Quantifying the economic cost of antibiotic resistance and the impact of related interventions rapid methodological review, conceptual framework and recommendations for future studies

BACKGROUND: Antibiotic resistance (ABR) poses a major threat to health and economic wellbeing worldwide. Reducing ABR will require government interventions to incentivise antibiotic development, prudent antibiotic use, infection control and deployment of partial substitutes such as rapid diagnostics and vaccines. The scale of such interventions needs to be calibrated to accurate and comprehensive estimates of the economic cost of ABR. METHODS: A conceptual framework for estimating costs attributable to ABR was developed based on previous literature highlighting methodological shortcomings in the field and additional deductive epidemiological and economic reasoning. The framework was supplemented by a rapid methodological review. RESULTS: The review identified 110 articles quantifying ABR costs. Most were based in high-income countries only (91/110), set in hospitals (95/110), used a healthcare provider or payer perspective (97/110), and used matched cohort approaches to compare costs of patients with antibiotic-resistant infections and antibiotic-susceptible infections (or no infection) (87/110). Better use of methods to correct biases and confounding when making this comparison is needed. Findings also need to be extended beyond their limitations in (1) time (projecting present costs into the future), (2) perspective (from the healthcare sector to entire societies and economies), (3) scope (from individuals to communities and ecosystems), and (4) space (from single sites to countries and the world). Analyses of the impact of interventions need to be extended to examine the impact of the intervention on ABR, rather than considering ABR as an exogeneous factor. CONCLUSIONS: Quantifying the economic cost of resistance will require greater rigour and innovation in the use of existing methods to design studies that accurately collect relevant outcomes and further research into new techniques for capturing broader economic outcomes

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Erythema over the site of a Bacillus Calmette-Guerin vaccination scar after receiving a dose of messenger RNA vaccine against SARS-CoV-2

10.1503/cmaj.210696-fCANADIAN MEDICAL ASSOCIATION JOURNAL19341E1614-E161

Bacillus Calmette-Guerin scar flare after an mRNA SARS-CoV-2 vaccine

10.1503/cmaj.210696CANADIAN MEDICAL ASSOCIATION JOURNAL19330E1178-E117

Disruption of IL-21 Signaling Affects T Cell-B Cell Interactions and Abrogates Protective Humoral Immunity to Malaria

<div><p>Interleukin-21 signaling is important for germinal center B-cell responses, isotype switching and generation of memory B cells. However, a role for IL-21 in antibody-mediated protection against pathogens has not been demonstrated. Here we show that IL-21 is produced by T follicular helper cells and co-expressed with IFN-γ during an erythrocytic-stage malaria infection of <i>Plasmodium chabaudi</i> in mice. Mice deficient either in IL-21 or the IL-21 receptor fail to resolve the chronic phase of <i>P</i>. <i>chabaudi</i> infection and <i>P</i>. <i>yoelii</i> infection resulting in sustained high parasitemias, and are not immune to re-infection. This is associated with abrogated <i>P</i>. <i>chabaudi</i>-specific IgG responses, including memory B cells. Mixed bone marrow chimeric mice, with T cells carrying a targeted disruption of the <i>Il21</i> gene, or B cells with a targeted disruption of the <i>Il21r</i> gene, demonstrate that IL-21 from T cells signaling through the IL-21 receptor on B cells is necessary to control chronic <i>P</i>. <i>chabaudi</i> infection. Our data uncover a mechanism by which CD4+ T cells and B cells control parasitemia during chronic erythrocytic-stage malaria through a single gene, <i>Il21</i>, and demonstrate the importance of this cytokine in the control of pathogens by humoral immune responses. These data are highly pertinent for designing malaria vaccines requiring long-lasting protective B-cell responses.</p></div

<i>P</i>. <i>chabaudi</i>-specific IgG B-cell responses are abrogated in the absence of IL-21 signaling.

