New approaches to gram-negative infections: A look at the pipeline
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The CDC recently reported that more than 2.8 million antibiotic-resistant infections occur in the United States every year, and 50% of the antibiotic-resistant threats are gram-negative bacteria.
A Pew Charitable Trusts analysis of antibiotics in clinical development showed that between 2014 and 2018, there were 67 drug candidates, of which 26 had activity against gram-negative bacteria. Of the antibiotics approved by the FDA between 2014 and 2019, 10 out of 13 have activity against gram-negative bacteria. However, new antibiotics are urgently needed because of the increase in infections caused by gram-negative bacteria, especially antibiotic-resistant strains. As of December 2019, there are 13 antibiotics undergoing phase 3 trials globally, and seven of these are currently being evaluated as treatment options for infections caused by gram-negative pathogens.
Novel BLIs
Cefepime/enmetazobactam
Enmetazobactam, formerly known as AAI101, is a novel penicillanic acid sulfone extended-spectrum beta-lactamase (ESBL) inhibitor. It has shown inhibitory activity against CTX-M, TEM, SHV and other Ambler class A beta-lactamases but does not enhance cefepime’s potency against Pseudomonas aeruginosa. Cefepime/enmetazobactam is intended to be a carbapenem-sparing option against ESBL-producing Enterobacteriaceae. Potential indications include complicated UTIs (cUTIs), including acute pyelonephritis (AP), complicated intra-abdominal infections (cIAIs) and hospital-acquired or ventilator-associated bacterial pneumonia. Cefepime/enmetazobactam was found to be superior to piperacillin/tazobactam in treating cUTIs in the ALLIUM phase 3 clinical trial. Success was defined as a combination of clinical cure and microbiological eradication, and it occurred in 273 of 345 (79.1%) patients in the cefepime/enmetazobactam group vs. 196 of 333 (58.9%) patients in the piperacillin/tazobactam group (95% CI, 14.3%-27.9%). In patients with ESBL-producing pathogens, success occurred in 56 of 76 (73.7%) patients receiving cefepime/enmetazobactam vs. 34 of 66 (51.6%) patients receiving piperacillin/tazobactam.
Cefepime/taniborbactam
Taniborbactam, formerly known as VNRX-5133, is a novel cyclic boronate beta-lactamase inhibitors (BLI) that blocks both serine- and metallo-beta-lactamases. Taniborbactam restores cefepime’s antibacterial activity against Enterobacteriaceae and P. aeruginosa-producing clinically important beta-lactamases, including CTX-M, KPC-, OXA-, NDM-, and VIM-type beta-lactamases. An in vitro study evaluated this drug combination against 500 urinary gram-negative bacilli from China and, when compared with ceftazidime/avibactam, cefepime/taniborbactam exhibited more potent activity against various ESBL-, AmpC, and metallo-beta-lactamase producers. A phase 3, randomized, double-blind, noninferiority study is currently underway assessing the safety and efficacy of cefepime/taniborbactam compared with meropenem in patients with cUTIs.
Sulbactam/durlobactam
Durlobactam, also known as ETX2514, is a novel, diazabicyclooctenone BLI that exhibits potent inhibition of class A, C and D beta-lactamases. In addition, it has shown in vitro activity against some Enterobacteriaceae. A phase 2 trial showed no significant difference in the safety and efficacy of sulbactam/durlobactam compared with imipenem-cilastatin in patients with cUTIs, including AP. Sulbactam/durlobactam has shown excellent in vitro activity against carbapenem-resistant Acinetobacter baumannii compared with colistin, amikacin, minocycline and sulbactam alone. A phase 3 trial is currently evaluating the efficacy and safety of sulbactam/durlobactam plus imipenem-cilastatin in comparison with colistin plus imipenem-cilastatin in patients with infections caused by A. baumannii-calcoaceticus complex (ATTACK trial).
