Written By: Abhinay Wadekar BPharm
Reviewed By: Pharmacally Editorial Team
ZAYNICH, also known as WCK-5222, is a novel antibiotic researched and developed by the Indian pharmaceutical company Wockhardt as a strategic response to the growing global crisis of multidrug-resistant (MDR) Gram-negative bacterial infections. This fixed-dose combination brings together cefepime, a fourth-generation cephalosporin, with zidebactam, a newly discovered beta-lactamase inhibitor that possesses a unique dual mechanism of action. Together, they aim to address infections caused by resistant Gram-negative bacteria.
Drug Information: Spotlight on Zidebactam
ZAYNICH consists of two components with complementary actions. Cefepime is a broad-spectrum, fourth-generation cephalosporin that has long been used to treat a wide range of infections caused by both Gram-positive and Gram-negative bacteria. The second component, zidebactam, is a novel bicyclo-acyl hydrazide compound designed to act as both a beta-lactamase inhibitor and a direct antibacterial agent. Unlike conventional inhibitors, zidebactam exhibits intrinsic antibacterial activity by targeting specific bacterial proteins essential for cell wall synthesis.
How Zidebactam Works
What makes zidebactam particularly innovative is its dual mechanism of action. First, it acts as a potent beta-lactamase inhibitor, protecting cefepime from degradation by a broad spectrum of beta-lactamases, including Ambler classes A, C, and some D enzymes. Second, it exerts direct antibacterial activity by binding strongly to penicillin-binding protein 2 (PBP2), an enzyme vital for bacterial cell wall synthesis. This two-pronged mechanism allows cefepime-zidebactam to remain effective even against bacteria that produce carbapenemases or possess other resistance mechanisms. The result is a broad and potent antibacterial profile that exerts action beyond the capabilities of older antibiotic-beta-lactamase inhibitor combinations.
Mechanism of Action
Traditional beta-lactamase inhibitors such as tazobactam and clavulanic acid, work solely by blocking beta-lactamase enzymes leaving antibiotics vulnerable to develop resistance by bacteria through other mechanism. Zidebactam overcomes this limitation through its ability to directly attack bacteria via PBP2 binding, thereby inhibiting cell wall synthesis even when resistance mechanisms are unrelated to beta-lactamase production. This dual action not only enhances efficacy but also reduces the likelihood of resistance development during treatment.
Clinical Trials: Design, Endpoints, and Results
The efficacy and safety of zidebactam was assessed in clinical trials. The ENHANCE-1 Phase III clinical trial was a randomized, multi-center, double-blind study designed to evaluate the safety and efficacy of ZAYNICH in patients with complicated urinary tract infections (cUTI) and acute pyelonephritis. Conducted across approximately 64 sites in the United States, Europe, Latin America, China, and India, around 530 adult patients with confirmed Gram-negative bacterial infections were enrolled and randomized to receive either ZAYNICH or meropenem the standard-of-care carbapenem used globally for such infections. The primary endpoint was a combined measure of clinical and microbiological cure assessed seven to fourteen days after therapy completion. Key secondary endpoints included clinical cure rates, microbiological eradication, and safety outcomes. Wockhardt conducted several investigator-initiated studies in India across tertiary care hospitals to assess ZAYNICH’s performance in real-world, drug-resistant infections such as hospital-acquired pneumonia, bloodstream infections, and complicated intra-abdominal infections.
ZAYNICH demonstrated high efficacy, achieving a clinical cure rate of 96.8% and a composite clinical-microbiological cure rate of 89%, compared with 68.4% in the meropenem arm. These findings indicate superior or at least non-inferior efficacy to carbapenems, even in infections caused by resistant Gram-negative organisms. In real-world studies from Indian tertiary centers, the drug achieved an overall clinical efficacy of approximately 98%, with microbiological eradication rates exceeding 90% across infection types. Specifically, clinical cure reached 100% in bloodstream infections, hospital-acquired pneumonia, and complicated intra-abdominal infections, and about 97% in cUTI cases. Treatment duration ranged from seven to twenty-one days depending on disease severity. Compassionate-use cases also reported positive outcomes in critically ill patients, including successful clearance of infections unresponsive to multiple other antibiotics. Collectively, these results position ZAYNICH as a highly promising option against multidrug-resistant Gram-negative infections.
