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ObjectiveTo assess the variation of effect estimates in the analysis of mortality and length of stay (LOS) in patients with infections caused by extended-spectrum beta-lactamase (ESBL)-producingEnterobacteriaceae.DesignSystematic review and meta-analysisMethodsLiterature search for clinical studies from 1 January 1960 to 1 October 2018 was conducted in PubMed. Primary outcomes were risk ratios (RRs) of all-cause and attributable mortality and weighted mean differences (WMDs) in LOS in patients with bloodstream infections (BSIs) and non-invasive infections. Any change in the effect estimates was assessed by grouping studies according to design, setting, economy-based country classification, reporting period, microbiological aetiology, infection type and adjustment for appropriateness of empirical treatment. The impact of ESBL production was calculated using random-effect meta-analysis and heterogeneity was evaluated by I2statistics and metaregression.ResultsEighty-four studies including 22 030 patients and 149 outcome measures were included in the meta-analysis. Most studies were retrospective cohorts from high-income countries, providing unadjusted estimates. ESBL production in patients with BSIs (56 studies) increased the RR for all-cause mortality by a factor of 1.70 (95% CI 1.52 to 1.90; p<0.001), attributable mortality (16 studies) by 1.75 (95% CI 1.448 to 2.108; p<0.001) and WMD in the intensive care unit by 3.07 days (95% CI 1.61 to 4.54; p<0.001). WMD in hospital LOS was significantly higher in BSIs (4.41 days; 95% CI 3.37 to 5.46; p<0.001) and non-invasive (2.19 days; 95% CI 1.56 to 2.81; p<0.001). Subgroup analyses showed variation of estimates by study design, population, strain and assessment of appropriateness of empiric treatment. High heterogeneity was observed in all analyses.ConclusionsCurrent evidence of the clinical burden of infections caused by ESBL-producing bacteria is highly heterogeneous and based mainly on unadjusted estimates derived from retrospective studies. Despite these limitations, ESBL production in strains causing BSIs seems associated with higher all-cause and attributable mortality and longer hospitalisation.

Introduction The primary outcome of the study was to evaluate the effect on 30 day mortality of the combination ceftazidime/avibactam + fosfomycin in the treatment of bloodstream infections (BSIs) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp). Materials and methods From October 2018 to March 2021, a retrospective, two-centre study was performed on patients with KPC-Kp BSI hospitalized at Sapienza University (Rome) and ISMETT-IRCCS (Palermo) and treated with ceftazidime/avibactam-containing regimens. A matched cohort (1:1) analysis was performed. Cases were patients receiving ceftazidime/avibactam + fosfomycin and controls were patients receiving ceftazidime/avibactam alone or in combination with in vitro non-active drugs different from fosfomycin (ceftazidime/avibactam ± other). Patients were matched for age, Charlson comorbidity index, ward of isolation (ICU or non-ICU), source of infection and severity of BSI, expressed as INCREMENT carbapenemase-producing Enterobacteriaceae (CPE) score. Results Overall, 221 patients were included in the study. Following the 1:1 match, 122 subjects were retrieved: 61 cases (ceftazidime/avibactam + fosfomycin) and 61 controls (ceftazidime/avibactam ± other). No difference in overall mortality emerged between cases and controls, whereas controls had more non-BSI KPC-Kp infections and a higher number of deaths attributable to secondary infections. Almost half of ceftazidime/avibactam + fosfomycin patients were prescribed fosfomycin without MIC fosfomycin availability. No difference in the outcome emerged after stratification for fosfomycin susceptibility availability and dosage. SARS-CoV-2 infection and ICS ≥ 8 independently predicted 30 day mortality, whereas an appropriate definitive therapy was protective. Conclusions Our data show that fosfomycin was used in the treatment of KPC-Kp BSI independently from having its susceptibility testing available. Although no difference was found in 30 day overall mortality, ceftazidime/avibactam + fosfomycin was associated with a lower rate of subsequent KPC-Kp infections and secondary infections than other ceftazidime/avibactam-based regimens.