Antibiotic prescriptions are often measured in days. But their effects on the gut microbiome may be measured in years. 

That’s one concerning finding from a recent study in Nature Medicine that examined antibiotic prescribing data and fecal metagenomic samples from nearly 15,000 adults in Sweden. Researchers found that several commonly used antibiotics were associated with reduced gut microbial diversity years after use. 

Clindamycin and fluoroquinolones showed some of the most pronounced associations, with detectable effects lasting up to eight years after treatment. A single course of clindamycin taken within the year before sampling was associated with an average of 47 fewer bacterial species detected in the gut. 

Concerns over antibiotics affecting gut health are nothing new. What has changed, however, is our ability to characterize and quantify the biological footprint of antibiotic exposure. Advances in sequencing technology and microbiome research have expanded our understanding of the trillions of microorganisms that inhabit the human body and how they help regulate digestion, metabolism, immune function, and overall health. That, in turn, has fueled interest in antimicrobial approaches designed to minimize microbiome disruption, from narrow-spectrum antibiotics and companion diagnostics to therapies designed to restore beneficial microbial communities and better prevent infection. 

The paradoxical business of antibiotics

But while these advances in microbiome science are reshaping how policymakers and researchers think about antimicrobial innovation, the yawning gap between scientific possibility and commercial reality is only widening. Calls for more targeted antibiotics often gloss over the fundamental market challenges that have stymied investment in antimicrobials and innovation in the field. Without action to address the forces that have hollowed out antibiotic research and development (R&D), many of these innovations may never advance far enough to reach patients. 

Investment in antibiotics remains appallingly low given the scale of the challenge. Of the approximately $26 billion invested in venture-backed biotechnology companies in 2024, only about $150 million, or 0.6%, went to companies developing antibacterials. That’s because there is no compellinginvestment thesis at the heart of the antibiotic market.

Calls for more targeted antibiotics often gloss over the fundamental market challenges that have stymied investment in antimicrobials and innovation in the field.

The business of antibiotics is paradoxical. The need for new antibiotics is urgent, yet the stewardship practices that preserve their effectiveness significantly limit their commercial potential, making it extraordinarily difficult to generate a return on investment. As a result, most large pharmaceutical companies have abandoned antibiotic R&D, leaving the majority of innovation to small, cash-strapped biotechs. 

Numerous biotechnology companies have advanced antibiotics through the clinic and obtained regulatory approval, only to declare bankruptcy or be sold for a fraction of invested capital. The most recent example is Iterum Therapeutics, which received US Food and Drug Administration approval for a broad-spectrum oral penem antibiotic but announced plans to wind down operations this spring, just seven months after bringing the drug to market. 

Investors are right to cast a jaundiced eye on antibiotics. If broad-spectrum antibiotics, which can be used against a wider range of pathogens and offer a larger potential market, have struggled to generate sustainable returns, how can a narrow-spectrum antibiotic realistically be expected to perform better without carrying a hefty price tag? 

That is what makes the growing interest in microbiome-sparing antibiotic innovation so tantalizingly frustrating. Many of the approaches that are most likely to preserve beneficial bacteria, including narrow-spectrum therapies, will inevitably target smaller patient populations, further constraining the drug’s commercial potential. It is the equivalent of asking antibiotic developers to do more with less, to raise hundreds of millions of dollars in a hostile financing environment to develop increasingly sophisticated therapies for a smaller segment of a market that already struggles to support products with broader use and larger patient populations.

One notable effort to address this challenge comes from Wellcome Leap, which recently launched its Focused Antibiotics program, committing $50 million to support efforts to reformulate existing antibiotics to target their activity at the site of infection, avoiding damage to beneficial bacteria while maintaining therapeutic efficacy.

A pressing need for supportive policy

Philanthropy, however, can take drug development only so far. For a problem as significant and costly as antimicrobial resistance, the type of innovation we need will emerge only if policymakers create the conditions for it to flourish. Until the downstream dysfunction of the antibiotic market is addressed, many promising innovations will be unable to advance through development and reach the patients who need them. 

If policymakers want antibiotics that are more precise and less disruptive to beneficial bacteria, they must create the market conditions that make them investable. That is the aim of pull incentives such as the PASTEUR Act, which would delink an antibiotic’s revenue from its sales volume, giving investors greater confidence that successful products will be rewarded and encouraging the kind of scientific risk-taking that true innovation requires. 

A well-designed pull incentive can also offer an elegant mechanism for encouraging microbiome-focused innovation. If the PASTEUR Act were enacted, lawmakers could design eligibility criteria that place greater emphasis on microbiome-sparing therapies and other innovative approaches that leverage beneficial bacteria to prevent or treat infection.

Thoughtful policy can help put us on the right path.

We are still in the early stages of microbiome research, and many questions remain. Do we even know enough to define harmful dysbiosis (microbiome imbalance)? How should we evaluate antimicrobial therapies that better preserve beneficial bacteria? 

As our understanding and appreciation of these microbial communities grows, so will our expectations for improved antibiotics. Ambition alone, however, will not take us there. But thoughtful policy can help put us on the right path.  

Dr. Skinner is CEO of the AMR Action Fund and a representative member of the Presidential Advisory Committee on Combating Antibiotic Resistance (PACCARB).