These are the most deadly pathogens — so why aren’t drug companies targeting them?

Antibiotics are among the greatest success stories in the history of medicine. They have saved millions of lives by turning once-deadly diseases into curable conditions. But the golden era of antibiotics has come to an end. 

Pathogens that were once vulnerable to antibiotics have evolved to resist them, largely due to the misuse and overuse of these drugs.

In 2015, the World Health Organization (WHO) declared antimicrobial resistance (AMR) a global emergency, issuing a comprehensive action plan that called for substantial investment in developing new medicines.

Yet, nine years later, that investment still falls far short of current and future needs.

The world continues to struggle against AMR, which claimed 1.3 million lives in 2019 and is projected to cause up to 10 million deaths by 2050 — far exceeding the toll of any type of cancer.

“Antimicrobial resistance is only getting worse, yet we’re not developing new, groundbreaking products fast enough to combat the most dangerous and deadly bacteria,” said Yukiko Nakatani, WHO’s interim assistant director-general for AMR, in June.

Meet the bad guys

Nature harbors countless dangerous pathogens, but some are particularly lethal.

The WHO has identified 15 families of pathogens that are resistant to existing medicines and should be prioritized in research for effective new treatments. While these pathogens may not be household names, they are very harmful and increasingly difficult to treat.

“Over the last 100 years, we’ve been using so many antibiotics that bacteria have become multi-drug resistant, meaning that some infections do not even respond to any of the antibiotics we have at the moment,” explained Martijn van Gerven, head of the AMR program at the Access to Medicines Foundation. “A lot of people are dying from infections that cannot be treated anymore.”

Six drug-resistant pathogens alone — Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa — claim close to 1 million lives every year.

The costs to the health care system and the global economy are also staggering. The World Bank concluded that, if unaddressed, antimicrobial resistance could cause a degree of economic damage comparable to the 2008 financial crisis and push 28 million people into poverty. But unlike the 2008 recession, there would be no immediate prospect of recovery.

The threat posed by these pathogens is especially dire in poorer countries, where access to life-saving drugs is more limited and health care systems struggle to manage infections swiftly and effectively. Low- and middle-income countries are the hardest hit by AMR, responsible for nearly 90 percent of associated deaths in 2019.

“In many poor countries there are no diagnostics available, and there is still widespread overuse of antibiotics — not only in humans, but also in animals,” explained van Gerven.

He pointed out that limited access to antibiotics also contributed to the spread of AMR, since patients are treated with the wrong drugs.

The end of the ‘golden era’

Developing new and effective antimicrobial drugs is a huge scientific challenge with high financial risk and the prospect of minimal reward.

The pace of discovery for new antimicrobials has slowed significantly since the so-called golden era in the 1950s and ’60s, when most of the antibiotics still in use today were developed. Most new products are merely variations of existing drugs, which increases the risk of them being ineffective.

The challenge is even more daunting for so-called reserve antibiotics — drugs that should only be used as a last-resort when mainstay antimicrobials have failed.

The WHO has acknowledged “there is no viable market for novel antibiotics,” adding that “the return on investment for new ‘reserve’ antibiotics does not cover the costs of development, manufacturing, and distribution.”

Developing a new antibiotic typically takes 10 to 15 years. Clinical trials are lengthy and complex, with most candidate drugs failing in the early stages of development. Even if a product makes it to market, it is rarely profitable as these drugs are meant to be reserved as a last resort.

By way of comparison, developing a cancer drug costs $640 million on average and brings in $1.7 billion a year in revenue. A new antimicrobial costs over $1 billion to develop and generates an annual revenue of just $46 million.

As a result, even companies that successfully bring new drugs to market often face financial ruin shortly thereafter, like biotech Achaogen.

The company spent 15 years developing a new antibiotic, plazomicin, to treat infections caused by a range of antimicrobial-resistant pathogens. The new drug was approved in the U.S. in 2018; in April 2019, Achaogen declared bankruptcy after reporting only $800,000 in sales in the previous year.

