Oral Carbapenems: Promise, Peril, and Pushbacks

Gram-negative bacterial resistance in the United States continues to increase. As it has spread to the community setting, common infections such as urinary tract infections (UTIs) have become increasingly difficult to manage using oral medications and may necessitate the use of intravenous antibiotics. For complicated UTIs, 1 in 5 patients will have an infection caused by an extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, which limits options when they also are resistant to fluoroquinolones and trimethoprim-sulfamethoxazole.¹

Tebipenem and sulopenem are carbapenems with oral formulations that have been studied in phase 3 trials.^2-5 Each typically has a broad spectrum of activity, including streptococci, methicillin-susceptible strains of staphylococci, Enterobacterales (including ESBL-producing strains), and many anaerobes. Notable exceptions to their useful activity include Enterococcus faecium, Clostridioides difficile, and many nonfermenting gram-negative bacilli such as Pseudomonas aeruginosa and Acinetobacter baumannii.^6-8

TEBIPENEM PIVOXIL HYDROBROMIDE (TEBIPENEM HBR)

Tebipenem pivoxil is a formulation of tebipenem marketed in Japan as Orapenem for the management of otitis media, sinusitis, and pneumonia in pediatric patients with difficult to treat infections. Tebipenem pivoxil is used to manage infections caused by penicillin-resistant Streptococcus pneumoniae and Haemophilus influenzae.^6,7 The drug has been reformulated as tebipenem HBr to improve stability and oral absorption. The oral bioavailability of tebipenem HBr is estimated to be 60%. It is rapidly converted to the active moiety, tebipenem, by carboxylesterases located in the intestinal epithelial cells.⁹ Tebipenem HBr is not metabolized by the liver or kidneys, but tebipenem undergoes renal elimination with 80% of the active metabolites excreted through the kidneys.¹⁰

The clinical efficacy and safety of tebipenem HBr for complicated urinary tract infections (cUTIs) were evaluated in a published double-blind, phase III, randomized clinical trial (NCT03788967) conducted at 101 sites in 15 different countries within central and eastern Europe, South Africa, and the United States. Patients were randomly assigned to either receive tebipenem HBr 600 mg by mouth every 8 hours or ertapenem (Invanz) 1 g intravenously every 24 hours for 7 to 10 days. The primary end point was a composite of clinical cure and microbiologic response, typical of trials for cUTIs. The median patient age was 58.1 years, and 50.8% of patients had a cUTI, with the remainder having acute pyelonephritis. Bacteremia was found in 11.5% of patients, and 19.7% of patients met criteria for systemic inflammatory response syndrome. Of the infecting pathogens, 90% were Enterobacterales, primarily Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Proteus mirabilis. ESBL production was detected in 23.4% of infecting pathogens, 39% of pathogens were fluoroquinolone nonsusceptible, and 43% of pathogens were resistant to trimethoprim-sulfamethoxazole. Tebipenem HBr was shown to be noninferior to intravenous ertapenem with respect to the primary end point (58.8% and 61.6%; weighted difference, –3.3%; 95% CI, –9.7 to 3.2). Tebipenem HBr was effective against common gram-negative pathogens, but the clinical response for ESBL-producing pathogens trended lower, with 83.9% response compared with 93.3% for ertapenem (difference, –9.50; 95% CI, –21.62 to 2.10).²

In January 2022, the FDA granted a priority review of a new drug application (NDA) for tebipenem HBr. The FDA then conducted an analysis of the microbiological intent-to-treat (micro-ITT) population separate from what was outlined in the original statistical analysis plan. From this analysis, the FDA concluded that the prespecified noninferiority margin of –12.5% was not met and halted the approval of the medication. Spero Therapeutics, the manufacturer of tebipenem HBr, released a statement shifting the company focus to other clinical therapeutics.¹¹ These actions leave tebipenem HBr’s fate uncertain.

SULOPENEM AND SULOPENEM ETZADROXIL/PROBENECID

Sulopenem is another carbapenem being developed for cUTIs. It is available in both an intravenous formulation as sulopenem and oral formulation as sulopenem etzadroxil with probenecid.¹² The pharmacokinetics and pharmacodynamics of sulopenem are similar to that of other intravenous carbapenems. Sulopenem etzadroxil is an esterified prodrug designed for oral administration. The oral bioavailability is estimated to be 20% to 34% under fasted conditions but can be increased when administered with food or probenecid. Food consumption increases the area under the curve (AUC) by 23.6%, and 500 mg of probenecid increases the AUC by 62%.^12,13 The oral formulation is being paired with probenecid.

