In June 2018, the US Food and Drug Administration approved plazomicin, sold as Zemdri, for complicated urinary tract infections, including kidney infections. Achaogen had designed it as a weapon against carbapenem-resistant Enterobacteriaceae, but the FDA turned down the bloodstream-infection indication, leaving the drug with a narrow urinary label. Carbapenem-resistant organisms are the kind of infections that kill people in hospitals when nothing else works. Plazomicin was effective against strains that would otherwise have been nearly untreatable, and it had cleared a pivotal Phase 3 trial.
In its first six months on the market, from the July 2018 launch to the end of the year, it generated about $800,000 in sales.
Achaogen, the company that developed it, filed for Chapter 11 bankruptcy in April 2019, ten months after FDA approval. The drug worked, and the FDA approved it. What sank the company was commercial logic: a narrow label, a small market, and hospitals holding the drug in reserve, as they should, for patients with few other options.
Its failure after approval was predictable, and the reasons reach well beyond one company.
The indifferent mechanism
Escherichia coli is the bacterium found in nearly every human gut, on the fingers of food workers and in the blood of patients with sepsis. Under ideal laboratory conditions it divides every twenty minutes, about seventy generations a day. In the gut it grows far more slowly, perhaps once every fifteen hours, but sheer numbers make up for the pace: the human body carries tens of trillions of bacteria. In any population of a trillion organisms, if a resistance mutation arises once per hundred million replications, it appears roughly ten thousand times in a single generation. Expose that population to an antibiotic that kills the susceptible bacteria, and the resistant variants reproduce unopposed.
The mechanism accelerates through horizontal gene transfer: bacteria can pass resistance genes between organisms without reproduction, across species lines, even across genera. Genes move most easily between bacteria that are genetically compatible and share a habitat, such as the human gut or a sewage plant, and over time those transfers build a shared pool of resistance genes spread across many species.
How resistance jumps between species
The three mechanisms of horizontal gene transfer are conjugation, transformation, and transduction. In conjugation, two bacterial cells make direct contact and a plasmid, a small circular piece of DNA, is copied from one cell to the other. That plasmid can carry multiple resistance genes at once. Transformation occurs when bacteria take up free DNA from their environment, including DNA from dead organisms. Transduction occurs when bacteriophages (viruses that infect bacteria) accidentally incorporate bacterial DNA and transfer it to a new host. None of these mechanisms requires the recipient to be the same species as the donor. A resistance gene that evolved in Salmonella in a chicken barn can, through this pathway, appear in Klebsiella pneumoniae in an intensive care unit. The patient in that ICU may have never touched a farm animal in their life.Resistance genes have been recovered from 30,000-year-old Beringian permafrost, including genes for resistance to beta-lactam, tetracycline and glycopeptide antibiotics and a vancomycin resistance element functionally similar to modern variants. Resistance itself is ancient; what is new is eighty years of selection pressure applied at industrial scale.
Alexander Fleming understood the mechanism before it became a widespread clinical problem. In his 1945 Nobel Prize lecture, he said: “Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.” He was describing exactly the condition under which resistant mutants are selected: enough antibiotic to kill susceptible bacteria, not enough to kill the resistant ones, which survive and multiply.
Penicillin was introduced for mass clinical use in 1943–1944. Penicillin-resistant Staphylococcus aureus had already been recognized in hospitals in 1942, and in 1947 Mary Barber at Hammersmith Hospital in London documented a growing burden of staphylococcal infections caused by penicillin-resistant strains. Resistance spread from the wards into the community: by the late 1960s, more than 80% of S. aureus isolates, in hospitals and outside them, were resistant to penicillin.
Resistance cannot be prevented; selection pressure is the cost of using antibiotics at all. The question is how to slow its accumulation while keeping a pipeline of new treatments that stays ahead of it. On both counts current efforts are failing, and the causes are built into the systems involved.
The largest reservoir
Agriculture is where the volume is. By the best global estimate, roughly three-quarters of the world’s antimicrobials go into food animals, about three times the amount used in people.
In the United States, sales of medically important antimicrobials for food-producing animals came to about 6,100 tonnes in 2023, more than a third below their 2015 peak, then rose by 16% in 2024.
