the outpatient setting. Frequent occurrence of postdischarge adverse events has been recognized as a problem in clinical practice.14 Primary care physicians are rarely involved in discussions about hospital discharge.15 A consensus conference including the American College of Physicians, Society of Hospital Medicine, and Society of General Internal Medicine, convened in July 2007 to address quality gaps in transitions of care between inpatient and outpatient settings. It identified 5 principles for effective care transitions: accountability, communication, timeliness, patient and family involvement, and respect for the hub of coordination of care.16 Recognizing gaps in care transition, hospitalists in a hospital‐based infusion program developed a model of care that successfully bridged the hospital‐to‐home care transition for patients who could return to hospital for daily antimicrobial infusions.17 In our system, ID physicians take ownership for directing parenteral antibiotic therapy for the episode of illness, specifying the physician, date, and time of follow‐up before the patient is discharged from hospital, thereby essentially satisfying the principles of effective care transitions identified. The purpose of the ID follow‐up is not to replace other follow‐up care for patients but to ensure safe transition of care while treating an episode of infection.

Attribution of identified contributions to the ID consultation could be done because our study was limited to CoPAT consultations. Such consultations typically occur when patients are deemed close to hospital discharge by the primary service. There should be little controversy about attribution of cognitive input in such consultations, because from the primary service's perspective, the patient is ready or almost ready to be discharged from hospital. It would be fair to state that most of the identified contributions in the study would not have occurred had it not been for the ID consultation.

We acknowledge that the study suffers from many limitations. The biggest limitation is that the contribution elements are defined by ID physicians and sought in the medical record by physicians from the same specialty. This arrangement certainly has potential for significant bias. To limit this bias, data collection was performed by physicians who had not participated in the care of the patient. In addition, we only could assess what was documented in the electronic health record. Our study found that alteration of antibiotic therapy was a substantial contribution, however, documentation of recommendation to change antibiotics in the medical record rarely specified exactly why the change was recommended. Reasons for antibiotic change recommendations included bug‐drug mismatch, minimum inhibitory concentration (MIC) considerations, pharmacokinetic considerations, adverse effects, convenience of dosing, drug interactions, and insurance coverage. However, it is not possible to quantify the specific contribution of each of these reasons, in a retrospective study, without making assumptions about why specific ID physicians made specific antibiotic change recommendations. There may have been more contributions that might not have been apparent on a retrospective chart review. The lack of a control group also lessens the impact of our findings. We could not have a control group, because no patient is discharged from the Cleveland Clinic on CoPAT without having been seen by an ID physician. Mandatory ID consultation for CoPAT has previously been shown to reduce costs,9 however, our study was not designed to evaluate cost.

The perceived value of ID consultation in our institution can be appreciated when one considers the longstanding institutional policy of requiring ID consultation for CoPAT.10, 11 The perpetuation of this tradition in the hospital is testament to the presumption that mandatory ID consultation is seen to be of value by the institution.

In summary, ID consultation in our institution contributes to the care of inpatients being considered for CoPAT by substantially reducing unnecessary parenteral antibiotic use, optimizing antibiotic therapy, recognizing need for additional testing before discharge from hospital, and by providing effective transition of care from the inpatient to the outpatient setting.

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References
  1. Porter ME,Teisberg EO.How physicians can change the future of health care.JAMA.2007;297:11031111.
  2. Wenzel RP.Value of the infectious diseases specialist.Clin Infect Dis.1997;24:456.
  3. Petrak RM,Sexton DJ,Butera ML, et al.The value of an infectious diseases specialist.Clin Infect Dis.2003;36:10131017.
  4. McQuillen DP,Petrak RM,Wasserman RB,Nahass RG,Scull JA,Martinelli LP.The value of infectious diseases specialists: non‐patient care activities.Clin Infect Dis.2008;47:10511063.
  5. Honda H,Krauss MJ,Jones JC,Olsen MA,Warren DK.The value of infectious diseases consultation in Staphylococcus aureus bacteremia.Am J Med.2010;123:631637.
  6. Lahey T,Shah R,Gittzus J,Schwartzman J,Kirkland K.Infectious diseases consultation lowers mortality from Staphylococcus aureus bacteremia.Medicine (Baltimore).2009;88:263267.
  7. Fowler VG,Sanders LL,Sexton DJ, et al.Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious diseases specialists: experience with 244 patients.Clin Infect Dis.1998;27:478486.
  8. Classen DC,Burke JP,Wenzel RP.Infectious diseases consultation: impact on outcomes for hospitalized patients and results of a preliminary study.Clin Infect Dis.1997;24:468470.
  9. Sharma R,Loomis W,Brown RB.Impact of mandatory inpatient infectious disease consultation on outpatient parenteral antibiotic therapy.Am J Med Sci.2005;330:6064.
  10. Rehm SJ,Weinstein AJ.Home intravenous antibiotic therapy: a team approach.Ann Intern Med.1983;99:388392.
  11. Gordon SM,Shrestha NK,Rehm SJ.Transitioning antimicrobial stewardship beyond the hospital: the Cleveland Clinic's community‐based parenteral anti‐infective therapy (CoPAT) program.J Hosp Med.2011;6(suppl 1):S24S30.
  12. Read RC,Cornaglia G,Kahlmeter G.Professional challenges and opportunities in clinical microbiology and infectious diseases in Europe.Lancet Infect Dis.2011;11:408415.
  13. Tice AD,Rehm SJ,Dalovisio JR, et al.Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines.Clin Infect Dis.2004;38:16511672.
  14. Tsilimingras D,Bates DW.Addressing postdischarge adverse events: a neglected area.Jt Comm J Qual Patient Saf.2008;34:8597.
  15. Kripalani S,LeFevre F,Phillips CO,Williams MV,Basaviah P,Baker DW.Deficits in communication and information transfer between hospital‐based and primary care physicians: implications for patient safety and continuity of care.JAMA.2007;297:831841.
  16. Snow V,Beck D,Budnitz T, et al.Transitions of Care Consensus policy statement: American College of Physicians, Society of General Internal Medicine, Society of Hospital Medicine, American Geriatrics Society, American College of Emergency Physicians, and Society for Academic Emergency Medicine.J Hosp Med.2009;4:364370.
  17. Nguyen HH.Hospitalist to home: outpatient parenteral antimicrobial therapy at an academic center.Clin Infect Dis.2010;51(suppl 2):S220S223.
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With dramatically increasing costs of healthcare, it has become increasingly necessary for healthcare providers to demonstrate value in the delivery of care. Porter and Teisberg have strongly advocated that healthcare reform efforts should focus on improving value rather than limiting cost, with value being defined as quality per unit cost.1 However, it has been pointed out that value means different things to different people.2 The biggest challenge in defining value stems mainly from the difficulty in defining quality, because it, too, means vastly different things to different people. Modern medicine is increasingly characterized by multidisciplinary care. With limited or shrinking resources, it will become necessary for individual specialists to describe and articulate, in quantitative terms, their specific contributions to the overall outcome of individual patients.

Previous publications have provided broad descriptions of the value provided by infectious disease (ID) specialists in the domains of sepsis, infection control, outpatient antibiotic therapy, antimicrobial stewardship, and directive care and teaching.3, 4 Studies have also shown the value of ID physicians in specific disease conditions. ID consultation is associated with lower mortality5, 6 and lower relapse rates7 in hospitalized patients with Staphylococcus aureus bacteremia. In another study evaluating the impact of ID consultants, patients seen by ID consultants had longer lengths of hospital stay, longer intensive care unit lengths of stay, and higher antibiotic costs than matched controls not seen by ID consultants.8 It can be argued that a major limitation of the study was that controls were not matched for the ID diagnosis, nor for the causative microorganisms, but it is clear that ID physicians are challenged to demonstrate their contribution to the care of patients.

A unique activity of ID physicians is the management of community‐based parenteral anti‐infective therapy (CoPAT). At Baystate Medical Center, a policy of mandatory ID consultation was instituted for patients leaving hospital on parenteral antibiotics. A study was conducted on the impact of predischarge ID consultation for 44 patients who were not already being followed by the ID service. The study documented change from intravenous (IV) to oral formulation, change of antibiotic choice, and change of dose/duration of treatment in a substantial proportion of patients.9 These are significant changes, but ID consultation contributes more than the themes explored in the study.

The purpose of this study was to evaluate the contribution of ID consultation when consulted for CoPAT, an activity specific to ID practice, in a different institution, and using an expanded definition of medical contribution.

METHODS

The Cleveland Clinic's Department of Infectious Disease has 24 staff physicians and 11 inpatient ID consultative services. These include: 2 solid organ transplant services; a bone marrow transplant and oncologic service; 2 infective endocarditis/cardiac device infection services; an intensive care unit (ICU) service; a bone and joint infection service; a neuroinfection service; and 3 general ID consult services. Consultative services are provided 7 days a week. At the Cleveland Clinic, ID consultation is required prior to discharge on parenteral antibiotic therapy.10, 11 ID consultation for CoPAT usually occurs when the primary service deems the patient is close to being discharged from hospital. This circumstance allows for assessing the specific contribution of ID physicians beyond that of the primary service and other consulting services.

Case Ascertainment

The study was approved by the institutional review board. In February 2010, an electronic form for requesting ID consultations had been introduced into the computerized provider order entry (CPOE) system at the Cleveland Clinic. One of the required questions on the form was whether the consultation was regarding CoPAT, with options of Yes, No, or Not sure. These electronic ID consultation requests were screened to identify consultation requests for this study.

Inclusion and Exclusion Criteria

All adult ID consultations between February 11, 2010 and May 15, 2010 for which the CoPAT consult? field was marked Yes were included in the study. All other consultations, including not sure for CoPAT, were excluded.

Definitions

The first ID consultation during a hospitalization was considered an initial consultation. ID consultations for patients whom an ID service had previously seen during the same hospitalization were deemed reconsultations. Value provided was defined as contribution of the ID consultation team in the following domains: 1) optimization of antimicrobial therapy, 2) significant change in patient assessment, 3) additional medical care contribution. Specific contributions included in each domain are outlined in Table 1.

Definitions of ID Contributions in the Identified Domains
  • Abbreviation: ID, infectious disease.

Domain 1: Optimization of antibiotic therapy
Alteration of an antibiotic (change of antibiotic or route of administration)
Defining duration of therapy
Identification of psychosocial factors (eg, injection drug use) that influence treatment
Domain 2: Significant change in patient assessment
Diagnosis of an infectious process
Better appreciation of extent of disease
Refutation of a false infectious disease diagnosis
Recognition of a noninfectious process needing urgent attention
Identification of a positive culture as contaminant/colonization
Recognition of a need for additional testing (testing needed to arrive at a diagnosis or clarify a treatment plan before a patient could be safely discharged from hospital)
Recognition of need for surgery/emnvasive intervention
Refutation of antibiotic allergy by history or allergy testing
Domain 3: Additional medical care contribution
Administration of vaccines
Identification of an unrecognized medical problem that needed to be addressed after discharge from hospital
Provision of effective transition of care (ensuring that the same ID physician who saw the patient in hospital followed the patient after discharge from hospital)

Data Collected

For each ID consultation episode, clinicians' notes were reviewed from the day of the ID consultation to the day the patient was discharged from hospital or the day the ID service signed off, whichever happened sooner. Results of recommended tests were followed up to determine if results led to a change in patient assessment. Data elements collected for each consultation episode included patient age, gender, race, date of hospitalization, date of discharge, date of ID consultation or reconsultation, primary service, and documentation of ID service contributions. Data were collected and entered in a Microsoft Access relational database. To minimize bias, the data collection was performed by physicians who had not participated in the care of the patient.

Analysis

The proportion of ID consultations in which the ID team contributed in the defined domains were enumerated, and described for the group overall and also separately for initial consultations and reconsultations.

RESULTS

In the time period studied, there were 1326 CPOE requests for ID consultation. The response to the question, CoPAT consult? was Yes for 304, No for 507, and Not sure for 515 requests. Of the 304 consultation requests marked Yes, 41 were excluded. Reasons for exclusion were: no ID consultation note (21), wrong service consulted (8), consultation request placed while the ID service was already following the patient (7), and duplicate consultation request (5). The remaining 263 consultation requests corresponded to 1 or more CoPAT consultation requests for 249 patients (across different hospitalizations). Of the 263 consultation requests, 172 were initial consultations, while the remaining 91 were reconsultations (patients not actively being followed by the ID service, but previously seen during the same hospitalization).

Consultation characteristics are outlined in Table 2. The most common group of infections for which CoPAT was sought was bone and joint infections, accounting for over 20% of the consultation requests. CoPAT consultations were requested a median of 4 days after hospitalization. Patients were discharged from hospital a median of 3 days after they were seen by the ID service. ID consultation did not delay discharge. The ID service usually saw the patient the same day, and followed the patient in hospital for a median of 1 day. There was no difference in hospital days after consult for patients who did not need antibiotics versus those who did.

Consultation Characteristics
Characteristic Initial Consultation [172] n (%)* Reconsultation [91] n (%)* Overall [263] n (%)*
  • Abbreviations: ID, infectious disease; IQR, interquartile range; IV, intravenous; SD, standard deviation.

  • Unless otherwise specified.

Patient age in years, mean (SD) 58 (14) 62 (13) 59 (14)
Male gender 98 (60) 91 (56) 149 (57)
Caucasian race 126 (73) 74 (81) 200 (76)
Services requesting consults (5 most common overall)
Medicine 41 (17) 14 (15) 55 (21)
Orthopedics 34 (14) 0 (0) 34 (13)
Hematology/Oncology 16 (7) 10 (11) 26 (10)
Cardiology 9 (4) 15 (16) 24 (9)
Gastroenterology 14 (6) 5 (5) 19 (7)
Consult diagnosis (5 most common overall)
Bone and joint infection 45 (26) 9 (10) 54 (21)
Skin or soft tissue infection or rash 21 (12) 8 (9) 29 (11)
Endocarditis or cardiac device infection 7 (4) 15 (16) 22 (8)
IV catheter or other endovascular infection 9 (5) 8 (9) 17 (6)
Urinary tract infection 12 (7) 5 (5) 17 (6)
Days from admission to ID consult, median (IQR) 4 (1‐11) 7 (2‐19) 4 (1‐14)
Days to respond to consult request, median (IQR) 0 (0‐1) 0 (0‐0) 0 (0‐0)
Days from ID consult to discharge, median (IQR) 3 (2‐7) 2 (1‐4.5) 3 (1‐6)

ID consultation provided value in at least 1 domain in 260 of the 263 consultations. This included optimization of antimicrobial treatment in 84%, significant alteration of patient assessment in 52%, and additional medical care contribution in 71% of consultations. Substantial contributions were made in all domains in both initial consultations and in reconsultations. Specific ID contributions within each of the domains are shown in Figure 1. There was wide overlap of contributions across the 3 domains for individual consultations (Figure 2), with contributions in all domains occurring in 34% of consultations. CoPAT was deemed not to be necessary in 27% of consultations. Among patients who did not require CoPAT, 60% received oral antibiotics and 40% were deemed not to need any antibiotics at hospital discharge. Among the patients discharged on CoPAT, a follow‐up appointment with a Cleveland Clinic ID physician familiar with the patient was set up 86% of the time; the rest either followed up with another physician or it was deemed that a scheduled follow‐up ID visit was not necessary.0

Figure 1
Specific infectious disease (ID) contributions with numbers of consultations in which they were made (total of 263 consultations).
Figure 2
Venn diagram showing overlap of contributions in the different domains for individual consultations.

DISCUSSION

Physicians practicing in the specialty of infectious diseases face challenges and opportunities, as they adapt to changing demands within hospital practice in regard to reimbursement in an Accountable Care environment. Other challenges include emerging infections, antimicrobial resistance, need for antimicrobial stewardship, and increasing numbers of immunocompromised patients.12 From a health systems perspective, the overall value of care provided by the entire organization, and overall outcomes, are ultimately what matter. However, healthcare administrators need an appreciation of contributions of individual providers and specialties to fairly allocate resources and compensation for care provided. Articulating unique contributions is particularly challenging for individuals or services that provide purely cognitive input. Shrinking healthcare resources makes it critically important for cognitive specialists to be able to define their unique role in the care of patients with complex problems.

Our study found that a major contribution of ID consultation for CoPAT is that the process identifies a large number of patients who do not need CoPAT, thus effecting a powerful antimicrobial stewardship function. In our study, CoPAT was deemed unnecessary 27% of the time. The Infectious Diseases Society of America practice guidelines on outpatient parenteral antimicrobial therapy emphasize the importance of careful evaluation of patients considered for parenteral antibiotics outside the hospital setting.13 The focus on careful selection of appropriate patients for CoPAT has been a cornerstone of the Cleveland Clinic model of care. Nearly 30 years ago, we found that outpatient parenteral antibiotic therapy was unnecessary or not feasible in 40% of the patients referred for evaluation.10 If we adjust the numbers with the assumption that reimbursement issues present at that time are now less of an issue, the proportion of patients who were referred for CoPAT but not discharged on it was 29%, a figure remarkably similar to that found in the current study.

Another major contribution of ID consultation is the provision of effective transition of care from the inpatient to the outpatient setting. Frequent occurrence of postdischarge adverse events has been recognized as a problem in clinical practice.14 Primary care physicians are rarely involved in discussions about hospital discharge.15 A consensus conference including the American College of Physicians, Society of Hospital Medicine, and Society of General Internal Medicine, convened in July 2007 to address quality gaps in transitions of care between inpatient and outpatient settings. It identified 5 principles for effective care transitions: accountability, communication, timeliness, patient and family involvement, and respect for the hub of coordination of care.16 Recognizing gaps in care transition, hospitalists in a hospital‐based infusion program developed a model of care that successfully bridged the hospital‐to‐home care transition for patients who could return to hospital for daily antimicrobial infusions.17 In our system, ID physicians take ownership for directing parenteral antibiotic therapy for the episode of illness, specifying the physician, date, and time of follow‐up before the patient is discharged from hospital, thereby essentially satisfying the principles of effective care transitions identified. The purpose of the ID follow‐up is not to replace other follow‐up care for patients but to ensure safe transition of care while treating an episode of infection.

Attribution of identified contributions to the ID consultation could be done because our study was limited to CoPAT consultations. Such consultations typically occur when patients are deemed close to hospital discharge by the primary service. There should be little controversy about attribution of cognitive input in such consultations, because from the primary service's perspective, the patient is ready or almost ready to be discharged from hospital. It would be fair to state that most of the identified contributions in the study would not have occurred had it not been for the ID consultation.

We acknowledge that the study suffers from many limitations. The biggest limitation is that the contribution elements are defined by ID physicians and sought in the medical record by physicians from the same specialty. This arrangement certainly has potential for significant bias. To limit this bias, data collection was performed by physicians who had not participated in the care of the patient. In addition, we only could assess what was documented in the electronic health record. Our study found that alteration of antibiotic therapy was a substantial contribution, however, documentation of recommendation to change antibiotics in the medical record rarely specified exactly why the change was recommended. Reasons for antibiotic change recommendations included bug‐drug mismatch, minimum inhibitory concentration (MIC) considerations, pharmacokinetic considerations, adverse effects, convenience of dosing, drug interactions, and insurance coverage. However, it is not possible to quantify the specific contribution of each of these reasons, in a retrospective study, without making assumptions about why specific ID physicians made specific antibiotic change recommendations. There may have been more contributions that might not have been apparent on a retrospective chart review. The lack of a control group also lessens the impact of our findings. We could not have a control group, because no patient is discharged from the Cleveland Clinic on CoPAT without having been seen by an ID physician. Mandatory ID consultation for CoPAT has previously been shown to reduce costs,9 however, our study was not designed to evaluate cost.

The perceived value of ID consultation in our institution can be appreciated when one considers the longstanding institutional policy of requiring ID consultation for CoPAT.10, 11 The perpetuation of this tradition in the hospital is testament to the presumption that mandatory ID consultation is seen to be of value by the institution.

In summary, ID consultation in our institution contributes to the care of inpatients being considered for CoPAT by substantially reducing unnecessary parenteral antibiotic use, optimizing antibiotic therapy, recognizing need for additional testing before discharge from hospital, and by providing effective transition of care from the inpatient to the outpatient setting.

With dramatically increasing costs of healthcare, it has become increasingly necessary for healthcare providers to demonstrate value in the delivery of care. Porter and Teisberg have strongly advocated that healthcare reform efforts should focus on improving value rather than limiting cost, with value being defined as quality per unit cost.1 However, it has been pointed out that value means different things to different people.2 The biggest challenge in defining value stems mainly from the difficulty in defining quality, because it, too, means vastly different things to different people. Modern medicine is increasingly characterized by multidisciplinary care. With limited or shrinking resources, it will become necessary for individual specialists to describe and articulate, in quantitative terms, their specific contributions to the overall outcome of individual patients.

Previous publications have provided broad descriptions of the value provided by infectious disease (ID) specialists in the domains of sepsis, infection control, outpatient antibiotic therapy, antimicrobial stewardship, and directive care and teaching.3, 4 Studies have also shown the value of ID physicians in specific disease conditions. ID consultation is associated with lower mortality5, 6 and lower relapse rates7 in hospitalized patients with Staphylococcus aureus bacteremia. In another study evaluating the impact of ID consultants, patients seen by ID consultants had longer lengths of hospital stay, longer intensive care unit lengths of stay, and higher antibiotic costs than matched controls not seen by ID consultants.8 It can be argued that a major limitation of the study was that controls were not matched for the ID diagnosis, nor for the causative microorganisms, but it is clear that ID physicians are challenged to demonstrate their contribution to the care of patients.

A unique activity of ID physicians is the management of community‐based parenteral anti‐infective therapy (CoPAT). At Baystate Medical Center, a policy of mandatory ID consultation was instituted for patients leaving hospital on parenteral antibiotics. A study was conducted on the impact of predischarge ID consultation for 44 patients who were not already being followed by the ID service. The study documented change from intravenous (IV) to oral formulation, change of antibiotic choice, and change of dose/duration of treatment in a substantial proportion of patients.9 These are significant changes, but ID consultation contributes more than the themes explored in the study.

The purpose of this study was to evaluate the contribution of ID consultation when consulted for CoPAT, an activity specific to ID practice, in a different institution, and using an expanded definition of medical contribution.

METHODS

The Cleveland Clinic's Department of Infectious Disease has 24 staff physicians and 11 inpatient ID consultative services. These include: 2 solid organ transplant services; a bone marrow transplant and oncologic service; 2 infective endocarditis/cardiac device infection services; an intensive care unit (ICU) service; a bone and joint infection service; a neuroinfection service; and 3 general ID consult services. Consultative services are provided 7 days a week. At the Cleveland Clinic, ID consultation is required prior to discharge on parenteral antibiotic therapy.10, 11 ID consultation for CoPAT usually occurs when the primary service deems the patient is close to being discharged from hospital. This circumstance allows for assessing the specific contribution of ID physicians beyond that of the primary service and other consulting services.

Case Ascertainment

The study was approved by the institutional review board. In February 2010, an electronic form for requesting ID consultations had been introduced into the computerized provider order entry (CPOE) system at the Cleveland Clinic. One of the required questions on the form was whether the consultation was regarding CoPAT, with options of Yes, No, or Not sure. These electronic ID consultation requests were screened to identify consultation requests for this study.

Inclusion and Exclusion Criteria

All adult ID consultations between February 11, 2010 and May 15, 2010 for which the CoPAT consult? field was marked Yes were included in the study. All other consultations, including not sure for CoPAT, were excluded.

Definitions

The first ID consultation during a hospitalization was considered an initial consultation. ID consultations for patients whom an ID service had previously seen during the same hospitalization were deemed reconsultations. Value provided was defined as contribution of the ID consultation team in the following domains: 1) optimization of antimicrobial therapy, 2) significant change in patient assessment, 3) additional medical care contribution. Specific contributions included in each domain are outlined in Table 1.

Definitions of ID Contributions in the Identified Domains
  • Abbreviation: ID, infectious disease.

Domain 1: Optimization of antibiotic therapy
Alteration of an antibiotic (change of antibiotic or route of administration)
Defining duration of therapy
Identification of psychosocial factors (eg, injection drug use) that influence treatment
Domain 2: Significant change in patient assessment
Diagnosis of an infectious process
Better appreciation of extent of disease
Refutation of a false infectious disease diagnosis
Recognition of a noninfectious process needing urgent attention
Identification of a positive culture as contaminant/colonization
Recognition of a need for additional testing (testing needed to arrive at a diagnosis or clarify a treatment plan before a patient could be safely discharged from hospital)
Recognition of need for surgery/emnvasive intervention
Refutation of antibiotic allergy by history or allergy testing
Domain 3: Additional medical care contribution
Administration of vaccines
Identification of an unrecognized medical problem that needed to be addressed after discharge from hospital
Provision of effective transition of care (ensuring that the same ID physician who saw the patient in hospital followed the patient after discharge from hospital)

Data Collected

For each ID consultation episode, clinicians' notes were reviewed from the day of the ID consultation to the day the patient was discharged from hospital or the day the ID service signed off, whichever happened sooner. Results of recommended tests were followed up to determine if results led to a change in patient assessment. Data elements collected for each consultation episode included patient age, gender, race, date of hospitalization, date of discharge, date of ID consultation or reconsultation, primary service, and documentation of ID service contributions. Data were collected and entered in a Microsoft Access relational database. To minimize bias, the data collection was performed by physicians who had not participated in the care of the patient.

