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For vertebral osteomyelitis, early switch to oral antibiotics is feasible
VIENNA – A 6-week course of antibiotics, with an early switch from intravenous to oral, appears to be a safe and appropriate option for some patients with pyogenic vertebral osteomyelitis.
A single-center retrospective study of 82 such patients found two treatment failures and two deaths over 1 year (4.8% failure rate). The patients who died were very elderly with serious comorbidities. The two treatment failures occurred in patients with methicillin-resistant coagulase-negative staphylococcal infections of a central catheter.
“Only two of the failures were due to inadequate antibiotic treatment,” Adrien Lemaignen, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. “Both patients experienced a relapse of bacteremia with the same bacteria a few days after antibiotic cessation in a context of conservative treatment of a catheter-related infection.”
Guidelines recently adopted by the Infectious Diseases Society of America inspired the study, said Dr. Lemaignen of University Hospital of Tours, France. The 2015 document calls for 6-8 weeks of antibiotics, depending upon the infective organism and whether infective endocarditis complicates management. All suggested antibiotic regimens call for initial IV therapy followed by oral, but there are no cut-and-dried recommendations about when to switch. The guideline notes one study in which patients switched to oral after about 2.7 weeks, with a 97% success rate.
Dr. Lemaignen and his colleagues set out to determine cure rates of early oral relay in 82 patients with pyogenic vertebral osteomyelitis (PVO). All patients were treated at a single center from 2011 to 2016. The team defined treatment failure as death, or persistence or relapse of infection in the first year after treatment.
All patients had culture-proven PVO that also was visible on imaging. Patients were excluded if they had any brucellar, fungal, or mycobacterial coinfections, or if they had infected spinal implants.
The mean age of the patients in the cohort was 66 years; 39% had some neuropathology. The mean C-reactive protein level was 115 mg/L. More than half of the cases (56%) involved the lumbar-sacral spine; 30% were thoracic, and the remainder, cervical. About one-fifth had multiple level involvement. There was epidural inflammation in 68%, epidural abscess in 13%, and extradural abscess in 26%.
Staphylococcus aureus was the most common pathogen (34%); two infections were methicillin resistant. Other infective organisms were streptococci (27%), Gram-negative bacilli (15%), and coagulase-negative staph (12%). A few patients had enterococci (5%) or polymicrobial infections (7%).
Infective endocarditis was present in 16 patients; this was associated with enterococcal and streptococcal infections.
Treatment varied by pathogen. Patients with S. aureus received penicillin or cefazolin with an oral relay to fluoroquinolone/rifampicin or clindamycin. Those with streptococci received amoxicillin with or without an aminoglycoside, followed by oral amoxicillin or clindamycin. Those with coagulase-negative streptococci received a glycopeptide with or without blasticidin, followed by fluoroquinolone/rifampicin. Patients with enterococcal infections got a third generation cephalosporin followed by an oral third generation cephalosporin or a fluoroquinolone.
All but six patients received 6 weeks of treatment.
The mean oral relay occurred on day 12, but 30 patients (36%) were able to switch before 7 days elapsed. Thirteen patients had to stay on the IV route for their entire treatment; 25% of this group had infective endocarditis. Six patients, all of whom had motor symptoms, also needed surgery.
The median follow-up was 358 days. During this time, there were two deaths and two treatment failures.
One death was a 93-year-old who had a controlled sepsis, but died at day 79 of a massive hematemesis. The other was an 80-year-old with an amoxicillin-resistant staph infection and decompensated cirrhosis who died at day 49.
There were also two treatment failures. Both of these patients had methicillin-resistant coagulase-negative staph infections of indwelling central catheters. One had a relapse 70 days after the end of IV therapy; the other relapsed on day 26 of treatment, after a 2-week course of oral antibiotics.
Not all patients were able to succeed with 6 weeks of therapy. Three needed prolonged treatment: One of these had an infected vascular prosthesis and two were immunocompromised patients who had cervical osteomyelitis with multiple abscesses.
In light of these results, Dr. Lemaignen said, “We can say confirm the safety of short IV treatment with an early oral relay in pyogenic vertebral osteomyelitis under real-life conditions, with 95% success rate and good functional outcomes at 6 months.”
He had no relevant financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
VIENNA – A 6-week course of antibiotics, with an early switch from intravenous to oral, appears to be a safe and appropriate option for some patients with pyogenic vertebral osteomyelitis.
A single-center retrospective study of 82 such patients found two treatment failures and two deaths over 1 year (4.8% failure rate). The patients who died were very elderly with serious comorbidities. The two treatment failures occurred in patients with methicillin-resistant coagulase-negative staphylococcal infections of a central catheter.
“Only two of the failures were due to inadequate antibiotic treatment,” Adrien Lemaignen, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. “Both patients experienced a relapse of bacteremia with the same bacteria a few days after antibiotic cessation in a context of conservative treatment of a catheter-related infection.”
Guidelines recently adopted by the Infectious Diseases Society of America inspired the study, said Dr. Lemaignen of University Hospital of Tours, France. The 2015 document calls for 6-8 weeks of antibiotics, depending upon the infective organism and whether infective endocarditis complicates management. All suggested antibiotic regimens call for initial IV therapy followed by oral, but there are no cut-and-dried recommendations about when to switch. The guideline notes one study in which patients switched to oral after about 2.7 weeks, with a 97% success rate.
Dr. Lemaignen and his colleagues set out to determine cure rates of early oral relay in 82 patients with pyogenic vertebral osteomyelitis (PVO). All patients were treated at a single center from 2011 to 2016. The team defined treatment failure as death, or persistence or relapse of infection in the first year after treatment.
All patients had culture-proven PVO that also was visible on imaging. Patients were excluded if they had any brucellar, fungal, or mycobacterial coinfections, or if they had infected spinal implants.
The mean age of the patients in the cohort was 66 years; 39% had some neuropathology. The mean C-reactive protein level was 115 mg/L. More than half of the cases (56%) involved the lumbar-sacral spine; 30% were thoracic, and the remainder, cervical. About one-fifth had multiple level involvement. There was epidural inflammation in 68%, epidural abscess in 13%, and extradural abscess in 26%.
Staphylococcus aureus was the most common pathogen (34%); two infections were methicillin resistant. Other infective organisms were streptococci (27%), Gram-negative bacilli (15%), and coagulase-negative staph (12%). A few patients had enterococci (5%) or polymicrobial infections (7%).
Infective endocarditis was present in 16 patients; this was associated with enterococcal and streptococcal infections.
Treatment varied by pathogen. Patients with S. aureus received penicillin or cefazolin with an oral relay to fluoroquinolone/rifampicin or clindamycin. Those with streptococci received amoxicillin with or without an aminoglycoside, followed by oral amoxicillin or clindamycin. Those with coagulase-negative streptococci received a glycopeptide with or without blasticidin, followed by fluoroquinolone/rifampicin. Patients with enterococcal infections got a third generation cephalosporin followed by an oral third generation cephalosporin or a fluoroquinolone.
All but six patients received 6 weeks of treatment.
The mean oral relay occurred on day 12, but 30 patients (36%) were able to switch before 7 days elapsed. Thirteen patients had to stay on the IV route for their entire treatment; 25% of this group had infective endocarditis. Six patients, all of whom had motor symptoms, also needed surgery.
The median follow-up was 358 days. During this time, there were two deaths and two treatment failures.
One death was a 93-year-old who had a controlled sepsis, but died at day 79 of a massive hematemesis. The other was an 80-year-old with an amoxicillin-resistant staph infection and decompensated cirrhosis who died at day 49.
There were also two treatment failures. Both of these patients had methicillin-resistant coagulase-negative staph infections of indwelling central catheters. One had a relapse 70 days after the end of IV therapy; the other relapsed on day 26 of treatment, after a 2-week course of oral antibiotics.
Not all patients were able to succeed with 6 weeks of therapy. Three needed prolonged treatment: One of these had an infected vascular prosthesis and two were immunocompromised patients who had cervical osteomyelitis with multiple abscesses.
In light of these results, Dr. Lemaignen said, “We can say confirm the safety of short IV treatment with an early oral relay in pyogenic vertebral osteomyelitis under real-life conditions, with 95% success rate and good functional outcomes at 6 months.”
He had no relevant financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
VIENNA – A 6-week course of antibiotics, with an early switch from intravenous to oral, appears to be a safe and appropriate option for some patients with pyogenic vertebral osteomyelitis.
A single-center retrospective study of 82 such patients found two treatment failures and two deaths over 1 year (4.8% failure rate). The patients who died were very elderly with serious comorbidities. The two treatment failures occurred in patients with methicillin-resistant coagulase-negative staphylococcal infections of a central catheter.
“Only two of the failures were due to inadequate antibiotic treatment,” Adrien Lemaignen, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. “Both patients experienced a relapse of bacteremia with the same bacteria a few days after antibiotic cessation in a context of conservative treatment of a catheter-related infection.”
Guidelines recently adopted by the Infectious Diseases Society of America inspired the study, said Dr. Lemaignen of University Hospital of Tours, France. The 2015 document calls for 6-8 weeks of antibiotics, depending upon the infective organism and whether infective endocarditis complicates management. All suggested antibiotic regimens call for initial IV therapy followed by oral, but there are no cut-and-dried recommendations about when to switch. The guideline notes one study in which patients switched to oral after about 2.7 weeks, with a 97% success rate.
Dr. Lemaignen and his colleagues set out to determine cure rates of early oral relay in 82 patients with pyogenic vertebral osteomyelitis (PVO). All patients were treated at a single center from 2011 to 2016. The team defined treatment failure as death, or persistence or relapse of infection in the first year after treatment.
All patients had culture-proven PVO that also was visible on imaging. Patients were excluded if they had any brucellar, fungal, or mycobacterial coinfections, or if they had infected spinal implants.
The mean age of the patients in the cohort was 66 years; 39% had some neuropathology. The mean C-reactive protein level was 115 mg/L. More than half of the cases (56%) involved the lumbar-sacral spine; 30% were thoracic, and the remainder, cervical. About one-fifth had multiple level involvement. There was epidural inflammation in 68%, epidural abscess in 13%, and extradural abscess in 26%.
Staphylococcus aureus was the most common pathogen (34%); two infections were methicillin resistant. Other infective organisms were streptococci (27%), Gram-negative bacilli (15%), and coagulase-negative staph (12%). A few patients had enterococci (5%) or polymicrobial infections (7%).
Infective endocarditis was present in 16 patients; this was associated with enterococcal and streptococcal infections.
Treatment varied by pathogen. Patients with S. aureus received penicillin or cefazolin with an oral relay to fluoroquinolone/rifampicin or clindamycin. Those with streptococci received amoxicillin with or without an aminoglycoside, followed by oral amoxicillin or clindamycin. Those with coagulase-negative streptococci received a glycopeptide with or without blasticidin, followed by fluoroquinolone/rifampicin. Patients with enterococcal infections got a third generation cephalosporin followed by an oral third generation cephalosporin or a fluoroquinolone.
All but six patients received 6 weeks of treatment.
The mean oral relay occurred on day 12, but 30 patients (36%) were able to switch before 7 days elapsed. Thirteen patients had to stay on the IV route for their entire treatment; 25% of this group had infective endocarditis. Six patients, all of whom had motor symptoms, also needed surgery.
The median follow-up was 358 days. During this time, there were two deaths and two treatment failures.
One death was a 93-year-old who had a controlled sepsis, but died at day 79 of a massive hematemesis. The other was an 80-year-old with an amoxicillin-resistant staph infection and decompensated cirrhosis who died at day 49.
There were also two treatment failures. Both of these patients had methicillin-resistant coagulase-negative staph infections of indwelling central catheters. One had a relapse 70 days after the end of IV therapy; the other relapsed on day 26 of treatment, after a 2-week course of oral antibiotics.
Not all patients were able to succeed with 6 weeks of therapy. Three needed prolonged treatment: One of these had an infected vascular prosthesis and two were immunocompromised patients who had cervical osteomyelitis with multiple abscesses.
In light of these results, Dr. Lemaignen said, “We can say confirm the safety of short IV treatment with an early oral relay in pyogenic vertebral osteomyelitis under real-life conditions, with 95% success rate and good functional outcomes at 6 months.”
He had no relevant financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
AT ECCMID 2017
Key clinical point:
Major finding: There were two treatment failures attributable to the antibiotic regimen, and two deaths that were not, for a total treatment success rate of 95%.
Data source: A retrospective cohort comprising 82 patients.
Disclosures: Dr. Lemaignen had no financial disclosures.
Ribaxamase prevented C. difficile infections by protecting microbiome
VIENNA – An investigational beta-lactamase reduced Clostridium difficile infections by 71% in patients receiving extended antibiotic therapy for respiratory infections but not by killing the opportunistic bacteria.
Rather, ribaxamase prevented C. difficile infections (CDI) by breaking down excess therapeutic antibiotics in the gut before they could injure an otherwise healthy microbiome, John Kokai-Kun, PhD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Ribaxamase is an oral enzyme that breaks the lactam ring in penicillins and cephalosporins. It’s formulated to release at a pH of 5.5 or higher, an environment that begins to develop in the upper small intestine near the bile duct – the same place that excess antibiotics are excreted.
“The drug is intended to be administered during, and for a short time after, intravenous administration of specific beta-lactam–containing antibiotics,” Dr. Kokai-Kun said. Ribaxamase doesn’t work on carbapenem-type antibiotics, he noted, and Synthetic Biologics is working on an effective enzyme for those as well.
In early human studies, ribaxamase was well tolerated and didn’t interfere with the pharmacokinetics of therapeutic antibiotics (Antimicrob Agents Chemother. 2017 Mar;61[3]:e02197-16). It’s also effective in patients who are taking a proton pump inhibitor, he said.
Dr. Kokai-Kun reported the results of a phase IIb study of 412 patients who received IV ceftriaxone for lower respiratory infections. They were assigned 1:1 to either 150 mg ribaxamase daily or placebo throughout the IV treatment and for 3 days after.
The primary endpoint was prevention of C. difficile infection. The secondary endpoint was prevention of non–C. difficile antibiotic-associated diarrhea. An exploratory endpoint examined the drug’s ability to protect the microbiome. Patients were monitored for 6 weeks after treatment stopped.
The cohort was a mean 70 years old. One-third of patients also received a macrolide during their hospitalization, and one-third were taking proton pump inhibitors. The respiratory infection cure rate was about 99% in both groups at both 72 hours and 4 weeks.
Eight patients in the placebo group (3.8%) and two in the active group (less than 1%) developed C. difficile infection. That translated to a statistically significant 71% risk reduction, with a P value of .027, Dr. Kokai-Kun said. Ribaxamase did not hit its secondary endpoint of preventing all-cause diarrhea or antibiotic-associated diarrhea that was not caused by C. difficile infection.
