Abstract: Globally, the antimicrobial resistance (AMR) crisis is raging, with an estimated 10 million deaths by 2050. The selection of suitable antibiotic therapy for the treatment of Gram-negative infections in ICU settings is extremely difficult, because the majority of patients have comorbidities and, more significantly, have been exposed to many antibiotics. Such prolonged exposures of antibiotics have been responsible for the selection of resistance development in Gram-negative pathogens.
The vital resistance mechanism acquired by the Gram-negative organisms is carbapenemases. These carbapenemases such as serine carbapenemases (KPC, OXA-48 like in Enterobacterales) and metallo-β-lactamases (NDM, VIM, IMP) are developed to establish substantial degrees of resistance to all cephalosporins as well as carbapenems. However, pharmaceutical companies are putting up efforts to develop novel antibiotics in order to combat such silent pandemic situation. Recently, USFDA approved the β-lactam/β-lactamase inhibitor combinations such as ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam and sulbactam/durlobactam has represented a step forward in treating multi-drug resistant (MDR) gram negative infections. However, such conventional way of combining β-lactamase inhibitors with β-lactams to restore their activity, which has been substantially desecrated due to the introduction and dissemination of several distinct β-lactamases. Though this approach aided in the discovery of a series of β-lactamase inhibitors to combat specific β-lactamases, the advent of additional mutant β-lactamases and the inability of these inhibitors to inhibit all four classes of β-lactamases highlight an enduring limitation of this approach. The classical β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam), are only able to inhibit class-A ESBLs and weak inhibition of AmpC enzymes, while diaza-bicyclo-octane (DBO) based inhibitors such as avibactam and relebactam only expand their spectrum to class C, OXA-48-like and KPC. These β-lactamase inhibitors are unable to inhibit class B metallo-β-lactamases (MBLs). Since, the recent β-lactamase inhibitors based on boronate moiety have a further extends coverage spectrum inclusive of few MBLs, however are unable to demonstrate reliable activity against Gram negatives expressing MBLs owing to their poor permeation within Gram negative cell. Furthermore, the Gram-negative pathogens through their genetic diversity are capable of selecting newer resistant variants of β-lactamases which escape from the inhibitory activity of even newer β-lactamase inhibitors. As a result, clinicians are always in dilemma for selection of an appropriate therapy option, regrettably, they have to rely on cocktail of two or more antibiotics.
Recently, a novel chemotype series known as bicyclo-acyl-hydrazide (BCH) has been explored, bypassing the traditional approach of β-lactam/β-lactamase inhibitor combination. The goal of this new group of molecule is to augment another action, namely binding and inhibition of penicillin binding protein (PBP), especially PBP 2 as well as ability to inhibit Class A and Class C β-lactamases. One of such molecule is zidebactam which is non-β-lactam agent showed high affinity binding towards PBP2 of all the clinically relevant Gram negatives including P. aeruginosa and A. baumannii. As a result, regardless of β-lactamases expressed by the organism, zidebactam potently synergises with PBP3 binding β-lactams, therefore designated as β-lactam enhancers (BLEs). Following extensive evaluations in vitro and translational animal model studies, zidebactam is in advanced clinical development in combination with cefepime. Translational PK/PD studies involving neutropenic murine lung and thigh infection studies have established potent pathogen eradication effects of cefepime/zidebactam when dosages to generate human exposures. Until now, studies have been undertaken, show that cefepime/zidebactam is highly efficacious against carbapenemases (including metallo-β-lactamase-producers) harbouring Enterobacterales, MDR Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter. All these organisms are considered high priority pathogens by World Health Organization (WHO) due to their ability to cause high mortality and morbidity.
A total of seven Phase 1 clinical studies have been conducted so far, establishing the safety and tolerability of the combination drug. Phase 1 studies include PK in subjects with renal impairment and pulmonary PK. The entire clinical development of cefepime/zidebactam was undertaken in US, under approval from regulatory agencies, US-FDA, NMPA (China) and CDSCO (DCGI).
Clinical data -First global use of triple action beta-lactam enhancer-based drug During the month of August 2022, a critically-ill patient with a complex XDR P. aeruginosa infection was admitted to our tertiary care hospital. With last-line antibiotics failing to eradicate the pathogen, the patient was successfully treated with cefepime/zidebactam. The drug was used first time worldwide by Dubey.et.al on compassionate ground after completion of phase-2 study with approval of governing authorities. Case was published in Annals of Clinical Microbiology and Antimicrobials (2023) 22:55 as “Compassionate use of a novel β-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM expressing Pseudomonas aeruginosa infection in an intra-abdominal infection-induced sepsis patient”. The organism repeatedly isolated from the patient was a New-Delhi Metallo-beta-lactamase producing XDR P. aeruginosa resistant to all existing antibiotic armentarium, susceptible only for cefepime-zidebactum. As polymyxin failed to rescue the patient, cefepime/zidebactum was administered under compassionate grounds leading to discharge of the patient in stable condition.
Susequently, under compassionate use after the approval from DCGI cefepime/zidebactam has used and saved life of 14 critically ill patients, infected with extreme drug resistant pathogens. These patients were treated with cefepime/zidebactam after none of the available antibiotics such as colistin, fosfomycin, ceftazidime/avibactam, ceftolozane/tazobactam could clear the infection/eradicate the pathogen. The compassionate use cases also established remarkable safety profile of Cefepime/zidebactam as some patients (severe chronic bone infections) were given this drug for 7-10 weeks.
Conclusion: Cefepime-Zidebactum is a novel beta lactam enhancer mechanism based combination drug, currently being studied in a global Phase 3 trial in adult patients with complicated urinary tract infection or acute pyelonephritis nearly 50% recruitment is completed. (ClinicalTrials. gov. identifier: NCT04979806). Zidebactam is distinguished from newer β-lactamase inhibitors such as avibactam and taniborbactam by means of an additional function; selective and high-affinity binding to penicillin-binding protein (PBP)-2. When combined with cefepime that targets PBP3, zidebactam synergistically enhances the bactericidal activity of cefepime, thus functioning as a “β-lactam-enhancer”. This combination therefore constitutes one of the ultimate treatment options in such contexts and will be a game changer for growing AMR problem.