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Although edaphic antibiotic resistance genes (ARGs) pose serious threats to human well-being, their spatially explicit patterns and responses to environmental constraints at the global scale are not well understood. This knowledge gap is hindering the global action plan on antibiotic resistance launched by the World Health Organization. Here, a global analysis of 1088 soil metagenomic samples detected 558 ARGs in soils, where ARG abundance in agricultural habitats was higher than that in nonagricultural habitats. Soil ARGs were mostly carried by clinical pathogens and gut microbes that mediated the control of climatic and anthropogenic factors to ARGs. We generated a global map of soil ARG abundance, where the identified microbial hosts, agricultural activities, and anthropogenic factors explained ARG hot spots in India, East Asia, Western Europe, and the United States. Our results highlight health threats from soil clinical pathogens carrying ARGs and determine regions prioritized to control soil antibiotic resistance worldwide.

Competing Interests: We declare no competing interests.

Competing Interests: RL reports grants from the Bill & Melinda Gates Foundation, outside the area of work commented on here.

Objective: To identify and compare antimicrobial treatment guidelines from African Union (AU) Member States., Methods: We reviewed national government agency and public health institutes' websites and communicated with country or regional focal points to identify existing treatment guidelines from AU Member States. We included guidelines if they contained disease-, syndrome- or pathogen-specific treatment recommendations and if those recommendations included antimicrobial name or class, dosage and therapy duration. The scope of the review was limited to infections and clinical syndromes that often have a bacterial cause. We assessed treatment guidelines for alignment with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. We compared treatment recommendations for various common bacterial infections or clinical syndromes described across national guidelines and those described in three World Health Organization guidelines., Findings: We identified 31 treatment guidelines from 20 of the 55 (36%) AU Member States; several countries had more than one treatment guideline that met our inclusion criteria. Fifteen (48%) guidelines from 10 countries have been published or updated since 2015. Methods used to develop the guidelines were not well described. No guidelines were developed according to the GRADE approach. Antimicrobial selection, dosage and duration of recommended therapies varied widely across guidelines for all infections and syndromes., Conclusion: AU Member States lack antimicrobial treatment guidelines that meet internationally accepted methods and that draw from local evidence about disease burden and antimicrobial susceptibility., ((c) 2022 The authors; licensee World Health Organization.)

The number of bacterial genomes deposited each year in public databases is growing exponentially. However, efforts to use these genomes to track trends in antimicrobial resistance (AMR) have been limited thus far. We used 22,102 genomes from public databases to track AMR trends in nontyphoidal Salmonella in food animals in the United States. In 2018, genomes deposited in public databases carried genes conferring resistance, on average, to 2.08 antimicrobial classes in poultry, 1.74 in bovines, and 1.28 in swine. This represents a decline in AMR of over 70% compared to the levels in 2000 in bovines and swine, and an increase of 13% for poultry. Trends in resistance inferred from genomic data showed good agreement with U.S. phenotypic surveillance data (weighted mean absolute difference ± standard deviation, 5.86% ± 8.11%). In 2018, resistance to 3rd-generation cephalosporins in bovines, swine, and poultry decreased to 9.97% on average, whereas in quinolones and 4th-generation cephalosporins, resistance increased to 12.53% and 3.87%, respectively. This was concomitant with a decrease of bla CMY-2 but an increase in bla CTX-M-65 and gyrA D87Y (encoding a change of D to Y at position 87). Core genome single-nucleotide polymorphism (SNP) phylogenies show that resistance to these antimicrobial classes was predominantly associated with Salmonella enterica serovar Infantis and, to a lesser extent, S. enterica serovar Typhimurium and its monophasic variant I 4,[5],12:i:-, whereas quinolone resistance was also associated with S. enterica serovar Dublin. Between 2000 and 2018, trends in serovar prevalence showed a composition shift where S. Next-generation sequencing has led to an exponential increase in the number of genomes deposited in public repositories. This growing volume of information presents opportunities to track the prevalence of genes conferring antimicrobial resistance (AMR), a growing threat to the health of humans and animals. Using 22,102 public genomes, we estimated that the prevalence of multidrug resistance (MDR) in the United States decreased in nontyphoidal Salmonella isolates recovered from bovines and swine between 2000 and 2018, whereas it increased in poultry. These trends are consistent with those detected by national surveillance systems that monitor resistance using phenotypic testing. However, using genomes, we identified that genes conferring resistance to critically important antimicrobials were associated with specific MDR serovars that could be the focus for future interventions. Our analysis illustrates the growing potential of public repositories to monitor AMR trends and shows that similar efforts could soon be carried out in other regions where genomic surveillance is increasing.S. Infantis increased. Our findings illustrate the growing potential of using genomes in public databases to track AMR in regions where sequencing capacities are currently expanding. IMPORTANCE Next-generation sequencing has led to an exponential increase in the number of genomes deposited in public repositories. This growing volume of information presents opportunities to track the prevalence of genes conferring antimicrobial resistance (AMR), a growing threat to the health of humans and animals. Using 22,102 public genomes, we estimated that the prevalence of multidrug resistance (MDR) in the United States decreased in nontyphoidal Salmonella isolates recovered from bovines and swine between 2000 and 2018, whereas it increased in poultry. These trends are consistent with those detected by national surveillance systems that monitor resistance using phenotypic testing. However, using genomes, we identified that genes conferring resistance to critically important antimicrobials were associated with specific MDR serovars that could be the focus for future interventions. Our analysis illustrates the growing potential of public repositories to monitor AMR trends and shows that similar efforts could soon be carried out in other regions where genomic surveillance is increasing.