Analysis

The proportion of ID consultations in which the ID team contributed in the defined domains were enumerated, and described for the group overall and also separately for initial consultations and reconsultations.

RESULTS

In the time period studied, there were 1326 CPOE requests for ID consultation. The response to the question, CoPAT consult? was Yes for 304, No for 507, and Not sure for 515 requests. Of the 304 consultation requests marked Yes, 41 were excluded. Reasons for exclusion were: no ID consultation note (21), wrong service consulted (8), consultation request placed while the ID service was already following the patient (7), and duplicate consultation request (5). The remaining 263 consultation requests corresponded to 1 or more CoPAT consultation requests for 249 patients (across different hospitalizations). Of the 263 consultation requests, 172 were initial consultations, while the remaining 91 were reconsultations (patients not actively being followed by the ID service, but previously seen during the same hospitalization).

Consultation characteristics are outlined in Table 2. The most common group of infections for which CoPAT was sought was bone and joint infections, accounting for over 20% of the consultation requests. CoPAT consultations were requested a median of 4 days after hospitalization. Patients were discharged from hospital a median of 3 days after they were seen by the ID service. ID consultation did not delay discharge. The ID service usually saw the patient the same day, and followed the patient in hospital for a median of 1 day. There was no difference in hospital days after consult for patients who did not need antibiotics versus those who did.

Consultation Characteristics
Characteristic Initial Consultation [172] n (%)* Reconsultation [91] n (%)* Overall [263] n (%)*
  • Abbreviations: ID, infectious disease; IQR, interquartile range; IV, intravenous; SD, standard deviation.

  • Unless otherwise specified.

Patient age in years, mean (SD) 58 (14) 62 (13) 59 (14)
Male gender 98 (60) 91 (56) 149 (57)
Caucasian race 126 (73) 74 (81) 200 (76)
Services requesting consults (5 most common overall)
Medicine 41 (17) 14 (15) 55 (21)
Orthopedics 34 (14) 0 (0) 34 (13)
Hematology/Oncology 16 (7) 10 (11) 26 (10)
Cardiology 9 (4) 15 (16) 24 (9)
Gastroenterology 14 (6) 5 (5) 19 (7)
Consult diagnosis (5 most common overall)
Bone and joint infection 45 (26) 9 (10) 54 (21)
Skin or soft tissue infection or rash 21 (12) 8 (9) 29 (11)
Endocarditis or cardiac device infection 7 (4) 15 (16) 22 (8)
IV catheter or other endovascular infection 9 (5) 8 (9) 17 (6)
Urinary tract infection 12 (7) 5 (5) 17 (6)
Days from admission to ID consult, median (IQR) 4 (1‐11) 7 (2‐19) 4 (1‐14)
Days to respond to consult request, median (IQR) 0 (0‐1) 0 (0‐0) 0 (0‐0)
Days from ID consult to discharge, median (IQR) 3 (2‐7) 2 (1‐4.5) 3 (1‐6)

ID consultation provided value in at least 1 domain in 260 of the 263 consultations. This included optimization of antimicrobial treatment in 84%, significant alteration of patient assessment in 52%, and additional medical care contribution in 71% of consultations. Substantial contributions were made in all domains in both initial consultations and in reconsultations. Specific ID contributions within each of the domains are shown in Figure 1. There was wide overlap of contributions across the 3 domains for individual consultations (Figure 2), with contributions in all domains occurring in 34% of consultations. CoPAT was deemed not to be necessary in 27% of consultations. Among patients who did not require CoPAT, 60% received oral antibiotics and 40% were deemed not to need any antibiotics at hospital discharge. Among the patients discharged on CoPAT, a follow‐up appointment with a Cleveland Clinic ID physician familiar with the patient was set up 86% of the time; the rest either followed up with another physician or it was deemed that a scheduled follow‐up ID visit was not necessary.0

Figure 1
Specific infectious disease (ID) contributions with numbers of consultations in which they were made (total of 263 consultations).
Figure 2
Venn diagram showing overlap of contributions in the different domains for individual consultations.

DISCUSSION

Physicians practicing in the specialty of infectious diseases face challenges and opportunities, as they adapt to changing demands within hospital practice in regard to reimbursement in an Accountable Care environment. Other challenges include emerging infections, antimicrobial resistance, need for antimicrobial stewardship, and increasing numbers of immunocompromised patients.12 From a health systems perspective, the overall value of care provided by the entire organization, and overall outcomes, are ultimately what matter. However, healthcare administrators need an appreciation of contributions of individual providers and specialties to fairly allocate resources and compensation for care provided. Articulating unique contributions is particularly challenging for individuals or services that provide purely cognitive input. Shrinking healthcare resources makes it critically important for cognitive specialists to be able to define their unique role in the care of patients with complex problems.

Our study found that a major contribution of ID consultation for CoPAT is that the process identifies a large number of patients who do not need CoPAT, thus effecting a powerful antimicrobial stewardship function. In our study, CoPAT was deemed unnecessary 27% of the time. The Infectious Diseases Society of America practice guidelines on outpatient parenteral antimicrobial therapy emphasize the importance of careful evaluation of patients considered for parenteral antibiotics outside the hospital setting.13 The focus on careful selection of appropriate patients for CoPAT has been a cornerstone of the Cleveland Clinic model of care. Nearly 30 years ago, we found that outpatient parenteral antibiotic therapy was unnecessary or not feasible in 40% of the patients referred for evaluation.10 If we adjust the numbers with the assumption that reimbursement issues present at that time are now less of an issue, the proportion of patients who were referred for CoPAT but not discharged on it was 29%, a figure remarkably similar to that found in the current study.

Another major contribution of ID consultation is the provision of effective transition of care from the inpatient to the outpatient setting. Frequent occurrence of postdischarge adverse events has been recognized as a problem in clinical practice.14 Primary care physicians are rarely involved in discussions about hospital discharge.15 A consensus conference including the American College of Physicians, Society of Hospital Medicine, and Society of General Internal Medicine, convened in July 2007 to address quality gaps in transitions of care between inpatient and outpatient settings. It identified 5 principles for effective care transitions: accountability, communication, timeliness, patient and family involvement, and respect for the hub of coordination of care.16 Recognizing gaps in care transition, hospitalists in a hospital‐based infusion program developed a model of care that successfully bridged the hospital‐to‐home care transition for patients who could return to hospital for daily antimicrobial infusions.17 In our system, ID physicians take ownership for directing parenteral antibiotic therapy for the episode of illness, specifying the physician, date, and time of follow‐up before the patient is discharged from hospital, thereby essentially satisfying the principles of effective care transitions identified. The purpose of the ID follow‐up is not to replace other follow‐up care for patients but to ensure safe transition of care while treating an episode of infection.

Attribution of identified contributions to the ID consultation could be done because our study was limited to CoPAT consultations. Such consultations typically occur when patients are deemed close to hospital discharge by the primary service. There should be little controversy about attribution of cognitive input in such consultations, because from the primary service's perspective, the patient is ready or almost ready to be discharged from hospital. It would be fair to state that most of the identified contributions in the study would not have occurred had it not been for the ID consultation.

We acknowledge that the study suffers from many limitations. The biggest limitation is that the contribution elements are defined by ID physicians and sought in the medical record by physicians from the same specialty. This arrangement certainly has potential for significant bias. To limit this bias, data collection was performed by physicians who had not participated in the care of the patient. In addition, we only could assess what was documented in the electronic health record. Our study found that alteration of antibiotic therapy was a substantial contribution, however, documentation of recommendation to change antibiotics in the medical record rarely specified exactly why the change was recommended. Reasons for antibiotic change recommendations included bug‐drug mismatch, minimum inhibitory concentration (MIC) considerations, pharmacokinetic considerations, adverse effects, convenience of dosing, drug interactions, and insurance coverage. However, it is not possible to quantify the specific contribution of each of these reasons, in a retrospective study, without making assumptions about why specific ID physicians made specific antibiotic change recommendations. There may have been more contributions that might not have been apparent on a retrospective chart review. The lack of a control group also lessens the impact of our findings. We could not have a control group, because no patient is discharged from the Cleveland Clinic on CoPAT without having been seen by an ID physician. Mandatory ID consultation for CoPAT has previously been shown to reduce costs,9 however, our study was not designed to evaluate cost.

The perceived value of ID consultation in our institution can be appreciated when one considers the longstanding institutional policy of requiring ID consultation for CoPAT.10, 11 The perpetuation of this tradition in the hospital is testament to the presumption that mandatory ID consultation is seen to be of value by the institution.

In summary, ID consultation in our institution contributes to the care of inpatients being considered for CoPAT by substantially reducing unnecessary parenteral antibiotic use, optimizing antibiotic therapy, recognizing need for additional testing before discharge from hospital, and by providing effective transition of care from the inpatient to the outpatient setting.

References
  1. Porter ME,Teisberg EO.How physicians can change the future of health care.JAMA.2007;297:11031111.
  2. Wenzel RP.Value of the infectious diseases specialist.Clin Infect Dis.1997;24:456.
  3. Petrak RM,Sexton DJ,Butera ML, et al.The value of an infectious diseases specialist.Clin Infect Dis.2003;36:10131017.
  4. McQuillen DP,Petrak RM,Wasserman RB,Nahass RG,Scull JA,Martinelli LP.The value of infectious diseases specialists: non‐patient care activities.Clin Infect Dis.2008;47:10511063.
  5. Honda H,Krauss MJ,Jones JC,Olsen MA,Warren DK.The value of infectious diseases consultation in Staphylococcus aureus bacteremia.Am J Med.2010;123:631637.
  6. Lahey T,Shah R,Gittzus J,Schwartzman J,Kirkland K.Infectious diseases consultation lowers mortality from Staphylococcus aureus bacteremia.Medicine (Baltimore).2009;88:263267.
  7. Fowler VG,Sanders LL,Sexton DJ, et al.Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious diseases specialists: experience with 244 patients.Clin Infect Dis.1998;27:478486.
  8. Classen DC,Burke JP,Wenzel RP.Infectious diseases consultation: impact on outcomes for hospitalized patients and results of a preliminary study.Clin Infect Dis.1997;24:468470.
  9. Sharma R,Loomis W,Brown RB.Impact of mandatory inpatient infectious disease consultation on outpatient parenteral antibiotic therapy.Am J Med Sci.2005;330:6064.
  10. Rehm SJ,Weinstein AJ.Home intravenous antibiotic therapy: a team approach.Ann Intern Med.1983;99:388392.
  11. Gordon SM,Shrestha NK,Rehm SJ.Transitioning antimicrobial stewardship beyond the hospital: the Cleveland Clinic's community‐based parenteral anti‐infective therapy (CoPAT) program.J Hosp Med.2011;6(suppl 1):S24S30.
  12. Read RC,Cornaglia G,Kahlmeter G.Professional challenges and opportunities in clinical microbiology and infectious diseases in Europe.Lancet Infect Dis.2011;11:408415.
  13. Tice AD,Rehm SJ,Dalovisio JR, et al.Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines.Clin Infect Dis.2004;38:16511672.
  14. Tsilimingras D,Bates DW.Addressing postdischarge adverse events: a neglected area.Jt Comm J Qual Patient Saf.2008;34:8597.
  15. Kripalani S,LeFevre F,Phillips CO,Williams MV,Basaviah P,Baker DW.Deficits in communication and information transfer between hospital‐based and primary care physicians: implications for patient safety and continuity of care.JAMA.2007;297:831841.
  16. Snow V,Beck D,Budnitz T, et al.Transitions of Care Consensus policy statement: American College of Physicians, Society of General Internal Medicine, Society of Hospital Medicine, American Geriatrics Society, American College of Emergency Physicians, and Society for Academic Emergency Medicine.J Hosp Med.2009;4:364370.
  17. Nguyen HH.Hospitalist to home: outpatient parenteral antimicrobial therapy at an academic center.Clin Infect Dis.2010;51(suppl 2):S220S223.
References
  1. Porter ME,Teisberg EO.How physicians can change the future of health care.JAMA.2007;297:11031111.
  2. Wenzel RP.Value of the infectious diseases specialist.Clin Infect Dis.1997;24:456.
  3. Petrak RM,Sexton DJ,Butera ML, et al.The value of an infectious diseases specialist.Clin Infect Dis.2003;36:10131017.
  4. McQuillen DP,Petrak RM,Wasserman RB,Nahass RG,Scull JA,Martinelli LP.The value of infectious diseases specialists: non‐patient care activities.Clin Infect Dis.2008;47:10511063.
  5. Honda H,Krauss MJ,Jones JC,Olsen MA,Warren DK.The value of infectious diseases consultation in Staphylococcus aureus bacteremia.Am J Med.2010;123:631637.
  6. Lahey T,Shah R,Gittzus J,Schwartzman J,Kirkland K.Infectious diseases consultation lowers mortality from Staphylococcus aureus bacteremia.Medicine (Baltimore).2009;88:263267.
  7. Fowler VG,Sanders LL,Sexton DJ, et al.Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious diseases specialists: experience with 244 patients.Clin Infect Dis.1998;27:478486.
  8. Classen DC,Burke JP,Wenzel RP.Infectious diseases consultation: impact on outcomes for hospitalized patients and results of a preliminary study.Clin Infect Dis.1997;24:468470.
  9. Sharma R,Loomis W,Brown RB.Impact of mandatory inpatient infectious disease consultation on outpatient parenteral antibiotic therapy.Am J Med Sci.2005;330:6064.
  10. Rehm SJ,Weinstein AJ.Home intravenous antibiotic therapy: a team approach.Ann Intern Med.1983;99:388392.
  11. Gordon SM,Shrestha NK,Rehm SJ.Transitioning antimicrobial stewardship beyond the hospital: the Cleveland Clinic's community‐based parenteral anti‐infective therapy (CoPAT) program.J Hosp Med.2011;6(suppl 1):S24S30.
  12. Read RC,Cornaglia G,Kahlmeter G.Professional challenges and opportunities in clinical microbiology and infectious diseases in Europe.Lancet Infect Dis.2011;11:408415.
  13. Tice AD,Rehm SJ,Dalovisio JR, et al.Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines.Clin Infect Dis.2004;38:16511672.
  14. Tsilimingras D,Bates DW.Addressing postdischarge adverse events: a neglected area.Jt Comm J Qual Patient Saf.2008;34:8597.
  15. Kripalani S,LeFevre F,Phillips CO,Williams MV,Basaviah P,Baker DW.Deficits in communication and information transfer between hospital‐based and primary care physicians: implications for patient safety and continuity of care.JAMA.2007;297:831841.
  16. Snow V,Beck D,Budnitz T, et al.Transitions of Care Consensus policy statement: American College of Physicians, Society of General Internal Medicine, Society of Hospital Medicine, American Geriatrics Society, American College of Emergency Physicians, and Society for Academic Emergency Medicine.J Hosp Med.2009;4:364370.
  17. Nguyen HH.Hospitalist to home: outpatient parenteral antimicrobial therapy at an academic center.Clin Infect Dis.2010;51(suppl 2):S220S223.
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Transitioning antimicrobial stewardship beyond the hospital: The cleveland clinic's community‐based parenteral anti‐infective therapy (CoPAT) program

. . . For the secret of the care of the patient is caring for the patient.Francis W. Peabody, October 21, 19251

Collaboration between members of a multidisciplinary team is a key component of an effective institutional antimicrobial stewardship program, which itself is a key component of optimizing the care of hospitalized patients being treated with antimicrobial agents for proven or suspected infectious diseases. However, patient care does not and should not end once the patient is discharged from the hospital. In fact, high‐quality, value‐based health care across the full range of a medical condition depends on planning for optimization of care within the hospital as well as transitions of care to the outpatient setting. This extended care plan includes collaboration with multiple members of the health care community, both inside and outside the institution. The current review examines 3 aspects of patient care across the full cycle of an infectious disease condition: (1) value‐based health care, (2) stewardship of antimicrobials, and (3) community‐based parenteral anti‐infective therapy (CoPAT) as a model for antimicrobial stewardship outside the institutional setting.

Value‐Based Health Care

Patients first want to know that the health care professionals treating them actually care about them as individuals, and only then are patients concerned about how much the medical team knows. Patient‐centered care is a critical component of value‐based health care, a term that was bandied about quite a bit during the recent and ongoing health care debate in the United States. But what exactly does it mean? First, value in health care is defined by health care outcomes as a function of or divided by the cost of delivery of care. As Dr. Michael Porter and Dr. Elizabeth Olmsted Teisberg delineated in their 2007 article in the Journal of the American Medical Association,2 as well as in the 2006 book Redefining Health Care,3 The purpose of the healthcare system is not to minimize costs but to deliver value to patients, that is, better health per dollar spent. As they discuss value, it is a patient‐centric measure, and is focused on individual patient (not just diagnosis‐related group) outcomes and the cost of care across the full cycle. In this way of looking at things, an episode of care goes beyond the treatment provided during the acute admission to also include the transition of care to the outpatient or posthospital setting.

The reforms proposed by Porter and Teisberg are best achieved when the participating health care institutions have developed an information technology platform able to integrate and fully measure care across the full cycle of a medical condition. Furthermore, there is strong evidence that patient value increases with physician and team experience and volume for a particular condition.2 High volumes tend to correlate with the development of better information technology, as well as the formation of dedicated teams with tailored facilities, and with a greater capacity for constructive feedback to improve patient outcomes. The more experience a physician and team have with the management of a particular medical condition, the greater is the opportunity to learn and refine practices to provide greater value to the patient.

The Institute of Medicine has recommended that all healthcare professionals should be educated to deliver patient‐centered care as members of an interdisciplinary team emphasizing evidence‐based practice, quality improvement, and informatics.4 As has been demonstrated for patients with congestive heart failure59 and other conditions,10, 11 outcomes improve when components of care are integrated (often by nurse‐directed teams), preparing for the transition of care from the hospital to the home.12 This concept is the basis for the community‐based parenteral anti‐infective therapy program (CoPAT) at the Cleveland Clinic as a model for antimicrobial stewardship for patients requiring parenteral antimicrobial therapy at the time of discharge from the inpatient setting.

Stewardship of Antimicrobials

The Merriam‐Webster dictionary alternatively defines a steward as: (1) an employee on a ship, airplane, bus, or train who manages the provisioning of food and attends to passengers or (2) one who actively manages affairs (manager).13 In the context of health care within an institution, one can think of clinicians as stewards or employees charged with managing patients and the drugs and other care they receive while they are attendants (passengers) at the institution. In the value‐based approach just discussed, where medical practice is organized around managing medical conditions for the entire care cycle, a medical steward would also be charged with managing or planning for patient care after discharge from the hospital or other institutional setting. Management or stewardship of antimicrobial agents is a key component of the care for patients with infectious diseases. In 2007, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America (IDSA/SHEA) presented guidelines to aid institutions in the development of an effective hospital‐based antimicrobial stewardship program (a more detailed overview of antimicrobial stewardship is presented in the accompanying supplemental article by Dr. Ohl).14 The focus of the IDSA/SHEA guidelines was on development of programs within hospitals. Although the authors acknowledged that antimicrobial stewardship is also important in outpatient clinics and long‐term care facilities, transition of antimicrobial management after patient discharge from the hospital was not a focus of the 2007 guidelines.

A key objective of antimicrobial stewardship is to optimize antimicrobial drug selection and dosing to improve clinical outcomes while reducing drug toxicity and other potential untoward consequences of antimicrobial therapy, including selection of opportunistic organisms (eg, Clostridium difficile) or emergence of multidrug resistance in pathogens.14 A secondary objective is to reduce overall health care costs,14 which ideally would include inpatient as well as outpatient costs and those related to hospital readmission due to the initial infection or its outpatient treatment. Useful metrics for evaluation of an antimicrobial stewardship program include measures of pathogen/drug mismatch, antimicrobial costs, incidence of redundant therapy, compliance with antimicrobial drug restrictions (if applicable), days undergoing antimicrobial therapy, and number of cases of intravenous to oral conversion.14

Although the IDSA/SHEA guidelines for institutional antimicrobial stewardship programs suggest that an infectious diseases physician and clinical pharmacist with infectious diseases training should be core members of a multidisciplinary stewardship team,14 many community hospitals or smaller institutions do not have an infectious diseases physician or a readily available infectious diseases specialist for consultation. Hospitalists are often very effective advocates of appropriate use of antimicrobials and may play a leadership role on institutional antimicrobial stewardship teams. A recent study demonstrated that a hospitalist‐delivered academic detailing intervention (which included an individual appraisal of the provider's prescription pattern) significantly improved patterns of antibiotic prescribing for inpatients.15

Community‐Based Parenteral Anti‐Infective Therapy as a Systems‐Based Approach to Antimicrobial Stewardship

A systems‐based approach for antimicrobial stewardship, CoPAT has been in operation at the Cleveland Clinic, a 1200‐bed hospital in downtown Cleveland, Ohio, since November 1979. The experiences of the authors and their colleagues demonstrate it to be a value‐based proposition for the patient that uses an antimicrobial stewardship platform. Also known as outpatient parenteral antimicrobial therapy (OPAT), CoPAT refers to the practice of administering antimicrobial therapy in the home or other outpatient settings, first introduced by Rucker and Harrison in 1974 in the context of outpatient management of cystic fibrosis.16 In the United States, CoPAT is a common practice today, and the IDSA has created practice guidelines for it.17

In 1983, Rehm and Weinstein coauthored an article describing their experiences at the Cleveland Clinic, in which selected patients were trained for home‐based antimicrobial therapy.12 Figure 1 illustrates the astronomical growth that has occurred over the years at the Cleveland Clinic in the number of patients discharged from the acute care center undergoing CoPAT (Gordon, unpublished data). It is anticipated that this growth will continue and in large part reflects the complexity of patients being seen and the desire to reduce length of stay. Evaluating the quality of any medical care is difficult, but there are 3 general approaches to assessing or measuring the quality of medical care: assessing the structure of care, assessing processes of care, and assessing outcomes.18 The quality of the CoPAT program at the Cleveland Clinic can be examined in the context of these 3 areas of assessment.

Figure 1
Cleveland Clinic Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) volumes by year (Gordon, unpublished data).

Settings or the Structure of Care

In a 1966 publication on quality of medical care evaluations, Donabedian described assessment of the structure of care as one of the primary approaches to measuring the quality of care.18 By structure, Donabedian meant the settings in which medical care takes place, including the adequacy of facilities and equipment, qualifications or expertise of medical staff and their organization, the administrative structure of the institution or institutional program of interest, and other administrative and related processes supporting and directing the delivery of care. Although the structure of care has the advantage of being concrete and relatively easy to assess, to be most meaningful, it ultimately needs to be related to the processes and outcomes of care.

With respect to the CoPAT program at the Cleveland Clinic main hospital, infectious diseases consultation is required for every patient being considered for discharge with parenteral antibiotics, whether the patient is going home or to another facility, including the clinic's own skilled nursing facility (SNF). Arrangements are then made for the delivery of antibiotics at home or in SNFs or long‐term acute care (LTAC) centers. The Cleveland Clinic CoPAT program does not use an outpatient infusion center.

The Cleveland Clinic uses a mandatory infectious diseases consultation for CoPAT because there are a number of important issues that need to be addressed before the patient is discharged, and for our system this is best accomplished by an infectious diseases specialist.12 For example, is antimicrobial therapy actually required in the first place? If it is, what is the optimal type, route, and duration of therapy? Are there other medical issues that need to be addressed? Decisions also need to be made about optimal vascular access and antimicrobial selection and administration, as well as arrangements being made for monitoring clinical and laboratory aspects. It is important that there is a smooth transition of care and prescheduled follow‐up in the outpatient clinic. The identification and use of an infectious diseases clinician directing the process leads to accountability. Notably, mandatory infectious disease consultation for outpatient parenteral antibiotic therapy has been used at Baystate Medical Center with improvement in reducing costs.19

The Process of Care

Assessments of the process of care involve examination of the particulars of medical care delivery, or whether what is recognized or accepted as good medical care has been applied. As discussed by Donabedian, process of care deals with issues such as the appropriateness and completeness of information obtained through clinical history, physical examination, and diagnostic tests; justification of diagnosis and therapy; technical competence in the performance of diagnostic and therapeutic procedures; and coordination and continuity of care.18

The CoPAT initiation process at the Cleveland Clinic is illustrated in Figure 2. It is a bundled process. As already mentioned, an infectious diseases consultation and evaluation is scheduled for all patients considered for CoPAT, after which a CoPAT form is completed and a follow‐up appointment made before the patient is discharged. In addition, the vascular access team is consulted and an appropriate vascular access device is placed in the patient prior to discharge. Likewise, a case manager is enlisted to identify a health care agency or SNF for patient placement or to determine whether the patient will receive home treatment. Once the appropriate setting is identified, the case manager transmits a completed CoPAT form to the health care agency or SNF, while forwarding a copy to the CoPAT nurse coordinator in the infectious disease department.

