Oral Carbapenems Are Failing to Break Through
Developing antibiotics is a tricky business. Although all new drug products in the United States have to go through the rigorous process of obtaining FDA approval, only anti-infectives face targets that change as the approval process is being completed. Antibiotics are the only class of medications of which use in one person affects the utility in another and that have generally declining utility across their life span.
The 10 by ’20 Initiative spearheaded by the Infectious Diseases Society of America, which aimed to produce 10 new antibiotics during the 21st century’s second decade, was successful, much to my amazement.1 In fact, 14 systemically active microbials were approved from 2010 to 2019: ceftaroline, dalbavancin, tedizolid, oritavancin, ceftolozane-tazobactam, ceftazidime-avibactam, delafloxacin, meropenem-vaborbactam, plazomicin, eravacycline, omadacycline, imipenem-cilastatin-relebactam, lefamulin, and cefiderocol. It was an impressive success, particularly against multidrug-resistant (MDR) gram-negative rod (GNR) infections previously treated with polymyxins or aminoglycosides.
However, look at that list and you will see a key omission: oral medications active against resistant GNRs. Although delafloxacin is active against many GNRs (including Pseudomonas aeruginosa), its activity against these organisms is not appreciably better than other fluoroquinolones.2
Omadacycline was evaluated in two Phase 2, adaptive-design studies in urinary tract infection (UTI), evaluating efficacy, safety, tolerability and pharmacokinetics in both uncomplicated UTI and pyelonephritis, a common subset of complicated UTI. In both studies, omadacycline showed generally comparable levels of clinical success to either nitrofurantoin or levofloxacin, as determined by the investigator’s assessment of clinical response at the post-treatment evaluation. However, the microbiological responses were generally lower than the comparator agents in those studies.
Thus, although the 2010s saw antibiotic development that we had not seen for many years, it left a major need unmet: the outpatient treatment of resistant GNR infections caused by high rates of resistance to fluoroquinolones, trimethoprim-sulfamethoxazole, and highly bioavailable β-lactams coupled with the limited utility of nitrofurantoin outside of uncomplicated cystitis. This leaves patients with UTIs with limited options, which oral carbapenems could address.
In the past 2 years, 2 oral agents completed phase 3 trials that could have addressed this need, specifically for UTIs. On page 8 of Contagion®, you will find a "News and Breakthroughs" piece I coauthored describing the bumpy road that these drugs, sulopenem and tebipenem, have faced.4 Unfortunately, the ending has not been a happy one because the US Food and Drug Administration (FDA) did not approve their new drug applications as submitted, sulopenem in 20215 and tebipenem in 2022.6
I do not take issue with this, but I do find the FDA decisions disheartening for 2 reasons. First is the obvious concern for a continued lack of options to treat our patients with resistant infections without using intravenous agents (and the challenges they involve). The second is the chorus of concerned clinicians who vocalized umbrage over the prospect of oral carbapenem availability. Conceptually, it is easy to see why: Carbapenems have been the most broad-spectrum and reliable agents for resistant GNR in hospitals since the approval of imipenem-cilastatin in 1985.7 Widespread use of carbapenems in outpatient settings could have major effects on the utility of these drugs for serious infections. However, the need for better outpatient options is real.
This is a challenge that we will need to address. Either or both agents could still be further studied and approved one day, but if they are not, then other oral agents with activity against MDR GNRs will be needed to take their place. The effort to develop and promote antimicrobial stewardship in outpatient settings is still nascent.8 Hopefully those who expressed fear at the concept of an oral carbapenem can help to champion outpatient stewardship as a solution to both the known problems of today and the unknown resistance issues of tomorrow.
References
1. Boucher HW. Have we made progress in the 10 X' 20 initiative? Contagion®. April 9, 2020. https://www.contagionlive.com/view/have-we-made-progress-in-the-10-20-initiative Accessed June 13, 2022.
2. Jorgensen SCJ, Mercuro NJ, Davis SL, Rybak MJ. Delafloxacin: place in therapy and review of microbiologic, clinical and pharmacologic properties. Infect Dis Ther. 2018;7(2):197-217. doi:10.1007/s40121-018-0198-x
3. Karlowsky JA, Steenbergen J, Zhanel GG. Microbiology and preclinical review of omadacycline. Clin Infect Dis. 2019;69(suppl 1):S6-S15. doi:10.1093/cid/ciz395
4. Kennedy K, and Gallagher J. Oral Carbapenems: Promise, Peril, and Pushbacks. Contagion July 2022.
5. Iterum Therapeutics receives complete response letter from u.s. food and drug administration for oral sulopenem. Iterum Therapeutics. July 26, 2021. Accessed June 13, 2022. https://www.iterumtx.com/news/press-releases/detail/73/iterum-therapeutics-receives-complete-response-letter-from
6. Spero Therapeutics announces new strategic direction focusing on advancing promising clinical-stage pipeline. Spero Therapeutics. May 3, 2022. Accessed June 13, 2022. https://investors.sperotherapeutics.com/news-releases/news-release-details/spero-therapeutics-announces-new-strategic-direction-focusing
7. Primaxin. Prescribing information. Merck & Co; 2016. Accessed June 13, 2022.
8. Core elements of outpatient antibiotic stewardship. CDC. Updated September 8, 2021. Accessed June 13, 2022. https://www.cdc.gov/antibiotic-use/core-elements/outpatient.html