Carbapenems
Sulopenem
Sulopenem is an AmpC-stable thiopenem that can be administered either intravenously or orally. The FDA has granted Qualified Infectious Diseases Product designations to both formulations for the following indications: UTIs, cIAIs, community-associated pneumonia, acute prostatitis, gonococcal urethritis, and pelvic inflammatory disease. The phase 3 Sulopenem for Resistant Enterobacteriaceae (SURE) clinical trial evaluated sulopenem against ertapenem, followed by oral ciprofloxacin plus metronidazole or amoxicillin/clavulanate in patients with cIAIs. In this study, sulopenem failed to meet nonnferiority of the primary outcome of clinical response on day 28 in the microbiologically modified intent-to-treat (micro-MITT) population, with a difference in outcomes of 4.7% (85.5% sulopenem, 90.2% ertapenem; 95% CI, –10.3% to 1%). The company developing sulopenem, Iterum Therapeutics, recently published a press release on the results of their phase 3 trial evaluating sulopenem for the treatment of uncomplicated UTIs (SURE1). In the quinolone- nonsusceptible micro-MITT, the overall response rate at test-of-cure visit was 62.6% in the sulopenem group compared with 36% in the ciprofloxacin group (percentage difference of 26.6%; 95% CI, 15.1-37.4. However, this benefit was not observed in the quinolone-susceptible micro-MITT population. The difference in overall response to treatment was likely driven by a greater number of asymptomatic bacteriuria in the sulopenem arm relative to those receiving ciprofloxacin, and its clinical significance requires further investigation.
Tebipenem
Tebipenem-pivoxil hydrobromide (TBPM-PI-HBr; formerly SPR994) is the oral prodrug of the carbapenem tebipenem. It is converted to the active metabolite in plasma and has activity against ESBL-producing Enterobacteriaceae. Tebipenem-pivoxil was first introduced in Japan in 2009, but TBPM-PI-HBr is a novel formulation. It is undergoing development as an oral carbapenem to treat UTIs. In vitro data suggest that tebipenem is more potent than imipenem and equipotent to meropenem against Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, and production of ESBL- and/or AmpC-beta-lactamases do not adversely affect its activity. Results are pending for a phase 3 trial that is comparing the efficacy, safety and pharmacokinetics of TBPM-PI-HBr against IV ertapenem in patients with cUTI or AP (ADAPT-PO).
Novel bacterial topoisomerase inhibitors
Gepotidacin
Gepotidacin, formerly known as GSK2140944, is a novel triazaacenaphthylene bacterial type-II topoisomerase inhibitor. It selectively inhibits bacterial DNA replication by interacting in a unique way on the GyrA subunit of bacterial DNA gyrase and the ParC subunit of bacterial topoisomerase IV. Gepotidacin is currently being evaluated in a phase 3 trial against nitrofurantoin for the treatment of uncomplicated UTIs. However, it has a limited gram-negative spectrum of coverage, and patients with a UTI due to P. aeruginosa or an Enterobacteriaceae other than E. coli are excluded from the trial. Although gepotidacin has not shown activity against Chlamydia trachomatis, its main potential indication may be for uncomplicated urogenital gonorrhea, including cases due to drug-resistant Neisseria gonorrhoeae. Despite its novel mechanism of action, emergence of resistance is still a concern because resistance was observed in three N. gonorrhoeae isolates during a phase 2 study.
Zoliflodacin
Zoliflodacin is a spiropyrimidinetrione with a novel mechanism of action because it targets the bacterial type-II topoisomerase (GyrB) and inhibits microbial synthesis by arresting the cleaved covalent gyrase complex and the formation of fused circular DNA. The effectiveness of this mechanism of action has been confirmed against ciprofloxacin- and ceftriaxone-resistant N. gonorrhoeae and fluoroquinolone-resistant and vancomycin-resistant Staphylococcus aureus strains. In addition, zoliflodacin has shown activity against C. trachomatis, C. pneumonia, Mycoplasma genitalium and Mycoplasma ureaplasma. A phase 2 trial comparing zoliflodacin against ceftriaxone alone showed that the majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin but not pharyngeal infections. A phase 3 trial is currently underway comparing zoliflodacin to ceftriaxone plus azithromycin for the treatment of uncomplicated gonorrhea.
In closing
Antibiotic resistance, especially drug-resistant N. gonorrhoeae, ESBL-producing Enterobacteriaceaeand carbapenem-resistance, is on the rise. Several new antibiotics active against gram-negative pathogens have been approved in recent years and more are currently on the pipeline. However, these potential new agents will require careful consideration of local epidemiological patterns and evaluation of which patients will safely benefit from them.
- References:
- Allecra Therapeutics. (2020). Allecra Therapeutics announces positive top-line results for phase 3 ALLIUM clinical trial of EXBLIFEP for complicated urinary tract Infections. [Press release.] February 25, 2020. https://www.globenewswire.com/news-release/2020/02/25/1989893/0/en/Allecra-Therapeutics-Announces-Positive-Top-Line-Results-for-Phase-3-ALLIUM-Clinical-Trial-of-EXBLIFEP-for-Complicated-Urinary-Tract-Infections.html. Accessed August 2, 2020.
