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Competing Interests: MB is the Executive Director of GARDP. KO is the Executive Director of CARB-X. J-AR is the Chief Executive Officer of the Wellcome Trust. We declare no other competing interests.

In June, 2023, the Council of the EU published a recommendation that the European Commission should contribute to the design and governance of an EU cross-country pull incentive to stimulate antimicrobial innovation and access. In this Personal View, we discuss six key considerations to support the implementation of the new pull incentive-ie, the size of the potential pull incentive and possible contributions of the member states, design of the incentive model, interplay of the new pull incentive with the proposed revisions of the EU pharmaceutical legislation, roles and responsibilities of both the EU and member states, balance between pull and push incentives, and global cooperation and responsibility. As the involvement of the member states with the EU pull incentive will be voluntary, member states should have confidence that the processes used to identify eligible antimicrobials, negotiate terms and conditions, and oversee access agreements are transparent, inclusive, and methodologically robust., Competing Interests: Declaration of interests MA declares consultancy fees from the European Observatory on Health Systems and Policies. AT declares consultancy fees from the Centre for Global Development. KO is the principal investigator and executive director of Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) and also declares honoraria for academic lectures at Tufts University, Memorial Sloan Kettering, and the Sanger Institute. EM declares no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The increasing number of bacterial infections globally that do not respond to any available antibiotics indicates a need to invest in-and ensure access to-new antibiotics, vaccines, and diagnostics. The traditional model of drug development, which depends on substantial revenues to motivate investment, is no longer economically viable without push and pull incentives. Moreover, drugs developed through these mechanisms are unlikely to be affordable for all patients in need, particularly in low-income and middle-income countries. New, publicly funded models based on public-private partnerships could support investment in antibiotics and novel alternatives, and lower patients' out-of-pocket costs, making drugs more accessible. Cost reductions can be achieved with public goods, such as clinical trial networks and platform-based quality assurance, manufacturing, and product development support. Preserving antibiotic effectiveness relies on accurate and timely diagnosis; however scaling up diagnostics faces technological, economic, and behavioural challenges. New technologies appeared during the COVID-19 pandemic, but there is a need for a deeper understanding of market, physician, and consumer behaviour to improve the use of diagnostics in patient management. Ensuring sustainable access to antibiotics also requires infection prevention. Vaccines offer the potential to prevent infections from drug-resistant pathogens, but funding for vaccine development has been scarce in this context. The High-Level Meeting of the UN General Assembly in 2024 offers an opportunity to rethink how research and development can be reoriented to serve disease management, prevention, patient access, and antibiotic stewardship., Competing Interests: Declaration of interests A meeting held to coordinate this Series paper was supported by the Bill & Melinda Gates Foundation (INV-055356 to RL) and the Africa Centres for Disease Control and Prevention (to all authors). Neither funder had any role in the design, writing, or decision to submit this paper for publication. RL has received grant funding from the National Science Foundation (CCF1918628). HW has received grant funding from Pfizer, the Wellcome Trust, ZonMW, the International Society of Antimicrobial Chemotherapy, and the International Centre for Antimicrobial Resistance Solutions; has received travel support from the European Society of Clinical Microbiology and Infectious Diseases to attend the European Congress of Clinical Microbiology and Infectious Diseases; has participated on the data safety monitoring board for the BCG PRIME trial; and has received research materials from Cepheid. PS is an employee of the Gates Foundation but authored this Series paper in her capacity as an individual expert on vaccines. KR received funding for the antimicrobial resistance landscape work in this Series paper from CARB-X and is currently employed by FIND. The views reflected in this Series paper are those of the authors and do not necessarily reflect those of the organisations with which they are affiliated. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved including those for text and data mining, AI training, and similar technologies.)

Background: Inaccessibility of medicines in low- and middle-income countries is a frequent challenge. Yet it is typically assumed that high-income countries have complete access to the full arsenal of medicines. This study tests this assumption for new antibacterials, which are saved as a last resort in order to prevent the development of resistance, resulting in insufficient revenues to offset costs. Prior studies report only regulatory approval, missing the important lag that occurs between approval and commercial launch, although some antibiotics never launch in some countries., Methods: We identified all antibacterials approved and launched in the G7 and 7 other high-income countries in Europe for the decade beginning 1 January 2010, using quantitative methods to explore associations., Results: Eighteen new antibacterials were identified. The majority were accessible in only 3 countries (United States, United Kingdom, and Sweden), with the remaining 11 high-income countries having access to less than half of them. European marketing authorization did not lead to automatic European access, as 14 of the antibacterials were approved by the European Medicines Agency but many fewer were commercially launched. There was no significant difference in access between "innovative" and "noninnovative" antibacterials. Median annual sales in the first launched market (generally the United States) for these 18 antibiotics were low, $16.2M., Conclusions: Patient access to new antibacterials is limited in some high-income countries including Canada, Japan, France, Germany, Italy, and Spain. With low expected sales, companies may have decided to delay or forego commercialization due to expectations of insufficient profitability., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