Although not a primary finding, ribaxamase also inhibited colonization by vancomycin-resistant enterococci, which occurred in about 70 (40%) patients in the placebo group and 40 (20%) in the ribaxamase group at both 72 hours and 4 weeks.
All patients contributed stool samples at baseline and after treatment for microbiome analysis. That portion of the study is still ongoing, Dr. Kokai-Kun said.
Synthetic Biologics sponsored the study and is developing ribaxamase. Dr. Kokai-Kun is the company’s vice president of nonclinical affairs.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – An investigational beta-lactamase reduced Clostridium difficile infections by 71% in patients receiving extended antibiotic therapy for respiratory infections but not by killing the opportunistic bacteria.
Rather, ribaxamase prevented C. difficile infections (CDI) by breaking down excess therapeutic antibiotics in the gut before they could injure an otherwise healthy microbiome, John Kokai-Kun, PhD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Ribaxamase is an oral enzyme that breaks the lactam ring in penicillins and cephalosporins. It’s formulated to release at a pH of 5.5 or higher, an environment that begins to develop in the upper small intestine near the bile duct – the same place that excess antibiotics are excreted.
“The drug is intended to be administered during, and for a short time after, intravenous administration of specific beta-lactam–containing antibiotics,” Dr. Kokai-Kun said. Ribaxamase doesn’t work on carbapenem-type antibiotics, he noted, and Synthetic Biologics is working on an effective enzyme for those as well.
In early human studies, ribaxamase was well tolerated and didn’t interfere with the pharmacokinetics of therapeutic antibiotics (Antimicrob Agents Chemother. 2017 Mar;61[3]:e02197-16). It’s also effective in patients who are taking a proton pump inhibitor, he said.
Dr. Kokai-Kun reported the results of a phase IIb study of 412 patients who received IV ceftriaxone for lower respiratory infections. They were assigned 1:1 to either 150 mg ribaxamase daily or placebo throughout the IV treatment and for 3 days after.
The primary endpoint was prevention of C. difficile infection. The secondary endpoint was prevention of non–C. difficile antibiotic-associated diarrhea. An exploratory endpoint examined the drug’s ability to protect the microbiome. Patients were monitored for 6 weeks after treatment stopped.
The cohort was a mean 70 years old. One-third of patients also received a macrolide during their hospitalization, and one-third were taking proton pump inhibitors. The respiratory infection cure rate was about 99% in both groups at both 72 hours and 4 weeks.
Eight patients in the placebo group (3.8%) and two in the active group (less than 1%) developed C. difficile infection. That translated to a statistically significant 71% risk reduction, with a P value of .027, Dr. Kokai-Kun said. Ribaxamase did not hit its secondary endpoint of preventing all-cause diarrhea or antibiotic-associated diarrhea that was not caused by C. difficile infection.
Although not a primary finding, ribaxamase also inhibited colonization by vancomycin-resistant enterococci, which occurred in about 70 (40%) patients in the placebo group and 40 (20%) in the ribaxamase group at both 72 hours and 4 weeks.
All patients contributed stool samples at baseline and after treatment for microbiome analysis. That portion of the study is still ongoing, Dr. Kokai-Kun said.
Synthetic Biologics sponsored the study and is developing ribaxamase. Dr. Kokai-Kun is the company’s vice president of nonclinical affairs.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – An investigational beta-lactamase reduced Clostridium difficile infections by 71% in patients receiving extended antibiotic therapy for respiratory infections but not by killing the opportunistic bacteria.
Rather, ribaxamase prevented C. difficile infections (CDI) by breaking down excess therapeutic antibiotics in the gut before they could injure an otherwise healthy microbiome, John Kokai-Kun, PhD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Ribaxamase is an oral enzyme that breaks the lactam ring in penicillins and cephalosporins. It’s formulated to release at a pH of 5.5 or higher, an environment that begins to develop in the upper small intestine near the bile duct – the same place that excess antibiotics are excreted.
“The drug is intended to be administered during, and for a short time after, intravenous administration of specific beta-lactam–containing antibiotics,” Dr. Kokai-Kun said. Ribaxamase doesn’t work on carbapenem-type antibiotics, he noted, and Synthetic Biologics is working on an effective enzyme for those as well.
In early human studies, ribaxamase was well tolerated and didn’t interfere with the pharmacokinetics of therapeutic antibiotics (Antimicrob Agents Chemother. 2017 Mar;61[3]:e02197-16). It’s also effective in patients who are taking a proton pump inhibitor, he said.
Dr. Kokai-Kun reported the results of a phase IIb study of 412 patients who received IV ceftriaxone for lower respiratory infections. They were assigned 1:1 to either 150 mg ribaxamase daily or placebo throughout the IV treatment and for 3 days after.
The primary endpoint was prevention of C. difficile infection. The secondary endpoint was prevention of non–C. difficile antibiotic-associated diarrhea. An exploratory endpoint examined the drug’s ability to protect the microbiome. Patients were monitored for 6 weeks after treatment stopped.
The cohort was a mean 70 years old. One-third of patients also received a macrolide during their hospitalization, and one-third were taking proton pump inhibitors. The respiratory infection cure rate was about 99% in both groups at both 72 hours and 4 weeks.
Eight patients in the placebo group (3.8%) and two in the active group (less than 1%) developed C. difficile infection. That translated to a statistically significant 71% risk reduction, with a P value of .027, Dr. Kokai-Kun said. Ribaxamase did not hit its secondary endpoint of preventing all-cause diarrhea or antibiotic-associated diarrhea that was not caused by C. difficile infection.
Although not a primary finding, ribaxamase also inhibited colonization by vancomycin-resistant enterococci, which occurred in about 70 (40%) patients in the placebo group and 40 (20%) in the ribaxamase group at both 72 hours and 4 weeks.
All patients contributed stool samples at baseline and after treatment for microbiome analysis. That portion of the study is still ongoing, Dr. Kokai-Kun said.
Synthetic Biologics sponsored the study and is developing ribaxamase. Dr. Kokai-Kun is the company’s vice president of nonclinical affairs.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT ECCMID 2017
Key clinical point:
Major finding: Ribaxamase reduced C. difficile infections by 71%, relative to a placebo.
Data source: The study randomized 412 patients to either placebo or ribaxamase in addition to their therapeutic antibiotics.
Disclosures: Synthetic Biologics sponsored the study and is developing ribaxamase. Dr. Kokai-Kun is the company’s vice president of nonclinical affairs.
Topical imiquimod boosted response to intradermal hepatitis B vaccine
VIENNA – Topical imiquimod appeared to enhance the immunogenicity of an intradermal hepatitis B vaccine in patients on renal replacement therapy.
Patients on hemodialysis or peritoneal dialysis who got the combination developed significantly higher seroprotection and antibody levels than those who got either the typical intramuscular vaccination or an intradermal vaccination on unprepared skin, Ivan Fan-Ngai Hung, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases. By 1 year, the protection and titers did begin to fall, but they still remained significantly higher than in the two comparator groups, said Dr. Hung, a clinical professor at the University of Hong Kong.
Dr. Hung and his colleagues have been investigating imiquimod’s immunogenicity-boosting potential for several years. Their initial murine work with an H1N1 influenza virus appeared in 2014 (Clin Vaccine Immunol. 2014 Apr;21[4]: 570-9). The investigators intraperitoneally immunized mice with a monovalent A(H1N1) vaccine combined with imiquimod (VIC) then intranasally inoculated them with a lethal dose of the virus. When compared with mice who received only vaccine, only imiquimod, or only placebo, the VIC group showed significantly greater and significantly longer survival. Virus-specific serum immunoglobulin M, IgG, and neutralizing antibodies were all significantly higher.
The investigators theorized that imiquimod, a Toll-like receptor 7 agonist, plays several key roles in boosting immune response, including inducing the differentiation and migration of dendritic cells, enhancing B cell differentiation, and increasing long-term B cell memory.
Within the past 2 years, the group has advanced to human influenza trials in healthy young adults and elders with comorbidities.
Both studies employed a 5% imiquimod cream delivering 250 mg of the drug. It was applied at the injection site 5 minutes before vaccination. In the elder study, 90% of the 91 subjects who got the combination achieved seroconversion, compared with 13% of those who got an intramuscular injection and 39% of those who got an intradermal injection plus placebo cream. The geometric mean titers went up faster and stayed elevated longer. The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (Clin Infect Dis. 2014;59[9]:1246-55).
The immunogenicity findings were similar in the study of 160 healthy young people. This study had a surprising twist too, Dr. Hung said in his talk. Not only did the combination significantly improve immunogenicity against the vaccine influenza strains, it increased immunogenicity against the nonvaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-2014 recommended vaccine (Lancet Inf Dis. 2016 Feb;16(2):209-18).
The study Dr. Hung presented in Vienna was an interim analysis of the first to apply this technique to a hepatitis B vaccine. It enrolled 69 patients (51 on peritoneal dialysis and 18 on hemodialysis). They were a mean 65 years old. All received 10 mcg of the Sci-B-Vac at baseline, 1 month, and 6 months. Vaccine was delivered in a trineedle unit designed for shallow intradermal penetration (MicronJet600; NanoPass Technologies) Group IQ received topical imiquimod along with the intradermal vaccine. Group ID received a placebo cream and the intradermal vaccine. Group IM received a placebo cream and an intramuscular vaccination.
Anti–hepatitis B titers were measured at baseline and at 1, 3, 6, and 12 months. The primary outcome was seroprotection at 1 month. The secondary outcomes were seroprotection at 3, 6, and 12 months; anti–hepatitis B antibody titer; and safety.
By 1 month, seroprotection was already significantly higher in the IQ group than in the ID and IM groups (60% vs. 50% and 38%, respectively).
By 3 months, the seroprotection rate in group IQ had risen to 85%. It remained elevated there at 6 months then tailed off to about 70% by 12 months. The ID and IM groups followed this same rising and falling curve but remained significantly lower at all time points. At 12 months, seroprotection was similar in both these groups – about 40%.
The anti–hepatitis B antibody titers told a similar story. Titers in the IQ group rose more rapidly and sharply, to 544 mIU/mL at 6 months and 566 mIU/mL at 12 months. The ID group also experienced a strong response, rising to 489 mIU/mL at 6 months. However, by 12 months, titer levels had dropped to 170 mIU/mL.
Titers in the IM group barely moved at all during the entire follow-up period, never rising above 21 mIU/mL.
There were no differences in systemic reactions among the three groups, but those who got the intradermal vaccines reported slightly more swelling and induration at the injection site.
“Since this is an interim analysis, we cannot determine long-term protection or antibody titers,” Dr. Hung cautioned. “However, we are starting a similar study in elderly patients and also one for those who are on low-dose immunosuppressants. We believe this regimen will also work for them.”
Dr. Hung has been on advisory boards for Pfizer and Gilead Sciences.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – Topical imiquimod appeared to enhance the immunogenicity of an intradermal hepatitis B vaccine in patients on renal replacement therapy.
Patients on hemodialysis or peritoneal dialysis who got the combination developed significantly higher seroprotection and antibody levels than those who got either the typical intramuscular vaccination or an intradermal vaccination on unprepared skin, Ivan Fan-Ngai Hung, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases. By 1 year, the protection and titers did begin to fall, but they still remained significantly higher than in the two comparator groups, said Dr. Hung, a clinical professor at the University of Hong Kong.
Dr. Hung and his colleagues have been investigating imiquimod’s immunogenicity-boosting potential for several years. Their initial murine work with an H1N1 influenza virus appeared in 2014 (Clin Vaccine Immunol. 2014 Apr;21[4]: 570-9). The investigators intraperitoneally immunized mice with a monovalent A(H1N1) vaccine combined with imiquimod (VIC) then intranasally inoculated them with a lethal dose of the virus. When compared with mice who received only vaccine, only imiquimod, or only placebo, the VIC group showed significantly greater and significantly longer survival. Virus-specific serum immunoglobulin M, IgG, and neutralizing antibodies were all significantly higher.
The investigators theorized that imiquimod, a Toll-like receptor 7 agonist, plays several key roles in boosting immune response, including inducing the differentiation and migration of dendritic cells, enhancing B cell differentiation, and increasing long-term B cell memory.
Within the past 2 years, the group has advanced to human influenza trials in healthy young adults and elders with comorbidities.
Both studies employed a 5% imiquimod cream delivering 250 mg of the drug. It was applied at the injection site 5 minutes before vaccination. In the elder study, 90% of the 91 subjects who got the combination achieved seroconversion, compared with 13% of those who got an intramuscular injection and 39% of those who got an intradermal injection plus placebo cream. The geometric mean titers went up faster and stayed elevated longer. The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (Clin Infect Dis. 2014;59[9]:1246-55).
The immunogenicity findings were similar in the study of 160 healthy young people. This study had a surprising twist too, Dr. Hung said in his talk. Not only did the combination significantly improve immunogenicity against the vaccine influenza strains, it increased immunogenicity against the nonvaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-2014 recommended vaccine (Lancet Inf Dis. 2016 Feb;16(2):209-18).
The study Dr. Hung presented in Vienna was an interim analysis of the first to apply this technique to a hepatitis B vaccine. It enrolled 69 patients (51 on peritoneal dialysis and 18 on hemodialysis). They were a mean 65 years old. All received 10 mcg of the Sci-B-Vac at baseline, 1 month, and 6 months. Vaccine was delivered in a trineedle unit designed for shallow intradermal penetration (MicronJet600; NanoPass Technologies) Group IQ received topical imiquimod along with the intradermal vaccine. Group ID received a placebo cream and the intradermal vaccine. Group IM received a placebo cream and an intramuscular vaccination.
Anti–hepatitis B titers were measured at baseline and at 1, 3, 6, and 12 months. The primary outcome was seroprotection at 1 month. The secondary outcomes were seroprotection at 3, 6, and 12 months; anti–hepatitis B antibody titer; and safety.
By 1 month, seroprotection was already significantly higher in the IQ group than in the ID and IM groups (60% vs. 50% and 38%, respectively).
By 3 months, the seroprotection rate in group IQ had risen to 85%. It remained elevated there at 6 months then tailed off to about 70% by 12 months. The ID and IM groups followed this same rising and falling curve but remained significantly lower at all time points. At 12 months, seroprotection was similar in both these groups – about 40%.
The anti–hepatitis B antibody titers told a similar story. Titers in the IQ group rose more rapidly and sharply, to 544 mIU/mL at 6 months and 566 mIU/mL at 12 months. The ID group also experienced a strong response, rising to 489 mIU/mL at 6 months. However, by 12 months, titer levels had dropped to 170 mIU/mL.
