WHO, CARB-X, and FDA Take Action on Antibiotic Resistance Crisis

The World Health Organization published blueprints to guide development of urgently needed new antibiotics for three types of bacterial infections. The three new target product profiles focus on severe multidrug-resistant gram-negative infections caused by carbapenem-resistant Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa; severe antibiotic-resistant gram-positive infections in immune-suppressed and critically ill patients, with a focus on Enterococcus faecium; and community-acquired and health care-associated bacterial meningitis.

The purpose of target product profiles is to help accelerate the drug development process—and establish priorities for researchers, funders, and developers—by outlining the desired characteristics for new antibiotics. They describe the intended use, target populations, mechanism of action, and route of administrations, and define clear targets for quality, safety, efficacy, pharmacokinetics, access, and affordability. They are intended to facilitate the most expeditious development of novel antibiotics addressing the greatest and most urgent public health needs posed by antimicrobial resistance.

All three of the targeted infection types are currently treated with antibiotics that are becoming less effective as drug resistance rises, and there are few candidates in the antibiotic pipeline to provide new treatment options. The aim of the three new target product profiles is to align antibacterial product development with the WHO's bacterial priority pathogens list, prioritize infections that lead to high morbidity and mortality, and incentivize and de-risk antibiotic development.

The scientific community has developed and approved new antibiotics in recent years, but this is unfortunately not sufficient to catch up with evolving drug-resistance bacteria, especially against those of greatest concern, according to the director of antimicrobial resistance at the WHO.

CARB-X announced that it's awarding $1.2 million to a research team at Harvard University to develop enhanced antibiotics for multidrug-resistant bacteria. The award will fund preclinical development of a new class of antibiotics that target the lipoprotein transport system in multidrug-resistant gram-negative bacterial pathogens—such as Escherichia coli and Klebsiella pneumoniae—that cause urinary tract infections, bloodstream infections, and pneumonia. Lipoproteins play a critical role in gram-negative bacteria's pathogenicity and drug resistance.

Drug-resistant E. coli and K. pneumoniae cause a significant number of life-threatening infections worldwide, yet the pipeline for novel gram-negative antibiotics remains dangerously thin. The award supports a highly differentiated approach that, if successful, targets these priority pathogens with a narrow-spectrum mechanism designed to overcome resistance without contributing to broader cross-resistance.

The award is the second that the group has received from CARB-X. In 2024, the team received $1.2 million to develop synthetically enhanced oral antibiotics for drug-resistant lower respiratory tract and skin and other soft-tissue infections. Since its founding in 2016, CARB-X has funded 123 early-stage projects designed to treat, prevent, and diagnose antibiotic-resistant infections. Fourteen of those projects are in late-stage clinical development, and three have reached the market.

The Food and Drug Administration has released new guidance for veterinary drug makers to define how long medically important antibiotics should be used in livestock. The document, published February 12 by the FDA's Center for Veterinary Medicine, provides recommendations to animal drug sponsors on how to add duration limits to medically important antibiotics used in food-producing animals for indications that currently have no set limits. Nearly 30% of all medically important antibiotics used in cows, pigs, and poultry on US farms have at least one indication without a defined duration of use, meaning farmers can use those antibiotics in animal feed for extended periods of time.

Guidance for Industry #273 says labeling for those products should be revised to include appropriate criteria regarding when to begin and end feeding of the antimicrobial drug. The revisions should include an approximate duration range that veterinarians should consider when treating an animal, as well as a maximum duration limit that should not be exceeded. The guidance, which is nonbinding, also suggests sponsors avoid instructions like "feed until market weight" to define the duration of use.

The FDA frames the document as part of its ongoing efforts to promote judicious use of medically important antibiotics, which are also used to treat human infections, in food-producing animals. More than two-thirds of all medically important antibiotics globally are sold to treat, control, and prevent bacterial infections in livestock and poultry.

While antibiotics are necessary for treating farm animals with bacterial infections, antibiotic stewardship advocates have long warned overuse and misuse of antibiotics in food-animal production threatens both animal and human health by promoting the emergence and spread of antimicrobial resistance, which reduces antibiotic effectiveness. Antimicrobial resistance is estimated to cause more than 1.2 million deaths annually.

Previous guidance issued by the FDA limited medically important antibiotic use on farms to disease treatment, control, and prevention and required a prescription and veterinary oversight for all antibiotic use. Prior to these changes, which were implemented in 2017, US farmers could use medically important antibiotics for growth promotion and could buy them over the counter. In 2018, the Center for Veterinary Medicine called for all antibiotics used in the feed and drinking water of food-producing animals to have "an appropriately targeted duration of use" in its five-year action plan for supporting antimicrobial stewardship in veterinary settings.

Critics say the guidance falls short of what is needed to adequately address the rise and spread of antimicrobial resistance. The problem is that the guidance directs drug makers to set antibiotic durations based solely on the health needs of the animal, and does not include mitigation of antimicrobial resistance, or potential impact on human health, as considerations for veterinary decision-making. The guidance is unlikely to have very much impact on how much antibiotics are being used, and therefore very unlikely to have any impact on resistance, according to critics.

A coalition of groups submitted comments to the FDA when the guidance was in draft form. Among their requests was that the FDA set a default maximum duration of 21 days for all covered antibiotics and require drug makers to provide microbial safety and efficacy data if they seek longer maximum durations. They also urged the FDA to ask sponsors to provide a definite, time-bound duration of use for each indication on a drug's label, in addition to the 21-day maximum duration.