Antimicrobial resistance (AMR) is a growing threat to the health of humans and animals that requires global actions. In high-income countries, surveillance systems helped inform policies to curb AMR in animals. In low- and middle-income countries (LMICs), demand for meat is rising, and developing policies against AMR is urgent. However, surveillance of AMR is at best nascent, and the current evidence base to inform policymakers is geographically heterogeneous. We present resistancebank.org, an online platform that centralizes information on AMR in animals from 1,285 surveys from LMICs. Surveys were conducted between 2000 and 2019 and include 22,403 resistance rates for pathogens isolated from chickens, cattle, sheep, and pigs. The platform is built as a shiny application that provides access to individual surveys, country-level reports, and maps of AMR at 10 × 10 kilometers resolution. The platform is accessed via any internet browser and enables users to upload surveys to strengthen a global database. resistancebank.org aims to be a focal point for sharing AMR data in LMICs and to help international funders prioritize their actions., (© 2021. The Author(s).)

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)-aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin-and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.

Background: The WHO Access, Watch, and Reserve (AWaRe) antibiotic classification framework aims to balance appropriate access to antibiotics and stewardship. We aimed to identify how patterns of antibiotic consumption in each of the AWaRe categories changed across countries over 15 years., Methods: Antibiotic consumption was classified into Access, Watch, and Reserve categories for 76 countries between 2000, and 2015, using quarterly national sample survey data obtained from IQVIA. We measured the proportion of antibiotic use in each category, and calculated the ratio of Access antibiotics to Watch antibiotics (access-to-watch index), for each country., Findings: Between 2000, and 2015, global per-capita consumption of Watch antibiotics increased by 90·9% (from 3·3 to 6·3 defined daily doses per 1000 inhabitants per day [DIDs]) compared with an increase of 26·2% (from 8·4 to 10·6 DIDs) in Access antibiotics. The increase in Watch antibiotic consumption was greater in low-income and middle-income countries (LMICs; 165·0%; from 2·0 to 5·3 DIDs) than in high-income countries (HICs; 27·9%; from 6·1 to 7·8 DIDs). The access-to-watch index decreased by 38·5% over the study period globally (from 2·6 to 1·6); 46·7% decrease in LMICs (from 3·0 to 1·6) and 16·7% decrease in HICs (from 1·8 to 1·5), and 37 (90%) of 41 LMICs had a decrease in their relative access-to-watch consumption. The proportion of countries in which Access antibiotics represented at least 60% of their total antibiotic consumption (the WHO national-level target) decreased from 50 (76%) of 66 countries in 2000, to 42 (55%) of 76 countries in 2015., Interpretation: Rapid increases in Watch antibiotic consumption, particularly in LMICs, reflect challenges in antibiotic stewardship. Without policy changes, the WHO national-level target of at least 60% of total antibiotic consumption being in the Access category by 2023, will be difficult to achieve. The AWaRe framework is an important measure of the effort to combat antimicrobial resistance and to ensure equal access to effective antibiotics between countries., Funding: US Centers for Disease Control and Prevention., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

There is increasing concern globally about the enormity of the threats posed by antimicrobial resistance (AMR) to human, animal, plant and environmental health. A proliferation of international, national and institutional reports on the problems posed by AMR and the need for antibiotic stewardship have galvanised attention on the global stage. However, the AMR community increasingly laments a lack of action, often identified as an 'implementation gap'. At a policy level, the design of internationally salient solutions that are able to address AMR's interconnected biological and social (historical, political, economic and cultural) dimensions is not straightforward. This multidisciplinary paper responds by asking two basic questions: (A) Is a universal approach to AMR policy and antibiotic stewardship possible? (B) If yes, what hallmarks characterise 'good' antibiotic policy? Our multistage analysis revealed four central challenges facing current international antibiotic policy: metrics, prioritisation, implementation and inequality. In response to this diagnosis, we propose three hallmarks that can support robust international antibiotic policy. Emerging hallmarks for good antibiotic policies are: Structural, Equitable and Tracked. We describe these hallmarks and propose their consideration should aid the design and evaluation of international antibiotic policies with maximal benefit at both local and international scales., Competing Interests: Competing interests: SH is Scientific Director of CIHR’s Institute of Population and Public Health and CIHR’s Scientific Co-Lead for Antimicrobial Resistance. He is Director of the WHO Collaborating Centre on Global Governance of Antimicrobial Resistance. KO in principal investigator of CARB-X, a project at Boston University (my employer), funded by three governments (US, UK and Germany) and two charitable foundations (Wellcome Trust and the Bill & Melinda Gates Foundation). CARB-X is a non-profit, making grants for preclinical antibacterial research. I do not view this as a conflict, but disclose in an abundance of caution. APR is the co-ordinator of the JPIAMR funded Network NEAR-AMR. ADS reports grants from ReAct-Action on Antibiotic Resistance and from Open Society Foundation during the conduct of the study. He served as Co-Convener of the UN Interagency Coordination Group on Antimicrobial Resistance (2018–2019), as a member of the Expert Commission on Addressing the Livestock Contribution to the Antibiotic Resistance Crisis (2016–2017), as a commissioned author to the UK Commission on AMR on 'A Framework for Costing the Lowering of Antimicrobial Use in Food Animal Production' (2016), as Head of the Secretariat of the Antibiotic Resistance Coalition, and as a Member of the Working Group on Antibiotic Resistance for the President’s Council of Advisors on Science and Technology (2013–2014)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Diarrhea is a leading cause of antibiotic consumption among children in low- and middle-income countries. While vaccines may prevent diarrhea infections for which children often receive antibiotics, the contribution of individual enteropathogens to antibiotic use is minimally understood. We used data from the Global Enteric Multicenter Study (GEMS) to estimate pathogen-specific incidence of antibiotic-treated diarrhea among children under five years old residing in six countries of sub-Saharan Africa and South Asia before rotavirus vaccine implementation. GEMS was an age-stratified, individually-matched case-control study. Stool specimens were obtained from children presenting to sentinel health clinics with newly-onset, acute diarrhea (including moderate-to-severe and less-severe diarrhea) as well as matched community controls without diarrhea. We used data from conventional and quantitative molecular diagnostic assays applied to stool specimens to estimate the proportion of antibiotic-treated diarrhea cases attributable to each pathogen. Antibiotics were administered or prescribed to 9,606 of 12,109 moderate-to-severe cases and 1,844 of 3,174 less-severe cases. Across all sites, incidence rates of clinically-attended, antibiotic-treated diarrhea were 12.2 (95% confidence interval: 9.0-17.8), 10.2 (7.4-13.9) and 1.9 (1.3-3.0) episodes per 100 child-years at risk at ages 6 weeks to 11 months, 12-23 months, and 24-59 months, respectively. Based on the recommendation for antibiotic treatment to be reserved for cases with dysentery, we estimated a ratio of 12.6 (8.6-20.8) inappropriately-treated diarrhea cases for each appropriately-treated case. Rotavirus, adenovirus serotypes 40/41, Shigella, sapovirus, Shiga toxin-producing Escherichia coli, and Cryptosporidium were the leading antibiotic-treated diarrhea etiologies. Rotavirus caused 29.2% (24.5-35.2%) of antibiotic-treated cases, including the largest share in both the first and second years of life. Shigella caused 14.9% (11.4-18.9%) of antibiotic-treated cases, and was the leading etiology at ages 24-59 months. Our findings should inform the prioritization of vaccines with the greatest potential to reduce antibiotic exposure among children., Competing Interests: JAL has received grants and consulting fees from Pfizer Inc. and Merck, Sharp, & Dohme unrelated to the submitted work. KLK has received grants from Merck, Sharp & Dohme unrelated to the submitted work. All other authors declare no competing interests exist.

