The growing problem with antibiotics

Five questions: Antibiotics trapped in a failing business model

The U.S. Food and Drug Administration (FDA) has recently approved a new antibacterial drug, Recarbrio™ (imipenem, cilastatin and relebactam), from Merck & Co. It is intended for adults with complicated urinary tract and intra-abdominal infections when most other treatments don't work.¹ Recarbrio should launch later this year, with an as-yet unknown price.²

At first glance, announcing a new antibiotic may not seem like big news. Compared to some of the high-profile new biologics, antibiotics are relatively inexpensive.³ And there’s nothing particularly innovative about the way Recarbrio is designed, either.²

The surprising part is that Merck launched a new antibiotic at all, because most of the giant pharmaceutical companies have virtually abandoned the antibiotic field. At least four major firms shut-down their antibiotics research programs just in 2018, simply because they couldn’t make enough money.⁴

The worrisome part is that, thanks to rapidly-growing antibiotic drug resistance, the need for innovative new antibiotics has never been greater.⁵

Here are five key questions and answers to help frame our understanding:

1. How big is the drug resistance problem?

The World Health Organization warns that we could be heading for “…a post-antibiotic era, in which common infections and minor injuries can once again kill.”⁶ How could this happen?

Antibiotic resistance is growing for two reasons, one unavoidable, the other, quite avoidable: 

·         The unavoidable problem is that every time we take an antibiotic, some resistant germs may survive and be left to grow and multiply. This is a quite natural process of evolution.⁷

·         The avoidable problem is the overuse and misuse of antibiotics.⁷

Livestock producers misuse antibiotics when they routinely feed human antibiotics to animals.⁶ Physicians also contribute. At least 30% of all outpatient antibiotic prescriptions and 20% to 50% of antibiotics prescribed in acute-care settings may be unnecessary or inappropriate.⁸

While inappropriate, these uses are at least legal. But there is an entire underground pattern of antibiotic misuse.

A recent study in the U.S. has found that 25% of those surveyed had used or intended to use antibiotics without a prescription. Almost 50% store antibiotics for future use, by saving medicines prescribed for themselves or others.⁹ In addition, there is a thriving black market, where antibiotics can be found without a prescription from “…flea markets, health food stores, friends or relatives, pet stores or online."⁹

People give a variety of reasons for self-medicating, but it can mean taking the wrong drug, or the wrong dose. In addition to not being cured, people are exposed to potential adverse side-effects – while speeding the rise of antibiotic resistance.⁹

The end result is antibiotic-resistant “superbugs” that can spread to other people and cause infections that most antibiotics cannot cure. One of the best-known examples is Methicillin-Resistant Staphylococcus Aureus (MRSA).⁷

Already today in the U.S. we see:

·         At least two million people infected with antibiotic-resistant bacteria every year.¹⁰

·         Up to eight million extra hospital days and additional follow-up doctor visits.⁵

·         $20 to $35 billion in direct health care costs each year.⁵

·         At least 23,000 people die every year.¹⁰

World-wide, a British government study predicts up to 10 million extra deaths per year within 30 years from antibiotic-resistant infections. That kind of mortality would play havoc with the world economy, causing a reduction in gross domestic product costing up to 100 trillion dollars.¹¹ 

2. Is the antibiotic pipeline keeping pace?

Since bacteria can develop resistance so quickly, we have to keep designing newer and better antibiotics – just to stay ahead of evolution.¹² The trouble is, we aren’t doing that.

As this graph shows, we have recently seen a small bump of new antibiotics coming to market after decades of steep declines. However, the Infectious Diseases Society of America stresses that even this increase leaves us with “…far too few treatment options available for multidrug resistant infections….” ¹³

^{CITATIONS: Adapted from: Brookings Institution. Antimicrobial Resistance: Antibiotics Stewardship and Innovation. June 12, 2014.
2013-2017 data from: Clinical Infectious Diseases.The Infectious Diseases Society of America’s 10 x ’20 Initiative. July 1, 2019.}

The most pressing need is for drugs aimed at what the World Health Organization calls "priority pathogens” – the most dangerous germs with few or no existing treatments.¹⁴ A study last year looked for antibiotics in the pipeline aimed at these high-priority drugs. Taken together, the most active companies in antibiotic development had only 28 antibiotics for high-priority pathogens in late-stage
development. ¹⁴

3. Why are there so few new antibiotics?

We can point to two main reasons: drug market economics and scientific hurdles. Unfortunately, in the antibiotics world, the economics and the science tend to rebound against each other in a negative way.

Economics

Antibiotics are usually fairly inexpensive compared to other drugs. Even new branded antibiotics usually cost less than $1,000 a day.¹⁵ This sounds like good news, but it isn’t.

