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UTIs: Why Did You Have to Go and Make Things so Complicated?

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Although hospitalizations due to urinary tract infections have increased, there are some investigational antibiotics in clinical trials. Here is a review of some of these therapies in the pipeline.

Infections caused by multidrug-resistant (MDR) organisms not only have financial implications but also negative clinical implications due to paucity of treatment options. While infections caused by MDR organisms are commonly associated with healthcare associated infections, there are a growing number of community acquired MDR infections.1 Enterobacterales account for over 80% of urinary tract infections, and the rate of extended-spectrum beta-lactamase (ESBL) producing Enterobacterales has increased to almost 20%.2

Hospitalizations due to urinary tract infections have increased, likely attributed to limited oral antibiotics for infections caused by resistant gram-negative organisms.3 Since 2019, following the approval of cefiderocol and imipenem-relebactam, there have been no new antibiotics approved to treat complicated urinary tract infections (cUTI). In June 2022, the FDA rejected the NDA for tebipenem which was considered a valuable asset in the antimicrobial armamentarium as it was a first-in class oral carbapenem for the treatment of cUTI caused by MDR organisms.4 Although tebipenem did not receive FDA approval, there are other antibiotics in the pipeline that are being investigated for the treatment of cUTI and pyelonephritis. (Table 1.)

Sulopenem
This is another novel carbapenem that is formulated both IV and oral, was being studied for the treatment of cUTI. In vitro it has demonstrated activity against gram-negative, gram-positive and anaerobic bacteria including resistant Enterobacterales making it a promising new antibiotic for ESBL producing organisms. Yet in the phase 3 SURE1 trial, a multi-center, double-blind study, comparing sulopenem to ciprofloxacin, sulopenem was not non-inferior to ciprofloxacin in patients with quinolone susceptible organisms. It only demonstrated superiority over ciprofloxacin in patients with cUTI caused by fluoroquinolone resistant pathogens.5 The SURE2 trial, comparing sulopenem to ertapenem, also failed to demonstrate non-inferiority in the treatment of cUTI.6 The FDA rejected the NDA for sulopenem and requested an additional clinical study using a different drug for comparison and recommended a non-clinical study to determine optimal dosing.7 In July 2022, Iterum Therapeutics reached an agreement with the FDA under the special protocol assessment process for a phase 3 clinical trial for oral sulopenem for the treatment of uncomplicated UTIs. Pending the results of this trial, Iterum may resubmit a new NDA in the future for oral sulopenem.8

Benapenem
Benapenem is a new parenteral carbapenem in development to treat severe infections including cUTI. The spectrum of activity and pharmacokinetic profile is similar to ertapenem. Benapenem has a longer half-life facilitating once-daily dosing and has activity against Gram-negative bacteria including ESBL-producing organisms, Gram-positives, and anaerobes. At this time phase 1 trials have completed indicating that benapenem is well tolerated in healthy volunteers.9 A phase 2/3 trial comparing once daily benapenem to ertapenem for cUTI and pyelonephritis has ended but results are not available at this time.10

Aztreonam-Avibactam
While ceftazidime-avibactam is an important antimicrobial in many CRE infections caused by serine-beta-lactamases (KPC, OXA48), it lacks activity against metallo-beta-lactamase (MBL) producing carbapenemases. Aztreonam is known to be stable against hydrolysis by MBLs but is susceptible to hydrolysis by serine beta-lactamases. By combining aztreonam and avibactam, the result is enhanced activity and aztreonam is “protected” from inactivation by serine beta-lactamases.11 Results from a phase 2 study (REJUVENATE) in complicated intra-abdominal infections showed that the drug was safe and achieved target attainment in over 90% of patients.12 The REVISIT trial is a phase 3, randomized, multicenter, open label, comparative study assessing the efficacy and safety of aztreonam-avibactam +/- metro versus meropenem +/- colistin for the treatment of serious infections due to gram negative bacteria (including urinary tract infections). The primary outcome measure is the proportion of participants with clinical cure at test-of-cure (day 28) in the intention-to-treat analysis.13 The trial is ongoing and trial results have not been released at this time. Emergence of recent resistance has been reported with OXA48 and NDM isolates which may limit use of this drug combination.14

Cefepime-Enmetazobactam
Cefepime in combination with enmetazobactam, a novel beta-lactamase inhibitor with potent activity against class A serine beta-lactamases (specifically ESBLs), is also being investigated. Enmetazobactam is a derivative of tazobactam with structural differences to enhance potent interactions with ESBL at the active site, enhance penetration into the periplasmic space, and extend half-life.15 After finding a favorable pharmacokinetic profile in a phase 1 study and high probability of target attainment with a good safety profile in a phase 2 study, cefepime-enmetazobactam was studied in a P hase 3 study in the treatment of complicated urinary tract infections and acute pyelonephritis.16