Vaccines may reduce the burden of antimicrobial resistance, in part by preventing infections for which treatment often includes the use of antibiotics 1-4 . However, the effects of vaccination on antibiotic consumption remain poorly understood-especially in low- and middle-income countries (LMICs), where the burden of antimicrobial resistance is greatest 5 . Here we show that vaccines that have recently been implemented in the World Health Organization's Expanded Programme on Immunization reduce antibiotic consumption substantially among children under five years of age in LMICs. By analysing data from large-scale studies of households, we estimate that pneumococcal conjugate vaccines and live attenuated rotavirus vaccines confer 19.7% (95% confidence interval, 3.4-43.4%) and 11.4% (4.0-18.6%) protection against antibiotic-treated episodes of acute respiratory infection and diarrhoea, respectively, in age groups that experience the greatest disease burden attributable to the vaccine-targeted pathogens 6,7 . Under current coverage levels, pneumococcal and rotavirus vaccines prevent 23.8 million and 13.6 million episodes of antibiotic-treated illness, respectively, among children under five years of age in LMICs each year. Direct protection resulting from the achievement of universal coverage targets for these vaccines could prevent an additional 40.0 million episodes of antibiotic-treated illness. This evidence supports the prioritization of vaccines within the global strategy to combat antimicrobial resistance 8 .

Background: Available data on antibiotic resistance in sub-Saharan Africa is limited despite its increasing threat to global public health. As there is no previous study on antibiotic resistance in patients with clinical features of healthcare-associated infections (HAIs) in Sierra Leone, research is needed to inform public health policies. Our study aimed to assess antibiotic resistance rates from isolates in the urine and sputum samples of patients with clinical features of HAIs., Methodology: We conducted a cross-sectional study of adult inpatients aged ≥18 years at Connaught Hospital, an urban tertiary care hospital in Freetown between February and June 2018., Results: Over the course of the study, we enrolled 164 patients. Risk factors for HAIs were previous antibiotic use (93.3%), comorbidities (58.5%) and age (≥65 years) (23.9%). Of the 164 samples, 89.6% were urine. Bacterial growth was recorded in 58.8% of cultured specimens; the type of specimen was an independent predictor of bacterial growth (p < 0.021). The most common isolates were Escherichia coli and Klebsiella pneumoniae; 29.2% and 19.0% in urine samples and 18.8% and 31.3% in sputum samples, respectively. The overall resistance rates were 58% for all extended-spectrum beta-lactamase (ESBL)-producing organisms, 13.4% for carbapenem-resistant non-lactose fermenting gram-negative bacilli, 8.7% for carbapenem-resistant Acinetobacter baumannii (CRAB) and 1.3% for carbapenem-resistant Enterobacteriaceae (CRE). There were no carbapenem-resistant P. aeruginosa (CRPA) isolates but all Staphylococcus aureus isolates were methicillin-resistant S. aureus., Conclusion: We demonstrated a high prevalence rate of ESBL-producing organisms which are a significant burden at the main tertiary hospital in Sierra Leone. Urgent action is needed to strengthen microbiological diagnostic infrastructure, initiate surveillance on antibiotic resistance and develop and implement policy framework on antibiotic stewardship.

Competing Interests: Competing interests: None declared.

