Will We Ever See Oral Carbapenems for ESBL Urinary Tract Infections?

Following the publication of the ADAPT-PO trial (NCT03788967), which demonstrates noninferiority of oral tebipenem pivoxil hydrobromide (tebipenem HBr) to intravenous (IV) ertapenem, the FDA announced that the reviewed data were insufficient for approval of oral tebipenem HBr.

Specifically, the FDA cited concerns about improper classification of trial participants that, when properly classified, resulted in tebipenem HBr no longer meeting noninferiority criteria. Spero Therapeutics, Inc, the manufacturer of tebipenem HBr, has announced a corporate restructuring while it prepares to meet with the FDA to address these concerns.^1,2

These announcements are the most recent in a series of disappointing outcomes in the development of oral carbapenem therapy for urinary tract infections (UTIs). Although the future development of oral carbapenems is not entirely clear, there are reasons for concern that the class may not help support a growing clinical need.

WHAT IS THE CLINICAL NEED FOR AN ORAL CARBAPENEM-BASED ANTIBIOTIC?

A 2019 CDC report identified extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae as a serious threat in antimicrobial resistance. That same report estimated there were nearly 200,000 ESBL infections in the United States during 2017, causing approximately 9100 deaths.³ In addition, between 2012 and 2017, the incidence of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), and carbapenem-resistant Enterobacteriaceae infections decreased, whereas the rate of ESBL infection increased from 37.55 to 57.12 cases per 10,000 hospitalizations (a 55% increase).

Most of these cases (> 80%) were classified as community onset.⁴ The most common ESBL-producing organism is Escherichia coli, which underscores the need for oral antibiotics that can effectively treat ESBL infections. Rates of ESBL-producing E coli vary by region in the United States, with significantly higher rates along each coastline.⁵ Rates range from 10.5% in the West North Central region (Minnesota, North and South Dakota, Nebraska, Kansas, Iowa, Missouri) to 29.6% in the Mid-Atlantic region (New York, Pennsylvania, Delaware, New Jersey).

Fluoroquinolones and trimethoprim-sulfamethoxazole (TMP-SMX) are the recommended oral options for complicated UTI (cUTI) and pyelonephritis caused by ESBL-producing infections, according to recent guidelines published by the Infectious Disease Society of America.⁶ Alarmingly, the rate of fluoroquinolone and TMP-SMX resistance against ESBL E coli in the United States is nearly 70% and 60%, respectively.⁵ Unfortunately, other oral antibiotics, such as nitrofurantoin and fosfomycin, are not recommended in cases of cUTI or pyelonephritis because of low concentration in the upper renal tract. Considering these factors, at least 60% of patients with cUTI or acute pyelonephritis caused by ESBL-producing bacteria have no viable oral antibiotics for treatment.

EXISTING ORAL CARBAPENEM ANTIBIOTICS

This is the niche that is supposed to be filled by the oral carbapenem class, a quest that has been progressing for the past 30 years. The first successful oral carbapenem, faropenem medoxomil, was approved for pediatric use in Japan in the early 2000s. It has broad activity against many Gram-positive and Gram-negative aerobes and anaerobes, and it is resistant to degradation by ESBLs and AmpC β-lactamases. It has no activity against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, VRE, or MRSA.

Approved indications in Japan include acute bacterial sinusitis, community-acquired pneumonia, acute exacerbation of chronic bronchitis, cUTI, and uncomplicated skin and soft tissue infections. Postmarketing surveillance of faropenem medoxomil showed sustained clinical effectiveness for assessed clinical conditions. Importantly, there was no appreciable change in the resistance patterns observed in common isolates.⁷

Despite multiple phase 1 and 2 trials, the FDA issued a nonapproval letter for faropenem medoxomil in 2006, citing concerns about validity of study populations and inability to verify diseases being treated, including community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute bacterial sinusitis, and uncomplicated skin and soft tissue infections. License holder Replidyne, Inc, ultimately abandoned the US market for faropenem medoxomil, with no current signs of revival.⁸

Sulopenem, an oral and IV carbapenem-class antibiotic, as well as tebipenem, an oral carbapenem, have also been in preclinical development pathways. Sulopenem is an IV and oral option to treat ESBL organisms, although it has limited activity against Pseudomonas and Burkholderia species. However, clinical data are notably limited. Iterum Therapeutics plc has released some conference abstracts, but there has not been a full peer-reviewed publication on the clinical efficacy of sulopenem in phase 2 or 3 trials. Data from the SURE-1 trial (NCT03354598) were presented in a late breaker session at IDWeek 2020. In the trial, adult women with pyuria, bacteriuria, and signs and symptoms of UTI were randomly assigned to sulopenem etzadroxil/probenecid or ciprofloxacin.

