Activity of Ceftolozane-Tazobactam against Carbapenem-Resistant, Non-Carbapenemase-Producing Pseudomonas aeruginosa and Associated Resistance Mechanisms

Abstract

Although carbapenems are effective for treating serious multidrug-resistant infections, carbapenem-resistant (CRPA) is now being reported worldwide. Ceftolozane-tazobactam (C/T) demonstrates activity against many multidrug-resistant isolates. We evaluated the activity of C/T and compared its activity to that of ceftazidime-avibactam (C/A) using a well-characterized collection of non-carbapenemase-producing CRPA isolates. Forty-two non-carbapenemase-producing CRPA isolates from a previous study (J. Y. Lee and K. S. Ko, Int J Antimicrob Agents 40:168-172, 2012, https://doi.org/10.1016/j.ijantimicag.2012.04.004) were included. All had been previously shown to be negative for ,, ,, , and by PCR. In the prior study, expression of ,, and several efflux pump genes had been defined by quantitative reverse transcription-PCR. Here, antimicrobial susceptibility was determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Time-kill curve assays were performed using three C/T- and C/A-susceptible CRPA isolates. Among 42 non-carbapenemase-producing CRPA isolates, overall susceptibility to C/T was 95.2%, compared to 71.4%, 42.9%, 23.8%, 21.4%, and 2.4% for C/A, ceftazidime, piperacillin-tazobactam, cefepime, and meropenem, respectively. The C/T resistance rate was significantly lower than that of C/A among isolates showing decreased and increased expression (5.1% versus 25.6%, = 0.025, and 4.3% versus 34.8%, = 0.022, respectively). In time-kill curve studies, C/T was less bactericidal than C/A against an isolate with decreased and increased expression. C/T was active against 95.2% of non-carbapenemase-producing CRPA clinical isolates. No apparent correlation of C/T MIC values with specific mutation-driven resistance mechanisms was noted.

<p>CP-CRE/non-CP-CRE Stratification And CRE Resistance Mechanism Determination Help In Better Managing CRE Bacteremia Using Ceftazidime–Avibactam And Aztreonam–Avibactam</p>

“…Giddins identified CAZ/AVI resistance in the newly emerging K. pneumoniae ST307 clonal background after only 12 days of CAZ/AVI exposure, with the induction of a 532G-T mutation in the bla KPC-2 gene leading to a D179Y protein substitution as the putative initial mechanism of CAZ/AVI resistance 31. The characterization of some CAZ/AVI-resistant Pseudomonas aeruginosa isolates demonstrated that the entry of CAZ/AVI into the periplasmic space depended on outer membrane permeability 32. Also, the patients infected with KPC2-producing CRE had no previous exposure to CAZ/AVI, but instead had frequent previous exposures to meropenem and cefepime.…”

Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections

“…The majority of carbapenem-resistant P. aeruginosa strains are susceptible to ceftazidime-avibactam [47]. Nonetheless, susceptibility of P. aeruginosa strains to ceftazidime-avibactam depends on the coexistence of various resistance mechanisms affecting porin channel function, efflux pump expression, and/or β-lactamase enzyme expression [48–50]. Ceftazidime-avibactam is not active against A. baumannii or S. maltophilia .…”

In Vivo Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa Arising by AmpC- and Non-AmpC-Mediated Pathways

“…The rise of multidrug-resistant (MDR) Pseudomonas aeruginosa threatens the use of available antibiotics, including carbapenems [1, 2]. The new cephalosporin/ β -lactamase inhibitor combination ceftolozane/tazobactam (C/T) has provided a viable alternative for treatment of infections due to MDR P. aeruginosa [1, 2]. Indeed, many reports have confirmed the success of C/T to combat these organisms [3, 4].…”