Novartis in July became the latest pharmaceutical company to shut down its antibiotics research projects.

The move comes as FDA commissioner Scott Gottlieb has expressed concern over the growing epidemic around antimicrobial resistance, which is when bacteria grow resistant to available medications.

New options to combat the resistant bacteria include antibiotic-combination therapy and bacteriophage therapy.

Just two years after Novartis announced it would embrace the challenge of searching for cures for life-threatening infections known as superbugs, the drugmaker said last week it would exit antibacterial and antiviral research.

Novartis' retreat follows a growing trend of big pharmaceutical companies — including AstraZeneca, Sanofi, and Allergan — that are exiting from this type of research because of a lack of profit.

That leaves Merck, Roche, GlaxoSmithKline, and Pfizer as the remaining pharmaceutical companies with active antibiotic programs, according to Nature Biotechnology. Only 12 antibiotics have been approved since 2000.

Ever since the invention of penicillin, antibiotic development has been a treadmill. Patients who took too little or too much antibiotics would evolutionarily select for stronger strains by killing off only the sensitive bacteria. Antibiotics were once a lucrative business before inventing new drugs to catch up with the evolution of resistant strains became exhausting.

Dr. Jean Patel, science team lead of antibiotic strategy and coordination unit at the CDC, said a fair number of active antibiotics used against bacteria actually come from small, startup-sized companies, that usually later get acquired by big pharma, which provides the infrastructure to complete clinical trials and market the drug. But with increasing numbers of big pharma firms backing out of antibiotic pursuits, it decreases the variety of new drugs that can be brought to market.

"The costs to develop a new antibiotic drug are no less expensive compared to development of drugs for other therapeutic areas, yet the commercial potential and return on investment for companies developing new antibiotics are significantly lower than drugs to treat chronic conditions such as diabetes or heart disease," said Gary Disbrow, deputy director of the Biomedical Advanced Research and Development Authority, which sits within the U.S. Department of Health and Human Services.

The lack of research from big pharma companies is a problem. Each year in the US at least 2 million people become infected with antibiotic-resistant bacteria, according to Centers for Disease Control and Prevention, and 23,000 people die each year as a direct result of these infections.

It's estimated that as many as 10 million people could die annually from superbugs by 2050 if nothing is done, according to a report commissioned by the UK.

The superbug supercrisis

The public threat from antibiotic-resistant superbugs is growing. Doctors recently warned that an emerging sexually transmitted infection could become an antibiotic-resistant superbug and lead to pelvic inflammatory disease, and ultimately infertility in women. A woman died in 2017 because she contracted a bug that resisted 26 different antibiotics — every antibiotic available in the US.

Antibiotic-resistant strains were also reported to be found in a huge portion of supermarket meats, which the World Health Organization says is a threat to food safety and security.

Why is there a rise in superbugs?

The overuse of prescription drugs and antibiotics in both humans and agriculture is one culprit, as is rise of antimicrobial chemicals in household products. Efforts are being invested into looking at alternatives like probiotics, prebiotics, enzymes, organic acids, immunostimulants, bacteriocins, bacteriophages, phytogenic feed additives, phytoncides, nanoparticles and essential oils for agricultural use. Climate change may also be contributing to growing antibiotic resistance.

Certain lifestyle factors like constantly using hand sanitizer and other antiseptics may decrease the body's microbial diversity. With fewer good bacteria in the body as defense, humans are more likely to become susceptible to bad, resistant ones. And the antibiotics one person takes can affect everyone because it's not the person who becomes immune; it's the strain of bacteria.

Antibiotic resistance appeared almost immediately after the advent of antibiotics. To companies, that didn't matter for a lot of years because there were always new antibiotics in the pipeline. But that slowed down and almost came to a stop starting about 15 years ago. Unlike almost every area of drug development, antibiotics will all eventually lose their effectiveness, because bacteria is good at evolving ways to defeat them.

The US is trying to do its part to combat these superbugs.

To encourage the costly development of new antibacterial drugs, FDA Commissioner Scott Gottlieb has mentioned the possibility of a reimbursement model for antibiotics that met certain criteria, primarily their ability to target dangerous, multi-drug resistant infections.

Both the CDC and the National Institute of Allergy and Infectious Diseases have developed strategic plans and solutions initiatives to fight antimicrobial resistance.

