AI-Generated Summary: This pharmacy school study tool compares cefepime-enmetazobactam (Exblifep) vs cefepime-zidebactam (Zaynich), highlighting key differences in their mechanisms of action, antibacterial spectra, dosing, and clinical applications. It emphasizes their activity against resistant Gram-negative bacteria, including the broader potential of cefepime-zidebactam against certain carbapenem-resistant pathogens, to help pharmacy students understand how these newer antibiotics differ.
Authored By: Alexis Daniels, Pharm.D. candidate 2027
Mentored By: Christina Rivera, PharmD, BCPS, BCIDP, AAHIV-M
Article Published 3 October 2026
Drug resistant gram negative bacteria are a major threat to human health worldwide. For example, rates of multidrug-resistant (MDR) Pseudomonas aeruginosa have steadily increased, with an estimated 32,600 infections occurring among hospitalized patients and approximately 2,700 deaths in the United States as of 2017 [1]. A retrospective cross-sectional study evaluating the rates of MDR P. aeruginosa in the U.S. found a resistance rate of 19.2% (3041/13,250 patients) in ICU patients with a carbapenem resistance rate of 12.5% (3,712/29,630 patients). The need for newer antimicrobials that can reliably treat infections caused by MDR gram negative bacilli, including P. aeruginosa, is readily apparent [2].
Looking to the drug development pipeline, two newer agents have been FDA-approved somewhat recently, both containing cefepime. This article will help contrast cefepime-enmetazobactam (Exblifep®) versus cefepime-zidebactam (Zaynich®).
Cefepime (Maxipime®) is a fourth-generation cephalosporin that displays activity against a variety of gram positive and gram negative bacteria. Importantly, cefepime has activity against P. aeruginosa and may be an option for chromosomal or plasmid-mediated AmpC-enzymes. Due to its broad spectrum of activity and stability against common resistance mechanisms, cefepime is an attractive agent for investigation in combination with novel β-lactamase inhibitors (BLI) for the treatment of MDR gram negatives. The question arises if adding a novel BLI to cefepime may expand its clinical utility in a meaningful way, and if so which Ambler class enzymes may be covered?
There are three cefepime-BLI combinations for your radar.
1st is cefepime-enmetazobactam (Exblifep®) which was FDA approved February 2024.
2nd is cefepime-zidebactam (Zaynich®) was FDA-approved May 2026.
3rd is cefepime-taniborbactam which remains in clinical development. There were hopes it would be FDA-approved by now, but February 2024 FDA issued a statement requiring additional clinical and manufacturing information. Its future status remains uncertain. Taniborbactam has been shown to be able to inhibit enzyme from Ambler class A, B, C, and D. Class B enzymes are a major area of need and taniborbactam can inhibit VIM, NDM, SPM-1, and GIM-1 (but not IMP).
Table comparing cefepime-enmetazobactam (Exblifep®) versus cefepime-zidebactam (Zaynich®)
| Cefepime-Enmetazobactam | Cefepime-Zidebactam | |
| Brand name | Exblifep | Zaynich |
| FDA Approval | February 2024 | May 2026 |
| FDA-approved for complicated UTI including pyelonephritis | Yes | Yes |
| Route | IV | IV |
| Adult dosing | 2.5 grams every 8 hours | 3 grams every 8 hours |
| Adjust dose with renal impairment | Change frequency at eGFR below 130 mL/min, change dose at eGFR below 60 mL/min | Change dose at eGFR below 60 mL/min, change frequency at eGFR below 30 mL/min |
| Infusion time | 4 hours | 1 hour |
| Adjust infusion time with renal impairment | Yes, to 2 hours | No |
| Ambler class A activity * | Yes | SYes |
| Ambler class B activity* | No | See text |
| Ambler class C activity* | Yes | Yes |
| Ambler class D activity* | No | See text |
| Warnings & precautions | Hypersensitivity, neurotoxicity, C. difficile infection | Hypersensitivity, neurotoxicity, C. difficile infection |
| Side effects | Elevated transaminases, elevated bilirubin, headache, infusion site reaction | Diarrhea, hypertension, headache, hypokalemia |
| Other | Lacks activity vs KPC, metallo-beta-lactamases, and some oxacillinases | Cefepime and zidebactam synergistically inhibit multiple PBPs when given together |
| Manufacturer | For Allecra Therapeutics | By ACS Dobfar S.p.A., for Wockhardt Suisse |
| Cost | Not released yet | Not released yet |
*Activity does not mean active against all enzymes in this category
Ambler Class Enzyme Examples
- Ambler class A enzyme examples: TEM, SHV, CTX-M, KPC
- Ambler class B enzyme examples: NDM, VIM, IMP
- Ambler class C enzyme examples: AmpC, CMY
- Ambler class D enzyme examples: OXA
See package insert microbiology data for more details with each drug, section 12.4 of the FDA labels.