Figure 2
Schematic of the Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) initiation process at the Cleveland Clinic.

An electronic health record system is used at the Cleveland Clinic to provide real‐time information relevant for patient management. In 2007, a structured data form for CoPAT start‐of‐care was created within the Cleveland Clinic hospital electronic health record (EHR). This form contains a number of elements relevant for setting up patients for transition to CoPAT. In particular, the electronic CoPAT form contains information about the infection(s) and microorganism(s) being treated, intravenous antibiotic(s) prescribed (including treatment stop date), concurrent oral antibiotics, premedication recommendations (if appropriate), and recommended monitoring of laboratory tests. In addition, the form contains the telephone and fax numbers of the CoPAT coordinator and the name of the responsible physician, including a scheduled appointment for follow‐up (Fig. 3). The staff physician is responsible for completing the electronic CoPAT form or prescription. This CoPAT prescription then becomes part of the patient's electronic record and is transmissible and viewable by anyone with access to the EHR. This is important in terms of follow‐up and care accountability: an infectious disease staff clinician is identified as the contact person for clinical issues when a patient is on CoPAT.

Figure 3
Electronic Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) form at the Cleveland Clinic.

After the patient is discharged, the CoPAT coordinator in the infectious disease department becomes responsible, together with the clinic's outpatient pharmacy, for reviewing laboratory results and notifying clinicians of potential problems that need to be addressed. These issues can pertain to laboratory findings, vascular access, or new symptoms or signs observed by the home nurse or patient. All this information is communicated via electronic health record messaging and/or through direct calls to the physician, when needed.

The CoPAT program has been widely accepted by internal customers of the Cleveland Clinic, which include hospitalists. This is probably because there is autonomy and accountability with the infectious diseases staff, the program or team is available 7 days per week, and the EHR facilitates communication. In addition, the use of infectious disease‐specific subspecialty groups (eg, bone marrow and solid‐organ transplant, bone and joint, and infective endocarditis groups) increases clinical credibility, as well as value received by patients of the clinic. Furthermore, the electronic CoPAT script facilitates discharge planning. CoPATs constitute approximately 25% of all ID consultation requests at the Cleveland Clinic and help to justify the 20 clinical ID clinical FTEs.

Outcomes of Medical Care

Assessment of medical care outcomes is another frequently used approach for measuring the quality of medical care.18 Medical care outcomes that have been examined as measures of quality of care include survival, number of hospital readmissions, time between discharge and readmissions, length of initial hospital stay and subsequent readmissions, quality of life, and health care costs. As has often been said, If you cannot measure it, you cannot manage it. The CoPAT program using the EHR has facilitated retrieval of structured reports in a format that provides clinicians with real‐time data enabling assessment of outcomes. By examining this data, the CoPAT team is in a better position to contemplate potential interventions for improving outpatient care and the value patients receive.

A 36‐month review of Cleveland Clinic CoPAT patient demographics from July 2007 to June 2010 demonstrated 6287 patients (56% male) had been prescribed 9471 courses of CoPAT (Gordon, unpublished data). Seventy‐nine percent of the patients were white, 16% African American, and 5% of other races. Most patients received 1 antibiotic per CoPAT course (79.1%), whereas 18.2%, 2.5%, and 0.2% received 2, 3, and 4 antibiotics per CoPAT course, respectively. Figure 4 highlights CoPAT distribution by source for anatomic site of infection. Bone and joint infections were the most common diagnoses associated with CoPAT at the Cleveland Clinic, followed by abdominal, cardiovascular, primary disseminated disease (eg, catheter‐associated bloodstream infections), and skin and soft‐tissue infection.

Figure 4
Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) distribution by anatomic site of infection for patients at the Cleveland Clinic during 2007–2009.

Figure 5 highlights the top‐10 pathogenic microorganisms in patients being discharged from the Cleveland Clinic with CoPAT, and the top‐10 antimicrobials prescribed for these patients. As can be seen, Staphylococcus aureus (methicillin susceptible and methicillin resistant) was the number one pathogen identified for patients undergoing CoPAT, followed by coagulase‐negative Staphylococcus and Enterococcus species. The most commonly identified gram‐negative bacteria among discharged patients was Pseudomonas aeruginosa. Only 2 of the top 10 pathogens were nonbacterial: Candida species and cytomegalovirus (CMV), the latter being the result of the high volume of transplantations performed at the clinic. With respect to the intravenous antimicrobials prescribed for patients undergoing CoPAT, the most commonly prescribed agent was vancomycin, followed by piperacillin/tazobactam. Of the 10 agents, only micafungin and ganciclovir were not antibacterial agents, indicating that the vast majority of patients discharged from the Cleveland Clinic with CoPAT had had bacterial, rather than fungal or viral, infections.

Figure 5
Top 10 microorganisms (A) and antimicrobials (B) prescribed for patients on Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) at the Cleveland Clinic during 2007–2009.

Of particular note, data collected from July 2007 through December 2008 demonstrated that more than 80% of patients discharged from the hospital with CoPAT did so with a prescheduled follow‐up visit. This patient‐centric measure is important because patients may not follow through with establishing appointments for follow‐up visits once discharge has already occurred. The Cleveland Clinic prides itself on making sure that a follow‐up appointment is actually made before the time of discharge for the vast majority of patients. The process also facilitates continuity of care with a specific infectious disease physician.

The various outcomes data collected by the Cleveland Clinic CoPAT Registry puts it in the position of being able to use the data to identify areas for improvement. Some of the projects made possible by the CoPAT Registry include analysis of: (1) outcomes of CoPAT in patients with bone and joint infections, (2) intensity of care in patients with cardiac and cardiac device infections while undergoing CoPAT, (3) C. difficile infections in patients undergoing CoPAT, and (4) emergency department (ED) visits or unanticipated readmissions in patients undergoing CoPAT. With respect to the last point, a 2009 article by Jencks and colleagues reported that 19.6% of the approximately 12 million Medicare beneficiaries who had been discharged from a hospital were rehospitalized within 30 days.20 Moreover, more than a third (34%) were rehospitalized within 90 days of discharge. It was estimated that no more than 10% of these readmissions were scheduled. More than 50% of patients with a medical condition who were rehospitalized within 30 days of discharge had not been billed for a physician visit between the time of discharge and hospitalization.20 This suggests that scheduling a follow‐up visit at the time of discharge might have reduced the need for many of these rehospitalizations. Unplanned rehospitalizations among the Medicare patients examined were not only relatively common but were also costly, resulting in an estimated $17.4 billion in additional Medicare costs.20 A New York Times editorial accompanying publication of the Jencks article noted that rehospitalizations and accompanying costs might be reduced by better discharge planning and closer cooperation between hospitals and physicians to ensure follow‐up care.21

At the Cleveland Clinic, data have recently been collected on the reasons for ED visits or hospital readmissions for patients receiving CoPAT at home through the Cleveland Clinic home care program. As illustrated in Figure 6, 24% of ED visits22 and 41% of hospital readmissions (Gordon, unpublished data) were for the infection being treated. Vascular access complications accounted for 23% of ED visits but only 2% of hospital readmissions. Nearly 50% of ED visits and 60% of hospital readmissions were for a reason unrelated to the infection being treated or CoPAT. It is hoped that closer examination of the data and perhaps additional analyses will suggest interventions to further reduce preventable readmissions or ED visits among patients discharged from the Cleveland Clinic on CoPAT.

Figure 6
Reasons for Emergency Department visits (A) or readmission to the hospital (B) while on Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) or within 30 days of its completion of patients receiving CoPAT at home through Cleveland Clinic Home Care, January 1, 2008, to December 31, 2008.

Conclusions

Attention to antimicrobial stewardship and patient care should not end once the patient is discharged from the hospital or other institutional setting. Patients expect and should receive value‐based health care across the full cycle of their medical condition, and it is the responsibility of those caring for them to prepare for and provide such care during as well as after hospital discharge. The CoPAT program at the Cleveland Clinic provides a model for the extension of antimicrobial stewardship into the outpatient setting. The effectiveness of the program depends on a patient‐centric approach involving coordination and use of the expertise of multiple members of a team dedicated to patient value and facilitated by hospital‐based EHRs specialized for optimizing the transition of care into the outpatient setting for all patients scheduled to receive CoPAT. The quality of medical care provided by the Cleveland Clinic or other hospitals can be accessed through measurements of the structure, processes, and outcomes of care provided by the respective institutions. The data obtained can then be used to further refine care to optimize outcomes and provide high value for the patients treated at the institution. Achieving and then maintaining high‐quality medical care that provides value to patients is an ongoing process that should never be taken for granted.

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References
  1. Davidson CS.The caring physician: the life of Dr. Francis W. Peabody [book review].N Engl J Med.1993;328:817818.
  2. Porter ME,Teisberg EO.How physicians can change the future of health care.JAMA.2007;297:11031111.
  3. Porter ME,Teisberg EO.Redefining Health Care: Creating Value‐Based Competition on Results.Boston, MA:Harvard Business Press;2006.
  4. Greiner AC, Knebel E, eds.Health Professions Education: A Bridge to Quality. Committee on the Health Professions Education Summit.Washington, DC:National Academies Press;2003.
  5. Naylor MD,Brooten D,Campbell R, et al.Comprehensive discharge planning and home follow‐up of hospitalized elders: a randomized clinical trial.JAMA.1999;281:613620.
  6. Naylor MD,Brooten DA,Campbell RL,Maislin G,McCauley KM,Schwartz JS.Transitional care of older adults hospitalized with heart failure: a randomized, controlled trial.J Am Geriatr Soc.2004;52:675684.
  7. Phillips CO,Wright SM,Kern DE,Singa RM,Shepperd S,Rubin HR.Comprehensive discharge planning with postdischarge support for older patients with congestive heart failure: a meta‐analysis.JAMA.2004;291:13581367.
  8. Rich MW,Beckham V,Wittenberg C,Leven CL,Freedland KE,Carney RM.A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure.N Engl J Med.1995;333:11901195.
  9. Stewart S,Vandenbroek AJ,Pearson S,Horowitz JD.Prolonged beneficial effects of a home‐based intervention on unplanned readmissions and mortality among patients with congestive heart failure.Arch Intern Med.1999;159:257261.
  10. Caplan GA,Williams AJ,Daly B,Abraham K.A randomized, controlled trial of comprehensive geriatric assessment and multidisciplinary intervention after discharge of elderly from the emergency department–the DEED II study.J Am Geriatr Soc.2004;52:14171423.
  11. Nikolaus T,Specht‐Leible N,Bach M,Oster P,Schlierf G.A randomized trial of comprehensive geriatric assessment and home intervention in the care of hospitalized patients.Age Ageing.1999;28:543550.
  12. Rehm SJ,Weinstein AJ.Home intravenous antibiotic therapy: a team approach.Ann Intern Med.1983;99:388392.
  13. Merriam‐Webster Dictionary Online. Definition of steward. Available at http://www.merriam‐webster.com/dictionary/steward. Accessed July 14,2010.
  14. Dellit TH,Owens RC,McGowan JE, et al.Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.Clin Infect Dis.2007;44:159177.
  15. Kisuule F,Wright S,Barreto J,Zenilman J.Improving antibiotic utilization among hospitalists: a pilot academic detailing project with a public health approach.J Hosp Med.2008;3:6470.
  16. Rucker RW,Harrison GM.Outpatient intravenous medications in the management of cystic fibrosis.Pediatrics.1974;54:358360.
  17. Tice AD,Rehm SJ,Dalovisio JR, et al.Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines.Clin Infect Dis.2004;38:16511672.
  18. Donabedian A.Evaluating the quality of medical care.Milbank Mem Fund Q.1966;44(Suppl):166206.
  19. Sharma R,Loomis W,Brown RB.Impact of mandatory inpatient infectious disease consultation on outpatient parenteral antibiotic therapy.Am J Med Sci.2005;330:6064.
  20. Jencks SF,Williams MV,Coleman EA.Rehospitalizations among patients in the Medicare fee‐for‐service program.N Engl J Med.2009;360:14181428.
  21. The New York Times. Editorial: Back in the Hospital Again. April 15, 2009. Available at http://www.nytimes.com/2009/04/16/opinion/16thu2.html. Accessed July 16,2010.
  22. Patel D,Shrestha NK,Gordon SM,Landers S,Jain AK,Rehm SJ.Emergency department visits of patients on community‐based parenteral anti‐infective therapy at home. Presented at the 47th annual meeting of IDSA, Philadelphia, PA, October 29‐November 1, 2009. Poster 462.
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. . . For the secret of the care of the patient is caring for the patient.Francis W. Peabody, October 21, 19251

Collaboration between members of a multidisciplinary team is a key component of an effective institutional antimicrobial stewardship program, which itself is a key component of optimizing the care of hospitalized patients being treated with antimicrobial agents for proven or suspected infectious diseases. However, patient care does not and should not end once the patient is discharged from the hospital. In fact, high‐quality, value‐based health care across the full range of a medical condition depends on planning for optimization of care within the hospital as well as transitions of care to the outpatient setting. This extended care plan includes collaboration with multiple members of the health care community, both inside and outside the institution. The current review examines 3 aspects of patient care across the full cycle of an infectious disease condition: (1) value‐based health care, (2) stewardship of antimicrobials, and (3) community‐based parenteral anti‐infective therapy (CoPAT) as a model for antimicrobial stewardship outside the institutional setting.

Value‐Based Health Care

Patients first want to know that the health care professionals treating them actually care about them as individuals, and only then are patients concerned about how much the medical team knows. Patient‐centered care is a critical component of value‐based health care, a term that was bandied about quite a bit during the recent and ongoing health care debate in the United States. But what exactly does it mean? First, value in health care is defined by health care outcomes as a function of or divided by the cost of delivery of care. As Dr. Michael Porter and Dr. Elizabeth Olmsted Teisberg delineated in their 2007 article in the Journal of the American Medical Association,2 as well as in the 2006 book Redefining Health Care,3 The purpose of the healthcare system is not to minimize costs but to deliver value to patients, that is, better health per dollar spent. As they discuss value, it is a patient‐centric measure, and is focused on individual patient (not just diagnosis‐related group) outcomes and the cost of care across the full cycle. In this way of looking at things, an episode of care goes beyond the treatment provided during the acute admission to also include the transition of care to the outpatient or posthospital setting.

The reforms proposed by Porter and Teisberg are best achieved when the participating health care institutions have developed an information technology platform able to integrate and fully measure care across the full cycle of a medical condition. Furthermore, there is strong evidence that patient value increases with physician and team experience and volume for a particular condition.2 High volumes tend to correlate with the development of better information technology, as well as the formation of dedicated teams with tailored facilities, and with a greater capacity for constructive feedback to improve patient outcomes. The more experience a physician and team have with the management of a particular medical condition, the greater is the opportunity to learn and refine practices to provide greater value to the patient.

The Institute of Medicine has recommended that all healthcare professionals should be educated to deliver patient‐centered care as members of an interdisciplinary team emphasizing evidence‐based practice, quality improvement, and informatics.4 As has been demonstrated for patients with congestive heart failure59 and other conditions,10, 11 outcomes improve when components of care are integrated (often by nurse‐directed teams), preparing for the transition of care from the hospital to the home.12 This concept is the basis for the community‐based parenteral anti‐infective therapy program (CoPAT) at the Cleveland Clinic as a model for antimicrobial stewardship for patients requiring parenteral antimicrobial therapy at the time of discharge from the inpatient setting.

Stewardship of Antimicrobials

The Merriam‐Webster dictionary alternatively defines a steward as: (1) an employee on a ship, airplane, bus, or train who manages the provisioning of food and attends to passengers or (2) one who actively manages affairs (manager).13 In the context of health care within an institution, one can think of clinicians as stewards or employees charged with managing patients and the drugs and other care they receive while they are attendants (passengers) at the institution. In the value‐based approach just discussed, where medical practice is organized around managing medical conditions for the entire care cycle, a medical steward would also be charged with managing or planning for patient care after discharge from the hospital or other institutional setting. Management or stewardship of antimicrobial agents is a key component of the care for patients with infectious diseases. In 2007, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America (IDSA/SHEA) presented guidelines to aid institutions in the development of an effective hospital‐based antimicrobial stewardship program (a more detailed overview of antimicrobial stewardship is presented in the accompanying supplemental article by Dr. Ohl).14 The focus of the IDSA/SHEA guidelines was on development of programs within hospitals. Although the authors acknowledged that antimicrobial stewardship is also important in outpatient clinics and long‐term care facilities, transition of antimicrobial management after patient discharge from the hospital was not a focus of the 2007 guidelines.

A key objective of antimicrobial stewardship is to optimize antimicrobial drug selection and dosing to improve clinical outcomes while reducing drug toxicity and other potential untoward consequences of antimicrobial therapy, including selection of opportunistic organisms (eg, Clostridium difficile) or emergence of multidrug resistance in pathogens.14 A secondary objective is to reduce overall health care costs,14 which ideally would include inpatient as well as outpatient costs and those related to hospital readmission due to the initial infection or its outpatient treatment. Useful metrics for evaluation of an antimicrobial stewardship program include measures of pathogen/drug mismatch, antimicrobial costs, incidence of redundant therapy, compliance with antimicrobial drug restrictions (if applicable), days undergoing antimicrobial therapy, and number of cases of intravenous to oral conversion.14

Although the IDSA/SHEA guidelines for institutional antimicrobial stewardship programs suggest that an infectious diseases physician and clinical pharmacist with infectious diseases training should be core members of a multidisciplinary stewardship team,14 many community hospitals or smaller institutions do not have an infectious diseases physician or a readily available infectious diseases specialist for consultation. Hospitalists are often very effective advocates of appropriate use of antimicrobials and may play a leadership role on institutional antimicrobial stewardship teams. A recent study demonstrated that a hospitalist‐delivered academic detailing intervention (which included an individual appraisal of the provider's prescription pattern) significantly improved patterns of antibiotic prescribing for inpatients.15

Community‐Based Parenteral Anti‐Infective Therapy as a Systems‐Based Approach to Antimicrobial Stewardship

A systems‐based approach for antimicrobial stewardship, CoPAT has been in operation at the Cleveland Clinic, a 1200‐bed hospital in downtown Cleveland, Ohio, since November 1979. The experiences of the authors and their colleagues demonstrate it to be a value‐based proposition for the patient that uses an antimicrobial stewardship platform. Also known as outpatient parenteral antimicrobial therapy (OPAT), CoPAT refers to the practice of administering antimicrobial therapy in the home or other outpatient settings, first introduced by Rucker and Harrison in 1974 in the context of outpatient management of cystic fibrosis.16 In the United States, CoPAT is a common practice today, and the IDSA has created practice guidelines for it.17

In 1983, Rehm and Weinstein coauthored an article describing their experiences at the Cleveland Clinic, in which selected patients were trained for home‐based antimicrobial therapy.12 Figure 1 illustrates the astronomical growth that has occurred over the years at the Cleveland Clinic in the number of patients discharged from the acute care center undergoing CoPAT (Gordon, unpublished data). It is anticipated that this growth will continue and in large part reflects the complexity of patients being seen and the desire to reduce length of stay. Evaluating the quality of any medical care is difficult, but there are 3 general approaches to assessing or measuring the quality of medical care: assessing the structure of care, assessing processes of care, and assessing outcomes.18 The quality of the CoPAT program at the Cleveland Clinic can be examined in the context of these 3 areas of assessment.

Figure 1
Cleveland Clinic Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) volumes by year (Gordon, unpublished data).

Settings or the Structure of Care

In a 1966 publication on quality of medical care evaluations, Donabedian described assessment of the structure of care as one of the primary approaches to measuring the quality of care.18 By structure, Donabedian meant the settings in which medical care takes place, including the adequacy of facilities and equipment, qualifications or expertise of medical staff and their organization, the administrative structure of the institution or institutional program of interest, and other administrative and related processes supporting and directing the delivery of care. Although the structure of care has the advantage of being concrete and relatively easy to assess, to be most meaningful, it ultimately needs to be related to the processes and outcomes of care.

With respect to the CoPAT program at the Cleveland Clinic main hospital, infectious diseases consultation is required for every patient being considered for discharge with parenteral antibiotics, whether the patient is going home or to another facility, including the clinic's own skilled nursing facility (SNF). Arrangements are then made for the delivery of antibiotics at home or in SNFs or long‐term acute care (LTAC) centers. The Cleveland Clinic CoPAT program does not use an outpatient infusion center.

The Cleveland Clinic uses a mandatory infectious diseases consultation for CoPAT because there are a number of important issues that need to be addressed before the patient is discharged, and for our system this is best accomplished by an infectious diseases specialist.12 For example, is antimicrobial therapy actually required in the first place? If it is, what is the optimal type, route, and duration of therapy? Are there other medical issues that need to be addressed? Decisions also need to be made about optimal vascular access and antimicrobial selection and administration, as well as arrangements being made for monitoring clinical and laboratory aspects. It is important that there is a smooth transition of care and prescheduled follow‐up in the outpatient clinic. The identification and use of an infectious diseases clinician directing the process leads to accountability. Notably, mandatory infectious disease consultation for outpatient parenteral antibiotic therapy has been used at Baystate Medical Center with improvement in reducing costs.19

The Process of Care

Assessments of the process of care involve examination of the particulars of medical care delivery, or whether what is recognized or accepted as good medical care has been applied. As discussed by Donabedian, process of care deals with issues such as the appropriateness and completeness of information obtained through clinical history, physical examination, and diagnostic tests; justification of diagnosis and therapy; technical competence in the performance of diagnostic and therapeutic procedures; and coordination and continuity of care.18

The CoPAT initiation process at the Cleveland Clinic is illustrated in Figure 2. It is a bundled process. As already mentioned, an infectious diseases consultation and evaluation is scheduled for all patients considered for CoPAT, after which a CoPAT form is completed and a follow‐up appointment made before the patient is discharged. In addition, the vascular access team is consulted and an appropriate vascular access device is placed in the patient prior to discharge. Likewise, a case manager is enlisted to identify a health care agency or SNF for patient placement or to determine whether the patient will receive home treatment. Once the appropriate setting is identified, the case manager transmits a completed CoPAT form to the health care agency or SNF, while forwarding a copy to the CoPAT nurse coordinator in the infectious disease department.

Figure 2
Schematic of the Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) initiation process at the Cleveland Clinic.

An electronic health record system is used at the Cleveland Clinic to provide real‐time information relevant for patient management. In 2007, a structured data form for CoPAT start‐of‐care was created within the Cleveland Clinic hospital electronic health record (EHR). This form contains a number of elements relevant for setting up patients for transition to CoPAT. In particular, the electronic CoPAT form contains information about the infection(s) and microorganism(s) being treated, intravenous antibiotic(s) prescribed (including treatment stop date), concurrent oral antibiotics, premedication recommendations (if appropriate), and recommended monitoring of laboratory tests. In addition, the form contains the telephone and fax numbers of the CoPAT coordinator and the name of the responsible physician, including a scheduled appointment for follow‐up (Fig. 3). The staff physician is responsible for completing the electronic CoPAT form or prescription. This CoPAT prescription then becomes part of the patient's electronic record and is transmissible and viewable by anyone with access to the EHR. This is important in terms of follow‐up and care accountability: an infectious disease staff clinician is identified as the contact person for clinical issues when a patient is on CoPAT.

Figure 3
Electronic Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) form at the Cleveland Clinic.

After the patient is discharged, the CoPAT coordinator in the infectious disease department becomes responsible, together with the clinic's outpatient pharmacy, for reviewing laboratory results and notifying clinicians of potential problems that need to be addressed. These issues can pertain to laboratory findings, vascular access, or new symptoms or signs observed by the home nurse or patient. All this information is communicated via electronic health record messaging and/or through direct calls to the physician, when needed.

The CoPAT program has been widely accepted by internal customers of the Cleveland Clinic, which include hospitalists. This is probably because there is autonomy and accountability with the infectious diseases staff, the program or team is available 7 days per week, and the EHR facilitates communication. In addition, the use of infectious disease‐specific subspecialty groups (eg, bone marrow and solid‐organ transplant, bone and joint, and infective endocarditis groups) increases clinical credibility, as well as value received by patients of the clinic. Furthermore, the electronic CoPAT script facilitates discharge planning. CoPATs constitute approximately 25% of all ID consultation requests at the Cleveland Clinic and help to justify the 20 clinical ID clinical FTEs.

Outcomes of Medical Care

Assessment of medical care outcomes is another frequently used approach for measuring the quality of medical care.18 Medical care outcomes that have been examined as measures of quality of care include survival, number of hospital readmissions, time between discharge and readmissions, length of initial hospital stay and subsequent readmissions, quality of life, and health care costs. As has often been said, If you cannot measure it, you cannot manage it. The CoPAT program using the EHR has facilitated retrieval of structured reports in a format that provides clinicians with real‐time data enabling assessment of outcomes. By examining this data, the CoPAT team is in a better position to contemplate potential interventions for improving outpatient care and the value patients receive.

