Sonya Tang Girdwood, MD, PhD

Bacterial infections are a common reason for pediatric hospital admissions in the United States.¹ Antibiotics are the mainstay of treatment, and whether to administer them intravenously (IV) or enterally is an important and, at times, challenging decision. Not all hospitalized patients with infections require IV antibiotics, and safe, effective early transitions to enteral therapy have been described for numerous infections.^2-7 However, guidelines describing the ideal initial route of antibiotic administration and when to transition to oral therapy are lacking.^5,7,8 This lack of high-quality evidence-based guidance may contribute to overuse of IV antibiotics for many hospitalized pediatric patients, even when safe and effective enteral options exist.⁹

Significant costs and harms are associated with the use of IV antibiotics. In particular, studies have demonstrated longer length of stay (LOS), increased costs, and worsened pain or anxiety related to complications (eg, phlebitis, extravasation injury, thrombosis, catheter-associated bloodstream infections) associated with IV antibiotics.^3,4,10-13 Earlier transition to enteral therapy, however, can mitigate these increased risks and costs.

The Centers for Disease Control and Prevention lists the transition from IV to oral antibiotics as a key stewardship intervention for improving antibiotic use.¹⁴ The Infectious Diseases Society of America (IDSA) antibiotic stewardship program guidelines strongly recommend the timely conversion from IV to oral antibiotics, stating that efforts focusing on this transition should be integrated into routine practice.¹⁵ There are a few metrics in the literature to measure this intervention, but none is universally used, and a modified delphi process could not reach consensus on IV-to-oral transition metrics.¹⁶

Few studies describe the opportunity to transition to enteral antibiotics in hospitalized patients with common bacterial infections or explore variation across hospitals. It is critical to understand current practice of antibiotic administration in order to identify opportunities to optimize patient outcomes and promote high-value care. Furthermore, few studies have evaluated the feasibility of IV-to-oral transition metrics using an administrative database. Thus, the aims of this study were to (1) determine opportunities to transition from IV to enteral antibiotics for pediatric patients hospitalized with common bacterial infections based on their ability to tolerate other enteral medications, (2) describe variation in transition practices among children’s hospitals, and (3) evaluate the feasibility of novel IV-to-oral transition metrics using an administrative database to inform stewardship efforts.

Study Design and Setting

This multicenter, retrospective cohort study used data from the Pediatric Health Information System (PHIS), an administrative and billing database containing encounter-level data from 52 tertiary care pediatric hospitals across the United States affiliated with the Children’s Hospital Association (Lenexa, Kansas). Hospitals submit encounter-level data, including demographics, medications, and diagnoses based on International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Data were de-identified at the time of submission, and data quality and reliability were assured by joint efforts between the Children’s Hospital Association and participating hospitals.

Study Population

This study included pediatric patients aged 60 days to 18 years who were hospitalized (inpatient or observation status) at one of the participating hospitals between January 1, 2017, and December 31, 2018, for one of the following seven common bacterial infections: community-acquired pneumonia (CAP), neck infection (superficial and deep), periorbital/orbital infection, urinary tract infection (UTI), osteomyelitis, septic arthritis, or skin and soft tissue infection (SSTI). The diagnosis cohorts were defined based on ICD-10-CM discharge diagnoses adapted from previous studies (Appendix Table 1).^3,17-23 To define a cohort of generally healthy pediatric patients with an acute infection, we excluded patients hospitalized in the intensive care unit, patients with nonhome discharges, and patients with complex chronic conditions.²⁴ We also excluded hospitals with incomplete data during the study period (n=1). The Institutional Review Board at Cincinnati Children’s Hospital Medical Center determined this study to be non–human-subjects research.

Outcomes

The primary outcomes were the number of opportunity days and the percent of days with opportunity to transition from IV to enteral therapy. Opportunity days, or days in which there was a potential opportunity to transition from IV to enteral antibiotics, were defined as days patients received only IV antibiotic doses and at least one enteral nonantibiotic medication, suggesting an ability to take enteral medications.¹³ We excluded days patients received IV antibiotics for which there was no enteral alternative (eg, vancomycin, Appendix Table 2). When measuring opportunity, to be conservative (ie, to underestimate rather than overestimate opportunity), we did not count as an opportunity day any day in which patients received both IV and enteral antibiotics. Percent opportunity, or the percent of days patients received antibiotics in which there was potential opportunity to transition from IV to enteral antibiotics, was defined as the number of opportunity days divided by number of inpatient days patients received enteral antibiotics or IV antibiotics with at least one enteral nonantibiotic medication (antibiotic days). Similar to opportunity days, antibiotic days excluded days patients were on IV antibiotics for which there was no enteral alternative. Based on our definition, a lower percent opportunity indicates that a hospital is using enteral antibiotics earlier during the hospitalization (earlier transition), while a higher percent opportunity represents later enteral antibiotic use (later transition).

Statistical Analysis

Demographic and clinical characteristics were summarized by diagnosis with descriptive statistics, including frequency with percentage, mean with standard deviation, and median with interquartile range (IQR). For each diagnosis, we evaluated aggregate opportunity days (sum of opportunity days among all hospitals), opportunity days per encounter, and aggregate percent opportunity using frequencies, mean with standard deviation, and percentages, respectively. We also calculated aggregate opportunity days for diagnosis-antibiotic combinations. To visually show variation in the percent opportunity across hospitals, we displayed the percent opportunity on a heat map, and evaluated percent opportunity across hospitals using chi-square tests. To compare the variability in the percent opportunity across and within hospitals, we used a generalized linear model with two fixed effects (hospital and diagnosis), and parsed the variability using the sum of squares. We performed a sensitivity analysis and excluded days that patients received antiemetic medications (eg, ondansetron, granisetron, prochlorperazine, promethazine), as these suggest potential intolerance of enteral medications. All statistical analyses were performed using SAS v.9.4 (SAS Institute Inc, Cary, North Carolina) and GraphPad Prism 8.0 (GraphPad Software Inc., San Diego, California), and P values < .05 were considered statistically significant.

During the 2-year study period, 100,103 hospitalizations met our inclusion criteria across 51 hospitals and seven diagnosis categories (Table 1). Diagnosis cohorts ranged in size from 1,462 encounters for septic arthritis to 35,665 encounters for neck infections. Overall, we identified 88,522 aggregate opportunity days on which there was an opportunity to switch from IV to enteral treatment in the majority of participants (percent opportunity, 57%).

Opportunity by Diagnosis

The number of opportunity days (aggregate and mean per encounter) and percent opportunity varied by diagnosis (Table 2). The aggregate number of opportunity days ranged from 3,693 in patients with septic arthritis to 25,359 in patients with SSTI, and mean opportunity days per encounter ranged from 0.9 in CAP to 2.8 in septic arthritis. Percent opportunity was highest for septic arthritis at 72.7% and lowest for CAP at 39.7%.

Variation in Opportunity Among Hospitals

The variation in the percent opportunity across hospitals was statistically significant for all diagnoses (Figure). Within hospitals, we observed similar practice patterns across diagnoses. For example, hospitals with a higher percent opportunity for one diagnosis tended to have higher percent opportunity for the other diagnoses (as noted in the top portion of the Figure), and those with lower percent opportunity for one diagnosis tended to also have lower percent opportunity for the other diagnoses studied (as noted in the bottom portion of the Figure). When evaluating variability in the percent opportunity, 45% of the variability was attributable to the hospital-effect and 35% to the diagnosis; the remainder was unexplained variability. Sensitivity analysis excluding days when patients received an antiemetic medication yielded no differences in our results.

Opportunity by Antibiotic

The aggregate number of opportunity days varied by antibiotic (Table 3). Intravenous antibiotics with the largest number of opportunity days included clindamycin (44,293), ceftriaxone (23,896), and ampicillin-sulbactam (15,484). Antibiotic-diagnosis combinations with the largest number of opportunity days for each diagnosis included ceftriaxone and ampicillin in CAP; clindamycin in cellulitis, SSTI, and neck infections; ceftriaxone in UTI; and cefazolin in osteomyelitis and septic arthritis.

In this multicenter study of pediatric patients hospitalized with common bacterial infections, there was the potential to transition from IV to enteral treatment in over half of the antibiotic days. The degree of opportunity varied by infection, antibiotic, and hospital. Antibiotics with a large aggregate number of opportunity days for enteral transition included clindamycin, which has excellent bioavailability; and ampicillin and ampicillin-sulbactam, which can achieve pharmacodynamic targets with oral equivalents.^25-29 The across-hospital variation for a given diagnosis suggests that certain hospitals have strategies in place which permit an earlier transition to enteral antibiotics compared to other institutions in which there were likely missed opportunities to do so. This variability is likely due to limited evidence, emphasizing the need for robust studies to better understand the optimal initial antibiotic route and transition time. Our findings highlight the need for, and large potential impact of, stewardship efforts to promote earlier transition for specific drug targets. This study also demonstrates the feasibility of obtaining two metrics—percent opportunity and opportunity days—from administrative databases to inform stewardship efforts within and across hospitals.

Opportunity days and percent opportunity varied among diagnoses. The variation in aggregate opportunity days was largely a reflection of the number of encounters: Diagnoses such as SSTI, neck infections, and CAP had a large number of both aggregate opportunity days and encounters. The range of opportunity days per encounter (0.9-2.5) suggests potential missed opportunities to transition to enteral antibiotics across all diagnoses (Table 2). The higher opportunity days per encounter in osteomyelitis and septic arthritis may be related to longer LOS and higher percent opportunity. Percent opportunity likely varied among diagnoses due to differences in admission and discharge readiness criteria, diagnostic evaluation, frequency of antibiotic administration, and evidence on the optimal route of initial antibiotics and when to transition to oral formulations. For example, we hypothesize that certain diagnoses, such as osteomyelitis and septic arthritis, have admission and discharge readiness criteria directly tied to the perceived need for IV antibiotics, which may limit in-hospital days on enteral antibiotics and explain the high percent opportunity that we observed. The high percent opportunity seen in musculoskeletal infections also may be due to delays in initiating targeted treatment until culture results were available. Encounters for CAP had the lowest percent opportunity; we hypothesize that this is because admission and discharge readiness may be determined by factors other than the need for IV antibiotics (eg, need for supplemental oxygen), which may increase days on enteral antibiotics and lead to a lower percent opportunity.³⁰

Urinary tract infection encounters had a high percent opportunity. As with musculoskeletal infection, this may be related to delays in initiating targeted treatment until culture results became available. Another reason for the high percent opportunity in UTI could be the common use of ceftriaxone, which, dosed every 24 hours, likely reduced the opportunity to transition to enteral antibiotics. There is strong evidence demonstrating no difference in outcomes based on antibiotic routes for UTI, and we would expect this to result in a low percent opportunity.^2,31 While the observed high opportunity in UTI may relate to an initial unknown diagnosis or concern for systemic infection, this highlights potential opportunities for quality improvement initiatives to promote empiric oral antibiotics in clinically stable patients hospitalized with suspected UTI.

There was substantial variation in percent opportunity across hospitals for a given diagnosis, with less variation across diagnoses for a given hospital. Variation across hospitals but consistency within individual hospitals suggests that some hospitals may promote earlier transition from IV to enteral antibiotics as standard practice for all diagnoses, while other hospitals continue IV antibiotics for the entire hospitalization, highlighting potential missed opportunities at some institutions. While emerging data suggest that traditional long durations of IV antibiotics are not necessary for many infections, the limited evidence on the optimal time to switch to oral antibiotics may have influenced this variation.^2-7 Many guidelines recommend initial IV antibiotics for hospitalized pediatric patients, but there are few studies comparing IV and enteral therapy.^2,5,9 Limited evidence leaves significant room for hospital culture, antibiotic stewardship efforts, reimbursement considerations, and/or hospital workflow to influence transition timing and overall opportunity at individual hospitals.^7,8,32-34 These findings emphasize the importance of research to identify optimal transition time and comparative effectiveness studies to evaluate whether initial IV antibiotics are truly needed for mild—and even severe—disease presentations. Since many patients are admitted for the perceived need for IV antibiotics, earlier use of enteral antibiotics could reduce rates of hospitalizations, LOS, healthcare costs, and resource utilization.

Antibiotics with a high number of opportunity days included clindamycin, ceftriaxone, ampicillin-sublactam, and ampicillin. Our findings are consistent with another study which found that most bioavailable drugs, including clindamycin, were administered via the IV route and accounted for a large number of antibiotic days.³⁵ The Infectious Diseases Society of America recommends that hospitals promote earlier transition to oral formulations for highly bioavailable drugs.⁷ Given the high bioavailability of clindamycin, its common use in high-frequency encounters such as SSTI and neck infections, and the fact that it accounted for a large number of opportunity days, quality improvement initiatives promoting earlier transition to oral clindamycin could have a large impact across health systems.^25,26 Additionally, although beta-lactam antibiotics such as amoxicillin and amoxicillin-sulbactam are not highly bioavailable, oral dosing can achieve sufficient serum concentrations to reach pharmacodynamic targets for common clinical indications; this could be an important quality improvement initiative.^27-29 Several single-site studies have successfully implemented quality improvement initiatives to promote earlier IV-to-enteral transition, with resulting reductions in costs and no adverse events noted, highlighting the feasibility and impact of such efforts.^13,36-38

This study also demonstrates the feasibility of collecting two metrics (percent opportunity and opportunity days) from administrative databases to inform IV-to-oral transition benchmarking and stewardship efforts. While there are several metrics in the literature for evaluating antibiotic transition (eg, days of IV or oral therapy, percentage of antibiotics given via the oral route, time to switch from IV to oral, and acceptance rate of suggested changes to antibiotic route), none are universally used or agreed upon.^15,16,39 The opportunity metrics used in this study have several strengths, including the feasibility of obtaining them from existing databases and the ability to account for intake of other enteral medications; the latter is not evaluated in other metrics. These opportunity metrics can be used together to identify the percent of time in which there is opportunity to transition and total number of days to understand the full extent of potential opportunity for future interventions. As demonstrated in this study, these metrics can be measured by diagnosis, antibiotic, or diagnosis-antibiotic combination, and they can be used to evaluate stewardship efforts at a single institution over time or compare efforts across hospitals.