FOR ALL LEARNERS AND TEACHERS OF INFECTIOUS DISEASES…
Cefepime-enmetazobactam (Exblifep®)
Cefepime-enmetazobactam (Exblifep®) is FDA-approved for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, in adults (≥18 years of age) caused by susceptible gram-negative bacteria.
Enmetazobactam is a novel penicillanic acid sulfone BLI that is similar in structure to tazobactam. Enmetazobactam contains an additional methyl group on the triazole ring that contributes to its zwitterionic structure, facilitating better bacterial cell penetration [3]. Enmetazobactam exhibits activity against class A β-lactamases, including extended-spectrum β-lactamases (ESBLs) such as CTX-M, TEM, and SHV.
While enmetazobactam does not have activity against class C and D β-lactamases, cefepime remains relatively stable to hydrolysis by AmpC β-lactamases while providing P. aeruginosa coverage, making the combination advantageous. The 2026 IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections recommends cefepime-enmetazobactam as an alternative for complicated urinary tract infections (cUTI) when preferred therapies are resistant, cannot be tolerated, or are associated with toxicity, as well as for infections outside of the urinary tract caused by ESBL-producing Enterobacterales [4].
Cefepime-enmetazobactam is available as an intravenous infusion containing 2 grams of cefepime and 0.5 grams of enmetazobactam (2.5 grams total), infused over 2 hours and dosed every 8 hours. Renal dose adjustments are indicated when eGFR is <60 mL/min.
Common adverse effects include elevated transaminases, elevated bilirubin, headache, and infusion site reactions. Important precautions include the risk of neurotoxicity (i.e. encephalopathy, aphasia, myoclonus, and seizures), hypersensitivity reactions associated with β-lactam antibiotics, and Clostridioides difficile-associated diarrhea [5].
The spectrum of activity for cefepime-enmetazobactam includes Streptococcus species, methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex. Relevant drug interactions and safety considerations include concomitant use with aminoglycosides, which may increase the risk of nephrotoxicity and ototoxicity, and diuretics, which also increase the risk of nephrotoxicity.
Cefepime-zidebactam (Zaynich®)
Cefepime-zidebactam (Zaynich®) is approved for cUTIs in adults, including pyelonephritis caused by susceptible gram-negative bacteria. Zidebactam is a novel BLI belonging to the diazabicyclooctane class, which also includes avibactam and relebactam [6]. Zidebactam binds with high affinity to penicillin-binding protein 2 (PBP2), providing direct antibacterial activity, while also inhibiting several clinically relevant β-lactamases and protecting cefepime from enzymatic hydrolysis. Interestingly, zidebactam acts as an “enhancer” and improves the pharmacodynamics of cefepime in vivo by decreasing the necessary percent T>MIC from 38.9% to 15.5% for 1-log10 kill [7].
Zidebactam exhibits activity against class A β-lactamases including ESBLs (i.e. CTX-M, SHV, TEM, and KPC) and class C β-lactamases including AmpC producers. Because cefepime-zidebactam received FDA approval after the publication of the 2026 IDSA Guidance, the current guidance does not yet provide recommendations regarding its use. Nonetheless, cefepime-zidebactam will have a role in the treatment of infections caused by multidrug-resistant P. aeruginosa and other multidrug-resistant gram-negative pathogens [8].
Cefepime-zidebactam is available as an intravenous infusion containing 2 grams of cefepime and 1 gram of zidebactam, infused over 1 hour and dosed every 8 hours. Renal dose adjustments are indicated when eGFR is <60 mL/min.
Common adverse effects of cefepime-zidebactam include diarrhea, hypertension, headache, and hypokalemia. Important precautions include hypersensitivity reactions associated with β-lactam antibiotics, neurotoxicity (i.e. encephalopathy, aphasia, myoclonus, and seizures), and Clostridioides difficile-associated diarrhea [8].