A 36‐month review of Cleveland Clinic CoPAT patient demographics from July 2007 to June 2010 demonstrated 6287 patients (56% male) had been prescribed 9471 courses of CoPAT (Gordon, unpublished data). Seventy‐nine percent of the patients were white, 16% African American, and 5% of other races. Most patients received 1 antibiotic per CoPAT course (79.1%), whereas 18.2%, 2.5%, and 0.2% received 2, 3, and 4 antibiotics per CoPAT course, respectively. Figure 4 highlights CoPAT distribution by source for anatomic site of infection. Bone and joint infections were the most common diagnoses associated with CoPAT at the Cleveland Clinic, followed by abdominal, cardiovascular, primary disseminated disease (eg, catheter‐associated bloodstream infections), and skin and soft‐tissue infection.

Figure 4
Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) distribution by anatomic site of infection for patients at the Cleveland Clinic during 2007–2009.

Figure 5 highlights the top‐10 pathogenic microorganisms in patients being discharged from the Cleveland Clinic with CoPAT, and the top‐10 antimicrobials prescribed for these patients. As can be seen, Staphylococcus aureus (methicillin susceptible and methicillin resistant) was the number one pathogen identified for patients undergoing CoPAT, followed by coagulase‐negative Staphylococcus and Enterococcus species. The most commonly identified gram‐negative bacteria among discharged patients was Pseudomonas aeruginosa. Only 2 of the top 10 pathogens were nonbacterial: Candida species and cytomegalovirus (CMV), the latter being the result of the high volume of transplantations performed at the clinic. With respect to the intravenous antimicrobials prescribed for patients undergoing CoPAT, the most commonly prescribed agent was vancomycin, followed by piperacillin/tazobactam. Of the 10 agents, only micafungin and ganciclovir were not antibacterial agents, indicating that the vast majority of patients discharged from the Cleveland Clinic with CoPAT had had bacterial, rather than fungal or viral, infections.

Figure 5
Top 10 microorganisms (A) and antimicrobials (B) prescribed for patients on Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) at the Cleveland Clinic during 2007–2009.

Of particular note, data collected from July 2007 through December 2008 demonstrated that more than 80% of patients discharged from the hospital with CoPAT did so with a prescheduled follow‐up visit. This patient‐centric measure is important because patients may not follow through with establishing appointments for follow‐up visits once discharge has already occurred. The Cleveland Clinic prides itself on making sure that a follow‐up appointment is actually made before the time of discharge for the vast majority of patients. The process also facilitates continuity of care with a specific infectious disease physician.

The various outcomes data collected by the Cleveland Clinic CoPAT Registry puts it in the position of being able to use the data to identify areas for improvement. Some of the projects made possible by the CoPAT Registry include analysis of: (1) outcomes of CoPAT in patients with bone and joint infections, (2) intensity of care in patients with cardiac and cardiac device infections while undergoing CoPAT, (3) C. difficile infections in patients undergoing CoPAT, and (4) emergency department (ED) visits or unanticipated readmissions in patients undergoing CoPAT. With respect to the last point, a 2009 article by Jencks and colleagues reported that 19.6% of the approximately 12 million Medicare beneficiaries who had been discharged from a hospital were rehospitalized within 30 days.20 Moreover, more than a third (34%) were rehospitalized within 90 days of discharge. It was estimated that no more than 10% of these readmissions were scheduled. More than 50% of patients with a medical condition who were rehospitalized within 30 days of discharge had not been billed for a physician visit between the time of discharge and hospitalization.20 This suggests that scheduling a follow‐up visit at the time of discharge might have reduced the need for many of these rehospitalizations. Unplanned rehospitalizations among the Medicare patients examined were not only relatively common but were also costly, resulting in an estimated $17.4 billion in additional Medicare costs.20 A New York Times editorial accompanying publication of the Jencks article noted that rehospitalizations and accompanying costs might be reduced by better discharge planning and closer cooperation between hospitals and physicians to ensure follow‐up care.21

At the Cleveland Clinic, data have recently been collected on the reasons for ED visits or hospital readmissions for patients receiving CoPAT at home through the Cleveland Clinic home care program. As illustrated in Figure 6, 24% of ED visits22 and 41% of hospital readmissions (Gordon, unpublished data) were for the infection being treated. Vascular access complications accounted for 23% of ED visits but only 2% of hospital readmissions. Nearly 50% of ED visits and 60% of hospital readmissions were for a reason unrelated to the infection being treated or CoPAT. It is hoped that closer examination of the data and perhaps additional analyses will suggest interventions to further reduce preventable readmissions or ED visits among patients discharged from the Cleveland Clinic on CoPAT.

Figure 6
Reasons for Emergency Department visits (A) or readmission to the hospital (B) while on Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) or within 30 days of its completion of patients receiving CoPAT at home through Cleveland Clinic Home Care, January 1, 2008, to December 31, 2008.

Conclusions

Attention to antimicrobial stewardship and patient care should not end once the patient is discharged from the hospital or other institutional setting. Patients expect and should receive value‐based health care across the full cycle of their medical condition, and it is the responsibility of those caring for them to prepare for and provide such care during as well as after hospital discharge. The CoPAT program at the Cleveland Clinic provides a model for the extension of antimicrobial stewardship into the outpatient setting. The effectiveness of the program depends on a patient‐centric approach involving coordination and use of the expertise of multiple members of a team dedicated to patient value and facilitated by hospital‐based EHRs specialized for optimizing the transition of care into the outpatient setting for all patients scheduled to receive CoPAT. The quality of medical care provided by the Cleveland Clinic or other hospitals can be accessed through measurements of the structure, processes, and outcomes of care provided by the respective institutions. The data obtained can then be used to further refine care to optimize outcomes and provide high value for the patients treated at the institution. Achieving and then maintaining high‐quality medical care that provides value to patients is an ongoing process that should never be taken for granted.

. . . For the secret of the care of the patient is caring for the patient.Francis W. Peabody, October 21, 19251

Collaboration between members of a multidisciplinary team is a key component of an effective institutional antimicrobial stewardship program, which itself is a key component of optimizing the care of hospitalized patients being treated with antimicrobial agents for proven or suspected infectious diseases. However, patient care does not and should not end once the patient is discharged from the hospital. In fact, high‐quality, value‐based health care across the full range of a medical condition depends on planning for optimization of care within the hospital as well as transitions of care to the outpatient setting. This extended care plan includes collaboration with multiple members of the health care community, both inside and outside the institution. The current review examines 3 aspects of patient care across the full cycle of an infectious disease condition: (1) value‐based health care, (2) stewardship of antimicrobials, and (3) community‐based parenteral anti‐infective therapy (CoPAT) as a model for antimicrobial stewardship outside the institutional setting.

Value‐Based Health Care

Patients first want to know that the health care professionals treating them actually care about them as individuals, and only then are patients concerned about how much the medical team knows. Patient‐centered care is a critical component of value‐based health care, a term that was bandied about quite a bit during the recent and ongoing health care debate in the United States. But what exactly does it mean? First, value in health care is defined by health care outcomes as a function of or divided by the cost of delivery of care. As Dr. Michael Porter and Dr. Elizabeth Olmsted Teisberg delineated in their 2007 article in the Journal of the American Medical Association,2 as well as in the 2006 book Redefining Health Care,3 The purpose of the healthcare system is not to minimize costs but to deliver value to patients, that is, better health per dollar spent. As they discuss value, it is a patient‐centric measure, and is focused on individual patient (not just diagnosis‐related group) outcomes and the cost of care across the full cycle. In this way of looking at things, an episode of care goes beyond the treatment provided during the acute admission to also include the transition of care to the outpatient or posthospital setting.

The reforms proposed by Porter and Teisberg are best achieved when the participating health care institutions have developed an information technology platform able to integrate and fully measure care across the full cycle of a medical condition. Furthermore, there is strong evidence that patient value increases with physician and team experience and volume for a particular condition.2 High volumes tend to correlate with the development of better information technology, as well as the formation of dedicated teams with tailored facilities, and with a greater capacity for constructive feedback to improve patient outcomes. The more experience a physician and team have with the management of a particular medical condition, the greater is the opportunity to learn and refine practices to provide greater value to the patient.

The Institute of Medicine has recommended that all healthcare professionals should be educated to deliver patient‐centered care as members of an interdisciplinary team emphasizing evidence‐based practice, quality improvement, and informatics.4 As has been demonstrated for patients with congestive heart failure59 and other conditions,10, 11 outcomes improve when components of care are integrated (often by nurse‐directed teams), preparing for the transition of care from the hospital to the home.12 This concept is the basis for the community‐based parenteral anti‐infective therapy program (CoPAT) at the Cleveland Clinic as a model for antimicrobial stewardship for patients requiring parenteral antimicrobial therapy at the time of discharge from the inpatient setting.

Stewardship of Antimicrobials

The Merriam‐Webster dictionary alternatively defines a steward as: (1) an employee on a ship, airplane, bus, or train who manages the provisioning of food and attends to passengers or (2) one who actively manages affairs (manager).13 In the context of health care within an institution, one can think of clinicians as stewards or employees charged with managing patients and the drugs and other care they receive while they are attendants (passengers) at the institution. In the value‐based approach just discussed, where medical practice is organized around managing medical conditions for the entire care cycle, a medical steward would also be charged with managing or planning for patient care after discharge from the hospital or other institutional setting. Management or stewardship of antimicrobial agents is a key component of the care for patients with infectious diseases. In 2007, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America (IDSA/SHEA) presented guidelines to aid institutions in the development of an effective hospital‐based antimicrobial stewardship program (a more detailed overview of antimicrobial stewardship is presented in the accompanying supplemental article by Dr. Ohl).14 The focus of the IDSA/SHEA guidelines was on development of programs within hospitals. Although the authors acknowledged that antimicrobial stewardship is also important in outpatient clinics and long‐term care facilities, transition of antimicrobial management after patient discharge from the hospital was not a focus of the 2007 guidelines.

A key objective of antimicrobial stewardship is to optimize antimicrobial drug selection and dosing to improve clinical outcomes while reducing drug toxicity and other potential untoward consequences of antimicrobial therapy, including selection of opportunistic organisms (eg, Clostridium difficile) or emergence of multidrug resistance in pathogens.14 A secondary objective is to reduce overall health care costs,14 which ideally would include inpatient as well as outpatient costs and those related to hospital readmission due to the initial infection or its outpatient treatment. Useful metrics for evaluation of an antimicrobial stewardship program include measures of pathogen/drug mismatch, antimicrobial costs, incidence of redundant therapy, compliance with antimicrobial drug restrictions (if applicable), days undergoing antimicrobial therapy, and number of cases of intravenous to oral conversion.14

Although the IDSA/SHEA guidelines for institutional antimicrobial stewardship programs suggest that an infectious diseases physician and clinical pharmacist with infectious diseases training should be core members of a multidisciplinary stewardship team,14 many community hospitals or smaller institutions do not have an infectious diseases physician or a readily available infectious diseases specialist for consultation. Hospitalists are often very effective advocates of appropriate use of antimicrobials and may play a leadership role on institutional antimicrobial stewardship teams. A recent study demonstrated that a hospitalist‐delivered academic detailing intervention (which included an individual appraisal of the provider's prescription pattern) significantly improved patterns of antibiotic prescribing for inpatients.15

Community‐Based Parenteral Anti‐Infective Therapy as a Systems‐Based Approach to Antimicrobial Stewardship

A systems‐based approach for antimicrobial stewardship, CoPAT has been in operation at the Cleveland Clinic, a 1200‐bed hospital in downtown Cleveland, Ohio, since November 1979. The experiences of the authors and their colleagues demonstrate it to be a value‐based proposition for the patient that uses an antimicrobial stewardship platform. Also known as outpatient parenteral antimicrobial therapy (OPAT), CoPAT refers to the practice of administering antimicrobial therapy in the home or other outpatient settings, first introduced by Rucker and Harrison in 1974 in the context of outpatient management of cystic fibrosis.16 In the United States, CoPAT is a common practice today, and the IDSA has created practice guidelines for it.17

In 1983, Rehm and Weinstein coauthored an article describing their experiences at the Cleveland Clinic, in which selected patients were trained for home‐based antimicrobial therapy.12 Figure 1 illustrates the astronomical growth that has occurred over the years at the Cleveland Clinic in the number of patients discharged from the acute care center undergoing CoPAT (Gordon, unpublished data). It is anticipated that this growth will continue and in large part reflects the complexity of patients being seen and the desire to reduce length of stay. Evaluating the quality of any medical care is difficult, but there are 3 general approaches to assessing or measuring the quality of medical care: assessing the structure of care, assessing processes of care, and assessing outcomes.18 The quality of the CoPAT program at the Cleveland Clinic can be examined in the context of these 3 areas of assessment.

Figure 1
Cleveland Clinic Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) volumes by year (Gordon, unpublished data).

Settings or the Structure of Care

In a 1966 publication on quality of medical care evaluations, Donabedian described assessment of the structure of care as one of the primary approaches to measuring the quality of care.18 By structure, Donabedian meant the settings in which medical care takes place, including the adequacy of facilities and equipment, qualifications or expertise of medical staff and their organization, the administrative structure of the institution or institutional program of interest, and other administrative and related processes supporting and directing the delivery of care. Although the structure of care has the advantage of being concrete and relatively easy to assess, to be most meaningful, it ultimately needs to be related to the processes and outcomes of care.

With respect to the CoPAT program at the Cleveland Clinic main hospital, infectious diseases consultation is required for every patient being considered for discharge with parenteral antibiotics, whether the patient is going home or to another facility, including the clinic's own skilled nursing facility (SNF). Arrangements are then made for the delivery of antibiotics at home or in SNFs or long‐term acute care (LTAC) centers. The Cleveland Clinic CoPAT program does not use an outpatient infusion center.

The Cleveland Clinic uses a mandatory infectious diseases consultation for CoPAT because there are a number of important issues that need to be addressed before the patient is discharged, and for our system this is best accomplished by an infectious diseases specialist.12 For example, is antimicrobial therapy actually required in the first place? If it is, what is the optimal type, route, and duration of therapy? Are there other medical issues that need to be addressed? Decisions also need to be made about optimal vascular access and antimicrobial selection and administration, as well as arrangements being made for monitoring clinical and laboratory aspects. It is important that there is a smooth transition of care and prescheduled follow‐up in the outpatient clinic. The identification and use of an infectious diseases clinician directing the process leads to accountability. Notably, mandatory infectious disease consultation for outpatient parenteral antibiotic therapy has been used at Baystate Medical Center with improvement in reducing costs.19

The Process of Care

Assessments of the process of care involve examination of the particulars of medical care delivery, or whether what is recognized or accepted as good medical care has been applied. As discussed by Donabedian, process of care deals with issues such as the appropriateness and completeness of information obtained through clinical history, physical examination, and diagnostic tests; justification of diagnosis and therapy; technical competence in the performance of diagnostic and therapeutic procedures; and coordination and continuity of care.18

The CoPAT initiation process at the Cleveland Clinic is illustrated in Figure 2. It is a bundled process. As already mentioned, an infectious diseases consultation and evaluation is scheduled for all patients considered for CoPAT, after which a CoPAT form is completed and a follow‐up appointment made before the patient is discharged. In addition, the vascular access team is consulted and an appropriate vascular access device is placed in the patient prior to discharge. Likewise, a case manager is enlisted to identify a health care agency or SNF for patient placement or to determine whether the patient will receive home treatment. Once the appropriate setting is identified, the case manager transmits a completed CoPAT form to the health care agency or SNF, while forwarding a copy to the CoPAT nurse coordinator in the infectious disease department.

Figure 2
Schematic of the Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) initiation process at the Cleveland Clinic.

An electronic health record system is used at the Cleveland Clinic to provide real‐time information relevant for patient management. In 2007, a structured data form for CoPAT start‐of‐care was created within the Cleveland Clinic hospital electronic health record (EHR). This form contains a number of elements relevant for setting up patients for transition to CoPAT. In particular, the electronic CoPAT form contains information about the infection(s) and microorganism(s) being treated, intravenous antibiotic(s) prescribed (including treatment stop date), concurrent oral antibiotics, premedication recommendations (if appropriate), and recommended monitoring of laboratory tests. In addition, the form contains the telephone and fax numbers of the CoPAT coordinator and the name of the responsible physician, including a scheduled appointment for follow‐up (Fig. 3). The staff physician is responsible for completing the electronic CoPAT form or prescription. This CoPAT prescription then becomes part of the patient's electronic record and is transmissible and viewable by anyone with access to the EHR. This is important in terms of follow‐up and care accountability: an infectious disease staff clinician is identified as the contact person for clinical issues when a patient is on CoPAT.

Figure 3
Electronic Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) form at the Cleveland Clinic.

After the patient is discharged, the CoPAT coordinator in the infectious disease department becomes responsible, together with the clinic's outpatient pharmacy, for reviewing laboratory results and notifying clinicians of potential problems that need to be addressed. These issues can pertain to laboratory findings, vascular access, or new symptoms or signs observed by the home nurse or patient. All this information is communicated via electronic health record messaging and/or through direct calls to the physician, when needed.

The CoPAT program has been widely accepted by internal customers of the Cleveland Clinic, which include hospitalists. This is probably because there is autonomy and accountability with the infectious diseases staff, the program or team is available 7 days per week, and the EHR facilitates communication. In addition, the use of infectious disease‐specific subspecialty groups (eg, bone marrow and solid‐organ transplant, bone and joint, and infective endocarditis groups) increases clinical credibility, as well as value received by patients of the clinic. Furthermore, the electronic CoPAT script facilitates discharge planning. CoPATs constitute approximately 25% of all ID consultation requests at the Cleveland Clinic and help to justify the 20 clinical ID clinical FTEs.

Outcomes of Medical Care

Assessment of medical care outcomes is another frequently used approach for measuring the quality of medical care.18 Medical care outcomes that have been examined as measures of quality of care include survival, number of hospital readmissions, time between discharge and readmissions, length of initial hospital stay and subsequent readmissions, quality of life, and health care costs. As has often been said, If you cannot measure it, you cannot manage it. The CoPAT program using the EHR has facilitated retrieval of structured reports in a format that provides clinicians with real‐time data enabling assessment of outcomes. By examining this data, the CoPAT team is in a better position to contemplate potential interventions for improving outpatient care and the value patients receive.

A 36‐month review of Cleveland Clinic CoPAT patient demographics from July 2007 to June 2010 demonstrated 6287 patients (56% male) had been prescribed 9471 courses of CoPAT (Gordon, unpublished data). Seventy‐nine percent of the patients were white, 16% African American, and 5% of other races. Most patients received 1 antibiotic per CoPAT course (79.1%), whereas 18.2%, 2.5%, and 0.2% received 2, 3, and 4 antibiotics per CoPAT course, respectively. Figure 4 highlights CoPAT distribution by source for anatomic site of infection. Bone and joint infections were the most common diagnoses associated with CoPAT at the Cleveland Clinic, followed by abdominal, cardiovascular, primary disseminated disease (eg, catheter‐associated bloodstream infections), and skin and soft‐tissue infection.

Figure 4
Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) distribution by anatomic site of infection for patients at the Cleveland Clinic during 2007–2009.

Figure 5 highlights the top‐10 pathogenic microorganisms in patients being discharged from the Cleveland Clinic with CoPAT, and the top‐10 antimicrobials prescribed for these patients. As can be seen, Staphylococcus aureus (methicillin susceptible and methicillin resistant) was the number one pathogen identified for patients undergoing CoPAT, followed by coagulase‐negative Staphylococcus and Enterococcus species. The most commonly identified gram‐negative bacteria among discharged patients was Pseudomonas aeruginosa. Only 2 of the top 10 pathogens were nonbacterial: Candida species and cytomegalovirus (CMV), the latter being the result of the high volume of transplantations performed at the clinic. With respect to the intravenous antimicrobials prescribed for patients undergoing CoPAT, the most commonly prescribed agent was vancomycin, followed by piperacillin/tazobactam. Of the 10 agents, only micafungin and ganciclovir were not antibacterial agents, indicating that the vast majority of patients discharged from the Cleveland Clinic with CoPAT had had bacterial, rather than fungal or viral, infections.

Figure 5
Top 10 microorganisms (A) and antimicrobials (B) prescribed for patients on Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) at the Cleveland Clinic during 2007–2009.

Of particular note, data collected from July 2007 through December 2008 demonstrated that more than 80% of patients discharged from the hospital with CoPAT did so with a prescheduled follow‐up visit. This patient‐centric measure is important because patients may not follow through with establishing appointments for follow‐up visits once discharge has already occurred. The Cleveland Clinic prides itself on making sure that a follow‐up appointment is actually made before the time of discharge for the vast majority of patients. The process also facilitates continuity of care with a specific infectious disease physician.

The various outcomes data collected by the Cleveland Clinic CoPAT Registry puts it in the position of being able to use the data to identify areas for improvement. Some of the projects made possible by the CoPAT Registry include analysis of: (1) outcomes of CoPAT in patients with bone and joint infections, (2) intensity of care in patients with cardiac and cardiac device infections while undergoing CoPAT, (3) C. difficile infections in patients undergoing CoPAT, and (4) emergency department (ED) visits or unanticipated readmissions in patients undergoing CoPAT. With respect to the last point, a 2009 article by Jencks and colleagues reported that 19.6% of the approximately 12 million Medicare beneficiaries who had been discharged from a hospital were rehospitalized within 30 days.20 Moreover, more than a third (34%) were rehospitalized within 90 days of discharge. It was estimated that no more than 10% of these readmissions were scheduled. More than 50% of patients with a medical condition who were rehospitalized within 30 days of discharge had not been billed for a physician visit between the time of discharge and hospitalization.20 This suggests that scheduling a follow‐up visit at the time of discharge might have reduced the need for many of these rehospitalizations. Unplanned rehospitalizations among the Medicare patients examined were not only relatively common but were also costly, resulting in an estimated $17.4 billion in additional Medicare costs.20 A New York Times editorial accompanying publication of the Jencks article noted that rehospitalizations and accompanying costs might be reduced by better discharge planning and closer cooperation between hospitals and physicians to ensure follow‐up care.21

At the Cleveland Clinic, data have recently been collected on the reasons for ED visits or hospital readmissions for patients receiving CoPAT at home through the Cleveland Clinic home care program. As illustrated in Figure 6, 24% of ED visits22 and 41% of hospital readmissions (Gordon, unpublished data) were for the infection being treated. Vascular access complications accounted for 23% of ED visits but only 2% of hospital readmissions. Nearly 50% of ED visits and 60% of hospital readmissions were for a reason unrelated to the infection being treated or CoPAT. It is hoped that closer examination of the data and perhaps additional analyses will suggest interventions to further reduce preventable readmissions or ED visits among patients discharged from the Cleveland Clinic on CoPAT.

Figure 6
Reasons for Emergency Department visits (A) or readmission to the hospital (B) while on Community‐Based Parenteral Anti‐Infective Therapy (CoPAT) or within 30 days of its completion of patients receiving CoPAT at home through Cleveland Clinic Home Care, January 1, 2008, to December 31, 2008.

Conclusions

Attention to antimicrobial stewardship and patient care should not end once the patient is discharged from the hospital or other institutional setting. Patients expect and should receive value‐based health care across the full cycle of their medical condition, and it is the responsibility of those caring for them to prepare for and provide such care during as well as after hospital discharge. The CoPAT program at the Cleveland Clinic provides a model for the extension of antimicrobial stewardship into the outpatient setting. The effectiveness of the program depends on a patient‐centric approach involving coordination and use of the expertise of multiple members of a team dedicated to patient value and facilitated by hospital‐based EHRs specialized for optimizing the transition of care into the outpatient setting for all patients scheduled to receive CoPAT. The quality of medical care provided by the Cleveland Clinic or other hospitals can be accessed through measurements of the structure, processes, and outcomes of care provided by the respective institutions. The data obtained can then be used to further refine care to optimize outcomes and provide high value for the patients treated at the institution. Achieving and then maintaining high‐quality medical care that provides value to patients is an ongoing process that should never be taken for granted.

