BACKGROUND: The problem of resistance to beta-lactam antibiotics, which is caused by ESBL and AmpC β-lactamases, is getting worse globally. Infections caused by bacterial isolates harboring these enzymes are difficult to treat with carbapenems being the sole effective treatment option for such infections. The objective of this study was to determine the frequency of ESBLs and AmpC-producing Gram-negative bacilli isolated from clinical specimens and to evaluate the sensitivity of cefepime-tazobactam combination against them.
METHODS: This is an observational cross-sectional study carried out on 100 Gram-negative bacilli at Theodor Bilharz Research Institute Hospital during the period from February 2015 to January 2016. ESBL production was screened by using the disc diffusion test followed by confirmation by the combined disc confirmatory test, the screening for AmpC production was conducted using the cefoxitin disc test, which was subsequently confirmed by the AmpC disc test. Isolates confirmed positive for ESBL and/ or AmpC production were investigated for their susceptibility to antibiotics.
RESULTS: Among 100 Gram-negative bacilli, 44 isolates were confirmed as ESBL producers by the combined disc confirmatory test out of 56 isolates that tested positive for ESBL production through the disc diffusion test. The presence of AmpC production was assessed using the cefoxitin disc test, 32 isolates were screened to be AmpC producers, and the AmpC disc test confirmed AmpC production in 9 isolates of them. Using the Mast® D68C set, 32 isolates were ESBL producers, 3 were AmpC producers, and 4 isolates were ESBL/AmpC co-producers. The highest sensitivity was to cefepime-tazobactam (91.48%) followed by the carbapenems.
CONCLUSIONS: Cefepime-tazobactam showed remarkable activity against ESBL and/or AmpC-producing Gram-negative bacilli and may be considered as a therapeutic alternative to carbapenems.

High-dose cefepime-tazobactam (1:1; WCK 4282), a novel antibacterial combination consisting of the β-lactamase inhibitor tazobactam and a fourth-generation cephalosporin, is under clinical development for the treatment of serious Gram-negative infections. A quality control (QC) study was performed to establish disk diffusion and MIC ranges for cefepime-tazobactam for multiple QC reference strains. The cefepime-tazobactam QC ranges for a fixed tazobactam MIC of 8 μg/ml and disk diffusion (30/20-μg disk) test methods were approved by the CLSI Subcommittee on Antimicrobial Susceptibility Testing in January 2015 and January 2016. These QC ranges will be important for accurate in vitro activity evaluations of cefepime-tazobactam when tested against clinical Gram-negative bacteria during clinical studies and routine patient care.

Cefepime-tazobactam (WCK 4282) is currently under clinical development for use at a dosage of 2 g/2 g every 8 h. A total of 7,981 isolates were collected from 146 medical centers (39 countries) in 2014 as a part of the SENTRY Antimicrobial Surveillance Program, and their susceptibilities to cefepime-tazobactam (with tazobactam at fixed concentrations of 4 and 8 μg/ml) were tested by a reference broth microdilution method. Isolates were mainly from patients with pneumonia (29.5%) and bloodstream infections (26.9%). Cefepime-tazobactam (with tazobactam at a fixed concentration of 8 μg/ml) and cefepime inhibited 96.9 and 87.9% of Enterobacteriaceae strains at ≤8 μg/ml. The activity of cefepime-tazobactam against Enterobacteriaceae strains was comparable to that of meropenem (96.7% of isolates were susceptible) and greater than that of piperacillin-tazobactam (87.7% susceptible). All Enterobacteriaceae species from the United States except Klebsiella pneumoniae had >99.0% of isolates inhibited by cefepime-tazobactam at ≤8/8 μg/ml. The prevalence of the extended-spectrum β-lactamase (ESBL)-screening-positive phenotype was the highest among Escherichia coli isolates in China (66.3%) and among K. pneumoniae isolates (58.0%) in Latin America. Cefepime-tazobactam at ≤8/8 μg/ml inhibited 98.7 and 71.3% of ESBL-screening-positive phenotype E. coli strains and K. pneumoniae strains, respectively. Meropenem showed limited activity against ESBL-screening-positive phenotype K. pneumoniae strains (69.6% susceptible). Cefepime-tazobactam was active against Enterobacter spp. (MIC50 and MIC90, 0.06 and 0.5 μg/ml, respectively), including ceftazidime-nonsusceptible isolates (96.1% of isolates were inhibited by cefepime-tazobactam at ≤8/8 μg/ml). The activity of cefepime-tazobactam against Pseudomonas aeruginosa (82.4 and 91.6% of isolates were inhibited by cefepime-tazobactam at ≤8/8 and ≤16/8 μg/ml, respectively) was comparable to that of meropenem and piperacillin-tazobactam (79.2% susceptible). In summary, cefepime-tazobactam was highly active against P. aeruginosa and Enterobacteriaceae strains, including ESBL-screening-positive phenotype E. coli strains and ceftazidime-nonsusceptible Enterobacter spp. These results support the further clinical development of the cefepime-tazobactam combination.