Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: 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. We therefore completed a systematic review and meta-analysis of available data from all low- and lower-middle-income countries (LLMICs) since 2010, with a focus on regional differences in Gram-negative infections and AMR. Methods and findings All studies published from 1 January 2010 to 21 April 2021 about microbiologically confirmed bloodstream infections or meningitis in neonates and AMR in LLMICs were assessed for eligibility. Small case series, studies with a small number of Gram-negative isolates (<10), and studies with a majority of isolates prior to 2010 were excluded. Main outcomes were pooled proportions of Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter and AMR. We included 88 studies (4 cohort studies, 3 randomised controlled studies, and 81 cross-sectional studies) comprising 10,458 Gram-negative isolates from 19 LLMICs. 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 55% to 65%). Klebsiella spp. was the most common, with a pooled proportion of 38% of Gram-negative sepsis (95% CI 33% to 43%). Regional differences were observed, with higher proportions of Acinetobacter spp. in Asia and Klebsiella spp. in Africa. Resistance to aminoglycosides and third-generation cephalosporins ranged from 42% to 69% and from 59% to 84%, respectively. Study limitations include significant heterogeneity among included studies, exclusion of upper-middle-income countries, and potential sampling bias, with the majority of studies from tertiary hospital settings, which may overestimate the burden caused by Gram-negative bacteria. Conclusions Gram-negative bacteria are an important cause of neonatal sepsis in LLMICs and are 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.

Zinc-based metal organic framework with antibacterial and anti-inflammatory properties for promoting wound healing

“…Once damaged by physiological diseases, the barrier will be broken, seriously affecting people’s physical and mental health. The exposed derma of skin wound surface can be easily damaged by many pathogenic factors like infection and inflammation [ 2 ], which finally delays the wound healing and further leads to septicemia [ 3 , 4 ]. Therefore, anti-microbial is of significance in skin wound healing.…”

Risk Factors for Mortality From Late-Onset Sepsis Among Preterm Very-Low-Birthweight Infants: A Single-Center Cohort Study From Singapore

“…Importantly, almost all (13/14, 93%) who had fulminant LOS were infected by a Gram-negative organism. The predominance of Gram-negative organisms in LOS have been reported in other units, many from NICUs in low-and middle-income countries (5,18,25,40). Shah et al hypothesized that the increasing usage of antibiotics in the antepartum and neonatal period may have contributed to the increasing trend of Gram-negative infections seen in these units (10).…”

“…This difference in microbial distribution is particularly important as Gram-negative infections among these high-risk infants have been associated with increased risk of fulminant sepsis and morbidities including bronchopulmonary dysplasia and neurological impairment, compared to other microorganism subtypes (1,9,20,(22)(23)(24). Increasing Gramnegative neonatal bacterial infections are also particularly concerning in low-and middle-income countries due to growing concerns of increasing levels of multi-drug bacterial resistance in these settings (25).…”

Performance Comparison of Infection Prediction Scores in a South African Neonatal Unit: A Retrospective Case-Control Study

“…As the Bekhof study was performed in a high-income setting with a Gram-positive HAI pathogen predominance, this may contribute to the difference in diagnostic accuracy when compared to our resource-limited setting. Neonates with Gram-negative HAI have a higher risk of adverse outcomes and death compared to Gram-positive HAI or no sepsis ( 44 , 45 ).…”