Objectives: Our study aimed to assess antibiotic use in adult inpatients in the context of limited laboratory services at the main tertiary hospital in Sierra Leone., Design: A cross-sectional study of consecutive adult inpatients (≥18 years) between October 2017 and February 2018 at Connaught Hospital in Freetown., Results: A total of 920 patients were interviewed, of which 753 (81.8%) had at least one antibiotic. Complete data was captured for 688 (91.0%) patients. The median age was 41 years and 52.8% were male. Fever was reported in 41.5% of patients, though 85.1% had no leukocyte count prior to antibiotic use and none had a bacterial culture. Indications for prescribing were surgical prophylaxis (15.7%), pneumonia (15.1%), and trauma (5.8%). Cephalosporins (25.9%), penicillins (23.2%), and imidazoles (20.8%) were commonly prescribed., Conclusion: We found high rates of antibiotic use, of which most was not based on laboratory evidence. Lack of oversight and microbiological support are drivers of poor prescribing in many developing countries, which lack financial resources and serve a sicker population. Greater investments are needed to establish antimicrobial stewardship programs and provide clinicians with diagnostic support to enable improvements in patient outcomes and curb the spread of antibiotic resistance., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Antimicrobial resistance (AMR) is a serious global threat driven by the overuse of drugs in humans, animals, as well as the contamination of natural environments with antimicrobial residues. In recent years, the rise of community-acquired infections resistant to antibiotics has drawn renewed attention to the environmental compartment, in particular for pathogens found in aquaculture systems. We quantified the prevalence of antibiotic resistance in Vibrios isolated from the Cochin Estuary as well as the adjoining shrimp farms, and seafood from markets. A total of 280 Vibrio strains were subjected to antimicrobial susceptibility testing and screened for the presence of bla TEM , bla CTX-M , and bla NDM-1 genes. All strains identified were resistant to at least three antimicrobials, and the percentage of drugs resistant per strain ranged from 16% up to 60%. All the strains from the estuary were resistant to amoxicillin, ampicillin, cephalothin, and colistin. Similarly, strains isolated from seafood were resistant to enrofloxacin, furazolidone, and trimethoprim, and all strains from shrimp farms were resistant to colistin. Plasmid-mediated antibiotic resistance was observed in 21% of the strains. In addition, the presence of bla NDM-1 gene was confirmed in 22.85% of the strains. The presence of multiple resistant phenotypes in vibrios, including resistance to last-resort compounds in domestic food sources, raises serious concerns for public health in the Cochin Estuary. Although localized in nature, our findings also have vital implications for the spread of AMR internationally, given the prominence of South India for seafood exports.

A recent analysis of antibiotics approved between 1999 and 2014, conducted by researchers at the Norwegian Institute of Public Health; the University of Oslo; the Center for Disease Dynamics, Economics & Policy (CDDEP); and Boston University, showed a lack of novelty and diversity regarding target pathogens and indications and a failure to address the most urgent resistance threats, including resistant Gram-negative bacteria. A global research and development strategy should incentivize development of broad-spectrum antibiotics for critically ill patients, as well as therapeutic alternatives to antibiotics, decreasing our dependence on traditional, small-molecule antibiotics.

Over 95% of post-mortem samples from the 1918 pandemic, which caused 50 to 100 million deaths, showed bacterial infection complications. The introduction of antibiotics in the 1940s has since reduced the risk of bacterial infections, but growing resistance to antibiotics could increase the toll from future influenza pandemics if secondary bacterial infections are as serious as in 1918, or even if they are less severe. We develop a valuation model of the option to withhold wide use of an antibiotic until significant outbreaks such as pandemic influenza or foodborne diseases are identified. Using real options theory, we derive conditions under which withholding wide use is beneficial, and calculate the option value for influenza pandemic scenarios that lead to secondary infections with a resistant Staphylococcus aureus strain. We find that the value of withholding an effective novel oral antibiotic can be positive and significant unless the pandemic is mild and causes few secondary infections with the resistant strain or if most patients can be treated intravenously. Although the option value is sensitive to parameter uncertainty, our results suggest that further analysis on a case-by-case basis could guide investment in novel agents as well as strategies on how to use them., (© 2019 John Wiley & Sons, Ltd.)

Objective: To estimate the proportion of over-the-counter antibiotic requests or consultations that resulted in non-prescription supply of antibiotics in community pharmacies globally., Methods: We systematically searched EMBASE, Medline and CINAHL databases for studies published from January 2000 to September 2017 reporting the frequency of non-prescription sale and supply of antibiotics in community pharmacies across the world. Additional articles were identified by checking reference lists and a Google Scholar search. A random effects meta-analysis was conducted to calculate pooled estimates of non-prescription supply of antibiotics., Results: Of the 3302 articles identified, 38 studies from 24 countries met the inclusion criteria and were included in the review. All the included countries with the exception of one, classified antibiotics as prescription-only medicines. The overall pooled proportion of non-prescription supply of antibiotics was 62% (95% CI 53-72). The pooled proportion of non-prescription supply of antibiotics following a patient request was 78% (95% CI 59-97) and based on community pharmacy staff recommendation was 58% (95% CI 48-68). The regional supply of non-prescription antibiotics was highest in South America, 78% (95% CI 72-84). Antibiotics were commonly supplied without a prescription to patients with symptoms of urinary tract infections (68%, 95% CI 42-93) and upper respiratory tract infections (67%, 95% CI 55-79). Fluoroquinolones and Penicillins respectively were the most commonly supplied antibiotic classes for these indications., Conclusion: Antibiotics are frequently supplied without prescription in many countries. This overuse of antibiotics could facilitate the development and spread of antibiotic resistance., (Copyright © 2018. Published by Elsevier Ltd.)

Demand for poultry meat is rising in low- and middle-countries, driving the expansion of large commercial farms where antimicrobials are used as surrogates for hygiene, good nutrition. This routine use of antimicrobials in animal production facilitates the emergence and spread of antibiotic-resistant pathogens. Despite potentially serious consequences for the animal industry, few studies have documented trends in antimicrobial use (AMU) at the farm-level in low- and middle-income countries. The objective of this study was to estimate AMU in a broiler chicken farm in Pakistan over a five-year period and to extrapolate national AMU in commercial broiler farming. Between 2013 and 2017, we monitored AMU in 30 flocks from a commercial broiler farm in Punjab, the most populous province of Pakistan. The amount of antimicrobials administered was calculated in milligram/population unit of the final flock weight (mg/fPU) and in used daily dose (UDD). The annual on-farm antimicrobial use was 250.84 mg of active ingredient per kilogram of the final flock weight. This consumption intensity exceeds the amount of antimicrobial used per kilogram of chicken of all countries in the world except China. Measured in mg per kg of final flock weight or population unit (fPU), medically important drugs such as colistin (31.39 mg/fPU), tylosin (41.71 mg/fPU), doxycycline (81.81 mg/fPU), and enrofloxacin (26.19 mg/fPU) were the most frequently used antimicrobials for prophylactic or therapeutic use. Lincomycin was the most frequently used antimicrobial used in-feed (29.09 mg/fPU). Our findings suggest that the annual consumption of antimicrobials in the broiler sector in Pakistan could be as high as 568 tons. This alarmingly high consumption estimate is the first baseline study on antimicrobial use in animals in Pakistan. Our findings call for immediate actions to reduce antimicrobial use in Pakistan, and countries with comparable farming practices.