References
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  8. Rich MW,Beckham V,Wittenberg C,Leven CL,Freedland KE,Carney RM.A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure.N Engl J Med.1995;333:11901195.
  9. Stewart S,Vandenbroek AJ,Pearson S,Horowitz JD.Prolonged beneficial effects of a home‐based intervention on unplanned readmissions and mortality among patients with congestive heart failure.Arch Intern Med.1999;159:257261.
  10. Caplan GA,Williams AJ,Daly B,Abraham K.A randomized, controlled trial of comprehensive geriatric assessment and multidisciplinary intervention after discharge of elderly from the emergency department–the DEED II study.J Am Geriatr Soc.2004;52:14171423.
  11. Nikolaus T,Specht‐Leible N,Bach M,Oster P,Schlierf G.A randomized trial of comprehensive geriatric assessment and home intervention in the care of hospitalized patients.Age Ageing.1999;28:543550.
  12. Rehm SJ,Weinstein AJ.Home intravenous antibiotic therapy: a team approach.Ann Intern Med.1983;99:388392.
  13. Merriam‐Webster Dictionary Online. Definition of steward. Available at http://www.merriam‐webster.com/dictionary/steward. Accessed July 14,2010.
  14. Dellit TH,Owens RC,McGowan JE, et al.Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.Clin Infect Dis.2007;44:159177.
  15. Kisuule F,Wright S,Barreto J,Zenilman J.Improving antibiotic utilization among hospitalists: a pilot academic detailing project with a public health approach.J Hosp Med.2008;3:6470.
  16. Rucker RW,Harrison GM.Outpatient intravenous medications in the management of cystic fibrosis.Pediatrics.1974;54:358360.
  17. Tice AD,Rehm SJ,Dalovisio JR, et al.Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines.Clin Infect Dis.2004;38:16511672.
  18. Donabedian A.Evaluating the quality of medical care.Milbank Mem Fund Q.1966;44(Suppl):166206.
  19. Sharma R,Loomis W,Brown RB.Impact of mandatory inpatient infectious disease consultation on outpatient parenteral antibiotic therapy.Am J Med Sci.2005;330:6064.
  20. Jencks SF,Williams MV,Coleman EA.Rehospitalizations among patients in the Medicare fee‐for‐service program.N Engl J Med.2009;360:14181428.
  21. The New York Times. Editorial: Back in the Hospital Again. April 15, 2009. Available at http://www.nytimes.com/2009/04/16/opinion/16thu2.html. Accessed July 16,2010.
  22. Patel D,Shrestha NK,Gordon SM,Landers S,Jain AK,Rehm SJ.Emergency department visits of patients on community‐based parenteral anti‐infective therapy at home. Presented at the 47th annual meeting of IDSA, Philadelphia, PA, October 29‐November 1, 2009. Poster 462.
References
  1. Davidson CS.The caring physician: the life of Dr. Francis W. Peabody [book review].N Engl J Med.1993;328:817818.
  2. Porter ME,Teisberg EO.How physicians can change the future of health care.JAMA.2007;297:11031111.
  3. Porter ME,Teisberg EO.Redefining Health Care: Creating Value‐Based Competition on Results.Boston, MA:Harvard Business Press;2006.
  4. Greiner AC, Knebel E, eds.Health Professions Education: A Bridge to Quality. Committee on the Health Professions Education Summit.Washington, DC:National Academies Press;2003.
  5. Naylor MD,Brooten D,Campbell R, et al.Comprehensive discharge planning and home follow‐up of hospitalized elders: a randomized clinical trial.JAMA.1999;281:613620.
  6. Naylor MD,Brooten DA,Campbell RL,Maislin G,McCauley KM,Schwartz JS.Transitional care of older adults hospitalized with heart failure: a randomized, controlled trial.J Am Geriatr Soc.2004;52:675684.
  7. Phillips CO,Wright SM,Kern DE,Singa RM,Shepperd S,Rubin HR.Comprehensive discharge planning with postdischarge support for older patients with congestive heart failure: a meta‐analysis.JAMA.2004;291:13581367.
  8. Rich MW,Beckham V,Wittenberg C,Leven CL,Freedland KE,Carney RM.A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure.N Engl J Med.1995;333:11901195.
  9. Stewart S,Vandenbroek AJ,Pearson S,Horowitz JD.Prolonged beneficial effects of a home‐based intervention on unplanned readmissions and mortality among patients with congestive heart failure.Arch Intern Med.1999;159:257261.
  10. Caplan GA,Williams AJ,Daly B,Abraham K.A randomized, controlled trial of comprehensive geriatric assessment and multidisciplinary intervention after discharge of elderly from the emergency department–the DEED II study.J Am Geriatr Soc.2004;52:14171423.
  11. Nikolaus T,Specht‐Leible N,Bach M,Oster P,Schlierf G.A randomized trial of comprehensive geriatric assessment and home intervention in the care of hospitalized patients.Age Ageing.1999;28:543550.
  12. Rehm SJ,Weinstein AJ.Home intravenous antibiotic therapy: a team approach.Ann Intern Med.1983;99:388392.
  13. Merriam‐Webster Dictionary Online. Definition of steward. Available at http://www.merriam‐webster.com/dictionary/steward. Accessed July 14,2010.
  14. Dellit TH,Owens RC,McGowan JE, et al.Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.Clin Infect Dis.2007;44:159177.
  15. Kisuule F,Wright S,Barreto J,Zenilman J.Improving antibiotic utilization among hospitalists: a pilot academic detailing project with a public health approach.J Hosp Med.2008;3:6470.
  16. Rucker RW,Harrison GM.Outpatient intravenous medications in the management of cystic fibrosis.Pediatrics.1974;54:358360.
  17. Tice AD,Rehm SJ,Dalovisio JR, et al.Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines.Clin Infect Dis.2004;38:16511672.
  18. Donabedian A.Evaluating the quality of medical care.Milbank Mem Fund Q.1966;44(Suppl):166206.
  19. Sharma R,Loomis W,Brown RB.Impact of mandatory inpatient infectious disease consultation on outpatient parenteral antibiotic therapy.Am J Med Sci.2005;330:6064.
  20. Jencks SF,Williams MV,Coleman EA.Rehospitalizations among patients in the Medicare fee‐for‐service program.N Engl J Med.2009;360:14181428.
  21. The New York Times. Editorial: Back in the Hospital Again. April 15, 2009. Available at http://www.nytimes.com/2009/04/16/opinion/16thu2.html. Accessed July 16,2010.
  22. Patel D,Shrestha NK,Gordon SM,Landers S,Jain AK,Rehm SJ.Emergency department visits of patients on community‐based parenteral anti‐infective therapy at home. Presented at the 47th annual meeting of IDSA, Philadelphia, PA, October 29‐November 1, 2009. Poster 462.
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Staphylococcus aureus: The new adventures of a legendary pathogen

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Staphylococcus aureus: The new adventures of a legendary pathogen

Staphylococcus aureus is rearing its ugly head in new and interesting ways, both in the hospital and in the community.

Rates of invasive infections with methicillin-resistant S aureus (MRSA) have been increasing both in the hospital and in the community, a trend that has attracted considerable interest in the lay media. Curiously, the most common community-associated MRSA strain, which up to now has been distinct from hospital-associated MRSA strains, is invading our hospitals. Alarmingly, vancomycin (Vancocin), the drug of last resort for MRSA infections for the past 40 years, does not seem to be as effective as it used to be.

This paper summarizes the changing epidemiology of S aureus, particularly the emergence of MRSA outside of the hospital; reviews the difficulties associated with S aureus bacteremia and its treatment in view of; some changes in vancomycin susceptibility; and appraises the old and new treatment options.

MRSA IS ON THE RISE IN THE HOSPITAL

S aureus, a gram-positive, coagulase-positive bacterium, is one of the leading nosocomial bloodstream pathogens, second only to coagulase-negative staphylococci.1 And the incidence of S aureus infections is increasing. MRSA in particular is increasingly causing infections throughout hospitals, including intensive care units. As of 2004, nearly two-thirds of isolates of S aureus from intensive care units were MRSA.2

MRSA infections are worse than methicillin-susceptible S aureus (MSSA) infections in terms of the rates of death and other undesirable outcomes.3 Several factors may be responsible: MRSA infection may be a marker of severity of illness (sicker patients may be more likely to have MRSA), our treatment for MRSA may not be as effective as it is for MSSA, and the organism may be inherently more virulent.

METHICILLIN RESISTANCE IS ALSO ON THE RISE IN THE COMMUNITY

Community-associated MRSA began emerging clinically about 10 years ago. It was first described in a cohort of children with necrotizing pneumonia in Minnesota, but soon other populations at risk began to emerge, such as residents of correctional facilities, men who had sex with men, competitive athletes (eg, fencers, wrestlers, and football players), and Alaskan natives and other native populations. A common factor in all these groups was close proximity of the members to each other. Later, it began to spread beyond these traditional risk groups into the community at large.

Community-associated MRSA strains have a characteristic pattern of antimicrobial susceptibility (see below). In the laboratory, they grow somewhat faster than health-care-associated MRSA strains, but not as fast as MSSA. They have a strong association with skin and soft-tissue infections: when you see a skin or soft-tissue infection, be it in an outpatient or an inpatient, think about MRSA. Their virulence varies, but rapid onset and progression of illness are quite common. Their most common strain in the United States at present is USA 300.

Case 1: A young woman with necrotizing fasciitis

A 21-year-old college student presented to our service in May 2004 with high fever and severe arm pain, which had been worsening for several days. She had been previously healthy, had not had any contact with the health care system, and had not received any antibiotics.

Figure 1. Necrotizing fasciitis due to community-associated methicillin-resistant Staphylococcus aureus.
Her arm was red and extremely painful (Figure 1). Pain out of proportion to findings is a cardinal sign of necrotizing fasciitis, and this is indeed what she had.

Her blood cultures were positive for MRSA, as were cultures of the deep tissue of the deltoid muscle and fascia when she underwent emergency surgical debridement. The infection required several additional surgical debridements and removal of one head of her deltoid muscle, but she was fortunate: in the past, some patients with this problem might have undergone radical amputation of the arm or even more extensive surgery. This patient continued to have positive blood cultures 4 days postoperatively, but she ultimately recovered, completing 28 days of daptomycin (Cubicin) therapy at a dose of 6 mg/kg every 24 hours. The last 10 days of daptomycin therapy were given at home via a percutaneous intravenous central catheter.

Comment. The epidemiology of MRSA infections is changing. More patients who have no traditional risk factors, specifically health care contact, are getting MRSA infections. A recent report from the US Centers for Disease Control and Prevention (CDC) indicates that the proportion of patients with invasive disease due to MRSA has doubled since 2001–2002.4 Part of the reason undoubtedly is that MRSA, particularly community-associated MRSA, often carries specific virulence factors that make it more invasive. The CDC estimated that in 2005 there were nearly 100,000 cases of invasive MRSA infection in the United States, and nearly a fifth of these infections resulted in death.

 

 

Resistance and virulence factors in community-associated MRSA

Most community-associated MRSA strains carry a mobile genetic element called type IV SCCmec (staphylococcal chromosomal cassettemec) that enhances its antimicrobial resistance. This genetic component was probably borrowed from coagulase-negative staphylococci, in which it is quite common but does not cause as much of a problem. It is now present in a wide range of S aureus strains. Most of the S aureus strains that carry type IV SCCmec are MRSA, but a few MSSA strains do carry it as well.

The potent toxin Panton-Valentine leukocidin is an extracellular product that is detected in fewer than 5% of hospital strains but is more common in community-associated strains. It kills leukocytes by forming pores in the cell membrane and causing skin necrosis in cutaneous infections. It is associated with skin abscesses and rapidly progressive necrotizing pneumonia in MSSA or MRSA.

Epidemiologic differences between community- and health-care-associated MRSA

Patients with community-associated MRSA infections tend to be younger than those who traditionally get health-care-associated MRSA infections: in a study from Naimi et al in 2003, the mean ages were 23 vs 68 years.5 A greater proportion of patients with community-associated MRSA strains are nonwhite.4,5

Most community-associated MRSA infections are of the skin and soft tissue (75% in the series from Naimi et al5), but this pathogen causes other infections as well. Bacteremia of unknown origin has been seen, as has necrotizing pneumonia. Most of the skin and soft-tissue infections are relatively superficial, such as folliculitis or furunculosis, but deeper tissue infections such as necrotizing fasciitis and pyomyositis have also been seen.6

The incidence of community-associated MRSA infections varies greatly by geographic region.7 The northeastern United States has so far been relatively spared, but in Atlanta, Houston, and Los Angeles up to 80% of cases of characteristic skin or soft-tissue infections seen in emergency or outpatient departments are due to community-associated MRSA. Physicians at the Texas Children’s Hospital in Houston assume that all skin or soft-tissue infections are due to community-associated MRSA unless proven otherwise.8

Differences in antibiotic susceptibility

Community-associated MRSA is more susceptible to various antibiotics than health-care-associated MRSA,5 but not by much. Strains are usually susceptible to vancomycin, tetracyclines, trimethoprim-sulfamethoxazole (Bactrim, Septra), and rifampin (Rifadin). Unlike hospital strains, a fair number of community-acquired strains are susceptible to clindamycin (Cleocin) in the laboratory, but with a caveat: some of these clindamycin-susceptible strains actually may harbor the tools for inducible resistance. In fact, they can become resistant to clindamycin even without being exposed to it.

The laboratory test for inducible clindamycin resistance is called the D test. After coating an agar plate with S aureus, the technician places erythromycin and clindamycin disks. If the erythromycin induces clindamycin resistance, the plate is clear of growth around the clindamycin disk except for the portion nearest the erythromycin disk, leaving a characteristic D-shaped area of lucency.

Risk factors for MRSA

Moran et al7 analyzed the risk factors for community-associated MRSA in patients with skin or soft-tissue infections seen in the emergency department. The infection was more likely to be due to community-associated MRSA if the patient was black, had used any antibiotic in the past month, had a history of MRSA infection, or had close contact with a person with a similar infection. Many patients interpreted the infections as spider bites because the lesions tended to have a dark center surrounded by a tender area. These infections were not associated with underlying illness. In some cases, community-associated MRSA skin infections have been associated with tattooing and even manicuring.

However, it is very difficult to distinguish between community-associated MRSA and MSSA skin and soft-tissue infections on the basis of clinical and epidemiologic characteristics. Miller et al9 studied a large group of patients in Los Angeles who were hospitalized with community-associated skin and soft-tissue S aureus infections. All the patients were followed up for 30 days after hospital discharge. Regardless of whether they had MRSA or MSSA, they had similar outcomes. Close contacts of the patients also tended to develop infection.

A key point from this and many other studies: patients were more likely to remain infected if they did not undergo incision and drainage. This key intervention is indicated for any patient who has a skin and soft-tissue infection with an undrained focus of infection.

 

 

COMMUNITY-ASSOCIATED MRSA IS INVADING THE HOSPITAL

In a new development, community-associated MRSA strains are now appearing in the hospital. This is not only because patients are bacteremic when they come in: patients in the hospital are getting nosocomial infections due to community-associated MRSA strains.

Seybold et al10 analyzed 116 cases of MRSA bloodstream infections in Atlanta, GA. In 9 (8%) of the cases the patient had not had any contact with the health care system within the past year, and these cases were classified as truly community-associated. Of the remaining 107 cases, 49 (42%) were nosocomial, and the USA 300 strain—the predominant community-associated MRSA strain—accounted for 10 (20%) of the nosocomial cases.

In the recent CDC study of invasive MRSA infections, Klevens et al4 reported that nearly a third of cases of bacteremia were due to community-associated MRSA, and these strains accounted for a greater proportion of cases of cellulitis and endocarditis than did health-care-associated strains.

In a study of hospital-associated MRSA, Maree et al11 found that the percentage of cases in which the bacteria carried the SCCmec type IV marker had increased from less than 20% in 1999 to more than 50% in 2004.

Comment. Suffice it to say that we are surrounded by MRSA. Community-associated MRSA is here to stay. It is even invading our hospitals, and we need to consider this very carefully when choosing antimicrobial therapy.

NAGGING QUESTIONS ABOUT VANCOMYCIN

Case 2: Vancomycin-intermediate S aureus (VISA) bacteremia and endocarditis

In December 2006 we saw a very ill 60-year-old woman who was hospitalized with MRSA bacteremia, pacemaker endocarditis, and superior vena cava thrombosis. Although she was treated with vancomycin and rifampin, her condition worsened, she had a stroke, and she developed renal failure. In a difficult operation, the pacemaker was removed, but the bacteremia persisted. In early February 2007 she underwent another difficult operation in which the superior vena cava clot was debrided, a right atrial clot was removed, and her mitral valve was replaced. Less than 2 weeks later, and despite ongoing vancomycin and rifampin therapy, the MRSA bacteremia recurred.

During the approximately 6 weeks that the patient had been receiving these antibiotics, the minimal inhibitory concentration (MIC) of rifampin against the S aureus isolate increased from less than 1 μg/mL (susceptible) to 2 μg/mL (resistant). The MIC of vancomycin went from 2 μg/mL (susceptible) to 4 μg/mL (intermediately susceptible). Vancomycin and rifampin were discontinued, and daptomycin and gentamicin (Garamycin) therapy were started. (Her daptomycin MIC was 0.5 μg/mL). The patient’s condition stabilized, and she was discharged to a long-term nursing facility. She had no relapse of MRSA bacteremia, but she died in early April of that year.

Is vancomycin becoming less effective? Degrees of vancomycin resistance

Vancomycin has been our stalwart for treating MRSA infections for more than 40 years but it is not working as well as it used to, at least in certain situations.

Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:3040–3045
Figure 2. Population analysis of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate S aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-susceptible S aureus (VSSA). The population analysis shows how many cells in a fixed number of cells (usually about 107 colony-forming units [CFU]) of each strain are resistant to various concentrations of vancomycin. VRSA is a highly resistant and homogeneously resistant strain, with 100% of the population growing at each of the vancomycin concentrations tested. VISA is intermediately resistant, with 100% of the population growing at 4 μg of vancomycin per mL and also with significant subpopulations growing at 8 μg/mL. hVISA demonstrates heterogeneous resistance, having subpopulations of cells with various levels of resistance to vancomycin and including small populations of vancomycin-intermediate resistant cells with growth at 8 μg of vancomycin per mL.
Various terms describe the degrees of susceptibility or resistance to vancomycin (Figure 2).12

VRSA (vancomycin-resistant S aureus) is rare. These fully resistant strains probably acquired a resistance mechanism (the vanA operon) from vancomycin-resistant enterococci. Infections tend to occur in patients simultaneously infected with both S aureus and vancomycin-resistant enterococci, giving the bacteria an opportunity to exchange genetic material.

VISA (vancomycin-intermediate S aureus) infections tend to occur in patients like the one described above who have had long-term vancomycin therapy. VISA strains appear to overproduce a matrix that captures vancomycin and keeps it from entering the cell. On electron microscopy, these bacteria have a very thick cell wall.13

Vancomycin tolerance is a state in which the bacteria are “stunned” or kept in check but not killed by vancomycin. That is manifested in the laboratory by a ratio of minimum bactericidal concentration to MIC greater than 32.

hVISA (heteroresistant VISA) is new and worrisome. These organisms have an overall MIC in the susceptible range, but within that population are individual isolates with an MIC that is much higher—in the intermediate or perhaps even in the resistant range.14

Reported rates of hVISA vary from less than 2% to as high as 76%, because the methods for detecting it are still very poorly standardized. The usual automated laboratory tests do not detect hVISA.

hVISA is probably clinically relevant, as evidence is emerging both in vitro and in vivo that the higher the MIC for vancomycin, the worse the clinical outcome.15 hVISA has been associated with failures of therapy in several situations, usually in cases of severe invasive or deep infection, endocarditis, and bacteremia with vertebral osteomyelitis where vancomycin concentrations at the site of infection may be suboptimal.16–19 While most hVISA strains that have been described were resistant to methicillin, some were susceptible.

The E test is emerging as the standard test for hVISA. This test uses a plastic strip that contains gradually increasing concentrations of vancomycin along its length. Placed in the culture dish, the strip inhibits growth of the organism at its high-concentration end but not at its low-concentration end. If the sample contains hVISA, the cutoff is not well defined, with a few colonies growing at higher concentrations.

 

 

New definition of vancomycin susceptibility

Recognizing that the MICs for vancomycin have been rising in the last few years, the Clinical and Laboratory Standards Institute last year changed the break points between susceptibility and resistance. The new definitions are:

  • Susceptible—an MIC of 2.0 μg/mL or less (formerly 4.0 μg/mL or less)
  • Intermediate—4.0 to 8.0 μg/mL (formerly 8.0 to 16 μg/mL)
  • Resistant—16 μg/mL or greater (formerly 32 μg/mL or greater).

One should pay attention to the MIC numbers on the laboratory reports, not just to the words “susceptible” or “not susceptible.” If the number is, say, 0.5 μg/mL or less, the organism should really be susceptible. If the number is 1 or 2, it is still in the susceptible range, but those are the organisms that may cause problems later on.

Further, even if the vancomycin MIC is in the susceptible range, higher MICs may affect outcomes. The average duration of MRSA bacteremia on therapy is 8 to 9 days, vs 3 to 4 days with MSSA bacteremia.20,21 But Sakoulas et al15 found that, in MRSA bacteremia, the success rate with vancomycin therapy was 56% if the MIC was 0.5 or lower, compared with 10% if the MIC was 1.0 to 2.0 μg/mL. Examined in another way, the success rate was 50% if the logarithm of killing was 6.27 colony-forming units per mL or greater, 23% if 4.71 to 6.26, and zero if less than 4.71.

Case 3: Prolonged MRSA bacteremia

In the summer of 2006, a 66-year-old woman with a history of gastric bypass and cirrhosis underwent a long stay in the surgical intensive care unit because of a recurrent enterocutaneous fistula and chronic renal insufficiency. On November 5th, she had a positive blood culture for MRSA, which was treated appropriately with vancomycin for 4 weeks. She was discharged to subacute care but came back 2 days later, again with MRSA bacteremia. At that time her Hickman catheter, which had been inserted for total parenteral nutrition because of the enterocutaneous fistula, was removed.

Transthoracic echocardiography revealed no vegetations, but her bacteremia persisted. Her mental status was poor this entire time: she was mute and could barely be awakened. We looked for clots and infected clots; duplex ultrasonographic examinations of all four extremities were negative. Finally, magnetic resonance imaging of her back—performed empirically because of the persistent bacteremia—revealed vertebral osteomyelitis at level T12-L1. We also noticed on serial evaluations that the vancomycin MIC for her organism increased from 0.5 to 2.0 μg/mL, so therapy was changed from vancomycin to daptomycin.

Her bacteremia cleared. Follow-up echocardiography was negative, but she had two subsequent relapses of MRSA bacteremia, one in April 2007 and one before she died in the summer of 2007.

Prolonged bacteremia: Is it vancomycin resistance, or something else?

The MRSA isolates that cause prolonged bacteremia seem to have certain characteristics.22 Higher MICs are probably associated with longer periods of bacteremia. But some genetic components within some strains of S aureus give them a survival advantage. They have less susceptibility to the body’s thrombin-induced platelet microbicidal protein. These isolates are not only associated with prolonged bacteremia: they are also associated with osteomyelitis, deep abscesses, endocarditis, recurrent infection, and increased death rate.22 Clinical laboratories do not test for these genetic components. One wonders whether our patient may have had an isolate with these mutations that gave it a survival advantage.

Do not use vancomycin for MSSA

Avoid using vancomycin for MSSA infections. It has been shown time and time again that MSSA infections do not respond as well to vancomycin as they do to beta-lactam antibiotics, specifically to the semisynthetic penicillins such as oxacillin and nafcillin, and even some of the first-generation cephalosporins. Chang et al23 found that patients with MSSA bacteremia had higher rates of persistent infections, relapse, and bacteriologic failure if they received vancomycin than if they received nafcillin.

Do vancomycin trough levels affect toxicity?

The vancomycin trough levels that we aimed for in the past (5 to 10 μg/mL) were probably too low. Today, we aim for trough levels of 15 to 20 μg/mL, and many physicians are aiming for 20 to 25 μg/mL. Part of the reason is that vancomycin MICs are higher than they used to be: in order to keep the vancomycin level above the MIC for a longer period of time, the vancomycin trough level needs to be higher. In theory, keeping the vancomycin levels above the MIC for longer periods should improve outcomes. Yet Fowler et al22 found that vancomycin trough levels among patients who had persistent MRSA bacteremia were actually higher than trough levels among those in whom the bacteremia resolved, although the difference was not statistically significant.

We measure the vancomycin trough level to make sure it is high enough (and give larger doses if it is not); among adults, peak levels need not be monitored on a routine basis because of the predictable pharmacokinetics of vancomycin.

Vancomycin toxicity can be either idiosyncratic or synergistic. Idiosyncratic toxicity occurs when a patient who has been on vancomycin for a long time develops a fixed rash, not associated with infusion. This is an immunologic phenomenon. It is a rare and very serious situation and may require steroid therapy.

Synergistic toxicity occurs when vancomycin is given with other nephrotoxic agents, notably gentamicin. Vancomycin plus gentamicin equals nephrotoxicity. Vancomycin alone is usually not nephrotoxic, but close monitoring of renal function parameters is warranted with the use of higher doses.24

 

 

IN UNEXPLAINED BACTEREMIA, LOOK FOR ENDOCARDITIS

In blood cultures from patients with bacteremia, S aureus is never a contaminant. Even if just one blood culture is positive for S aureus, believe that S aureus is the culprit.

Reports in the 1950s suggested that at least half of patients who had S aureus bacteremia had endocarditis,25 leading to recommendations that all patients with S aureus bacteremia without an obvious primary source of infection should be evaluated for endocarditis. Subsequent estimates were lower, in the range of 15% to 25%.26,27 However, throughout the world S aureus endocarditis continues to have a very high mortality rate: at least a third of patients die.28

Clinical criteria (community acquisition, no primary focus, and metastatic sequelae) were developed to try to predict the risk of endocarditis in bacteremic patients.26 However, these criteria did not work very well. The clinical definition of endocarditis has evolved. The criteria of von Reyn et al29 from 1981 did not use echocardiography as part of the definition, but the 1994 Duke criteria,30 which were refined31 in 2000, use both clinical and echocardiographic parameters.