The phase 3 study, ALLIUM, was a multi-center, randomized, controlled, double-blind, global study. They enrolled 1034 patients who received either cefepime-enmetazobactam or piperacillin/tazobactam. The primary efficacy endpoint was the composite of clinical cure and microbiologic eradication at test-of-cure visit in the microbiological modified intention-to-treat (m-MITT) population. Cefepime-enmetazobactam demonstrated superiority in the primary endpoint, with an overall composite clinical and microbiological success of 79.1% compared with 58.9% for piperacillin-tazobactam. In a subgroup of ESBL producing organisms, cefepime-enmetazobactam demonstrated superiority over piperacillin-tazobactam as well with a difference of 30% between the treatment groups.16 Cefepime-enmetazobactam has received Qualified Infectious Disease Product (QIDP) and Fast Track designation by the FDA. The company, Allecra, signed a license and supply agreement with a European company in early 2022 for the drug’s use in Europe.15 There are no updates on when Allecra plans to submit for NDA in the US.

Cefepime-Taniborbactam
Taniborbactam, a new cyclic boronate beta-lactamase inhibitor, is being developed with cefepime for the treatment of beta-lactamase producing organisms including ESBLs, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa. Cefepime-taniborbactam was granted QIDP and Fast Track designation by the US FDA.17 In the CERTAIN-1 trial, a non-inferiority, randomized, double blind phase-3 study, cefepime-taniborbactam was evaluated against meropenem in the treatment of cUTI including pyelonephritis. The trial enrolled 611 adult patients who were treated with either cefepime-taniborbactam or meropenem for 7 days. In a press release from the company, cefepime-taniborbactam demonstrated statistical noninferiority for the primary efficacy endpoint of composite clinical and microbiological response at the test of cure visit in the microbiological intent-to-treat population (microITT). In the microITT population 70% of patients treated with cefepime-taniborbactam had clinical and microbiologic cure compared to 58% in the meropenem treated group. Complete trial data has not been released at this time. Cefepime-taniborbactam is on track for NDA submission in the fourth quarter of 2022 and may offer a new treatment option for cUTI caused by MDR organisms.17

Sulbactam/Durlobactam
Durlobactam is a next generation beta-lactamase inhibitor with a broad spectrum of activity against Ambler class A, C and D serine β-lactamases that is being investigated in combination with sulbactam.18 In phase 1 and 2 trials, sulbactam-durlobactam was well tolerated.19,20 Data from the phase 3 ATTACK trial was presented at the European Congress of Clinical Microbiology and Infectious Diseases conference in April, 2022. The ATTACK trial was a two part trial. The first part was a randomized, blinded noninferiority study comparing sulbactam-durlobactam to colistin in the treatment of hospital-acquired and ventilator associated bacterial pneumonia, or bacteremia caused by Acinetobacter baumanii-calcoaceticus complex. The second part was an open label study that enrolled patients with Acinetobacter baumanii-calcoaceticus complex infections who did not tolerate colistins or had colistin resistant pathogens.

The primary efficacy endpoint, 28 day all-cause mortality in the carbapenem resistant cohort, was 19% and 32.3% for sulbactam-durlobactam versus colistin, respectively. Furthermore, sulbactam-durlobactam demonstrated a better safety profile compared to colistin. Rates of nephrotoxicity during therapy were significantly less in the sulbactam-durlobactam group; 13.2% versus 37.6% in the colistin group.21 According to Entasis Therapeutics’ business update, the company was on track for NDA submission to the FDA mid-2022.22 If approved, sulbactam–durlobactam will be an important treatment option for patients with serious and life-threatening infections caused by Acinetobacter species, including carbapenem-resistant strains.

References

1. 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

2. 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

3. Simmering JE, Tang F, Cavanaugh JE, Polgreen LA, Polgreen PM. The Increase in Hospitalizations for Urinary Tract Infections and the Associated Costs in the United States, 1998–2011. Open Forum Infect Dis. 2017;4(1):ofw281. doi:10.1093/ofid/ofw281

4. Spero Therapeutics Receives Complete Response Letter from U.S. Food and Drug Administration for Tebipenem HBr New Drug Application | Spero Therapeutics, Inc. Accessed September 8, 2022. https://investors.sperotherapeutics.com/news-releases/news-release-details/spero-therapeutics-receives-complete-response-letter-us-food-and

5. Dunne MW, Das AF, Zelasky M, Akinapelli K, Boucher H, Aronin SI. LB-1. 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(Supplement_1):S844. doi:10.1093/ofid/ofaa515.1898

6. 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

7. Iterum Therapeutics Receives Complete Response Letter from U.S. Food and Drug Administration for Oral Sulopenem. Iterum Therapeutics plc. Accessed September 8, 2022. https://www.iterumtx.com/news/press-releases/detail/73/iterum-therapeutics-receives-complete-response-letter-from

8. Iterum Therapeutics Reports Second Quarter 2022 Financial Results. Iterum Therapeutics plc. Accessed September 8, 2022. https://ir.iterumtx.com/press-releases/detail/93/iterum-therapeutics-reports-second-quarter-2022-financial

