Bacterial resistance to antibiotics continues to be a global problem, but pharmaceutical developments are not keeping pace with mutations in antibiotics. While international stakeholders recognize the severity of antimicrobial resistance to public health, new breakthroughs in technology are needed to combat this threat.
In 1928, the accidental discovery of penicillin by Sir Alexander Fleming was heralded as a miracle for combating infectious disease. He famously wrote that he didn’t intend to revolutionize all medicine by discovering the world’s first antibiotic. However, 12 years later, the first signs of penicillin-resistant Staphylococcus were seen. By 1945, Fleming warned in a New York Times interview that penicillin’s misuse could lead bacteria becoming resistant to the drug.
Today, that concern has been made reality: drug-resistant bacteria have been found on every continent and in every country. In the United States, at least 2 million people per year are infected by antibiotic-resistant bacteria, and approximately 23,000 people die, according to the Centers for Disease Control and Prevention (CDC). Globally, 700,000 people die from drug-resistant diseases each year, and 230,000 of those deaths are from multidrug-resistant tuberculosis alone. By 2050, antibiotic resistance may be responsible for up to 10 million global deaths per year and could create economic damage on par with the 2008-2009 global financial crisis, according to the World Health Organization (WHO).
While antimicrobial resistance occurs naturally over time, the use of antibiotics when a person has a viral infection is accelerating this problem. “The improper use of an antibiotic, such as not taking the correct dose for the proper time frame or giving leftover antibiotics to a friend highly contributes to the problem,” said Aileen M Marty, MD, FCAP, professor of infectious diseases in the department of humanities, health and society at Herbert Wertheim College of Medicine, Florida International University.
WHO estimates that over half of antibiotics worldwide are “administered inappropriately,” including using them to treat viral infections and prescribing patients the wrong antibiotic, which can increase resistance. Resistance of Klebsiella pneumoniae to carbapenem antibiotics, Escherichia coli to fluoroquinolone, gonorrhea to third-generation cephalosporin, and of Staphylococcus aureus to methicillin (MRSA) have left many infections difficult to treat in patients.
“The more we expose bacteria to resistance, the more it evolves,” explained Kelly Cawcutt, MD, MS, FACP, an infectious diseases and critical care medicine physician and associate director of infection prevention and hospital epidemiology at the University of Nebraska Medical Center in Omaha. “Bacteria continues to outsmart and outpace our developments.”
From a population health standpoint, antimicrobial resistance (AMR) is also a significant problem for people living in areas of the world where there is poor hygiene, polluted water supplies, crowded urban areas, civil conflicts, and concentrations of immunocompromised people. While everyone is affected by antibiotic resistance, the people for whom it hits hardest are those who have undergone surgery, organ transplantation, chemotherapy, or are otherwise immunocompromised.
In September 2018, the CDC and the United States government launched the AMR Challenge at the United Nations General Assembly in New York, NY where international organizations are encouraged to submit actions plans on tracking and collecting data, preventing and controlling infection, using antibiotics, decreasing use of antibiotics in the environment, improving sanitation, and investing in and developing vaccines to combat AMR. As of June 2019, 210 organizations from 20 countries—which includes 167 organizations in the United States—have signed on to the effort.
One of these organizations, Qiagen, has promised to launch a database available to the global research community that combines “publicly available genomic findings, scientific literature and phenotype data” to help address the issue of antibiotic resistance.
Research in this area is focused on prevention and overcoming antibiotic resistance. To that end, the CDC has developed the One Health concept, which recognizes that infectious disease in humans is a public health issue and connected to antibiotic use in animals and the environment. In a 2008 study published in Nature, “Global trends in emerging infectious diseases” researchers found 60.3% of emerging infectious disease are spread from animals to humans, and 54.3% of emerging infectious diseases were bacteria or rickettsia, with a significant number of drug-resistant microbes.
The Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB) has recognized this intersection between human health and animal health in their 2018 report on infection prevent and antibiotic stewardship. “We are integrating the work of veterinarians, environmentalists, pharmacists, doctors, dentists, and diagnosticians to arrive at comprehensive solutions,” Dr Marty, who is a voting member of the PACCARB, told First Report Managed Care. These efforts range from banning antibiotic use for growth-promotion in food-producing animals, to funding development of new diagnostics and next-generation antibiotics, and educating the public as well as health care workers on antibiotic stewardship, she said.
