The world is running out of weapons to fight against the threat of superbugs. Every year, antibiotics – the medicines that inhibit or destroy harmful bacteria – lose their efficacy as these superbugs develop ways to protect themselves against them.  

A 2022 report published in Lancet estimated that close to 5 million deaths in 2019 were associated with bacterial antimicrobial resistance. Without effective antibiotics, infections that used to be easy to treat will become a serious health threat. However, the antibiotic development pipeline is on the brink of collapse after major pharma pulled out of the market for more profitable prospects. 

Considering the high stakes and complexity of this problem, a collective effort from healthcare, government, and industry is needed.  

The cost of developing a new antibiotic

“There are barriers throughout all of antibiotic development, right from the beginning of scientific research to commercialization, getting market approval, distribution and ongoing supply,” says Matthew Renwick, an internal medicine doctor at the University of British Columbia who studies the economics of antibiotic development. Researchers estimate that it costs $1.5 billion to develop a single new antibiotic. Meanwhile, the median annual sales of these antibiotics are only about $48 million per drug. This sales is in stark contrast with other widely-used drugs such as oncology drugs, which have a median development cost of $648 million and a median revenue of $1.6 billion.

Like other pharmaceutics, antibiotics development is an arduous and costly feat that takes between 8-18 years. However, the way antibiotics are used is unique from other therapeutic classes, says Renwick. Various healthcare organizations have created guidelines for sustainable antimicrobial stewardship, which promotes the responsible use of antibiotics to curb the rampant spread of resistant organisms. While the intent is to ensure the longevity of efficacious antibiotics, good stewardship often means that novel antibiotics are being shelved and only used as a last resort. Preserving efficacious new antibiotics lead to low manufacturing volume, and with the expectedly low market price to match generic drugs, the overall return-on-investment is poor and financially unsustainable for many pharmaceutical companies.  

“The development of novel antibiotics really hasn’t kept pace with the resistance rates that are steadily climbing,” says Renwick. Without a new innovation, the patent-centric incentivization of therapeutic development doesn’t really work for antibiotics. 

On the other hand, investment strategies based on both push and pull incentivization could provide better support for future antibiotic development. A ‘push’ mechanism focuses on lowering antibiotic development and discovery costs from the government through financial support such as providing research funding for clinical trials and offering tax incentives. One example of such an initiative is CARB-X, or the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, which is a global nonprofit that supports efforts to fight antibiotic resistance, including but not limited to antibiotic development.

A ‘pull’ mechanism refers to a post-development reward that ensures future antibiotic revenues. Such incentives, like the Swedish and UK pilot subscription model and the US PASTEUR Act, could include reimbursement schemes and acceleration of market approvals. A model by Kevin Outterson from Boston University estimated about a $4.2 billion pull incentive is required over a 10-year period based on a global subscription model. Renwick argues that for the most part, there is less emphasis on pull funding and more on push funding, especially in the earlier stage of development.

Earlier this year, Boston Consulting Group released a comprehensive report assessing the antimicrobial market. In it, they suggested subscription-based pull funding, where a fixed or minimum revenue is given in exchange for a guaranteed antimicrobial supply, has the best chance of sustaining antibiotic innovation. This assessment takes into account the likelihood of the pull-funding model meeting six target success factors of antimicrobial innovation, including (1) more viable ecosystems that foster global investments and attract talents (2) long-term funding for continuous innovation (3) potential for rewarding the best-in-class antibiotics (as opposed to first-to-market), (4) ensuring product availability, (5) promoting appropriate antimicrobial stewardship by decoupling revenue from sales volume, and (6) providing global access to a novel antibiotic in countries that contribute to the program. 

Preserving last resort antibiotics 

“For every drug that is successful, ten other drugs fail,” says Vu Truong, CEO of Aridis Pharmaceuticals, which focuses on antibacterial and antiviral monoclonal antibodies. “When you think about the [developmental] cost, you are not paying just for that successful drug, you are also paying for the other 10 that failed.” 

Apart from overcoming the financial hurdles, new antibiotics development needs to consider appropriate study designs that show benefits over existing antibiotics in order to be clinically successful. According to Truong, many antibiotics end up being shelved either because physicians wanted to save them for a “rainy day” or because there is a lack of clinical evidence to show that they are better than existing antibiotics. In other words, they are not going to end up being the first-line antibiotic. 

“The vast majority of antibiotics have been brought into the market using a non-inferiority trial design,” says Truong. This type of  study design shows that the antibiotics are at least as good or just as good as the standard of care. This makes it hard to convince physicians to choose this new antibiotic over existing ones without data that shows better efficacy, safety, and clinical outcome. 

In order for new antibiotics to appeal to the healthcare payers, they should also demonstrate the potential to save hospital costs. This includes reducing the overall cost of keeping patients in the ICU, reducing mortality rates, and improving the cure rate. “We should be able to quantify exactly down to the dollar how much we are saving the payer,” says Truong.