Stratton et al32 performed transthoracic echocardiography in 14 patients with bacteremia and found 1 patient with cryptic tricuspid infective endocarditis. Bayer et al33 subsequently reported that of 72 patients with bacteremia, 6 (18%) of those who had no clinical findings suggestive of infectious endocarditis had findings on echocardiography that led to changes in their regimen. Adding echocardiography to three clinical risk factors increased the sensitivity of diagnosing endocarditis from 70% to 85% with a specificity of 100% and predictive value of 96%.

The Duke criteria call for transesophageal echocardiography, which is not feasible in some patients, eg, those with cirrhosis and esophageal varices.

S aureus endocarditis has changed over the years as our patient population has changed, and MRSA endocarditis tends to hit some of our most vulnerable patients. In a study by Miro et al34 in 2005, MRSA was the leading pathogen in patients who were diagnosed with S aureus endocarditis in 1990 or later. We will only see these numbers go up. Patients with diabetes tend to have more MRSA, and of diabetic patients with MRSA endocarditis, 30% to 40% die in the hospital.

Indications for surgery

Certain conditions are indications for surgery among patients with endocarditis, and no antibiotic will cure the endocarditis if the patient has one of these conditions, eg:

  • Persistent bacteremia during antibiotic therapy
  • Recurrent emboli
  • Heart failure that cannot be controlled
  • Perivalvular or myocardial abscesses
  • Large vegetations
  • Early prosthetic valve infection
  • Certain arrhythmias.

How long should S aureus bacteremia be treated?

In cases of bacteremia in which endocarditis has been ruled out and removable foci of infection (eg, intravascular catheters) have been removed, some evidence indicates that treatment for 2 weeks would be as effective as the 4 to 6 weeks that we would use for endocarditis or other severe or invasive infections.35 The issue is controversial. If the patient has had frequent hospitalizations or a chronic medical condition I would hesitate to treat for less than 4 weeks, even if the infection appears to be associated with a removable focus.

Treatment of endocarditis

In the guidelines for treatment of endocarditis from the American Heart Association and Infectious Diseases Society of America,36 all the recommendations are relatively old and many of them are somewhat empiric—they are not based on evidence from randomized clinical trials. Rather, they are best opinions based on clinical experience and some observational studies over the years.

For MSSA. In cases of native-valve endocarditis, oxacillin (Bactocill), nafcillin (Unipen), or another semisynthetic beta-lactam antibiotic is recommended. For penicillin-allergic patients, we have other options, such as cefazolin (Ancef, Kefzol).

Combination therapy is frequently recommended for native valve endocarditis as well as for prosthetic valve endocarditis, with either rifampin or gentamicin along with a primary agent. There is some evidence that one can clear staphylococcal bacteremia a day or two more quickly by use of combination therapy with nafcillin plus an aminoglycoside than with nafcillin alone.37,38 For MSSA-associated endocarditis, vancomycin does not work as well as beta-lactam antibiotics.39,40

Korzeniowski and Sande37 and Chambers et al38 reported that the mean duration of bacteremia was 3.4 days for patients treated with nafcillin alone and 2.9 days for those treated with nafcillin plus an aminoglycoside. These studies led to consideration of a short course of gentamicin to clear the bacteremia quickly.

With MRSA, bacteremia often requires a week or more to clear. Levine et al21 reported a study in 42 patients, mostly injection-drug users, with right-sided native-valve endocarditis. The median duration of bacteremia was 7 days in patients who received vancomycin alone vs 9 days in those who received vancomycin plus rifampin; however, some patients were bacteremic for up to 27 days. Fever persisted for a median of 7 days, probably partly due to septic pulmonary emboli. Three patients died, and three required valve replacement.

 

 

NEW ANTIBIOTICS

Several new antibiotics are active against gram-positive cocci.41–44 However, the majority of them have not been prospectively studied for treating bacteremia or endocarditis.

Quinupristin/dalfopristin (Synercid) has not been formally studied for treatment of MRSA bacteremia or endocarditis. There are a few case reports of its use in these conditions.45 Quinupristin/dalfopristin is bacteriostatic, and its use may be associated with phlebitis, myalgias, and arthralgias.46

Linezolid (Zyvox) is approved for treatment of complicated skin and soft-tissue infections and for hospital-acquired pneumonia. There have been no specific studies of linezolid in the treatment of S aureus bacteremia or endocarditis. However, Shorr et al47 retrospectively looked at the bacteremic patients in five previous studies of linezolid vs vancomycin and found 144 cases of S aureus bacteremia, half of which were due to MRSA. Of 53 assessable patients with MRSA bacteremia, the primary infection was cured in 14 (56%) of the linezolid patients and 13 (46%) of the vancomycin patients.

The oral form is 100% bioavailable. One should avoid concomitant use of serotonin-reuptake inhibitors because of the risk of serotonin syndrome. Adverse effects include altered taste sensation and peripheral neuropathy. There are other potential toxicities, including hematologic changes (thrombocytopenia, leukopenia) and metabolic effects (lactic acidosis), so clinical and laboratory monitoring is important.48 The role of linezolid in the treatment of patients with S aureus bacteremia or endocarditis remains to be defined.

Daptomycin is indicated for complicated skin and soft-tissue infections, bacteremia, and right-sided endocarditis due to S aureus. Fowler et al20 found that daptomycin was not inferior to beta-lactam antibiotics for treatment of MSSA bacteremia and right-sided endocarditis, and for MRSA infections it outperformed vancomycin, but the difference was not statistically significant.

The dosing interval should be increased from once every 24 hours to every 48 hours if the creatinine clearance is 30 mL/minute or less. Adverse effects include myalgia, rhabdomyolysis (rare), and elevations in creatine phosphokinase. Reports of rising MICs during daptomycin therapy, in some cases associated with persistent infection,49 suggest that careful attention be paid to dosing and clinical monitoring.

Tigecycline (Tygacil) is indicated for complicated skin and soft-tissue infections and complicated intra-abdominal infections due to susceptible organisms. It is active against both MSSA and MRSA, but clinical experience with its use in invasive infections is somewhat limited.50 The dose of tigecycline should be reduced in advanced cirrhosis. Adverse effects include nausea and vomiting.

Telavancin, dalbavancin, and oritavancin, investigational parenteral antibiotics that are derivatives of vancomycin, are in clinical trials. The pharmacokinetic activity of these agents is of interest: telavancin is being studied with a once-daily dosing interval and dalbavancin’s half-life allows once-weekly dosing. In a limited trial, dalbavancin was found to be safe and effective in the treatment of catheter-related bloodstream infections.51 None of the antibiotics in this group has been studied for treatment of S aureus endocarditis. Telavancin therapy has been associated with rash, hypokalemia, QT prolongation, and creatinine elevations. Gastrointestinal symptoms have been reported with the use of dalbavancin.

Ceftobiprole, another investigational agent, is the only cephalosporin antibiotic that is active against MRSA. It is given every 12 hours. Adverse effects include nausea and taste disturbance.

Iclaprim is a novel diaminopyrimidine and a dihydrofolate reductase inhibitor. In vitro, it is active against gram-positive bacteria, including MRSA, VISA, and VRSA; clinical investigations at this point are limited to the treatment of skin and soft-tissue infections.

References
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  17. Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother 2003; 47:12621266.
  18. Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogenous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004; 38:448451.
  19. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521528.
  20. Fowler VG, Boucher HW, Corey GR, et al. S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653665.
  21. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115:674680.
  22. Fowler VG, Sakoulas G, McIntyre LM, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis 2004; 190:11401149.
  23. Chang FY, Peacock JE, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore) 2003; 82:333339.
  24. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006; 166:21382144.
  25. Wilson R, Hamburger M. Fifteen years’ experience with staphylococcus septicemia in a large city hospital; analysis of fifty-five cases in the Cincinnati General Hospital 1940 to 1954. Am J Med 1957; 22:437457.
  26. Nolan CM, Beaty HN. Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med 1976; 60:495500.
  27. Shah M, Watanakunakorn C. Changing patterns of Staphylococcus aureus bacteremia. Am J Med Sci 1979; 278:115121.
  28. Fowler VG, Miro JM, Hoen B, et al ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293:30123021. Erratum in: JAMA 2005; 294:900.
  29. Von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective endocarditis: an analysis based on strict case definition. Ann Intern Med 1981; 94:505518.
  30. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96:200209.
  31. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30:633638.
  32. Stratton JR, Werner JA, Pearlman AS, Janko CL, Kliman S, Jackson MC. Bacteremia and the heart. Serial echocardiographic findings in 80 patients with documented or suspected bacteremia. Am J Med 1982; 73:851858.
  33. Bayer AS, Lam K, Ginzton L, Normal DC, Chiu CY, Ward JI. Staphylococcus aureus bacteremia. Clinical, serologic, and echocardiographic findings in patients with and without endocarditis. Arch Intern Med 1987; 147:457462.
  34. Miro JM, Anguera I, Cabell CH, et al International Collaboration on Endocarditis Merged Database Study Group. Staphylococcus aureus native valve infective endocarditis: report of 566 episodes from the International Collaboration on Endocarditis Merged Database. Clin Infect Dis 2005; 41:507–514. Erratum in: Clin Infect Dis 2005; 41:10751077.
  35. Jernigan JA, Farr BM. Short-course therapy of catheter-related Staphylococcus aureus bacteremia: a meta-analysis. Ann Intern Med 1993; 119:304311.
  36. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394e434. Erratum in: Circulation 2005; 112:2373. Circulation 2007; 115:e408.
  37. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med 1982; 97:496503.
  38. Chambers HF, Korzeniowski OM, Sande MA. Staphylococcus aureus endocarditis: clinical manifestations in addicts and nonaddicts. Medicine (Baltimore) 1983; 62:170177.
  39. Gentry CA, Rodvold KA, Novak RM, Hershow RC, Naderer OJ. Retrospective evaluation of therapies for Staphylococcus aureus endocarditis. Pharmacotherapy 1997; 17:990997.
  40. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34:12271231.
  41. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003; 36:473481.
  42. Rybak MJ. Therapeutic options for Gram-positive infections. J Hosp Infect 2001; 49 suppl A:S25S32.
  43. Micek ST. Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2007; 45 suppl 3:S184S190.
  44. Appelbaum PC, Jacobs MR. Recently approved and investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria. Curr Opin Microbiol 2005; 8:510517.
  45. Drew RH, Perfect JR, Srinath L, Kirkimilis E, Dowzicky M, Talbot GH for the Synercid Emergency-Use Study Group. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. J Antimicrob Chemother 2000; 46:775784.
  46. Lamb HM, Figgitt DP, Faulds D. Quinupristin/dalfopristin: a review of its use in the management of serious gram-positive infections. Drugs 1999; 58:10611097.
  47. Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother 2005; 56:923929.
  48. Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50:15991602.
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  50. Munoz-Price LS, Lolans K, Quinn JP. Four cases of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections treated with tigecycline. Scand J Infect Dis 2006; 38:10811084.
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Staphylococcus aureus is rearing its ugly head in new and interesting ways, both in the hospital and in the community.

Rates of invasive infections with methicillin-resistant S aureus (MRSA) have been increasing both in the hospital and in the community, a trend that has attracted considerable interest in the lay media. Curiously, the most common community-associated MRSA strain, which up to now has been distinct from hospital-associated MRSA strains, is invading our hospitals. Alarmingly, vancomycin (Vancocin), the drug of last resort for MRSA infections for the past 40 years, does not seem to be as effective as it used to be.

This paper summarizes the changing epidemiology of S aureus, particularly the emergence of MRSA outside of the hospital; reviews the difficulties associated with S aureus bacteremia and its treatment in view of; some changes in vancomycin susceptibility; and appraises the old and new treatment options.

MRSA IS ON THE RISE IN THE HOSPITAL

S aureus, a gram-positive, coagulase-positive bacterium, is one of the leading nosocomial bloodstream pathogens, second only to coagulase-negative staphylococci.1 And the incidence of S aureus infections is increasing. MRSA in particular is increasingly causing infections throughout hospitals, including intensive care units. As of 2004, nearly two-thirds of isolates of S aureus from intensive care units were MRSA.2

MRSA infections are worse than methicillin-susceptible S aureus (MSSA) infections in terms of the rates of death and other undesirable outcomes.3 Several factors may be responsible: MRSA infection may be a marker of severity of illness (sicker patients may be more likely to have MRSA), our treatment for MRSA may not be as effective as it is for MSSA, and the organism may be inherently more virulent.

METHICILLIN RESISTANCE IS ALSO ON THE RISE IN THE COMMUNITY

Community-associated MRSA began emerging clinically about 10 years ago. It was first described in a cohort of children with necrotizing pneumonia in Minnesota, but soon other populations at risk began to emerge, such as residents of correctional facilities, men who had sex with men, competitive athletes (eg, fencers, wrestlers, and football players), and Alaskan natives and other native populations. A common factor in all these groups was close proximity of the members to each other. Later, it began to spread beyond these traditional risk groups into the community at large.

Community-associated MRSA strains have a characteristic pattern of antimicrobial susceptibility (see below). In the laboratory, they grow somewhat faster than health-care-associated MRSA strains, but not as fast as MSSA. They have a strong association with skin and soft-tissue infections: when you see a skin or soft-tissue infection, be it in an outpatient or an inpatient, think about MRSA. Their virulence varies, but rapid onset and progression of illness are quite common. Their most common strain in the United States at present is USA 300.

Case 1: A young woman with necrotizing fasciitis

A 21-year-old college student presented to our service in May 2004 with high fever and severe arm pain, which had been worsening for several days. She had been previously healthy, had not had any contact with the health care system, and had not received any antibiotics.

Figure 1. Necrotizing fasciitis due to community-associated methicillin-resistant Staphylococcus aureus.
Her arm was red and extremely painful (Figure 1). Pain out of proportion to findings is a cardinal sign of necrotizing fasciitis, and this is indeed what she had.

Her blood cultures were positive for MRSA, as were cultures of the deep tissue of the deltoid muscle and fascia when she underwent emergency surgical debridement. The infection required several additional surgical debridements and removal of one head of her deltoid muscle, but she was fortunate: in the past, some patients with this problem might have undergone radical amputation of the arm or even more extensive surgery. This patient continued to have positive blood cultures 4 days postoperatively, but she ultimately recovered, completing 28 days of daptomycin (Cubicin) therapy at a dose of 6 mg/kg every 24 hours. The last 10 days of daptomycin therapy were given at home via a percutaneous intravenous central catheter.

Comment. The epidemiology of MRSA infections is changing. More patients who have no traditional risk factors, specifically health care contact, are getting MRSA infections. A recent report from the US Centers for Disease Control and Prevention (CDC) indicates that the proportion of patients with invasive disease due to MRSA has doubled since 2001–2002.4 Part of the reason undoubtedly is that MRSA, particularly community-associated MRSA, often carries specific virulence factors that make it more invasive. The CDC estimated that in 2005 there were nearly 100,000 cases of invasive MRSA infection in the United States, and nearly a fifth of these infections resulted in death.

 

 

Resistance and virulence factors in community-associated MRSA

Most community-associated MRSA strains carry a mobile genetic element called type IV SCCmec (staphylococcal chromosomal cassettemec) that enhances its antimicrobial resistance. This genetic component was probably borrowed from coagulase-negative staphylococci, in which it is quite common but does not cause as much of a problem. It is now present in a wide range of S aureus strains. Most of the S aureus strains that carry type IV SCCmec are MRSA, but a few MSSA strains do carry it as well.

The potent toxin Panton-Valentine leukocidin is an extracellular product that is detected in fewer than 5% of hospital strains but is more common in community-associated strains. It kills leukocytes by forming pores in the cell membrane and causing skin necrosis in cutaneous infections. It is associated with skin abscesses and rapidly progressive necrotizing pneumonia in MSSA or MRSA.

Epidemiologic differences between community- and health-care-associated MRSA

Patients with community-associated MRSA infections tend to be younger than those who traditionally get health-care-associated MRSA infections: in a study from Naimi et al in 2003, the mean ages were 23 vs 68 years.5 A greater proportion of patients with community-associated MRSA strains are nonwhite.4,5

Most community-associated MRSA infections are of the skin and soft tissue (75% in the series from Naimi et al5), but this pathogen causes other infections as well. Bacteremia of unknown origin has been seen, as has necrotizing pneumonia. Most of the skin and soft-tissue infections are relatively superficial, such as folliculitis or furunculosis, but deeper tissue infections such as necrotizing fasciitis and pyomyositis have also been seen.6

The incidence of community-associated MRSA infections varies greatly by geographic region.7 The northeastern United States has so far been relatively spared, but in Atlanta, Houston, and Los Angeles up to 80% of cases of characteristic skin or soft-tissue infections seen in emergency or outpatient departments are due to community-associated MRSA. Physicians at the Texas Children’s Hospital in Houston assume that all skin or soft-tissue infections are due to community-associated MRSA unless proven otherwise.8

Differences in antibiotic susceptibility

Community-associated MRSA is more susceptible to various antibiotics than health-care-associated MRSA,5 but not by much. Strains are usually susceptible to vancomycin, tetracyclines, trimethoprim-sulfamethoxazole (Bactrim, Septra), and rifampin (Rifadin). Unlike hospital strains, a fair number of community-acquired strains are susceptible to clindamycin (Cleocin) in the laboratory, but with a caveat: some of these clindamycin-susceptible strains actually may harbor the tools for inducible resistance. In fact, they can become resistant to clindamycin even without being exposed to it.

The laboratory test for inducible clindamycin resistance is called the D test. After coating an agar plate with S aureus, the technician places erythromycin and clindamycin disks. If the erythromycin induces clindamycin resistance, the plate is clear of growth around the clindamycin disk except for the portion nearest the erythromycin disk, leaving a characteristic D-shaped area of lucency.

Risk factors for MRSA

Moran et al7 analyzed the risk factors for community-associated MRSA in patients with skin or soft-tissue infections seen in the emergency department. The infection was more likely to be due to community-associated MRSA if the patient was black, had used any antibiotic in the past month, had a history of MRSA infection, or had close contact with a person with a similar infection. Many patients interpreted the infections as spider bites because the lesions tended to have a dark center surrounded by a tender area. These infections were not associated with underlying illness. In some cases, community-associated MRSA skin infections have been associated with tattooing and even manicuring.

However, it is very difficult to distinguish between community-associated MRSA and MSSA skin and soft-tissue infections on the basis of clinical and epidemiologic characteristics. Miller et al9 studied a large group of patients in Los Angeles who were hospitalized with community-associated skin and soft-tissue S aureus infections. All the patients were followed up for 30 days after hospital discharge. Regardless of whether they had MRSA or MSSA, they had similar outcomes. Close contacts of the patients also tended to develop infection.

A key point from this and many other studies: patients were more likely to remain infected if they did not undergo incision and drainage. This key intervention is indicated for any patient who has a skin and soft-tissue infection with an undrained focus of infection.

 

 

COMMUNITY-ASSOCIATED MRSA IS INVADING THE HOSPITAL

In a new development, community-associated MRSA strains are now appearing in the hospital. This is not only because patients are bacteremic when they come in: patients in the hospital are getting nosocomial infections due to community-associated MRSA strains.

Seybold et al10 analyzed 116 cases of MRSA bloodstream infections in Atlanta, GA. In 9 (8%) of the cases the patient had not had any contact with the health care system within the past year, and these cases were classified as truly community-associated. Of the remaining 107 cases, 49 (42%) were nosocomial, and the USA 300 strain—the predominant community-associated MRSA strain—accounted for 10 (20%) of the nosocomial cases.

In the recent CDC study of invasive MRSA infections, Klevens et al4 reported that nearly a third of cases of bacteremia were due to community-associated MRSA, and these strains accounted for a greater proportion of cases of cellulitis and endocarditis than did health-care-associated strains.

In a study of hospital-associated MRSA, Maree et al11 found that the percentage of cases in which the bacteria carried the SCCmec type IV marker had increased from less than 20% in 1999 to more than 50% in 2004.

Comment. Suffice it to say that we are surrounded by MRSA. Community-associated MRSA is here to stay. It is even invading our hospitals, and we need to consider this very carefully when choosing antimicrobial therapy.

NAGGING QUESTIONS ABOUT VANCOMYCIN

Case 2: Vancomycin-intermediate S aureus (VISA) bacteremia and endocarditis

In December 2006 we saw a very ill 60-year-old woman who was hospitalized with MRSA bacteremia, pacemaker endocarditis, and superior vena cava thrombosis. Although she was treated with vancomycin and rifampin, her condition worsened, she had a stroke, and she developed renal failure. In a difficult operation, the pacemaker was removed, but the bacteremia persisted. In early February 2007 she underwent another difficult operation in which the superior vena cava clot was debrided, a right atrial clot was removed, and her mitral valve was replaced. Less than 2 weeks later, and despite ongoing vancomycin and rifampin therapy, the MRSA bacteremia recurred.

During the approximately 6 weeks that the patient had been receiving these antibiotics, the minimal inhibitory concentration (MIC) of rifampin against the S aureus isolate increased from less than 1 μg/mL (susceptible) to 2 μg/mL (resistant). The MIC of vancomycin went from 2 μg/mL (susceptible) to 4 μg/mL (intermediately susceptible). Vancomycin and rifampin were discontinued, and daptomycin and gentamicin (Garamycin) therapy were started. (Her daptomycin MIC was 0.5 μg/mL). The patient’s condition stabilized, and she was discharged to a long-term nursing facility. She had no relapse of MRSA bacteremia, but she died in early April of that year.

Is vancomycin becoming less effective? Degrees of vancomycin resistance

Vancomycin has been our stalwart for treating MRSA infections for more than 40 years but it is not working as well as it used to, at least in certain situations.

Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:3040–3045
Figure 2. Population analysis of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate S aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-susceptible S aureus (VSSA). The population analysis shows how many cells in a fixed number of cells (usually about 107 colony-forming units [CFU]) of each strain are resistant to various concentrations of vancomycin. VRSA is a highly resistant and homogeneously resistant strain, with 100% of the population growing at each of the vancomycin concentrations tested. VISA is intermediately resistant, with 100% of the population growing at 4 μg of vancomycin per mL and also with significant subpopulations growing at 8 μg/mL. hVISA demonstrates heterogeneous resistance, having subpopulations of cells with various levels of resistance to vancomycin and including small populations of vancomycin-intermediate resistant cells with growth at 8 μg of vancomycin per mL.
Various terms describe the degrees of susceptibility or resistance to vancomycin (Figure 2).12

VRSA (vancomycin-resistant S aureus) is rare. These fully resistant strains probably acquired a resistance mechanism (the vanA operon) from vancomycin-resistant enterococci. Infections tend to occur in patients simultaneously infected with both S aureus and vancomycin-resistant enterococci, giving the bacteria an opportunity to exchange genetic material.

VISA (vancomycin-intermediate S aureus) infections tend to occur in patients like the one described above who have had long-term vancomycin therapy. VISA strains appear to overproduce a matrix that captures vancomycin and keeps it from entering the cell. On electron microscopy, these bacteria have a very thick cell wall.13

Vancomycin tolerance is a state in which the bacteria are “stunned” or kept in check but not killed by vancomycin. That is manifested in the laboratory by a ratio of minimum bactericidal concentration to MIC greater than 32.

hVISA (heteroresistant VISA) is new and worrisome. These organisms have an overall MIC in the susceptible range, but within that population are individual isolates with an MIC that is much higher—in the intermediate or perhaps even in the resistant range.14

Reported rates of hVISA vary from less than 2% to as high as 76%, because the methods for detecting it are still very poorly standardized. The usual automated laboratory tests do not detect hVISA.

hVISA is probably clinically relevant, as evidence is emerging both in vitro and in vivo that the higher the MIC for vancomycin, the worse the clinical outcome.15 hVISA has been associated with failures of therapy in several situations, usually in cases of severe invasive or deep infection, endocarditis, and bacteremia with vertebral osteomyelitis where vancomycin concentrations at the site of infection may be suboptimal.16–19 While most hVISA strains that have been described were resistant to methicillin, some were susceptible.

The E test is emerging as the standard test for hVISA. This test uses a plastic strip that contains gradually increasing concentrations of vancomycin along its length. Placed in the culture dish, the strip inhibits growth of the organism at its high-concentration end but not at its low-concentration end. If the sample contains hVISA, the cutoff is not well defined, with a few colonies growing at higher concentrations.

 

 

New definition of vancomycin susceptibility

Recognizing that the MICs for vancomycin have been rising in the last few years, the Clinical and Laboratory Standards Institute last year changed the break points between susceptibility and resistance. The new definitions are:

  • Susceptible—an MIC of 2.0 μg/mL or less (formerly 4.0 μg/mL or less)
  • Intermediate—4.0 to 8.0 μg/mL (formerly 8.0 to 16 μg/mL)
  • Resistant—16 μg/mL or greater (formerly 32 μg/mL or greater).

One should pay attention to the MIC numbers on the laboratory reports, not just to the words “susceptible” or “not susceptible.” If the number is, say, 0.5 μg/mL or less, the organism should really be susceptible. If the number is 1 or 2, it is still in the susceptible range, but those are the organisms that may cause problems later on.