Safety Profile
In clinical trials, ZAYNICH was well tolerated, and its safety profile was comparable to cefepime alone. No new or unexpected safety concerns were identified during the studies. The adverse effects observed were generally mild and typical of beta-lactam antibiotics, such as mild gastrointestinal disturbances or infusion-related reactions. Importantly, there were no reports of serious adverse events attributable specifically to zidebactam, supporting its potential for safe clinical use.
Broader Implications
ZAYNICH marks a historic achievement for Indian pharmaceutical innovation, representing the country’s first original antibiotic discovery in nearly three decades. It demonstrates a shift from India’s traditional focus on generic drug manufacturing toward genuine pharmaceutical innovation. Globally, ZAYNICH has the potential to transform the management of MDR Gram-negative infections by providing a safer and more effective alternative to last-resort antibiotics such as colistin. Its success could also encourage further investment in antibiotic research, particularly in regions that have long relied on generic drug production.
Regulatory Status
In the United States, Wockhardt has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration for ZAYNICH (cefepime + zidebactam) for the treatment of complicated urinary tract infections, including acute pyelonephritis. The FDA has already granted the drug Qualified Infectious Disease Product (QIDP) and Fast Track designations, recognizing its potential role in addressing serious drug-resistant infections. In Europe, Wockhardt plans to file a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) based on data from the global Phase III ENHANCE-1 trial. Outside these regions, ZAYNICH has been studied in multiple countries, including China and several Latin American and European sites, but no marketing approvals have yet been reported. In India, where the drug was originally developed, Wockhardt is in the final stages of preparing its submission to the Central Drugs Standard Control Organization (CDSCO) for domestic marketing authorization.
ZAYNICH (cefepime + zidebactam) combines the proven activity of a fourth-generation cephalosporin with the novel dual action of a next-generation beta-lactamase inhibitor. Early clinical evidence highlights its strong efficacy, good safety profile, and significant potential in treating infections caused by MDR Gram-negative bacteria. While careful regulatory oversight and antimicrobial stewardship will be crucial to preserve its long-term effectiveness, ZAYNICH represents a major step forward in the global fight against antimicrobial resistance. Dr. Habil Khorakiwala, Founder Chairman of Wockhardt, has described WCK-5222 (Zaynich) as a “game-changer” in treating multidrug resistance. Rajeev Soman, infectious diseases specialist and lead author in a European Journal case report, noted the challenges in treating skull-base bone infections especially in immunocompromised patients, and said that the antibiotic had to reach the infected site in adequate concentrations and be active against extreme-drug-resistant bugs. He emphasized how other treatments had failed before Zidebactam/Cefepime was used. V. Balaji, a clinical microbiologist who co-authored that case, commented that the pathogen in that patient (NDM-producing Pseudomonas aeruginosa) had resistance mechanisms that inactivate last-line safe antibiotic meropenem, among others, underscoring the need for new options such as Zaynich.
References
Wockhardt. Zaynich® (Zidebactam/Cefepime, WCK-5222) achieves over 97% efficacy in clinical study for serious infections caused by meropenem-resistant Gram-negative pathogens [press release]. Wockhardt; 13th Jan 2025. https://www.wockhardt.com/wp-content/uploads/2025/01/zaynich-pr-13-jan-2025.pdf
Wockhardt’s novel antibiotic ‘Zaynich’ expected to receive USFDA approval in 2025, Medpath, https://trial.medpath.com/news/0dd8864657d5fd4b/wockhardt-s-novel-antibiotic-zaynich-expected-to-receive-usfda-approval-in-2025
India develops powerful, homegrown antibiotic to tackle multi-drug-resistant bacteria, Times of India, 03 Oct 2025, https://timesofindia.indiatimes.com/life-style/health-fitness/health-news/india-develops-powerful-homegrown-antibiotic-after-30-years-shorter-dosage-greater-efficacy-and-more/articleshow/124284378.cms
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