Promoting antimicrobial stewardship

Once an antibiotic is made available to a physician, the challenge is knowing how to prescribe them well. According to Stan Deresinski, clinical professor of medicine at Stanford University and co-medical director of Stanford’s antimicrobial stewardship program, antibiotic prescribers are driven by a number of things. This includes everything from the fear of a lawsuit to the desire to take the path of least resistance due to fatigue, as well as all sorts of psychological motivations, says Deresinski. In some countries, he said, the issue is monetary. Certain physicians might receive a portion of their income from prescribing antibiotics. These factors make understanding prescriber behavior a complex issue to tackle. 

While international and national guidelines are available, effective antibiotic stewardship needs to be considered on a case-by-case basis depending on what technology and facilities are available. 

Deresinski and his team collaborate with the World Health Organization to help introduce guidelines to lower and middle-income countries. “Any guideline we have is useful for them at the national level, but it has to be adapted to their circumstance,” says Deresinski. “One of the problems in those countries is that some patients are being overtreated with antibiotics, whereas others don’t have access [to antibiotics].”

When it comes to establishing local guidelines, support from hospital administration, as well as cooperation from all prescribing physicians, is important to ensure adherence. However, this can be difficult. “You need to have support, both moral and physical – or you won’t have the resources to do anything significant,” says Deresinski. At times, this means working with real conflicts and ‘big egos’ within the hospital, he says. 

In Deresinski’s opinion, reaching a zero-defect antimicrobial stewardship – where every single antibiotic prescription is exactly matched with its intended use –  is an ideal that will never be reached. “We don’t have the technology or the human psychological makeup to allow it at this time, and probably ever.” Nevertheless, it is a goal to keep improving.

One of the reasons why antibiotic prescriptions are not straightforward is the fact that infection presentation is often unequivocal. When a patient walks into a physician’s office with a suspected infection, the physician will first examine their medical history. According to Maryrose Laguio-Vila, MD, an infectious disease physician and the medical director of the Antimicrobial Stewardship Program at Rochester Regional Health System, the patient’s ability to express their clinical concerns will determine what tests the physician will order. 

However, this process is not foolproof. Sometimes patients, especially older individuals, may have illnesses that make them confused and unable to convey their medical history clearly, which makes it difficult for the clinician to decide which test to order, says Laguio-Vila. 

“Your clinician suspicion for a problem at an infection site will help you judge whether the test result is a true positive indicating an active infection or a false positive indicating colonization,” Laguio-Villa says. For example, if a person has respiratory symptoms, and the clinician orders a urine culture, a positive culture may be falsely attributed to a urinary tract infection. “The quality of the test depends on the person ordering the test,” says Laguio-Vila.

According to Laguio-Vila, at the moment, much of the decision-making does rely on the clinician’s experience and expertise. Ideally, we need a test that can discriminate whether someone’s immune system is reacting to bacteria, virus, or neither, says Laguio-Vila. It will be even more helpful if the test can differentiate between bacteria colonization or infection, she says.

Tackling antimicrobial resistance with diagnostics

Today, many companies have invested in rapid or point-of-care diagnostics to help clinicians in antibiotic decision-making. “Diagnostics as a whole really helps in monitoring the spread of antimicrobial resistance,” says Kelly Khomtchouk, lead scientist at Specific Diagnostics, which develops rapid antibiotic susceptibility tests for bacterial infections in blood. Despite the need for rapid diagnostics, the current process for getting new technologies to the market is still very slow. 

“Certain resistance profiles can be very difficult to capture in a variety of ways, both genotypic and phenotypic,” says Khomtchouk. For organisms whose resistance organisms are in low abundance, it can be difficult to enroll enough specimens to meet the FDA marketing approval for a new diagnostic. According to Khomtchouk, there is a lack of guidance and historical data, so companies are often left to “venture into their own risk assessment” and wonder whether what they are doing is sufficient. 

A big barrier to diagnostics development is cost, says Khomtchouk. “Cost is exorbitantly high and this includes paying external sites to enroll samples, doing tests internally to validate different parameters of your product, and the initial R&D leading to the launch of the trial.”

At the same time, it is important for hospitals to have the data from a reliable test to be able to quickly ascertain the source of infection. “I think that companies have a big role in this,” says Khomtchouk. “Industry can improve a lot of current surveillance methods.”

Collaboration from various sectors is needed to ensure the progress of diagnostic technology development and that new products fit the market need. “Feedback from regulatory officials will be extremely useful and many clinicians have now realized this problem and agreed to serve in advisory roles,” Khomtchouk says. 

An ongoing battle

Tackling antimicrobial resistance is a multifactorial problem that requires a robust contribution from healthcare, industry, and government alike. It is an effort that requires a viable ecosystem consisting of a sustainable financial model, innovative research and responsible stewardship. While significant efforts have been put into developing better antibiotics and diagnostics, substantial measures are still needed to make a stride in the fight against this silent pandemic.