New developments in treating gram-negative infections
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Gram-negative bacteria comprise most of the CDC and WHO’s lists of critical and urgent antibiotic-resistant organism threats.
The problem of gram-negative resistance was exacerbated by the COVID-19 pandemic, according to a special report published by the CDC in 2022, which showed increasing rates of infections caused by carbapenem-resistant Acinetobacter (CRAB), carbapenem-resistant Enterobacterales (CRE), extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, and multidrug-resistant Pseudomonas aeruginosa (MDR-PA) from 2019 to 2020.
These increases reversed a trend of decreasing or stable rates of these infections from 2017 to 2019. Even though there are many tools to help combat this increasing resistance, including infection prevention and antimicrobial stewardship, there is a continued need for the development of new antimicrobials.
There were six new agents for gram-negative infections approved from 2014 until 2019 but no approvals in 2020 to 2022. More recently, there has been movement in the gram-negative antibiotic pipeline, with one FDA approval in 2023, new FDA submissions and some more submissions expected soon.
FDA approves sulbactam-durlobactam
The FDA approved sulbactam-durlobactam, a beta-lactam/beta-lactamase inhibitor, in May 2023 for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC).
The approval was supported by data from the ATTACK phase 3 noninferiority trial, which compared sulbactam-durlobactam to colistin plus imipenem in both arms for HABP/VABP or bacteremia caused by ABC.
The rate of 28-day all-cause mortality was 19% in the sulbactam-durlobactam arm and 32% in the colistin group, demonstrating sulbactam-durlobactam’s noninferiority.
This agent is unique in that it is a targeted antimicrobial only for ABC and will generally be used only in CRAB.
Current FDA submissions
The companies that developed cefepime-enmetazobactam and cefepime-taniborbactam have both submitted new drug applications (NDAs) for the treatment of adult patients with complicated UTIs (cUTI), including pyelonephritis. The FDA has granted both priority review with a target action date of Feb. 22, 2024.
Cefepime-enmetazobactam is a novel beta lactam/beta-lactamase inhibitor combination, with enmetazobactam restoring cefepime against beta-lactamase-producing organisms. It was studied in the phase 3 ALLIUM randomized controlled trial (RCT) against piperacillin-tazobactam for cUTI or acute pyelonephritis. The primary outcome of the noninferiority trial was overall treatment success at day 14.
The primary outcome occurred in 79.1% with cefepime-enmetazobactam compared with 58.9% with piperacillin-tazobactam, meeting noninferiority and superiority for overall clinical cure.
The study was performed before the lowering of piperacillin-tazobactam breakpoints by the Clinical & Laboratory Standards Institute in 2022, leaving the possibility of an unequal comparison as some isolates in the study would now be considered resistant to piperacillin-tazobactam. However, the ALLIUM study group re-analyzed data using the updated breakpoints and the primary outcome remained similar at 79.1% vs. 60.3%. The role of cefepime-enmetazobactam in clinical practice appears to be as a carbapenem-sparing option for ESBLs.
Cefepime-taniborbactam is another novel beta lactam/beta-lactamase inhibitor combination. Taniborbactam restores activity of cefepime against ESBLs and CREs, including those caused by serine and metallo-beta lactamases (MBLs), and MDR-PA.
The noninferiority phase 3 CERTAIN-1 RCT compared cefepime-taniborbactam against meropenem for cUTI, including pyelonephritis.
Cefepime-taniborbactam was noninferior and superior to meropenem in the primary efficacy composite endpoint of microbiologic and clinical success at the test-of-cure (TOC) visit (day 19 to 23), achieving success in 70% of patients compared with 58% in the meropenem group.
The CERTAIN-2 trial will compare the combination treatment to meropenem for HABP/VABP. This trial was scheduled to commence in December 2023 and is expected to be completed in 2026.
Cefepime-taniborbactam may be used for many resistant gram-negative organisms such as CRE and MDR-PA, including those resistant to other gram-negative agents approved in the last decade.
Expected FDA submissions
Aztreonam-avibactam is a beta lactam/beta-lactamase inhibitor combination in which avibactam restores aztreonam’s activity against MBLs. The open-label phase 3 REVISIT study compared it (with or without metronidazole) against meropenem (with or without colistin) for patients hospitalized with complicated intra-abdominal infections (cIAI) or HABP/VABP due to gram-negative resistant bacteria. This includes MBL-producers with limited or no treatment options.
The majority of the 422 patients in the trial (around 75%) had cIAI, with Escherichia coli being the most common organism and 3.7% of patients having an MBL-producing organism.
