In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial

Abstract

Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

Novel Siderophore Cephalosporin and Combinations of Cephalosporins with β-Lactamase Inhibitors as an Advancement in Treatment of Ventilator-Associated Pneumonia

“…The combination obtained MIC 50 /MIC 90 values for individual pathogens causing VABP as follows: MDR P. aeruginosa (8/64 mg/L, strain sensitivity 34.8%) and MDR K. pneumoniae (0.5/1.0 mg/L, sensitivity 75%). The REPROVE study confirmed previous reports on the superiority to comparators of the antimicrobial activity profile of CAZ-AVI against MDR GNB causing VABP [84,85].…”

Is Ceftazidime/Avibactam an Option for Serious Infections Due to Extended-Spectrum-β-Lactamase- and AmpC-Producing Enterobacterales ?: a Systematic Review and Meta-analysis

“…Clinical response rates for these 75 patients at TOC in the ceftazidime/ avibactam and carbapenem arms were 28/34 (82%) and 29/41 (71%), and microbiological response rates were 23/34 (68%) and 23/41 (56%), respectively. The number of patients infected with an ESBL-producing pathogen was reported to be 61, yet no outcome data pertaining to this patient population were reported (25).…”

Anti-Pseudomonas aeruginosa Vaccines and Therapies: An Assessment of Clinical Trials

“…Antibiotics will still be essential in combating P. aeruginosa infections. For example, other clinical trials have examined newer combinations of beta-lactamases, polymyxins, and alternative formulations, such as liposomal or inhalation, for traditional antibiotics against P. aeruginosa infections [201,[306][307][308][309][310][311][312][313][314][315][316][317][318][319][320][321]. However, the continuous use of these antibiotics will likely lead to the emergence of multi-drug-resistant P. aeruginosa mutants.…”