Background: Despite the urgent need for new, effective antibiotics, few antibiotics of value have entered the market during the past decades. Therefore, incentives have been developed to stimulate antibiotic R&D. For these incentives to be effective, geographic availability for recently approved antibiotics needs to be better understood. In this study, we analyze geographic availability and market introduction of antibiotics approved between 1999 and 2014., Material and Method: We identified antibiotics, considered new chemical entities (NCEs) for systemic use approved globally between 1999 and 2014, from national medicine agencies' lists of approved drugs, and data from the WHO Collaborating Center for Drug Statistics. Geographic availability was mapped using sales data from IQVIA, and analyzed with regards to class, indication, safety, and origin., Results: Of the 25 identified NCEs, only 12 had registered sales in more than 10 countries. NCEs with the widest geographic availability had registered sales in more than 70 countries within a ten-year timeframe and 30 countries within a three-year timeframe, spreading across five different geographic regions and three country income classes. Half (52%) of the NCEs had an indication for infections caused by antibiotic- resistant bacteria, little diversity was seen regarding target pathogen and indication. Antibiotics originated from and/or marketed by companies from the US or Europe had greater geographic availability compared to Japanese antibiotics, which seldom reached outside of Asia. For 20 NCEs developers chose to fully or partially sublicense marketing rights to a number of companies of different sizes., Conclusion: Our findings show great variation in geographic availability of antibiotics, indicating that availability in multiple regions and country income classes is possible, but rarely seen within a few years of market authorization. Sublicensing agreements between multiple companies was common practice. Moreover, differences were seen between countries regarding benefit/risk evaluations and company behavior. These findings could be a potential source of uncertainties, and create barriers to assure that working antibiotics are developed and made available according to public health needs., Competing Interests: We have the following interests. This research was partly funded by the DRIVE-AB Consortium, which aims to transform the way policymakers stimulate innovation, sustainable use, and equitable availability of antibiotics to meet unmet public health needs. DRIVE-AB is supported by the IMI Joint Undertaking under the DRIVE-AB grant agreement number 115618, the resources of which are composed of financial contribution from the European Union’s 7th Framework Programme and the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contribution. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Background: Understanding of the factors driving global antimicrobial resistance is limited. We analysed antimicrobial resistance and antibiotic consumption worldwide versus many potential contributing factors., Methods: Using three sources of data (ResistanceMap, the WHO 2014 report on antimicrobial resistance, and contemporary publications), we created two global indices of antimicrobial resistance for 103 countries using data from 2008 to 2014: Escherichia coli resistance-the global average prevalence of E coli bacteria that were resistant to third-generation cephalosporins and fluoroquinolones, and aggregate resistance-the combined average prevalence of E coli and Klebsiella spp resistant to third-generation cephalosporins, fluoroquinolones, and carbapenems, and meticillin-resistant Staphylococcus aureus. Antibiotic consumption data were obtained from the IQVIA MIDAS database. The World Bank DataBank was used to obtain data for governance, education, gross domestic product (GDP) per capita, health-care spending, and community infrastructure (eg, sanitation). A corruption index was derived using data from Transparency International. We examined associations between antimicrobial resistance and potential contributing factors using simple correlation for a univariate analysis and a logistic regression model for a multivariable analysis., Findings: In the univariate analysis, GDP per capita, education, infrastructure, public health-care spending, and antibiotic consumption were all inversely correlated with the two antimicrobial resistance indices, whereas higher temperatures, poorer governance, and the ratio of private to public health expenditure were positively correlated. In the multivariable regression analysis (confined to the 73 countries for which antibiotic consumption data were available) considering the effect of changes in indices on E coli resistance (R 2 0·54) and aggregate resistance (R 2 0·75), better infrastructure (p=0·014 and p=0·0052) and better governance (p=0·025 and p<0·0001) were associated with lower antimicrobial resistance indices. Antibiotic consumption was not significantly associated with either antimicrobial resistance index in the multivariable analysis (p=0·64 and p=0·070)., Interpretation: Reduction of antibiotic consumption will not be sufficient to control antimicrobial resistance because contagion-the spread of resistant strains and resistance genes-seems to be the dominant contributing factor. Improving sanitation, increasing access to clean water, and ensuring good governance, as well as increasing public health-care expenditure and better regulating the private health sector are all necessary to reduce global antimicrobial resistance., Funding: None., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Reducing inappropriate prescribing is key to mitigating antibiotic resistance, particularly in acute care settings. Clinicians' prescribing decisions are influenced by their judgments and actual or perceived patient expectations. Fuzzy trace theory predicts that patients and clinicians base such decisions on categorical gist representations that reflect the bottom-line understanding of information about antibiotics. However, due to clinicians' specialized training, the categorical gists driving clinicians' and patients' decisions might differ, which could result in mismatched expectations and inefficiencies in targeting interventions. We surveyed clinicians and patients from 2 large urban academic hospital emergency departments (EDs) and a sample of nonpatient subjects regarding their gist representations of antibiotic decisions, as well as relevant knowledge and expectations. Results were analyzed using exploratory factor analysis (EFA) and multifactor regression. In total, 149 clinicians (47% female; 74% white), 519 online subjects (45% female; 78% white), and 225 ED patients (61% female; 56% black) completed the survey. While clinicians demonstrated greater knowledge of antibiotics and concern about side effects than patients, the predominant categorical gist for both patients and clinicians was "why not take a risk," which compares the status quo of remaining sick to the possibility of benefit from antibiotics. This gist also predicted expectations and prior prescribing in the nonpatient sample. Other representations reflected the gist that "germs are germs" conflating bacteria and viruses, as well as perceptions of side effects and efficacy. Although individually rational, reliance on the "why not take a risk" representation can lead to socially suboptimal results, including antibiotic resistance and individual patient harm due to adverse events. Changing this representation could alter clinicians' and patients' expectations, suggesting opportunities to reduce overprescribing.