These findings should be interpreted in the context of important limitations. First, we attempted to characterize potential opportunity to transition to enteral medications based on a patient’s ability to tolerate nonenteral medications. However, there are other factors that could limit the opportunity to transition that we could not account for with an administrative dataset, including the use of antibiotics prior to admission, disease progression, severity of illness, and malabsorptive concerns. Thus, though we may have overestimated the true opportunity to transition to enteral antibiotics, it is unlikely that this would account for all of the variation in transition times that we observed across hospitals. Second, while our study required patients to have one of seven types of infection, we did not exclude any additional infectious diagnoses (eg, concurrent bacteremia, Clostridioides difficile, otitis media) that could have driven the choice of antibiotic type and modality. Although emerging evidence is supporting earlier transitions to oral therapy, bacteremia is typically treated with IV antibiotics; this may have led to an overestimation of true opportunity.⁴⁰ “Clostridioides” difficile and otitis media are typically treated with enteral therapy; concurrent infections such as these may have led to an underestimation of opportunity given the fact that, based on our definition, the days on which patients received both IV and enteral antibiotics were not counted as opportunity days. Third, because PHIS uses billing days to capture medication use, we were unable to distinguish transitions that occurred early in the day vs those that took place later in the day. This could have led to an underestimation of percent opportunity, particularly for diagnoses with a short LOS; it also likely led to an underestimation of the variability observed across hospitals. Fourth, because we used an administrative dataset, we are unable to understand reasoning behind transitioning time from IV to oral antibiotics, as well as provider, patient, and institutional level factors that influenced these decisions.

Children hospitalized with bacterial infections often receive IV antibiotics, and the timing of transition from IV to enteral antibiotics varies significantly across hospitals. Further research is needed to compare the effectiveness of IV and enteral antibiotics and better define criteria for transition to enteral therapy. We identified ample opportunities for quality improvement initiatives to promote earlier transition, which have the potential to reduce healthcare utilization and promote optimal patient-directed high-value care.

Bacterial infections are a common reason for pediatric hospital admissions in the United States.¹ Antibiotics are the mainstay of treatment, and whether to administer them intravenously (IV) or enterally is an important and, at times, challenging decision. Not all hospitalized patients with infections require IV antibiotics, and safe, effective early transitions to enteral therapy have been described for numerous infections.^2-7 However, guidelines describing the ideal initial route of antibiotic administration and when to transition to oral therapy are lacking.^5,7,8 This lack of high-quality evidence-based guidance may contribute to overuse of IV antibiotics for many hospitalized pediatric patients, even when safe and effective enteral options exist.⁹

Significant costs and harms are associated with the use of IV antibiotics. In particular, studies have demonstrated longer length of stay (LOS), increased costs, and worsened pain or anxiety related to complications (eg, phlebitis, extravasation injury, thrombosis, catheter-associated bloodstream infections) associated with IV antibiotics.^3,4,10-13 Earlier transition to enteral therapy, however, can mitigate these increased risks and costs.

The Centers for Disease Control and Prevention lists the transition from IV to oral antibiotics as a key stewardship intervention for improving antibiotic use.¹⁴ The Infectious Diseases Society of America (IDSA) antibiotic stewardship program guidelines strongly recommend the timely conversion from IV to oral antibiotics, stating that efforts focusing on this transition should be integrated into routine practice.¹⁵ There are a few metrics in the literature to measure this intervention, but none is universally used, and a modified delphi process could not reach consensus on IV-to-oral transition metrics.¹⁶

Few studies describe the opportunity to transition to enteral antibiotics in hospitalized patients with common bacterial infections or explore variation across hospitals. It is critical to understand current practice of antibiotic administration in order to identify opportunities to optimize patient outcomes and promote high-value care. Furthermore, few studies have evaluated the feasibility of IV-to-oral transition metrics using an administrative database. Thus, the aims of this study were to (1) determine opportunities to transition from IV to enteral antibiotics for pediatric patients hospitalized with common bacterial infections based on their ability to tolerate other enteral medications, (2) describe variation in transition practices among children’s hospitals, and (3) evaluate the feasibility of novel IV-to-oral transition metrics using an administrative database to inform stewardship efforts.

Study Design and Setting

This multicenter, retrospective cohort study used data from the Pediatric Health Information System (PHIS), an administrative and billing database containing encounter-level data from 52 tertiary care pediatric hospitals across the United States affiliated with the Children’s Hospital Association (Lenexa, Kansas). Hospitals submit encounter-level data, including demographics, medications, and diagnoses based on International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Data were de-identified at the time of submission, and data quality and reliability were assured by joint efforts between the Children’s Hospital Association and participating hospitals.

Study Population

This study included pediatric patients aged 60 days to 18 years who were hospitalized (inpatient or observation status) at one of the participating hospitals between January 1, 2017, and December 31, 2018, for one of the following seven common bacterial infections: community-acquired pneumonia (CAP), neck infection (superficial and deep), periorbital/orbital infection, urinary tract infection (UTI), osteomyelitis, septic arthritis, or skin and soft tissue infection (SSTI). The diagnosis cohorts were defined based on ICD-10-CM discharge diagnoses adapted from previous studies (Appendix Table 1).^3,17-23 To define a cohort of generally healthy pediatric patients with an acute infection, we excluded patients hospitalized in the intensive care unit, patients with nonhome discharges, and patients with complex chronic conditions.²⁴ We also excluded hospitals with incomplete data during the study period (n=1). The Institutional Review Board at Cincinnati Children’s Hospital Medical Center determined this study to be non–human-subjects research.

Outcomes

The primary outcomes were the number of opportunity days and the percent of days with opportunity to transition from IV to enteral therapy. Opportunity days, or days in which there was a potential opportunity to transition from IV to enteral antibiotics, were defined as days patients received only IV antibiotic doses and at least one enteral nonantibiotic medication, suggesting an ability to take enteral medications.¹³ We excluded days patients received IV antibiotics for which there was no enteral alternative (eg, vancomycin, Appendix Table 2). When measuring opportunity, to be conservative (ie, to underestimate rather than overestimate opportunity), we did not count as an opportunity day any day in which patients received both IV and enteral antibiotics. Percent opportunity, or the percent of days patients received antibiotics in which there was potential opportunity to transition from IV to enteral antibiotics, was defined as the number of opportunity days divided by number of inpatient days patients received enteral antibiotics or IV antibiotics with at least one enteral nonantibiotic medication (antibiotic days). Similar to opportunity days, antibiotic days excluded days patients were on IV antibiotics for which there was no enteral alternative. Based on our definition, a lower percent opportunity indicates that a hospital is using enteral antibiotics earlier during the hospitalization (earlier transition), while a higher percent opportunity represents later enteral antibiotic use (later transition).

Statistical Analysis

Demographic and clinical characteristics were summarized by diagnosis with descriptive statistics, including frequency with percentage, mean with standard deviation, and median with interquartile range (IQR). For each diagnosis, we evaluated aggregate opportunity days (sum of opportunity days among all hospitals), opportunity days per encounter, and aggregate percent opportunity using frequencies, mean with standard deviation, and percentages, respectively. We also calculated aggregate opportunity days for diagnosis-antibiotic combinations. To visually show variation in the percent opportunity across hospitals, we displayed the percent opportunity on a heat map, and evaluated percent opportunity across hospitals using chi-square tests. To compare the variability in the percent opportunity across and within hospitals, we used a generalized linear model with two fixed effects (hospital and diagnosis), and parsed the variability using the sum of squares. We performed a sensitivity analysis and excluded days that patients received antiemetic medications (eg, ondansetron, granisetron, prochlorperazine, promethazine), as these suggest potential intolerance of enteral medications. All statistical analyses were performed using SAS v.9.4 (SAS Institute Inc, Cary, North Carolina) and GraphPad Prism 8.0 (GraphPad Software Inc., San Diego, California), and P values < .05 were considered statistically significant.

During the 2-year study period, 100,103 hospitalizations met our inclusion criteria across 51 hospitals and seven diagnosis categories (Table 1). Diagnosis cohorts ranged in size from 1,462 encounters for septic arthritis to 35,665 encounters for neck infections. Overall, we identified 88,522 aggregate opportunity days on which there was an opportunity to switch from IV to enteral treatment in the majority of participants (percent opportunity, 57%).

Opportunity by Diagnosis

The number of opportunity days (aggregate and mean per encounter) and percent opportunity varied by diagnosis (Table 2). The aggregate number of opportunity days ranged from 3,693 in patients with septic arthritis to 25,359 in patients with SSTI, and mean opportunity days per encounter ranged from 0.9 in CAP to 2.8 in septic arthritis. Percent opportunity was highest for septic arthritis at 72.7% and lowest for CAP at 39.7%.

Variation in Opportunity Among Hospitals

The variation in the percent opportunity across hospitals was statistically significant for all diagnoses (Figure). Within hospitals, we observed similar practice patterns across diagnoses. For example, hospitals with a higher percent opportunity for one diagnosis tended to have higher percent opportunity for the other diagnoses (as noted in the top portion of the Figure), and those with lower percent opportunity for one diagnosis tended to also have lower percent opportunity for the other diagnoses studied (as noted in the bottom portion of the Figure). When evaluating variability in the percent opportunity, 45% of the variability was attributable to the hospital-effect and 35% to the diagnosis; the remainder was unexplained variability. Sensitivity analysis excluding days when patients received an antiemetic medication yielded no differences in our results.

Opportunity by Antibiotic

The aggregate number of opportunity days varied by antibiotic (Table 3). Intravenous antibiotics with the largest number of opportunity days included clindamycin (44,293), ceftriaxone (23,896), and ampicillin-sulbactam (15,484). Antibiotic-diagnosis combinations with the largest number of opportunity days for each diagnosis included ceftriaxone and ampicillin in CAP; clindamycin in cellulitis, SSTI, and neck infections; ceftriaxone in UTI; and cefazolin in osteomyelitis and septic arthritis.

In this multicenter study of pediatric patients hospitalized with common bacterial infections, there was the potential to transition from IV to enteral treatment in over half of the antibiotic days. The degree of opportunity varied by infection, antibiotic, and hospital. Antibiotics with a large aggregate number of opportunity days for enteral transition included clindamycin, which has excellent bioavailability; and ampicillin and ampicillin-sulbactam, which can achieve pharmacodynamic targets with oral equivalents.^25-29 The across-hospital variation for a given diagnosis suggests that certain hospitals have strategies in place which permit an earlier transition to enteral antibiotics compared to other institutions in which there were likely missed opportunities to do so. This variability is likely due to limited evidence, emphasizing the need for robust studies to better understand the optimal initial antibiotic route and transition time. Our findings highlight the need for, and large potential impact of, stewardship efforts to promote earlier transition for specific drug targets. This study also demonstrates the feasibility of obtaining two metrics—percent opportunity and opportunity days—from administrative databases to inform stewardship efforts within and across hospitals.

Opportunity days and percent opportunity varied among diagnoses. The variation in aggregate opportunity days was largely a reflection of the number of encounters: Diagnoses such as SSTI, neck infections, and CAP had a large number of both aggregate opportunity days and encounters. The range of opportunity days per encounter (0.9-2.5) suggests potential missed opportunities to transition to enteral antibiotics across all diagnoses (Table 2). The higher opportunity days per encounter in osteomyelitis and septic arthritis may be related to longer LOS and higher percent opportunity. Percent opportunity likely varied among diagnoses due to differences in admission and discharge readiness criteria, diagnostic evaluation, frequency of antibiotic administration, and evidence on the optimal route of initial antibiotics and when to transition to oral formulations. For example, we hypothesize that certain diagnoses, such as osteomyelitis and septic arthritis, have admission and discharge readiness criteria directly tied to the perceived need for IV antibiotics, which may limit in-hospital days on enteral antibiotics and explain the high percent opportunity that we observed. The high percent opportunity seen in musculoskeletal infections also may be due to delays in initiating targeted treatment until culture results were available. Encounters for CAP had the lowest percent opportunity; we hypothesize that this is because admission and discharge readiness may be determined by factors other than the need for IV antibiotics (eg, need for supplemental oxygen), which may increase days on enteral antibiotics and lead to a lower percent opportunity.³⁰

Urinary tract infection encounters had a high percent opportunity. As with musculoskeletal infection, this may be related to delays in initiating targeted treatment until culture results became available. Another reason for the high percent opportunity in UTI could be the common use of ceftriaxone, which, dosed every 24 hours, likely reduced the opportunity to transition to enteral antibiotics. There is strong evidence demonstrating no difference in outcomes based on antibiotic routes for UTI, and we would expect this to result in a low percent opportunity.^2,31 While the observed high opportunity in UTI may relate to an initial unknown diagnosis or concern for systemic infection, this highlights potential opportunities for quality improvement initiatives to promote empiric oral antibiotics in clinically stable patients hospitalized with suspected UTI.

There was substantial variation in percent opportunity across hospitals for a given diagnosis, with less variation across diagnoses for a given hospital. Variation across hospitals but consistency within individual hospitals suggests that some hospitals may promote earlier transition from IV to enteral antibiotics as standard practice for all diagnoses, while other hospitals continue IV antibiotics for the entire hospitalization, highlighting potential missed opportunities at some institutions. While emerging data suggest that traditional long durations of IV antibiotics are not necessary for many infections, the limited evidence on the optimal time to switch to oral antibiotics may have influenced this variation.^2-7 Many guidelines recommend initial IV antibiotics for hospitalized pediatric patients, but there are few studies comparing IV and enteral therapy.^2,5,9 Limited evidence leaves significant room for hospital culture, antibiotic stewardship efforts, reimbursement considerations, and/or hospital workflow to influence transition timing and overall opportunity at individual hospitals.^7,8,32-34 These findings emphasize the importance of research to identify optimal transition time and comparative effectiveness studies to evaluate whether initial IV antibiotics are truly needed for mild—and even severe—disease presentations. Since many patients are admitted for the perceived need for IV antibiotics, earlier use of enteral antibiotics could reduce rates of hospitalizations, LOS, healthcare costs, and resource utilization.

