cefepime/tazobactam (WCK 4282) / Wockhardt - LARVOL DELTA

Towards optimizing cefepime/tazobactam (WCK 4282) exposure to achieve efficacy against piperacillin/tazobactam-resistant ESBL infections: dose recommendations for various renal functions, including intermittent haemodialysis, in healthy individuals. (PubMed, J Antimicrob Chemother) - "The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L."

Journal • Infectious Disease • Renal Disease

Study of Cefepime-tazobactam (FEP-TAZ) in Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) (clinicaltrials.gov) - P3 | N=1004 | Not yet recruiting | Sponsor: Wockhardt | Trial completion date: Apr 2025 ➔ Feb 2026 | Trial primary completion date: Mar 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Infectious Disease • Nephrology

WCK 4282 (cefepime/tazobactam, FEP/TAZ): determination of tazobactam pharmacodynamic targets (PDTs) in presence of cefepime employing piperacillin/tazobactam-resistant ESBL or OXA-48-like-expressing Enterobacterales (ECCMID 2023) - No abstract available

PK/PD data

In vitro microbiologic activity of WCK 4282 (high-dose cefepime/tazobactam combination) against OXA-1-harbouring, ESBL-phenotype E. coli and K. pneumoniae clinical isolates (ECCMID 2023) - No abstract available

Preclinical • Infectious Disease • Pneumonia

Study of Cefepime-tazobactam (FEP-TAZ) in Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) (clinicaltrials.gov) - P3 | N=1004 | Not yet recruiting | Sponsor: Wockhardt | Trial completion date: May 2021 ➔ Apr 2025 | Trial primary completion date: Aug 2020 ➔ Mar 2025

Trial completion date • Trial primary completion date • Infectious Disease • Nephrology

Cefepime pharmacodynamic targets against Enterobacterales employing neutropenic murine lung infection and in vitro pharmacokinetic models. (PubMed, J Antimicrob Chemother) - "Both in vivo and in vitro studies showed that cefepime's pharmacodynamic requirements are lower than generally reported for cephalosporins (50%-70% fT>MIC). The lower requirement for cefepime could be linked with factors such as cefepime's better permeation properties and multiple PBP affinity-driven enhanced bactericidal action."

Journal • PK/PD data • Preclinical • Infectious Disease • Respiratory Diseases

Pharmacodynamics of WCK 4282 (high-dose cefepime plus tazobactam) against β-lactamase producing E.coli (ECCMID 2022) - No abstract available

PK/PD data

Ensuring Robustness in Quality of Antibiotic Susceptibility Test Discs for Four Novel Antibiotics. (PubMed, Biomed Chromatogr) - "This methodology has several limitations such as it is time consuming, requires trained manpower, wider acceptance criteria of zone of inhibitions causing ambiguity in judging the small variations in the drug concentration etc. To overcome these issues we have developed and validated high performance liquid chromatographic (HPLC) methods for determination of strength of AST discs for in-house researched antibiotics namely Levonadifloxacin/WCK 771, Nafithromycin/WCK 4873, Cefepime-Tazobactam/WCK 4282 and Cefepime-Zidebactam/WCK 5222. The developed methods are efficient in terms of time and can be very well conducted in quality control laboratory during release as well as stability evaluation of AST disc. Application of HPLC methods for determination of strength of AST disc ensure undoubted quality and indirectly better selection of drug to treat bacterial infections in clinics."

Journal • Infectious Disease

Antimicrobial Activity of High-Dose Cefepime-tazobactam (WCK 4282) against a Large Collection of Gram-negative Organisms Collected Worldwide in 2018 and 2019. (PubMed, Int J Infect Dis) - "The results of this in vitro study support clinical development of cefepime-tazobactam as carbapenem sparing option to treat infections caused by Enterobacterales and P. aeruginosa, including multidrug-resistant isolates."