Bacteria commonly live in dense and genetically diverse communities associated with surfaces. In these communities, competition for resources and space is intense, and yet we understand little of how this affects the spread of antibiotic-resistant strains. Here, we study interactions between antibiotic-resistant and susceptible strains using in vitro competition experiments in the opportunistic pathogen Pseudomonas aeruginosa and in silico simulations. Selection for intracellular resistance to streptomycin is very strong in colonies, such that resistance is favoured at very low antibiotic doses. In contrast, selection for extracellular resistance to carbenicillin is weak in colonies, and high doses of antibiotic are required to select for resistance. Manipulating the density and spatial structure of colonies reveals that this difference is partly explained by the fact that the local degradation of carbenicillin by β-lactamase-secreting cells protects neighbouring sensitive cells from carbenicillin. In addition, we discover a second unexpected effect: the inducible elongation of cells in response to carbenicillin allows sensitive cells to better compete for the rapidly growing colony edge. These combined effects mean that antibiotic treatment can select against antibiotic-resistant strains, raising the possibility of treatment regimes that suppress sensitive strains while limiting the rise of antibiotic resistance. We argue that the detailed study of bacterial interactions will be fundamental to understanding and overcoming antibiotic resistance.

Background: Information about antimicrobial use is scarce and poorly understood among neonatal intensive care units (NICUs) in India. In this study, we describe antimicrobial use in eight NICUs using four point prevalence surveys (PPSs)., Methods: As part of the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children (GARPEC) study, one-day, cross-sectional, hospital-based PPSs were conducted four times between 1 February 2016 and 28 February 2017 in eight NICUs. Using a standardized web-based electronic data entry form, detailed data were collected for babies on antimicrobials., Results: A total of 403 babies were admitted to NICUs across all survey days, and 208 (51.6%) were prescribed one or more antimicrobials. Among 208 babies, 155 (74.5%) were prescribed antimicrobials for treatment of an active infection. Among 155 babies with an active infection, treatment was empiric in 109 (70.3%). Sepsis (108, 49.1%) was the most common reason for prescribing antimicrobials. Amikacin (17%) followed by meropenem (12%) were the two most commonly prescribed antimicrobials. For community-acquired sepsis, piperacillin-tazobactam (17.5%) was the most commonly prescribed drug. A combination of ampicillin and gentamicin was prescribed in only two babies (5%)., Conclusions: The recommended first-line antimicrobial agents, ampicillin and gentamicin, were rarely prescribed in Indian NICUs for community acquired neonatal sepsis., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Antibiotic resistance mechanisms originating in low- and middle- income countries are among the most common worldwide. Reducing unnecessary antibiotic use in India, the world's largest antibiotic consumer, is crucial to control antimicrobial resistance globally. Limited data describing factors influencing Indian clinicians to start or stop antibiotics are available., Methods: Febrile adults and children admitted to a public tertiary care hospital in Pune, India, were enrolled. Antibiotic usage and clinical history were recorded. Immunoassays for mosquito-borne disease and bacterial cultures were performed by protocol and clinician-directed testing. Clinical factors were assessed for association with empiric antibiotic initiation and discontinuation by day 5 using multivariable logistic regression and propensity score-matched Cox proportional hazard models., Results: Among 1486 participants, 683 (82%) adults and 614 (94%) children received empiric antibiotics. Participants suspected of having mosquito-borne disease were less likely to receive empiric antibiotics (adjusted odds ratio [AOR], 0.5; 95% confidence interval [CI], .4-.8). Empiric antibiotics were discontinued in 450 (35%) participants by day 5. Dengue or malaria testing performed before day 4 was positive in 162 (12%) participants, and was associated with antibiotic discontinuation (AOR, 1.7; 95% CI, 1.2-2.4). In a propensity score-matched model accounting for admission suspicion of mosquito-borne disease, positive dengue or malaria tests increased hazard of antibiotic discontinuation (hazard ratio, 1.6; 95% CI, 1.2-2.0)., Conclusions: Most patients with acute febrile illness in an Indian public hospital setting receive empiric antibiotics. Mosquito-borne disease identification is associated with reduced empiric antibiotic use and faster antibiotic discontinuation.

Tracking antibiotic consumption patterns over time and across countries could inform policies to optimize antibiotic prescribing and minimize antibiotic resistance, such as setting and enforcing per capita consumption targets or aiding investments in alternatives to antibiotics. In this study, we analyzed the trends and drivers of antibiotic consumption from 2000 to 2015 in 76 countries and projected total global antibiotic consumption through 2030. Between 2000 and 2015, antibiotic consumption, expressed in defined daily doses (DDD), increased 65% (21.1-34.8 billion DDDs), and the antibiotic consumption rate increased 39% (11.3-15.7 DDDs per 1,000 inhabitants per day). The increase was driven by low- and middle-income countries (LMICs), where rising consumption was correlated with gross domestic product per capita (GDPPC) growth ( P = 0.004). In high-income countries (HICs), although overall consumption increased modestly, DDDs per 1,000 inhabitants per day fell 4%, and there was no correlation with GDPPC. Of particular concern was the rapid increase in the use of last-resort compounds, both in HICs and LMICs, such as glycylcyclines, oxazolidinones, carbapenems, and polymyxins. Projections of global antibiotic consumption in 2030, assuming no policy changes, were up to 200% higher than the 42 billion DDDs estimated in 2015. Although antibiotic consumption rates in most LMICs remain lower than in HICs despite higher bacterial disease burden, consumption in LMICs is rapidly converging to rates similar to HICs. Reducing global consumption is critical for reducing the threat of antibiotic resistance, but reduction efforts must balance access limitations in LMICs and take account of local and global resistance patterns., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

In a policy forum, Daniel Schar and colleagues discuss the need for surveillance of antimicrobial consumption in animals in low- and middle-income countries and propose the establishment of antimicrobial consumption monitoring systems.