Titers in the IM group barely moved at all during the entire follow-up period, never rising above 21 mIU/mL.
There were no differences in systemic reactions among the three groups, but those who got the intradermal vaccines reported slightly more swelling and induration at the injection site.
“Since this is an interim analysis, we cannot determine long-term protection or antibody titers,” Dr. Hung cautioned. “However, we are starting a similar study in elderly patients and also one for those who are on low-dose immunosuppressants. We believe this regimen will also work for them.”
Dr. Hung has been on advisory boards for Pfizer and Gilead Sciences.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – Topical imiquimod appeared to enhance the immunogenicity of an intradermal hepatitis B vaccine in patients on renal replacement therapy.
Patients on hemodialysis or peritoneal dialysis who got the combination developed significantly higher seroprotection and antibody levels than those who got either the typical intramuscular vaccination or an intradermal vaccination on unprepared skin, Ivan Fan-Ngai Hung, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases. By 1 year, the protection and titers did begin to fall, but they still remained significantly higher than in the two comparator groups, said Dr. Hung, a clinical professor at the University of Hong Kong.
Dr. Hung and his colleagues have been investigating imiquimod’s immunogenicity-boosting potential for several years. Their initial murine work with an H1N1 influenza virus appeared in 2014 (Clin Vaccine Immunol. 2014 Apr;21[4]: 570-9). The investigators intraperitoneally immunized mice with a monovalent A(H1N1) vaccine combined with imiquimod (VIC) then intranasally inoculated them with a lethal dose of the virus. When compared with mice who received only vaccine, only imiquimod, or only placebo, the VIC group showed significantly greater and significantly longer survival. Virus-specific serum immunoglobulin M, IgG, and neutralizing antibodies were all significantly higher.
The investigators theorized that imiquimod, a Toll-like receptor 7 agonist, plays several key roles in boosting immune response, including inducing the differentiation and migration of dendritic cells, enhancing B cell differentiation, and increasing long-term B cell memory.
Within the past 2 years, the group has advanced to human influenza trials in healthy young adults and elders with comorbidities.
Both studies employed a 5% imiquimod cream delivering 250 mg of the drug. It was applied at the injection site 5 minutes before vaccination. In the elder study, 90% of the 91 subjects who got the combination achieved seroconversion, compared with 13% of those who got an intramuscular injection and 39% of those who got an intradermal injection plus placebo cream. The geometric mean titers went up faster and stayed elevated longer. The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (Clin Infect Dis. 2014;59[9]:1246-55).
The immunogenicity findings were similar in the study of 160 healthy young people. This study had a surprising twist too, Dr. Hung said in his talk. Not only did the combination significantly improve immunogenicity against the vaccine influenza strains, it increased immunogenicity against the nonvaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-2014 recommended vaccine (Lancet Inf Dis. 2016 Feb;16(2):209-18).
The study Dr. Hung presented in Vienna was an interim analysis of the first to apply this technique to a hepatitis B vaccine. It enrolled 69 patients (51 on peritoneal dialysis and 18 on hemodialysis). They were a mean 65 years old. All received 10 mcg of the Sci-B-Vac at baseline, 1 month, and 6 months. Vaccine was delivered in a trineedle unit designed for shallow intradermal penetration (MicronJet600; NanoPass Technologies) Group IQ received topical imiquimod along with the intradermal vaccine. Group ID received a placebo cream and the intradermal vaccine. Group IM received a placebo cream and an intramuscular vaccination.
Anti–hepatitis B titers were measured at baseline and at 1, 3, 6, and 12 months. The primary outcome was seroprotection at 1 month. The secondary outcomes were seroprotection at 3, 6, and 12 months; anti–hepatitis B antibody titer; and safety.
By 1 month, seroprotection was already significantly higher in the IQ group than in the ID and IM groups (60% vs. 50% and 38%, respectively).
By 3 months, the seroprotection rate in group IQ had risen to 85%. It remained elevated there at 6 months then tailed off to about 70% by 12 months. The ID and IM groups followed this same rising and falling curve but remained significantly lower at all time points. At 12 months, seroprotection was similar in both these groups – about 40%.
The anti–hepatitis B antibody titers told a similar story. Titers in the IQ group rose more rapidly and sharply, to 544 mIU/mL at 6 months and 566 mIU/mL at 12 months. The ID group also experienced a strong response, rising to 489 mIU/mL at 6 months. However, by 12 months, titer levels had dropped to 170 mIU/mL.
Titers in the IM group barely moved at all during the entire follow-up period, never rising above 21 mIU/mL.
There were no differences in systemic reactions among the three groups, but those who got the intradermal vaccines reported slightly more swelling and induration at the injection site.
“Since this is an interim analysis, we cannot determine long-term protection or antibody titers,” Dr. Hung cautioned. “However, we are starting a similar study in elderly patients and also one for those who are on low-dose immunosuppressants. We believe this regimen will also work for them.”
Dr. Hung has been on advisory boards for Pfizer and Gilead Sciences.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT ECCMID 2017
Key clinical point:
Major finding: By 1 month, seroprotection was significantly higher in the imiquimod group than in those who got an intradermal vaccination without imiquimod and those who had an intramuscular injection only (60% vs. 50% and 38%, respectively).
Data source: The four-armed randomized study comprised 69 patients on hemodialysis or peritoneal dialysis.
Disclosures: Dr. Hung has served on advisory boards for Pfizer and Gilead Sciences.
Dalbavancin proves highly effective in osteomyelitis
VIENNA – Two infusions of the long-acting lipoglycopeptide antibiotic dalbavancin showed a favorable clinical benefit for treatment of adult osteomyelitis in a phase II study.
Dalbavancin (Dalvance) showed positive results while avoiding the complexities of standard therapies that require longer, more frequent dosing, Urania Rappo, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Dalbavancin already is approved for acute bacterial skin and skin structure infections, and its long terminal half-life of 14 days and high bone penetration made it a natural candidate for evaluation in the treatment of osteomyelitis, said Dr. Rappo, director of clinical development (anti-infectives) at Allergan, which markets the drug and sponsored the study.
Dalbavancin is a glycopeptide antibiotic with a lipid tail that prolongs its half-life, compared with other drugs in this category, such as vancomycin and teicoplanin, to which it is structurally related. It is highly potent against gram-positive bacterial infections, including methicillin-resistant Staphylococcus aureus.
The drug’s MIC90 for S. aureus is 0.06 mcg/mL; vancomycin’s, in comparison, is 1 mcg/mL. A 2015 bone penetration study found that the bone level 12 hours after a 1,000-mg infusion was 6.3 mcg/g. This remained elevated for 14 days; the concentration at 2 weeks was 4 mcg/g (Antimicrob Agents Chemother. 2015 Apr;59[4]:1849-55).
“The mean bone-to-plasma penetration ratio was 13%, and drug levels in bone were very similar to free drug levels in serum, so we expect that much of this is free drug in the bone, available for antimicrobial activity,” Dr. Rappo noted. “It’s not only long lasting, but highly potent, meaning we need less drug to kill the infecting organism.”
Dalbavancin was administered as two 1,500-mg IV infusions, 1 week apart in Dr. Rappo’s randomized, open-label, phase II study – the first clinical trial to examine the drug’s effect in osteomyelitis in adults. The study is ongoing; she presented interim results on 68 patients, 59 of whom took dalbavancin. The nine patients in the standard-of-care arm were treated according to the investigator’s clinical judgment. Vancomycin was the most commonly employed therapy. Three patients received vancomycin infusions for 4 weeks. Four received a regimen of 4-16 days of intravenous vancomycin followed by intravenous linezolid or levofloxacin to complete a 4- to 6-week course of therapy. Adjunctive aztreonam was permitted for presumed coinfection with a gram-negative pathogen and a switch to oral antibiotic for gram-negative coverage was allowed after clinical improvement.
The primary endpoint was clinical cure at 42 days in the clinically evaluable population, defined as recovery without need for further antibiotic therapy. Failure was defined as the need for additional antibiotics; more than 6 weeks of treatment in the comparator arm; new purulence; amputation due to infection progression; or death. Indeterminate response was defined as loss to follow-up or amputation due to vascular insufficiency.
There were several secondary endpoints: clinical improvement at day 21, including changes in C-reactive protein level and clinical response in patients who had follow-up at days 42, 180, and 365.
In the dalbavancin arm, patients had a mean age of 51 years. All had undergone surgical debridement and bone culture. The most common site of infection was the foot or leg (about 83%). The baseline mean CRP level was 41.8 mg/L. About half of the patients had methicillin-susceptible S. aureus on bone culture. Coagulase-negative staphylococci were present in 20%. About 22% had gram-negative pathogens, mostly present in a mixed infection along with gram-positive pathogens. Five patients (three on dalbavancin, two on standard of care) discontinued the study drug early because they were solely infected with gram-negative pathogens.
At day 42, clinical cure was seen in all the dalbavancin patients and six of the standard treatment patients. In the group with treatment data out to 180 days (54 on dalbavancin and 5 on standard therapy), clinical cure rates were similar.
At 180 days, clinical cure continued in 93% of the dalbavancin patients (50 of 54). Two patients were defined as failures, and two patients were indeterminate because of loss to follow-up. In the standard therapy group at 180 days, four of five standard therapy patients maintained clinical cure; none of these patients has reached the 365-day outcome.
There were no treatment-emergent adverse events (TEAEs) in the standard therapy group. In the dalbavancin group, 10 patients experienced TEAEs, only one of whom had TEAEs related to the study drug, which were not serious, Dr. Rappo said.
This study was performed at a single center in the Ukraine, and an additional phase II study in the United States has begun, she added.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – Two infusions of the long-acting lipoglycopeptide antibiotic dalbavancin showed a favorable clinical benefit for treatment of adult osteomyelitis in a phase II study.
Dalbavancin (Dalvance) showed positive results while avoiding the complexities of standard therapies that require longer, more frequent dosing, Urania Rappo, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Dalbavancin already is approved for acute bacterial skin and skin structure infections, and its long terminal half-life of 14 days and high bone penetration made it a natural candidate for evaluation in the treatment of osteomyelitis, said Dr. Rappo, director of clinical development (anti-infectives) at Allergan, which markets the drug and sponsored the study.
Dalbavancin is a glycopeptide antibiotic with a lipid tail that prolongs its half-life, compared with other drugs in this category, such as vancomycin and teicoplanin, to which it is structurally related. It is highly potent against gram-positive bacterial infections, including methicillin-resistant Staphylococcus aureus.
The drug’s MIC90 for S. aureus is 0.06 mcg/mL; vancomycin’s, in comparison, is 1 mcg/mL. A 2015 bone penetration study found that the bone level 12 hours after a 1,000-mg infusion was 6.3 mcg/g. This remained elevated for 14 days; the concentration at 2 weeks was 4 mcg/g (Antimicrob Agents Chemother. 2015 Apr;59[4]:1849-55).
“The mean bone-to-plasma penetration ratio was 13%, and drug levels in bone were very similar to free drug levels in serum, so we expect that much of this is free drug in the bone, available for antimicrobial activity,” Dr. Rappo noted. “It’s not only long lasting, but highly potent, meaning we need less drug to kill the infecting organism.”
Dalbavancin was administered as two 1,500-mg IV infusions, 1 week apart in Dr. Rappo’s randomized, open-label, phase II study – the first clinical trial to examine the drug’s effect in osteomyelitis in adults. The study is ongoing; she presented interim results on 68 patients, 59 of whom took dalbavancin. The nine patients in the standard-of-care arm were treated according to the investigator’s clinical judgment. Vancomycin was the most commonly employed therapy. Three patients received vancomycin infusions for 4 weeks. Four received a regimen of 4-16 days of intravenous vancomycin followed by intravenous linezolid or levofloxacin to complete a 4- to 6-week course of therapy. Adjunctive aztreonam was permitted for presumed coinfection with a gram-negative pathogen and a switch to oral antibiotic for gram-negative coverage was allowed after clinical improvement.
The primary endpoint was clinical cure at 42 days in the clinically evaluable population, defined as recovery without need for further antibiotic therapy. Failure was defined as the need for additional antibiotics; more than 6 weeks of treatment in the comparator arm; new purulence; amputation due to infection progression; or death. Indeterminate response was defined as loss to follow-up or amputation due to vascular insufficiency.
There were several secondary endpoints: clinical improvement at day 21, including changes in C-reactive protein level and clinical response in patients who had follow-up at days 42, 180, and 365.
In the dalbavancin arm, patients had a mean age of 51 years. All had undergone surgical debridement and bone culture. The most common site of infection was the foot or leg (about 83%). The baseline mean CRP level was 41.8 mg/L. About half of the patients had methicillin-susceptible S. aureus on bone culture. Coagulase-negative staphylococci were present in 20%. About 22% had gram-negative pathogens, mostly present in a mixed infection along with gram-positive pathogens. Five patients (three on dalbavancin, two on standard of care) discontinued the study drug early because they were solely infected with gram-negative pathogens.
At day 42, clinical cure was seen in all the dalbavancin patients and six of the standard treatment patients. In the group with treatment data out to 180 days (54 on dalbavancin and 5 on standard therapy), clinical cure rates were similar.
At 180 days, clinical cure continued in 93% of the dalbavancin patients (50 of 54). Two patients were defined as failures, and two patients were indeterminate because of loss to follow-up. In the standard therapy group at 180 days, four of five standard therapy patients maintained clinical cure; none of these patients has reached the 365-day outcome.
There were no treatment-emergent adverse events (TEAEs) in the standard therapy group. In the dalbavancin group, 10 patients experienced TEAEs, only one of whom had TEAEs related to the study drug, which were not serious, Dr. Rappo said.
This study was performed at a single center in the Ukraine, and an additional phase II study in the United States has begun, she added.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – Two infusions of the long-acting lipoglycopeptide antibiotic dalbavancin showed a favorable clinical benefit for treatment of adult osteomyelitis in a phase II study.
Dalbavancin (Dalvance) showed positive results while avoiding the complexities of standard therapies that require longer, more frequent dosing, Urania Rappo, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Dalbavancin already is approved for acute bacterial skin and skin structure infections, and its long terminal half-life of 14 days and high bone penetration made it a natural candidate for evaluation in the treatment of osteomyelitis, said Dr. Rappo, director of clinical development (anti-infectives) at Allergan, which markets the drug and sponsored the study.
Dalbavancin is a glycopeptide antibiotic with a lipid tail that prolongs its half-life, compared with other drugs in this category, such as vancomycin and teicoplanin, to which it is structurally related. It is highly potent against gram-positive bacterial infections, including methicillin-resistant Staphylococcus aureus.
