Estimating the number of infections caused by antibiotic-resistant Escherichia coli and Klebsiella pneumoniae in 2014: a modelling study

Background: The number of infections caused by resistant organisms is largely unknown. We estimated the number of infections worldwide that are caused by the WHO priority pathogens third-generation cephalosporin-resistant and carbapenem-resistant Escherichia coli and Klebsiella pneumoniae. Methods: We calculated a uniform weighted mean incidence of serious infections caused by antibiotic-susceptible E coli and K pneumoniae using data from 17 countries. Using this uniform incidence, as well as population sizes and country-specific resistance levels, we estimated the number of infections caused by third-generation cephalosporin-resistant and carbapenem-resistant E coli and K pneumoniae in 193 countries in 2014. We also calculated interval estimates derived from changing the fixed incidence of susceptible infections to 1 SD below and above the weighted mean. We compared an additive model with combination models in which resistant infections were replaced by susceptible infections. We distinguished between higher-certainty regions (those with good-quality data sources for resistance levels and resistance ≤30%), moderate-certainty regions (those with good-quality data sources for resistance levels and including some countries with resistance >30%), and low-certainty regions (those in which good-quality data sources for resistance levels were unavailable for countries comprising at least 20% of the region's population, regardless of resistance level). Findings: Using the additive model, we estimated that third-generation cephalosporin-resistant E coli and K pneumoniae caused 6·4 million (interval estimate 3·5–9·2) bloodstream infections and 50·1 million (27·5–72·8) serious infections in 2014; estimates were 5·5 million (3·0–7·9) bloodstream infections and 43·1 million (23·6–62·2) serious infections in the 25% replacement model, 4·6 million (2·5–6·6) bloodstream infections and 36·0 million (19·7–52·2) serious infections in the 50% replacement model, and 3·7 million (2·0–5·3) bloodstream infections and 28·9 million (15·8–41·9) serious infections in the 75% replacement model. Carbapenem-resistant strains caused 0·5 million (0·3–0·7) bloodstream infections and 3·1 million (1·8–4·5) serious infections based on the additive model, 0·5 million (0·3–0·7) bloodstream infections and 3·0 million (1·7–4·3) serious infections based on the 25% replacement model, 0·4 million (0·2–0·6) bloodstream infections and 2·8 million (1·6–4·1) serious infections based on the 50% replacement model, and 0·4 million (0·2–0·6) bloodstream infections and 2·7 million (1·5–3·8) serious infections based on the 75% replacement model. Interpretation: To our knowledge, this study is the first to report estimates of the global number of infections caused by antibiotic-resistant priority pathogens. Uncertainty stems from scant data on resistance levels from low-income and middle-income countries and insufficient knowledge regarding resistance dynamics when resistance is high. Funding: Innovative Medicines Initiative

EpideMiology and control measures of outBreaks due to Antibiotic-Resistant orGanisms in EurOpe (EMBARGO): a systematic review protocol

Improving our understanding of outbreaks due to antibiotic-resistant bacteria (ARB) and their control is critical in the current public health scenario. The threat of outbreaks due to ARB requires multifaceted efforts. However, a global overview of epidemiological characteristics of outbreaks due to ARB and effective infection control measures is missing. In this paper, we describe the protocol of a systematic review aimed at mapping and characterising the epidemiological aspects of outbreaks due to ARB and infection control measures in European countries

Clinical and Genetic Tumor Characteristics of Responding and Non-Responding Patients to PD-1 Inhibition in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success

Choice of non-inferiority (NI) margins does not protect against degradation of treatment effects on an average--an observational study of registered and published NI trials.

OBJECTIVE:NI margins have to be chosen appropriately to control the risk of degradation of treatment effects in non-inferiority (NI) trials. We aimed to study whether the current choice of NI margins protects sufficiently against a degradation of treatment effect on an average. STUDY DESIGN AND SETTING:NI trials reflecting current practice were assembled and for each trial, the NI margin was translated into a likelihood of degradation. The likelihood of degradation was calculated as the conditional probability of a treatment being harmful given that it is declared non-inferior in the trial, using simulation. Its distribution among the NI trials was then studied to assess the potential risk of degradation. RESULTS:The median (lower/upper quartile) NI margin among 112 binary outcome NI trials corresponded to an odds ratio of 0.57(0.45, 0.66), while among 38 NI trials with continuous outcome, to a Cohen's d of -0.42(-0.54, -0.31) and a hazard ratio of 0.82(0.73, 0.86) among 24 survival outcome NI trials. Overall, the median likelihood of degradation was 56% (45%, 62%). CONCLUSION:Only two fifths of the current NI trials had a likelihood of degradation lower than 50%, suggesting that, in majority of the NI trials, there is no sufficient protection against degradation on an average. We suggest a third hurdle for the choice of NI margins, thus contributing a sufficient degree of protection

Hospital antimicrobial stewardship: the way forward - Authors' reply

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Trial characteristics of the Non-inferiority trials studied.

<p>Trial characteristics of the Non-inferiority trials studied.</p

Distribution of the likelihood of degradation among the current NI trials.

<p>The diamonds represent the worst possible likelihood of degradation values and the dot represents the median likelihood of degradation in the moderate scenario.</p

Flowchart of identification of non-inferiority trials and their margins – a) registered trials from trials register data b) published trials from four major journals.

<p>Flowchart of identification of non-inferiority trials and their margins – a) registered trials from trials register data b) published trials from four major journals.</p

Distribution of non-inferiority margins in the NI trials for continuous outcomes.

<p>Distribution of non-inferiority margins in the NI trials for continuous outcomes.</p