The clinical efficacy and safety of sulopenem etzadroxil/probenecid were first studied for the treatment of uncomplicated UTIs in adult women. Patients were randomly assigned to receive either sulopenem etzadroxil/probenecid (500 mg/500 mg) by mouth twice daily for 5 days with 3 days of placebo or ciprofloxacin 250 mg by mouth twice daily for 3 days with 5 days of placebo. The primary outcome was overall success, which was a composite outcome of clinical and microbiologic success. The data analysis in this trial included both a microbiologic modified ITT resistant (micro-MITT R) and microbiologic modified ITT susceptible (micro-MITT S) population. These populations included all randomly assigned patients who received at least 1 dose of study drug and had a baseline uropathogen that was either nonsusceptible or susceptible to ciprofloxacin, respectively. As expected, sulopenem etzadroxil/probenecid was superior to ciprofloxacin in the micro- MITT R population with an overall success rate of 62.2% with sulopenem etzadroxil/probenecid and 36.0% with ciprofloxacin (difference, 26.2%; 95% CI, 15.1-37.4). For the micro-MITT S population, sulopenem etzadroxil/probenecid was not noninferior to ciprofloxacin with overall success rates of 66.8% and 78.6%, respectively (difference, –11.8%; 95% CI, –18.0 to –5.6).³

Following the oral-only study, a study focusing on an intravenous to oral strategy of sulopenem formulations was conducted to assess the clinical efficacy and safety of intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid for complicated UTIs. Patients were randomly assigned to receive either sulopenem 1000 mg intravenously for 5 days followed by sulopenem etzadroxil/probenecid (500 mg/500 mg) by mouth twice daily for 7 to 10 days of total treatment or ertapenem 1 g intravenously for 5 days followed by ciprofloxacin 500 mg by mouth twice daily (or amoxicillin-clavulanate if patient was ciprofloxacin resistant) for 7 to 10 total days of treatment. The primary outcome was the same as the previous trial. The intravenous and oral combination of sulopenem was not found to be noninferior to the combination of ertapenem and ciprofloxacin (67.8% vs 73.0%; difference, –6.1%; 95% CI, –12.0 to –0.1). This trial did not investigate complicated UTIs caused by multidrug resistant pathogens.⁴ In the previous 2 trials, the failure was hypothesized to be due to lower rates of asymptomatic bacteriuria, resulting in microbiologic failure in the patients treated with ciprofloxacin. The combination of intravenous and oral sulopenem also was investigated in complicated intra-abdominal infections and did not meet noninferiority criteria compared to the combination of ertapenem with step down to ciprofloxacin and metronidazole.⁵ Three clinical trials were completed and unfortunately all 3 missed their end points. The manufacturing company, Iterum Therapeutics, applied for an NDA based on results from the trial (NCT03354598) completed in uncomplicated UTIs that showed sulopenem etzadroxil/probenecid could be used for infections caused by fluoroquinolone-resistant pathogens. The FDA denied this request and required more supporting evidence to approve the medication. The manufacturing company, Iterum Therapeutics, is working with external vendors to design a clinical trial to provide additional evidence for the FDA.¹⁴

SUMMARY

The approval of an effective oral carbapenem could change the way complicated UTIs caused by multidrug resistant organisms are managed. It could help reduce health care–related costs associated with the need for intravenous therapy by either preventing hospital admission or reducing hospital length of stay. However, the prospect of an oral carbapenem raises concern among health care professionals with regard to misuse further leading to antimicrobial resistance. Currently, tebipenem pivoxil, marketed in Japan as Orapenem for pediatric infections, is not recommended in first-line use but can be used after other antibiotics fail.¹⁶ The potential availability of oral carbapenems may worry infectious diseases clinicians, but they would increase options for oral therapy of infections currently treated parenterally. However, it seems these agents are not likely to be available as soon as once anticipated.