The drug’s MIC90 for S. aureus is 0.06 mcg/mL; vancomycin’s, in comparison, is 1 mcg/mL. A 2015 bone penetration study found that the bone level 12 hours after a 1,000-mg infusion was 6.3 mcg/g. This remained elevated for 14 days; the concentration at 2 weeks was 4 mcg/g (Antimicrob Agents Chemother. 2015 Apr;59[4]:1849-55).
“The mean bone-to-plasma penetration ratio was 13%, and drug levels in bone were very similar to free drug levels in serum, so we expect that much of this is free drug in the bone, available for antimicrobial activity,” Dr. Rappo noted. “It’s not only long lasting, but highly potent, meaning we need less drug to kill the infecting organism.”
Dalbavancin was administered as two 1,500-mg IV infusions, 1 week apart in Dr. Rappo’s randomized, open-label, phase II study – the first clinical trial to examine the drug’s effect in osteomyelitis in adults. The study is ongoing; she presented interim results on 68 patients, 59 of whom took dalbavancin. The nine patients in the standard-of-care arm were treated according to the investigator’s clinical judgment. Vancomycin was the most commonly employed therapy. Three patients received vancomycin infusions for 4 weeks. Four received a regimen of 4-16 days of intravenous vancomycin followed by intravenous linezolid or levofloxacin to complete a 4- to 6-week course of therapy. Adjunctive aztreonam was permitted for presumed coinfection with a gram-negative pathogen and a switch to oral antibiotic for gram-negative coverage was allowed after clinical improvement.
The primary endpoint was clinical cure at 42 days in the clinically evaluable population, defined as recovery without need for further antibiotic therapy. Failure was defined as the need for additional antibiotics; more than 6 weeks of treatment in the comparator arm; new purulence; amputation due to infection progression; or death. Indeterminate response was defined as loss to follow-up or amputation due to vascular insufficiency.
There were several secondary endpoints: clinical improvement at day 21, including changes in C-reactive protein level and clinical response in patients who had follow-up at days 42, 180, and 365.
In the dalbavancin arm, patients had a mean age of 51 years. All had undergone surgical debridement and bone culture. The most common site of infection was the foot or leg (about 83%). The baseline mean CRP level was 41.8 mg/L. About half of the patients had methicillin-susceptible S. aureus on bone culture. Coagulase-negative staphylococci were present in 20%. About 22% had gram-negative pathogens, mostly present in a mixed infection along with gram-positive pathogens. Five patients (three on dalbavancin, two on standard of care) discontinued the study drug early because they were solely infected with gram-negative pathogens.
At day 42, clinical cure was seen in all the dalbavancin patients and six of the standard treatment patients. In the group with treatment data out to 180 days (54 on dalbavancin and 5 on standard therapy), clinical cure rates were similar.
At 180 days, clinical cure continued in 93% of the dalbavancin patients (50 of 54). Two patients were defined as failures, and two patients were indeterminate because of loss to follow-up. In the standard therapy group at 180 days, four of five standard therapy patients maintained clinical cure; none of these patients has reached the 365-day outcome.
There were no treatment-emergent adverse events (TEAEs) in the standard therapy group. In the dalbavancin group, 10 patients experienced TEAEs, only one of whom had TEAEs related to the study drug, which were not serious, Dr. Rappo said.
This study was performed at a single center in the Ukraine, and an additional phase II study in the United States has begun, she added.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Key clinical point:
Major finding: At 42 days, 100% of patients taking the drug were clear of infection.
Data source: A phase II trial involving 68 patients, 59 of whom were randomized to the study drug; the remainder were on standard treatment.
Disclosures: Allergan sponsored the study; Dr. Rappo is a company employee.
Adjunctive rifampicin doesn’t improve any outcome in S. aureus bacteremia
VIENNA – When given in conjunction with an antibiotic, rifampicin didn’t improve treatment response or mortality in patients with Staphylococcus aureus bacteremia, either in an overall analysis or in any of 18 subgroups.
The only hints of benefit associated with the drug were decreases in treatment failure and recurrence, but the numbers needed to treat were excessive (29 and 26, respectively). They didn’t translate into any long-term survival benefit and couldn’t balance out other findings that rifampicin increased drug interactions and complicated treatment, Guy Thwaites, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases.
He presented the results of the randomized, placebo-controlled ARREST (Adjunctive Rifampicin to Reduce Early Mortality From Staphylococcus aureus bacteremia) study. ARREST was conducted at 29 sites in the United Kingdom. It enrolled 758 adults with proven S. aureus bacteremia who were already on standard antibiotic therapy and switched them to either adjunctive rifampicin or placebo for 2 weeks. Clinicians could choose rifampicin in either 600 mg or 900 mg, oral or IV formulations, once or twice daily doses.
Patients were followed with clinical assessments and blood cultures for 12 weeks and for overall mortality for 102 weeks. The primary endpoint was bacteriologically confirmed treatment failure or recurrence by week 12.
Patients were a mean of 65 years old. Most infections (64%) were community acquired, with the remainder associated with a stay in a health care facility, and 6% were methicillin resistant. Serious comorbidities were common, including cancer (17%), chronic lung disease (12%), kidney disease (18%), and diabetes (30%).
The largest portion of infections (40%) had a deep focus, including native cardiac valve or joint, prosthetic cardiac valve or implant, and deep tissue infections. Other sites of infection were indwelling lines, skin/soft tissue, surgical sites, pneumonia, and urinary tract. For 18%, no specific focus was ever established.
Rifampicin was initiated a mean of 68 hours after main antibiotic therapy. Most patients (86%) received it orally, in the 900-mg dose (78%). The mean rifampicin treatment duration was 13 days.
Treatment failure rates through week 12 were practically identical for rifampicin and placebo (17.5% vs. 18.9%) in the overall analysis. Clinical failure or recurrence through week 12 was also similar for rifampicin and placebo (21.4% vs. 22.9%). Dr. Thwaites didn’t present all 18 subgroup analyses but said the results were similar no matter how patients were divided.
There was no significant difference in 12-week mortality for rifampicin vs. placebo (15.7% vs. 14.8%). There were 112 deaths, 56 in each group. Of these, 28 were directly related to the S. aureus infection. There was no difference in long-term survival measured at 102 weeks.
When an independent endpoint review committee examined some of the composite endpoints separately, it determined that rifampicin did confer a significant advantage in both bacterial and clinical recurrence. However, 29 patients needed to be treated to avoid a bacteriologic recurrence and 26 to avoid a clinical recurrence. Two cases of rifampicin resistance developed.
One-quarter of the group experienced serious adverse events. Dr. Thwaites didn’t review these but said they were evenly distributed between the groups. He also said that rifampicin was associated with an increase in drug-drug interactions, some of which required changing the backbone antibiotic.
There was a small, but nonsignificant, increase in acute kidney injury in the rifampicin group.
The study was funded by the National Institute of Health Research in the United Kingdom. Dr. Thwaites had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – When given in conjunction with an antibiotic, rifampicin didn’t improve treatment response or mortality in patients with Staphylococcus aureus bacteremia, either in an overall analysis or in any of 18 subgroups.
The only hints of benefit associated with the drug were decreases in treatment failure and recurrence, but the numbers needed to treat were excessive (29 and 26, respectively). They didn’t translate into any long-term survival benefit and couldn’t balance out other findings that rifampicin increased drug interactions and complicated treatment, Guy Thwaites, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases.
He presented the results of the randomized, placebo-controlled ARREST (Adjunctive Rifampicin to Reduce Early Mortality From Staphylococcus aureus bacteremia) study. ARREST was conducted at 29 sites in the United Kingdom. It enrolled 758 adults with proven S. aureus bacteremia who were already on standard antibiotic therapy and switched them to either adjunctive rifampicin or placebo for 2 weeks. Clinicians could choose rifampicin in either 600 mg or 900 mg, oral or IV formulations, once or twice daily doses.
Patients were followed with clinical assessments and blood cultures for 12 weeks and for overall mortality for 102 weeks. The primary endpoint was bacteriologically confirmed treatment failure or recurrence by week 12.
Patients were a mean of 65 years old. Most infections (64%) were community acquired, with the remainder associated with a stay in a health care facility, and 6% were methicillin resistant. Serious comorbidities were common, including cancer (17%), chronic lung disease (12%), kidney disease (18%), and diabetes (30%).
The largest portion of infections (40%) had a deep focus, including native cardiac valve or joint, prosthetic cardiac valve or implant, and deep tissue infections. Other sites of infection were indwelling lines, skin/soft tissue, surgical sites, pneumonia, and urinary tract. For 18%, no specific focus was ever established.
Rifampicin was initiated a mean of 68 hours after main antibiotic therapy. Most patients (86%) received it orally, in the 900-mg dose (78%). The mean rifampicin treatment duration was 13 days.
Treatment failure rates through week 12 were practically identical for rifampicin and placebo (17.5% vs. 18.9%) in the overall analysis. Clinical failure or recurrence through week 12 was also similar for rifampicin and placebo (21.4% vs. 22.9%). Dr. Thwaites didn’t present all 18 subgroup analyses but said the results were similar no matter how patients were divided.
There was no significant difference in 12-week mortality for rifampicin vs. placebo (15.7% vs. 14.8%). There were 112 deaths, 56 in each group. Of these, 28 were directly related to the S. aureus infection. There was no difference in long-term survival measured at 102 weeks.
When an independent endpoint review committee examined some of the composite endpoints separately, it determined that rifampicin did confer a significant advantage in both bacterial and clinical recurrence. However, 29 patients needed to be treated to avoid a bacteriologic recurrence and 26 to avoid a clinical recurrence. Two cases of rifampicin resistance developed.
One-quarter of the group experienced serious adverse events. Dr. Thwaites didn’t review these but said they were evenly distributed between the groups. He also said that rifampicin was associated with an increase in drug-drug interactions, some of which required changing the backbone antibiotic.
There was a small, but nonsignificant, increase in acute kidney injury in the rifampicin group.
The study was funded by the National Institute of Health Research in the United Kingdom. Dr. Thwaites had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – When given in conjunction with an antibiotic, rifampicin didn’t improve treatment response or mortality in patients with Staphylococcus aureus bacteremia, either in an overall analysis or in any of 18 subgroups.
The only hints of benefit associated with the drug were decreases in treatment failure and recurrence, but the numbers needed to treat were excessive (29 and 26, respectively). They didn’t translate into any long-term survival benefit and couldn’t balance out other findings that rifampicin increased drug interactions and complicated treatment, Guy Thwaites, MD, said at the European Conference on Clinical Microbiology and Infectious Diseases.
He presented the results of the randomized, placebo-controlled ARREST (Adjunctive Rifampicin to Reduce Early Mortality From Staphylococcus aureus bacteremia) study. ARREST was conducted at 29 sites in the United Kingdom. It enrolled 758 adults with proven S. aureus bacteremia who were already on standard antibiotic therapy and switched them to either adjunctive rifampicin or placebo for 2 weeks. Clinicians could choose rifampicin in either 600 mg or 900 mg, oral or IV formulations, once or twice daily doses.
Patients were followed with clinical assessments and blood cultures for 12 weeks and for overall mortality for 102 weeks. The primary endpoint was bacteriologically confirmed treatment failure or recurrence by week 12.
Patients were a mean of 65 years old. Most infections (64%) were community acquired, with the remainder associated with a stay in a health care facility, and 6% were methicillin resistant. Serious comorbidities were common, including cancer (17%), chronic lung disease (12%), kidney disease (18%), and diabetes (30%).
The largest portion of infections (40%) had a deep focus, including native cardiac valve or joint, prosthetic cardiac valve or implant, and deep tissue infections. Other sites of infection were indwelling lines, skin/soft tissue, surgical sites, pneumonia, and urinary tract. For 18%, no specific focus was ever established.
Rifampicin was initiated a mean of 68 hours after main antibiotic therapy. Most patients (86%) received it orally, in the 900-mg dose (78%). The mean rifampicin treatment duration was 13 days.
Treatment failure rates through week 12 were practically identical for rifampicin and placebo (17.5% vs. 18.9%) in the overall analysis. Clinical failure or recurrence through week 12 was also similar for rifampicin and placebo (21.4% vs. 22.9%). Dr. Thwaites didn’t present all 18 subgroup analyses but said the results were similar no matter how patients were divided.
There was no significant difference in 12-week mortality for rifampicin vs. placebo (15.7% vs. 14.8%). There were 112 deaths, 56 in each group. Of these, 28 were directly related to the S. aureus infection. There was no difference in long-term survival measured at 102 weeks.
When an independent endpoint review committee examined some of the composite endpoints separately, it determined that rifampicin did confer a significant advantage in both bacterial and clinical recurrence. However, 29 patients needed to be treated to avoid a bacteriologic recurrence and 26 to avoid a clinical recurrence. Two cases of rifampicin resistance developed.
One-quarter of the group experienced serious adverse events. Dr. Thwaites didn’t review these but said they were evenly distributed between the groups. He also said that rifampicin was associated with an increase in drug-drug interactions, some of which required changing the backbone antibiotic.
There was a small, but nonsignificant, increase in acute kidney injury in the rifampicin group.
The study was funded by the National Institute of Health Research in the United Kingdom. Dr. Thwaites had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Key clinical point:
Major finding: Treatment failure was nearly identical with rifampicin and placebo (17.5% vs. 18.9%).
Data source: A placebo-controlled trial enrolling 758 adults.
Disclosures: The study was funded by the National Institute of Health Research in the United Kingdom. Dr. Thwaites had no financial disclosures.
For bone and joint infections, oral antibiotics match IV, cost less
VIENNA – Oral antibiotic therapy is just as effective as intravenous treatment in curing bone and joint infections, but costs about $3,500 less.
Treating these infections with oral agents also “improves patient autonomy, as it’s not necessary to have IV lines at home,” and represents a generally wiser use of powerful antibiotics, Matthew Scarborough, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
OVIVA (Oral vs. Intravenous Antibiotics for Bone and Joint Infection) was conducted at 26 sites in the United Kingdom. It randomized 1,054 adults with bone or joint infections to 6 weeks of either oral or intravenous treatment.
An important aspect of the trial was that both oral and IV treatment choices were made before randomization, Dr. Scarborough said. However, the decisions on what drug to use were left up to the treating physician and depended on the infection site and pathogen.
The primary outcome was definite treatment failure (bacteriologic, histologic, and clinical). Patients were followed for 1 year.
Patients were a median of 60 years old. All had surgical treatment before antibiotic therapy, including debridement and, in those with implants, removal of infected devices. The lower limb was involved in 81%, including hip, knee, and foot. The infection was in an upper limb in 10% and in the spine in 7%.
Staphylococcus aureus was present in 38% of cases, coagulase-negative staphylococci in 27%, and streptococci in 15%. Gram-negative bacteria were found in 22%.
