1414. Inoculum Effect of Piperacillin/Tazobactam Concentration on Emergence of Resistance in Klebsiella aerogenes
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
  • Custodio ID Week Poster (003).jpg (499.3 kB)
  • Background: Piperacillin/tazobactam (PTZ) is a carbapenem-sparing option for AmpC-repressed organisms. Current strategies of dosing PTZ focus on prolonging fT>minimum inhibitory concentration (MIC), lowering C:MIC ratios. The objective of this study is to determine the effect of physiologic PTZ concentration on the emergence of resistance among clinical isolates of Klebsiella aerogenes (KA).

    Methods: Fifteen clinical KA from respiratory cultures had MICs determined by broth microdilution for PTZ and Etest for ceftriaxone (CRO) and cefepime (FEP). The presence of resistant mutants was determined using Muller-Hinton agar with increasing concentrations of CRO and PTZ. Five isolates with the highest selected MIC underwent time-kill (TK) studies with PTZ compared with CRO and FEP at high inoculum (HI) (7.0 log10 CFU/mL) and low inoculum (LI) (5.0 log10 CFU/mL). Concentrations used in TK studies simulated lung epithelial lining fluid for free peak of a prolonged infusion of PTZ (20µg/mL; PTZ20) and the average AUC0-24 (10µg/mL; PTZ10), continuous infusion FEP (8µg/mL), and the average AUC0-24 concentration of CRO (6µg/mL).

    Results: MICs for PTZ, FEP and CRO ranged from 2-8, 0.47 and 0.094-0.125 µg/mL, respectively. Mutant selection for both PTZ and CRO occurred for 5 isolates. In TK studies at HI FEP was the only agent to demonstrate bactericidal activity with reduction of 5.0 ± 0.7 log10 CFU/mL. Reductions for PTZ20 and PTZ10 were 0.21±0.18 and 0.05±0.16 log10 CFU/mL, respectively. CRO demonstrated regrowth of 0.5±0.3 log10 CFU/mL. Interestingly, the susceptibility before and after TK did not differ for the PTZ groups, whereas all CRO-exposed isolates had become resistant. At LI, PTZ20 and PTZ10 had improved activity with reductions of 3.0± 0.4 and 2.8±0.5 log10 CFU/mL, respectively. CRO was also more active at LI but with regrowth for 2/5 isolates.

    Conclusion: In studies simulating conditions of pneumonia, PTZ demonstrated significant inoculum-dependent killing regardless of baseline MIC. CRO demonstrated selection for resistance at HI and variably at LI. FEP was the only antimicrobial associated with bactericidal activity at HI. Resistance to PTZ was seen on agar plates although not in TK studies. Dosing strategies to optimize cidality are warranted.

    Marco Custodio, PharmD1, Beverly Anderson, BA1, Daniel Sanchez, BS1, Keenan Ryan, PharmD, PhC2, Carla Walraven, PharmD, MS2 and Renee-Claude Mercier, PharmD3, (1)University of New Mexico, Albquerque, NM, (2)University of New Mexico Health Sciences Center, Albuquerque, NM, (3)University of New Mexico College of Pharmacy, University of New Mexico College of Pharmacy, Albquerque, NM


    M. Custodio, None

    B. Anderson, None

    D. Sanchez, None

    K. Ryan, None

    C. Walraven, None

    R. C. Mercier, None

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