Much of that farm use has gone to growth promotion and mass prophylaxis. Growth promotion means giving sub-therapeutic doses to healthy animals; it increases feed efficiency and weight gain through mechanisms that remain incompletely understood, probably involving changes to gut microbiota. Mass prophylaxis means treating entire crowded herds or flocks with antibiotics to prevent infection in conditions where individual disease spread is near-certain. Neither targets a specific pathogen in a specific sick animal, and growth promotion runs on low doses chosen for economic rather than microbiological reasons.
Why sub-therapeutic doses are the worst case
The relevant microbiological concept is the minimum inhibitory concentration (MIC): the lowest concentration of an antibiotic that prevents visible bacterial growth. Doses above MIC kill or halt susceptible bacteria. Doses below MIC do not stop susceptible bacteria, but they slow them just enough to tilt the competition: in the laboratory, concentrations several hundred times below the MIC can still enrich resistant bacteria, and concentrations a quarter to a tenth of the MIC can select brand-new resistant mutants. Growth promotion feeds low doses to entire animal populations over extended periods. This is the condition Fleming named in 1945: "exposing his microbes to non-lethal quantities of the drug." An antibiotic administered therapeutically to a sick patient for seven to ten days at doses above MIC is a far smaller evolutionary opportunity than months of sub-therapeutic exposure across hundreds of millions of animals. Low doses given for months to whole herds are, from the bacteria's perspective, close to ideal for developing resistance.In 1998, Denmark stopped antibiotic growth promotion in broiler chickens and finishing pigs; weaner pigs followed in 1999. Total antibiotic use in Danish food animals fell by more than half between 1994 and 2001. Meanwhile, between 1992 and 2008, Danish swine production grew by nearly 50%. The cost increase per pig from birth to slaughter was approximately one euro. The World Health Organization assessed the Danish ban and found no significant harm overall to animal health or farmer income, although weaned pigs suffered more diarrhoea and deaths for a time after the change.
The United States caught up on January 1, 2017, nearly two decades after Denmark. On that date, growth-promotion uses of medically important antibiotics in animal feed and water ended, and every remaining feed use moved under veterinary oversight through the Veterinary Feed Directive. The rules still leave substantial room for “therapeutic” and preventive use that functions in practice as prophylaxis for chronically overcrowded conditions. The FDA had proposed banning penicillins and tetracyclines in feed as early as 1977, then let the proposal sit for decades. Measured from the first official warning, the American response took forty-eight years. That warning was the Swann Report, published in November 1969, which recommended restricting penicillin and tetracyclines in animal feed. Its core logic was accepted in 1969 and acted on in the US in 2017.
Global veterinary antibiotic use is projected to keep growing. Acosta and colleagues, Van Boeckel among them, estimate that under business as usual, global antibiotic use in livestock will climb by nearly 30% between 2019 and 2040, to about 143,000 tonnes, driven by growing livestock numbers and how intensively they are dosed.
Agriculture is a large, organized industry with political weight in most countries. Cross-border coordination is required, because unilateral restriction creates economic disadvantage for complying producers, as Denmark’s producers understood when they accepted the one-euro premium. And in lower-income agricultural economies, where livestock represent a primary protein source and farm incomes are thin, the economic stakes are more complex than in Denmark.
Fleming named the mechanism in 1945, and livestock farming still doses whole herds and flocks with antibiotics by the tens of thousands of tonnes.
The bankruptcy of success
Developing a new antibiotic costs an estimated $1.3 billion all-in, counting the cost of capital, failed trials and regulatory requirements. The timeline runs ten to fifteen years from early-stage research to approval. These figures are in line with the average cost of bringing any new medicine to market.
The commercial profiles are not comparable. A cancer drug approved for, say, metastatic non-small-cell lung cancer may be used as first- or second-line treatment, often for many months or years, priced at $150,000 to $300,000 per patient per year, with a market made up of every eligible patient worldwide.
A new antibiotic against carbapenem-resistant organisms will be held in reserve, correctly, for the infections that older drugs can no longer treat. Clinicians are trained to steward it, meaning to use it only where it is needed. A course of treatment is seven to fourteen days. Payer expectations, shaped by decades of cheap generics, keep antibiotic prices at commodity levels. The population of patients who will receive it in any given year is small by design.
Kevin Outterson, then executive director of CARB-X, put it bluntly in 2020: “If you invent a mediocre antibiotic, your sales will be low; if you develop a great antibiotic, your sales will be lower.” A clinically excellent antibiotic is held in reserve, so it sells in low volume, and the revenue from that volume ends in bankruptcy.