Antibiotics with a high number of opportunity days included clindamycin, ceftriaxone, ampicillin-sublactam, and ampicillin. Our findings are consistent with another study which found that most bioavailable drugs, including clindamycin, were administered via the IV route and accounted for a large number of antibiotic days.³⁵ The Infectious Diseases Society of America recommends that hospitals promote earlier transition to oral formulations for highly bioavailable drugs.⁷ Given the high bioavailability of clindamycin, its common use in high-frequency encounters such as SSTI and neck infections, and the fact that it accounted for a large number of opportunity days, quality improvement initiatives promoting earlier transition to oral clindamycin could have a large impact across health systems.^25,26 Additionally, although beta-lactam antibiotics such as amoxicillin and amoxicillin-sulbactam are not highly bioavailable, oral dosing can achieve sufficient serum concentrations to reach pharmacodynamic targets for common clinical indications; this could be an important quality improvement initiative.^27-29 Several single-site studies have successfully implemented quality improvement initiatives to promote earlier IV-to-enteral transition, with resulting reductions in costs and no adverse events noted, highlighting the feasibility and impact of such efforts.^13,36-38

This study also demonstrates the feasibility of collecting two metrics (percent opportunity and opportunity days) from administrative databases to inform IV-to-oral transition benchmarking and stewardship efforts. While there are several metrics in the literature for evaluating antibiotic transition (eg, days of IV or oral therapy, percentage of antibiotics given via the oral route, time to switch from IV to oral, and acceptance rate of suggested changes to antibiotic route), none are universally used or agreed upon.^15,16,39 The opportunity metrics used in this study have several strengths, including the feasibility of obtaining them from existing databases and the ability to account for intake of other enteral medications; the latter is not evaluated in other metrics. These opportunity metrics can be used together to identify the percent of time in which there is opportunity to transition and total number of days to understand the full extent of potential opportunity for future interventions. As demonstrated in this study, these metrics can be measured by diagnosis, antibiotic, or diagnosis-antibiotic combination, and they can be used to evaluate stewardship efforts at a single institution over time or compare efforts across hospitals.

These findings should be interpreted in the context of important limitations. First, we attempted to characterize potential opportunity to transition to enteral medications based on a patient’s ability to tolerate nonenteral medications. However, there are other factors that could limit the opportunity to transition that we could not account for with an administrative dataset, including the use of antibiotics prior to admission, disease progression, severity of illness, and malabsorptive concerns. Thus, though we may have overestimated the true opportunity to transition to enteral antibiotics, it is unlikely that this would account for all of the variation in transition times that we observed across hospitals. Second, while our study required patients to have one of seven types of infection, we did not exclude any additional infectious diagnoses (eg, concurrent bacteremia, Clostridioides difficile, otitis media) that could have driven the choice of antibiotic type and modality. Although emerging evidence is supporting earlier transitions to oral therapy, bacteremia is typically treated with IV antibiotics; this may have led to an overestimation of true opportunity.⁴⁰ “Clostridioides” difficile and otitis media are typically treated with enteral therapy; concurrent infections such as these may have led to an underestimation of opportunity given the fact that, based on our definition, the days on which patients received both IV and enteral antibiotics were not counted as opportunity days. Third, because PHIS uses billing days to capture medication use, we were unable to distinguish transitions that occurred early in the day vs those that took place later in the day. This could have led to an underestimation of percent opportunity, particularly for diagnoses with a short LOS; it also likely led to an underestimation of the variability observed across hospitals. Fourth, because we used an administrative dataset, we are unable to understand reasoning behind transitioning time from IV to oral antibiotics, as well as provider, patient, and institutional level factors that influenced these decisions.

Children hospitalized with bacterial infections often receive IV antibiotics, and the timing of transition from IV to enteral antibiotics varies significantly across hospitals. Further research is needed to compare the effectiveness of IV and enteral antibiotics and better define criteria for transition to enteral therapy. We identified ample opportunities for quality improvement initiatives to promote earlier transition, which have the potential to reduce healthcare utilization and promote optimal patient-directed high-value care.

Bacterial infections are a common reason for pediatric hospital admissions in the United States.¹ Antibiotics are the mainstay of treatment, and whether to administer them intravenously (IV) or enterally is an important and, at times, challenging decision. Not all hospitalized patients with infections require IV antibiotics, and safe, effective early transitions to enteral therapy have been described for numerous infections.^2-7 However, guidelines describing the ideal initial route of antibiotic administration and when to transition to oral therapy are lacking.^5,7,8 This lack of high-quality evidence-based guidance may contribute to overuse of IV antibiotics for many hospitalized pediatric patients, even when safe and effective enteral options exist.⁹

Significant costs and harms are associated with the use of IV antibiotics. In particular, studies have demonstrated longer length of stay (LOS), increased costs, and worsened pain or anxiety related to complications (eg, phlebitis, extravasation injury, thrombosis, catheter-associated bloodstream infections) associated with IV antibiotics.^3,4,10-13 Earlier transition to enteral therapy, however, can mitigate these increased risks and costs.

The Centers for Disease Control and Prevention lists the transition from IV to oral antibiotics as a key stewardship intervention for improving antibiotic use.¹⁴ The Infectious Diseases Society of America (IDSA) antibiotic stewardship program guidelines strongly recommend the timely conversion from IV to oral antibiotics, stating that efforts focusing on this transition should be integrated into routine practice.¹⁵ There are a few metrics in the literature to measure this intervention, but none is universally used, and a modified delphi process could not reach consensus on IV-to-oral transition metrics.¹⁶

Few studies describe the opportunity to transition to enteral antibiotics in hospitalized patients with common bacterial infections or explore variation across hospitals. It is critical to understand current practice of antibiotic administration in order to identify opportunities to optimize patient outcomes and promote high-value care. Furthermore, few studies have evaluated the feasibility of IV-to-oral transition metrics using an administrative database. Thus, the aims of this study were to (1) determine opportunities to transition from IV to enteral antibiotics for pediatric patients hospitalized with common bacterial infections based on their ability to tolerate other enteral medications, (2) describe variation in transition practices among children’s hospitals, and (3) evaluate the feasibility of novel IV-to-oral transition metrics using an administrative database to inform stewardship efforts.

Study Design and Setting

This multicenter, retrospective cohort study used data from the Pediatric Health Information System (PHIS), an administrative and billing database containing encounter-level data from 52 tertiary care pediatric hospitals across the United States affiliated with the Children’s Hospital Association (Lenexa, Kansas). Hospitals submit encounter-level data, including demographics, medications, and diagnoses based on International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Data were de-identified at the time of submission, and data quality and reliability were assured by joint efforts between the Children’s Hospital Association and participating hospitals.

Study Population

This study included pediatric patients aged 60 days to 18 years who were hospitalized (inpatient or observation status) at one of the participating hospitals between January 1, 2017, and December 31, 2018, for one of the following seven common bacterial infections: community-acquired pneumonia (CAP), neck infection (superficial and deep), periorbital/orbital infection, urinary tract infection (UTI), osteomyelitis, septic arthritis, or skin and soft tissue infection (SSTI). The diagnosis cohorts were defined based on ICD-10-CM discharge diagnoses adapted from previous studies (Appendix Table 1).^3,17-23 To define a cohort of generally healthy pediatric patients with an acute infection, we excluded patients hospitalized in the intensive care unit, patients with nonhome discharges, and patients with complex chronic conditions.²⁴ We also excluded hospitals with incomplete data during the study period (n=1). The Institutional Review Board at Cincinnati Children’s Hospital Medical Center determined this study to be non–human-subjects research.

Outcomes

The primary outcomes were the number of opportunity days and the percent of days with opportunity to transition from IV to enteral therapy. Opportunity days, or days in which there was a potential opportunity to transition from IV to enteral antibiotics, were defined as days patients received only IV antibiotic doses and at least one enteral nonantibiotic medication, suggesting an ability to take enteral medications.¹³ We excluded days patients received IV antibiotics for which there was no enteral alternative (eg, vancomycin, Appendix Table 2). When measuring opportunity, to be conservative (ie, to underestimate rather than overestimate opportunity), we did not count as an opportunity day any day in which patients received both IV and enteral antibiotics. Percent opportunity, or the percent of days patients received antibiotics in which there was potential opportunity to transition from IV to enteral antibiotics, was defined as the number of opportunity days divided by number of inpatient days patients received enteral antibiotics or IV antibiotics with at least one enteral nonantibiotic medication (antibiotic days). Similar to opportunity days, antibiotic days excluded days patients were on IV antibiotics for which there was no enteral alternative. Based on our definition, a lower percent opportunity indicates that a hospital is using enteral antibiotics earlier during the hospitalization (earlier transition), while a higher percent opportunity represents later enteral antibiotic use (later transition).

Statistical Analysis

Demographic and clinical characteristics were summarized by diagnosis with descriptive statistics, including frequency with percentage, mean with standard deviation, and median with interquartile range (IQR). For each diagnosis, we evaluated aggregate opportunity days (sum of opportunity days among all hospitals), opportunity days per encounter, and aggregate percent opportunity using frequencies, mean with standard deviation, and percentages, respectively. We also calculated aggregate opportunity days for diagnosis-antibiotic combinations. To visually show variation in the percent opportunity across hospitals, we displayed the percent opportunity on a heat map, and evaluated percent opportunity across hospitals using chi-square tests. To compare the variability in the percent opportunity across and within hospitals, we used a generalized linear model with two fixed effects (hospital and diagnosis), and parsed the variability using the sum of squares. We performed a sensitivity analysis and excluded days that patients received antiemetic medications (eg, ondansetron, granisetron, prochlorperazine, promethazine), as these suggest potential intolerance of enteral medications. All statistical analyses were performed using SAS v.9.4 (SAS Institute Inc, Cary, North Carolina) and GraphPad Prism 8.0 (GraphPad Software Inc., San Diego, California), and P values < .05 were considered statistically significant.

During the 2-year study period, 100,103 hospitalizations met our inclusion criteria across 51 hospitals and seven diagnosis categories (Table 1). Diagnosis cohorts ranged in size from 1,462 encounters for septic arthritis to 35,665 encounters for neck infections. Overall, we identified 88,522 aggregate opportunity days on which there was an opportunity to switch from IV to enteral treatment in the majority of participants (percent opportunity, 57%).

Opportunity by Diagnosis

The number of opportunity days (aggregate and mean per encounter) and percent opportunity varied by diagnosis (Table 2). The aggregate number of opportunity days ranged from 3,693 in patients with septic arthritis to 25,359 in patients with SSTI, and mean opportunity days per encounter ranged from 0.9 in CAP to 2.8 in septic arthritis. Percent opportunity was highest for septic arthritis at 72.7% and lowest for CAP at 39.7%.

Variation in Opportunity Among Hospitals

The variation in the percent opportunity across hospitals was statistically significant for all diagnoses (Figure). Within hospitals, we observed similar practice patterns across diagnoses. For example, hospitals with a higher percent opportunity for one diagnosis tended to have higher percent opportunity for the other diagnoses (as noted in the top portion of the Figure), and those with lower percent opportunity for one diagnosis tended to also have lower percent opportunity for the other diagnoses studied (as noted in the bottom portion of the Figure). When evaluating variability in the percent opportunity, 45% of the variability was attributable to the hospital-effect and 35% to the diagnosis; the remainder was unexplained variability. Sensitivity analysis excluding days when patients received an antiemetic medication yielded no differences in our results.

Opportunity by Antibiotic

The aggregate number of opportunity days varied by antibiotic (Table 3). Intravenous antibiotics with the largest number of opportunity days included clindamycin (44,293), ceftriaxone (23,896), and ampicillin-sulbactam (15,484). Antibiotic-diagnosis combinations with the largest number of opportunity days for each diagnosis included ceftriaxone and ampicillin in CAP; clindamycin in cellulitis, SSTI, and neck infections; ceftriaxone in UTI; and cefazolin in osteomyelitis and septic arthritis.

In this multicenter study of pediatric patients hospitalized with common bacterial infections, there was the potential to transition from IV to enteral treatment in over half of the antibiotic days. The degree of opportunity varied by infection, antibiotic, and hospital. Antibiotics with a large aggregate number of opportunity days for enteral transition included clindamycin, which has excellent bioavailability; and ampicillin and ampicillin-sulbactam, which can achieve pharmacodynamic targets with oral equivalents.^25-29 The across-hospital variation for a given diagnosis suggests that certain hospitals have strategies in place which permit an earlier transition to enteral antibiotics compared to other institutions in which there were likely missed opportunities to do so. This variability is likely due to limited evidence, emphasizing the need for robust studies to better understand the optimal initial antibiotic route and transition time. Our findings highlight the need for, and large potential impact of, stewardship efforts to promote earlier transition for specific drug targets. This study also demonstrates the feasibility of obtaining two metrics—percent opportunity and opportunity days—from administrative databases to inform stewardship efforts within and across hospitals.

Opportunity days and percent opportunity varied among diagnoses. The variation in aggregate opportunity days was largely a reflection of the number of encounters: Diagnoses such as SSTI, neck infections, and CAP had a large number of both aggregate opportunity days and encounters. The range of opportunity days per encounter (0.9-2.5) suggests potential missed opportunities to transition to enteral antibiotics across all diagnoses (Table 2). The higher opportunity days per encounter in osteomyelitis and septic arthritis may be related to longer LOS and higher percent opportunity. Percent opportunity likely varied among diagnoses due to differences in admission and discharge readiness criteria, diagnostic evaluation, frequency of antibiotic administration, and evidence on the optimal route of initial antibiotics and when to transition to oral formulations. For example, we hypothesize that certain diagnoses, such as osteomyelitis and septic arthritis, have admission and discharge readiness criteria directly tied to the perceived need for IV antibiotics, which may limit in-hospital days on enteral antibiotics and explain the high percent opportunity that we observed. The high percent opportunity seen in musculoskeletal infections also may be due to delays in initiating targeted treatment until culture results were available. Encounters for CAP had the lowest percent opportunity; we hypothesize that this is because admission and discharge readiness may be determined by factors other than the need for IV antibiotics (eg, need for supplemental oxygen), which may increase days on enteral antibiotics and lead to a lower percent opportunity.³⁰

Urinary tract infection encounters had a high percent opportunity. As with musculoskeletal infection, this may be related to delays in initiating targeted treatment until culture results became available. Another reason for the high percent opportunity in UTI could be the common use of ceftriaxone, which, dosed every 24 hours, likely reduced the opportunity to transition to enteral antibiotics. There is strong evidence demonstrating no difference in outcomes based on antibiotic routes for UTI, and we would expect this to result in a low percent opportunity.^2,31 While the observed high opportunity in UTI may relate to an initial unknown diagnosis or concern for systemic infection, this highlights potential opportunities for quality improvement initiatives to promote empiric oral antibiotics in clinically stable patients hospitalized with suspected UTI.