To address the complex challenge of global antimicrobial resistance (AMR), a pandemic treaty should include mechanisms that 1) equitably address the access gap for antimicrobials, diagnostic technologies, and alternative therapies; 2) equitably conserve antimicrobials to sustain effectiveness and access across time and space; 3) equitably finance the investment, discovery, development, and distribution of new technologies; and 4) equitably finance and establish greater upstream and midstream infection prevention measures globally. Biodiversity, climate, and nuclear governance offer lessons for addressing these challenges.

In the wake of COVID-19, the World Health Organization established an Intergovernmental Negotiating Body to negotiate a new instrument for pandemic prevention, preparedness, and response. This special issue of the Journal of Law, Medicine & Ethics brings together multidisciplinary scholarship to address the question of whether antimicrobial resistance should be included in this new instrument. Drawing from disciplines including law, anthropology, history, public health, public policy, economics, and veterinary medicine, this special issue explores the inclusion of AMR within the Pandemic Instrument from three perspectives: first, through the lens of global AMR governance, second, from the perspective of technical governance challenges and opportunities affecting the global ability to address AMR and future pandemics, and third, from the perspective of pandemic instrument mechanisms for strengthening global AMR governance. Each paper makes a concrete recommendation with respect to the importance of including AMR within the scope of the pandemic instrument.

Antimicrobial resistance is a serious challenge to the success and sustainability of our healthcare systems. There has been increasing policy attention given to antimicrobial resistance in the last few years, and increased amounts of funding have been channeled into funding for research and development of antimicrobial agents. Nevertheless, manufacturers doubt whether there will be a market for new antimicrobial technologies sufficient to enable them to recoup their investment. Health technology assessment (HTA) has a critical role in creating confidence that if valuable technologies can be developed they will be reimbursed at a level that captures their true value. We identify 3 deficiencies of current HTA processes for appraising antimicrobial agents: a methods-centric approach rather than problem-centric approach for dealing with new challenges, a lack of tools for thinking about changing patterns of infection, and the absence of an approach to epidemiological risks. We argue that, to play their role more effectively, HTA agencies need to broaden their methodological tool kit, design and communicate their analysis to a wider set of users, and incorporate long-term policy goals, such as containing resistance, as part of their evaluation criteria alongside immediate health gains., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Antibacterial medicines should be foundational for modern medicine-a key part of the infrastructure of contemporary practice. Recently, however, antibacterials have struggled commercially. Even with "push" incentives (grants paid before regulatory approval), antibacterials have failed on the market because revenues are tied to volume sold. There are policy initiatives under way in the United States and United Kingdom that explore paying for exceptional antibacterials with "pull" incentives (paid after regulatory approval) by delinking the payments from volume via other payment formats such as market entry rewards and subscriptions. This article discusses these initiatives but also proposes an expected net present value model for calculating the global incentives required to create a functional antibacterial market, exploring options such as antibacterial subscriptions, market entry rewards, push incentives, higher prices, and drug development through charitable efforts. The model estimates that current push incentives should be continued, but governments must also enact pull incentives that will add several billion dollars to the global revenue stream of a highly innovative antibacterial, reduced by any grants received supporting clinical development of that product. The amounts in the proposed Pioneering Antibiotic Subscriptions to End Upsurging Resistance (PASTEUR) Act of 2021 and a UK pilot program are well within the bounds of an effective antibacterial pull incentive.