For those patients randomized to IV therapy, glycopeptides and cephalosporins were most commonly employed (41% and 33%, respectively). For oral therapy, quinolones and penicillins were most common (37% and 16%). Most patients (74%) continued antibiotic treatment for more than 6 weeks. Forty patients were lost to follow-up.
In the primary intent-to-treat analysis, the failure rate was 13% for oral therapy and 14% for IV therapy, not a significant difference. Results were similar in the other analyses, including a modified intent to treat with only patients who had complete 1-year data, and a per-protocol analysis. All of the point prevalence numbers favored oral therapy, but crossed the null. Curves in the time-to-treatment-failure analysis were virtually superimposable, as were curves in time to discontinuation of therapy.
Another subgroup analysis examined treatment failure by infective organism; again, there were no significant treatment differences in any of the pathogen subgroups examined (S. aureus, coagulase-negative staph, streptococci species, and other gram-negative bacteria).
Nor did the type of antibiotic significantly affect failure rate, Dr. Scarborough noted. The median length of stay was 14 days for patients on IV treatment and 11 days for those taking oral medications. The incidence of serious adverse events was very similar – about 86% in each group.
On a visual analog scale that assessed health-related quality of life, patients taking oral treatment reported better mobility, self-care, and activity level, and less pain, discomfort, anxiety, and depression than those taking IV medications.
Cost represented the other significant difference between the groups. Over 1 year, the mean IV treatment cost was the equivalent of $17,152, and the mean oral treatment cost was $13,611 – a significant difference of $3,541.
“This represents a potential savings to the National Health Service of 16-25 million pounds sterling ($20.6 million-$32.3 million) per year,” Dr. Scarborough said. “All coming at no expense of good clinical outcomes.”
OVIVA was sponsored by the U.K. National Institute of Health Research. Dr. Scarborough had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – Oral antibiotic therapy is just as effective as intravenous treatment in curing bone and joint infections, but costs about $3,500 less.
Treating these infections with oral agents also “improves patient autonomy, as it’s not necessary to have IV lines at home,” and represents a generally wiser use of powerful antibiotics, Matthew Scarborough, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
OVIVA (Oral vs. Intravenous Antibiotics for Bone and Joint Infection) was conducted at 26 sites in the United Kingdom. It randomized 1,054 adults with bone or joint infections to 6 weeks of either oral or intravenous treatment.
An important aspect of the trial was that both oral and IV treatment choices were made before randomization, Dr. Scarborough said. However, the decisions on what drug to use were left up to the treating physician and depended on the infection site and pathogen.
The primary outcome was definite treatment failure (bacteriologic, histologic, and clinical). Patients were followed for 1 year.
Patients were a median of 60 years old. All had surgical treatment before antibiotic therapy, including debridement and, in those with implants, removal of infected devices. The lower limb was involved in 81%, including hip, knee, and foot. The infection was in an upper limb in 10% and in the spine in 7%.
Staphylococcus aureus was present in 38% of cases, coagulase-negative staphylococci in 27%, and streptococci in 15%. Gram-negative bacteria were found in 22%.
For those patients randomized to IV therapy, glycopeptides and cephalosporins were most commonly employed (41% and 33%, respectively). For oral therapy, quinolones and penicillins were most common (37% and 16%). Most patients (74%) continued antibiotic treatment for more than 6 weeks. Forty patients were lost to follow-up.
In the primary intent-to-treat analysis, the failure rate was 13% for oral therapy and 14% for IV therapy, not a significant difference. Results were similar in the other analyses, including a modified intent to treat with only patients who had complete 1-year data, and a per-protocol analysis. All of the point prevalence numbers favored oral therapy, but crossed the null. Curves in the time-to-treatment-failure analysis were virtually superimposable, as were curves in time to discontinuation of therapy.
Another subgroup analysis examined treatment failure by infective organism; again, there were no significant treatment differences in any of the pathogen subgroups examined (S. aureus, coagulase-negative staph, streptococci species, and other gram-negative bacteria).
Nor did the type of antibiotic significantly affect failure rate, Dr. Scarborough noted. The median length of stay was 14 days for patients on IV treatment and 11 days for those taking oral medications. The incidence of serious adverse events was very similar – about 86% in each group.
On a visual analog scale that assessed health-related quality of life, patients taking oral treatment reported better mobility, self-care, and activity level, and less pain, discomfort, anxiety, and depression than those taking IV medications.
Cost represented the other significant difference between the groups. Over 1 year, the mean IV treatment cost was the equivalent of $17,152, and the mean oral treatment cost was $13,611 – a significant difference of $3,541.
“This represents a potential savings to the National Health Service of 16-25 million pounds sterling ($20.6 million-$32.3 million) per year,” Dr. Scarborough said. “All coming at no expense of good clinical outcomes.”
OVIVA was sponsored by the U.K. National Institute of Health Research. Dr. Scarborough had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
VIENNA – Oral antibiotic therapy is just as effective as intravenous treatment in curing bone and joint infections, but costs about $3,500 less.
Treating these infections with oral agents also “improves patient autonomy, as it’s not necessary to have IV lines at home,” and represents a generally wiser use of powerful antibiotics, Matthew Scarborough, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
OVIVA (Oral vs. Intravenous Antibiotics for Bone and Joint Infection) was conducted at 26 sites in the United Kingdom. It randomized 1,054 adults with bone or joint infections to 6 weeks of either oral or intravenous treatment.
An important aspect of the trial was that both oral and IV treatment choices were made before randomization, Dr. Scarborough said. However, the decisions on what drug to use were left up to the treating physician and depended on the infection site and pathogen.
The primary outcome was definite treatment failure (bacteriologic, histologic, and clinical). Patients were followed for 1 year.
Patients were a median of 60 years old. All had surgical treatment before antibiotic therapy, including debridement and, in those with implants, removal of infected devices. The lower limb was involved in 81%, including hip, knee, and foot. The infection was in an upper limb in 10% and in the spine in 7%.
Staphylococcus aureus was present in 38% of cases, coagulase-negative staphylococci in 27%, and streptococci in 15%. Gram-negative bacteria were found in 22%.
For those patients randomized to IV therapy, glycopeptides and cephalosporins were most commonly employed (41% and 33%, respectively). For oral therapy, quinolones and penicillins were most common (37% and 16%). Most patients (74%) continued antibiotic treatment for more than 6 weeks. Forty patients were lost to follow-up.
In the primary intent-to-treat analysis, the failure rate was 13% for oral therapy and 14% for IV therapy, not a significant difference. Results were similar in the other analyses, including a modified intent to treat with only patients who had complete 1-year data, and a per-protocol analysis. All of the point prevalence numbers favored oral therapy, but crossed the null. Curves in the time-to-treatment-failure analysis were virtually superimposable, as were curves in time to discontinuation of therapy.
Another subgroup analysis examined treatment failure by infective organism; again, there were no significant treatment differences in any of the pathogen subgroups examined (S. aureus, coagulase-negative staph, streptococci species, and other gram-negative bacteria).
Nor did the type of antibiotic significantly affect failure rate, Dr. Scarborough noted. The median length of stay was 14 days for patients on IV treatment and 11 days for those taking oral medications. The incidence of serious adverse events was very similar – about 86% in each group.
On a visual analog scale that assessed health-related quality of life, patients taking oral treatment reported better mobility, self-care, and activity level, and less pain, discomfort, anxiety, and depression than those taking IV medications.
Cost represented the other significant difference between the groups. Over 1 year, the mean IV treatment cost was the equivalent of $17,152, and the mean oral treatment cost was $13,611 – a significant difference of $3,541.
“This represents a potential savings to the National Health Service of 16-25 million pounds sterling ($20.6 million-$32.3 million) per year,” Dr. Scarborough said. “All coming at no expense of good clinical outcomes.”
OVIVA was sponsored by the U.K. National Institute of Health Research. Dr. Scarborough had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT ECCMID 2017
Key clinical point:
Major finding: At 1 year, cure rates were identical, but oral treatment cost about $3,500 less than IV treatment.
Data source: The study randomized 1,054 patients.
Disclosures: OVIVA was sponsored by the U.K. National Institute of Health Research. Dr. Scarborough had no financial disclosures.
WHO’s malaria pilot vaccine: No silver bullet, but a potential strike at malaria’s heart
EXPERT ANALYSIS FROM ECCMID 2017
VIENNA – The first malaria vaccine to enter a national pilot project is not a silver bullet against the disease that kills half a million every year, but it still might be powerful enough to significantly reduce global disease burden, and even impact transmission, according to infectious disease specialist Nick Beeching, MD.
The vaccine, RTS,S (Mosquirix; GlaxoSmithKline), will be tested in three African countries beginning next year, the World Health Organization announced on April 25. The pilot programs will target 720,000 children aged 5-17 months in high-risk areas of the three countries.
Even though it’s the first malaria vaccine to pass its pivotal phase III trial, RTS,S isn’t terribly effective by any standards, said Dr. Beeching of the Royal Liverpool (England) University.
April 25, 2017, is World Malaria Day, and Anthony S. Fauci, MD, and B. Fenton Hall, MD, PhD, of the U.S. National Institute of Allergy and Infectious Diseases, said in a statement, “Safe and effective vaccines are critical tools for future efforts to control, eliminate, and, ultimately, eradicate malaria. NIAID is supporting the development of numerous malaria vaccine candidates, 10 of which are in clinical trials. In 2015, an estimated 212 million new malaria cases and 429,000 deaths occurred. Nearly 90% of these cases were among children under the age of 5 years in Africa, where malaria claims the life of a child every 2 minutes.”
GSK has been working on this vaccine since 1985, according to the company’s RTS,S literature. It is a recombinant protein that targets the circumsporozoite protein of the Plasmodium falciparum parasite at an early stage, before it enters the liver and begins to embed in erythrocytes. The aim, Dr. Beeching said, was to develop an antigen that would mobilize the immune system from the moment a mosquito injected the sporozoites through a bite, “well before they have a chance to hide in the liver.”
The 2- and 3-year follow-up results of the phase III trial, conducted in 15,500 children, were published in the Lancet in 2015. RTS,S was administered as a three-dose series, plus a booster dose, beginning at 5 months of age. The primary immunizations were given with a minimum 4-week interval between doses, with the booster administered 18 months after the last dose.
The primary series reduced clinical cases by 26%. With the booster dose, cases were reduced by 39% overall. The vaccine averted 1,774 episodes of clinical malaria per 1,000 vaccinated children, and 983 cases per 1,000 vaccinated infants. But vaccine efficacy waned over time, disappearing completely in children who got only the three-dose series. The booster dose improved response stability somewhat; during the 12 months after the fourth dose, vaccine efficacy was about 25%.
Based on these results, GSK received approval from the European Medicines Agency in 2015, and the WHO recommended a large-scale implementation of the vaccine be carried out last year. GSK will provide the vaccine at no cost, and each country’s government will decide which regions to include in the pilot study.
This real-world use will put RTS,S to the ultimate test, Dr. Beeching said: “There is always the practical problem of how do you get four doses of vaccine into people. It’s easy to do in a clinical trial, but the operations and the logistics of getting it right on the ground are what really matter. We don’t know how good less than four doses would be, and we still don’t know how long the protective effect of the full series plus booster will last. I think there’s concern that it might wane with time.”
Still, he said, even a 39% reduction in disease burden is worth aggressively pursuing, not only because of the thousands of children’s lives that could be saved, but because unvaccinated children and adults could potentially be protected as well: “We could see a knock-on effect. By reducing the burden of malaria in children, it may also reduce transmission to other people who haven’t been vaccinated.”
The vaccine certainly won’t eradicate malaria, Dr. Beeching said. It needs to be viewed as an addition to WHO’s core vector control strategy, which includes insecticide-impregnated bed nets and mosquito eradication programs.
Cost is an unresolved issue. According to the Malaria Vaccine Initiative, which is partnering with GSK to launch RTS,S, the company won’t charge for the vaccine in the pilot project, and is committed to making sure the children who need it get it.
“In many African countries, childhood vaccines are provided at no cost to children or their families, thanks to existing international and national financing mechanisms,” the company said in a press release. “The RTS,S partnership anticipates that similar mechanisms would be implemented for a malaria vaccine. A shared goal is to have the cost of a malaria vaccine not be a barrier to access.
“GSK has previously stated that the price of RTS,S will cover the cost of manufacturing the vaccine together with a small return of around 5%, which will be reinvested in research and development for next-generation malaria vaccines or vaccines against other neglected tropical diseases.”
Finally, Dr. Beeching said, there’s no way to know to know how long any malaria vaccine would retain its effectiveness.
“Making a malaria vaccine has been a dream for years, and a tough one. The antigens change according to the stage of the parasite, and there is always continuous genetic variation. So there is a possibility of escape from vaccine coverage. These are very clever parasites,” he said.
Dr. Beeching has no financial interest in the vaccine.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
EXPERT ANALYSIS FROM ECCMID 2017
VIENNA – The first malaria vaccine to enter a national pilot project is not a silver bullet against the disease that kills half a million every year, but it still might be powerful enough to significantly reduce global disease burden, and even impact transmission, according to infectious disease specialist Nick Beeching, MD.
The vaccine, RTS,S (Mosquirix; GlaxoSmithKline), will be tested in three African countries beginning next year, the World Health Organization announced on April 25. The pilot programs will target 720,000 children aged 5-17 months in high-risk areas of the three countries.
Even though it’s the first malaria vaccine to pass its pivotal phase III trial, RTS,S isn’t terribly effective by any standards, said Dr. Beeching of the Royal Liverpool (England) University.
April 25, 2017, is World Malaria Day, and Anthony S. Fauci, MD, and B. Fenton Hall, MD, PhD, of the U.S. National Institute of Allergy and Infectious Diseases, said in a statement, “Safe and effective vaccines are critical tools for future efforts to control, eliminate, and, ultimately, eradicate malaria. NIAID is supporting the development of numerous malaria vaccine candidates, 10 of which are in clinical trials. In 2015, an estimated 212 million new malaria cases and 429,000 deaths occurred. Nearly 90% of these cases were among children under the age of 5 years in Africa, where malaria claims the life of a child every 2 minutes.”
GSK has been working on this vaccine since 1985, according to the company’s RTS,S literature. It is a recombinant protein that targets the circumsporozoite protein of the Plasmodium falciparum parasite at an early stage, before it enters the liver and begins to embed in erythrocytes. The aim, Dr. Beeching said, was to develop an antigen that would mobilize the immune system from the moment a mosquito injected the sporozoites through a bite, “well before they have a chance to hide in the liver.”
The 2- and 3-year follow-up results of the phase III trial, conducted in 15,500 children, were published in the Lancet in 2015. RTS,S was administered as a three-dose series, plus a booster dose, beginning at 5 months of age. The primary immunizations were given with a minimum 4-week interval between doses, with the booster administered 18 months after the last dose.
