In Vitro Activity of Ceftolozane/Tazobactam (CXA-201) versus Pseudomonas aeruginosa Isolates Obtained from Patients in Canadian Hospitals: CANWARD 2011

Background:   Cephalosporin resistance among P. aeruginosa isolates is mediated, in part, by production of an AmpC beta-lactamase.  Ceftolozane, a novel anti-pseudomonal cephalosporin, demonstrates reduced affinity for AmpC beta-lactamases and improved binding to P. aeruginosa penicillin binding proteins relative to ceftazidime.  The purpose of this study was to evaluate the in vitro activity of ceftolozane in combination with tazobactam (ceftolozane/tazobactam: formerly CXA-201) versus P. aeruginosa clinical isolates obtained from patients in Canadian hospitals.

Methods:   From January through October 2011, 15 sentinel Canadian hospitals submitted pathogens from patients attending hospital clinics, emergency rooms, medical and surgical wards, and intensive care units (CANWARD).  Each centre was asked to submit pathogens (consecutive, one per patient/infection site) from blood (100), respiratory (100), urine (25), and wound/IV (25) infections.  Susceptibility testing was performed using CLSI broth microdilution.  Doubling concentrations of ceftolozane were evaluated in combination with a fixed concentration of tazobactam (4 µg/mL).

Results:   In total, 330 P. aeruginosa isolates were obtained as a part of CANWARD.  The antimicrobial susceptibility profile of these isolates is presented below.

 

Antimicrobial	MIC50 (µg/mL)	MIC90 (µg/mL)	Range	Susceptibility Breakpoint	% Susceptible
<>Amikacin	4	8	≤1 to >64	≤16	94.6
Cefepime	4	16	≤0.25 to >64	≤8	86.1
Ceftazidime	2	32	≤0.25 to >32	≤8	85.2
Ceftolozane/ tazobactam	0.5	1	≤0.12 to >64	Not defined	Not defined
Ciprofloxacin	0.25	4	≤0.06 to >16	≤1	78.2
Colistin	1	2	0.25 to 16	≤2	95.5
Gentamicin	1	8	≤0.5 to >32	≤4	88.2
Meropenem	0.5	4	≤0.03 to >32	≤2	84.2
Piperacillin/ Tazobactam	4	64	≤1 to >512	≤16/4	84.6

Twenty-three isolates (7.0%) were multi-drug resistant (MDR = resistant to at least 3 different antimicrobial classes).  The MIC₉₀ values for ceftolozane/tazobactam, cefepime, and ceftazidime versus the MDR isolates were 8 µg/mL, 32 µg/mL, and >32 µg/mL, respectively.

Conclusion:   Ceftolozane/tazobactam demonstrated improved in vitro activity (16-32 fold lower MIC₉₀ value) over ceftazidime and cefepime versus a collection of 330 P. aeruginosa clinical isolates.  Over 90% of MDR P. aeruginosa isolates were inhibited by ≤8 µg/mL of ceftolozane/tazobactam.