Gram-Negative Neonatal Sepsis in Low- and Middle- Income Countries: How Appropriate are the WHO Recommended Empirical Sepsis Antibiotic Regimens? A Systematic Review and Meta-Analysis

Abstract

Background: Neonatal sepsis is a significant global health issue associated with marked regional disparities in mortality. Antimicrobial resistance (AMR) is a growing concern in Gram-negative organisms which increasingly predominate in neonatal sepsis, and existing WHO empirical antibiotic recommendations may no longer be appropriate. Previous systematic reviews have been limited to specific low- and middle-income countries (LMICs). We therefore completed a systematic review and meta-analysis of available data from all LMICs since 2010, with a focus on regional differences in Gram-negative infections and AMR. Methods: All studies published from 2010 with microbiologically confirmed bloodstream infections or meningitis in neonates and AMR from LMICs were assessed for eligibility. Small case series or number of Gram-negative isolates (<10), and studies with a majority of isolates prior to 2010 were excluded. Main outcomes were pooled proportions of E.coli, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter and AMR. Findings: We included 75 studies comprising 17,066 positive blood cultures from 16 LMICs. No studies were identified outside of Africa and Asia. The estimated pooled proportion of neonatal sepsis caused by Gram-negative organisms was 60% (95% CI 54-65%). Klebsiella spp was the most common, with a pooled proportion of 37% of Gram-negative sepsis (95% CI 32-43%). Resistance to aminoglycosides and 3rd generation cephalosporins ranged from 42-69% and 59-84%, respectively. Interpretation: Gram-negative bacteria are an important cause of neonatal sepsis in LMICs and associated with significant rates of resistance to WHO recommended first and second line empirical antibiotics. AMR surveillance should underpin region-specific empirical treatment recommendations. Meanwhile, a significant global commitment to accessible and effective antimicrobials for neonates is required. Funding Statement: Sophie CH Wen is supported by a Queensland Health Clinical Research Fellowship. Geoff Spurling, David L Paterson, Adam D Irwin, and Colleen L Lau are supported by National Health and Medical Research Council (NHMRC) Investigator Grants. Declaration of Interests: None to declare.