Unlike a new drug for, say, cancer, the last thing we want when a new antibiotic is approved is for everyone to start using it right away. To prevent, or at least delay, having it develop resistance, we want to hold it in reserve as long as possible.¹⁵  And so there are a variety of rules and other norms designed to make sure that this is the case.¹⁶

Naturally, this means that initial sales are low. For example, Teflaro® (ceftaroline fosamil) is one of the very few drugs effective against multidrug-resistant pathogens like MRSA. It saw annual sales of just $130 million from 2016 through 2018.¹⁷

And Teflaro did relatively well among its peers. A 2017 study found that only five of the 16 antibiotics introduced between 2000 and 2015 had annual sales of $100 million or more.¹⁵

One biotech executive summarized the situation this way: “We want biotechs and pharma to create new products, but we don’t want them to sell any.”¹⁸

Low sales like these are not just disappointing. As the pharma giants leave the antibiotic market, the space has been filled by much smaller companies, which often don’t have the resources to survive while they wait for a sales upturn. Consequently, many such companies have gone bankrupt.¹⁹

Scientific hurdles

But if antibiotics are hard to sell, they are even harder to make. This is certainly the case for the innovative new drugs we need most.

One of the things that antibiotic experts worry about is that antibiotic designers tend not to make novel new drugs. Instead, they make small changes that are just different enough from the existing drug to bypass known resistance mechanisms.²⁰

The advantage to this approach is that since the mechanism of action and potential side effects are well understood, the approval processes is smoother. Unfortunately, many small changes actually help to increase antibiotic resistance by repeatedly creating very similar drugs.²⁰

One promising new approach to antibiotics involves the use of a type of virus that infects bacteria called bacteriophages (phages).²¹But for phages to become truly useful we may need to make them synthetically. This will require groundbreaking – and expensive – advances in basic science, like CRISPR gene splicing.²¹

This brings us back around to the fundamental question: How can we encourage new treatments, when the potential profits are so tenuous?

4. Where do we go from here?

The high cost of developing new antibiotics has led to a number of proposals designed to lure more drug companies into the field:

·         In the U.S., the 21st Century Cures Act provides a faster approval pathway for critically-needed antibacterial and antifungal drugs.²²

·         Other ideas would offer a one billion-dollar reward for companies creating certain priority antimicrobials.¹⁴ Or, companies might receive additional months or years of “transferable” marketing exclusivity.^{18, 23}

But not everyone is convinced that even a billion dollars will be enough to entice a major pharma company to re-enter the market.¹⁴ And extended exclusivities could mean higher prices for far longer than might otherwise be the case.²³

5. What are some practical next-steps?

It seems safe to predict that – at some point – governments will feel compelled to take steps to ensure an adequate supply of new antibiotics. What form that may take, we can’t know.

Some people wonder if the traditional profit-making structure of the pharma business simply can’t produce the antibiotics we need.¹⁷ One such is Jim O’Neill, the former chief economist of Goldman Sachs, who chaired the British government’s two-year review on antimicrobial resistance. He has said that antibiotic R&D needs to be taken away from the pharmaceutical makers, while we build a completely different kind of drug-making organization —a government institute, an international nonprofit, or even a utility. ²⁴

This would be a drastic step, to be sure. In the meantime, in the absence of new drugs, it is crucial to practice good antibiotic stewardship in order to protect the effectiveness of existing drugs.¹⁶

·         In clinical setting like hospitals and geriatric care centers, there is an increasing emphasis on preventing improper antibiotic use.

·         OptumRx is primarily concerned with promoting sound antibiotic use, by making sure that they are taken as directed.

How OptumRx can help:

At OptumRx, we want people to be able to access the antibiotic their physician prescribes for them, so our formulary tiers guide members to the lowest-cost options. We apply standard utilization management (UM) strategies like prior authorization (PA) sparingly. This is because appropriate antibiotic prescribing depends on many factors, including sensitivity of the organism, location and severity of the infection, patient co-morbidities, etc.

In those cases where a prescription is rejected because of the need for a PA, we make sure to proactively contact the member and their physician. We want to be certain that they understand the PA process, offer alternatives, and generally avoid hindering access and the risk reinfection or antibiotic resistance.

In addition, proper medication adherence is especially important with antibiotics, where missed doses or stopping early can lead to antibiotic resistance. The OptumRx mobile app helps members stay adherent to their prescriptions. Members can set reminders to prompt them to take their medication at the right time of day, in the right dosage, and the right number of times. 

https://www.optum.com/resources/library/antibiotics.html?o=optum:OwnedSocial:RX_8.1_2019:LI:RX:LRN:19q2rgm09dm19:n_a:n_a:n_a:n_a:n_a