Journal • Infectious Disease

Cefepime/tazobactam compared with other tazobactam combinations against problem Gram-negative bacteria. (PubMed, Int J Antimicrob Agents) - "On this basis, Wockhardt are developing cefepime/tazobactam (WCK 4282) as a 2+2g q8h combination with 90 min infusion. Overall, cefepime/tazobactam has a spectrum exceeding those of piperacillin/tazobactam and ceftolozane/tazobactam and resembling or exceeding that of carbapenems. Used as a 'new-combination of old-agents' it has genuine potential to be 'carbapenem-sparing'."

Journal • Infectious Disease • Pneumonia

Resistance Trends of Klebsiella pneumoniae Causing Urinary Tract Infections in Chongqing, 2011-2019. (PubMed, Infect Drug Resist) - "Piperacillin/tazobactam and cefepime resistance levels went up from 4.4% to 25.7% and from 18.2% to 30.5%, respectively. However, ceftazidime and aztreonam resistance levels were relatively stable, fluctuating between 21.8% and 35.6%, 32.2% and 39.4%, respectively. There is a significant upward tendency in carbapenem resistance rate and a downward tendency in ESBL-production rate in K. pneumoniae isolates from UTIs, and continuous surveillance is necessary in the future."

Journal • Infectious Disease • Nephrology • Pneumonia

What do beta-lactams add to vancomycin or daptomycin in the treatment of patients with methicillin-resistant Staphylococcus aureus bacteraemia? A review. (PubMed, Postgrad Med J) - "Observational studies used ceftaroline, cefazolin, piperacillin/tazobactam or cefepime among the beta-lactams. Nephrotoxicity in clinical trials precludes the use of combination therapy mainly with cloxacillin or flucloxacillin, but systematic reviews have not found a significant difference in this point in observational studies with other beta-lactams. The role of other beta-lactams such as ceftaroline should be thoroughly studied in these patients."

Clinical • Journal • Review • Infectious Disease

Comparison of acute kidney injury in patients prescribed vancomycin in combination with piperacillin-tazobactam or cefepime for diabetic foot infections. (PubMed, J Investig Med) - "VAN+PTZ was also associated with higher total hospital charges at US$99,742.83 (IQR US$69,342.50-US$165,549.59) compared with US$74,260.25 (IQR US$48,446.88-US$107,396.99) in the VAN+CFP arm (p<0.001). In conclusion, VAN+CFP should be the preferred empiric regimen in patients with severe DFI."

Clinical • Combination therapy • Journal • Acute Kidney Injury • Diabetes • Infectious Disease • Metabolic Disorders • Nephrology • Renal Disease

In vivo activity of WCK 4282 (high-dose cefepime/tazobactam) against serine β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa in the neutropenic murine thigh infection model. (PubMed, J Antimicrob Chemother) - "Human-simulated exposures of WCK 4282 produced in vivo efficacy against ESBL/cephalosporinase-producing, piperacillin/tazobactam- and ceftolozane/tazobactam-non-susceptible Enterobacterales and P. aeruginosa. These findings support further development of this combination as a carbapenem-sparing agent."

Journal • Preclinical • Infectious Disease • Neutropenia • Pneumonia

Impact of combining vancomycin with piperacillin/tazobactam or with meropenem on vancomycin-induced nephrotoxicity. (PubMed, Intern Emerg Med) - "Vancomycin (VAN) is a broad-spectrum antibiotic against Gram-positive cocci used empirically with other broad-spectrum antibiotics, such as piperacillin/tazobactam (TZP), cefepime, or meropenem (MEM). This study showed that combining MEM with VAN did not offer the benefit of a lower rate of AKI compared with a combination with TZP. Therefore, patients with no risk factors for infections resistant to TZP can continue to receive TZP with VAN without risking AKI development."