The primary series reduced clinical cases by 26%. With the booster dose, cases were reduced by 39% overall. The vaccine averted 1,774 episodes of clinical malaria per 1,000 vaccinated children, and 983 cases per 1,000 vaccinated infants. But vaccine efficacy waned over time, disappearing completely in children who got only the three-dose series. The booster dose improved response stability somewhat; during the 12 months after the fourth dose, vaccine efficacy was about 25%.
Based on these results, GSK received approval from the European Medicines Agency in 2015, and the WHO recommended a large-scale implementation of the vaccine be carried out last year. GSK will provide the vaccine at no cost, and each country’s government will decide which regions to include in the pilot study.
This real-world use will put RTS,S to the ultimate test, Dr. Beeching said: “There is always the practical problem of how do you get four doses of vaccine into people. It’s easy to do in a clinical trial, but the operations and the logistics of getting it right on the ground are what really matter. We don’t know how good less than four doses would be, and we still don’t know how long the protective effect of the full series plus booster will last. I think there’s concern that it might wane with time.”
Still, he said, even a 39% reduction in disease burden is worth aggressively pursuing, not only because of the thousands of children’s lives that could be saved, but because unvaccinated children and adults could potentially be protected as well: “We could see a knock-on effect. By reducing the burden of malaria in children, it may also reduce transmission to other people who haven’t been vaccinated.”
The vaccine certainly won’t eradicate malaria, Dr. Beeching said. It needs to be viewed as an addition to WHO’s core vector control strategy, which includes insecticide-impregnated bed nets and mosquito eradication programs.
Cost is an unresolved issue. According to the Malaria Vaccine Initiative, which is partnering with GSK to launch RTS,S, the company won’t charge for the vaccine in the pilot project, and is committed to making sure the children who need it get it.
“In many African countries, childhood vaccines are provided at no cost to children or their families, thanks to existing international and national financing mechanisms,” the company said in a press release. “The RTS,S partnership anticipates that similar mechanisms would be implemented for a malaria vaccine. A shared goal is to have the cost of a malaria vaccine not be a barrier to access.
“GSK has previously stated that the price of RTS,S will cover the cost of manufacturing the vaccine together with a small return of around 5%, which will be reinvested in research and development for next-generation malaria vaccines or vaccines against other neglected tropical diseases.”
Finally, Dr. Beeching said, there’s no way to know to know how long any malaria vaccine would retain its effectiveness.
“Making a malaria vaccine has been a dream for years, and a tough one. The antigens change according to the stage of the parasite, and there is always continuous genetic variation. So there is a possibility of escape from vaccine coverage. These are very clever parasites,” he said.
Dr. Beeching has no financial interest in the vaccine.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
EXPERT ANALYSIS FROM ECCMID 2017
VIENNA – The first malaria vaccine to enter a national pilot project is not a silver bullet against the disease that kills half a million every year, but it still might be powerful enough to significantly reduce global disease burden, and even impact transmission, according to infectious disease specialist Nick Beeching, MD.
The vaccine, RTS,S (Mosquirix; GlaxoSmithKline), will be tested in three African countries beginning next year, the World Health Organization announced on April 25. The pilot programs will target 720,000 children aged 5-17 months in high-risk areas of the three countries.
Even though it’s the first malaria vaccine to pass its pivotal phase III trial, RTS,S isn’t terribly effective by any standards, said Dr. Beeching of the Royal Liverpool (England) University.
April 25, 2017, is World Malaria Day, and Anthony S. Fauci, MD, and B. Fenton Hall, MD, PhD, of the U.S. National Institute of Allergy and Infectious Diseases, said in a statement, “Safe and effective vaccines are critical tools for future efforts to control, eliminate, and, ultimately, eradicate malaria. NIAID is supporting the development of numerous malaria vaccine candidates, 10 of which are in clinical trials. In 2015, an estimated 212 million new malaria cases and 429,000 deaths occurred. Nearly 90% of these cases were among children under the age of 5 years in Africa, where malaria claims the life of a child every 2 minutes.”
GSK has been working on this vaccine since 1985, according to the company’s RTS,S literature. It is a recombinant protein that targets the circumsporozoite protein of the Plasmodium falciparum parasite at an early stage, before it enters the liver and begins to embed in erythrocytes. The aim, Dr. Beeching said, was to develop an antigen that would mobilize the immune system from the moment a mosquito injected the sporozoites through a bite, “well before they have a chance to hide in the liver.”
The 2- and 3-year follow-up results of the phase III trial, conducted in 15,500 children, were published in the Lancet in 2015. RTS,S was administered as a three-dose series, plus a booster dose, beginning at 5 months of age. The primary immunizations were given with a minimum 4-week interval between doses, with the booster administered 18 months after the last dose.
The primary series reduced clinical cases by 26%. With the booster dose, cases were reduced by 39% overall. The vaccine averted 1,774 episodes of clinical malaria per 1,000 vaccinated children, and 983 cases per 1,000 vaccinated infants. But vaccine efficacy waned over time, disappearing completely in children who got only the three-dose series. The booster dose improved response stability somewhat; during the 12 months after the fourth dose, vaccine efficacy was about 25%.
Based on these results, GSK received approval from the European Medicines Agency in 2015, and the WHO recommended a large-scale implementation of the vaccine be carried out last year. GSK will provide the vaccine at no cost, and each country’s government will decide which regions to include in the pilot study.
This real-world use will put RTS,S to the ultimate test, Dr. Beeching said: “There is always the practical problem of how do you get four doses of vaccine into people. It’s easy to do in a clinical trial, but the operations and the logistics of getting it right on the ground are what really matter. We don’t know how good less than four doses would be, and we still don’t know how long the protective effect of the full series plus booster will last. I think there’s concern that it might wane with time.”
Still, he said, even a 39% reduction in disease burden is worth aggressively pursuing, not only because of the thousands of children’s lives that could be saved, but because unvaccinated children and adults could potentially be protected as well: “We could see a knock-on effect. By reducing the burden of malaria in children, it may also reduce transmission to other people who haven’t been vaccinated.”
The vaccine certainly won’t eradicate malaria, Dr. Beeching said. It needs to be viewed as an addition to WHO’s core vector control strategy, which includes insecticide-impregnated bed nets and mosquito eradication programs.
Cost is an unresolved issue. According to the Malaria Vaccine Initiative, which is partnering with GSK to launch RTS,S, the company won’t charge for the vaccine in the pilot project, and is committed to making sure the children who need it get it.
“In many African countries, childhood vaccines are provided at no cost to children or their families, thanks to existing international and national financing mechanisms,” the company said in a press release. “The RTS,S partnership anticipates that similar mechanisms would be implemented for a malaria vaccine. A shared goal is to have the cost of a malaria vaccine not be a barrier to access.
“GSK has previously stated that the price of RTS,S will cover the cost of manufacturing the vaccine together with a small return of around 5%, which will be reinvested in research and development for next-generation malaria vaccines or vaccines against other neglected tropical diseases.”
Finally, Dr. Beeching said, there’s no way to know to know how long any malaria vaccine would retain its effectiveness.
“Making a malaria vaccine has been a dream for years, and a tough one. The antigens change according to the stage of the parasite, and there is always continuous genetic variation. So there is a possibility of escape from vaccine coverage. These are very clever parasites,” he said.
Dr. Beeching has no financial interest in the vaccine.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
After the epidemic, Ebola’s destructive power still haunts survivors
VIENNA – The Ebola crisis may be over in Sierra Leone, but the suffering is not.
The last patient from the epidemic was discharged in February 2016, but 78% of survivors now appear to have one or more sequelae of the infection. Some problems are mild, but some are so debilitating that life may never be the same.
Janet Scott, MD, of the University of Liverpool (England), heads a task force studying Ebola’s lingering aftereffects. These fall into four categories, Dr. Scott said at the European Society of Clinical Microbiology and Infectious Diseases annual congress: musculoskeletal pain, headache, eye problems, and psychological disorders.
They add up to an enormous risk of disability – survivors are more than 200 times more likely than controls to express at least moderate disability.
Dr. Scott and her team of researchers are partnering with clinicians and data managers in the Ebola treatment unit in the 34th Regimental Military Hospital (MH34) in Freetown, Sierra Leone. In Sierra Leone alone, she said, there were nearly 9,000 cases and 3,500 deaths from the virus; about 5,000 patients survived. So far, Dr. Scott and her team have collected data on about 500 patients for whom they also provide free health care.
The project has six arms, each headed by an expert: clinical care, data collection, disability, neurology, ophthalmology, and psychiatry.
The team sees patients in a large tent sectioned by a plywood wall*. Wireless Internet access, which she said is “enormously expensive” in Sierra Leone, has been donated by Omline Business Communications*. It’s the team’s lifeline, allowing them to transmit data between Freetown and participating units around the world. Members also Skype regularly, talking with patients and with each other.
All patients who come into the clinic have an initial visit that includes collection of demographics, their Ebola and clinical history (including an exploration of comorbidities), a maternal health screening for women, vital signs and symptom assessment, medication dispensing, and a treatment plan.
Then they visit the specialists, either onsite or through local referral*. These specialist modules include joints, eyes, headache, ears, neurology, cardiac, respiratory, gastrointestinal, renal and urologic, reproductive health for both genders, and psychiatry.
Last year, Dr. Scott published initial data on 44 patients. At ECCMID 2017, she expanded that report to include 203 survivors. They spanned all ages, but about 67% were in their most productive adult years, aged 20-39 years.
Her findings are striking: About 78% report musculoskeletal pain, with many saying they have trouble walking even short distances, climbing stairs, or picking up their children.
Headache was the next most common problem, reported by nearly 40%. About 15% report ocular problems, which include anterior uveitis, cataracts – even in very young children – and retinal lesions. Abdominal and chest pain affect about 10% of the survivors.
Although she didn’t present specific numbers, Dr. Scott also said that many of the survivors experience psychological sequelae, including insomnia, anxiety, and depression. Whether this is related to viral pathology isn’t clear; it could be a not-unexpected response to the trauma of living through the epidemic.
“Many of these people have lost their entire family, and those that are left now shun them,” she said in a live video interview on Facebook. “It’s almost like a post-traumatic stress reaction.”
The other symptoms probably are related to the disease pathology, she observed. “Unfortunately, we don’t have all the clinical details of the acute phase for everyone, but for those for whom we do have details, we are seeing correlation between some of the problems with viral loads at admission, and even episodes of becoming unconscious during the acute illness.”
Patrick Howlett, MD, of the King’s Sierra Leone Partnership, Freetown, leads the neurology study. So far, the researchers have collected data on 19 patients with severe neurological consequences. Of those, 12 (63%) experienced a period of unconsciousness during their acute Ebola episode. In a comparator group of 21 with nonsevere neurologic sequelae, 33% had experienced unconsciousness.
Headache was present in nine (47%) of the patients. Migraine was the most common diagnosis. “We don’t have money for migraine medications, but fortunately, most of our migraine patients seem to be doing well on beta blockers,” Dr. Scott said.
CT scans were performed on 17 patients: three showed cerebral or cerebellar atrophy and two had confirmed stroke.
The brain injuries were severe in two, including a 42-year-old with extensive gliosis in the left middle cerebral artery region and a dilated left ventricle secondary to loss of volume in that hemisphere. A 12-year-old girl showed extensive parietal and temporal lobe atrophy. She is now so disabled that her family can’t care for her at home.
Other neurological problems include peripheral neuropathy, brachial plexus neuropathy, and asymmetric lower limb muscular atrophy.
Paul Steptoe, MD, an ophthalmic registrar from St. Paul’s Eye Unit at the Royal Liverpool Hospital, heads the eye study. He has observed dense cataracts, even in children, and anterior uveitis that has blinded some patients. There is concern about live virus persisting in vitreal fluid, but two eye taps have been negative, Dr. Scott said.
The most exciting recent finding, however, was made possible by the donation of a digital retinal camera, which “enabled us to get dozens of amazing images,” Dr. Scott said. With it, Dr. Steptoe conducted a case-control study of 81 Ebola survivors and 106 community controls. The findings of this study are potentially very, very important, Dr. Scott said.
“The first thing we found out is that retinal scarring is pervasive in our control patients,” she said. “There is just a lot of it out here in the community. But more interesting is that Dr. Steptoe seems to have identified a characteristic retinal lesion seen only in our survivors. It could be evidence of neurotropic aspects of the Ebola virus.”
The lesions occurred in 12 (15%) of the survivors and none of the controls. They are of a striking and consistent shape: straight-edged and sharply angulated. The lesions are only on the surface of the retina and do not penetrate into deeper levels. Nor do they interfere with vision. Dr. Steptoe has proposed that they take their angular shape from the retina’s underlying structures. His paper documenting this finding has been accepted and will be published shortly in the journal Emerging Infectious Diseases.
All of the post-Ebola sequelae add up to general disability for survivors, Dr. Scott said. Soushieta Jagadesh, of the* Liverpool School of Tropical Medicine, is conducting a disability survey. The comparison between 27 survivors and 54 community controls employed the Washington Group extended disability questionnaire. “We noted major limitations 1 year after discharge in mobility, vision, cognition, and affect,” Dr. Scott said.
The hazard ratios for these issues are enormous: Overall, compared with controls, survivors were 23 times more likely to have some level of disability. They were 94 times more likely to have walking limitations and 65 times more likely to have problems with stairs. Survivors were over 200 times more likely to have moderate disability than were their unaffected neighbors.
If funding for the project is renewed – and Dr. Scott admitted this is an “if,” not a “when” – caring for and studying these survivors will continue. Just in this one city, she said, the need is huge.
According to data from the U.S. Centers for Disease Control and Prevention, more than 17,000 patients in Sierra Leone, Liberia, and Guinea survived the 2014 Ebola outbreak.
If the assessments of Freetown survivors hold true across this population, thousands of survivors face life-limiting sequelae of the disease.
“We still have patients walk in every day with musculoskeletal pain, headaches, and ocular issues,” Dr. Scott said. “At the beginning of the epidemic, we were just focusing on containing it and reducing transmission. Now, we are faced with the long-term consequences.”
The Wellcome Trust supported the study. The authors have been awarded a grant from the Enhancing Research Activity in Epidemic Situations (ERAES) program, funded by the Wellcome Trust to support further research into the sequelae of Ebola virus disease.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
*This story was updated May 2, 2017.
VIENNA – The Ebola crisis may be over in Sierra Leone, but the suffering is not.
The last patient from the epidemic was discharged in February 2016, but 78% of survivors now appear to have one or more sequelae of the infection. Some problems are mild, but some are so debilitating that life may never be the same.