References

1. Talan DA, Takhar SS, Krishnadasan A, et al. Emergence of extended-spectrum β-lactamase urinary tract infections among hospitalized emergency department patients in the United States. Ann Emerg Med. 2021;77(1):32-43. doi:10.1016/j.annemergmed.2020.08.022
2. Eckburg PB, Muir L, Critchley IA, et al. Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection. N Engl J Med. 2022;386(14):1327-1338. doi:10.1056/NEJMoa2105462
3. Dunne MW, Das AF, Zelasky M, et al. Efficacy and safety of oral sulopenem etzadroxil/probenecid versus oral ciprofloxacin in the treatment of uncomplicated urinary tract infections (uUTI) in adult women: results from the SURE-1 trial. Open Forum Infect Dis. 2020:7(suppl 1):S844. doi:10.1093/ofid/ofaa515.1898
4. Dunne MW, Aronin SI. Efficacy and safety of intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid versus intravenous ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate in the treatment of complicated urinary tract infections (cUTI): results from the SURE-2 trial. Open Forum Infect Dis. 2020:7(suppl 1):S636. doi:10.1093/ofid/ofaa439.1417
5. Iterum Therapeutics. Iterum Therapeutics announces topline results from phase 3 clinical trial of oral and IV sulopenem for the treatment of complicated intra-abdominal infections. December 10, 2019. Accessed July 11, 2022. https://www.iterumtx.com/news/press-releases/detail/29/iterumtherapeutics-announces-topline-results-from-phase-3.
6. Sodhi V, Kronsberg KA, Clark M, Cho JC. Tebipenem pivoxil hydrobromide—no PICC, no problem! Pharmacotherapy. 2021;41(9):748-761. doi:10.1002/phar.2614
7. Mahalingam A, Shenoy B. Tebipenem: A novel oral carbapenem. Pediatr Inf Dis 2020;2(1):25-28. doi:10.5005/jp-journals-10081-1237
8. Zhanel GG, Pozdirca M, Golden AR, et al. Sulopenem: an intravenous and oral penem for the treatment of urinary tract infections due to multidrug-resistant bacteria. Drugs. 2022;82(5):533-557. doi:10.1007/s40265-022-01688-1
9. Kato K, Shirasaka Y, Kuraoka E, et al. Intestinal absorption mechanism of tebipenem pivoxil, a novel oral carbapenem: involvement of human OATP family in apical membrane transport. Mol Pharm. 2010;7(5):1747-1756. doi:10.1021/mp100130b
10. Nakashima M, Morita J, Aizawa K. Pharmacokinetics and safety of oral carbapenem antibiotic tebipenem pivoxil tablets in healthy male volunteers. Jpn J Chemother. 2009;57(suppl 1):82-89.
11. Spero Therapeutics. Spero Therapeutics announces new strategic direction focusing on advancing promising clinical-stage pipeline. May 3, 2022. Accessed May 26, 2022. https://investors.sperotherapeutics.com/news-releases/news-release-details/spero-therapeutics-announces-new-strategic-direction-focusing
12. Iterum Therapeutics. Our promise: responding to medical need. Accessed May 26, 2022. https://www.iterumtx.com/our-science/our-promise
13. Chandra R, Hazra A, Skogerboe T, Labadie R, Kirby D, Soma K. Pharmacokinetics (PK), safety and tolerability of single oral doses of PF-03709270, with and without co-administration of probenecid. Poster presented at: 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC.
14. Dunne M, Dunzo E, Puttagunta S. A phase 1 study to assess the pharmacokinetics of sulopenem etzadroxil (PF-03709270). Poster presented at: IDWeek 2017; October 4-8, 2017; San Diego, CA.
15. Iterum Therapeutics. Iterum Therapeutics provides update from FDA Type A Meeting regarding oral sulopenem. September 28, 2022. Accessed May 26, 2022. https://www.iterumtx.com/news/press-releases/detail/78/iterum-therapeutics-provides-update-from-fda-type-a-meeting
16. Hayashi T, Kitamura K, Hashimoto S, et al. Clinical practice guidelines for the diagnosis and management of acute otitis media in children-2018 update. Auris Nasus Larynx. 2020;47(4):493-526. doi:10.1016/j.anl.2020.05.019
17. Lacasse E, Brouillette E, Larose A, Parr T, Rubio A, Malouin F. In vitro activity of tebipenem (SPR859) against penicillin-binding proteins of gram-negative and gram-positive bacteria. Antimicrob Agents Chemother. 2019;63(4):e02181-e02218. doi:10.1128/AAC.02181-18
18. Nakashima M, Morita J, Aizawa K. Pharmacokinetics and safety of tebipenem pivoxil tablets in healthy volunteers and in patients with reduced renal function. Jpn J Chemother. 2009;57(suppl 1):109-112
19. Shihyakugari A, Miki A, Nakamoto N, Satoh H, Sawada Y. First case report of suspected onset of convulsive seizures due to coadministration of valproic acid and tebipenem. Int J Clin Pharmacol Ther. 2015;53(1):92-96. doi:10.5414/CP202188