To develop plazomicin, Achaogen raised about $770 million over fifteen years: about a quarter from public grants, a little from philanthropy and about 70% from capital markets. BARDA, the Biomedical Advanced Research and Development Authority, contributed $124.4 million of that total through contracts beginning in 2010.
Melinta Therapeutics held four FDA-approved antibiotics: Baxdela, Orbactiv, Vabomere and Minocin for injection. In the first nine months of 2019 they brought in $41 million in product sales. The company had an accumulated deficit of nearly $1 billion, and in December 2019 it filed for Chapter 11, with its lenders taking over the company in exchange for $140 million of secured debt.
Acquisition costs and debt weighed on the company, but a single flawed product or botched launch cannot explain the failure: four clinically effective antibiotics, all approved, together brought in nowhere near enough revenue to sustain it.
Tetraphase Pharmaceuticals developed Xerava (eravacycline), approved in 2018 for complicated intra-abdominal infections. Xerava generated $3.6 million in net sales for all of 2019. In 2020 La Jolla Pharmaceutical Company bought Tetraphase for $43 million in upfront cash, against a peak market capitalization that had once been close to $1.8 billion. The asset hadn’t failed clinically. Its commercial profile followed the same logic: a drug that works against resistant infections is used only when older drugs won’t do, and it earns accordingly.
The pipeline reflects these outcomes. Between 2010 and 2020, the FDA approved just 17 new antibacterial drugs, and the small companies that sponsored them almost all went bankrupt or sold out at a loss. The large pharmaceutical companies that once sustained antibiotic R&D have largely left: AstraZeneca spun its antibiotic research out into Entasis Therapeutics and sold the rest of its antibiotics business to Pfizer, Sanofi handed its infectious-disease research to Evotec, and Novartis shut its antibacterial research, all between 2015 and 2018. In 2025 the WHO counted 90 antibacterials in clinical development, of which only 15 qualify as innovative. The preclinical pipeline remains active, but nearly all the companies working on it are small firms, which the WHO says “highlights the fragility of the R&D ecosystem.”
What a "new antibiotic class" means
Antibiotic classes are defined by chemical structure, and the members of a class usually share a mechanism of action — what the drug does to the bacterial cell. Beta-lactams disrupt cell wall synthesis. Fluoroquinolones inhibit DNA gyrase and topoisomerase IV. Macrolides target the bacterial ribosome. A new compound within an existing class can overcome some resistance mechanisms, but bacteria already resistant to the class often stay resistant. A new class offers the best chance of attacking the cell in a way bacteria haven't encountered before, though even a new chemical class can hit a familiar target. New classes have become rare.
Oxazolidinones, patented by DuPont in 1978 as plant treatments and published as antibacterials in 1987, reached patients as linezolid in 2000. Daptomycin, retapamulin and fidaxomicin, approved between 2003 and 2011, opened new classes too, but all were built on scaffolds identified decades earlier, and all are approved only for Gram-positive infections. New chemistry has arrived only in a trickle since: bedaquiline, a Janssen drug approved in 2012, attacks the energy-generating ATP synthase of the tuberculosis bacterium, and GSK's gepotidacin, approved in March 2025 for urinary tract infections, is the first triazaacenaphthylene, the first new class of oral antibiotic for that condition in nearly 30 years.The newest arrival is zoliflodacin. The FDA approved it on December 12, 2025, for uncomplicated urogenital gonorrhea. It’s a spiropyrimidinetrione, the first of its class: it attacks DNA gyrase, the enzyme fluoroquinolones also target, but in a different way, and it keeps its potency against a fluoroquinolone-resistant form of the enzyme. It was discovered at AstraZeneca and carried forward by its spin-out Entasis Therapeutics (now part of Innoviva). It reached approval because GARDP, the Global Antibiotic Research and Development Partnership, sponsored and led the pivotal Phase 3 trial. GARDP is a not-for-profit launched in 2016 by the World Health Organization and the Drugs for Neglected Diseases initiative, and it holds the rights to bring the drug to more than three-quarters of the world’s countries.
One interpretation of zoliflodacin is that it proves the system eventually works: that patience and persistence can produce a new mechanism even without structural change. The record argues against it: in nearly four decades, commercial pharmaceutical R&D has produced only a handful of new antibiotic classes. Even zoliflodacin, born in a big-company laboratory, reached patients only because GARDP, a not-for-profit created because commercial incentives were insufficient, paid for and ran the decisive trial.