Janet Scott, MD, of the University of Liverpool (England), heads a task force studying Ebola’s lingering aftereffects. These fall into four categories, Dr. Scott said at the European Society of Clinical Microbiology and Infectious Diseases annual congress: musculoskeletal pain, headache, eye problems, and psychological disorders.
They add up to an enormous risk of disability – survivors are more than 200 times more likely than controls to express at least moderate disability.
Dr. Scott and her team of researchers are partnering with clinicians and data managers in the Ebola treatment unit in the 34th Regimental Military Hospital (MH34) in Freetown, Sierra Leone. In Sierra Leone alone, she said, there were nearly 9,000 cases and 3,500 deaths from the virus; about 5,000 patients survived. So far, Dr. Scott and her team have collected data on about 500 patients for whom they also provide free health care.
The project has six arms, each headed by an expert: clinical care, data collection, disability, neurology, ophthalmology, and psychiatry.
The team sees patients in a large tent sectioned by a plywood wall*. Wireless Internet access, which she said is “enormously expensive” in Sierra Leone, has been donated by Omline Business Communications*. It’s the team’s lifeline, allowing them to transmit data between Freetown and participating units around the world. Members also Skype regularly, talking with patients and with each other.
All patients who come into the clinic have an initial visit that includes collection of demographics, their Ebola and clinical history (including an exploration of comorbidities), a maternal health screening for women, vital signs and symptom assessment, medication dispensing, and a treatment plan.
Then they visit the specialists, either onsite or through local referral*. These specialist modules include joints, eyes, headache, ears, neurology, cardiac, respiratory, gastrointestinal, renal and urologic, reproductive health for both genders, and psychiatry.
Last year, Dr. Scott published initial data on 44 patients. At ECCMID 2017, she expanded that report to include 203 survivors. They spanned all ages, but about 67% were in their most productive adult years, aged 20-39 years.
Her findings are striking: About 78% report musculoskeletal pain, with many saying they have trouble walking even short distances, climbing stairs, or picking up their children.
Headache was the next most common problem, reported by nearly 40%. About 15% report ocular problems, which include anterior uveitis, cataracts – even in very young children – and retinal lesions. Abdominal and chest pain affect about 10% of the survivors.
Although she didn’t present specific numbers, Dr. Scott also said that many of the survivors experience psychological sequelae, including insomnia, anxiety, and depression. Whether this is related to viral pathology isn’t clear; it could be a not-unexpected response to the trauma of living through the epidemic.
“Many of these people have lost their entire family, and those that are left now shun them,” she said in a live video interview on Facebook. “It’s almost like a post-traumatic stress reaction.”
The other symptoms probably are related to the disease pathology, she observed. “Unfortunately, we don’t have all the clinical details of the acute phase for everyone, but for those for whom we do have details, we are seeing correlation between some of the problems with viral loads at admission, and even episodes of becoming unconscious during the acute illness.”
Patrick Howlett, MD, of the King’s Sierra Leone Partnership, Freetown, leads the neurology study. So far, the researchers have collected data on 19 patients with severe neurological consequences. Of those, 12 (63%) experienced a period of unconsciousness during their acute Ebola episode. In a comparator group of 21 with nonsevere neurologic sequelae, 33% had experienced unconsciousness.
Headache was present in nine (47%) of the patients. Migraine was the most common diagnosis. “We don’t have money for migraine medications, but fortunately, most of our migraine patients seem to be doing well on beta blockers,” Dr. Scott said.
CT scans were performed on 17 patients: three showed cerebral or cerebellar atrophy and two had confirmed stroke.
The brain injuries were severe in two, including a 42-year-old with extensive gliosis in the left middle cerebral artery region and a dilated left ventricle secondary to loss of volume in that hemisphere. A 12-year-old girl showed extensive parietal and temporal lobe atrophy. She is now so disabled that her family can’t care for her at home.
Other neurological problems include peripheral neuropathy, brachial plexus neuropathy, and asymmetric lower limb muscular atrophy.
Paul Steptoe, MD, an ophthalmic registrar from St. Paul’s Eye Unit at the Royal Liverpool Hospital, heads the eye study. He has observed dense cataracts, even in children, and anterior uveitis that has blinded some patients. There is concern about live virus persisting in vitreal fluid, but two eye taps have been negative, Dr. Scott said.
The most exciting recent finding, however, was made possible by the donation of a digital retinal camera, which “enabled us to get dozens of amazing images,” Dr. Scott said. With it, Dr. Steptoe conducted a case-control study of 81 Ebola survivors and 106 community controls. The findings of this study are potentially very, very important, Dr. Scott said.
“The first thing we found out is that retinal scarring is pervasive in our control patients,” she said. “There is just a lot of it out here in the community. But more interesting is that Dr. Steptoe seems to have identified a characteristic retinal lesion seen only in our survivors. It could be evidence of neurotropic aspects of the Ebola virus.”
The lesions occurred in 12 (15%) of the survivors and none of the controls. They are of a striking and consistent shape: straight-edged and sharply angulated. The lesions are only on the surface of the retina and do not penetrate into deeper levels. Nor do they interfere with vision. Dr. Steptoe has proposed that they take their angular shape from the retina’s underlying structures. His paper documenting this finding has been accepted and will be published shortly in the journal Emerging Infectious Diseases.
All of the post-Ebola sequelae add up to general disability for survivors, Dr. Scott said. Soushieta Jagadesh, of the* Liverpool School of Tropical Medicine, is conducting a disability survey. The comparison between 27 survivors and 54 community controls employed the Washington Group extended disability questionnaire. “We noted major limitations 1 year after discharge in mobility, vision, cognition, and affect,” Dr. Scott said.
The hazard ratios for these issues are enormous: Overall, compared with controls, survivors were 23 times more likely to have some level of disability. They were 94 times more likely to have walking limitations and 65 times more likely to have problems with stairs. Survivors were over 200 times more likely to have moderate disability than were their unaffected neighbors.
If funding for the project is renewed – and Dr. Scott admitted this is an “if,” not a “when” – caring for and studying these survivors will continue. Just in this one city, she said, the need is huge.
According to data from the U.S. Centers for Disease Control and Prevention, more than 17,000 patients in Sierra Leone, Liberia, and Guinea survived the 2014 Ebola outbreak.
If the assessments of Freetown survivors hold true across this population, thousands of survivors face life-limiting sequelae of the disease.
“We still have patients walk in every day with musculoskeletal pain, headaches, and ocular issues,” Dr. Scott said. “At the beginning of the epidemic, we were just focusing on containing it and reducing transmission. Now, we are faced with the long-term consequences.”
The Wellcome Trust supported the study. The authors have been awarded a grant from the Enhancing Research Activity in Epidemic Situations (ERAES) program, funded by the Wellcome Trust to support further research into the sequelae of Ebola virus disease.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
*This story was updated May 2, 2017.
VIENNA – The Ebola crisis may be over in Sierra Leone, but the suffering is not.
The last patient from the epidemic was discharged in February 2016, but 78% of survivors now appear to have one or more sequelae of the infection. Some problems are mild, but some are so debilitating that life may never be the same.
Janet Scott, MD, of the University of Liverpool (England), heads a task force studying Ebola’s lingering aftereffects. These fall into four categories, Dr. Scott said at the European Society of Clinical Microbiology and Infectious Diseases annual congress: musculoskeletal pain, headache, eye problems, and psychological disorders.
They add up to an enormous risk of disability – survivors are more than 200 times more likely than controls to express at least moderate disability.
Dr. Scott and her team of researchers are partnering with clinicians and data managers in the Ebola treatment unit in the 34th Regimental Military Hospital (MH34) in Freetown, Sierra Leone. In Sierra Leone alone, she said, there were nearly 9,000 cases and 3,500 deaths from the virus; about 5,000 patients survived. So far, Dr. Scott and her team have collected data on about 500 patients for whom they also provide free health care.
The project has six arms, each headed by an expert: clinical care, data collection, disability, neurology, ophthalmology, and psychiatry.
The team sees patients in a large tent sectioned by a plywood wall*. Wireless Internet access, which she said is “enormously expensive” in Sierra Leone, has been donated by Omline Business Communications*. It’s the team’s lifeline, allowing them to transmit data between Freetown and participating units around the world. Members also Skype regularly, talking with patients and with each other.
All patients who come into the clinic have an initial visit that includes collection of demographics, their Ebola and clinical history (including an exploration of comorbidities), a maternal health screening for women, vital signs and symptom assessment, medication dispensing, and a treatment plan.
Then they visit the specialists, either onsite or through local referral*. These specialist modules include joints, eyes, headache, ears, neurology, cardiac, respiratory, gastrointestinal, renal and urologic, reproductive health for both genders, and psychiatry.
Last year, Dr. Scott published initial data on 44 patients. At ECCMID 2017, she expanded that report to include 203 survivors. They spanned all ages, but about 67% were in their most productive adult years, aged 20-39 years.
Her findings are striking: About 78% report musculoskeletal pain, with many saying they have trouble walking even short distances, climbing stairs, or picking up their children.
Headache was the next most common problem, reported by nearly 40%. About 15% report ocular problems, which include anterior uveitis, cataracts – even in very young children – and retinal lesions. Abdominal and chest pain affect about 10% of the survivors.
Although she didn’t present specific numbers, Dr. Scott also said that many of the survivors experience psychological sequelae, including insomnia, anxiety, and depression. Whether this is related to viral pathology isn’t clear; it could be a not-unexpected response to the trauma of living through the epidemic.
“Many of these people have lost their entire family, and those that are left now shun them,” she said in a live video interview on Facebook. “It’s almost like a post-traumatic stress reaction.”
The other symptoms probably are related to the disease pathology, she observed. “Unfortunately, we don’t have all the clinical details of the acute phase for everyone, but for those for whom we do have details, we are seeing correlation between some of the problems with viral loads at admission, and even episodes of becoming unconscious during the acute illness.”
Patrick Howlett, MD, of the King’s Sierra Leone Partnership, Freetown, leads the neurology study. So far, the researchers have collected data on 19 patients with severe neurological consequences. Of those, 12 (63%) experienced a period of unconsciousness during their acute Ebola episode. In a comparator group of 21 with nonsevere neurologic sequelae, 33% had experienced unconsciousness.
Headache was present in nine (47%) of the patients. Migraine was the most common diagnosis. “We don’t have money for migraine medications, but fortunately, most of our migraine patients seem to be doing well on beta blockers,” Dr. Scott said.
CT scans were performed on 17 patients: three showed cerebral or cerebellar atrophy and two had confirmed stroke.
The brain injuries were severe in two, including a 42-year-old with extensive gliosis in the left middle cerebral artery region and a dilated left ventricle secondary to loss of volume in that hemisphere. A 12-year-old girl showed extensive parietal and temporal lobe atrophy. She is now so disabled that her family can’t care for her at home.
Other neurological problems include peripheral neuropathy, brachial plexus neuropathy, and asymmetric lower limb muscular atrophy.
Paul Steptoe, MD, an ophthalmic registrar from St. Paul’s Eye Unit at the Royal Liverpool Hospital, heads the eye study. He has observed dense cataracts, even in children, and anterior uveitis that has blinded some patients. There is concern about live virus persisting in vitreal fluid, but two eye taps have been negative, Dr. Scott said.
The most exciting recent finding, however, was made possible by the donation of a digital retinal camera, which “enabled us to get dozens of amazing images,” Dr. Scott said. With it, Dr. Steptoe conducted a case-control study of 81 Ebola survivors and 106 community controls. The findings of this study are potentially very, very important, Dr. Scott said.
“The first thing we found out is that retinal scarring is pervasive in our control patients,” she said. “There is just a lot of it out here in the community. But more interesting is that Dr. Steptoe seems to have identified a characteristic retinal lesion seen only in our survivors. It could be evidence of neurotropic aspects of the Ebola virus.”
The lesions occurred in 12 (15%) of the survivors and none of the controls. They are of a striking and consistent shape: straight-edged and sharply angulated. The lesions are only on the surface of the retina and do not penetrate into deeper levels. Nor do they interfere with vision. Dr. Steptoe has proposed that they take their angular shape from the retina’s underlying structures. His paper documenting this finding has been accepted and will be published shortly in the journal Emerging Infectious Diseases.
All of the post-Ebola sequelae add up to general disability for survivors, Dr. Scott said. Soushieta Jagadesh, of the* Liverpool School of Tropical Medicine, is conducting a disability survey. The comparison between 27 survivors and 54 community controls employed the Washington Group extended disability questionnaire. “We noted major limitations 1 year after discharge in mobility, vision, cognition, and affect,” Dr. Scott said.
The hazard ratios for these issues are enormous: Overall, compared with controls, survivors were 23 times more likely to have some level of disability. They were 94 times more likely to have walking limitations and 65 times more likely to have problems with stairs. Survivors were over 200 times more likely to have moderate disability than were their unaffected neighbors.
If funding for the project is renewed – and Dr. Scott admitted this is an “if,” not a “when” – caring for and studying these survivors will continue. Just in this one city, she said, the need is huge.
According to data from the U.S. Centers for Disease Control and Prevention, more than 17,000 patients in Sierra Leone, Liberia, and Guinea survived the 2014 Ebola outbreak.
If the assessments of Freetown survivors hold true across this population, thousands of survivors face life-limiting sequelae of the disease.
“We still have patients walk in every day with musculoskeletal pain, headaches, and ocular issues,” Dr. Scott said. “At the beginning of the epidemic, we were just focusing on containing it and reducing transmission. Now, we are faced with the long-term consequences.”
The Wellcome Trust supported the study. The authors have been awarded a grant from the Enhancing Research Activity in Epidemic Situations (ERAES) program, funded by the Wellcome Trust to support further research into the sequelae of Ebola virus disease.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
*This story was updated May 2, 2017.
AT ECCMID 2017
Monotherapy as good as combo for antibiotic-resistant infections in low-risk patients
VIENNA – A single, well-targeted antibiotic may be enough to effectively combat serous bloodstream infections in patients who have a low baseline mortality risk.
Among these patients, overall mortality was similar among those receiving a single antibiotic and those getting multiple antibiotics (35% vs. 41%). Patients with a high baseline mortality risk, however, did experience a significant 44% survival benefit when treated with a combination regimen, Jesus Rodríguez-Baño, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
The finding is important when considering the ever-increasing imperative of antibiotic stewardship, Dr. Rodríguez-Baño said in an interview.
“In areas where these pathogens are common, particularly in intensive care units, where they can become epidemic and infect many patients, the overuse of combination therapy will be fueling the problem,” said Dr. Rodríguez-Baño, head of infectious diseases and clinical microbiology at the University Hospital Virgin Macarena, Seville, Spain. “This is a way to avoid the overuse of some broad-spectrum antibiotics. Selecting the patients who should not receive combination therapy may significantly reduce the total consumption” on a unit.