Infection is the second leading cause of death in patients with cancer. Loss of efficacy in antibiotics due to antibiotic resistance in bacteria is an urgent threat against the continuing success of cancer therapy. In this review, the authors focus on recent updates on the impact of antibiotic resistance in the cancer setting, particularly on the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). This review highlights the health and financial impact of antibiotic resistance in patients with cancer. Furthermore, the authors recommend measures to control the emergence of antibiotic resistance, highlighting the risk factors associated with cancer care. A lack of data in the etiology of infections, specifically in oncology patients in United States, is identified as a concern, and the authors advocate for a centralized and specialized surveillance system for patients with cancer to predict and prevent the emergence of antibiotic resistance. Finding better ways to predict, prevent, and treat antibiotic-resistant infections will have a major positive impact on the care of those with cancer., (© 2021 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The diagnosis-related group (DRG) is a payment system introduced to standardize healthcare costs. However, reimbursement for treatment of infections does not always cover costs., Methods: We used 2015-2018 data from 92 US hospitals in the Becton Dickinson Insights Research Database to compare the financial burden of hospital admissions within non-infection DRGs for patients with a bacterial infection (INF+) versus those without an infection (INF-). Included patients were adults with a hospital length of stay (LOS) ≥3 days and evidence of infection. Multi-variable adjusted analyses via generalized linear mixed models were used to evaluate the impact of an infection on outcomes., Results: We analyzed data from 133,423 INF+ admissions and 170,531 INF- admissions. Infections were associated with an approximately two-fold increase in model-estimated LOS (9.2 vs 4.8 d; P < .001) and intensive care unit LOS (5.1 vs 2.8 d; P < .001). The average additional hospital cost for INF+ versus INF- admissions was $10,326 per admission (P < .001) and the average loss after reimbursement was $1,067 (P = .006). Only private insurance payers had a positive margin., Conclusions: Current reimbursement options for infections result in significant hospital financial burden. Reimbursement models should be reconsidered to enable adoption of costlier diagnostics and antimicrobials., (Copyright © 2021 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

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.

Objectives/purpose: The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level., Methods: GAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. For this project, the Network operated by means of Delphi rounds, teleconferences and face-to-face meetings. The resulting costing framework takes a bottom-up approach to incorporate all relevant costs imposed by an AMR bacterial microbe in a patient, in an animal, or in the environment up through to the societal level., Results: The framework itemizes the epidemiological data as well as the direct and indirect cost components needed to build a realistic cost picture for AMR. While the framework lists a large number of relevant pathogens for which this framework could be used to explore the costs, the framework is sufficiently generic to facilitate the costing of other resistant pathogens, including those of other aetiologies., Conclusion: In order to conduct cost-effectiveness analyses to choose amongst different AMR-related interventions at local level, the costing of AMR should be done according to local epidemiological priorities and local health service norms. Yet the use of a common framework across settings allows for the results of such studies to contribute to cumulative estimates that can serve as the basis of broader policy decisions at the international level such as how to steer R&D funding and how to prioritize AMR amongst other issues. Indeed, it is only by building a realistic cost picture that we can make informed decisions on how best to tackle major health threats.

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.)

While antibiotics are a key infrastructure underpinning modern medicine, evolution will continue to undermine their effectiveness, requiring continuous investment to sustain antibiotic effectiveness. The antibiotic R&D ecosystem is in peril, moving towards collapse. Key stakeholders have identified pull incentives such as Market Entry Rewards or subscription models as the key long-term solution. If substantial Market Entry Rewards or other pull incentives become possible, there is every reason to expect that for-profit companies will return to the antibiotic field. However, the political and financial will to develop such Market Entry Rewards or other similar incentives may be difficult to muster in the timeframes needed to prevent further diminishment of antibiotic research and development, especially if large drug companies are seen as substantial beneficiaries of these taxpayer-funded pull incentives. Bridging solutions are required from private actors in the interim. This article explores potential solutions led by private actors, including (1) traditional for-profit companies; (2) non-profit enterprises; and (3) public benefit corporations with lower profit expectations, akin to a public utility. All face similar commercial struggles, but nonprofits and public benefit corporations can accept lower profit expectations and might be more politically attractive recipients of pull incentives., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of non-traditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work, focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.

In 2013, a Lancet Infectious Diseases Commission described the state of antimicrobial resistance worldwide. Since then, greater awareness of the public health ramifications of antimicrobial resistance has led to national actions and global initiatives, including a resolution at the high-level meeting of the UN General Assembly in 2016. Progress in addressing this issue has ranged from a ban on irrational drug combinations in India to commitments to ban colistin as a growth promoter in animals, improve hospital infection control, and implement better antimicrobial stewardship. Funds have been mobilised, and regulatory barriers to new antibiotic development have been relaxed. These efforts have been episodic and uneven across countries, however. Sustained funding for antimicrobial resistance and globally harmonised targets to monitor progress are still urgently needed. Except for in a few leading countries, antimicrobial resistance has not captured the sustained focus of national leaders and country-level actors, including care providers., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In the face of rising rates of antibacterial resistance, many responses are being pursued in parallel, including 'non-traditional' antibacterial agents (agents that are not small-molecule drugs and/or do not act by directly targeting bacterial components necessary for bacterial growth). In this Perspective, we argue that the distinction between traditional and non-traditional agents has only limited relevance for regulatory purposes. Rather, most agents in both categories can and should be developed using standard measures of clinical efficacy demonstrated with non-inferiority or superiority trial designs according to existing regulatory frameworks. There may, however, be products with non-traditional goals focused on population-level benefits that would benefit from extension of current paradigms. Discussion of such potential paradigms should be undertaken by the development community.

