Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial

Summary

Background

Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms.

Methods

NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996).

Findings

Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group).

Interpretation

In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants.

Funding

EU Seventh Framework Programme for research, technological development and demonstration.

Introduction

Neonatal sepsis is a major public health concern, with about 3 million cases per year worldwide.¹ Coagulase-negative staphylococci are skin and gut commensal bacteria and the most frequently isolated organisms in late onset sepsis in high-income countries,² particularly occurring in hospitals as a central line-associated bloodstream infection. Although overall mortality rates are low,³ coagulase-negative staphylococci-associated late onset sepsis is associated with neurodevelopmental sequelae.⁴ Coagulase-negative staphylococci are often multidrug resistant,⁵ and the global emergence of vancomycin heteroresistant organisms is concerning, especially the increasing reports in infants.6, 7

Research in context

Evidence before this study

Neonatal sepsis is a global health priority. Coagulase-negative staphylococci are the most frequently identified organisms in neonatal late onset sepsis in high-income countries, and babies with low birthweight have the greatest associated morbidity and mortality. Vancomycin is the main treatment of late onset sepsis caused by coagulase-negative staphylococci. Before the NeoVanc trial, commencing in March 2017, we searched PubMed, ClinicalTrials.gov, and ISRCTN. We identified two randomised controlled trials (RCTs) of neonatal vancomycin registered in the past 20 years. These two RCTs recruited 220 babies; one was an active control trial comparing cefazolin and vancomycin, and the other compared continuous and intermittent infusion with pharmacokinetic endpoints.

The NeoVanc programme completed preclinical studies that informed the optimal dosing regimen evaluated in this RCT. The NeoVanc hollow fibre infection model and animal model determined that more frequent dosing might be beneficial in facilitating bacterial killing and discouraging the development of vancomycin resistance. A clinical bridging study established that more frequent dosing led to a quicker and more efficient reduction in C-reactive protein, particularly in infants younger than 29 weeks postmenstrual age, and the study supported a shorter vancomycin course. A retrospective study by Linder and colleagues found that infants with sepsis with an uncomplicated clinical course, treated for coagulase-negative staphylococci and who were given vancomycin for 5 days after a positive blood culture had similar outcomes to those treated for longer durations. A novel neonatal vancomycin pharmacokinetic model was developed as part of the NeoVanc programme on the basis of a population pharmacokinetic meta-analysis, which included 4894 vancomycin concentrations from 1631 infants. This model supported the need for more frequent dosing in infants younger than 29 weeks postmenstrual age and predicted an optimised regimen with a 25 mg/kg loading dose of vancomycin. The use of a loading dose of 25 mg/kg has been supported by the Infectious Diseases Society of America for the treatment of meticillin-resistant Staphylococcus aureus in seriously unwell adults and children.

Added value of this study

To our knowledge, NeoVanc is the first RCT to evaluate a loading dose of vancomycin in conjunction with intermittent dosing for neonatal sepsis, as well as the largest neonatal vancomycin clinical efficacy trial. We identified an ototoxicity safety signal, potentially associated with the use of a loading dose or more frequent dosing, or both, in infants younger than 29 weeks postmenstrual age, which has not previously been recognised in this population. Additionally, no clear advantage was seen for adopting a shorter 5 day (± 1) course compared with a standard 10 day (± 2) course of vancomycin for infants with serious clinical or confirmed sepsis. The adapted European Medicines Agency neonatal sepsis criteria were used as inclusion criteria in our study and successfully identified infants with serious clinical sepsis, with more than 40% positive baseline blood cultures.

Implications of all the available evidence

There is no evidence for reducing the vancomycin course duration to 5 ± 1 days in infants with sepsis because no benefit was identified. A vancomycin loading dose and more frequent dosing in infants younger than 29 weeks postmenstrual age should not be recommended because of a possible ototoxicity safety signal. Collection of long-term neonatal vancomycin hearing data is in progress.

Vancomycin is the most widely used antibiotic for Gram-positive late onset sepsis.⁸ Neonatal vancomycin dosing and durations of treatment vary markedly,⁹ leading to different drug exposures.¹⁰ Robust infant pharmacokinetic, safety, and clinical efficacy data for different dosing strategies are scarce,¹¹ and the NeoVanc project attempted to address this gap.

Preclinical components of the NeoVanc programme included a hollow-fibre infection model, a rabbit model, and a population pharmacokinetic meta-analysis (appendix p 3). This work and a clinical bridging study¹² determined that frequent dosing facilitated bacterial killing and led to quicker reduction in C-reactive protein, whereas continuous infusions appeared to select for vancomycin heteroresistance. The neonatal pharmacokinetic model suggested that standard dosing regimens had low vancomycin target attainment and supported the use of a loading dose to shorten the time to achieve therapeutic concentrations when combined with more frequent dosing in infants younger than 29 weeks postmenstrual age.¹³ The clinical bridging study and the pharmacokinetic model indicated the need for more frequent dosing in infants younger than 29 weeks postmenstrual age, in whom it can take days to achieve therapeutic concentrations. A vancomycin loading dose is routinely given in adults and has been used in infants preceding continuous infusion;¹⁴ however, the loading dose is novel within the context of intermittent dosing. The subsequent optimised dosing regimen for the NeoVanc randomised clinical trial (RCT) was a short course (5 ± 1 days) of vancomycin with a loading dose and more frequent dosing in infants younger than 29 weeks postmenstrual age than in the standard of care with no loading dose (vancomycin for 10 ± 2 days). Shorter vancomycin durations are supported by retrospective analyses.¹⁵ A non-inferiority design was selected because shorter treatment was not expected to lead to higher efficacy than longer treatment but might possibly result in secondary benefits, including reduced rates of antimicrobial resistance and reduced toxic effects because of lower overall vancomycin exposure.

Potential toxicity of vancomycin includes nephrotoxicity and ototoxicity. Neonatal vancomycin safety studies have historically been underpowered and relied on retrospective analyses of routinely collected data,¹⁶ and robust, preclinical, neonatal vancomycin ototoxicity models are scarce.

This NeoVanc study aimed to use a loading dose of vancomycin to provide faster target attainment with a new, shorter optimised regimen compared with the standard dosing regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. The overall aim was to test whether the efficacy of the optimised regimen, which included a loading dose, was non-inferior to the standard regimen.