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.
Inhaled nitric oxide (iNO) can reduce pulmonary arterial hypertension and improve oxygenation in some patients with severe respiratory or heart failure. Despite this, iNO has not been found to improve survival. This study aimed to perform a local practice audit to assess the mortality predictors of critically ill patients who had received iNO as therapy for pulmonary hypertension and respiratory or heart failure. A retrospective audit in a single tertiary centre intensive care unit of patients receiving iNO was conducted between 2004 and 2009. The indications for iNO use, comorbidities, severity of illness, organ function, oxygenation, Sequential Organ Failure Assessment scores, patterns of iNO use, adverse events and outcomes were reviewed. In 215 patients receiving iNO, improvement in oxygenation after one hour from iNO commencement did not predict either intensive care unit (P=0.36) or hospital (P=0.72) mortality. The independent risk factors for intensive care unit mortality were worsening Sequential Organ Failure Assessment scores within 24 hours of commencing iNO (adjusted odds ratio 1.07, 95% confidence interval 1.05 to 1.18), the Charlson Comorbidity Score (adjusted odds ratio 1.49, 95% confidence interval 1.16 to 1.91) and the peak methaemoglobin concentration in arterial blood while receiving iNO (adjusted odds ratio 2.67, 95% confidence interval 1.42 to 4.96). Inhaled nitric oxide as salvage therapy for severe respiratory failure in critically ill patients is not routinely justified. Increased methaemoglobin concentration during iNO therapy, even when predominantly less than 3%, is associated with increased mortality.
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