There was substantial variation in percent opportunity across hospitals for a given diagnosis, with less variation across diagnoses for a given hospital. Variation across hospitals but consistency within individual hospitals suggests that some hospitals may promote earlier transition from IV to enteral antibiotics as standard practice for all diagnoses, while other hospitals continue IV antibiotics for the entire hospitalization, highlighting potential missed opportunities at some institutions. While emerging data suggest that traditional long durations of IV antibiotics are not necessary for many infections, the limited evidence on the optimal time to switch to oral antibiotics may have influenced this variation.^2-7 Many guidelines recommend initial IV antibiotics for hospitalized pediatric patients, but there are few studies comparing IV and enteral therapy.^2,5,9 Limited evidence leaves significant room for hospital culture, antibiotic stewardship efforts, reimbursement considerations, and/or hospital workflow to influence transition timing and overall opportunity at individual hospitals.^7,8,32-34 These findings emphasize the importance of research to identify optimal transition time and comparative effectiveness studies to evaluate whether initial IV antibiotics are truly needed for mild—and even severe—disease presentations. Since many patients are admitted for the perceived need for IV antibiotics, earlier use of enteral antibiotics could reduce rates of hospitalizations, LOS, healthcare costs, and resource utilization.

Antibiotics with a high number of opportunity days included clindamycin, ceftriaxone, ampicillin-sublactam, and ampicillin. Our findings are consistent with another study which found that most bioavailable drugs, including clindamycin, were administered via the IV route and accounted for a large number of antibiotic days.³⁵ The Infectious Diseases Society of America recommends that hospitals promote earlier transition to oral formulations for highly bioavailable drugs.⁷ Given the high bioavailability of clindamycin, its common use in high-frequency encounters such as SSTI and neck infections, and the fact that it accounted for a large number of opportunity days, quality improvement initiatives promoting earlier transition to oral clindamycin could have a large impact across health systems.^25,26 Additionally, although beta-lactam antibiotics such as amoxicillin and amoxicillin-sulbactam are not highly bioavailable, oral dosing can achieve sufficient serum concentrations to reach pharmacodynamic targets for common clinical indications; this could be an important quality improvement initiative.^27-29 Several single-site studies have successfully implemented quality improvement initiatives to promote earlier IV-to-enteral transition, with resulting reductions in costs and no adverse events noted, highlighting the feasibility and impact of such efforts.^13,36-38

This study also demonstrates the feasibility of collecting two metrics (percent opportunity and opportunity days) from administrative databases to inform IV-to-oral transition benchmarking and stewardship efforts. While there are several metrics in the literature for evaluating antibiotic transition (eg, days of IV or oral therapy, percentage of antibiotics given via the oral route, time to switch from IV to oral, and acceptance rate of suggested changes to antibiotic route), none are universally used or agreed upon.^15,16,39 The opportunity metrics used in this study have several strengths, including the feasibility of obtaining them from existing databases and the ability to account for intake of other enteral medications; the latter is not evaluated in other metrics. These opportunity metrics can be used together to identify the percent of time in which there is opportunity to transition and total number of days to understand the full extent of potential opportunity for future interventions. As demonstrated in this study, these metrics can be measured by diagnosis, antibiotic, or diagnosis-antibiotic combination, and they can be used to evaluate stewardship efforts at a single institution over time or compare efforts across hospitals.

These findings should be interpreted in the context of important limitations. First, we attempted to characterize potential opportunity to transition to enteral medications based on a patient’s ability to tolerate nonenteral medications. However, there are other factors that could limit the opportunity to transition that we could not account for with an administrative dataset, including the use of antibiotics prior to admission, disease progression, severity of illness, and malabsorptive concerns. Thus, though we may have overestimated the true opportunity to transition to enteral antibiotics, it is unlikely that this would account for all of the variation in transition times that we observed across hospitals. Second, while our study required patients to have one of seven types of infection, we did not exclude any additional infectious diagnoses (eg, concurrent bacteremia, Clostridioides difficile, otitis media) that could have driven the choice of antibiotic type and modality. Although emerging evidence is supporting earlier transitions to oral therapy, bacteremia is typically treated with IV antibiotics; this may have led to an overestimation of true opportunity.⁴⁰ “Clostridioides” difficile and otitis media are typically treated with enteral therapy; concurrent infections such as these may have led to an underestimation of opportunity given the fact that, based on our definition, the days on which patients received both IV and enteral antibiotics were not counted as opportunity days. Third, because PHIS uses billing days to capture medication use, we were unable to distinguish transitions that occurred early in the day vs those that took place later in the day. This could have led to an underestimation of percent opportunity, particularly for diagnoses with a short LOS; it also likely led to an underestimation of the variability observed across hospitals. Fourth, because we used an administrative dataset, we are unable to understand reasoning behind transitioning time from IV to oral antibiotics, as well as provider, patient, and institutional level factors that influenced these decisions.

Children hospitalized with bacterial infections often receive IV antibiotics, and the timing of transition from IV to enteral antibiotics varies significantly across hospitals. Further research is needed to compare the effectiveness of IV and enteral antibiotics and better define criteria for transition to enteral therapy. We identified ample opportunities for quality improvement initiatives to promote earlier transition, which have the potential to reduce healthcare utilization and promote optimal patient-directed high-value care.

Vancomycin, a glycopeptide antibiotic, has been used for decades, yet knowledge gaps remain regarding the most appropriate dosing approach to optimize therapeutic effect while avoiding adverse effects in all patient populations. A committee composed of members of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists reviewed data available since publication of the original 2009 vancomycin dosing guidelines to provide new recommendations regarding vancomycin dosing and serum concentration–monitoring in the empiric treatment of presumed or confirmed methicillin-resistant Staphylococcus aureus (MRSA) infections.¹

The new guidelines provide 25 recommendations encompassing the following topics: vancomycin dosing and monitoring in adult, pediatric, and neonate care; vancomycin minimum inhibitory concentration (MIC) susceptibility testing; continuous infusion vs intermittent infusion; loading doses; dosing in obesity; and dosing in patients on hemodialysis and continuous renal replacement therapy. Because hospitalists in pediatric and adult care frequently prescribe vancomycin for empiric and targeted treatment of serious infections, they have a vested interest in ensuring optimal vancomycin outcomes (ie, best efficacy with least toxicity) with use of therapeutic drug monitoring and personalized dosing of vancomycin. Thus, it is important for hospitalists to be aware of the updated guideline and pivotal changes regarding therapeutic drug monitoring. In this guideline review, we will focus on the major differences from the 2009 guideline, specifically regarding therapeutic monitoring in adults and children.

The guideline includes pharmacology language and terminology with which many clinicians may not be familiar. To better understand the rationale for the guideline changes, a few concepts will be reviewed. Overall, antibiotics are dosed based on preclinical studies to determine the needed drug exposure for optimal efficacy. β-Lactams, for example, are optimally dosed with longer drug exposure time above the MIC of the infectious organism. Alternatively, area under the concentration time curve (AUC) describes the efficacy and toxicity of many other antibiotics. Since AUC is derived from products of concentration (mg/L) and time (hours), the units are often mg × h/L. For vancomycin, both drug exposure (ie, AUC) and organism susceptibility (ie, MIC) are incorporated to determine optimal drug exposure, with the ratio of AUC to MIC being the ideal marker. Therapeutic drug monitoring of vancomycin has classically been conducted with trough concentration monitoring, but with the updated guideline, there will be a transition to AUC monitoring that will affect patient care and experience.

The following is a summary of recommendations 1 to 6:

• In adults, the optimal drug exposure for vancomycin should be an AUC to MIC ratio of 400 to 600 for MRSA, with the assumption of MIC to be 1 mg/L (evidence quality: A-II).
  • The preferred method to monitor AUC is with a clinical statistical software that uses two blood samples (1 to 2 hours after completion of infusion and at the end of a dosing interval [ie, trough]) (evidence quality: A-II).
  • An alternative approach would be to use first-order pharmacokinetic equations at steady state with a peak and trough (evidence quality: A-II).

• These approaches replace the previously recommended trough-only monitoring. AUC-targeted exposure should generally be achieved within 48 hours; severity of infection does not justify higher AUC goals. Once the goal AUC is achieved, once-weekly monitoring is recommended for hemodynamically stable patients, but more frequent or daily monitoring is advised in patients at high risk of nephrotoxicity or who are hemodynamically unstable (evidence quality: B-II).

The currently accepted optimal drug exposure for vancomycin is an AUC to MIC ratio of 400 to 600 to maximize efficacy and minimize nephrotoxicity.² Due to clinical inconvenience of performing AUC-based monitoring for vancomycin in the past, previous guidelines recommended using trough concentrations as a surrogate marker for an AUC to MIC ratio, with the goal trough being 15 to 20 mg/L for serious MRSA infections.³ However, trough values may not correlate well with AUC. For example, a trough of 15 mg/L may represent an AUC ranging from 400 to 1000 mg × h/L over 24 hours. Without knowing an accurate AUC, there is risk for ineffective bactericidal activity with low AUCs or nephrotoxicity with high AUCs. Compared with trough-only monitoring, AUC-guided dosing is associated with decreased risk of acute kidney injury.^4,5 Therefore, the recommendation to transition to two-sample collection with a peak and trough was included.

Software programs are now readily available to compute the AUC and work best with peak and trough values rather than a single trough value because computing with two concentrations will rely more on specific patient data than it does on previously published vancomycin models. Trough-only monitoring (and without the support of clinical software) may still be possible when the exposures needed are further from the toxic range. To this end, trough-only monitoring may be reasonable when infections are not MRSA and are less invasive (eg, cellulitis) since the guideline found insufficient evidence for AUC monitoring in these scenarios. While specific targets are not provided, a plethora of historical literature demonstrated low kidney injury rates when troughs were maintained between 5 to 10 mg/L.

The following is a summary of recommendations 18 to 20:

• In pediatric care, based on a target AUC to MIC ratio of 400 to 600 with the assumption of MIC to be 1 mg/L, initial vancomycin dosage for MRSA is as follows (evidence quality: A-II) :
  • 60 to 80 mg/kg per day, divided into four doses, each given 6 hours apart, for children 3 months and older but younger than 12 years
  • 60 to 70 mg/kg per day, divided into four doses, each given 6 hours apart, for children 12 years and older
• As recommended in adults, use of a statistical software program to measure AUC is the optimal approach in pediatric care because it can account for age, weight, and renal function, which should be monitored closely. Monitoring should begin within 48 hours of therapy. Vancomycin AUC and trough concentrations should be less than 800 µg × h/mL over 24 hours and 15 µg/mL, respectively, to minimize acute kidney injury (evidence quality: A-II).

All the recommendations for pediatrics are new for the updated guideline. Pediatric data to support these recommendations are fewer in comparison with adult literature. Given MRSA infections are felt to be similar in adults and children, many pediatric recommendations are extrapolated from adult data and recommendations. The strongest level of evidence in children is the association of acute kidney injury with higher vancomycin exposure, especially with troughs exceeding 15 to 20 mg/L.⁶ In addition, one pediatric study found an AUC exposure of greater than 800 mg × h/L over 24 hours was strongly associated with risk for acute kidney injury.⁷ These findings suggest that high vancomycin exposure correlates with nephrotoxicity, so with AUC monitoring, the goal exposure should be less than 800 mg × hr/L over 24 hours.

Only one study has evaluated statistical software and prediction of AUC in pediatrics.⁸ A two-concentration approach (peak and trough) outperformed trough-only monitoring for accuracy and precision in determining AUC. While limited to one study, the results are similar to the studies completed in adults, thereby leading to the recommendation of the two-concentration technique in children.

Prospective outcome data are lacking, but multiple retrospective studies have examined S aureus bacteremia in children. Thus far, there have been no studies that have determined the optimal vancomycin exposure required for successful outcomes.^9,10 The proven risks of toxicity are the primary driver for the pediatric guideline change with the outcomes extrapolated from adult data.

Methods in Preparing Guideline

The main strength of the guideline is that the committee was represented by multiple organizations, which created a multidisciplinary panel of pharmacists and infectious disease physicians with clinical and research expertise in vancomycin dosing. Evidence was graded using an adaptation from the Canadian Task Force on the Periodic Health Examination.¹¹ The draft was peer-reviewed by the society organizations and allowed for comments, suggestions, and recommendations.

Sources of Potential Conflict of Interest or Bias

Disclosures of all authors were reported and identified in the guideline. While many members are involved with pharmaceutical companies through research or speakers’ roles, vancomycin, a generic drug, should have minimal conflicts of interest or bias from this involvement.

Generalizability

Implementation of vancomycin AUC dosing will be hospital dependent due to the implementation-related increase in human resources and the cost of clinical software; many hospital systems do not already have the software integrated into their clinical practice. Local guidelines will have to be developed to help clinicians determine which clinical situations require AUC-based dosing vs trough-only monitoring. Pharmacists at many hospitals are primarily responsible for vancomycin monitoring and provide dosing recommendations to physicians. Depending on a hospital system’s decision, the workload to determine the optimal vancomycin dose may increase, and it will be important to have close collaboration between hospitalists, pharmacists, and infectious diseases clinicians to appropriately educate clinicians who might be required to dose/monitor vancomycin. One potential way to decrease the burden of monitoring with two concentrations is to use specialized software that can perform complex assessments with only a single concentration. These software applications will still require serious collaboration of the aforementioned practitioners to implement. The variation in guideline adoption will likely be even more significant in pediatrics because the literature is extrapolated and the increased blood draws can be more problematic in pediatric patients.

Furthermore, clinicians should understand the dosing guideline is specifically addressing treatment of MRSA infections and extrapolation to other organisms such as coagulase-negative staphylococcal or methicillin-susceptible S aureus infections should be cautioned. Another caveat to note is that, when the MRSA isolate has an MIC of 2 mg/L or higher, these infections are associated with poor outcomes when vancomycin is used and alternative agents are recommended.

Research gaps still remain with appropriate vancomycin drug exposure. In pediatrics, determining the appropriate AUC target will be important given that current recommendations extrapolate from adult data. Future studies can focus on prospective outcome data in both pediatric and adult patients for infections outside of bacteremia or pneumonia, notably central nervous system and osteomyelitis infections. Thresholds for kidney injury will need to be more clearly defined for both adult and pediatric patients. There should also be research emphasis on the appropriate dosing for other non-MRSA invasive infections, notably coagulase-negative staphylococcal infections.

