Background Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen-drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date. MethodsWe estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23 pathogens and 88 pathogen-drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drugresistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the global and regional level. FindingsOn the basis of our predictive statistical models, there were an estimated 4•95 million (3•62-6•57) deaths associated with bacterial AMR in 2019, including 1•27 million (95% UI 0•911-1•71) deaths attributable to bacterial AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27•3 deaths per 100 000 (20•9-35•3), and lowest in Australasia, at 6•5 deaths (4•3-9•4) per 100 000. Lower respiratory infections accounted for more than 1•5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000-1 270 000) deaths attributable to AMR and 3•57 million (2•62-4•78) deaths associated with AMR in 2019. One pathogen-drug combination, meticillinresistant S aureus, caused more than 100 000 deaths attributa...

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Host control of Mycobacterium tuberculosis is dependent on the activation of CD4+ T cells secreting IFN-γ and their recruitment to the site of infection. The development of more efficient vaccines against tuberculosis requires detailed understanding of the induction and maintenance of T cell immunity. Cytokines important for the development of cell-mediated immunity include IL-12 and IL-23, which share the p40 subunit and the IL-12Rβ1 signaling chain. To explore the differential effect of IL-12 and IL-23 during M. tuberculosis infection, we used plasmids expressing IL-23 (p2AIL-23) or IL-12 (p2AIL-12) alone in dendritic cells or macrophages from IL-12p40−/− mice. In the absence of the IL-12/IL-23 axis, immunization with a DNA vaccine expressing the M. tuberculosis Ag85B induced a limited Ag-specific T cell response and no control of M. tuberculosis infection. Codelivery of p2AIL-23 or p2AIL-12 with DNA85B induced strong proliferative and IFN-γ-secreting T cell responses equivalent to those observed in wild-type mice immunized with DNA85B. This response resulted in partial protection against aerosol M. tuberculosis; however, the protective effect was less than in wild-type mice owing to the requirement for IL-12 or IL-23 for the optimal expansion of IFN-γ-secreting T cells. Interestingly, bacillus Calmette-Guérin immune T cells generated in the absence of IL-12 or IL-23 were deficient in IFN-γ production, but exhibited a robust IL-17 secretion associated with a degree of protection against pulmonary infection. Therefore, exogenous IL-23 can complement IL-12 deficiency for the initial expansion of Ag-specific T cells and is not essential for the development of potentially protective IL-17-secreting T cells.

BackgroundValuation of the economic cost of antimicrobial resistance (AMR) is important for decision making and should be estimated accurately. Highly variable or erroneous estimates may alarm policy makers and hospital administrators to act, but they also create confusion as to what the most reliable estimates are and how these should be assessed. This study aimed to assess the quality of methods used in studies that quantify the costs of AMR and to determine the best available evidence of the incremental cost of these infections.MethodsIn this systematic review, we searched PubMed, Embase, Cinahl, Cochrane databases and grey literature sources published between January 2012 and October 2016. Articles reporting the additional burden of Enterococcus spp., Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) resistant versus susceptible infections were sourced. The included studies were broadly classified as reporting oncosts from the healthcare/hospital/hospital charges perspective or societal perspective. Risk of bias was assessed based on three methodological components: (1) adjustment for length of stay prior to infection onset and consideration of time-dependent bias, (2) adjustment for comorbidities or severity of disease, and (3) adjustment for inappropriate antibiotic therapy.ResultsOf 1094 identified studies, we identified 12 peer-reviewed articles and two reports that quantified the economic burden of clinically important resistant infections. Two studies used multi-state modelling to account for the timing of infection minimising the risk of time dependent bias and these were considered to generate the best available cost estimates. Studies report an additional CHF 9473 per extended-spectrum beta-lactamases -resistant Enterobacteriaceae bloodstream infections (BSI); additional €3200 per third-generation cephalosporin resistant Enterobacteriaceae BSI; and additional €1600 per methicillin-resistant S. aureus (MRSA) BSI. The remaining studies either partially adjusted or did not consider the timing of infection in their analysis.ConclusionsImplementation of AMR policy and decision-making should be guided only by reliable, unbiased estimates of effect size. Generating these estimates requires a thorough understanding of important biases and their impact on measured outcomes. This will ensure that researchers, clinicians, and other key decision makers concerned with increasing public health threat of AMR are accurately guided by the best available evidence.Electronic supplementary materialThe online version of this article (10.1186/s13756-019-0472-z) contains supplementary material, which is available to authorized users.