9. Zhao CY, Lv Y, Zhu Y, et al. A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers. Antimicrob Agents Chemother. 2019;63(3):e02188-18. doi:10.1128/AAC.02188-18

10. Sihuan Pharmaceutical Holdings Group Ltd. A Phase 2, Randomized, Double-Blind, Positive-Control, Multicenter, Prospective Study to Assess Efficacy and Safety of Intravenous Benapenem in Patients With Complicated Urinary Tract Infection (CUTI) or Acute Pyelonephritis (AP). clinicaltrials.gov; 2020. Accessed September 5, 2022. https://clinicaltrials.gov/ct2/show/NCT04505683

11. Crandon JL, Nicolau DP. Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-β-lactamase producers. Antimicrob Agents Chemother. 2013;57(7):3299-3306. doi:10.1128/AAC.01989-12

12. Cornely OA, Cisneros JM, Torre-Cisneros J, et al. Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study. J Antimicrob Chemother. 2020;75(3):618-627. doi:10.1093/jac/dkz497

13. Pfizer. A Phase 3 Prospective, Randomized, Multicenter, Open Label, Central Assessor Blinded, Parallel Group, Comparative Study To Determine The Efficacy, Safety And Tolerability Of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem±Colistin (MER±COL) For The Treatment Of Serious Infections Due To Gram Negative Bacteria, Including Metallo Β Lactamase (MBL) - Producing Multidrug Resistant Pathogens, For Which There Are Limited Or No Treatment Options. clinicaltrials.gov; 2022. Accessed September 5, 2022. https://clinicaltrials.gov/ct2/show/NCT03329092

14. Nordmann P, Yao Y, Falgenhauer L, Sadek M, Imirzalioglu C, Chakraborty T. Recent Emergence of Aztreonam-Avibactam Resistance in NDM and OXA-48 Carbapenemase-Producing Escherichia coli in Germany. Antimicrob Agents Chemother. 65(11):e01090-21. doi:10.1128/AAC.01090-21

15. Cefepime-enmetazobactam. Accessed September 7, 2022. https://allecra.com/more-cefepime

16. Kaye K, Belley A, Lahlou O. Outcomes of the Novel β-lactam/β-lactamase Inhibitor Combination of Cefepime-Enmetazobactam versus Piperacillin-Tazobactam in Adult Patients with Complicated Urinary Tract Infections – The ALLIUM Phase 3 Trial. ESCMID. Published online 2020. Accessed August 3, 2022. https://www.escmid.org/fileadmin/src/media/PDFs/Abstractbook2020_05.05.2020_Part5.pdf#page=131

17. Venatorx Pharmaceuticals Announces Positive Results for Phase 3 Clinical Trial (CERTAIN-1) of Cefepime-Taniborbactam for Treatment of cUTI. Published March 10, 2022. Accessed September 7, 2022. https://www.businesswire.com/news/home/20220310005341/en/Venatorx-Pharmaceuticals-Announces-Positive-Results-for-Phase-3-Clinical-Trial-CERTAIN-1-of-Cefepime-Taniborbactam-for-Treatment-of-cUTI

18. Shapiro AB, Moussa SH, McLeod SM, Durand-Réville T, Miller AA. Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam. Front Microbiol. 2021;12. Accessed September 7, 2022. https://www.frontiersin.org/articles/10.3389/fmicb.2021.709974

19. O’Donnell J, Preston RA, Mamikonyan G, Stone E, Isaacs R. Pharmacokinetics, Safety, and Tolerability of Intravenous Durlobactam and Sulbactam in Subjects with Renal Impairment and Healthy Matched Control Subjects. Antimicrob Agents Chemother. 2019;63(9):e00794-19. doi:10.1128/AAC.00794-19

20. Sagan O, Yakubsevitch R, Yanev K, et al. Pharmacokinetics and Tolerability of Intravenous Sulbactam-Durlobactam with Imipenem-Cilastatin in Hospitalized Adults with Complicated Urinary Tract Infections, Including Acute Pyelonephritis. Antimicrob Agents Chemother. 2020;64(3):e01506-19. doi:10.1128/AAC.01506-19

21. Inc ETH. Entasis Therapeutics Presents Efficacy and Safety Data from Landmark Phase 3 ATTACK Trial at ECCMID 2022 Conference. GlobeNewswire News Room. Published April 26, 2022. Accessed September 8, 2022. https://www.globenewswire.com/news-release/2022/04/26/2429001/0/en/Entasis-Therapeutics-Presents-Efficacy-and-Safety-Data-from-Landmark-Phase-3-ATTACK-Trial-at-ECCMID-2022-Conference.html

22. Entasis Therapeutics Announces First Quarter 2022 Financial Results and Provides Business Update. Accessed September 7, 2022. https://www.sec.gov/Archives/edgar/data/1724344/000155837022006042/ettx-20220427xex99d1.htm