In the combined primary analysis, sulopenem was noninferior to ciprofloxacin, but these findings appear to be related to superiority in quinolone nonsusceptible isolates (62% of whom still had a clinical response to ciprofloxacin compared with 83% of the sulopenem group).⁹ Recently presented data on the SURE-2 trial (NCT03357614) of oral stepdown sulopenem vs IV ertapenem did not demonstrate noninferiority.¹⁰ Iterum Therapeutics submitted a new drug application, but the FDA has requested at least 1 more well-designed clinical trial against a different comparator drug and further nonclinical data to determine an optimal dosing regimen.¹¹

Regarding tebipenem, the recently published results of the ADAPT-PO trial, a successful noninferiority trial comparing tebipenem HBr with IV ertapenem for cUTI and pyelonephritis, warrant deeper examination. There was significant microbiologic failure in both groups, although this did not impact the overall study results.¹² The FDA requested additional clarifications, citing discrepancies in the classification of patients. When reclassified, tebipenem did not meet the criteria for noninferiority. As outlined above, Spero Therapeutics is currently working with the FDA to address these concerns but is restructuring to focus on other therapeutic products.¹

CURRENT BARRIERS TO ORAL CARBAPENEM THERAPY

Sulopenem, an oral and IV carbapenem-class antibiotic, as well as tebipenem, an oral carbapenem, have also been in preclinical development pathways. Sulopenem is an IV and oral option to treat ESBL organisms, although it has limited activity against Pseudomonas and Burkholderia species. However, clinical data are notably limited. Iterum Therapeutics plc has released some conference abstracts, but there has not been a full peer-reviewed publication on the clinical efficacy of sulopenem in phase 2 or 3 trials.

Data from the SURE-1 trial (NCT03354598) What, then, are the barriers to an oral carbapenem-based antibiotic? Neither sulopenem nor tebipenem have demonstrated noninferiority compared with IV ertapenem at present. One barrier to approval may be in the definitions of cure recommended by the FDA in clinical trials for UTI. This includes both a clinical and microbiologic cure. To meet this requirement, a late test of cure at least 5 days after completion of therapy and then 21 to 28 days post randomization, both showing less than 1000 colony-forming units of the pathogen in urine cultures to meet the end point.¹³ Both sulopenem and tebipenem struggled to get above 60% microbiologic cure at the late testof-cure visit despite high early clearance rates, which are equivalent to or worse than comparator drugs at the late test-of-cure visit.^10,12

Other barriers also involve the pharmacokinetic properties of these agents. Under ideal conditions, sulopenem is 20.1% to 33.6% orally bioavailable, which can be boosted by administration with food and the inclusion of probenecid to the formulation (as sulopenem etzadroxil/probenecid). Urine concentrations are variable, with 35.5% of unchanged dose recovered in healthy volunteers without the addition of probenecid, which increases the renal tubular secretion.¹⁴ Tebipenem HBr is more orally bioavailable at an estimated 50% to 60%, with active metabolites excreted mostly through the kidneys. Tebipenem concentrations in urine range from 38% to 64% of the administered dose, and in patients with renal impairments, it has a longer elimination halflife and higher area under the curve (AUC). However, in patients with worse renal function, less of the drug is eliminated over time, decreasing overall AUC. In patients with severe renal function, only 38% was eliminated vs 55% to 64% of patients with moderately impaired renal function.^15,16

Additionally, there are limitations regarding the effectiveness of some of these carbapenem antibiotics. Faropenem and sulopenem have broad activity, but some pathogens, including P aeruginosa and Burkholderia cepacia demonstrate high intrinsic resistance to the carbapenem class, despite lacking a carbapenem-hydrolyzing β-lactamase.¹⁷ In general, sulopenem is less potent against Gram-negative organisms (4- to 32-fold increased minimum inhibitory concentration, 50% compared with IV ertapenem and meropenem), although it may be better against Enterobacter spp. It is not active against P aeruginosa.¹⁴ Tebipenem HBr fairs better against P aeruginosa, but in vitro and in vivo studies of the activity of tebipenem HBr have demonstrated minimum inhibitory concentrations of greater than or equal to 4 μg/mL, which calls into question the effectiveness in clinical models, as the necessary doses may not be well tolerated.¹⁸

WHERE DO WE GO FROM HERE?