Dr Scheetz reported personal fees for consulting for Achaogen, SIGA technologies, and for serving on an advisory board for Paratek; grants from Merck and Co, Allecra, Nevakar, and SuperTrans Medical; personal fees from Hall, Booth, Smith, PC, and Chambless, Higdon, Richardson, Katz & Griggs, LLP, for consulting and expert testimony, outside the submitted work. In addition, Dr. Scheetz has patent US 2019 / 0099500 A1 pending. Dr Murphy reported having received fees from Becton Dickinson for participation to review IDSA guidelines on gastroenteritis. Dr Tang Girdwood has nothing to disclose.

Dr Murphy and Dr Tang Girdwood are supported by the National Institute of Child Health and Development Cincinnati Pediatric Clinical Pharmacology Postdoctoral Training Program (5T32HD069054-09). Dr Tang Girdwood is also supported by the Cincinnati Children’s Hospital Medical Center Arnold W Strauss Fellow Award and Cincinnati Children’s Hospital Medical Center Hospital Medicine Fellow Award. Dr Scheetz is supported in part by the National Institute of Allergy and Infectious Diseases award (R21AI149026). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Vancomycin, a glycopeptide antibiotic, has been used for decades, yet knowledge gaps remain regarding the most appropriate dosing approach to optimize therapeutic effect while avoiding adverse effects in all patient populations. A committee composed of members of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists reviewed data available since publication of the original 2009 vancomycin dosing guidelines to provide new recommendations regarding vancomycin dosing and serum concentration–monitoring in the empiric treatment of presumed or confirmed methicillin-resistant Staphylococcus aureus (MRSA) infections.¹

The new guidelines provide 25 recommendations encompassing the following topics: vancomycin dosing and monitoring in adult, pediatric, and neonate care; vancomycin minimum inhibitory concentration (MIC) susceptibility testing; continuous infusion vs intermittent infusion; loading doses; dosing in obesity; and dosing in patients on hemodialysis and continuous renal replacement therapy. Because hospitalists in pediatric and adult care frequently prescribe vancomycin for empiric and targeted treatment of serious infections, they have a vested interest in ensuring optimal vancomycin outcomes (ie, best efficacy with least toxicity) with use of therapeutic drug monitoring and personalized dosing of vancomycin. Thus, it is important for hospitalists to be aware of the updated guideline and pivotal changes regarding therapeutic drug monitoring. In this guideline review, we will focus on the major differences from the 2009 guideline, specifically regarding therapeutic monitoring in adults and children.

The guideline includes pharmacology language and terminology with which many clinicians may not be familiar. To better understand the rationale for the guideline changes, a few concepts will be reviewed. Overall, antibiotics are dosed based on preclinical studies to determine the needed drug exposure for optimal efficacy. β-Lactams, for example, are optimally dosed with longer drug exposure time above the MIC of the infectious organism. Alternatively, area under the concentration time curve (AUC) describes the efficacy and toxicity of many other antibiotics. Since AUC is derived from products of concentration (mg/L) and time (hours), the units are often mg × h/L. For vancomycin, both drug exposure (ie, AUC) and organism susceptibility (ie, MIC) are incorporated to determine optimal drug exposure, with the ratio of AUC to MIC being the ideal marker. Therapeutic drug monitoring of vancomycin has classically been conducted with trough concentration monitoring, but with the updated guideline, there will be a transition to AUC monitoring that will affect patient care and experience.

The following is a summary of recommendations 1 to 6:

• In adults, the optimal drug exposure for vancomycin should be an AUC to MIC ratio of 400 to 600 for MRSA, with the assumption of MIC to be 1 mg/L (evidence quality: A-II).
  • The preferred method to monitor AUC is with a clinical statistical software that uses two blood samples (1 to 2 hours after completion of infusion and at the end of a dosing interval [ie, trough]) (evidence quality: A-II).
  • An alternative approach would be to use first-order pharmacokinetic equations at steady state with a peak and trough (evidence quality: A-II).

• These approaches replace the previously recommended trough-only monitoring. AUC-targeted exposure should generally be achieved within 48 hours; severity of infection does not justify higher AUC goals. Once the goal AUC is achieved, once-weekly monitoring is recommended for hemodynamically stable patients, but more frequent or daily monitoring is advised in patients at high risk of nephrotoxicity or who are hemodynamically unstable (evidence quality: B-II).

The currently accepted optimal drug exposure for vancomycin is an AUC to MIC ratio of 400 to 600 to maximize efficacy and minimize nephrotoxicity.² Due to clinical inconvenience of performing AUC-based monitoring for vancomycin in the past, previous guidelines recommended using trough concentrations as a surrogate marker for an AUC to MIC ratio, with the goal trough being 15 to 20 mg/L for serious MRSA infections.³ However, trough values may not correlate well with AUC. For example, a trough of 15 mg/L may represent an AUC ranging from 400 to 1000 mg × h/L over 24 hours. Without knowing an accurate AUC, there is risk for ineffective bactericidal activity with low AUCs or nephrotoxicity with high AUCs. Compared with trough-only monitoring, AUC-guided dosing is associated with decreased risk of acute kidney injury.^4,5 Therefore, the recommendation to transition to two-sample collection with a peak and trough was included.

Software programs are now readily available to compute the AUC and work best with peak and trough values rather than a single trough value because computing with two concentrations will rely more on specific patient data than it does on previously published vancomycin models. Trough-only monitoring (and without the support of clinical software) may still be possible when the exposures needed are further from the toxic range. To this end, trough-only monitoring may be reasonable when infections are not MRSA and are less invasive (eg, cellulitis) since the guideline found insufficient evidence for AUC monitoring in these scenarios. While specific targets are not provided, a plethora of historical literature demonstrated low kidney injury rates when troughs were maintained between 5 to 10 mg/L.

The following is a summary of recommendations 18 to 20:

• In pediatric care, based on a target AUC to MIC ratio of 400 to 600 with the assumption of MIC to be 1 mg/L, initial vancomycin dosage for MRSA is as follows (evidence quality: A-II) :
  • 60 to 80 mg/kg per day, divided into four doses, each given 6 hours apart, for children 3 months and older but younger than 12 years
  • 60 to 70 mg/kg per day, divided into four doses, each given 6 hours apart, for children 12 years and older
• As recommended in adults, use of a statistical software program to measure AUC is the optimal approach in pediatric care because it can account for age, weight, and renal function, which should be monitored closely. Monitoring should begin within 48 hours of therapy. Vancomycin AUC and trough concentrations should be less than 800 µg × h/mL over 24 hours and 15 µg/mL, respectively, to minimize acute kidney injury (evidence quality: A-II).

All the recommendations for pediatrics are new for the updated guideline. Pediatric data to support these recommendations are fewer in comparison with adult literature. Given MRSA infections are felt to be similar in adults and children, many pediatric recommendations are extrapolated from adult data and recommendations. The strongest level of evidence in children is the association of acute kidney injury with higher vancomycin exposure, especially with troughs exceeding 15 to 20 mg/L.⁶ In addition, one pediatric study found an AUC exposure of greater than 800 mg × h/L over 24 hours was strongly associated with risk for acute kidney injury.⁷ These findings suggest that high vancomycin exposure correlates with nephrotoxicity, so with AUC monitoring, the goal exposure should be less than 800 mg × hr/L over 24 hours.

Only one study has evaluated statistical software and prediction of AUC in pediatrics.⁸ A two-concentration approach (peak and trough) outperformed trough-only monitoring for accuracy and precision in determining AUC. While limited to one study, the results are similar to the studies completed in adults, thereby leading to the recommendation of the two-concentration technique in children.

Prospective outcome data are lacking, but multiple retrospective studies have examined S aureus bacteremia in children. Thus far, there have been no studies that have determined the optimal vancomycin exposure required for successful outcomes.^9,10 The proven risks of toxicity are the primary driver for the pediatric guideline change with the outcomes extrapolated from adult data.

Methods in Preparing Guideline

The main strength of the guideline is that the committee was represented by multiple organizations, which created a multidisciplinary panel of pharmacists and infectious disease physicians with clinical and research expertise in vancomycin dosing. Evidence was graded using an adaptation from the Canadian Task Force on the Periodic Health Examination.¹¹ The draft was peer-reviewed by the society organizations and allowed for comments, suggestions, and recommendations.

Sources of Potential Conflict of Interest or Bias

Disclosures of all authors were reported and identified in the guideline. While many members are involved with pharmaceutical companies through research or speakers’ roles, vancomycin, a generic drug, should have minimal conflicts of interest or bias from this involvement.

Generalizability

Implementation of vancomycin AUC dosing will be hospital dependent due to the implementation-related increase in human resources and the cost of clinical software; many hospital systems do not already have the software integrated into their clinical practice. Local guidelines will have to be developed to help clinicians determine which clinical situations require AUC-based dosing vs trough-only monitoring. Pharmacists at many hospitals are primarily responsible for vancomycin monitoring and provide dosing recommendations to physicians. Depending on a hospital system’s decision, the workload to determine the optimal vancomycin dose may increase, and it will be important to have close collaboration between hospitalists, pharmacists, and infectious diseases clinicians to appropriately educate clinicians who might be required to dose/monitor vancomycin. One potential way to decrease the burden of monitoring with two concentrations is to use specialized software that can perform complex assessments with only a single concentration. These software applications will still require serious collaboration of the aforementioned practitioners to implement. The variation in guideline adoption will likely be even more significant in pediatrics because the literature is extrapolated and the increased blood draws can be more problematic in pediatric patients.

Furthermore, clinicians should understand the dosing guideline is specifically addressing treatment of MRSA infections and extrapolation to other organisms such as coagulase-negative staphylococcal or methicillin-susceptible S aureus infections should be cautioned. Another caveat to note is that, when the MRSA isolate has an MIC of 2 mg/L or higher, these infections are associated with poor outcomes when vancomycin is used and alternative agents are recommended.

Research gaps still remain with appropriate vancomycin drug exposure. In pediatrics, determining the appropriate AUC target will be important given that current recommendations extrapolate from adult data. Future studies can focus on prospective outcome data in both pediatric and adult patients for infections outside of bacteremia or pneumonia, notably central nervous system and osteomyelitis infections. Thresholds for kidney injury will need to be more clearly defined for both adult and pediatric patients. There should also be research emphasis on the appropriate dosing for other non-MRSA invasive infections, notably coagulase-negative staphylococcal infections.

Dr Scheetz reported personal fees for consulting for Achaogen, SIGA technologies, and for serving on an advisory board for Paratek; grants from Merck and Co, Allecra, Nevakar, and SuperTrans Medical; personal fees from Hall, Booth, Smith, PC, and Chambless, Higdon, Richardson, Katz & Griggs, LLP, for consulting and expert testimony, outside the submitted work. In addition, Dr. Scheetz has patent US 2019 / 0099500 A1 pending. Dr Murphy reported having received fees from Becton Dickinson for participation to review IDSA guidelines on gastroenteritis. Dr Tang Girdwood has nothing to disclose.

Dr Murphy and Dr Tang Girdwood are supported by the National Institute of Child Health and Development Cincinnati Pediatric Clinical Pharmacology Postdoctoral Training Program (5T32HD069054-09). Dr Tang Girdwood is also supported by the Cincinnati Children’s Hospital Medical Center Arnold W Strauss Fellow Award and Cincinnati Children’s Hospital Medical Center Hospital Medicine Fellow Award. Dr Scheetz is supported in part by the National Institute of Allergy and Infectious Diseases award (R21AI149026). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Vancomycin, a glycopeptide antibiotic, has been used for decades, yet knowledge gaps remain regarding the most appropriate dosing approach to optimize therapeutic effect while avoiding adverse effects in all patient populations. A committee composed of members of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists reviewed data available since publication of the original 2009 vancomycin dosing guidelines to provide new recommendations regarding vancomycin dosing and serum concentration–monitoring in the empiric treatment of presumed or confirmed methicillin-resistant Staphylococcus aureus (MRSA) infections.¹

The new guidelines provide 25 recommendations encompassing the following topics: vancomycin dosing and monitoring in adult, pediatric, and neonate care; vancomycin minimum inhibitory concentration (MIC) susceptibility testing; continuous infusion vs intermittent infusion; loading doses; dosing in obesity; and dosing in patients on hemodialysis and continuous renal replacement therapy. Because hospitalists in pediatric and adult care frequently prescribe vancomycin for empiric and targeted treatment of serious infections, they have a vested interest in ensuring optimal vancomycin outcomes (ie, best efficacy with least toxicity) with use of therapeutic drug monitoring and personalized dosing of vancomycin. Thus, it is important for hospitalists to be aware of the updated guideline and pivotal changes regarding therapeutic drug monitoring. In this guideline review, we will focus on the major differences from the 2009 guideline, specifically regarding therapeutic monitoring in adults and children.

The guideline includes pharmacology language and terminology with which many clinicians may not be familiar. To better understand the rationale for the guideline changes, a few concepts will be reviewed. Overall, antibiotics are dosed based on preclinical studies to determine the needed drug exposure for optimal efficacy. β-Lactams, for example, are optimally dosed with longer drug exposure time above the MIC of the infectious organism. Alternatively, area under the concentration time curve (AUC) describes the efficacy and toxicity of many other antibiotics. Since AUC is derived from products of concentration (mg/L) and time (hours), the units are often mg × h/L. For vancomycin, both drug exposure (ie, AUC) and organism susceptibility (ie, MIC) are incorporated to determine optimal drug exposure, with the ratio of AUC to MIC being the ideal marker. Therapeutic drug monitoring of vancomycin has classically been conducted with trough concentration monitoring, but with the updated guideline, there will be a transition to AUC monitoring that will affect patient care and experience.

The following is a summary of recommendations 1 to 6:

• In adults, the optimal drug exposure for vancomycin should be an AUC to MIC ratio of 400 to 600 for MRSA, with the assumption of MIC to be 1 mg/L (evidence quality: A-II).
  • The preferred method to monitor AUC is with a clinical statistical software that uses two blood samples (1 to 2 hours after completion of infusion and at the end of a dosing interval [ie, trough]) (evidence quality: A-II).
  • An alternative approach would be to use first-order pharmacokinetic equations at steady state with a peak and trough (evidence quality: A-II).