<p>(A) IgG, (B) IgG subtypes (day 32 post-infection) and (C) IgM antibodies specific for a lysate of <i>P</i>. <i>chabaudi</i>-infected rbc determined by ELISA. Antibody units (AU) were calculated based on the <i>P</i>. <i>chabaudi</i>-specific antibody levels of a hyper-immune standard plasma defined as 1000 U. In the cases where levels of antibodies were below background, arbitrary values of 2 log lower than the mean value observed in WT C57BL/6 mice were set to be able to perform the statistical test. (D) MSP1₂₁-specific IgG-producing ASC in BM obtained from one femur and one tibia, and (E) MBC per spleen, determined by ELISPOT 32 days post-infection. Statistical significance was obtained using the Kruskal-Wallis test comparing each time point with its respective basal level (day 0 post-infection) (*, P<0.05; **, P<0.01), or comparing with the data obtained from the WT C57BL/6 group (# #, P<0.01). The Mann Whitney U test was used in the case of IgG subtypes, comparing <i>Il21</i>^<i>-/-</i> vs WT C57BL/6 mice (#, P<0.05). Bars represent median values. Data are representative of at least two independent experiments and were obtained in groups of 3–8 mice per time point.</p

Mice deficient in IL-21 signaling fail to develop immunity to a secondary <i>P</i>. <i>chabaudi</i> infection.

<p>(A) Scheme describing the experimental approach. CQ = chloroquine. (B and C) <i>P</i>. <i>chabaudi</i>-infected mice were treated with chloroquine to eliminate parasitemia as described in the <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004715#sec009" target="_blank">materials and methods</a>, and re-infected with 10⁵<i>P</i>. <i>chabaudi-</i>infected rbc (day 0 post-secondary infection). The graphs show the course of secondary <i>P</i>. <i>chabaudi</i> infection in WT C57BL/6 (black circles), <i>Il21</i>^<i>-/-</i> (red circles) and <i>Il21r</i>^<i>-/-</i> (brown circles) mice; course of primary infection in <i>Il21</i>^<i>-/-</i> (gray circles) and <i>Il21r</i>^<i>-/-</i> (gray squares) are overlaid. (D and E) Number of Tfh cells per spleen post-primary and secondary infection, respectively. (F and G) Number of IFN-γ⁺CD4⁺ T cells per spleen post-primary and secondary infection, respectively. Data are representative of two independent experiments and are obtained in groups of 3–10 mice per time point. Statistical significance was obtained using Mann Whitney U test (**, P<0.01) or Kruskal-Wallis test (#, P<0.05). Error bars correspond to mean ± SEM.</p

IL-21 is produced during <i>P</i>. <i>chabaudi</i> infection and required to control chronic infection.

<p>(A) IL-21 mRNA in spleen cells of <i>P</i>. <i>chabaudi</i>-infected mice measured by real-time quantitative RT-PCR. Parasitemia (B) and total rbc counts (C) were determined in WT C57BL/6 (closed circles), <i>Il21</i>^<i>-/-</i> (open circles) and <i>Il21r</i>^<i>-/-</i> (open squares) mice. (D) Individual examples of spleens from <i>Il21r</i>^<i>-/-</i> (a) <i>Il21</i>^<i>-/-</i> (b) and WT C57BL/6 (c) mice at day 120 post-infection, and a spleen from an age-matched WT C57BL/6 naïve mouse (d). Bar, 1 cm. (E) Total number of nucleated live splenocytes were determined with a hemocytometer in WT C57BL/6 (black bars), <i>Il21</i>^<i>-/-</i> (open bars) and <i>Il21r</i>^<i>-/-</i> (stripped bars) mice. (F) Numbers of Ter119⁺ and Ter119^– cells in the spleen of WT C57BL/6 (black bars) and <i>Il21r</i>^<i>-/-</i> (striped bars) at day 32 post-infection. Data are representative of two or more independent experiments and are obtained in groups of 5–10 mice per time point. Statistical significance was obtained using Mann Whitney U test or Kruskal-Wallis test. *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001. Error bars correspond to mean ± SEM.</p

IL-21 is co-expressed with IFN-γ and IL-10 during <i>P</i>. <i>chabaudi</i> infection.

<p>(A-C) Flow cytometry plots showing individual examples for days 8 and 15 post-infection of different cytokine combinations studied in CD3⁺CD4⁺ T cells from the spleen of WT C57BL/6 mice. (D) IL-21-producing CD4⁺ T cells (red) overlaid on the plots corresponding to IFN-γ vs IL-10 on gated CD3⁺CD4⁺ T cells. Cumulative data showing the percentage (E) and total numbers (F) of IL-21-producing CD4⁺ T cells co-expressing IFN-γ, IL-4 and IL-10 in the spleen of WT C57BL/6 mice. The differential combination of expression (+) or absence of expression (–) of each cytokine (indicated in the bottom left) is shown for each subset at different days post-infection. Data are representative of at least two independent experiments and were obtained in groups of 4–6 mice per time point. Statistical significance was obtained using the Kruskal-Wallis test comparing each time point, corresponding to each cytokine combination with its respective basal level (day 0 post-infection). *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001. Bars represent median values.</p