Background: TZP is one of the most widely used antimicrobials; however, recent findings have identified E. coli strains that are Pan-β-Lactam-Susceptible [i.e., all cephalosporins, monobactams and carbapenems (PBL-S)], but resistant to TZP in vitro. Genotypic profiling revealed TZP-R was associated with deleted or dysfunctional porins (Mediavilla JR et al., Abst 1181 IDweek 2015). We assessed the in vivo significance of these resistance determinates in an immunocompromised murine pneumonia model using humanized exposures of TZP.
Methods: 18 clinical isolates of E. coli, 8 TZP susceptible (TZP-S)/PBL-S and 10 genotypically confirmed TZP-R/PBL-S, were utilized. Prior to inclusion in the model, MICs for all organisms were confirmed in triplicate via broth microdilution. Pharmacokinetic studies were undertaken to establish a murine dosing regimen that provided a profile similar to that of the 4.5g q6h regimen in man. Groups of 6 mice were inoculated and 2 h later were injected subcutaneously with the humanized TZP dosing regimen. After 24 h, animals were euthanized, lungs excised, and antibacterial activity was measured as the change in lung bacterial density (Log10 CFU) relative to the starting inoculum (0h).
Results: TZP MICs were as follows: TZP-S/PBL-S, n=8, range 2-16 mcg/mL; TZP-R/PBL-S, n=10, range 256-≥2048 mcg/mL. All isolates grew well in untreated controls. The humanized TZP regimen achieved > 2-log kill against 5 TZP-S/PBL-S isolates and ≥ 1-log kill against the remaining 3 isolates (Figure 1). Despite the TZP-R phenotype, humanized dosing of TZP resulted in ≥ 2-log kill against 2 TZP-R/PBL-S (MIC ≥ 2048), ≥ 1-log kill against 6 and stasis against the remaining 2 isolates (Figure 1). Repeat MICs of TZP-R isolates recovered from treated mice revealed similar pre-exposure values.
Conclusion: This study revealed overt discordance between the in vitro resistance profile and in vivo efficacy of human exposures TZP against this novel TZP-R/PBL-S phenotypic profile. These observations combined with the recovery of TZP-R isolates with similar MICs to that of pretreatment values suggests reduced in vivo express of this phenotype. Additional investigations are warranted to evaluate the clinical implications of this TZP-R/PBL-S phenotype.
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