• These approaches replace the previously recommended trough-only monitoring. AUC-targeted exposure should generally be achieved within 48 hours; severity of infection does not justify higher AUC goals. Once the goal AUC is achieved, once-weekly monitoring is recommended for hemodynamically stable patients, but more frequent or daily monitoring is advised in patients at high risk of nephrotoxicity or who are hemodynamically unstable (evidence quality: B-II).

The currently accepted optimal drug exposure for vancomycin is an AUC to MIC ratio of 400 to 600 to maximize efficacy and minimize nephrotoxicity.² Due to clinical inconvenience of performing AUC-based monitoring for vancomycin in the past, previous guidelines recommended using trough concentrations as a surrogate marker for an AUC to MIC ratio, with the goal trough being 15 to 20 mg/L for serious MRSA infections.³ However, trough values may not correlate well with AUC. For example, a trough of 15 mg/L may represent an AUC ranging from 400 to 1000 mg × h/L over 24 hours. Without knowing an accurate AUC, there is risk for ineffective bactericidal activity with low AUCs or nephrotoxicity with high AUCs. Compared with trough-only monitoring, AUC-guided dosing is associated with decreased risk of acute kidney injury.^4,5 Therefore, the recommendation to transition to two-sample collection with a peak and trough was included.

Software programs are now readily available to compute the AUC and work best with peak and trough values rather than a single trough value because computing with two concentrations will rely more on specific patient data than it does on previously published vancomycin models. Trough-only monitoring (and without the support of clinical software) may still be possible when the exposures needed are further from the toxic range. To this end, trough-only monitoring may be reasonable when infections are not MRSA and are less invasive (eg, cellulitis) since the guideline found insufficient evidence for AUC monitoring in these scenarios. While specific targets are not provided, a plethora of historical literature demonstrated low kidney injury rates when troughs were maintained between 5 to 10 mg/L.

The following is a summary of recommendations 18 to 20:

• In pediatric care, based on a target AUC to MIC ratio of 400 to 600 with the assumption of MIC to be 1 mg/L, initial vancomycin dosage for MRSA is as follows (evidence quality: A-II) :
  • 60 to 80 mg/kg per day, divided into four doses, each given 6 hours apart, for children 3 months and older but younger than 12 years
  • 60 to 70 mg/kg per day, divided into four doses, each given 6 hours apart, for children 12 years and older
• As recommended in adults, use of a statistical software program to measure AUC is the optimal approach in pediatric care because it can account for age, weight, and renal function, which should be monitored closely. Monitoring should begin within 48 hours of therapy. Vancomycin AUC and trough concentrations should be less than 800 µg × h/mL over 24 hours and 15 µg/mL, respectively, to minimize acute kidney injury (evidence quality: A-II).

All the recommendations for pediatrics are new for the updated guideline. Pediatric data to support these recommendations are fewer in comparison with adult literature. Given MRSA infections are felt to be similar in adults and children, many pediatric recommendations are extrapolated from adult data and recommendations. The strongest level of evidence in children is the association of acute kidney injury with higher vancomycin exposure, especially with troughs exceeding 15 to 20 mg/L.⁶ In addition, one pediatric study found an AUC exposure of greater than 800 mg × h/L over 24 hours was strongly associated with risk for acute kidney injury.⁷ These findings suggest that high vancomycin exposure correlates with nephrotoxicity, so with AUC monitoring, the goal exposure should be less than 800 mg × hr/L over 24 hours.

Only one study has evaluated statistical software and prediction of AUC in pediatrics.⁸ A two-concentration approach (peak and trough) outperformed trough-only monitoring for accuracy and precision in determining AUC. While limited to one study, the results are similar to the studies completed in adults, thereby leading to the recommendation of the two-concentration technique in children.

Prospective outcome data are lacking, but multiple retrospective studies have examined S aureus bacteremia in children. Thus far, there have been no studies that have determined the optimal vancomycin exposure required for successful outcomes.^9,10 The proven risks of toxicity are the primary driver for the pediatric guideline change with the outcomes extrapolated from adult data.

Methods in Preparing Guideline

The main strength of the guideline is that the committee was represented by multiple organizations, which created a multidisciplinary panel of pharmacists and infectious disease physicians with clinical and research expertise in vancomycin dosing. Evidence was graded using an adaptation from the Canadian Task Force on the Periodic Health Examination.¹¹ The draft was peer-reviewed by the society organizations and allowed for comments, suggestions, and recommendations.

Sources of Potential Conflict of Interest or Bias

Disclosures of all authors were reported and identified in the guideline. While many members are involved with pharmaceutical companies through research or speakers’ roles, vancomycin, a generic drug, should have minimal conflicts of interest or bias from this involvement.

Generalizability

Implementation of vancomycin AUC dosing will be hospital dependent due to the implementation-related increase in human resources and the cost of clinical software; many hospital systems do not already have the software integrated into their clinical practice. Local guidelines will have to be developed to help clinicians determine which clinical situations require AUC-based dosing vs trough-only monitoring. Pharmacists at many hospitals are primarily responsible for vancomycin monitoring and provide dosing recommendations to physicians. Depending on a hospital system’s decision, the workload to determine the optimal vancomycin dose may increase, and it will be important to have close collaboration between hospitalists, pharmacists, and infectious diseases clinicians to appropriately educate clinicians who might be required to dose/monitor vancomycin. One potential way to decrease the burden of monitoring with two concentrations is to use specialized software that can perform complex assessments with only a single concentration. These software applications will still require serious collaboration of the aforementioned practitioners to implement. The variation in guideline adoption will likely be even more significant in pediatrics because the literature is extrapolated and the increased blood draws can be more problematic in pediatric patients.

Furthermore, clinicians should understand the dosing guideline is specifically addressing treatment of MRSA infections and extrapolation to other organisms such as coagulase-negative staphylococcal or methicillin-susceptible S aureus infections should be cautioned. Another caveat to note is that, when the MRSA isolate has an MIC of 2 mg/L or higher, these infections are associated with poor outcomes when vancomycin is used and alternative agents are recommended.

Research gaps still remain with appropriate vancomycin drug exposure. In pediatrics, determining the appropriate AUC target will be important given that current recommendations extrapolate from adult data. Future studies can focus on prospective outcome data in both pediatric and adult patients for infections outside of bacteremia or pneumonia, notably central nervous system and osteomyelitis infections. Thresholds for kidney injury will need to be more clearly defined for both adult and pediatric patients. There should also be research emphasis on the appropriate dosing for other non-MRSA invasive infections, notably coagulase-negative staphylococcal infections.

Dr Scheetz reported personal fees for consulting for Achaogen, SIGA technologies, and for serving on an advisory board for Paratek; grants from Merck and Co, Allecra, Nevakar, and SuperTrans Medical; personal fees from Hall, Booth, Smith, PC, and Chambless, Higdon, Richardson, Katz & Griggs, LLP, for consulting and expert testimony, outside the submitted work. In addition, Dr. Scheetz has patent US 2019 / 0099500 A1 pending. Dr Murphy reported having received fees from Becton Dickinson for participation to review IDSA guidelines on gastroenteritis. Dr Tang Girdwood has nothing to disclose.

Dr Murphy and Dr Tang Girdwood are supported by the National Institute of Child Health and Development Cincinnati Pediatric Clinical Pharmacology Postdoctoral Training Program (5T32HD069054-09). Dr Tang Girdwood is also supported by the Cincinnati Children’s Hospital Medical Center Arnold W Strauss Fellow Award and Cincinnati Children’s Hospital Medical Center Hospital Medicine Fellow Award. Dr Scheetz is supported in part by the National Institute of Allergy and Infectious Diseases award (R21AI149026). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Challenges in conducting and completing studies of drugs in vulnerable populations, such as hospitalized children, include weak study designs and lack of sufficient sample sizes to achieve adequate power.¹ Limitations in the amount of blood that can be safely drawn in children and low parental consent rates due to concerns for anemia or pain, if venipuncture is required, lead to an insufficient number of patients enrolled in traditional clinical studies.² Thus, sample size targets are often not met. Recognizing the limited pediatric data for many drugs routinely prescribed off-label in children, the Food and Drug Administration implemented the Best Pharmaceuticals Children Act and the Pediatric Research Equity Act (PREA) in 2003; these legislative acts require clinical studies to assess the safety and efficacy of new drugs in children.¹ While studies conducted under these acts have provided important information for the clinical care of children, only one-third of mandatory pediatric postmarketing studies of the 114 new drugs and new indications subject to PREA requirements between 2007 and 2014 had been completed within seven years.³

Despite the challenges in conducting studies of drugs in children, robust pediatric data must be generated in children, especially in those with medical complexity or with chronic medical diseases and who have significant risk of experiencing adverse drug events. Data in adults cannot simply be extrapolated to children. In addition, studies from healthy children may not apply to hospitalized pediatric patients because of significant physiologic changes that occur in children who are ill enough to be hospitalized. Opportunistic sampling can provide robust drug disposition data and overcome some of the challenges encountered by traditional drug studies. In this Methodologic Progress Note, we describe the utility of opportunistic sampling as a research tool for hospitalists, in partnership with clinical pharmacologists, to study drug pharmacokinetics (PK) in hospitalized children.

Opportunistic sampling relies on the use of blood samples that are ordered for clinical purposes, and its use is endorsed by the Pediatric Trials Network.^2,5 Opportunistic sampling approaches have two types: sparse sampling and scavenged or remnant sampling. In sparse opportunistic sampling, additional blood is obtained at the same time clinical samples are ordered, avoiding the need for additional punctures.⁵ This approach requires bedside personnel to obtain additional blood that is sent to the research team for further processing. Scavenged sampling relies on leftover residual blood from clinical samples.^2,5 After the clinical laboratory performs the laboratory test ordered by the clinical team, the research team can scavenge residual blood for measurement of drug concentrations. When drug concentrations are measured from multiple patients, clinical pharmacologists can perform population PK modeling to characterize the pharmacokinetics of the drug and its variability within the population level.

The Figure shows how scavenged samples from hypothetical patients could be used to generate a PK curve. In this example, three patients are admitted for osteomyelitis and treated with the same antibiotic administered every eight hours, as shown by the theoretical concentration versus time profiles in the top panel. To determine the effectiveness of treatment and timing of transition to enteral antibiotics, the clinical team orders C-reactive protein (CRP) approximately every 48 hours for each patient. Each patient has his/her first dose of antibiotic at a different time of day depending on the time of admission or surgical drainage. Therefore, the timing of the blood draw with respect to the most recent antibiotic dose varies between patients even if blood draws are ordered at the same time for all patients (ie, 4 am lab draw). For patient 1, the blood draws occur approximately three to five hours after the second and eighth antibiotic doses (Figure, top panel). After the clinical laboratory measures the CRP, the research team scavenges residual blood from the lab samples and measures antibiotic concentrations. The antibiotic concentrations are then plotted on a concentration vs time after most recent dose. (Figure, bottom panel). Patient 2 has blood drawn five to seven hours after the first and seventh antibiotic doses. The third patient has blood drawn within two hours after the second and eighth antibiotic doses. As more samples are collected from additional patients, population PK modeling provides a robust description of the central tendency of the concentration vs time profile. More important, as more patients are included, the interpatient variability in concentrations can be described within the population, which often cannot be performed well with the smaller numbers of patients enrolled in traditional PK studies.

Opportunistic sampling has advantages over traditional intensive PK studies that often require multiple blood draws (typically >8-10) within one dosing interval to adequately describe the phases of absorption, distribution, metabolism, and elimination. The number of vascular punctures can be painful if blood cannot be drawn from existing vascular access, and the large amount of blood (sometimes >1 mL/sample) required for these studies can be impractical, burdensome, and even dangerous in young children and neonates. Scavenged sampling reduces the risk of anemia because no additional blood is drawn beyond what is obtained for clinical purposes, and it does not disrupt nursing workflow or add to nursing workload. Approval to use scavenged blood requires approval from the institutional review board. At some institutions, the consent to treat form on admission may address the use of scavenged samples and therefore allow for waiver of consent. In addition, the consent process may occur retroactively after samples are collected. These methods lead to increased enrollment.

Limitations in this approach are that drugs may degrade over time in whole blood or processed samples. Therefore, the process by which the clinical laboratory stores the residual blood after clinical tests must be understood, and the stability of the drug or metabolite of interest in blood or plasma over time must be ensured. In addition, residual blood may not be present after a clinical test, and recording times of the drug administration and lab draws may be inaccurate.^2,5

Challenges in conducting and completing studies of drugs in vulnerable populations, such as hospitalized children, include weak study designs and lack of sufficient sample sizes to achieve adequate power.¹ Limitations in the amount of blood that can be safely drawn in children and low parental consent rates due to concerns for anemia or pain, if venipuncture is required, lead to an insufficient number of patients enrolled in traditional clinical studies.² Thus, sample size targets are often not met. Recognizing the limited pediatric data for many drugs routinely prescribed off-label in children, the Food and Drug Administration implemented the Best Pharmaceuticals Children Act and the Pediatric Research Equity Act (PREA) in 2003; these legislative acts require clinical studies to assess the safety and efficacy of new drugs in children.¹ While studies conducted under these acts have provided important information for the clinical care of children, only one-third of mandatory pediatric postmarketing studies of the 114 new drugs and new indications subject to PREA requirements between 2007 and 2014 had been completed within seven years.³

Despite the challenges in conducting studies of drugs in children, robust pediatric data must be generated in children, especially in those with medical complexity or with chronic medical diseases and who have significant risk of experiencing adverse drug events. Data in adults cannot simply be extrapolated to children. In addition, studies from healthy children may not apply to hospitalized pediatric patients because of significant physiologic changes that occur in children who are ill enough to be hospitalized. Opportunistic sampling can provide robust drug disposition data and overcome some of the challenges encountered by traditional drug studies. In this Methodologic Progress Note, we describe the utility of opportunistic sampling as a research tool for hospitalists, in partnership with clinical pharmacologists, to study drug pharmacokinetics (PK) in hospitalized children.

