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.

Carbapenem sparing regimens are needed for the treatment of ESBL/AmpC producing Enterobacterales infections. We sought to compare the clinical efficacy of ceftazidime/avibactam and carbapenems against ESBL/AmpC producing Enterobacterales spp. A systematic review and meta-analysis of randomized controlled trials comparing ceftazidime/avibactam with carbapenems for the treatment of ESBL/AmpC producing Enterobacterales was conducted. Five RCTs with ESBLs/AmpC specific outcome data were compiled. Of the 246 patients infected with an ESBL producing microorganism in the ceftazidime/avibactam arm, 224 (91%) had a clinical response at TOC versus 240 of 271 (89%) patients in the carbapenem arm (RR 1.02, 95% CI 0.97–1.08, P=0.45, I2=0%). Clinical response for AmpC producers in the ceftazidime/avibactam and carbapenem arms were 32/40 (80%) and 37/42 (88%), respectively (RR 0.91, 95% CI 0.76–1.10, P=0.35, I2=0%). Microbiological response and mortality rates were not reported specifically for ESBL/AmpC producers. Ceftazidime/avibactam may be a carbapenem-sparing option for the treatment of mild to moderate complicated urinary tract and intraabdominal infections caused by ESBL producing Enterobacterales spp. and the data are limited to provide any conclusive recommendations for the AmpC producers. Care should be taken before extrapolating this to severe infections, given that the representation of this population in the reviewed studies was negligible. Ceftazidime/avibactam is a costly drug active against carbapenem resistant microorganisms, and should be used judiciously to preserve its activity against these.

Objectives Enterobacterales producing ESBL (ESBL-E) have been notable for their rapid expansion in community settings. This systematic review and meta-analysis aimed to summarize evidence investigating the association between ESBL-E infection and adverse clinical outcomes, defined as bacteraemia, sepsis or septic shock, and all-cause mortality in adult patients. Methods Database search was conducted in PubMed, Scopus and EMBASE. In general, studies were screened for effect estimates of ESBL-E colonization or infection on clinical outcomes with non-ESBL-producing Enterobacterales as comparator, adult populations and molecular ascertainment of ESBL gene. Meta-analysis was performed using the inverse variance heterogeneity model. Results Eighteen studies were identified, including 1399 ESBL-E and 3200 non-ESBL-E infected patients. Sixteen of these studies included only bacteraemic patients. Mortality was studied in 17 studies and ESBL-E infection was significantly associated with higher odds of mortality compared with non-ESBL-producing Enterobacterales infection (OR = 1.70, 95% CI: 1.15–2.49, I2=58.3%). However, statistical significance did not persist when adjusted estimates were pooled (aOR = 1.67, 95% CI: 0.52–5.39, I2=78.1%). Septic shock was studied in seven studies and all included only bacteraemic patients. No association between ESBL-E infection and shock was found (OR = 1.23, 95% CI: 0.75–2.02, I2=14.8%). Only one study investigated the association between ESBL-E infection and bacteraemia. Conclusions Infections by ESBL-E appear to be significantly associated with mortality but not septic shock. Available studies investigating bacteraemia and shock as an intermediate outcome of ESBL-E infections are lacking. Future studies investigating the relationship between clinical outcomes and molecular characteristics of resistant strains are further warranted, along with studies investigating this in non-bacteraemic patients.

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This systematic review and meta-analysis evaluated the clinical efficacy and safety of carbapenems for the treatment of complicated urinary tract infections (cUTIs) with the comparators being new antibiotics evaluated for this indication. We searched 13 electronical databases for published randomised controlled trials (RCTs) and completed and/or ongoing trials. The search terms were developed by using the PICOS framework. Pooled efficacy estimates of composite cure (clinical success and microbiological eradication) favour the new antibiotic groups, although this is not statistically significant [risk ratio (RR)=0.91; 95% confidence interval (CI); 0.79-1.04]. A pooled estimate examining clinical response alone showed no difference between treatment arms (RR=1.00; 95% CI: 0.96-1.05), however, new antibiotic treatments were superior to carbapenems for microbiological response (RR=0.85; 95% CI: 0.79-0.91). New antibiotic treatments demonstrated a superior microbiological response compared to carbapenems in clinical trials of cUTI, despite an absence of carbapenem resistance. However, it is noteworthy that the clinical response and safety profile of new antibiotics were not different from carbapenems.