Beyond Approval: Finding the Right Place for Emerging Gram-Negative Antibiotics

The Gram-negative antibiotic pipeline has grown considerably in recent years, addressing carbapenem-resistant Acinetobacter baumannii (CRAB), difficult-to-treat (DTR) Pseudomonas aeruginosa, and other multidrug-resistant organisms (MDRO) that once left clinicians few options. This progress is worth celebrating, but raises an important question: does FDA approval tell us where a drug belongs in practice?

Approval confirms safety and efficacy in controlled trials but says little about prioritization against existing therapies, which patients benefit most, or where evidence is still lacking; questions clinicians must answer themselves.

We examine newly approved Gram-negative agents (Table 1)^1-15 using three questions that matter more than spectrum of activity: what unmet need did each drug address? What does the evidence support, and where does it fall short? How should stewardship guide its use?

When New Drugs Clearly Fill an Unmet Need

Sulbactam-durlobactam fulfills a therapeutic need for CRAB infections. Aztreonam-avibactam offers an important option for New Delhi metallo-beta-lactamase (NDM)-producing carbapenem-resistant Enterobacterales (CRE), replacing separate administration of ceftazidime-avibactam plus aztreonam. Its approval matters given growing resistance to cefiderocol,^16,17 the only other NDM agent.

When the Evidence is Still Catching Up

Cefepime-enmetazobactam offers a carbapenem-sparing option for extended spectrum beta-lactamase (ESBL) infections, although the evidence is largely limited to urinary tract infections (UTI),⁸ without comparative data against carbapenems. Its thrice-daily intravenous dosing is less convenient for outpatient use than once-daily ertapenem. It lacks reliable activity against Klebsiella pneumoniae carbapenemase (KPC)- or metallo-beta-lactamase (MBL)-producing CRE but shows high in vitro activity against OXA-48-like producers (~96%),^6,7 suggesting potential as a ceftazidime-avibactam alternative, although clinically unproven.

Cefepime-zidebactam offers broader coverage, with potent activity against CRE (KPC, MBL, and OXA-48-like) and DTR Pseudomonas aeruginosa,^6,11,18 including isolates resistant to ceftazidime-avibactam and ceftolozane-tazobactam.¹⁸ Evidence remains limited to in vitro data^6,11,18 and case reports,^19,20 as the pivotal trial excluded meropenem-resistant infections.¹⁰ Use should be limited to infections resistant to other options, preserving activity against NDM for the future.

Tebipenem is an oral carbapenem option for ESBL urinary tract infections resistant to conventional oral agents, although stewardship is needed to prevent outpatient overuse. Gepotidacin offers a first-in-class oral option for uncomplicated UTI with a novel mechanism that may limit cross-resistance, but its role beyond this indication remains undefined.

Regulatory approval makes these agents available for MDRO treatment; however, pivotal trials often exclude or underrepresent MDRO patients due to enrollment challenges and confounding factors.^5,8,10 Real-world, post-approval studies remain necessary to confirm effectiveness in the populations these drugs are meant to serve.

Stewardship in the Era of Antibiotic Innovation

Novelty is not synonymous with necessity. Each new agent should be judged against one standard: does it solve a problem existing therapies cannot, in a patient population where evidence supports its use? If so, it’s an invaluable addition to the shrinking arsenal. When unclear, reflexive adoption risks needless cost, avoidable resistance pressure, and misuse in patients who would have fared just as well on an older agent.

Matching therapy to resistance mechanisms, not the newest option, is the discipline stewardship demands, increasingly aided by rapid diagnostics. Stewardship programs exist not to gatekeep innovation but to ensure evidence-based use.

These recently approved Gram-negative agents represent meaningful progress against MDROs. However, their value will not come from indiscriminately replacing existing therapies but from addressing specific gaps where evidence shows improved outcomes. Stewardship should keep pace with, not outrun, the evidence.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied health care professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

References
1.Viscardi S, Lipska P, Niezgódka P, Duda-Madej A. Sulbactam-Durlobactam in the Treatment of Multidrug-Resistant Acinetobacter baumannii: A Narrative Review. Antibiotics (Basel). 2026;15(5):499. Published 2026 May 16. doi:10.3390/antibiotics15050499

2.Kaye KS, Shorr AF, Wunderink RG, et al. Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023;23(9):1072-1084. doi:10.1016/S1473-3099(23)00184-6

3.Kang Y, Xie L, Yang J, Cui J. Optimal treatment of ceftazidime-avibactam and aztreonam-avibactam against bloodstream infections or lower respiratory tract infections caused by extensively drug-resistant or pan drug-resistant (XDR/PDR) Pseudomonas aeruginosa. Front Cell Infect Microbiol. 2023;13:1023948. Published 2023 Jun 28. doi:10.3389/fcimb.2023.1023948

4.Daikos GL, Cisneros JM, Carmeli Y, et al. Aztreonam-avibactam for the treatment of serious infections caused by metallo-β-lactamase-producing Gram-negative pathogens: a Phase 3 randomized trial (ASSEMBLE). JAC Antimicrob Resist. 2025;7(4):dlaf131. Published 2025 Jul 28. doi:10.1093/jacamr/dlaf131

