Expanding antibiotic, vaccine, and diagnostics development and access to tackle antimicrobial resistance.

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.

Patient Access in 14 High-Income Countries to New Antibacterials Approved by the US Food and Drug Administration, European Medicines Agency, Japanese Pharmaceuticals and Medical Devices Agency, or Health Canada, 2010-2020.

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.

A Pandemic Instrument Can Start Turning Collective Problems into Collective Solutions by Governing the Common-Pool Resource of Antimicrobial Effectiveness.

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.

Introduction: AMR Belongs in the Pandemic Instrument.

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.

Estimating The Appropriate Size Of Global Pull Incentives For Antibacterial Medicines.

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.

Antimicrobial Resistance: Is Health Technology Assessment Part of the Solution or Part of the Problem?

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.

Antibiotic resistance in the patient with cancer: Escalating challenges and paths forward.

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.

The effect of generic market entry on antibiotic prescriptions in the United States.

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.

The impact of infections on reimbursement in 92 US hospitals, 2015-2018.

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.

A one health framework to estimate the cost of antimicrobial resistance.

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.

Setting the standard: multidisciplinary hallmarks for structural, equitable and tracked antibiotic policy.

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.

Evaluating for-profit public benefit corporations as an additional structure for antibiotic development and commercialization.

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.

The Lancet Infectious Diseases Commission on antimicrobial resistance: 6 years later.

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.