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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.

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.With rising rates of antibiotic resistance, it is essential that new antibiotics are developed. In this Review, Theuretzbacher et al. take stock of the preclinical antibiotic pipeline and discuss challenges and opportunities for the discovery and development of novel antibacterial therapies.

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.

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.

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.

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. Non-traditional antibacterial agents are challenging to develop. In this Perspective, the authors argue that the distinction between traditional and non-traditional agents has only limited relevance for regulatory purposes, although products with non-traditional goals focused on population-level benefits might benefit from extension of current paradigms.

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.

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. 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. 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. 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.

Policy declarations from the G7 and other high-level meetings call for increased incentives for antimicrobial research and development (R&D). Governments fund push incentives like CARB-X and GARDP, and G7 countries are now designing pull incentives—financial rewards given to manufacturers post-market authorization that are intended to encourage the creation and introduction of novel antimicrobials. Germany has declared previously at the G7 that it has developed a pull incentive that will increase revenues from sales of important new antimicrobials, principally by exempting them from some aspects of health technology benefit assessments and reference pricing, which should result in higher prices. This policy move is the latest in a series of reforms that aim to improve the marketability of antimicrobials in Germany. This paper examines Germany’s reforms and contributes to the ongoing debate about the merits of its approach in light of R&D and access issues impacting the country, particularly in comparison to pull incentives such as revenue guarantees or subscriptions that delink revenue from sales volume. We find that in order for Germany to produce the same impact on antimicrobial revenues as a delinked pull incentive, it either needs to increase the volume of antimicrobials used or increase prices for these drugs by as much as 3.3-times current values.