The architecture of a fix
Proposals to repair the antibiotic market divide into push and pull incentives.
Push incentives fund the upfront cost of research through NIH grants, BARDA contracts and CARB-X, a global non-profit partnership led by Boston University and funded by BARDA, Wellcome, the UK and German governments, the Gates Foundation and others. Since its 2016 launch, CARB-X has invested more than $500 million in early-stage antibacterial products. Push incentives exist and have been effective at moving compounds through development pipelines. Achaogen had BARDA money behind it and still went bankrupt ten months after approval.
Pull incentives work differently. They promise a downstream reward, such as a payment, a prize or an extended revenue stream, for a drug that reaches patients. In the purest versions, such as subscriptions, the reward is fully delinked from sales volume, and the value of the antibiotic is recognized regardless of how many doses are dispensed.
The United Kingdom piloted the most concrete version. In June 2022, NHS England signed subscription contracts with Shionogi for cefiderocol and Pfizer for ceftazidime-avibactam, paying each company a fixed annual fee of up to about £10 million, regardless of how many doses NHS hospitals used, under three-year contracts that can run for up to ten. The NHS was paying for the drugs to be available rather than for the doses used. In 2024 the government made the scheme permanent, with a £100 million annual budget and contracts worth £5 million to £20 million a year.
Kevin Outterson has estimated that a global pull incentive strong enough to restore commercial viability would need to be worth roughly $220 to $480 million per drug a year for ten years, with a best estimate of about $310 million a year, shared among the world’s wealthy countries. The NHS contracts deliver up to £10 million a year: roughly $13 million.
On its own, Britain’s payment is a small fraction of the global total. Outterson counts it as a fair contribution, but only if the other wealthy countries pay their share too.
In the United States, the PASTEUR Act (Pioneering Antimicrobial Subscriptions to End Upsurging Resistance) was reintroduced in Congress in February 2026. It would establish federal subscription contracts of $75 million to $300 million per drug per year, delinked from sales volume and funded through the Department of Health and Human Services, at a total cost of about $6 billion. One economic estimate puts the return at $28 for every dollar spent over 30 years, counting reduced healthcare costs and prevented deaths. The bill has been introduced in various forms since 2020 without reaching a floor vote.
The EU has gone further. Its pharmaceutical reform, endorsed by member states in March 2026 and formally adopted by the Council in September, will create transferable exclusivity vouchers once the European Parliament gives its final approval. A developer of a priority antibiotic would earn an extra year of regulatory data protection, which it could apply to another, more profitable drug (provided that drug’s EU sales stayed below €490 million a year in each of its first four years on the market) or sell once to another company. Médecins Sans Frontières has opposed the vouchers on the grounds that they transfer development costs onto patients who need those other drugs.
The reason none of this has been implemented at scale is itself a structural problem. Antibiotics are global public goods. A new antibiotic developed at US government expense, through PASTEUR Act subscriptions, could reach patients in France, Germany, Japan, Bangladesh and elsewhere through exports, licensing deals and, eventually, generic manufacture. No single country captures the full value of its investment. The classic collective action logic of public goods applies: each nation has incentive to let others pay for development while benefiting from the result. Aaron Kesselheim and Kevin Outterson were already making this argument, and proposing new financial incentives to answer it, more than fifteen years ago.
PASTEUR Act subscriptions could reward recently approved drugs quickly, but new drugs drawn in from early discovery would take ten to fifteen years to reach patients. On current trends, antimicrobial resistance is projected to directly cause 39 million deaths between 2025 and 2050. Better care of severe infections and better access to antibiotics could avert 92 million deaths over the same period, while a pipeline of new drugs against Gram-negative bacteria could on its own avert 11 million deaths from resistance.
The shape of the failure
Achaogen’s drug worked and there was no obvious villain, yet the company did not survive. The drugs needed to treat 2035’s resistant infections need to enter development now, and there is no commercial incentive to develop them; the PASTEUR Act, which would create one, has not passed. Global agricultural antibiotic reform, which would slow the resistance clock, moves on political timescales that bear no relationship to biological ones.
Zoliflodacin, a new class with a new mechanism, was carried over the line by a not-for-profit and approved in December 2025 for one bacterial infection. The pipeline for everything else runs on the same market logic that destroyed Achaogen.
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