Neonatal vancomycin trial found loading with more frequent dosing over shorter time comparable to standard regimen but adversely affected hearing.
The efficacy of a vancomycin loading dose with more frequent dosing and shorter duration of treatment was comparable to standard dosing regimens for gram-positive sepsis in infants but with heightened risk for impaired hearing, in the largest neonatal vancomycin efficacy trial to date.
The investigated dosing regimen was derived from preclinical studies conducted in the NeoVanc project, a European collaborative coordinated by Penta, an international independent research network focusing on child health, which also conducted this phase 2b open-label clinical trial.
"Neonatal sepsis is a global health priority with around 3 million cases per year worldwide," stated the trial report lead author, Lousie Hill, MBChB, PhD, Pediatric Infectious Diseases, St George's University, London, UK, in an NeoVanc statement. "Premature babies and infants in the first 3 months of life represent a particularly vulnerable group because their immune systems are not yet full developed.
"In Europe, coagulase-negative staphylococci are the most frequently identified bacteria in neonatal late onset sepsis and vancomyin is the antibiotic most commonly used to treat them. However, despite being used for over 50 years, there are very few studies comparing different dosing regimens of vancomycin," Hill said.
In their preclinical studies with hollow fiber infection models and animal models, the investigators found indications that increasing the frequency of dosing might increase bactericidal effectiveness in a shorter time, and posited that the shorter duration of treatment could help avert development of vancomycin resistance. An exploratory clinical bridging study, as well as retrospective analysis of response after 5 days in trials with longer treatment supported this approach.
These pre-trial studies demonstrated more efficient reduction in C-reactive protein, particularly in infants younger than 29 weeks postmenstrual age.The use of a loading dose to initiate the more frequently dosed but shorter regimen was drawn, in part, from guidelines from the Infectious Diseases Society of America guideline for treating methicillin-resistant staphyloccoccus aureus. The investigators note, however, their study could be the first to investigate the utility of a loading dose with intermittent dosing for neonatal sepsis.
The trial randomized 242 infants from 22 neonatal intensive care units on a 1:1 ratio to receive the investigational dosing regimen of 25mg/kg loading followed by 15mg/kg every 12 or 8 hours, depending on postmenstrual age, for 5±1 days (n=120); or a standard regimen with no loading dose and 15mg/kg every 24, 12 or 8 hours, depending on age, for 10±2 days (n=122).The infants had at least 3 clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion.
The primary end-point was meeting criteria of cure at 10±1 days after end of the respective vancomycin regimen, including no indication of clinically or microbiologically significant relapse or new infection requiring anti-staphyloccoccal antibiotics for more than 24 hours within 10 days of the completed regimen.
Hill and colleagues reported this outcome was achieved in 71% of the investigational group and 79% of those receiving the standard vancomycin regimen, which confirmed non-inferiority.
Abnormal hearing tests, however, were detected in 30% of the group on the investigational regimen, compared to 15% of those on standard treatment. With the potential hearing safety signal, Hill and colleagues indicated that they could not recommend the test regimen.
"The results show that there is no clear advantage for adopting a shorter 5-day course, with a loading dose, over the standard 10-day course in infants under 3 months of age with severe sepsis," principal investigator Michael Sharland, MD, Pediatric Infectious Diseases, St George's University, announced in the NeoVanc press release.
Sharland indicated that there would be a follow-up study to collect long-term hearing data on those infants who were affected, particularly in relation to the use of the shorter treatment regimen.