We compared antibiotic prescribing for children with and those without an underlying chronic condition associated with increased risk for invasive pneumococcal disease. Children with a chronic condition had significantly greater cumulative exposure to antibiotics and higher rates of prescriptions per person-year than those without a chronic condition; this population is at increased risk for the emergence of multidrug-resistant pathogens., (© The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

The need for new "pull" incentives to stimulate antibiotic R&D is widely recognized. Due to the global diversity of health systems, combined with different challenges faced by antibiotics used in different types of healthcare settings, there is no one-size-fits-all solution. Instead, different "pull" incentives should be tailored to local contexts, priorities, and antibiotic types. Policymakers and industry should collaborate to identify appropriate solutions at the local, regional, and global levels.

Background: Antibiotic innovation has dwindled to dangerously low levels in the past 30 years. Since resistance continues to evolve, this innovation deficit can have perilous consequences on patients. A number of new incentives have been suggested to stimulate greater antibacterial drug innovation. To design effective solutions, a greater understanding is needed of actual antibiotic discovery and development costs and timelines. Small and medium-sized enterprises (SMEs) undertake most discovery and early phase development for antibiotics and other drugs. This paper attempts to gather a better understanding of SMEs' targets, costs, and durations related to discovery and early phase development of antibacterial therapies., Methods: DRIVE-AB, a project focused on developing new economic incentives to stimulate antibacterial innovation, held a European stakeholder meeting in February 2015. All SMEs invited to this meeting ( n  = 44) were subsequently sent a survey to gather more data regarding their areas of activity, completed and expected development costs and timelines, and business models., Results: Twenty-five companies responded to the survey. Respondents were primarily small companies each focusing on developing 1 to 3 new antibiotics, focused on pathogens of public health importance. Most have not yet completed any clinical trials. They have reported ranges of discovery and development out-of-pocket costs that appear to be less expensive than other studies of general pharmaceutical research and development (R&D) costs. The duration ranges reported for completing each phase of R&D are highly variable when compared to previously published general pharmaceutical innovation average durations. However, our sample population is small and may not be fully representative of all relevant antibiotic SMEs., Conclusions: The data collected by this study provide important insights and estimates about R&D in European SMEs focusing on antibiotics, which can be combined with other data to design incentives to stimulate antibacterial innovation. The variation implies that costs and durations are difficult to generalize due to the unique characteristics of each antibiotic project and depend on individual business strategies and circumstances., Competing Interests: Approval was sought for the research portfolio from the Norwegian Committees for Medical and Health Research in December 2015. The Committee determined in February 2016 that ethical approval was unnecessary since the research did not involve patients, animals or other biological substances. Written, informed consent was not obtained from survey respondents. However, they were informed that the data from the survey would be held strictly confidential and that their participation was completely voluntary with no impact on any interaction with the research project DRIVE-AB, its partners, the European Union, or any government.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs., Methods: We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria., Findings: We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier., Interpretation: Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae, and H pylori., Funding: World Health Organization., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A weak antibiotic pipeline and the increase in drug-resistant pathogens have led to calls for more new antibiotics. Eight new antibiotics were approved by the U.S. Food and Drug Administration (FDA) between January 2010 and December 2015: ceftaroline, fidaxomicin, bedaquiline, dalbavancin, tedizolid, oritavancin, ceftolozane-tazobactam, and ceftazidime-avibactam. This study evaluates the development course and pivotal trials of these antibiotics for their innovativeness, development process, documented patient outcomes, and cost. Data sources were FDA approval packages and databases (January 2010 to December 2015); the Red Book (Truven Health Analytics); Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (FDA); and supplementary information from company filings, press releases, and media reports. Four antibiotics were approved for acute bacterial skin and skin-structure infection. Seven had similar mechanisms of action to those of previously approved drugs. Six were initially developed by small to midsized companies, and 7 are currently marketed by 1 of 3 large companies. The drugs spent a median of 6.2 years in clinical trials (interquartile range [IQR], 5.4 to 8.8 years) and 8 months in FDA review (IQR, 7.5 to 8 months). The median number of patients enrolled in the pivotal trials was 666 (IQR, 553 to 739 patients; full range, 44 to 1005 patients), and median trial duration was 18 months (IQR, 15 to 22 months). Seven drugs were approved on the basis of pivotal trials evaluating noninferiority. One drug demonstrated superiority on an exploratory secondary end point, 2 showed decreased efficacy in patients with renal insufficiency, and 1 showed increased mortality compared with older drugs. Seven of the drugs are substantially more expensive than their trial comparators. Limitations are that future research may show benefit to patients, new drugs from older classes may show superior effectiveness in specific patient populations, and initial U.S. prices for each new antibiotic were obtained from public sources. Recently marketed antibiotics are more expensive but have been approved without evidence of clinical superiority.

