The Antibiotic Landscape Against CRE

The threat of drug-resistant microorganisms is not a novel one and even as Sir Alexander Fleming developed the first antibiotic, he raised concern for misuse and the possibility of resistance. According to Business Insider, Fleming said, “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism.”

Carbapenem-resistant Enterobacteriaceae (CRE) is one such organism that causes high morbidity and mortality on an international level. This family of germs is especially hard to treat and often detected in individuals who are more susceptible to infections including those in nursing homes and health care settings or have invasive medical devices like urinary catheters and intravenous catheters.

Perhaps one of the biggest challenges though with combatting CRE, is the drying pipeline for antibiotics. There are a lot of components that go into antimicrobial resistance, from agriculture use to poor prescribing habits, but trying to combat it through novel drug development has proven to be a monumental hurdle.

A new study, published in Antimicrobial Agents and Chemotherapy by Cornelius J. Clancy, MD, and M. Hong Nguyen, MD, both of the University of Pittsburgh, assessed the size of the United States market for antibiotics that are effective against CRE. As they noted, there are considerable financial hurdles for those countries seeking to develop such drugs.

The authors pointed out that the main drugs to treat CRE (ceftazidime-avibactam, meropenem-vaborbactam and plazomicin) totaled $101 million in sales from February 2018 to January 2019 and that the current annual United States market for a new anti-CRE antibiotic would total $289 million. Roughly 3 new antimicrobial agents were used to treat 23% of CRE infections in the United States during the duration of the study.

“In a survey of US hospital-based pharmacists, the new drugs were positioned as first-line against 67.5% of CRE infections. Therefore, we estimated the drugs were employed against only 35% (range: 23% to 62%) of CRE infections in which 55 their use was expected based on positioning,” Clancy and Nguyen wrote.

Ultimately, the authors pointed to antimicrobials against CRE as a case study for those challenges facing any pharmaceutical company wishing to develop a new antibiotic. Even in the face of a major and unmet medical need, the return on those anti-CRE drugs has been lackluster, which does little to encourage companies to invest in not only the drugs, but also research and development. As they noted, “To put our data in perspective, a billion dollars in incentives is believed to be necessary to assure viability of a new antibiotic. To be profitable and sustainable, new biopharmaceutical companies generally target about $300 million in annual revenue.”

Following their assessment of the market for CRE drugs, the authors emphasized a need for new antibiotic development models and likely reimbursement reform. They pointed to a financial “pull” incentive to maintain sustainability and reforms to in-hospitals reimbursement for antibiotics against those highly resistant organisms. Another suggestion was to classify antibiotics against those high-priority, multidrug-resistant organisms as “orphan drugs”, which means their developers would receive a research and development tax credit, fee waivers, and extended market exclusivity.

Overall, Clancy and Nguyen brought forward a very painful reminder of the challenges in bringing new antibiotics to market, but also provided helpful suggestions that could change the game in combatting antimicrobial resistance.