Journal • Acute Kidney Injury • Nephrology • Renal Disease

In Vivo Activity of WCK 4282 (High-Dose Cefepime/Tazobactam) against Serine-β-lactamase-Producing Enterobacterales and Pseudomonas aeruginosa in the Neutropenic Murine Lung Infection Model. (PubMed, Antimicrob Agents Chemother) - "Treatment mice received HSR of cefepime, meropenem (control for serine carbapenemase expression with low inoculum experiments), or WCK 4282 human-simulated regimens. WCK 4282 provided variable activity among mice infected with standard or lower inoculums of OXA-48-like-producers. WCK 4282 exposures provided 0.53±1.07 log CFU/lung growth against KPC-producers at standard versus bacteriostasis (-0.15±0.54 change in log CFU/lung) at low inoculum. WCK 4282 produced potent in vivo activity against ESBL- and cephalosporinase-producing Enterobacterales and P. aeruginosa, and potential activity against OXA-48-like-producing Enterobacterales in a neutropenic pneumonia model."

Journal • Preclinical • Infectious Disease • Neutropenia • Pneumonia • Respiratory Diseases

[VIRTUAL] Assessment of the In Vivo Activity of Human-Simulated Exposure of WCK 4282 (High Dose Cefepime [FEP]-Tazobactam [TZB]) against Enterobacterales (EB) and Pseudomonas aeruginosa (PA) in the Neutropenic Murine Thigh Infection Model (IDWeek 2020) - "Per CLSI, 19, 18, and 17 isolates were cefepime, ceftolozane/tazobactam, and piperacillin/tazobactam (TZP) non-susceptible, respectively. WCK 4282, a novel TZB containing regimen, resulted in enhance in vitro potency against ESBL/CSase and OXA-48-like producers. Humanized exposures of WCK 4282 produced substantial kill in vivo against ESBL/CSase producers with MICs ≤ 16 mg/L including FEP resistant/TZP non-susceptible PA. These data support further evaluations of WCK 4282 as a carbapenem-sparing regimen for ESBL/cephalosporinase harboring strains."

Preclinical • Infectious Disease

[VIRTUAL] In Vivo Efficacy of WCK 4282 (High Dose Cefepime [FEP]-Tazobactam [TZB]) Against β-Lactamase-Producing (BLP) Gram-Negative Bacteria in a Neutropenic Murine Pneumonia Model (IDWeek 2020) - "WCK 4282 (FEP 2g-TZB 2g) maximizes systemic exposure of TZB and restores FEP activity against piperacillin-tazobactam (TZP) resistant isolates in vitro... Clinical isolates (14 EB and 2 PA) with in vitro resistance to FEP, ceftolozane-tazobactam, and TZP (EB isolates) were used... WCK 4282 produced potent in vivo activity against ESBL- and AmpC-harboring Gram-negative isolates and limited activity among serine carbapenamase-producers in a pneumonia model at clinically achievable exposures. Further studies are warranted to delineate WCK 4282’s spectrum of activity and susceptibility breakpoint."

Preclinical • Infectious Disease

Study of Cefepime-tazobactam (FEP-TAZ) in Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) (clinicaltrials.gov) - P3; N=0; Withdrawn; Sponsor: Wockhardt; N=1004 ➔ 0; Trial completion date: Dec 2020 ➔ May 2021; Not yet recruiting ➔ Withdrawn; Trial primary completion date: Dec 2020 ➔ Aug 2020

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Infectious Disease • Nephrology

Single-Center Investigation of the Pharmacokinetics of WCK 4282 (Cefepime-Tazobactam Combination) in Renal Impairment. (PubMed, Antimicrob Agents Chemother) - P1 | "The findings suggest that dose adjustments for WCK 4282 will be required according to the degree of renal impairment. A single infusion of WCK 4282 was found to be safe and well tolerated in subjects with normal and impaired renal function."

Clinical • Journal • PK/PD data • Chronic Kidney Disease • Nephrology • Renal Disease

[VIRTUAL] Outcomes of the novel β-lactam/β-lactamase inhibitor combination of cefepime-enmetazobactam versus piperacillin-tazobactam in adult patients with complicated urinary tract infections – the ALLIUM phase 3 trial (ECCMID 2020) - "Treatment of cUTI/AP patients with cefepime-enmetazobactam exhibits superior treatment outcomes to piperacillin-tazobactam. Cefepime-enmetazobactam is intended as a new empiric carbapenem-sparing option in settings where 3GC resistance mediated by ESBL is prevalent."

