Ceftolozane/Tazobactam, a Promising Therapy for ESBL Infections

PHILADELPHIA, PA—Ceftolozane/tazobactam provides an empiric treatment option for infections caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, according to data presented at IDWeek 2014.

Results of a pooled analysis of randomized Phase 3 trials showed that “ceftolozane/tazobactam achieved high clinical and microbiological cure rates in patients with complicated urinary tract and complicated intra-abdominal ESBL infections,” reported Myra C. Popejoy, PharmD, of Cubist Pharmaceuticals, Inc., Lexington, MA.

The clinical cure rates were 97% for the ceftolozane/tazobactam arms compared with 85% for the clinical comparators; microbiological eradication was achieved in 80% and 61% of patients, respectively.

“At a breakpoint of 8mg/L, 90% of ESBL-producing Enterobacteriaceae were susceptible to ceftolozane/tazobactam,” she noted. In the complicated urinary tract infection trials, approximately 20% of patients were susceptible to levofloxacin, while in the complicated intra-abdominal infection trials, meropenem resistance was less than 5%.

“Ceftolozane/tazobactam is a novel anti-pseudomonal cephalosporin with a well-established β-lactamase inhibitor that has potent in vitro activity against most ESBL-producing Enterobacteriaceae and drug-resistant Pseudomonas aeruginosa,” she noted.

Dr. Popejoy and colleagues evaluated data from the Phase 3 ASPECT (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam) trials in patients with complicated intra-abdominal and complicated urinary tract infections to describe the characteristics and clinical and microbiologic outcomes of patients infected with ESBL-producing Enterobacteriaceae.

Patients with complicated urinary tract infection received 7 days of intravenous ceftolozane/tazobactam or levofloxacin; those with complicated intra-abdominal infection received 4–14 days of ceftolozane/tazobactam plus metronidazole or meropenem. Clinical and microbiological outcomes were determined 5–9 days after treatment in patients with complicated urinary tract infection and 24–32 days after initiation of treatment in those with complicated intra-abdominal infection.

Of the 1,346 patients in the pooled microbiologically evaluable population, 153 (11.4%) had an ESBL-producing Enterobacteriaceae identified at baseline, the investigators reported, which were primarily E. coli (n=106), K. pneumoniae (n=29). Among 95 of 150 patients (63.3%), the most prevalent enzymes were CTX-M-14 and CTX-M-15, “which are the most common ESBLs worldwide, and are often associated with multidrug resistance in E. coli and K. pneumoniae,” Dr. Popejoy reported.

“Against these highly resistant clinical isolates, ceftolozane/tazobactam demonstrated greater in vitro activity than ceftazidime, cefepime, piperacillin/tazobactam, ciprofloxacin, levofloxacin, gentamicin, and aztreonam,” she added. Compared with those with no ESBL-producing Enterobacteriaceae at baseline, those with ESBL-producing Enterobacteriaceae were ≥65 years of age (30.7% vs. 21.3%) and had a higher incidence of renal impairment.

On June 19, 2014, Cubist Pharmaceuticals announced that the FDA assigned a Prescription Drug User Fee Act (PDUFA) action date of December 21, 2014. The company is seeking approval of ceftolozane/tazobactam for the treatment of complicated urinary tract infections and complicated intra-abdominal infections.

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