In Vitro Comparison of Ceftolozane-Tazobactam to Traditional Beta-Lactams and Ceftolozane-Tazobactam as an Alternative to Combination Antimicrobial Therapy for Pseudomonas aeruginosa

Abstract

Guidelines for the treatment of sepsis, febrile neutropenia, and hospitalacquired pneumonia caused by Pseudomonas aeruginosa include empirical regimens incorporating two antibiotics from different classes with activity against P. aeruginosa for select at-risk patients to increase the likelihood that the organism will be susceptible to at least one agent. The activity against P. aeruginosa and the rates of cross-resistance of ceftolozane-tazobactam were compared to those of the ␤-lactam comparators cefepime, ceftazidime, piperacillin-tazobactam, and meropenem alone and cumulatively with ciprofloxacin or tobramycin. Nonurine P. aeruginosa isolates were collected from adult inpatients at 44 geographically diverse U.S. hospitals. MICs were determined using reference broth microdilution methods. Of the 1,257 isolates collected, 29% were from patients in intensive care units and 39% were from respiratory sites. The overall rate of susceptibility to ceftolozane-tazobactam was high at 97%, whereas it was 72 to 76% for cefepime, ceftazidime, piperacillin-tazobactam, and meropenem. The rate of nonsusceptibility to all four comparator ␤-lactams was 11%; of the isolates nonsusceptible to the four comparator ␤-lactams, 80% remained susceptible to ceftolozane-tazobactam. Among the isolates nonsusceptible to the tested ␤-lactam comparators, less than half were susceptible to ciprofloxacin. By comparison, approximately 80% of the ␤-lactam-nonsusceptible isolates were susceptible to tobramycin, for overall cumulative susceptibility rates of 94 to 95%, nearly 10% higher than that of the ciprofloxacin-␤-lactam combinations and approaching that of ceftolozane-tazobactam as a single agent. The rates of susceptibility to ceftolozane-tazobactam were consistently high, with little observable crossresistance. Ceftolozane-tazobactam monotherapy performed at or above the level of commonly utilized combination therapies on the basis of in vitro susceptibilities. Ceftolozane-tazobactam should be considered for use in patients at high risk for resistant P. aeruginosa infection and as an alternative to empirical combination therapy, especially for patients unable to tolerate aminoglycosides.KEYWORDS Pseudomonas aeruginosa, antimicrobial resistance, ceftolozanetazobactam, combination treatment, resistance P seudomonas aeruginosa is a notorious cause of nosocomial infection both within the United States and around the world. The CDC's National Healthcare Safety Network lists P. aeruginosa as the seventh most common cause of health careassociated infection, accounting for 8% of all reported cases (1), while other surveillance

Carbapenem-Nonsusceptible Pseudomonas aeruginosa Isolates from Intensive Care Units in the United States: a Potential Role for New β-Lactam Combination Agents

“…The lower resistance rate observed may be due to those authors' composite assessment of isolates from respiratory tract, bloodstream, urine, and skin/wound infections, compared with our assessment of respiratory tract and bloodstream isolates only. This finding highlights the significance of culture source in the interpretation of resistance patterns, as noted in several other studies (22,23).…”

“…Fortunately, the unmet need for safe and reliable therapies for these pathogens has seen the development and approval of several ␤-lactam combination agents (i.e., ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem-vaborbactam). Although not included in this study, ceftolozane-tazobactam has consistently demonstrated potent in vitro activity against P. aeruginosa that is similar to if not greater than that of ceftazidime-avibactam in large surveillance studies (22,32,35). Importantly, the addition of tazobactam does little to enhance the activity of ceftolozane against P. aeruginosa.…”

<p>Colistin Plus Carbapenem versus Colistin Monotherapy in the Treatment of Carbapenem-Resistant <em>Acinetobacter baumannii</em> Pneumonia</p>

“…Other studies have reported other drugs to be active against CRAB 19,20 and several new drugs have been introduced in the real world with effects against MDR or XDR gram-negative bacteria. 21,22 Whether combination therapy with newer antibiotic agents (such as ceftolozanetazobactam or ceftazidime-avibactam) or other agents are useful options in this clinical context remains unknown and conclusions on the efficacy of combination therapy for these infections should not be drawn from the results of this trial before evaluation of newer drugs.…”

Multicenter Evaluation of the Etest Gradient Diffusion Method for Ceftolozane-Tazobactam Susceptibility Testing of Enterobacteriaceae and Pseudomonas aeruginosa

“…Additionally, C/T was noninferior to levofloxacin for the treatment of cUTIs, including pyelonephritis (4), which was mainly attributable to high rates of levofloxacin-resistant isolates among cUTI-causing bacteria (5,6). In vitro, C/T inhibits the growth of a high percentage of bacterial isolates from the medically important Enterobacteriaceae family and Pseudomonas aeruginosa, outperforming several current first-line antibiotics for the treatment of multidrug-resistant (MDR) organisms (3,(7)(8)(9)(10)(11)(12)(13)(14). Nevertheless, resistance to C/T has been observed, emphasizing the need for C/T susceptibility testing in clinical microbiology laboratories (15)(16)(17).…”