Opportunistic sampling relies on the use of blood samples that are ordered for clinical purposes, and its use is endorsed by the Pediatric Trials Network.^2,5 Opportunistic sampling approaches have two types: sparse sampling and scavenged or remnant sampling. In sparse opportunistic sampling, additional blood is obtained at the same time clinical samples are ordered, avoiding the need for additional punctures.⁵ This approach requires bedside personnel to obtain additional blood that is sent to the research team for further processing. Scavenged sampling relies on leftover residual blood from clinical samples.^2,5 After the clinical laboratory performs the laboratory test ordered by the clinical team, the research team can scavenge residual blood for measurement of drug concentrations. When drug concentrations are measured from multiple patients, clinical pharmacologists can perform population PK modeling to characterize the pharmacokinetics of the drug and its variability within the population level.

The Figure shows how scavenged samples from hypothetical patients could be used to generate a PK curve. In this example, three patients are admitted for osteomyelitis and treated with the same antibiotic administered every eight hours, as shown by the theoretical concentration versus time profiles in the top panel. To determine the effectiveness of treatment and timing of transition to enteral antibiotics, the clinical team orders C-reactive protein (CRP) approximately every 48 hours for each patient. Each patient has his/her first dose of antibiotic at a different time of day depending on the time of admission or surgical drainage. Therefore, the timing of the blood draw with respect to the most recent antibiotic dose varies between patients even if blood draws are ordered at the same time for all patients (ie, 4 am lab draw). For patient 1, the blood draws occur approximately three to five hours after the second and eighth antibiotic doses (Figure, top panel). After the clinical laboratory measures the CRP, the research team scavenges residual blood from the lab samples and measures antibiotic concentrations. The antibiotic concentrations are then plotted on a concentration vs time after most recent dose. (Figure, bottom panel). Patient 2 has blood drawn five to seven hours after the first and seventh antibiotic doses. The third patient has blood drawn within two hours after the second and eighth antibiotic doses. As more samples are collected from additional patients, population PK modeling provides a robust description of the central tendency of the concentration vs time profile. More important, as more patients are included, the interpatient variability in concentrations can be described within the population, which often cannot be performed well with the smaller numbers of patients enrolled in traditional PK studies.

Opportunistic sampling has advantages over traditional intensive PK studies that often require multiple blood draws (typically >8-10) within one dosing interval to adequately describe the phases of absorption, distribution, metabolism, and elimination. The number of vascular punctures can be painful if blood cannot be drawn from existing vascular access, and the large amount of blood (sometimes >1 mL/sample) required for these studies can be impractical, burdensome, and even dangerous in young children and neonates. Scavenged sampling reduces the risk of anemia because no additional blood is drawn beyond what is obtained for clinical purposes, and it does not disrupt nursing workflow or add to nursing workload. Approval to use scavenged blood requires approval from the institutional review board. At some institutions, the consent to treat form on admission may address the use of scavenged samples and therefore allow for waiver of consent. In addition, the consent process may occur retroactively after samples are collected. These methods lead to increased enrollment.

Limitations in this approach are that drugs may degrade over time in whole blood or processed samples. Therefore, the process by which the clinical laboratory stores the residual blood after clinical tests must be understood, and the stability of the drug or metabolite of interest in blood or plasma over time must be ensured. In addition, residual blood may not be present after a clinical test, and recording times of the drug administration and lab draws may be inaccurate.^2,5

Challenges in conducting and completing studies of drugs in vulnerable populations, such as hospitalized children, include weak study designs and lack of sufficient sample sizes to achieve adequate power.¹ Limitations in the amount of blood that can be safely drawn in children and low parental consent rates due to concerns for anemia or pain, if venipuncture is required, lead to an insufficient number of patients enrolled in traditional clinical studies.² Thus, sample size targets are often not met. Recognizing the limited pediatric data for many drugs routinely prescribed off-label in children, the Food and Drug Administration implemented the Best Pharmaceuticals Children Act and the Pediatric Research Equity Act (PREA) in 2003; these legislative acts require clinical studies to assess the safety and efficacy of new drugs in children.¹ While studies conducted under these acts have provided important information for the clinical care of children, only one-third of mandatory pediatric postmarketing studies of the 114 new drugs and new indications subject to PREA requirements between 2007 and 2014 had been completed within seven years.³

Despite the challenges in conducting studies of drugs in children, robust pediatric data must be generated in children, especially in those with medical complexity or with chronic medical diseases and who have significant risk of experiencing adverse drug events. Data in adults cannot simply be extrapolated to children. In addition, studies from healthy children may not apply to hospitalized pediatric patients because of significant physiologic changes that occur in children who are ill enough to be hospitalized. Opportunistic sampling can provide robust drug disposition data and overcome some of the challenges encountered by traditional drug studies. In this Methodologic Progress Note, we describe the utility of opportunistic sampling as a research tool for hospitalists, in partnership with clinical pharmacologists, to study drug pharmacokinetics (PK) in hospitalized children.

Opportunistic sampling relies on the use of blood samples that are ordered for clinical purposes, and its use is endorsed by the Pediatric Trials Network.^2,5 Opportunistic sampling approaches have two types: sparse sampling and scavenged or remnant sampling. In sparse opportunistic sampling, additional blood is obtained at the same time clinical samples are ordered, avoiding the need for additional punctures.⁵ This approach requires bedside personnel to obtain additional blood that is sent to the research team for further processing. Scavenged sampling relies on leftover residual blood from clinical samples.^2,5 After the clinical laboratory performs the laboratory test ordered by the clinical team, the research team can scavenge residual blood for measurement of drug concentrations. When drug concentrations are measured from multiple patients, clinical pharmacologists can perform population PK modeling to characterize the pharmacokinetics of the drug and its variability within the population level.

The Figure shows how scavenged samples from hypothetical patients could be used to generate a PK curve. In this example, three patients are admitted for osteomyelitis and treated with the same antibiotic administered every eight hours, as shown by the theoretical concentration versus time profiles in the top panel. To determine the effectiveness of treatment and timing of transition to enteral antibiotics, the clinical team orders C-reactive protein (CRP) approximately every 48 hours for each patient. Each patient has his/her first dose of antibiotic at a different time of day depending on the time of admission or surgical drainage. Therefore, the timing of the blood draw with respect to the most recent antibiotic dose varies between patients even if blood draws are ordered at the same time for all patients (ie, 4 am lab draw). For patient 1, the blood draws occur approximately three to five hours after the second and eighth antibiotic doses (Figure, top panel). After the clinical laboratory measures the CRP, the research team scavenges residual blood from the lab samples and measures antibiotic concentrations. The antibiotic concentrations are then plotted on a concentration vs time after most recent dose. (Figure, bottom panel). Patient 2 has blood drawn five to seven hours after the first and seventh antibiotic doses. The third patient has blood drawn within two hours after the second and eighth antibiotic doses. As more samples are collected from additional patients, population PK modeling provides a robust description of the central tendency of the concentration vs time profile. More important, as more patients are included, the interpatient variability in concentrations can be described within the population, which often cannot be performed well with the smaller numbers of patients enrolled in traditional PK studies.

Opportunistic sampling has advantages over traditional intensive PK studies that often require multiple blood draws (typically >8-10) within one dosing interval to adequately describe the phases of absorption, distribution, metabolism, and elimination. The number of vascular punctures can be painful if blood cannot be drawn from existing vascular access, and the large amount of blood (sometimes >1 mL/sample) required for these studies can be impractical, burdensome, and even dangerous in young children and neonates. Scavenged sampling reduces the risk of anemia because no additional blood is drawn beyond what is obtained for clinical purposes, and it does not disrupt nursing workflow or add to nursing workload. Approval to use scavenged blood requires approval from the institutional review board. At some institutions, the consent to treat form on admission may address the use of scavenged samples and therefore allow for waiver of consent. In addition, the consent process may occur retroactively after samples are collected. These methods lead to increased enrollment.

Limitations in this approach are that drugs may degrade over time in whole blood or processed samples. Therefore, the process by which the clinical laboratory stores the residual blood after clinical tests must be understood, and the stability of the drug or metabolite of interest in blood or plasma over time must be ensured. In addition, residual blood may not be present after a clinical test, and recording times of the drug administration and lab draws may be inaccurate.^2,5

Hospitalized children with inadequate fluid intake are often administered maintenance intravenous fluids (IVFs) to support metabolic needs and sensible losses. Historically, hypotonic IVFs have been the standard, based on theoretical water and electrolyte requirements for estimated energy expenditure.¹ However, when combined with increased levels of arginine vasopressin (AVP) seen in acutely ill children which impairs free-water excretion,² hypotonic IVF can result in hyponatremia. The recently published guideline by the American Academy of Pediatrics (AAP)³ is the first to provide an evidence-based recommendation on the use of maintenance IVF therapy in children.

Patients between the ages of 28 days and 18 years should receive isotonic solutions with appropriate potassium chloride and dextrose for maintenance IVFs (evidence quality: high; recommendation strength: strong)

Isotonic fluids, such as 0.9% NaCl (normal saline), Hartmann solution and PlasmaLyte, contain a sodium concentration similar to that of plasma (135-144 mEq/L). Lactated Ringer solution (LR) is near-isotonic (sodium 130 mEq/L), but was not used in any of the reviewed studies and therefore not included in the recommendation. Excluded are patients with neurosurgical disorders, congenital or acquired cardiac disease, hepatic disease, cancer, renal dysfunction, diabetes insipidus, voluminous watery diarrhea, severe burns, or patients in the neonatal intensive care unit.

The primary benefit of the AAP recommendation is the reduced risk of iatrogenic hyponatremia and its associated sequelae, including complications or impact on cost of care. The number needed to treat with isotonic fluids was 7.5 to prevent any hyponatremia and 27.8 to prevent moderate hyponatremia (<130 mEq/L). Increases in readmission rates, length of stay, and cost of hospitalization have been reported in a recent meta-analysis reviewing the economic burden of hyponatremia in both adults and children.⁴

Potential harms from the use of isotonic fluids include hypernatremia, hyperchloremic metabolic acidosis, and fluid overload, although available data have not demonstrated an increased risk of these complications. In light of a recent normal saline (NS) shortage in the United States, limited availability is also a consideration. Plasmalyte is more costly than NS and is currently incompatible with the addition of dextrose.

Methods in Preparing Guideline

The guideline development committee included broad representation by pediatric experts in primary care, hospital medicine, emergency medicine, critical care medicine, nephrology, anesthesiology, surgery and quality improvement, as well as a guideline methodologist/informatician and epidemiologist.

Search strategies from recently published systematic reviews of clinical trials comparing isotonic with hypotonic maintenance IVFs were used to identify studies eligible for inclusion. A total of 17 studies with 2,455 total patients were initially identified and included. One additional study meeting inclusion criteria was found after the committee convened and excluded from the guideline.⁵ Three reviewers from the subcommittee performed a structured critical appraisal of each article. The methods of each trial were assessed for risk-of-bias in multiple domains, including randomization, allocation concealment, performance, detection, attrition and reporting. Forest plots were generated using random-effects models and Mantel-Haenzel statistics with the outcome of hyponatremia. The guideline underwent review by various stakeholders including AAP councils, committees, and sections, and individuals considered experts in the field.

A strength of the guideline is the high quality of the evidence and the consistent findings. All of the included studies were randomized clinical trials and the number of included patients was large. Of the 17 included studies, 16 reported a risk ratio favoring isotonic fluids over hypotonic fluids in the prevention of developing hyponatremia; the results of the study that favored hypotonic fluids were not statistically significant on their own. A sensitivity analysis was performed to exclude one study with a 20% weight, determined by multiple factors such as sample size, confidence interval, and an unusually high rate of hyponatremia in the isotonic and hypotonic fluids groups (33.3 % and 70%, respectively).⁶ After exclusion, there was no change in the overall estimated risk in hypotonic fluids leading to hyponatremia. Only one trial had two sources of high risk of bias (allocation concealment, attrition) and the remaining had only low or unclear risk of biases in the various domains.

The study that was excluded due to its late identification similarly shows increased risk of hyponatremia in groups administered hypotonic fluids (risk ratio 6.5-8.5), and would likely not affect the estimated risk.⁵

Despite differences in types of patients enrolled, rate of administered fluids, type of IVF, frequency of lab testing, and study duration, the I² (degree of heterogeneity) of the forest plot of all included studies remained low at 14% and the increased risk of hyponatremia from hypotonic fluids remained consistent.

Due to study design differences, a limitation of the guideline is that no recommendation is made regarding the type of isotonic fluids and the rate of IVF administration. Additionally, due to the low frequency of clinically significant sequelae of hyponatremia, such as hyponatremic encephalopathy, it remains uncertain how many patients would need to be treated with isotonic fluids to prevent a rare but potentially devastating event.

Sources of Potential Conflict of Interest or Bias

The guideline was developed and funded by the AAP. A formal conflict of interest management policy was followed, and subcommittee members had no conflicts of interests or financial relationships relevant to the guideline to disclose.

Generalizability

Given the large number of patients included in the studies and heterogeneity of the population included, the recommendation applies to most patients cared for by pediatric hospitalists. Several patient exclusions relevant to the pediatric hospitalist deserve mention: neonates, kidney disease, and voluminous diarrhea. Neonates under the age of 28 days, including febrile neonates, are excluded from the guideline because of the immature concentrating abilities of neonatal kidneys. Patients with renal impairment were excluded from the guideline recommendation because several studies excluded patients with kidney disease. Hospitalists often care for children who sustain prerenal acute kidney injury from severe dehydration. In this condition, the kidney conserves water through the release of AVP. While an excluded population, these patients would be even more susceptible to develop hyponatremia if administered hypotonic fluids. Patients with “voluminous diarrhea” are excluded from the guideline because those with gastroenteritis with ongoing losses may require IVFs at rates higher than maintenance, and are particularly vulnerable to electrolyte derangements. The guideline, however, does not define voluminous diarrhea, leaving it to the discretion of the treating clinician.

Finally, it is critical to mention that IVF should be considered a therapy to be judiciously used, and discontinued when possible. While the guideline addresses the choice of fluid composition, alternatives to orally or enterally hydrate a patient are always preferred.