The primary outcome was clinical cure at TOC visit in the intent-to-treat (ITT) population and clinically evaluable patients. The overall clinical cure rate in the ITT group was 68.4% in the aztreonam-avibactam group compared with 65.7% in the meropenem group. The cure rate for cIAI was 76.4% for aztreonam-avibactam vs. 74% with meropenem. For HABP/VABP, it was 45.9% vs. 41.7%. It was expected that the regulatory process for getting aztreonam-avibactam approved would start in late 2023. This could offer an option for CREs, especially those caused by an MBL-producing organism.
Gepotidacin is a new triazaacenaphthylene antibiotic that inhibits DNA replication by inhibiting two type II topoisomerase enzymes. It has activity against a wide range of gram-positive and gram-negative pathogens.
The EAGLE-2 and EAGLE-3 phase 3 RCTs compared gepotidacin with nitrofurantoin for uncomplicated UTIs (uUTIs) among female adults and adolescents. The primary endpoint was a composite of clinical resolution and microbiologic eradication at TOC visit, 10 to 13 days after initiation of treatment.
The studies were stopped early after interim data from a predefined interim analysis met efficacy and futility stopping criteria, as determined by independent data monitoring committee, and GSK announced plans for an FDA submission. The primary endpoint for gepotidacin was met in EAGLE-2 (50.6% vs. 47% in the nitrofurantoin group) and EAGLE-3 (58.5% vs. 43.6%), with EAGLE-3 also demonstrating statistical superiority.
Gepotidacin would offer an oral option for treatment of uUTIs that maybe resistant to current therapies.
Nonapproved FDA submissions
Two NDA submissions for gram-negative agents — sulopenem and tebipenem — were not approved by the FDA in recent years.
Sulopenem is a thiopenem with IV and oral formulations that was studied for cIAI, cUTI and uUTI. The FDA announced in July 2021 that an NDA filed for uUTI was not approvable in present form. In response, another phase 3 trial was initiated in October 2022 to investigate sulopenem compared with amoxicillin-clavulanate for uUTI. That trial is expected to finish in March 2024. Sulopenem could help fill the need to have more oral options for ESBLs, AmpC or fluroquinolone-resistant Enterobacterales.
Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against Enterobacterales, including ESBL-producing and fluoroquinolone-resistant strains. An NDA was filed for treatment of cUTI in January 2022, but in June 2022, the FDA said it could not be approved in its present form and that additional data were needed. This was after a separate FDA analysis of the ADAPT-PO trial resulted in the prespecified noninferiority margin not being met. A new phase 3 clinical trial has been designed, PIVOT-PO, which incorporated feedback from the FDA. It was set to start enrollment at end of 2023.
All these developments indicate that the gram-negative antibiotic pipeline is moving forward.
References:
- Butler MS, et al. J Antibiot. 2023;doi:10.1038/s41429-023-00629-8.
- Carmeli Y, et al. Abstract 2893 A. Presented at: IDWeek; Oct. 11-15, 2023; Boston.
- CDC. COVID-19: U.S. impact on antimicrobial resistance, special report 2022. https://stacks.cdc.gov/view/cdc/119025.
- Hsu C-K, et al. JAMA. 2023;doi:10.1001/jama.2022.22870.
- Kaye KS, et al. Lancet Infect Dis. 2023;doi:10.1016/S1473-3099(23)00184-6.
- Kaye KS, et al. JAMA. 2022;doi:10.1001/jama.2022.17034.
- Kaye KS, et al. JAMA. 2023;doi:10.1001/jama.2022.22873.
- McGovern PC, et al. Open Forum Infect Dis. 2022;doi:10.1093/ofid/ofac492.022.
- Wagenlehner F, et al. JAC Antimicrob Resist. 2023;doi:10.1093/jacamr/dlad077.035.
- Positive results announced in largest pivotal phase 3 trial of a first-in-class oral antibiotic to treat uncomplicated gonorrhea. https://gardp.org/positive-results-announced-in-largest-pivotal-phase-3-trial-of-a-first-in-class-oral-antibiotic-to-treat-uncomplicated-gonorrhoea/. Published Nov. 1, 2023. Accessed Jan. 1, 2024.
For more information:
Kelly M. Percival, PharmD, BCPS, BCIDP, is a clinical pharmacy specialist in infectious diseases at the University of Iowa Hospitals & Clinics. Percival can be reached at kelly-percival@uiowa.edu.
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