WHO recently launched a new tool, called AWaRe, which classifies antibiotics into access, watch and reserve groups, that will inform users of what antibiotics to use for which infections as well as what antibiotics should be always available in health care settings, kept in reserve, or used as a last resort.
“We need our patients and prescribers to all realize that using antibiotics is not without risks,” said Dr Cawcutt. “We must conserve antibiotics to help slow the continued evolution of antibiotic resistance.”
Incentivizing Pharmaceutical Companies
Another major issue with antibiotic resistance is the drug pipeline itself. Antibiotics kill bacteria in a variety of ways, said Dr Marty, including inhibiting the synthesis of bacterial cell walls, affecting DNA and RNA, proteins or metabolic needs of bacteria. However, the companies that develop antibiotics are not discovering new classes of antibiotics to fight these resistant diseases. A report by The Pew Charitable Trusts in 2016 noted that all antibiotics currently in development have been derived from an antibiotic class discovered in 1984 or earlier.
Without a new class of antibiotic in the pipeline, bacteria that become resistant to one or more of these can become a significant threat to the population, and pharmaceutical companies and other stakeholders may not be able to catch up in time.
“[I]t takes years to find a compound that may work as a future antibiotic,” said Dr Cawcutt. “That compound then needs to go through rigorous testing to ensure it works in lab first, then it must be tested for what dose would be effective in humans and for safety in healthy people. If deemed effective and safe, then it can move on toward clinical trials in patients to see if the drug works. This process takes years and is very expensive.”
Some researchers are turning to older antibiotics as a stopgap. The antibiotic colistin, which fell out of favor because of nephrotoxic side effects, now remains one of the last treatment options for patients with multidrug-resistant gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii and K. pneumoniae. Other older antibiotics, such as fosfomycin, fusidic acid, cotrimoxazole, aminoglycosides and chloramphenicol, have also been considered as antibiotics to be use while antibiotic drug discovery catches up.
That is not to say pharmaceutical companies are not developing solutions. “The early work where many new antibiotic molecules were derived by extracting them from existing organisms has mostly been exhausted,” said Dr Marty. “With that said, new work on that hinges on advances in molecular biology is showing us new avenues for creating new antimicrobials.”
Paratek Pharmaceuticals recently announced the release of their antibiotic Nuzyra (omadacycline), a modernized tetracycline, to help combat community-acquired bacterial pneumonia (CABP) and acute skin and skin structure infections (ABSSSI). RedHill BioPharma’s Talicia, a combination of two antibiotics and a proton pump inhibitor, was recently submitted to FDA for treatment of Helicobacter pylori.
However, even as new antibiotics come on the market, the tendency is to keep them in reserve, rather than use them right away, said Dr Cawcutt. “The drive to create new antibiotics has been low historically, because they are one of the few drugs that if created and effective, we actually try not to use unless absolutely necessary given the risks of resistance developing,” she said. “This is contrast to something like a new cholesterol medication, that if it’s more effective, everyone wants to start using right away.
That creates a disincentive in the market to develop these new drugs, because the drug developer cannot recoup their return on investment of the antibiotic until it is used. “Governmental support and grants to pursue development of new antibiotics is one step in the right direction for improving this,” said Dr Cawcutt. Some companies are already doing this: the global non-profit partnership CARB-X, led by Boston University, provides funding for antibacterial research.
Thinking Outside of Antibiotics
Outside of antibiotic drug discovery, some companies are developing innovative ways to combat infection from antibiotic-resistant bacteria. The health care solutions company
Vital Vio, based in New York, is using antimicrobial LED lighting to kill bacteria, mold and fungi. In health care settings, continuous visible light disinfection has been effective at killing MRSA, vancomycin-resistant enterococci, multidrug-resistant A. baumannii and Clostridium difficile.
“When you think about a local environmental space, managed care, we’re a helping hand within the ceiling to impact those germs on surfaces so that they don’t grow to a point where a patient can put their hand on it and pick up a MRSA from a bedside table,” Explained Colleen Costello, CEO of Vital Vio.
As more hospital-acquired infections are coming into the community, cases of community-acquired infections in school, athletic, or other public settings are becoming increasingly more common. There will be need to create new tools to combat antimicrobial resistance outside of relying on antibiotics, said Ms Costello.
“Antibiotics will also always be a critical part of our treatment process,” said Ms Costello. “But wouldn’t it be better if the germs never got to the patient? We need a lot more research and development around how can we manipulate other technologies in order to actually try to create safer public health considerations for people.”