While the guideline strongly recommends isotonic fluids for maintenance therapy, the choice of isotonic fluid remains with the clinician. Most included studies used NS for their isotonic groups, but Hartmann’s solution and Plasmalyte were represented in a few studies. LR, one of the more widely used balanced solutions, though slightly hypotonic (130 mEq/L), was not studied. The exclusion of LR from the included studies is unfortunate, as the benefit of balanced solutions compared to NS after significant fluid resuscitation has been shown in the setting of severe sepsis and shock.⁷ Hyperchloremic metabolic acidosis after fluid resuscitation with NS has raised concern about continuing NS as maintenance fluid and possibly worsening acidosis or hyperchloremia and its adverse effects.⁸ Further studies on the potential benefit of LR as maintenance fluid, or the potential harms of unbalanced solutions as maintenance fluids in the setting of significant resuscitation are needed.

Disclosures

The authors have nothing to disclose.

Hospitalized children with inadequate fluid intake are often administered maintenance intravenous fluids (IVFs) to support metabolic needs and sensible losses. Historically, hypotonic IVFs have been the standard, based on theoretical water and electrolyte requirements for estimated energy expenditure.¹ However, when combined with increased levels of arginine vasopressin (AVP) seen in acutely ill children which impairs free-water excretion,² hypotonic IVF can result in hyponatremia. The recently published guideline by the American Academy of Pediatrics (AAP)³ is the first to provide an evidence-based recommendation on the use of maintenance IVF therapy in children.

Patients between the ages of 28 days and 18 years should receive isotonic solutions with appropriate potassium chloride and dextrose for maintenance IVFs (evidence quality: high; recommendation strength: strong)

Isotonic fluids, such as 0.9% NaCl (normal saline), Hartmann solution and PlasmaLyte, contain a sodium concentration similar to that of plasma (135-144 mEq/L). Lactated Ringer solution (LR) is near-isotonic (sodium 130 mEq/L), but was not used in any of the reviewed studies and therefore not included in the recommendation. Excluded are patients with neurosurgical disorders, congenital or acquired cardiac disease, hepatic disease, cancer, renal dysfunction, diabetes insipidus, voluminous watery diarrhea, severe burns, or patients in the neonatal intensive care unit.

The primary benefit of the AAP recommendation is the reduced risk of iatrogenic hyponatremia and its associated sequelae, including complications or impact on cost of care. The number needed to treat with isotonic fluids was 7.5 to prevent any hyponatremia and 27.8 to prevent moderate hyponatremia (<130 mEq/L). Increases in readmission rates, length of stay, and cost of hospitalization have been reported in a recent meta-analysis reviewing the economic burden of hyponatremia in both adults and children.⁴

Potential harms from the use of isotonic fluids include hypernatremia, hyperchloremic metabolic acidosis, and fluid overload, although available data have not demonstrated an increased risk of these complications. In light of a recent normal saline (NS) shortage in the United States, limited availability is also a consideration. Plasmalyte is more costly than NS and is currently incompatible with the addition of dextrose.

Methods in Preparing Guideline

The guideline development committee included broad representation by pediatric experts in primary care, hospital medicine, emergency medicine, critical care medicine, nephrology, anesthesiology, surgery and quality improvement, as well as a guideline methodologist/informatician and epidemiologist.

Search strategies from recently published systematic reviews of clinical trials comparing isotonic with hypotonic maintenance IVFs were used to identify studies eligible for inclusion. A total of 17 studies with 2,455 total patients were initially identified and included. One additional study meeting inclusion criteria was found after the committee convened and excluded from the guideline.⁵ Three reviewers from the subcommittee performed a structured critical appraisal of each article. The methods of each trial were assessed for risk-of-bias in multiple domains, including randomization, allocation concealment, performance, detection, attrition and reporting. Forest plots were generated using random-effects models and Mantel-Haenzel statistics with the outcome of hyponatremia. The guideline underwent review by various stakeholders including AAP councils, committees, and sections, and individuals considered experts in the field.

A strength of the guideline is the high quality of the evidence and the consistent findings. All of the included studies were randomized clinical trials and the number of included patients was large. Of the 17 included studies, 16 reported a risk ratio favoring isotonic fluids over hypotonic fluids in the prevention of developing hyponatremia; the results of the study that favored hypotonic fluids were not statistically significant on their own. A sensitivity analysis was performed to exclude one study with a 20% weight, determined by multiple factors such as sample size, confidence interval, and an unusually high rate of hyponatremia in the isotonic and hypotonic fluids groups (33.3 % and 70%, respectively).⁶ After exclusion, there was no change in the overall estimated risk in hypotonic fluids leading to hyponatremia. Only one trial had two sources of high risk of bias (allocation concealment, attrition) and the remaining had only low or unclear risk of biases in the various domains.

The study that was excluded due to its late identification similarly shows increased risk of hyponatremia in groups administered hypotonic fluids (risk ratio 6.5-8.5), and would likely not affect the estimated risk.⁵

Despite differences in types of patients enrolled, rate of administered fluids, type of IVF, frequency of lab testing, and study duration, the I² (degree of heterogeneity) of the forest plot of all included studies remained low at 14% and the increased risk of hyponatremia from hypotonic fluids remained consistent.

Due to study design differences, a limitation of the guideline is that no recommendation is made regarding the type of isotonic fluids and the rate of IVF administration. Additionally, due to the low frequency of clinically significant sequelae of hyponatremia, such as hyponatremic encephalopathy, it remains uncertain how many patients would need to be treated with isotonic fluids to prevent a rare but potentially devastating event.

Sources of Potential Conflict of Interest or Bias

The guideline was developed and funded by the AAP. A formal conflict of interest management policy was followed, and subcommittee members had no conflicts of interests or financial relationships relevant to the guideline to disclose.

Generalizability

Given the large number of patients included in the studies and heterogeneity of the population included, the recommendation applies to most patients cared for by pediatric hospitalists. Several patient exclusions relevant to the pediatric hospitalist deserve mention: neonates, kidney disease, and voluminous diarrhea. Neonates under the age of 28 days, including febrile neonates, are excluded from the guideline because of the immature concentrating abilities of neonatal kidneys. Patients with renal impairment were excluded from the guideline recommendation because several studies excluded patients with kidney disease. Hospitalists often care for children who sustain prerenal acute kidney injury from severe dehydration. In this condition, the kidney conserves water through the release of AVP. While an excluded population, these patients would be even more susceptible to develop hyponatremia if administered hypotonic fluids. Patients with “voluminous diarrhea” are excluded from the guideline because those with gastroenteritis with ongoing losses may require IVFs at rates higher than maintenance, and are particularly vulnerable to electrolyte derangements. The guideline, however, does not define voluminous diarrhea, leaving it to the discretion of the treating clinician.

Finally, it is critical to mention that IVF should be considered a therapy to be judiciously used, and discontinued when possible. While the guideline addresses the choice of fluid composition, alternatives to orally or enterally hydrate a patient are always preferred.

While the guideline strongly recommends isotonic fluids for maintenance therapy, the choice of isotonic fluid remains with the clinician. Most included studies used NS for their isotonic groups, but Hartmann’s solution and Plasmalyte were represented in a few studies. LR, one of the more widely used balanced solutions, though slightly hypotonic (130 mEq/L), was not studied. The exclusion of LR from the included studies is unfortunate, as the benefit of balanced solutions compared to NS after significant fluid resuscitation has been shown in the setting of severe sepsis and shock.⁷ Hyperchloremic metabolic acidosis after fluid resuscitation with NS has raised concern about continuing NS as maintenance fluid and possibly worsening acidosis or hyperchloremia and its adverse effects.⁸ Further studies on the potential benefit of LR as maintenance fluid, or the potential harms of unbalanced solutions as maintenance fluids in the setting of significant resuscitation are needed.

Disclosures

The authors have nothing to disclose.

Hospitalized children with inadequate fluid intake are often administered maintenance intravenous fluids (IVFs) to support metabolic needs and sensible losses. Historically, hypotonic IVFs have been the standard, based on theoretical water and electrolyte requirements for estimated energy expenditure.¹ However, when combined with increased levels of arginine vasopressin (AVP) seen in acutely ill children which impairs free-water excretion,² hypotonic IVF can result in hyponatremia. The recently published guideline by the American Academy of Pediatrics (AAP)³ is the first to provide an evidence-based recommendation on the use of maintenance IVF therapy in children.

Patients between the ages of 28 days and 18 years should receive isotonic solutions with appropriate potassium chloride and dextrose for maintenance IVFs (evidence quality: high; recommendation strength: strong)

Isotonic fluids, such as 0.9% NaCl (normal saline), Hartmann solution and PlasmaLyte, contain a sodium concentration similar to that of plasma (135-144 mEq/L). Lactated Ringer solution (LR) is near-isotonic (sodium 130 mEq/L), but was not used in any of the reviewed studies and therefore not included in the recommendation. Excluded are patients with neurosurgical disorders, congenital or acquired cardiac disease, hepatic disease, cancer, renal dysfunction, diabetes insipidus, voluminous watery diarrhea, severe burns, or patients in the neonatal intensive care unit.

The primary benefit of the AAP recommendation is the reduced risk of iatrogenic hyponatremia and its associated sequelae, including complications or impact on cost of care. The number needed to treat with isotonic fluids was 7.5 to prevent any hyponatremia and 27.8 to prevent moderate hyponatremia (<130 mEq/L). Increases in readmission rates, length of stay, and cost of hospitalization have been reported in a recent meta-analysis reviewing the economic burden of hyponatremia in both adults and children.⁴

Potential harms from the use of isotonic fluids include hypernatremia, hyperchloremic metabolic acidosis, and fluid overload, although available data have not demonstrated an increased risk of these complications. In light of a recent normal saline (NS) shortage in the United States, limited availability is also a consideration. Plasmalyte is more costly than NS and is currently incompatible with the addition of dextrose.

Methods in Preparing Guideline

The guideline development committee included broad representation by pediatric experts in primary care, hospital medicine, emergency medicine, critical care medicine, nephrology, anesthesiology, surgery and quality improvement, as well as a guideline methodologist/informatician and epidemiologist.

Search strategies from recently published systematic reviews of clinical trials comparing isotonic with hypotonic maintenance IVFs were used to identify studies eligible for inclusion. A total of 17 studies with 2,455 total patients were initially identified and included. One additional study meeting inclusion criteria was found after the committee convened and excluded from the guideline.⁵ Three reviewers from the subcommittee performed a structured critical appraisal of each article. The methods of each trial were assessed for risk-of-bias in multiple domains, including randomization, allocation concealment, performance, detection, attrition and reporting. Forest plots were generated using random-effects models and Mantel-Haenzel statistics with the outcome of hyponatremia. The guideline underwent review by various stakeholders including AAP councils, committees, and sections, and individuals considered experts in the field.

A strength of the guideline is the high quality of the evidence and the consistent findings. All of the included studies were randomized clinical trials and the number of included patients was large. Of the 17 included studies, 16 reported a risk ratio favoring isotonic fluids over hypotonic fluids in the prevention of developing hyponatremia; the results of the study that favored hypotonic fluids were not statistically significant on their own. A sensitivity analysis was performed to exclude one study with a 20% weight, determined by multiple factors such as sample size, confidence interval, and an unusually high rate of hyponatremia in the isotonic and hypotonic fluids groups (33.3 % and 70%, respectively).⁶ After exclusion, there was no change in the overall estimated risk in hypotonic fluids leading to hyponatremia. Only one trial had two sources of high risk of bias (allocation concealment, attrition) and the remaining had only low or unclear risk of biases in the various domains.

The study that was excluded due to its late identification similarly shows increased risk of hyponatremia in groups administered hypotonic fluids (risk ratio 6.5-8.5), and would likely not affect the estimated risk.⁵

Despite differences in types of patients enrolled, rate of administered fluids, type of IVF, frequency of lab testing, and study duration, the I² (degree of heterogeneity) of the forest plot of all included studies remained low at 14% and the increased risk of hyponatremia from hypotonic fluids remained consistent.

Due to study design differences, a limitation of the guideline is that no recommendation is made regarding the type of isotonic fluids and the rate of IVF administration. Additionally, due to the low frequency of clinically significant sequelae of hyponatremia, such as hyponatremic encephalopathy, it remains uncertain how many patients would need to be treated with isotonic fluids to prevent a rare but potentially devastating event.

Sources of Potential Conflict of Interest or Bias

The guideline was developed and funded by the AAP. A formal conflict of interest management policy was followed, and subcommittee members had no conflicts of interests or financial relationships relevant to the guideline to disclose.

Generalizability

Given the large number of patients included in the studies and heterogeneity of the population included, the recommendation applies to most patients cared for by pediatric hospitalists. Several patient exclusions relevant to the pediatric hospitalist deserve mention: neonates, kidney disease, and voluminous diarrhea. Neonates under the age of 28 days, including febrile neonates, are excluded from the guideline because of the immature concentrating abilities of neonatal kidneys. Patients with renal impairment were excluded from the guideline recommendation because several studies excluded patients with kidney disease. Hospitalists often care for children who sustain prerenal acute kidney injury from severe dehydration. In this condition, the kidney conserves water through the release of AVP. While an excluded population, these patients would be even more susceptible to develop hyponatremia if administered hypotonic fluids. Patients with “voluminous diarrhea” are excluded from the guideline because those with gastroenteritis with ongoing losses may require IVFs at rates higher than maintenance, and are particularly vulnerable to electrolyte derangements. The guideline, however, does not define voluminous diarrhea, leaving it to the discretion of the treating clinician.

Finally, it is critical to mention that IVF should be considered a therapy to be judiciously used, and discontinued when possible. While the guideline addresses the choice of fluid composition, alternatives to orally or enterally hydrate a patient are always preferred.

While the guideline strongly recommends isotonic fluids for maintenance therapy, the choice of isotonic fluid remains with the clinician. Most included studies used NS for their isotonic groups, but Hartmann’s solution and Plasmalyte were represented in a few studies. LR, one of the more widely used balanced solutions, though slightly hypotonic (130 mEq/L), was not studied. The exclusion of LR from the included studies is unfortunate, as the benefit of balanced solutions compared to NS after significant fluid resuscitation has been shown in the setting of severe sepsis and shock.⁷ Hyperchloremic metabolic acidosis after fluid resuscitation with NS has raised concern about continuing NS as maintenance fluid and possibly worsening acidosis or hyperchloremia and its adverse effects.⁸ Further studies on the potential benefit of LR as maintenance fluid, or the potential harms of unbalanced solutions as maintenance fluids in the setting of significant resuscitation are needed.

Disclosures

The authors have nothing to disclose.