Clinical • P3 data • Nephrology

Antimicrobial activity of high-dose extended infusion cefepime-tazobactam (WCK 4282) tested against Gram-negative organisms collected from medical centres located in Europe and the Asia-Pacific region in 2018 (ECCMID 2019) - "Against Enterobacteriaceae (n=3,607), cefepime-tazobactam inhibited 98.2% of isolates at ≤16 mg/L (96.5% at ≤2 mg/L; CLSI low dose), with spectrum of activity similar to meropenem (97.6% susceptible [S]) and greater than ceftolozane-tazobactam (89.2%S) and piperacillin-tazobactam (82.8%S). Cefepime-tazobactam demonstrated potent activity against Enterobacteriaceae, including multidrug-resistant, ESBL-phenotype, and ceftazidime-nonsusceptible isolates, and P. aeruginosa isolated in hospitals from EUR and APAC. Cefepime-tazobactam may represent a valuable option for treating serious infections caused by gram-negative bacilli, including multidrug-resistant isolates."

Infectious Disease • Pneumonia • Respiratory Diseases

Comparative Antimicrobial Susceptibility of Gram-Negative Bacteria Isolated from Patients with Bloodstream Infections and Pneumonia when Tested against Tazobactam Combinations (IDWeek 2019) - "We compared the susceptibility (S) of gram-negative bacilli (GNB) from patients with bloodstream infections (BSI) and pneumonia (PN) against FEP-TAZ, piperacillin-tazobactam (PIP-TAZ), and ceftolozane-tazobactam (C-T)...The percentage of isolates inhibited at ≤8 mg/L (CLSI, cefepime high dose) and at ≤ 16 mg/L (pharmacokinetic/pharmacodynamic [PK/PD] S breakpoint based on extended infusion and high dosage) of FEP-TAZ were evaluated.Results : FEP-TAZ (MIC50/90, 0.06/0.25 mg/L) was the most active TAZ combination against Enterobacterales (ENT) with a spectrum similar to that of meropenem (MEM; 99.3/97.2%S for BSI/PN), ceftazidime-avibactam (CAZ-AVI; 99.8/99.9%S), and amikacin (AMK; 99.3/98.3%S) and retained good activity against ceftriaxone-non-S (CRO-NS) and multidrug-resistant (MDR) ENT (Table)...FEP-TAZ was the most active TAZ combination tested against GNB isolated from patients with BSI and PN from US hospitals and exhibited greater spectrum than the carbapenems. The..."

Clinical

Antimicrobial Activity of Novel β-Lactamase Inhibitor Combinations Tested against Organisms Causing Complicated Urinary Tract Infections in United States Medical Centers (IDWeek 2019) - "We evaluated the potency and spectrum of activity of FEP-TAZ, ceftolozane-tazobactam (C-T), ceftazidime-avibactam (CAZ-AVI), and comparators tested against gram-negative bacilli (GNB) causing complicated urinary tract infections (cUTIs) in United States (US) hospitals.Methods : In 2018, 3,023 GNBisolates (1/patient) were consecutively collected and susceptibility tested against FEP-TAZ (TAZ at fixed 8 mg/L) and comparators by reference broth microdilution methods...FEP-TAZ and CAZ-AVI exhibited complete activity against EC, whereas C-T and piperacillin-tazobactam (PIP-TAZ) were active against 91.5% and 88.1% of ESBL-phenotype EC isolates, respectively...Against P. aeruginosa (PSA), FEP-TAZ inhibited 97.6% of isolates at ≤16 mg/L, with spectrum of activity similar to CAZ-AVI (96.4%S), C-T (99.4%S) and AMK (97.6%S), and greater than MEM (85.5%S) and PIP-TAZ (87.3%S).Conclusion : FEP-TAZ showed potent activity against ENT and PSA isolated in US hospitals in 2018, with..."