Ceftolozane/Tazobactam Provides Greater Coverage than Beta-Lactams for P. auroginosa

SAN FRANCISCO, CA—Ceftolozane/tazobactam exhibited potent antimicrobial activity when tested against Pseudomonas aeruginosa isolates from US medical centers, including multidrug-resistant strains, a study reported at IDWeek 2013.

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In addition, the agent provided greater coverage than the currently available beta-lactams for the treatment of this infection, Helio Sader, MD, PhD, of JMI Laboratories, Inc., North Liberty, IA, and colleagues reported.

Ceftolozane/tazobactam is a novel oxyimino-aminothiazolyl cephalosporin currently in Phase 3 trials for the treatment of complicated urinary tract infections (cUTI), complicated intra-abdominal infections  (cIAI) and nosocomial pneumonia (NP). The agent has shown activity against against P. aeruginosa and most extended spectrum beta-lactamase-(ESBL)-producing Enterobacteriaceae. Tazobactam, a β-lactamase inhibitor protects ceftolozane from hydrolysis and broadens coverage.

In this study, Dr. Sader and colleagues evaluated the activity of ceftolozane/tazobactam and several antimicrobial comparators tested against 1,971 P. aeruginosa isolates consecutively collected by the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) in 2011–2012 from 32 US medical centers. Isolates came primarily from bloodstream infections, skin and skin structure infections, pneumonia aspirates, urinary tract infections, and intra-abdominal infections from hospitalized patients.

The ESBL phenotype was defined as a MIC of ≥2μg/mL for ceftazidime, ceftriaxone, or aztreonam. Multi-drug resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacteria were classified using the following antimicrobials and their CLSI non-susceptibility MIC breakpoints: ceftazidime (≥16μg/mL), piperacillin/tazobactam (≥32/4μg/mL), meropenem (≥4μg/mL), levofloxacin (≥4μg/mL), gentamicin (≥8μg/mL), and colistin (≥4μg/mL). The other agents tested were cefepime, doripenem, ciprofloxacin, and amikacin. Ceftolozane/tazobactam was tested with tazobactam at a fixed 4µg/mL.

Ceftolozane/tazobactam (MIC50/90, 0.5/2µg/mL) was fourfold to 16-fold more active than ceftazidime (MIC50/90, 2/32µg/mL; 82.9% susceptibility) and inhibited 98.5% and 96.1% of isolates at MIC of ≤8µg/mL and ≤4µg/mL, respectively. The highest ceftolozane/tazobactam MIC among ceftazidime-susceptible strains was 4µg/mL (99.8% inhibited at ≤2µg/mL).

Ceftolozane/tazobactam also inhibited 91.1% of ceftazidime nonsusceptible (MIC50/90, 4/8µg/mL) and 92.8% of meropenem nonsusceptible (MIC50/90, 1/8µg/mL) isolates of P. aeruginosa at ≤8µg/mL.

Among P. aeruginosa strains nonsusceptible to ceftazidime and meropenem (183 strains), ceftolozane/tazobactam (MIC50/90, 4/32µg/mL) inhibited 83.6% at ≤8µg/mL. Ceftolozane/tazobactam was also active against strains nonsusceptible to meropenem, ceftazidime, and piperacillin/tazobactam (85.1% inhibited at ≤8µg/mL), they reported.

At MIC ≤8µg/ml, ceftolozane/tazobactam inhibited 92.0% and 87.9% of P. aeruginosa isolates nonsusceptible to gentamicin and ciprofloxacin, respectively. Among P. aeruginosa strains nonsusceptible to gentamicin and ciprofloxacin (149 strains), ceftolozane/tazobactam inhibited 89.9% at ≤8µg/mL.

Of the 87.6% (99/113) of strains nonsusceptible to ciprofloxacin, gentamicin, and meropenem, the ceftolozane/tazobactam MIC was ≤8µg/mL.

Overall, the most active agents were ceftolozane/tazobactam (MIC50/90, 0.5/2µg/mL), colistin (MIC50/90, 1/2µg/mL; 99.1% susceptible) and amikacin (MIC50/90, 2/8 µg/mL; 97.4% susceptible).

“Susceptibility rates for ceftazidime (82.9%), cefepime (82.4%), piperacillin/tazobactam (76.8%), meropenem (80.3%), doripenem (83.4%), ciprofloxacin (77.8%) and gentamicin (89.2%) were lower than ceftolozane/tazobactam at ≤8 (98.5%) or ≤4µg/mL (96.1%),” Dr. Sader concluded.

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