Further, even if the vancomycin MIC is in the susceptible range, higher MICs may affect outcomes. The average duration of MRSA bacteremia on therapy is 8 to 9 days, vs 3 to 4 days with MSSA bacteremia.20,21 But Sakoulas et al15 found that, in MRSA bacteremia, the success rate with vancomycin therapy was 56% if the MIC was 0.5 or lower, compared with 10% if the MIC was 1.0 to 2.0 μg/mL. Examined in another way, the success rate was 50% if the logarithm of killing was 6.27 colony-forming units per mL or greater, 23% if 4.71 to 6.26, and zero if less than 4.71.

Case 3: Prolonged MRSA bacteremia

In the summer of 2006, a 66-year-old woman with a history of gastric bypass and cirrhosis underwent a long stay in the surgical intensive care unit because of a recurrent enterocutaneous fistula and chronic renal insufficiency. On November 5th, she had a positive blood culture for MRSA, which was treated appropriately with vancomycin for 4 weeks. She was discharged to subacute care but came back 2 days later, again with MRSA bacteremia. At that time her Hickman catheter, which had been inserted for total parenteral nutrition because of the enterocutaneous fistula, was removed.

Transthoracic echocardiography revealed no vegetations, but her bacteremia persisted. Her mental status was poor this entire time: she was mute and could barely be awakened. We looked for clots and infected clots; duplex ultrasonographic examinations of all four extremities were negative. Finally, magnetic resonance imaging of her back—performed empirically because of the persistent bacteremia—revealed vertebral osteomyelitis at level T12-L1. We also noticed on serial evaluations that the vancomycin MIC for her organism increased from 0.5 to 2.0 μg/mL, so therapy was changed from vancomycin to daptomycin.

Her bacteremia cleared. Follow-up echocardiography was negative, but she had two subsequent relapses of MRSA bacteremia, one in April 2007 and one before she died in the summer of 2007.

Prolonged bacteremia: Is it vancomycin resistance, or something else?

The MRSA isolates that cause prolonged bacteremia seem to have certain characteristics.22 Higher MICs are probably associated with longer periods of bacteremia. But some genetic components within some strains of S aureus give them a survival advantage. They have less susceptibility to the body’s thrombin-induced platelet microbicidal protein. These isolates are not only associated with prolonged bacteremia: they are also associated with osteomyelitis, deep abscesses, endocarditis, recurrent infection, and increased death rate.22 Clinical laboratories do not test for these genetic components. One wonders whether our patient may have had an isolate with these mutations that gave it a survival advantage.

Do not use vancomycin for MSSA

Avoid using vancomycin for MSSA infections. It has been shown time and time again that MSSA infections do not respond as well to vancomycin as they do to beta-lactam antibiotics, specifically to the semisynthetic penicillins such as oxacillin and nafcillin, and even some of the first-generation cephalosporins. Chang et al23 found that patients with MSSA bacteremia had higher rates of persistent infections, relapse, and bacteriologic failure if they received vancomycin than if they received nafcillin.

Do vancomycin trough levels affect toxicity?

The vancomycin trough levels that we aimed for in the past (5 to 10 μg/mL) were probably too low. Today, we aim for trough levels of 15 to 20 μg/mL, and many physicians are aiming for 20 to 25 μg/mL. Part of the reason is that vancomycin MICs are higher than they used to be: in order to keep the vancomycin level above the MIC for a longer period of time, the vancomycin trough level needs to be higher. In theory, keeping the vancomycin levels above the MIC for longer periods should improve outcomes. Yet Fowler et al22 found that vancomycin trough levels among patients who had persistent MRSA bacteremia were actually higher than trough levels among those in whom the bacteremia resolved, although the difference was not statistically significant.

We measure the vancomycin trough level to make sure it is high enough (and give larger doses if it is not); among adults, peak levels need not be monitored on a routine basis because of the predictable pharmacokinetics of vancomycin.

Vancomycin toxicity can be either idiosyncratic or synergistic. Idiosyncratic toxicity occurs when a patient who has been on vancomycin for a long time develops a fixed rash, not associated with infusion. This is an immunologic phenomenon. It is a rare and very serious situation and may require steroid therapy.

Synergistic toxicity occurs when vancomycin is given with other nephrotoxic agents, notably gentamicin. Vancomycin plus gentamicin equals nephrotoxicity. Vancomycin alone is usually not nephrotoxic, but close monitoring of renal function parameters is warranted with the use of higher doses.24

 

 

IN UNEXPLAINED BACTEREMIA, LOOK FOR ENDOCARDITIS

In blood cultures from patients with bacteremia, S aureus is never a contaminant. Even if just one blood culture is positive for S aureus, believe that S aureus is the culprit.

Reports in the 1950s suggested that at least half of patients who had S aureus bacteremia had endocarditis,25 leading to recommendations that all patients with S aureus bacteremia without an obvious primary source of infection should be evaluated for endocarditis. Subsequent estimates were lower, in the range of 15% to 25%.26,27 However, throughout the world S aureus endocarditis continues to have a very high mortality rate: at least a third of patients die.28

Clinical criteria (community acquisition, no primary focus, and metastatic sequelae) were developed to try to predict the risk of endocarditis in bacteremic patients.26 However, these criteria did not work very well. The clinical definition of endocarditis has evolved. The criteria of von Reyn et al29 from 1981 did not use echocardiography as part of the definition, but the 1994 Duke criteria,30 which were refined31 in 2000, use both clinical and echocardiographic parameters.

Stratton et al32 performed transthoracic echocardiography in 14 patients with bacteremia and found 1 patient with cryptic tricuspid infective endocarditis. Bayer et al33 subsequently reported that of 72 patients with bacteremia, 6 (18%) of those who had no clinical findings suggestive of infectious endocarditis had findings on echocardiography that led to changes in their regimen. Adding echocardiography to three clinical risk factors increased the sensitivity of diagnosing endocarditis from 70% to 85% with a specificity of 100% and predictive value of 96%.

The Duke criteria call for transesophageal echocardiography, which is not feasible in some patients, eg, those with cirrhosis and esophageal varices.

S aureus endocarditis has changed over the years as our patient population has changed, and MRSA endocarditis tends to hit some of our most vulnerable patients. In a study by Miro et al34 in 2005, MRSA was the leading pathogen in patients who were diagnosed with S aureus endocarditis in 1990 or later. We will only see these numbers go up. Patients with diabetes tend to have more MRSA, and of diabetic patients with MRSA endocarditis, 30% to 40% die in the hospital.

Indications for surgery

Certain conditions are indications for surgery among patients with endocarditis, and no antibiotic will cure the endocarditis if the patient has one of these conditions, eg:

  • Persistent bacteremia during antibiotic therapy
  • Recurrent emboli
  • Heart failure that cannot be controlled
  • Perivalvular or myocardial abscesses
  • Large vegetations
  • Early prosthetic valve infection
  • Certain arrhythmias.

How long should S aureus bacteremia be treated?

In cases of bacteremia in which endocarditis has been ruled out and removable foci of infection (eg, intravascular catheters) have been removed, some evidence indicates that treatment for 2 weeks would be as effective as the 4 to 6 weeks that we would use for endocarditis or other severe or invasive infections.35 The issue is controversial. If the patient has had frequent hospitalizations or a chronic medical condition I would hesitate to treat for less than 4 weeks, even if the infection appears to be associated with a removable focus.

Treatment of endocarditis

In the guidelines for treatment of endocarditis from the American Heart Association and Infectious Diseases Society of America,36 all the recommendations are relatively old and many of them are somewhat empiric—they are not based on evidence from randomized clinical trials. Rather, they are best opinions based on clinical experience and some observational studies over the years.

For MSSA. In cases of native-valve endocarditis, oxacillin (Bactocill), nafcillin (Unipen), or another semisynthetic beta-lactam antibiotic is recommended. For penicillin-allergic patients, we have other options, such as cefazolin (Ancef, Kefzol).

Combination therapy is frequently recommended for native valve endocarditis as well as for prosthetic valve endocarditis, with either rifampin or gentamicin along with a primary agent. There is some evidence that one can clear staphylococcal bacteremia a day or two more quickly by use of combination therapy with nafcillin plus an aminoglycoside than with nafcillin alone.37,38 For MSSA-associated endocarditis, vancomycin does not work as well as beta-lactam antibiotics.39,40

Korzeniowski and Sande37 and Chambers et al38 reported that the mean duration of bacteremia was 3.4 days for patients treated with nafcillin alone and 2.9 days for those treated with nafcillin plus an aminoglycoside. These studies led to consideration of a short course of gentamicin to clear the bacteremia quickly.

With MRSA, bacteremia often requires a week or more to clear. Levine et al21 reported a study in 42 patients, mostly injection-drug users, with right-sided native-valve endocarditis. The median duration of bacteremia was 7 days in patients who received vancomycin alone vs 9 days in those who received vancomycin plus rifampin; however, some patients were bacteremic for up to 27 days. Fever persisted for a median of 7 days, probably partly due to septic pulmonary emboli. Three patients died, and three required valve replacement.

 

 

NEW ANTIBIOTICS

Several new antibiotics are active against gram-positive cocci.41–44 However, the majority of them have not been prospectively studied for treating bacteremia or endocarditis.

Quinupristin/dalfopristin (Synercid) has not been formally studied for treatment of MRSA bacteremia or endocarditis. There are a few case reports of its use in these conditions.45 Quinupristin/dalfopristin is bacteriostatic, and its use may be associated with phlebitis, myalgias, and arthralgias.46

Linezolid (Zyvox) is approved for treatment of complicated skin and soft-tissue infections and for hospital-acquired pneumonia. There have been no specific studies of linezolid in the treatment of S aureus bacteremia or endocarditis. However, Shorr et al47 retrospectively looked at the bacteremic patients in five previous studies of linezolid vs vancomycin and found 144 cases of S aureus bacteremia, half of which were due to MRSA. Of 53 assessable patients with MRSA bacteremia, the primary infection was cured in 14 (56%) of the linezolid patients and 13 (46%) of the vancomycin patients.

The oral form is 100% bioavailable. One should avoid concomitant use of serotonin-reuptake inhibitors because of the risk of serotonin syndrome. Adverse effects include altered taste sensation and peripheral neuropathy. There are other potential toxicities, including hematologic changes (thrombocytopenia, leukopenia) and metabolic effects (lactic acidosis), so clinical and laboratory monitoring is important.48 The role of linezolid in the treatment of patients with S aureus bacteremia or endocarditis remains to be defined.

Daptomycin is indicated for complicated skin and soft-tissue infections, bacteremia, and right-sided endocarditis due to S aureus. Fowler et al20 found that daptomycin was not inferior to beta-lactam antibiotics for treatment of MSSA bacteremia and right-sided endocarditis, and for MRSA infections it outperformed vancomycin, but the difference was not statistically significant.

The dosing interval should be increased from once every 24 hours to every 48 hours if the creatinine clearance is 30 mL/minute or less. Adverse effects include myalgia, rhabdomyolysis (rare), and elevations in creatine phosphokinase. Reports of rising MICs during daptomycin therapy, in some cases associated with persistent infection,49 suggest that careful attention be paid to dosing and clinical monitoring.

Tigecycline (Tygacil) is indicated for complicated skin and soft-tissue infections and complicated intra-abdominal infections due to susceptible organisms. It is active against both MSSA and MRSA, but clinical experience with its use in invasive infections is somewhat limited.50 The dose of tigecycline should be reduced in advanced cirrhosis. Adverse effects include nausea and vomiting.

Telavancin, dalbavancin, and oritavancin, investigational parenteral antibiotics that are derivatives of vancomycin, are in clinical trials. The pharmacokinetic activity of these agents is of interest: telavancin is being studied with a once-daily dosing interval and dalbavancin’s half-life allows once-weekly dosing. In a limited trial, dalbavancin was found to be safe and effective in the treatment of catheter-related bloodstream infections.51 None of the antibiotics in this group has been studied for treatment of S aureus endocarditis. Telavancin therapy has been associated with rash, hypokalemia, QT prolongation, and creatinine elevations. Gastrointestinal symptoms have been reported with the use of dalbavancin.

Ceftobiprole, another investigational agent, is the only cephalosporin antibiotic that is active against MRSA. It is given every 12 hours. Adverse effects include nausea and taste disturbance.

Iclaprim is a novel diaminopyrimidine and a dihydrofolate reductase inhibitor. In vitro, it is active against gram-positive bacteria, including MRSA, VISA, and VRSA; clinical investigations at this point are limited to the treatment of skin and soft-tissue infections.

Staphylococcus aureus is rearing its ugly head in new and interesting ways, both in the hospital and in the community.

Rates of invasive infections with methicillin-resistant S aureus (MRSA) have been increasing both in the hospital and in the community, a trend that has attracted considerable interest in the lay media. Curiously, the most common community-associated MRSA strain, which up to now has been distinct from hospital-associated MRSA strains, is invading our hospitals. Alarmingly, vancomycin (Vancocin), the drug of last resort for MRSA infections for the past 40 years, does not seem to be as effective as it used to be.

This paper summarizes the changing epidemiology of S aureus, particularly the emergence of MRSA outside of the hospital; reviews the difficulties associated with S aureus bacteremia and its treatment in view of; some changes in vancomycin susceptibility; and appraises the old and new treatment options.

MRSA IS ON THE RISE IN THE HOSPITAL

S aureus, a gram-positive, coagulase-positive bacterium, is one of the leading nosocomial bloodstream pathogens, second only to coagulase-negative staphylococci.1 And the incidence of S aureus infections is increasing. MRSA in particular is increasingly causing infections throughout hospitals, including intensive care units. As of 2004, nearly two-thirds of isolates of S aureus from intensive care units were MRSA.2

MRSA infections are worse than methicillin-susceptible S aureus (MSSA) infections in terms of the rates of death and other undesirable outcomes.3 Several factors may be responsible: MRSA infection may be a marker of severity of illness (sicker patients may be more likely to have MRSA), our treatment for MRSA may not be as effective as it is for MSSA, and the organism may be inherently more virulent.

METHICILLIN RESISTANCE IS ALSO ON THE RISE IN THE COMMUNITY

Community-associated MRSA began emerging clinically about 10 years ago. It was first described in a cohort of children with necrotizing pneumonia in Minnesota, but soon other populations at risk began to emerge, such as residents of correctional facilities, men who had sex with men, competitive athletes (eg, fencers, wrestlers, and football players), and Alaskan natives and other native populations. A common factor in all these groups was close proximity of the members to each other. Later, it began to spread beyond these traditional risk groups into the community at large.

Community-associated MRSA strains have a characteristic pattern of antimicrobial susceptibility (see below). In the laboratory, they grow somewhat faster than health-care-associated MRSA strains, but not as fast as MSSA. They have a strong association with skin and soft-tissue infections: when you see a skin or soft-tissue infection, be it in an outpatient or an inpatient, think about MRSA. Their virulence varies, but rapid onset and progression of illness are quite common. Their most common strain in the United States at present is USA 300.

Case 1: A young woman with necrotizing fasciitis

A 21-year-old college student presented to our service in May 2004 with high fever and severe arm pain, which had been worsening for several days. She had been previously healthy, had not had any contact with the health care system, and had not received any antibiotics.

Figure 1. Necrotizing fasciitis due to community-associated methicillin-resistant Staphylococcus aureus.
Her arm was red and extremely painful (Figure 1). Pain out of proportion to findings is a cardinal sign of necrotizing fasciitis, and this is indeed what she had.

Her blood cultures were positive for MRSA, as were cultures of the deep tissue of the deltoid muscle and fascia when she underwent emergency surgical debridement. The infection required several additional surgical debridements and removal of one head of her deltoid muscle, but she was fortunate: in the past, some patients with this problem might have undergone radical amputation of the arm or even more extensive surgery. This patient continued to have positive blood cultures 4 days postoperatively, but she ultimately recovered, completing 28 days of daptomycin (Cubicin) therapy at a dose of 6 mg/kg every 24 hours. The last 10 days of daptomycin therapy were given at home via a percutaneous intravenous central catheter.

Comment. The epidemiology of MRSA infections is changing. More patients who have no traditional risk factors, specifically health care contact, are getting MRSA infections. A recent report from the US Centers for Disease Control and Prevention (CDC) indicates that the proportion of patients with invasive disease due to MRSA has doubled since 2001–2002.4 Part of the reason undoubtedly is that MRSA, particularly community-associated MRSA, often carries specific virulence factors that make it more invasive. The CDC estimated that in 2005 there were nearly 100,000 cases of invasive MRSA infection in the United States, and nearly a fifth of these infections resulted in death.

 

 

Resistance and virulence factors in community-associated MRSA

Most community-associated MRSA strains carry a mobile genetic element called type IV SCCmec (staphylococcal chromosomal cassettemec) that enhances its antimicrobial resistance. This genetic component was probably borrowed from coagulase-negative staphylococci, in which it is quite common but does not cause as much of a problem. It is now present in a wide range of S aureus strains. Most of the S aureus strains that carry type IV SCCmec are MRSA, but a few MSSA strains do carry it as well.

The potent toxin Panton-Valentine leukocidin is an extracellular product that is detected in fewer than 5% of hospital strains but is more common in community-associated strains. It kills leukocytes by forming pores in the cell membrane and causing skin necrosis in cutaneous infections. It is associated with skin abscesses and rapidly progressive necrotizing pneumonia in MSSA or MRSA.

Epidemiologic differences between community- and health-care-associated MRSA

Patients with community-associated MRSA infections tend to be younger than those who traditionally get health-care-associated MRSA infections: in a study from Naimi et al in 2003, the mean ages were 23 vs 68 years.5 A greater proportion of patients with community-associated MRSA strains are nonwhite.4,5

Most community-associated MRSA infections are of the skin and soft tissue (75% in the series from Naimi et al5), but this pathogen causes other infections as well. Bacteremia of unknown origin has been seen, as has necrotizing pneumonia. Most of the skin and soft-tissue infections are relatively superficial, such as folliculitis or furunculosis, but deeper tissue infections such as necrotizing fasciitis and pyomyositis have also been seen.6

The incidence of community-associated MRSA infections varies greatly by geographic region.7 The northeastern United States has so far been relatively spared, but in Atlanta, Houston, and Los Angeles up to 80% of cases of characteristic skin or soft-tissue infections seen in emergency or outpatient departments are due to community-associated MRSA. Physicians at the Texas Children’s Hospital in Houston assume that all skin or soft-tissue infections are due to community-associated MRSA unless proven otherwise.8

Differences in antibiotic susceptibility

Community-associated MRSA is more susceptible to various antibiotics than health-care-associated MRSA,5 but not by much. Strains are usually susceptible to vancomycin, tetracyclines, trimethoprim-sulfamethoxazole (Bactrim, Septra), and rifampin (Rifadin). Unlike hospital strains, a fair number of community-acquired strains are susceptible to clindamycin (Cleocin) in the laboratory, but with a caveat: some of these clindamycin-susceptible strains actually may harbor the tools for inducible resistance. In fact, they can become resistant to clindamycin even without being exposed to it.

The laboratory test for inducible clindamycin resistance is called the D test. After coating an agar plate with S aureus, the technician places erythromycin and clindamycin disks. If the erythromycin induces clindamycin resistance, the plate is clear of growth around the clindamycin disk except for the portion nearest the erythromycin disk, leaving a characteristic D-shaped area of lucency.

Risk factors for MRSA

Moran et al7 analyzed the risk factors for community-associated MRSA in patients with skin or soft-tissue infections seen in the emergency department. The infection was more likely to be due to community-associated MRSA if the patient was black, had used any antibiotic in the past month, had a history of MRSA infection, or had close contact with a person with a similar infection. Many patients interpreted the infections as spider bites because the lesions tended to have a dark center surrounded by a tender area. These infections were not associated with underlying illness. In some cases, community-associated MRSA skin infections have been associated with tattooing and even manicuring.

However, it is very difficult to distinguish between community-associated MRSA and MSSA skin and soft-tissue infections on the basis of clinical and epidemiologic characteristics. Miller et al9 studied a large group of patients in Los Angeles who were hospitalized with community-associated skin and soft-tissue S aureus infections. All the patients were followed up for 30 days after hospital discharge. Regardless of whether they had MRSA or MSSA, they had similar outcomes. Close contacts of the patients also tended to develop infection.

A key point from this and many other studies: patients were more likely to remain infected if they did not undergo incision and drainage. This key intervention is indicated for any patient who has a skin and soft-tissue infection with an undrained focus of infection.

 

 

COMMUNITY-ASSOCIATED MRSA IS INVADING THE HOSPITAL

In a new development, community-associated MRSA strains are now appearing in the hospital. This is not only because patients are bacteremic when they come in: patients in the hospital are getting nosocomial infections due to community-associated MRSA strains.

Seybold et al10 analyzed 116 cases of MRSA bloodstream infections in Atlanta, GA. In 9 (8%) of the cases the patient had not had any contact with the health care system within the past year, and these cases were classified as truly community-associated. Of the remaining 107 cases, 49 (42%) were nosocomial, and the USA 300 strain—the predominant community-associated MRSA strain—accounted for 10 (20%) of the nosocomial cases.

In the recent CDC study of invasive MRSA infections, Klevens et al4 reported that nearly a third of cases of bacteremia were due to community-associated MRSA, and these strains accounted for a greater proportion of cases of cellulitis and endocarditis than did health-care-associated strains.

In a study of hospital-associated MRSA, Maree et al11 found that the percentage of cases in which the bacteria carried the SCCmec type IV marker had increased from less than 20% in 1999 to more than 50% in 2004.

Comment. Suffice it to say that we are surrounded by MRSA. Community-associated MRSA is here to stay. It is even invading our hospitals, and we need to consider this very carefully when choosing antimicrobial therapy.

NAGGING QUESTIONS ABOUT VANCOMYCIN

Case 2: Vancomycin-intermediate S aureus (VISA) bacteremia and endocarditis

In December 2006 we saw a very ill 60-year-old woman who was hospitalized with MRSA bacteremia, pacemaker endocarditis, and superior vena cava thrombosis. Although she was treated with vancomycin and rifampin, her condition worsened, she had a stroke, and she developed renal failure. In a difficult operation, the pacemaker was removed, but the bacteremia persisted. In early February 2007 she underwent another difficult operation in which the superior vena cava clot was debrided, a right atrial clot was removed, and her mitral valve was replaced. Less than 2 weeks later, and despite ongoing vancomycin and rifampin therapy, the MRSA bacteremia recurred.

During the approximately 6 weeks that the patient had been receiving these antibiotics, the minimal inhibitory concentration (MIC) of rifampin against the S aureus isolate increased from less than 1 μg/mL (susceptible) to 2 μg/mL (resistant). The MIC of vancomycin went from 2 μg/mL (susceptible) to 4 μg/mL (intermediately susceptible). Vancomycin and rifampin were discontinued, and daptomycin and gentamicin (Garamycin) therapy were started. (Her daptomycin MIC was 0.5 μg/mL). The patient’s condition stabilized, and she was discharged to a long-term nursing facility. She had no relapse of MRSA bacteremia, but she died in early April of that year.

Is vancomycin becoming less effective? Degrees of vancomycin resistance

Vancomycin has been our stalwart for treating MRSA infections for more than 40 years but it is not working as well as it used to, at least in certain situations.

Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:3040–3045
Figure 2. Population analysis of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate S aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-susceptible S aureus (VSSA). The population analysis shows how many cells in a fixed number of cells (usually about 107 colony-forming units [CFU]) of each strain are resistant to various concentrations of vancomycin. VRSA is a highly resistant and homogeneously resistant strain, with 100% of the population growing at each of the vancomycin concentrations tested. VISA is intermediately resistant, with 100% of the population growing at 4 μg of vancomycin per mL and also with significant subpopulations growing at 8 μg/mL. hVISA demonstrates heterogeneous resistance, having subpopulations of cells with various levels of resistance to vancomycin and including small populations of vancomycin-intermediate resistant cells with growth at 8 μg of vancomycin per mL.
Various terms describe the degrees of susceptibility or resistance to vancomycin (Figure 2).12

VRSA (vancomycin-resistant S aureus) is rare. These fully resistant strains probably acquired a resistance mechanism (the vanA operon) from vancomycin-resistant enterococci. Infections tend to occur in patients simultaneously infected with both S aureus and vancomycin-resistant enterococci, giving the bacteria an opportunity to exchange genetic material.

VISA (vancomycin-intermediate S aureus) infections tend to occur in patients like the one described above who have had long-term vancomycin therapy. VISA strains appear to overproduce a matrix that captures vancomycin and keeps it from entering the cell. On electron microscopy, these bacteria have a very thick cell wall.13

Vancomycin tolerance is a state in which the bacteria are “stunned” or kept in check but not killed by vancomycin. That is manifested in the laboratory by a ratio of minimum bactericidal concentration to MIC greater than 32.

hVISA (heteroresistant VISA) is new and worrisome. These organisms have an overall MIC in the susceptible range, but within that population are individual isolates with an MIC that is much higher—in the intermediate or perhaps even in the resistant range.14

Reported rates of hVISA vary from less than 2% to as high as 76%, because the methods for detecting it are still very poorly standardized. The usual automated laboratory tests do not detect hVISA.

hVISA is probably clinically relevant, as evidence is emerging both in vitro and in vivo that the higher the MIC for vancomycin, the worse the clinical outcome.15 hVISA has been associated with failures of therapy in several situations, usually in cases of severe invasive or deep infection, endocarditis, and bacteremia with vertebral osteomyelitis where vancomycin concentrations at the site of infection may be suboptimal.16–19 While most hVISA strains that have been described were resistant to methicillin, some were susceptible.