A global response to the chronic shortfall in antibiotic innovation is urgently needed to combat antimicrobial resistance. Here, we introduce CARB-X, a new global public-private partnership that will invest more than US$350 million in the next 5 years to accelerate the progression of a diverse portfolio of innovative antibacterial products into clinical trials.

Kevin Outterson and colleagues outline a model to address access, conservation, and innovation of antibiotics.

A serious need to spur antibiotic innovation has arisen because of the lack of antibiotics to combat certain conditions and the overuse of other antibiotics leading to greater antibiotic resistance. In response to this need, proposals have been made to Congress to fund antibiotic research through a voucher program for new antibiotics, which would delay generic entry for any drug, even potential blockbuster lifesaving generics. We find this proposal to be inefficient, in part because of the mismatch between the private value of the voucher and the public value of the antibiotic innovation. However, vouchers have the political advantage in the United States of being able to raise sufficient amounts of money without annual appropriations from Congress. We propose that if antibiotic vouchers are to be considered, the design should include dollar and time caps to limit their volatility, sufficient advance notice to protect generic manufacturers, and market-based linkages between the value of the voucher and the value of the antibiotic innovation. We also explore a second option: The federal government could auction vouchers to the highest bidders and use the money to create an antibiotics innovation fund., (Project HOPE—The People-to-People Health Foundation, Inc.)

Despite the life-saving ability of antibiotics and their importance as a key enabler of all of modern health care, their effectiveness is now threatened by a rising tide of resistance. Unfortunately, the antibiotic pipeline does not match health needs because of challenges in discovery and development, as well as the poor economics of antibiotics. Discovery and development are being addressed by a range of public-private partnerships; however, correcting the poor economics of antibiotics will need an overhaul of the present business model on a worldwide scale. Discussions are now converging on delinking reward from antibiotic sales through prizes, milestone payments, or insurance-like models in which innovation is rewarded with a fixed series of payments of a predictable size. Rewarding all drugs with the same payments could create perverse incentives to produce drugs that provide the least possible innovation. Thus, we propose a payment model using a graded array of benchmarked rewards designed to encourage the development of antibiotics with the greatest societal value, together with appropriate worldwide access to antibiotics to maximise human health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Securing access to effective antimicrobials is one of the greatest challenges today. Until now, efforts to address this issue have been isolated and uncoordinated, with little focus on sustainable and international solutions. Global collective action is necessary to improve access to life-saving antimicrobials, conserving them, and ensuring continued innovation. Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. WHO alone will not be able to drive these actions. It will require a multisector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In March 2015, the Dag Hammarskjöld Foundation convened a workshop in Uppsala, Sweden to address questions about antibiotic resistance, in partnership with the Global Strategy Lab, the Journal of Law, Medicine & Ethics (JLME), the Norwegian Institute of Public Health, and ReAct - Action on Antibiotic Resistance. Eleven concise articles were commissioned to explore whether ABR depended on global collective action, and if so, what tools could help states and non-state actors to achieve it. This article introduces that collection, which is found in an online-only symposium at aslme.org., (© 2015 American Society of Law, Medicine & Ethics, Inc.)

Multidrug-resistant bacterial diseases pose serious and growing threats to human health. While innovation is important to all areas of health research, it is uniquely important in antibiotics. Resistance destroys the fruit of prior research, making it necessary to constantly innovate to avoid falling back into a pre-antibiotic era. But investment is declining in antibiotics, driven by competition from older antibiotics, the cost and uncertainty of the development process, and limited reimbursement incentives. Good public health practices curb inappropriate antibiotic use, making return on investment challenging in payment systems based on sales volume. We assess the impact of recent initiatives to improve antibiotic innovation, reflecting experience with all sixty-seven new molecular entity antibiotics approved by the Food and Drug Administration since 1980. Our analysis incorporates data and insights derived from several multistakeholder initiatives under way involving governments and the private sector on both sides of the Atlantic. We propose three specific reforms that could revitalize innovations that protect public health, while promoting long-term sustainability: increased incentives for antibiotic research and development, surveillance, and stewardship; greater targeting of incentives to high-priority public health needs, including reimbursement that is delinked from volume of drug use; and enhanced global collaboration, including a global treaty., (Project HOPE—The People-to-People Health Foundation, Inc.)