With these limitations in mind, where do we stand on ESBL UTI treatment? We may still see either sulopenem or tebipenem make it to market in some form, but both have had issues clearing the clinical trial barriers to FDA approval and require additional clinical data. If they are not available, several potential agents are currently in development. OMNIvance (QPX7728), ETX0282CPDP, and VNRX-7145 are oral β-lactamase inhibitors that, when paired with a β-lactam, can greatly restore the antimicrobial activity against ESBLs and other resistant pathogens.

Unfortunately, these agents and others are still within early phase 1 and 2 clinical trials and will take time to be approved.^19,20 Until then, our oral treatment options for ESBL cUTI and pyelonephritis will remain quite limited.

References

1.Spero Therapeutics receives complete response letter from U.S. Food and Drug Administration for tebipenem HBr new drug application. News release. Spero Therapeutics, Inc; June 27, 2022. Accessed June 27, 2022. https://investors.sperotherapeutics.com/news-releases/news-release-details/spero-therapeutics-receives-complete-response-letter-us-food-and

2.Spero Therapeutics announces new strategic direction focusing on advancing promising clinical-stage pipeline. News release. Spero Therapeutics, Inc; May 3, 2022. Accessed July 27, 2022. https://investors.sperotherapeutics.com/news-releases/news-release-details/spero-therapeutics-announces-new-strategic-direction-focusing

3.Antibiotic resistance threats in the United States, 2019. CDC.https://stacks.cdc.gov/view/cdc/82532 Accessed June 27, 2022.

4.Jernigan JA, Hatfield KM, Wolford H, et al. Multidrug-resistant bacterial infections in U.S. hospitalized patients, 2012-2017. N Engl J Med. 2020;382(14):1309-1319. doi:10.1056/NEJMoa1914433

5.Critchley IA, Cotroneo N, Pucci MJ, Mendes R. The burden of antimicrobial resistance among urinary tract isolates of Escherichia coli in the United States in 2017. PLoS One. 2019;14(12):e0220265. doi:10.1371/journal.pone.0220265

6.Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America 2022 guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin Infect Dis. Published online April 19, 2022. doi:10.1093/cid/ciac268

7.Gettig JP, Crank CW, Philbrick AH. Faropenem medoxomil. Ann Pharmacother. 2008;42(1):80-90. doi:10.1345/aph.1G232

8.FDA rejects Replidyne’s antibiotic. News release. Fierce Biotech; October 22, 2006. Accessed June 28, 2022. https://www.fiercebiotech.com/regulatory/fda-rejects-replidyne-s-antibiotic

9.Dunne MW, Das AF, Zelasky M, Akinapelli K, Boucher H, Aronin SI. 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

10. 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

11. Iterum Therapeutics presented data at the 32nd European Congress of Clinical Microbiology and Infectious Diseases. News release. Iterum Therapeutics plc; April 25, 2022. Accessed July 19, 2022. https://www.iterumtx.com/news/press-releases/detail/87/iterum-therapeutics-presented-data-at-the-32nd-european

12. 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

13. Center for Drug Evaluation and Research. Complicated urinary tract infections: developing drugs for treatment. FDA; 2018. Updated May 7, 2020. Accessed June 28, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/complicated-urinary-tract-infections-developing-drugs-treatment

14. 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

15. Patel G, Rodvold KA, Gupta VK, et al. Pharmacokinetics of oral tebipenem pivoxil hydrobromide in subjects with various degrees of renal impairment. Antimicrob Agents Chemother. 2022;66(5):e0240721. doi:10.1128/aac.02407-21

16. Eckburg PB, Jain A, Walpole S, et al. Safety, pharmacokinetics, and food effect of tebipenem pivoxil hydrobromide after single and multiple ascending oral doses in healthy adult subjects. Antimicrob Agents Chemother. 2019;63(9):e00618-19. doi:10.1128/AAC.00618-19

17. Schurek KN, Wiebe R, Karlowsky JA, Rubinstein E, Hoban DJ, Zhanel GG. Faropenem: review of a new oral penem. Expert Rev Anti Infect Ther. 2007;5(2):185-198. doi:10.1586/14787210.5.2.185

18. Cotroneo N, Rubio A, Critchley IA, Pillar C, Pucci MJ. In vitro and in vivo characterization of tebipenem, an oral carbapenem. Antimicrob Agents Chemother. 2020;64(8):e02240-19. doi:10.1128/AAC.02240-19

19. Antibiotics currently in global clinical development. Pew Charitable Trusts. Updated March 9, 2021. Accessed July 27, 2022. http://pew.org/1YkUFkT

20. Veeraraghavan B, Bakthavatchalam YD, Sahni RD. Oral antibiotics in clinical development for community-acquired urinary tract infections. Infect Dis Ther. 2021;10(4):1815-1835. doi:10.1007/s40121-021-00509-4