The E test is emerging as the standard test for hVISA. This test uses a plastic strip that contains gradually increasing concentrations of vancomycin along its length. Placed in the culture dish, the strip inhibits growth of the organism at its high-concentration end but not at its low-concentration end. If the sample contains hVISA, the cutoff is not well defined, with a few colonies growing at higher concentrations.

 

 

New definition of vancomycin susceptibility

Recognizing that the MICs for vancomycin have been rising in the last few years, the Clinical and Laboratory Standards Institute last year changed the break points between susceptibility and resistance. The new definitions are:

  • Susceptible—an MIC of 2.0 μg/mL or less (formerly 4.0 μg/mL or less)
  • Intermediate—4.0 to 8.0 μg/mL (formerly 8.0 to 16 μg/mL)
  • Resistant—16 μg/mL or greater (formerly 32 μg/mL or greater).

One should pay attention to the MIC numbers on the laboratory reports, not just to the words “susceptible” or “not susceptible.” If the number is, say, 0.5 μg/mL or less, the organism should really be susceptible. If the number is 1 or 2, it is still in the susceptible range, but those are the organisms that may cause problems later on.

Further, even if the vancomycin MIC is in the susceptible range, higher MICs may affect outcomes. The average duration of MRSA bacteremia on therapy is 8 to 9 days, vs 3 to 4 days with MSSA bacteremia.20,21 But Sakoulas et al15 found that, in MRSA bacteremia, the success rate with vancomycin therapy was 56% if the MIC was 0.5 or lower, compared with 10% if the MIC was 1.0 to 2.0 μg/mL. Examined in another way, the success rate was 50% if the logarithm of killing was 6.27 colony-forming units per mL or greater, 23% if 4.71 to 6.26, and zero if less than 4.71.

Case 3: Prolonged MRSA bacteremia

In the summer of 2006, a 66-year-old woman with a history of gastric bypass and cirrhosis underwent a long stay in the surgical intensive care unit because of a recurrent enterocutaneous fistula and chronic renal insufficiency. On November 5th, she had a positive blood culture for MRSA, which was treated appropriately with vancomycin for 4 weeks. She was discharged to subacute care but came back 2 days later, again with MRSA bacteremia. At that time her Hickman catheter, which had been inserted for total parenteral nutrition because of the enterocutaneous fistula, was removed.

Transthoracic echocardiography revealed no vegetations, but her bacteremia persisted. Her mental status was poor this entire time: she was mute and could barely be awakened. We looked for clots and infected clots; duplex ultrasonographic examinations of all four extremities were negative. Finally, magnetic resonance imaging of her back—performed empirically because of the persistent bacteremia—revealed vertebral osteomyelitis at level T12-L1. We also noticed on serial evaluations that the vancomycin MIC for her organism increased from 0.5 to 2.0 μg/mL, so therapy was changed from vancomycin to daptomycin.

Her bacteremia cleared. Follow-up echocardiography was negative, but she had two subsequent relapses of MRSA bacteremia, one in April 2007 and one before she died in the summer of 2007.

Prolonged bacteremia: Is it vancomycin resistance, or something else?

The MRSA isolates that cause prolonged bacteremia seem to have certain characteristics.22 Higher MICs are probably associated with longer periods of bacteremia. But some genetic components within some strains of S aureus give them a survival advantage. They have less susceptibility to the body’s thrombin-induced platelet microbicidal protein. These isolates are not only associated with prolonged bacteremia: they are also associated with osteomyelitis, deep abscesses, endocarditis, recurrent infection, and increased death rate.22 Clinical laboratories do not test for these genetic components. One wonders whether our patient may have had an isolate with these mutations that gave it a survival advantage.

Do not use vancomycin for MSSA

Avoid using vancomycin for MSSA infections. It has been shown time and time again that MSSA infections do not respond as well to vancomycin as they do to beta-lactam antibiotics, specifically to the semisynthetic penicillins such as oxacillin and nafcillin, and even some of the first-generation cephalosporins. Chang et al23 found that patients with MSSA bacteremia had higher rates of persistent infections, relapse, and bacteriologic failure if they received vancomycin than if they received nafcillin.

Do vancomycin trough levels affect toxicity?

The vancomycin trough levels that we aimed for in the past (5 to 10 μg/mL) were probably too low. Today, we aim for trough levels of 15 to 20 μg/mL, and many physicians are aiming for 20 to 25 μg/mL. Part of the reason is that vancomycin MICs are higher than they used to be: in order to keep the vancomycin level above the MIC for a longer period of time, the vancomycin trough level needs to be higher. In theory, keeping the vancomycin levels above the MIC for longer periods should improve outcomes. Yet Fowler et al22 found that vancomycin trough levels among patients who had persistent MRSA bacteremia were actually higher than trough levels among those in whom the bacteremia resolved, although the difference was not statistically significant.

We measure the vancomycin trough level to make sure it is high enough (and give larger doses if it is not); among adults, peak levels need not be monitored on a routine basis because of the predictable pharmacokinetics of vancomycin.

Vancomycin toxicity can be either idiosyncratic or synergistic. Idiosyncratic toxicity occurs when a patient who has been on vancomycin for a long time develops a fixed rash, not associated with infusion. This is an immunologic phenomenon. It is a rare and very serious situation and may require steroid therapy.

Synergistic toxicity occurs when vancomycin is given with other nephrotoxic agents, notably gentamicin. Vancomycin plus gentamicin equals nephrotoxicity. Vancomycin alone is usually not nephrotoxic, but close monitoring of renal function parameters is warranted with the use of higher doses.24

 

 

IN UNEXPLAINED BACTEREMIA, LOOK FOR ENDOCARDITIS

In blood cultures from patients with bacteremia, S aureus is never a contaminant. Even if just one blood culture is positive for S aureus, believe that S aureus is the culprit.

Reports in the 1950s suggested that at least half of patients who had S aureus bacteremia had endocarditis,25 leading to recommendations that all patients with S aureus bacteremia without an obvious primary source of infection should be evaluated for endocarditis. Subsequent estimates were lower, in the range of 15% to 25%.26,27 However, throughout the world S aureus endocarditis continues to have a very high mortality rate: at least a third of patients die.28

Clinical criteria (community acquisition, no primary focus, and metastatic sequelae) were developed to try to predict the risk of endocarditis in bacteremic patients.26 However, these criteria did not work very well. The clinical definition of endocarditis has evolved. The criteria of von Reyn et al29 from 1981 did not use echocardiography as part of the definition, but the 1994 Duke criteria,30 which were refined31 in 2000, use both clinical and echocardiographic parameters.

Stratton et al32 performed transthoracic echocardiography in 14 patients with bacteremia and found 1 patient with cryptic tricuspid infective endocarditis. Bayer et al33 subsequently reported that of 72 patients with bacteremia, 6 (18%) of those who had no clinical findings suggestive of infectious endocarditis had findings on echocardiography that led to changes in their regimen. Adding echocardiography to three clinical risk factors increased the sensitivity of diagnosing endocarditis from 70% to 85% with a specificity of 100% and predictive value of 96%.

The Duke criteria call for transesophageal echocardiography, which is not feasible in some patients, eg, those with cirrhosis and esophageal varices.

S aureus endocarditis has changed over the years as our patient population has changed, and MRSA endocarditis tends to hit some of our most vulnerable patients. In a study by Miro et al34 in 2005, MRSA was the leading pathogen in patients who were diagnosed with S aureus endocarditis in 1990 or later. We will only see these numbers go up. Patients with diabetes tend to have more MRSA, and of diabetic patients with MRSA endocarditis, 30% to 40% die in the hospital.

Indications for surgery

Certain conditions are indications for surgery among patients with endocarditis, and no antibiotic will cure the endocarditis if the patient has one of these conditions, eg:

  • Persistent bacteremia during antibiotic therapy
  • Recurrent emboli
  • Heart failure that cannot be controlled
  • Perivalvular or myocardial abscesses
  • Large vegetations
  • Early prosthetic valve infection
  • Certain arrhythmias.

How long should S aureus bacteremia be treated?

In cases of bacteremia in which endocarditis has been ruled out and removable foci of infection (eg, intravascular catheters) have been removed, some evidence indicates that treatment for 2 weeks would be as effective as the 4 to 6 weeks that we would use for endocarditis or other severe or invasive infections.35 The issue is controversial. If the patient has had frequent hospitalizations or a chronic medical condition I would hesitate to treat for less than 4 weeks, even if the infection appears to be associated with a removable focus.

Treatment of endocarditis

In the guidelines for treatment of endocarditis from the American Heart Association and Infectious Diseases Society of America,36 all the recommendations are relatively old and many of them are somewhat empiric—they are not based on evidence from randomized clinical trials. Rather, they are best opinions based on clinical experience and some observational studies over the years.

For MSSA. In cases of native-valve endocarditis, oxacillin (Bactocill), nafcillin (Unipen), or another semisynthetic beta-lactam antibiotic is recommended. For penicillin-allergic patients, we have other options, such as cefazolin (Ancef, Kefzol).

Combination therapy is frequently recommended for native valve endocarditis as well as for prosthetic valve endocarditis, with either rifampin or gentamicin along with a primary agent. There is some evidence that one can clear staphylococcal bacteremia a day or two more quickly by use of combination therapy with nafcillin plus an aminoglycoside than with nafcillin alone.37,38 For MSSA-associated endocarditis, vancomycin does not work as well as beta-lactam antibiotics.39,40

Korzeniowski and Sande37 and Chambers et al38 reported that the mean duration of bacteremia was 3.4 days for patients treated with nafcillin alone and 2.9 days for those treated with nafcillin plus an aminoglycoside. These studies led to consideration of a short course of gentamicin to clear the bacteremia quickly.

With MRSA, bacteremia often requires a week or more to clear. Levine et al21 reported a study in 42 patients, mostly injection-drug users, with right-sided native-valve endocarditis. The median duration of bacteremia was 7 days in patients who received vancomycin alone vs 9 days in those who received vancomycin plus rifampin; however, some patients were bacteremic for up to 27 days. Fever persisted for a median of 7 days, probably partly due to septic pulmonary emboli. Three patients died, and three required valve replacement.

 

 

NEW ANTIBIOTICS

Several new antibiotics are active against gram-positive cocci.41–44 However, the majority of them have not been prospectively studied for treating bacteremia or endocarditis.

Quinupristin/dalfopristin (Synercid) has not been formally studied for treatment of MRSA bacteremia or endocarditis. There are a few case reports of its use in these conditions.45 Quinupristin/dalfopristin is bacteriostatic, and its use may be associated with phlebitis, myalgias, and arthralgias.46

Linezolid (Zyvox) is approved for treatment of complicated skin and soft-tissue infections and for hospital-acquired pneumonia. There have been no specific studies of linezolid in the treatment of S aureus bacteremia or endocarditis. However, Shorr et al47 retrospectively looked at the bacteremic patients in five previous studies of linezolid vs vancomycin and found 144 cases of S aureus bacteremia, half of which were due to MRSA. Of 53 assessable patients with MRSA bacteremia, the primary infection was cured in 14 (56%) of the linezolid patients and 13 (46%) of the vancomycin patients.

The oral form is 100% bioavailable. One should avoid concomitant use of serotonin-reuptake inhibitors because of the risk of serotonin syndrome. Adverse effects include altered taste sensation and peripheral neuropathy. There are other potential toxicities, including hematologic changes (thrombocytopenia, leukopenia) and metabolic effects (lactic acidosis), so clinical and laboratory monitoring is important.48 The role of linezolid in the treatment of patients with S aureus bacteremia or endocarditis remains to be defined.

Daptomycin is indicated for complicated skin and soft-tissue infections, bacteremia, and right-sided endocarditis due to S aureus. Fowler et al20 found that daptomycin was not inferior to beta-lactam antibiotics for treatment of MSSA bacteremia and right-sided endocarditis, and for MRSA infections it outperformed vancomycin, but the difference was not statistically significant.

The dosing interval should be increased from once every 24 hours to every 48 hours if the creatinine clearance is 30 mL/minute or less. Adverse effects include myalgia, rhabdomyolysis (rare), and elevations in creatine phosphokinase. Reports of rising MICs during daptomycin therapy, in some cases associated with persistent infection,49 suggest that careful attention be paid to dosing and clinical monitoring.

Tigecycline (Tygacil) is indicated for complicated skin and soft-tissue infections and complicated intra-abdominal infections due to susceptible organisms. It is active against both MSSA and MRSA, but clinical experience with its use in invasive infections is somewhat limited.50 The dose of tigecycline should be reduced in advanced cirrhosis. Adverse effects include nausea and vomiting.

Telavancin, dalbavancin, and oritavancin, investigational parenteral antibiotics that are derivatives of vancomycin, are in clinical trials. The pharmacokinetic activity of these agents is of interest: telavancin is being studied with a once-daily dosing interval and dalbavancin’s half-life allows once-weekly dosing. In a limited trial, dalbavancin was found to be safe and effective in the treatment of catheter-related bloodstream infections.51 None of the antibiotics in this group has been studied for treatment of S aureus endocarditis. Telavancin therapy has been associated with rash, hypokalemia, QT prolongation, and creatinine elevations. Gastrointestinal symptoms have been reported with the use of dalbavancin.

Ceftobiprole, another investigational agent, is the only cephalosporin antibiotic that is active against MRSA. It is given every 12 hours. Adverse effects include nausea and taste disturbance.

Iclaprim is a novel diaminopyrimidine and a dihydrofolate reductase inhibitor. In vitro, it is active against gram-positive bacteria, including MRSA, VISA, and VRSA; clinical investigations at this point are limited to the treatment of skin and soft-tissue infections.

References
  1. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39:309371. Erratum in: Clin Infect Dis 2004; 39:1093.
  2. US Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance (NNIS) System. Campaign to prevent antimicrobial resistance. www.cdc.gov/drugresistance/healthcare/ha/HASlideSet.ppt.
  3. Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med 2002; 162:22292235.
  4. Klevens RM, Morrison MA, Nadle J, et al; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298:17631771.
  5. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290:29762984.
  6. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005; 352:14451453.
  7. Moran GJ, Krishnadasan A, Gorwitz RJ, et al EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355:666674.
  8. Mishaan AM, Mason EO, Martinez-Aquilar G, et al. Emergence of a predominant clone of community-acquired Staphylococcus aureus among children in Houston, Texas. Pediatr Infect Dis J 2005; 24:201206.
  9. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S. aureus infection: a prospective investigation. Clin Infect Dis 2007; 44:471482.
  10. Seybold U, Kourbatova EV, Johnson JG, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis 2006; 42:647656.
  11. Maree CL, Daum RS, Boyle-Vavra S, Matayoshi K, Miller LG. Community-associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerg Infect Dis 2007; 13:236242.
  12. Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:30403045.
  13. Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999; 340:517523.
  14. Schwaber MJ, Wright SB, Carmeli Y, et al. Clinical implications of varying degrees of vancomycin susceptibility in methicillin-resistant Staphylococcus aureus bacteremia. Emerg Infect Dis 2003; 9:657–664. Erratum in: Emerg Infect Dis 2004; 10:160.
  15. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004; 42:23982402.
  16. Naimi TS, Anderson D, O’Boyle C, et al. Vancomycin-intermediate Staphylococcus aureus with phenotypic susceptibility to methicillin in a patient with recurrent bacteremia. Clin Infect Dis 2003; 36:16091612.
  17. Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother 2003; 47:12621266.
  18. Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogenous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004; 38:448451.
  19. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521528.
  20. Fowler VG, Boucher HW, Corey GR, et al. S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653665.
  21. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115:674680.
  22. Fowler VG, Sakoulas G, McIntyre LM, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis 2004; 190:11401149.
  23. Chang FY, Peacock JE, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore) 2003; 82:333339.
  24. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006; 166:21382144.
  25. Wilson R, Hamburger M. Fifteen years’ experience with staphylococcus septicemia in a large city hospital; analysis of fifty-five cases in the Cincinnati General Hospital 1940 to 1954. Am J Med 1957; 22:437457.
  26. Nolan CM, Beaty HN. Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med 1976; 60:495500.
  27. Shah M, Watanakunakorn C. Changing patterns of Staphylococcus aureus bacteremia. Am J Med Sci 1979; 278:115121.
  28. Fowler VG, Miro JM, Hoen B, et al ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293:30123021. Erratum in: JAMA 2005; 294:900.
  29. Von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective endocarditis: an analysis based on strict case definition. Ann Intern Med 1981; 94:505518.
  30. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96:200209.
  31. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30:633638.
  32. Stratton JR, Werner JA, Pearlman AS, Janko CL, Kliman S, Jackson MC. Bacteremia and the heart. Serial echocardiographic findings in 80 patients with documented or suspected bacteremia. Am J Med 1982; 73:851858.
  33. Bayer AS, Lam K, Ginzton L, Normal DC, Chiu CY, Ward JI. Staphylococcus aureus bacteremia. Clinical, serologic, and echocardiographic findings in patients with and without endocarditis. Arch Intern Med 1987; 147:457462.
  34. Miro JM, Anguera I, Cabell CH, et al International Collaboration on Endocarditis Merged Database Study Group. Staphylococcus aureus native valve infective endocarditis: report of 566 episodes from the International Collaboration on Endocarditis Merged Database. Clin Infect Dis 2005; 41:507–514. Erratum in: Clin Infect Dis 2005; 41:10751077.
  35. Jernigan JA, Farr BM. Short-course therapy of catheter-related Staphylococcus aureus bacteremia: a meta-analysis. Ann Intern Med 1993; 119:304311.
  36. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394e434. Erratum in: Circulation 2005; 112:2373. Circulation 2007; 115:e408.
  37. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med 1982; 97:496503.
  38. Chambers HF, Korzeniowski OM, Sande MA. Staphylococcus aureus endocarditis: clinical manifestations in addicts and nonaddicts. Medicine (Baltimore) 1983; 62:170177.
  39. Gentry CA, Rodvold KA, Novak RM, Hershow RC, Naderer OJ. Retrospective evaluation of therapies for Staphylococcus aureus endocarditis. Pharmacotherapy 1997; 17:990997.
  40. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34:12271231.
  41. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003; 36:473481.
  42. Rybak MJ. Therapeutic options for Gram-positive infections. J Hosp Infect 2001; 49 suppl A:S25S32.
  43. Micek ST. Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2007; 45 suppl 3:S184S190.
  44. Appelbaum PC, Jacobs MR. Recently approved and investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria. Curr Opin Microbiol 2005; 8:510517.
  45. Drew RH, Perfect JR, Srinath L, Kirkimilis E, Dowzicky M, Talbot GH for the Synercid Emergency-Use Study Group. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. J Antimicrob Chemother 2000; 46:775784.
  46. Lamb HM, Figgitt DP, Faulds D. Quinupristin/dalfopristin: a review of its use in the management of serious gram-positive infections. Drugs 1999; 58:10611097.
  47. Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother 2005; 56:923929.
  48. Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50:15991602.
  49. Boucher HW, Sakoulas G. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007; 45:601608.
  50. Munoz-Price LS, Lolans K, Quinn JP. Four cases of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections treated with tigecycline. Scand J Infect Dis 2006; 38:10811084.
  51. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis 2005; 40:37480.
References
  1. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39:309371. Erratum in: Clin Infect Dis 2004; 39:1093.
  2. US Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance (NNIS) System. Campaign to prevent antimicrobial resistance. www.cdc.gov/drugresistance/healthcare/ha/HASlideSet.ppt.
  3. Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med 2002; 162:22292235.
  4. Klevens RM, Morrison MA, Nadle J, et al; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298:17631771.
  5. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290:29762984.
  6. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005; 352:14451453.
  7. Moran GJ, Krishnadasan A, Gorwitz RJ, et al EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355:666674.
  8. Mishaan AM, Mason EO, Martinez-Aquilar G, et al. Emergence of a predominant clone of community-acquired Staphylococcus aureus among children in Houston, Texas. Pediatr Infect Dis J 2005; 24:201206.
  9. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S. aureus infection: a prospective investigation. Clin Infect Dis 2007; 44:471482.
  10. Seybold U, Kourbatova EV, Johnson JG, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis 2006; 42:647656.
  11. Maree CL, Daum RS, Boyle-Vavra S, Matayoshi K, Miller LG. Community-associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerg Infect Dis 2007; 13:236242.
  12. Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:30403045.
  13. Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999; 340:517523.
  14. Schwaber MJ, Wright SB, Carmeli Y, et al. Clinical implications of varying degrees of vancomycin susceptibility in methicillin-resistant Staphylococcus aureus bacteremia. Emerg Infect Dis 2003; 9:657–664. Erratum in: Emerg Infect Dis 2004; 10:160.
  15. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004; 42:23982402.
  16. Naimi TS, Anderson D, O’Boyle C, et al. Vancomycin-intermediate Staphylococcus aureus with phenotypic susceptibility to methicillin in a patient with recurrent bacteremia. Clin Infect Dis 2003; 36:16091612.
  17. Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother 2003; 47:12621266.
  18. Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogenous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004; 38:448451.
  19. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521528.
  20. Fowler VG, Boucher HW, Corey GR, et al. S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653665.
  21. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115:674680.
  22. Fowler VG, Sakoulas G, McIntyre LM, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis 2004; 190:11401149.
  23. Chang FY, Peacock JE, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore) 2003; 82:333339.
  24. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006; 166:21382144.
  25. Wilson R, Hamburger M. Fifteen years’ experience with staphylococcus septicemia in a large city hospital; analysis of fifty-five cases in the Cincinnati General Hospital 1940 to 1954. Am J Med 1957; 22:437457.
  26. Nolan CM, Beaty HN. Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med 1976; 60:495500.
  27. Shah M, Watanakunakorn C. Changing patterns of Staphylococcus aureus bacteremia. Am J Med Sci 1979; 278:115121.
  28. Fowler VG, Miro JM, Hoen B, et al ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293:30123021. Erratum in: JAMA 2005; 294:900.
  29. Von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective endocarditis: an analysis based on strict case definition. Ann Intern Med 1981; 94:505518.
  30. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96:200209.
  31. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30:633638.
  32. Stratton JR, Werner JA, Pearlman AS, Janko CL, Kliman S, Jackson MC. Bacteremia and the heart. Serial echocardiographic findings in 80 patients with documented or suspected bacteremia. Am J Med 1982; 73:851858.
  33. Bayer AS, Lam K, Ginzton L, Normal DC, Chiu CY, Ward JI. Staphylococcus aureus bacteremia. Clinical, serologic, and echocardiographic findings in patients with and without endocarditis. Arch Intern Med 1987; 147:457462.
  34. Miro JM, Anguera I, Cabell CH, et al International Collaboration on Endocarditis Merged Database Study Group. Staphylococcus aureus native valve infective endocarditis: report of 566 episodes from the International Collaboration on Endocarditis Merged Database. Clin Infect Dis 2005; 41:507–514. Erratum in: Clin Infect Dis 2005; 41:10751077.
  35. Jernigan JA, Farr BM. Short-course therapy of catheter-related Staphylococcus aureus bacteremia: a meta-analysis. Ann Intern Med 1993; 119:304311.
  36. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394e434. Erratum in: Circulation 2005; 112:2373. Circulation 2007; 115:e408.
  37. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med 1982; 97:496503.
  38. Chambers HF, Korzeniowski OM, Sande MA. Staphylococcus aureus endocarditis: clinical manifestations in addicts and nonaddicts. Medicine (Baltimore) 1983; 62:170177.
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Issue
Cleveland Clinic Journal of Medicine - 75(3)
Issue
Cleveland Clinic Journal of Medicine - 75(3)
Page Number
177-180, 183-186, 190-192
Page Number
177-180, 183-186, 190-192
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Staphylococcus aureus: The new adventures of a legendary pathogen
Display Headline
Staphylococcus aureus: The new adventures of a legendary pathogen
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KEY POINTS

  • Community-associated MRSA infections tend to affect patients younger than those who traditionally get hospital-associated MRSA infections. Most of these infections are of the skin and soft tissues, but this pathogen can also affect deeper tissues, and bacteremia and necrotizing pneumonia have been reported.
  • For patients with skin and soft-tissue infections due to MRSA, incision and drainage rather than antibiotic therapy is often the key intervention.
  • Vancomycin has been our stalwart for treating MRSA infections for more than 40 years, but it is not working as well as it used to, at least in certain situations. Vancomycin should not be used to treat infections due to methicillin-susceptible S aureus.
  • Needed are better understanding of the factors that influence persistent S aureus bacteremia, well-controlled, prospective studies, and continued antibiotic development.
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