In this study, we retrospectively evaluated clinical outcomes of 75 patients with dual colistin- and carbapenem-resistant Klebsiella pneumoniae bloodstream infections over a 5-year period in a single tertiary care hospital in India. We observed a high in-hospital mortality rate of 69.3%. Our findings indicate the urgent need for new antibiotics to treat these infections., (Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Adherence to evidence-based antibiotic therapy guidelines for treatment of upper respiratory tract infections (URIs) varies widely among clinicians. Understanding this variability is key for reducing inappropriate prescribing., Objective: To measure how emergency department (ED) clinicians' perceptions of antibiotic prescribing risks affect their decision-making., Design: Clinician survey based on fuzzy-trace theory, a theory of medical decision-making, combined with retrospective data on prescribing outcomes for URI/pneumonia visits in two EDs. The survey predicts the categorical meanings, or gists, that individuals derive from given information., Participants: ED physicians, residents, and physician assistants (PAs) who completed surveys and treated patients with URI/pneumonia diagnoses between August 2014 and December 2015., Main Measures: Gists derived from survey responses and their association with rates of antibiotic prescribing per visit., Key Results: Of 4474 URI/pneumonia visits, 2874 (64.2%) had an antibiotic prescription. However, prescribing rates varied from 7% to 91% for the 69 clinicians surveyed (65.2% response rate). Clinicians who framed therapy-prescribing decisions as a categorical choice between continued illness and possibly beneficial treatment ("why not take a risk?" gist, which assumes antibiotic therapy is essentially harmless) had higher rates of prescribing (OR 1.28 [95% CI, 1.06-1.54]). Greater agreement with the "antibiotics may be harmful" gist was associated with lower prescribing rates (OR 0.81 [95% CI, 0.67-0.98])., Conclusions: Our results indicate that clinicians who perceive prescribing as a categorical choice between patients remaining ill or possibly improving from therapy are more likely to prescribe antibiotics. However, this strategy assumes that antibiotics are essentially harmless. Clinicians who framed decision-making as a choice between potential harms from therapy and continued patient illness (e.g., increased appreciation of potential harms) had lower prescribing rates. These results suggest that interventions to reduce inappropriate prescribing should emphasize the non-negligible possibility of serious side effects.

Importance: Potential research participants may assume that randomized trials comparing new interventions with older interventions always hypothesize greater efficacy for the new intervention, as in superiority trials. However, antibiotic trials frequently use "noninferiority" hypotheses allowing a degree of inferior efficacy deemed "clinically acceptable" compared with an older effective drug, in exchange for nonefficacy benefits (eg, decreased adverse effects). Considering these different benefit-harm trade-offs, proper informed consent necessitates supplying different information on the purposes of superiority and noninferiority trials., Objective: To determine the degree to which the study purpose is explained to potential participants in randomized clinical trials of antibiotics and the degree to which study protocols justify their selection of noninferiority hypotheses and amount of "clinically acceptable" inferiority., Design and Setting: Cross-sectional analysis of study protocols, statistical analysis plans (SAPs), and informed consent forms (ICFs) from clinical study reports submitted to the European Medicines Agency. The ICFs were read by both methodologists and patient investigators., Main Outcomes and Measures: Protocols and SAPs were used as the reference standard to determine prespecified primary hypothesis and record rationale for selection of noninferiority hypotheses and noninferiority margins. This information was cross-referenced against ICFs to determine whether ICFs explained the study purpose., Results: We obtained trial documents from 78 randomized trials with prespecified efficacy hypotheses (6 superiority, 72 noninferiority) for 17 antibiotics conducted between 1991 and 2011 that enrolled 39 407 patients. Fifty were included in the ICF analysis. All ICFs contained sections describing study purpose; however, none consistently conveyed study hypothesis to both methodologists and patient investigators. Methodologists found that 1 of 50 conveyed a study purpose. Patient investigators found that 11 of 50 conveyed a study purpose, 7 accurately and 4 inaccurately compared with the reference standard. Seventy-one of 72 noninferiority trial protocols or SAPs provided no rationale for selection of noninferiority hypothesis. None provided a clinical rationale for the chosen amount of decreased efficacy., Conclusions and Relevance: Patients were not accurately informed of study purpose, which raises questions regarding the ethics of informed consent in antibiotic trials. Noninferiority and superiority trials entail different benefit-harm trade-offs that must be conveyed for ethical informed consent.

Didier Wernli and colleagues discuss the role of monitoring in countering antimicrobial resistance.

