Antimicrobial stewardship and the antibiotic market: why “Reserve” drugs require new economic models

The World Health Organization (WHO) Access-Watch-Reserve (AWaRe) classification is a cornerstone of the global strategy against antimicrobial resistance. ¹ However, it contains a fundamental paradox that directly undermines the development of new drugs: Reserve antibiotics, by definition, must remain exclusively as a last option in the treatment of multidrug-resistant pathogens. ²

This restriction is appropriate from a public health perspective, as it reduces selective pressure and preserves the drug’s effectiveness for the future. But from a commercial standpoint, it is devastating.

Developing an antibiotic entails enormous costs—about 1.4 billion dollars for each approved drug. ³ The company investing these funds must recover its capital through sales. A Reserve antibiotic will have extremely low and predictably stable sales volumes over time, since it must remain a last-line option. When only a small fraction of patients with severe infections can receive the drug—and only when nothing else works—the economic return becomes marginal, insufficient to justify the initial investment. ⁴ This creates an irreducible structural problem. Market forces cannot solve it: the industry cannot increase sales volumes without violating the stewardship principle that justifies the very existence of the category. Nor can it apply a “premium pricing” strategy—charging very high prices to compensate for low volumes—because public health systems, especially in low- and middle-income countries where resistance is most severe, cannot afford prohibitively expensive drugs. ⁵ According to a WHO report, only 12 new antibiotics were approved between 2017 and 2021, with 10 belonging to existing classes that are prone to resistance. ⁶

As a result, large pharmaceutical companies have progressively abandoned antibiotic research, turning instead to drugs for chronic diseases, where the traditional commercial model works: high volumes, prolonged treatment duration, and large profit margins. ⁷ Research on Reserve antibiotics has remained primarily in the hands of small biotech firms and academic institutions—lack the capital needed to complete costly clinical trials and navigate complex regulatory processes. ⁸ This is the real issue to address: the inherently “restrictive” nature of Reserve antibiotics is simultaneously necessary for stewardship and incompatible with standard economic incentives.

This is the real issue to address: the inherently “restrictive” nature of Reserve antibiotics is simultaneously necessary for stewardship and incompatible with standard economic incentives. This is not simply a matter of “insufficient profit,” but a structural conflict between the public objective and the commercial model.

The solution requires innovation in the incentive structures themselves. Alternative models—such as market-entry rewards decoupled from sales volume, direct public funding, structured public–private partnerships, and subscription-based agreements that guarantee predictable revenue regardless of prescriptions—represent attempts to reconcile these two imperatives.^9,10

In Italy, Agenzia Italiana del Farmaco (AIFA) has classified “Reserve” antibiotics as innovative medicines with automatic access to the Innovative Medicines Fund, ¹¹ supported by 100 million euros. In France, Germany, and the United States, implemented interventions have primarily focused on granting exemptions from standard cost-containment mechanisms to allow higher prices for selected antibacterial agents; in the United States, additional measures include extended market exclusivity and accelerated regulatory review for certain antibacterials. The United Kingdom is piloting a subscription-based model based on fixed annual payments to manufacturers in exchange for guaranteed continuous supply, while Sweden is testing contracts that ensure a minimum annual revenue for selected antibacterial products. ¹²

Reserve antibiotics face a conflict between stewardship and commercial viability, threatening future innovation. Coordinated action by regulators, policymakers, and supranational agencies is urgently needed, including incentive-based models to ensure sustainable development and the availability of these critical drugs.