Such cautionary tales are far from rare and have scared many big players out of the market. Several large international pharmaceutical companies have abandoned the development of antimicrobials, halted development programs, or laid off research teams. 

Research in this field is now mostly conducted by small biotechs that struggle to secure public funding and sustain their operations in the long term. Staying in business is challenging when profits, if they materialize, are decades away.

The challenges of AMR research make it far less attractive as a destination of investment than other global health priorities like malaria and HIV, which receive a lot more funding despite having a lower or comparable death toll. 

Researchers are also leaving the field in droves due to dwindling investment and scarce job opportunities. According to a review published by the AMR Industry Alliance, there are approximately 3,000 researchers in this field, versus 46,000 for cancer and 5,000 for HIV/AIDS.

An imbalanced pipeline

The pipeline for new antimicrobial drugs has gotten marginally healthier in recent years, “but we’re still so far away from what we need,” said van Gerven. He argued that “hundreds” of new medicines would be needed — many more than the few dozen in development.

The WHO’s latest report on antibacterial development found that the number of products in the pipeline increased from 80 in 2021 to 97 in 2023, indicating that some resources are being directed toward the field. However, of the 128 programs reported since 2017, only 13 drugs have received market approval. Of these, only two are classified as “innovative” by the WHO. The remaining 11 are based on existing agents with known resistance.

Van Gerven also pointed to issues of “access and stewardship” whereby drugmakers were not catering to those most vulnerable to AMR, like children and people in poorer countries.

High-income countries dominate both funding for, and research into, new antimicrobial drugs. They are also set to become the biggest market for these products.

A study by the Global AMR R&D Hub modeling future sales for certain new antimicrobials found that while low- and middle-income countries would suffer a higher health burden than high-income ones, they would generate only 30 percent of the global revenue.

The authors of the report pointed to a “worsening access gap, whereby the antibiotics that work are not available in the parts of the world at the scale where the need is dominant and growing most rapidly.”

How to fix a broken system

Faced with the shortcomings of the private sector, governments and international organizations have stepped in to fill the gap.

Public and philanthropic efforts to the tune of $1.6-$1.8 billion a year have focused on ‘push’ incentives — measures to encourage the early stages of development, like grants and partnerships. But considering the financial challenges faced by companies in the sector, these measures alone are not enough.

“You need a mix of ‘push’ and ‘pull’ incentives,” explained van Gerven. So-called pull incentives provide market revenue guarantees for companies.

The U.K. was first to trial a Netflix-like subscription model whereby manufacturers are paid a fixed annual fee for a set period in return for a guaranteed supply of antimicrobials. The advantage is its predictability: both for drugmakers’ financial sustainability, and for countries’ access to life-saving drugs.

This model has now been rolled out to all new antibiotics targeting the WHO’s priority pathogens, with a maximum payment of £20 million a year.

Some researchers, however, have argued that the system results in overpaying for medicines and that there is still not enough evidence to assess the scheme’s success.

The subscription model has sparked interest — but little action. Sweden and Japan have piloted similar schemes, while the U.S. and the EU are both mulling market entry initiatives — with the PASTEUR Act in the U.S. and revenue guarantees in Europe — but progress has been slow.

Meanwhile, the EU is also updating its pharmaceutical regulation, debating a new incentive to develop antibiotics in the form of a market monopoly bonus that could be applied to any other medicine in a company’s portfolio.

Van Gerven said that while the public sector’s efforts constitute a step in the right direction, they are “not sustainable” and could only temporarily fill the gap left by drugmakers.

“The upcoming U.N. high level meeting [on antimicrobial resistance] focuses on what countries can do, but we shouldn’t forget pharmaceutical companies have an inherent responsibility in this field,” he said. “We really need their resources, their capacity and their expertise.”