- Arends SJR, et al. Antimicrob Agents Chemother. 2019;doi:101128/AAC.02618-18.
- CDC. Antibiotic resistance threats in the United States, 2019. 2020. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed August 2, 2020
- Entasis Therapeutics. Study to evaluate the efficacy and safety of intravenous sulbactam-ETX2514 in the treatment of patients with infections caused by Acinetobacter baumannii-calcoaceticus complex (ATTACK). Available from: https://clinicaltrials.gov/ct2/show/NCT03894046. NLM identifier: NCT03894046. Accessed July 13, 2020.
- GlaxoSmithKline. A study evaluating efficacy and safety of gepotidacin compared with ceftriaxone plus azithromycin in the treatment of uncomplicated urogenital gonorrhea. Available from: https://clinicaltrials.gov/ct2/show/NCT04010539. NLM identifier: NCT04010539. Accessed July 13, 2020.
- GlaxoSmithKline. A study to evaluate efficacy and safety of gepotidacin in the treatment of uncomplicated urinary tract infection. Available from: https://clinicaltrials.gov/ct2/show/NCT04020341. NLM identifier: NCT04020341. Accessed July 13, 2020.
- Global Antibiotics Research and Development Partnership. Zoliflodacin in uncomplicated gonorrhoea. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03959527. NLM identifier: NCT03959527. Accessed July 13, 2020.
- Hamrick JC, et al. Antimicrob Agents Chemother. 2020;doi:10.1128/AAC.01963-19.
- Iterum Therapeutics. (2019). Iterum Therapeutics announces topline results from phase 3 clinical trial of oral and IV sulopenem for the treatment of complicated intra-abdominal infections. [Press release.] December 10, 2019. https://www.globenewswire.com/news-release/2019/12/10/1958907/0/en/Iterum-Therapeutics-Announces-Topline-Results-from-Phase-3-Clinical-Trial-of-Oral-and-IV-Sulopenem-for-the-Treatment-of-Complicated-Intra-abdominal-Infections.html. Accessed on August 2, 2020.
- Iterum Therapeutics, PLC. Press release [June 29, 2020]. GlobeNewswire. Accessed on July 13, 2020: http://www.globenewswire.com/news-release/2020/06/29/2054608/0/en/Iterum-Therapeutics-Announces-Topline-Results-from-its-Phase-3-Clinical-Trial-of-Oral-Sulopenem-for-the-Treatment-of-Uncomplicated-Urinary-Tract-Infections.html.
- Karlowsky JA, et al. Antimicrob Agents Chemother. 2019;doi10.1128/AAC.01832-18.
- Kim W. Review of antibiotics in clinical development pipeline. The Pew Charitable Trusts. https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/enhancing-clinical-trial-enterprise-antibacterial-drug-development-united-states-11182019-11192019#event-materials. Accessed August 2, 2020.
- Morrissey I, et al. Antimicrob Agents Chemother. 2019;doi:10.1128/AAC.00514-19.
- Pew Charitable Trusts. Antibiotics currently in global clinical development. https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development. Accessed August 2, 2020.
- Sagan O, et al. Antimicrob Agents Chemother. 2020;doi:10.1128/AAC.01506-19.
- Seifert H, et al. J Antimicrob Chemother. 2020.doi:10.1093/jac/dkaa208.
- Spero Therapeutics. Study to assess the efficacy, safety and pharmacokinetics of orally administered tebipenem pivoxil hydrobromide (SPR994) compared to intravenous ertapenem in patients with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) (ADAPT-PO). Available from: https://clinicaltrials.gov/ct2/show/NCT03788967?cond=tebipenem&draw=2&rank=6. NLM identifier: NCT03788967. Accessed July 13, 2020.
- Taylor SN, et al. Clin Infect Dis. 2018;doi:10.1093/cid/ciy145.
- Taylor SN, et al. N Engl J Med. 2018;10.1056/NEJMoa1706988.
- VenatoRx Pharmaceuticals, Inc. Safety and efficacy study of cefepime/VNRX-5133 in patients with complicated urinary tract infections. Available from: https://clinicaltrials.gov/ct2/show/NCT03840148. NLM identifier: NCT03840148. Accessed July 12, 2020.
- For more information:
- Axel A. Vazquez Deida, PharmD, is an MPH-epidemiology student at the University of Nebraska Medical Center and an infectious diseases-trained pharmacist. Vazquez Deida can be reached at axel.vazquezdeida@unmc.edu.
- Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
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