Objective: The widespread use of antibiotics in humans and animals has contributed to growing rates of antibiotic resistance. Previously treatable bacterial infections now require the last line of antibiotics or are untreatable. The current antibiotic of last resort for carbapenem-resistant Gram-negative bacterial infections is often colistin. Evidence for the shifting pattern of colistin resistance and how the international community should respond are discussed in this review., Methods: The literature on colistin resistance was reviewed., Results: Plasmid-mediated colistin resistance encoded by mcr-1 was first documented in China during the routine surveillance of food animals. This has been followed by similar reports across a wide geographic area, in humans, animals, and the environment. The mcr-1 gene has been reported among human isolates in 29 countries, related to environmental samples in four countries, and in food animals and other animals in 28 countries. More recently, a second gene encoding resistance, mcr-2, has been isolated from porcine and bovine Escherichia coli., Conclusion: The emergence and horizontal transmission of colistin resistance highlights the need for heightened stewardship efforts across the One Health platform for this antibiotic of last resort, and indeed for all antibiotics used in animals and humans., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate the association between the income status of a country and the prevalence of antimicrobial resistance (AMR) in the three most common bacteria causing infections in hospitals and in the community: third-generation cephalosporin (3GC)-resistant Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), and 3GC-resistant Klebsiella species., Methods: Using 2013-2014 country-specific data from the ResistanceMap repository and the World Bank, the association between the prevalence of AMR in invasive samples and the gross national income (GNI) per capita was investigated through linear regression with robust standard errors. To account for non-linear association with the dependent variable, GNI per capita was log-transformed., Results: The models predicted an 11.3% (95% confidence interval (CI) 6.5-16.2%), 18.2% (95% CI 11-25.5%), and 12.3% (95% CI 5.5-19.1%) decrease in the prevalence of 3GC-resistant E. coli, 3GC-resistant Klebsiella species, and MRSA, respectively, for each log GNI per capita. The association was stronger for 3GC-resistant E. coli and Klebsiella species than for MRSA., Conclusions: A significant negative association between GNI per capita and the prevalence of MRSA and 3GC-resistant E. coli and Klebsiella species was found. These results underscore the urgent need for new policies aimed at reducing AMR in resource-poor settings., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: There have been no long-term studies on trends in antibiotic resistance (ABR) on a national scale in India. Using a private laboratory network, the ABR patterns of organisms most commonly associated with bacteremia, obtained from patients across India between 2008 and 2014, were examined., Methods: A retrospective study of patient blood cultures collected over a 7-year period (January 1, 2008-December 31, 2014) was conducted. Data on the microorganism(s) identified and their antimicrobial susceptibility were obtained from SRL Diagnostics (Mumbai, India)., Results: Of 135268 blood cultures, 18695 (14%) had at least one identified pathogen. In addition to continual high rates of methicillin-resistant Staphylococcus aureus (MRSA; approximately 44.2%), high resistance to nalidixic acid among Salmonella Typhi (98%) was observed, and carbapenem resistance increased in both Escherichia coli (7.8% to 11.5%; p=0.332) and Klebsiella pneumoniae (41.5% to 56.6%; p<0.001). Carbapenem resistance was also stable and high for both Acinetobacter species (approximately 69.6%) and Pseudomonas aeruginosa (approximately 49%). Resistance was also detected to colistin in the Gram-negatives and to vancomycin and linezolid in S. aureus., Conclusion: Increasing resistance to antibiotics of last-resort, particularly among Gram-negatives, suggests an urgent need for new antibiotics and improved antimicrobial stewardship programs in India., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Ramanan Laxminarayan and Ranjit Roy Chaudhury examine the factors encouraging the emergence of antibiotic resistance in India, the implications nationally and internationally, and what might be done to help.

Recent years have seen substantial improvements in life expectancy and access to antimicrobials, especially in low-income and lower-middle-income countries, but increasing pathogen resistance to antimicrobials threatens to roll back this progress. Resistant organisms in health-care and community settings pose a threat to survival rates from serious infections, including neonatal sepsis and health-care-associated infections, and limit the potential health benefits from surgeries, transplants, and cancer treatment. The challenge of simultaneously expanding appropriate access to antimicrobials, while restricting inappropriate access, particularly to expensive, newer generation antimicrobials, is unique in global health and requires new approaches to financing and delivering health care and a one-health perspective on the connections between pathogen transmission in animals and humans. Here, we describe the importance of effective antimicrobials. We assess the disease burden caused by limited access to antimicrobials, attributable to resistance to antimicrobials, and the potential effect of vaccines in restricting the need for antibiotics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The declining efficacy of existing antibiotics potentially jeopardises outcomes in patients undergoing medical procedures. We investigated the potential consequences of increases in antibiotic resistance on the ten most common surgical procedures and immunosuppressing cancer chemotherapies that rely on antibiotic prophylaxis in the USA., Methods: We searched the published scientific literature and identified meta-analyses and reviews of randomised controlled trials or quasi-randomised controlled trials (allocation done on the basis of a pseudo-random sequence-eg, odd/even hospital number or date of birth, alternation) to estimate the efficacy of antibiotic prophylaxis in preventing infections and infection-related deaths after surgical procedures and immunosuppressing cancer chemotherapy. We varied the identified effect sizes under different scenarios of reduction in the efficacy of antibiotic prophylaxis (10%, 30%, 70%, and 100% reductions) and estimated the additional number of infections and infection-related deaths per year in the USA for each scenario. We estimated the percentage of pathogens causing infections after these procedures that are resistant to standard prophylactic antibiotics in the USA., Findings: We estimate that between 38·7% and 50·9% of pathogens causing surgical site infections and 26·8% of pathogens causing infections after chemotherapy are resistant to standard prophylactic antibiotics in the USA. A 30% reduction in the efficacy of antibiotic prophylaxis for these procedures would result in 120,000 additional surgical site infections and infections after chemotherapy per year in the USA (ranging from 40,000 for a 10% reduction in efficacy to 280,000 for a 70% reduction in efficacy), and 6300 infection-related deaths (range: 2100 for a 10% reduction in efficacy, to 15,000 for a 70% reduction). We estimated that every year, 13,120 infections (42%) after prostate biopsy are attributable to resistance to fluoroquinolones in the USA., Interpretation: Increasing antibiotic resistance potentially threatens the safety and efficacy of surgical procedures and immunosuppressing chemotherapy. More data are needed to establish how antibiotic prophylaxis recommendations should be modified in the context of increasing rates of resistance., Funding: DRIVE-AB Consortium., (Copyright © 2015 Elsevier Ltd. All rights reserved.)