In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-β-Lactam-Susceptible Klebsiella pneumoniae Strains

Abstract

Recent findings have identified Klebsiella pneumoniae strains that are pan-␤-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro. We assessed the efficacy of a humanized exposure of piperacillin-tazobactam (TZP) against 12 TZP-R/PBL-S K. pneumoniae isolates in an immunocompromised murine lung infection model. Discordance between the in vitro resistance profile and the in vivo efficacy of human-simulated TZP exposures against this phenotypic profile was observed. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.KEYWORDS piperacillin-tazobactam, Klebsiella pneumoniae, antibiotic resistance P iperacillin-tazobactam (TZP) continues to be a workhorse antimicrobial in hospitals globally due to its broad coverage, particularly against Pseudomonas and Enterobacteriaceae species. As multidrug-resistant (MDR) Gram-negative pathogens evolve, the potency of the most frequently used agents, including TZP, deteriorates (1).Previously we identified Escherichia coli and Klebsiella pneumoniae strains resistant to TZP but pan-susceptible to other ␤-lactams (TZP-R/PBL-S), including cephalosporins, carbapenems, and monobactams in vitro (2, 3). The mechanism behind this resistance profile is thought to be attributable to a porin mutation, although the contribution of TEM-1 ␤-lactamase may also play a role (4). While further delineation of the mechanism is required, insights regarding the clinical consequences of this novel phenotype are of interest due to the extensive use of empirical TZP in debilitated hospitalized patients. In an attempt to better understand the clinical implications of this resistant phenotype, an initial in vivo murine study was conducted using humanized TZP exposures and E. coli isolates displaying this resistant phenotype (3). Interestingly, this study demonstrated an overt in vitro/in vivo discordance, as humanized TZP exposures were found to produce substantive killing, despite phenotypically and genotypically confirmed resistance. Herein, we sought to characterize the efficacy of the humanized TZP regimen against K. pneumoniae displaying this novel phenotype to gain new insights regarding treatment challenges for this important nosocomial pathogen.Sixteen K. pneumoniae strains, 12 displaying the TZP-R/PBL-S phenotype and 4 the TZP-susceptible (TZP-S) phenotype, collected during the conduct of the previously noted surveillance program, were included in the current investigation (2). Prior to the in vivo studies, the TZP MICs were reconfirmed in triplicate using broth microdilution methods according to the 2016 Clinical and Laboratory Standards Institute guidelines

Epidemiology of Bloodstream Infections Caused by Escherichia coli and Klebsiella pneumoniae That Are Piperacillin-Tazobactam-Nonsusceptible but Ceftriaxone-Susceptible

“…Despite these concerns, we did not identify an increase in 30-day mortality or need for ICU transfer in patients with TZP-NS/CRO-S Ec and Kp bacteremia who were empirically treated with TZP compared with those empirically treated with cephalosporins and carbapenems. This unexpected finding is consistent with those of murine pneumonia models of infection with TZP-NS/CRO-S Ec and Kp [15, 16]. In these in vivo studies, TZP exposure resulted in bacterial killing that was similar in mice infected with TZP-NS/CRO-S strains compared with those infected with TZP-S strains.…”

Extensive Gene Amplification as a Mechanism for Piperacillin-Tazobactam Resistance in Escherichia coli

“…TZP resistance in this case may not translate into clinical resistance of the organism in a patient therapeutic setting, where higher concentrations of tazobactam could be obtained. In support of this theory, neutropenic mice infected with bacteria identified as TZP resistant by BMD, but susceptible to other classes of β-lactams, were successfully treated with humanized exposures of TZP ( 40 , 41 ).…”

“…Furthermore, E. coli 907355 isolates were not collected prior to and over the course of the antibiotic therapy. Future studies in mice might address whether bla TEM-1 amplification occurs in E. coli 907355 during host infection ( 40 , 41 ). Recently, McGann et al reported that aph1 amplification occurred in Acinetobacter baumanii during tobramycin treatment of an infected patient, leading to antibiotic therapy failure ( 36 ).…”

Assessment of the In Vivo Activity of SPR741 in Combination with Azithromycin against Multidrug-Resistant Enterobacteriaceae Isolates in the Neutropenic Murine Thigh Infection Model

“…Although these results are suggestive of efficacy, confirmation of their applicability and translation in the context of in vivo studies is required. In vitro-in vivo discordances have been observed previously, and thus, efficacy cannot be reliably extrapolated based on in vitro data alone (10)(11)(12). a C T , threshold concentration.…”