A4. Treatment of antimicrobial resistant infections
David P. Nicolau, PharmD
Disclosure: Allergan plc: Grant/Research Support
Liofilchem: Grant/Research Support
Melinta Therapeutics: Grant/Research Support, Speaker's Bureau
Merck & Co., Inc.: Grant/Research Support, Speaker's Bureau
Nabriva Therapeutics: Grant/Research Support
Pfizer Inc.: Speaker's Bureau
VenatoRx Pharmaceuticals, Inc.: Grant/Research Support
Wockhardt Bio AG: Grant/Research Support
Background : MBLs, which require Zn for catalytic activity, are a major contributor to high-level β-lactam resistance when tested using conventional CAMHB. We have previously reported marked reductions in meropenem (MEM) MICs in Zn-depleted media (Chelex-CAMHB and EDTA-CAMHB; Zn [C] <0.002 mg/L) compared with conventional CAMHB (Zn [C] 0.959 mg/L) against a variety of MBL-producing isolates, whereas Zn-depletion had no impact on levofloxacin (LVX) MICs (ASM Microbe 2019, San Francisco. Abstract P508). To explore in vivo implications, we evaluated the efficacy of MEM human simulated regimen (HSR) against MBL-producing isolates in a murine pneumonia model. In addition, LVX HSR was examined for model validation.
Methods : Nine MBL-producing isolates (NDM, n=5; VIM, n=2; IMP, n=2) were utilized. CAMHB, Chelex-CAMHB, and EDTA-CAMHB MEM MICs ranged from 16 - > 64, ≤ 0.0625 - 0.5, and ≤ 0.0625 - 0.5 mg/L, respectively. LVX MICs ranged from ≤ 0.0625 – > 64 mg/L. Neutropenic lung infected ICR mice received a MEM HSR of 2g q8h [1.5h infusion], 2 lower MEM exposures or LVX 750 mg q24h HSR. Zn [C] were determined in the epithelial lining fluid (ELF) of infected mice.
Results : LVX displayed predictable in vivo efficacy consistent with its phenotypic profile irrespective of the media utilized for MIC testing (Figure). Despite attaining zero %T> MIC using values generated in CAMHB, MEM HSR produced marked bacterial reductions against all MBL-producing isolates (Figure). Reductions in MEM exposures produced bacterial killing concordant with its pharmacodynamic profile using Zn-depleted CAMHB MIC values. Zn [C] in infected murine ELF were undetectable i.e., < 0.002 mg/L.
Conclusion : Our results indicate that MEM in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in Zn-depleted media for MBL-producing Enterobacteriaceae. These observations are consistent with the case reports describing positive outcomes in MBL-infected patients following treatment with carbapenems (Infection 2018;46:1–13). Our translational data suggest that the use of conventional CAMHB for MBL susceptibility testing is inappropriate in distinguishing meaningful in vivo resistance given that Zn [C] are supraphysiologic in conventional CAMHB and negligible at infection sites.