The retrospective study, dubbed INCREMENT, was conducted at 37 hospitals in 10 countries. It enrolled patients with bloodstream infections caused by extended-spectrum beta-lactamase- or carbapenemase-producing Enterobacteriaceae. Dr. Rodríguez-Baño reported results for 437 patients whose infections were caused by the carbapenemase-producing strain.
It was simultaneously published in Lancet Infectious Diseases (Lancet Inf Dis 2017; DOI: http://dx.doi.org/10.1016/S1473-3099(17)30228-1).
These patients were a mean of 66 years old; most (60%) were male. The primary infective agent was Klebsiella pneumonia (86%); most infections were nosocomial. The origin of infections varied, but most (80%) arose from places other than the urinary or biliary tract. Sources were vascular catheters, pneumonia, intraabdominal, and skin and soft tissue. About half of the patients were in severe sepsis or septic shock when treated.
The group was first divided into those who received appropriate or inappropriate therapy (78% vs. 22%). Appropriate therapy was considered to be the early administration of a drug that could effectively target the infective organism. Next, those who got appropriate therapy were parsed by whether they received mono- or combination therapy (61%, 39%). Finally, these patients were stratified by a specially designed mortality risk score, the INCREMENT Carbapenemase-Producing Enterobacteriaceae (CPE) Mortality Score (Mayo Clinic Proceedings. doi.org/10.1016/j.mayocp.2016.06.024).
- Severe sepsis or shock at presentation (5 points)
- Pitt score of 6 or more (4 points)
- Charlson comorbidity index of 2 or more (3 points)
- Source of bloodstream infection other than urinary or biliary tract (3 points)
- Inappropriate empirical therapy and inappropriate early targeted therapy (2 points)
Patients were considered low risk if they had a score of 0-7, and high of they had a score of 8 or more.
The risk assessment took is quick, easy to figure, and extremely important, Dr. Rodríguez-Baño noted. “This is a very easy-to-use tool that can help us make many patient management decisions. All of the information is already available in the patient’s chart, so it doesn’t require any additional assessments. It’s a very good way to individualize treatment.”
In the initial analysis, all-cause mortality at 30 days was 22% lower among patients who received appropriate early therapy than those who did not (38.5% vs. 60.6%). This translated to a 55% decrease in the risk of death (HR 0.45 in the fully adjusted model).
The investigators next turned their attention toward the group that received appropriate therapy. All-cause 30-day mortality was 41% in those who got monotherapy and 34.8% among those who got combination therapy..
Finally, this group was stratified according to the INCREMENT-CPE mortality risk score.
In the low-risk category, combination therapy did not confer a survival advantage over monotherapy. Death occurred in 20% of those getting monotherapy and 24% receiving combination treatment – not a significant difference (HR 1.21).
Combination therapy did, however, confer a significant survival benefit in the high-risk group. Death occurred in 62% of those receiving monotherapy and 48% of those receiving combination therapy – a 44% risk reduction (HR 0.56).
As long as they were appropriately targeted against the infective organism, all drugs used in the high-mortality risk group were similarly effective at reducing the risk of death. Compared to colistin monotherapy, a combination that included tigecycline reduced the risk of death by 55% (HR 0.45); combination with aminoglycosides by 58% (HR 0.42); and combination with carbapenems by 44% (HR 0.56).
A secondary analysis of this group determined that time was a critical factor in survival. Each day delay after day 2 significantly increased the risk of death, Dr. Rodríguez-Baño said. This 48-hour period gives clinicians a chance to wait for the culture and antibiogram to return, and then choose and initiate the best treatment. Before the results come back, empiric antibiotic therapy is appropriate, but changes should be made immediately after the results come back.
“We tend to think we must give the very best antibiotic at the very first moment that we see a patient with a serious infection,” he said. “But what we found is that it’s not critical to give the perfect antibiotic on the first day. It is critical, however, to give the correct one once you know which bacteria is causing the infection. Since it takes 48 hours for those results to come back, this is perfect timing.”
INCREMENT was funded in large part by the Spanish Network for Research in Infectious Diseases. Dr. Rodríguez-Baño has been a scientific advisor for Merck, AstraZeneca, and InfectoPharm.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
VIENNA – A single, well-targeted antibiotic may be enough to effectively combat serous bloodstream infections in patients who have a low baseline mortality risk.
Among these patients, overall mortality was similar among those receiving a single antibiotic and those getting multiple antibiotics (35% vs. 41%). Patients with a high baseline mortality risk, however, did experience a significant 44% survival benefit when treated with a combination regimen, Jesus Rodríguez-Baño, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
The finding is important when considering the ever-increasing imperative of antibiotic stewardship, Dr. Rodríguez-Baño said in an interview.
“In areas where these pathogens are common, particularly in intensive care units, where they can become epidemic and infect many patients, the overuse of combination therapy will be fueling the problem,” said Dr. Rodríguez-Baño, head of infectious diseases and clinical microbiology at the University Hospital Virgin Macarena, Seville, Spain. “This is a way to avoid the overuse of some broad-spectrum antibiotics. Selecting the patients who should not receive combination therapy may significantly reduce the total consumption” on a unit.
The retrospective study, dubbed INCREMENT, was conducted at 37 hospitals in 10 countries. It enrolled patients with bloodstream infections caused by extended-spectrum beta-lactamase- or carbapenemase-producing Enterobacteriaceae. Dr. Rodríguez-Baño reported results for 437 patients whose infections were caused by the carbapenemase-producing strain.
It was simultaneously published in Lancet Infectious Diseases (Lancet Inf Dis 2017; DOI: http://dx.doi.org/10.1016/S1473-3099(17)30228-1).
These patients were a mean of 66 years old; most (60%) were male. The primary infective agent was Klebsiella pneumonia (86%); most infections were nosocomial. The origin of infections varied, but most (80%) arose from places other than the urinary or biliary tract. Sources were vascular catheters, pneumonia, intraabdominal, and skin and soft tissue. About half of the patients were in severe sepsis or septic shock when treated.
The group was first divided into those who received appropriate or inappropriate therapy (78% vs. 22%). Appropriate therapy was considered to be the early administration of a drug that could effectively target the infective organism. Next, those who got appropriate therapy were parsed by whether they received mono- or combination therapy (61%, 39%). Finally, these patients were stratified by a specially designed mortality risk score, the INCREMENT Carbapenemase-Producing Enterobacteriaceae (CPE) Mortality Score (Mayo Clinic Proceedings. doi.org/10.1016/j.mayocp.2016.06.024).
- Severe sepsis or shock at presentation (5 points)
- Pitt score of 6 or more (4 points)
- Charlson comorbidity index of 2 or more (3 points)
- Source of bloodstream infection other than urinary or biliary tract (3 points)
- Inappropriate empirical therapy and inappropriate early targeted therapy (2 points)
Patients were considered low risk if they had a score of 0-7, and high of they had a score of 8 or more.
The risk assessment took is quick, easy to figure, and extremely important, Dr. Rodríguez-Baño noted. “This is a very easy-to-use tool that can help us make many patient management decisions. All of the information is already available in the patient’s chart, so it doesn’t require any additional assessments. It’s a very good way to individualize treatment.”
In the initial analysis, all-cause mortality at 30 days was 22% lower among patients who received appropriate early therapy than those who did not (38.5% vs. 60.6%). This translated to a 55% decrease in the risk of death (HR 0.45 in the fully adjusted model).
The investigators next turned their attention toward the group that received appropriate therapy. All-cause 30-day mortality was 41% in those who got monotherapy and 34.8% among those who got combination therapy..
Finally, this group was stratified according to the INCREMENT-CPE mortality risk score.
In the low-risk category, combination therapy did not confer a survival advantage over monotherapy. Death occurred in 20% of those getting monotherapy and 24% receiving combination treatment – not a significant difference (HR 1.21).
Combination therapy did, however, confer a significant survival benefit in the high-risk group. Death occurred in 62% of those receiving monotherapy and 48% of those receiving combination therapy – a 44% risk reduction (HR 0.56).
As long as they were appropriately targeted against the infective organism, all drugs used in the high-mortality risk group were similarly effective at reducing the risk of death. Compared to colistin monotherapy, a combination that included tigecycline reduced the risk of death by 55% (HR 0.45); combination with aminoglycosides by 58% (HR 0.42); and combination with carbapenems by 44% (HR 0.56).
A secondary analysis of this group determined that time was a critical factor in survival. Each day delay after day 2 significantly increased the risk of death, Dr. Rodríguez-Baño said. This 48-hour period gives clinicians a chance to wait for the culture and antibiogram to return, and then choose and initiate the best treatment. Before the results come back, empiric antibiotic therapy is appropriate, but changes should be made immediately after the results come back.
“We tend to think we must give the very best antibiotic at the very first moment that we see a patient with a serious infection,” he said. “But what we found is that it’s not critical to give the perfect antibiotic on the first day. It is critical, however, to give the correct one once you know which bacteria is causing the infection. Since it takes 48 hours for those results to come back, this is perfect timing.”
INCREMENT was funded in large part by the Spanish Network for Research in Infectious Diseases. Dr. Rodríguez-Baño has been a scientific advisor for Merck, AstraZeneca, and InfectoPharm.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
VIENNA – A single, well-targeted antibiotic may be enough to effectively combat serous bloodstream infections in patients who have a low baseline mortality risk.
Among these patients, overall mortality was similar among those receiving a single antibiotic and those getting multiple antibiotics (35% vs. 41%). Patients with a high baseline mortality risk, however, did experience a significant 44% survival benefit when treated with a combination regimen, Jesus Rodríguez-Baño, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
The finding is important when considering the ever-increasing imperative of antibiotic stewardship, Dr. Rodríguez-Baño said in an interview.
“In areas where these pathogens are common, particularly in intensive care units, where they can become epidemic and infect many patients, the overuse of combination therapy will be fueling the problem,” said Dr. Rodríguez-Baño, head of infectious diseases and clinical microbiology at the University Hospital Virgin Macarena, Seville, Spain. “This is a way to avoid the overuse of some broad-spectrum antibiotics. Selecting the patients who should not receive combination therapy may significantly reduce the total consumption” on a unit.
The retrospective study, dubbed INCREMENT, was conducted at 37 hospitals in 10 countries. It enrolled patients with bloodstream infections caused by extended-spectrum beta-lactamase- or carbapenemase-producing Enterobacteriaceae. Dr. Rodríguez-Baño reported results for 437 patients whose infections were caused by the carbapenemase-producing strain.
It was simultaneously published in Lancet Infectious Diseases (Lancet Inf Dis 2017; DOI: http://dx.doi.org/10.1016/S1473-3099(17)30228-1).
These patients were a mean of 66 years old; most (60%) were male. The primary infective agent was Klebsiella pneumonia (86%); most infections were nosocomial. The origin of infections varied, but most (80%) arose from places other than the urinary or biliary tract. Sources were vascular catheters, pneumonia, intraabdominal, and skin and soft tissue. About half of the patients were in severe sepsis or septic shock when treated.
The group was first divided into those who received appropriate or inappropriate therapy (78% vs. 22%). Appropriate therapy was considered to be the early administration of a drug that could effectively target the infective organism. Next, those who got appropriate therapy were parsed by whether they received mono- or combination therapy (61%, 39%). Finally, these patients were stratified by a specially designed mortality risk score, the INCREMENT Carbapenemase-Producing Enterobacteriaceae (CPE) Mortality Score (Mayo Clinic Proceedings. doi.org/10.1016/j.mayocp.2016.06.024).
- Severe sepsis or shock at presentation (5 points)
- Pitt score of 6 or more (4 points)
- Charlson comorbidity index of 2 or more (3 points)
- Source of bloodstream infection other than urinary or biliary tract (3 points)
- Inappropriate empirical therapy and inappropriate early targeted therapy (2 points)
Patients were considered low risk if they had a score of 0-7, and high of they had a score of 8 or more.
The risk assessment took is quick, easy to figure, and extremely important, Dr. Rodríguez-Baño noted. “This is a very easy-to-use tool that can help us make many patient management decisions. All of the information is already available in the patient’s chart, so it doesn’t require any additional assessments. It’s a very good way to individualize treatment.”
In the initial analysis, all-cause mortality at 30 days was 22% lower among patients who received appropriate early therapy than those who did not (38.5% vs. 60.6%). This translated to a 55% decrease in the risk of death (HR 0.45 in the fully adjusted model).
The investigators next turned their attention toward the group that received appropriate therapy. All-cause 30-day mortality was 41% in those who got monotherapy and 34.8% among those who got combination therapy..
Finally, this group was stratified according to the INCREMENT-CPE mortality risk score.
In the low-risk category, combination therapy did not confer a survival advantage over monotherapy. Death occurred in 20% of those getting monotherapy and 24% receiving combination treatment – not a significant difference (HR 1.21).
Combination therapy did, however, confer a significant survival benefit in the high-risk group. Death occurred in 62% of those receiving monotherapy and 48% of those receiving combination therapy – a 44% risk reduction (HR 0.56).
As long as they were appropriately targeted against the infective organism, all drugs used in the high-mortality risk group were similarly effective at reducing the risk of death. Compared to colistin monotherapy, a combination that included tigecycline reduced the risk of death by 55% (HR 0.45); combination with aminoglycosides by 58% (HR 0.42); and combination with carbapenems by 44% (HR 0.56).
A secondary analysis of this group determined that time was a critical factor in survival. Each day delay after day 2 significantly increased the risk of death, Dr. Rodríguez-Baño said. This 48-hour period gives clinicians a chance to wait for the culture and antibiogram to return, and then choose and initiate the best treatment. Before the results come back, empiric antibiotic therapy is appropriate, but changes should be made immediately after the results come back.
“We tend to think we must give the very best antibiotic at the very first moment that we see a patient with a serious infection,” he said. “But what we found is that it’s not critical to give the perfect antibiotic on the first day. It is critical, however, to give the correct one once you know which bacteria is causing the infection. Since it takes 48 hours for those results to come back, this is perfect timing.”
INCREMENT was funded in large part by the Spanish Network for Research in Infectious Diseases. Dr. Rodríguez-Baño has been a scientific advisor for Merck, AstraZeneca, and InfectoPharm.
msullivan@frontlinemedcom.com
On Twitter @Alz_gal
Key clinical point:
Major finding: Among these patients, correctly targeted monotherapy decreased the risk of death by 44% – just about the same risk reduction as conferred by combination therapy.
Data source: The INCREMENT retrospective study comprised 437 patients.
Disclosures: INCREMENT was funded in large part by the Spanish Network for Research in Infectious Diseases. Dr. Rodríguez-Baño has been a scientific advisor for Merck, AstraZeneca, and InfectoPharm.