5.Carmeli Y, Cisneros JM, Paul M, et al. Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by Gram-negative bacteria (REVISIT): a descriptive, multinational, open-label, phase 3, randomised trial. Lancet Infect Dis. 2025;25(2):218-230. doi:10.1016/S1473-3099(24)00499-7

6.Dutkiewicz M, Jousset AB, de Swardt H, et al. In vitro susceptibility of cefepime-enmetazobactam, cefepime-taniborbactam and cefepime-zidebactam towards carbapenemase-producing Enterobacterales. J Antimicrob Chemother. 2026;81(1):dkaf440. doi:10.1093/jac/dkaf440

7.Bonnin RA, Jeannot K, Santerre Henriksen A, Quevedo J, Dortet L. In vitro activity of cefepime-enmetazobactam on carbapenem-resistant Gram negatives. Clin Microbiol Infect. 2025;31(2):240-249. doi:10.1016/j.cmi.2024.09.031

8.Kaye KS, Belley A, Barth P, et al. Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial. JAMA. 2022;328(13):1304-1314. doi:10.1001/jama.2022.17034

9.Arshad N, Azzam W, Zilberberg MD, Shorr AF. Acinetobacter baumannii Complex Infections: New Treatment Options in the Antibiotic Pipeline. Microorganisms. 2025;13(2):356. Published 2025 Feb 7. doi:10.3390/microorganisms13020356

10.Genov P, Mladenov B, Slaitas D, et al. P-1209. Efficacy of β-lactam Enhancer Based Zidebactam-Cefepime Combination (WCK 5222) versus Meropenem in Adults with Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) in a Global, Randomized, Double-blind, Phase 3 Trial. Open Forum Infect Dis. 2026;13(Suppl 1):ofaf695.1402. Published 2026 Jan 11. doi:10.1093/ofid/ofaf695.1402

11.Sader HS, Mendes RE, Duncan LR, Carvalhaes CG, Castanheria M. Antimicrobial activity of cefepime/zidebactam (WCK 5222), a β-lactam/β-lactam enhancer combination, against clinical isolates of Gram-negative bacteria collected worldwide (2018-19). J Antimicrob Chemother. 2022;77(10):2642-2649. doi:10.1093/jac/dkac233

12.Hong DK, Ascioglu S, Bhatt N, et al. 173. Oral Tebipenem Pivoxil Hydrobromide versus Intravenous Imipenem-Cilastatin in Patients with Complicated Urinary Tract Infections or Acute Pyelonephritis: Efficacy and Safety Results from the Phase 3 PIVOT-PO study. Open Forum Infect Dis. 2026;13(Suppl 1):ofaf695.003. Published 2026 Jan 11. doi:10.1093/ofid/ofaf695.003

13.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

14.Wagenlehner F, Perry CR, Hooton TM, et al. Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials. Lancet. 2024;403(10428):741-755. doi:10.1016/S0140-6736(23)02196-7

15. Ross JDC, Wilson J, Workowski KA, et al. Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhoea (EAGLE-1): a phase 3 randomised, open-label, non-inferiority, multicentre study. Lancet. 2025;405(10489):1608-1620. doi:10.1016/S0140-6736(25)00628-2

16. Lu Y, Lan P, Xu W, et al. High prevalence of cefiderocol resistance in carbapenem-resistant Escherichia coli: A warning from multicenter clinical data in China. J Infect. 2025;91(3):106563. doi:10.1016/j.jinf.2025.106563

17. Baltas I, Patel T, Soares AL. Resistance profiles of carbapenemase-producing Enterobacterales in a large centre in England: are we already losing cefiderocol?. J Antimicrob Chemother. 2025;80(1):59-67. doi:10.1093/jac/dkae367

18.Lepak AJ, Zhao M, Andes DR. WCK 5222 (Cefepime/Zidebactam) Pharmacodynamic Target Analysis against Metallo-β-lactamase producing Enterobacteriaceae in the Neutropenic Mouse Pneumonia Model. Antimicrob Agents Chemother. 2019;63(12):e01648-19. doi:10.1128/AAC.01648-19

19.Shah P, Neeravi A, Karthik R, et al. Successful use of cefepime/zidebactam in deep-seated infections due to extensively drug-resistant Pseudomonas aeruginosa: A case series. J Glob Antimicrob Resist. 2025;44:464-469. doi:10.1016/j.jgar.2025.07.009

20. Tirlangi PK, Wanve BS, Dubbudu RR, et al. Successful Use of Cefepime-Zidebactam (WCK 5222) as a Salvage Therapy for the Treatment of Disseminated Extensively Drug-Resistant New Delhi Metallo-β-Lactamase-Producing Pseudomonas aeruginosa Infection in an Adult Patient with Acute T-Cell Leukemia. Antimicrob Agents Chemother. 2023;67(8):e0050023. doi:10.1128/aac.00500-23