Congress increased CDC's funding to combat antibiotic resistance in 2018 to $168 million, a $5 million increase over last fiscal year, and tasked it with the effort to contain, protect and prevent superbug spread. But prevention is just one aspect of the crisis. The CDC also tries to monitor new drugs that become active to ensure they are not underused or overused.

"We try to hold on to new drugs that come into market and use them prudently so they can remain active for longer," said the CDC's Patel. "This antibiotic stewardship is good for public health but not good for drug companies trying to turn a profit on their initial investment."

Patel said that because of this there's a need for novel types of therapeutics, and also for diagnostic companies that can detect resistance early on so that it can be contained and eradicated before it spreads.

What's in the pipeline for antibiotics

There are two ways researchers are hoping to tackle antibiotic resistance. While there's a hefty research force dedicated to product development of therapeutic treatments, there's also a good chunk of research dedicated to understanding the mechanisms of resistance, including how it happens and how it spreads.

In early July, researchers at the European Molecular Biology Laboratory in Germany combined different antibiotics to take out drug-resistant strains and found sweet spots where certain combinations worked perfectly without damaging healthy bacteria. However, sometimes, combinations would actually make both drugs less effective. Ana Rita Brochado, an author of the study, said that what happens is that bacteria have protective systems that become activated with the addition of the second drug, which shields them against the antibiotics.

The drug combinations that worked well together were very species specific, meaning they only worked for certain strains of resistant bacteria and were not all-encompassing. "I think there's a lot of potential for using combinations, but we do need to understand a lot more about mechanisms behind antibiotic action so we can fully understand why they are different from bacteria to bacteria and what each antibiotic is doing to the bacteria's defense, not just the drug target," said Brochado.

The treatment is being tested out in mice and bacteria extracted from humans.

Researchers have even gone as far as to revive a 100-year-old, discontinued method to battle bacteria: bacteriophage therapy.

"It's a back-to-the-future kind of remedy," said Steffanie Strathdee, chief of the division of global public health in the department of medicine at University of California at San Diego. "It's tapping into the body's own microbial arms race."

Strathdee's husband contracted an infection while on vacation in 2015 and fell into a coma after the gut-superbug resisted multiple antibiotics. In a case study now made famous, Strathdee dug up buried research on so-called phages, which are viruses that infect bacteria, in search of a cure. After finding a phage that matched up with the resistant bacteria and injecting it into his bloodstream, Strathdee's husband woke up from the coma.

Since then, phage therapy has been used successfully to treat five other patients. After the discovery of the antibiotics in the 1920s, phages were relegated to the back burner. The trickiest part lies in finding the matching phage, characterizing it and purifying it so that it's safe for patient use.

Phage therapy is an experimental treatment used by doctors at UC San Diego Health and the demand has been so high that they've opened a new center. Since it's not yet approved in the US, patients need approval from the FDA for emergency use to access it.

Strathdee and her team of scientists at UCSD have partnered with two startups, AmpliPhi Biosciences and Adaptive Phage Therapeutics, to compile a phage library and create personalized phage cocktails for patients. They noticed that bacteria became resensitized and started responding to antibiotics after interacting with phages, said Strathdee.

Understanding the science and makeup of bacteria can also help scientists devise new ways to destroy it. To stay ahead of the mutation, many scientists are sequencing the genomes of resistant microbes to track their evolution and spread.

There are also external funds from CARB-X and BARDA — a part of the Department of Health and Human Services — to encourage development of new therapeutic agents and encourage drugs to come to market.

On the front end of drug development, there's a lot of work being done. Dr. John Farley, deputy director of the office of antimicrobial products at the Food and Drug Administration, says the agency teams up with small and midsize companies to study bacteria pathways and develop drugs.

There has been government-wide response to seek funding to move drugs into clinical trials and advance them through the approval process. Programs like Generating Antibiotic Incentives Now and LPAD also aim to attract external investment for the back end of drug development.

"I don't think anyone thinks the pipeline is as strong as it needs to be," said Farley. "There are economic challenges that still remain that's at the heart of all of this."

In the antibiotic clinical pipeline, one new drug application has been submitted to the FDA for clinical approval and two new drugs have been approved. In clinical development, there are 16 drugs in phase 1, 14 in phase 2, and 15 in phase 3, according to a report by PEW. But medical experts say the number of drugs in development aren't nearly enough to address superbugs.

"There's relatively little in the pipeline that actually tackles the most serious resistant organisms that are out there today," said Allan Coukell, senior director of drugs and medical devices at the Pew Charitable Trusts.