The spectrum of activity for cefepime-zidebactam includes Streptococcus species, methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae complex, and P. aeruginosa. Cefepime-zidebactam has demonstrated in vitro activity against Enterobacterales producing class A, B, C, and D β-lactamases, as well as P. aeruginosa isolates with elevated AmpC expression, MBLs, OXA enzymes, KPC, and PBP mutations[8]. This broad in vitro activity likely reflects the combination’s β-lactamase inhibition and zidebactam’s high-affinity PBP2 binding. Relevant drug interactions and safety considerations are similar to those of cefepime-enmetazobactam.
Closing Comments
With the continued increase in resistant gram-negative infections, especially P. aeruginosa, cefepime-enmetazobactam and cefepime-zidebactam offer additional treatment options when first-line therapies are ineffective due to resistance.
Cefepime-enmetazobactam has a role in treating ESBL-producing Enterobacterales and may gain greater utilization with more clinical outcomes data.
Cefepime-zidebactam has the potential for use in treating both MDR Enterobacterales and P. aeruginosa due to zidebactam’s dual mechanism of potent PBP2 binding and β-lactamase inhibition.
Both drugs may see greater utilization in the treatment of Gram-negative infections; however, additional clinical outcomes data as well as economic information are needed to further define their roles in therapy.
References & Readings
- https://www.cdc.gov/antimicrobial-resistance/data-research/threats/#pse
- Puzniak L, DePestel DD, Yu K, Ye G, Gupta V. Epidemiology and regional variation of nonsusceptible and multidrug-resistant Pseudomonas aeruginosa isolates from intensive versus non-intensive care units across multiple centers in the United States. Diagn Microbiol Infect Dis. 2021;99(2):115172. doi:10.1016/j.diagmicrobio.2020.115172
- Bhowmick T, Canton R, Pea F, et al. Cefepime-enmetazobactam: first approved cefepime-β- lactamase inhibitor combination for multi-drug resistant Enterobacterales. Future Microbiol. 2025;20(4):277-286. doi:10.1080/17460913.2025.2468112
- Tamma PD, Bonomo RA, Heil EL, Justo JA, Satlin MJ, Mathers AJ. Infectious Diseases Society of America 2026 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin Infect Dis. Published online August 8, 2026. doi:10.1093/cid/ciag481
- Exblifep. Package Insert. Allecra Therapeutics SAS; 2024. Accessed September 1, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216165s000lbl.Pdf
- Katsarou A, Stathopoulos P, Tzvetanova ID, Asimotou CM, Falagas ME. β-Lactam/β-Lactamase Inhibitor Combination Antibiotics Under Development. Pathogens. 2025;14(2):168. Published 2025 Feb 8. doi:10.3390/pathogens14020168
- Livermore DM, Mushtaq S, Warner M, Vickers A, Woodford N. In vitro activity of cefepime/zidebactam (WCK 5222) against Gram-negative bacteria. J Antimicrob Chemother. 2017;72(5):1373-1385. doi:10.1093/jac/dkw593
- Zaynich. Package Insert. Wockhardt Suisse USA LLC; 2026. Accessed September 12, 2026.
Disclosures: All contributors have nothing to disclose. The views and opinions in this article represent those of the authors and do not necessarily reflect the policy or position of any past, present, or potential future employer. Artificial intelligence was used for copy-editing and review for accuracy.
About The Author
Alexis Daniels, Pharm.D. candidate 2027, is a fourth-year pharmacy student at the University of Colorado Skaggs School of Pharmacy & Pharmaceutical Sciences.
During her time at CU, Alexis has served as president of the University of Colorado Chapter of the American College of Clinical Pharmacy (ACCP) and vice president of the Alpha Theta Chapter of Rho Chi. She is also involved with the ACCP Infectious Diseases PRN and Pediatric Pharmacy Association.
Alexis currently serves as a Chief Pharmacy Intern at the University of Colorado Hospital, where she participates in antimicrobial and anticoagulation stewardship and helps coordinate the pharmacy intern program. She also works as a Clinical Informatics Research Intern with the University of Colorado School of Medicine, supporting research related to guideline-directed medication therapy for heart failure.
Her research experience includes pediatric clinical pharmacy research, neuroscience research, and immunology research, with work resulting in a publication in Cellular and Molecular Immunology. Alexis is a 2026 recipient of the local ACCP Student of the Year Award and the Edward and Karen Skaff Scholarship. She plans to pursue PGY1 and PGY2 residency training, with professional interests in critical care, infectious diseases, and pediatrics.
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