1979. In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam (Caz-Avi), Aztreonam (ATM), and Tigecycline (TGC) Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing (NDM) Klebsiella pneumoniae (KP) in a Murine Lung Infection Model
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Background: Previously we have demonstrated in vivo Caz-Avi activity against NDM Enterobacteriaceae despite high MICs [MacVane S et al., AAC 2014;58(11):7007-9]. This in vitro/in vivo discordance was attributed to the broad enzyme inhibition of Caz-Avi and the poor in vivo expression of NDM. Herein, we assess potential synergistic combinations in vitro and in vivo against a multi-drug resistant KP harboring NDM that could guide management of MDR infections.

Methods: Molecular characterizations of the KP isolate revealed NDM, OXA-48, and CTX-M. MICs were determined for Caz-Avi, TGC, and ATM using E-test strips on inoculated Mueller-Hinton agar. Furthermore, a 90° angle was created at the intersection between the scales at the respective MICs of these agents. The fractional inhibitory concentration index (ΣFIC) was calculated to assess synergy. Additionally, groups of 6 mice were inoculated and 2h later were injected subcutaneously with the humanized regimens of Caz-Avi 2.5g q8h, TGC 100mg q12h and 50mg q12h, ATM 2g q6h alone and in combination. After 24h, 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: In vitro, MICs were 1, ≥256, and ≥256 µg/mL for TCG, ATM, and Caz-Avi, respectively. Caz-Avi and ATM demonstrated synergy with a ΣFIC <0.5, while no synergy was recognized with Caz-Avi and TGC. In the murine lung model, Caz-Avi alone demonstrated a >2-log10 reduction in CFU, while TGC and ATM demonstrated ≥1.4 log10 CFU growth. As a result of the activity of Caz-Avi, no in vivo synergy was observed with the combinations as opposed to in vitro results.

Conclusion: Despite the high MICs observed for individual compounds, in vitro synergy was demonstrated with Caz-Avi and ATM. The humanized dose of Caz-Avi monotherapy resulted in extensive in vivo killing and as a result synergy was not observed with combinations. Further investigation is required to determine the clinical utility of Caz-Avi as monotherapy or in combination with other agents in the face of evolving metallo-β-lactamases.

Marguerite Monogue, PharmD, Center for Anti-Infective Research and Development at Hartford Hospital, Hartford, CT, Lilian M. Abbo, MD, UNIVERSITY OF MIAMI. DIVISION OF INFECTIOUS DISEASES, MIAMI, FL, Rossana Rosa, MD, Division of Infectious Diseases Jackson Health System, Miami, FL, Octavio Martinez, PhD, Pathology, University of Miami Miller School of Medicine, Miami, FL and David P. Nicolau, PharmD, FCCP, FIDSA, Center for Anti-Infective Research & Development at Hartford Hospital, Hartford, CT

Disclosures:

M. Monogue, None

L. M. Abbo, None

R. Rosa, None

O. Martinez, None

D. P. Nicolau, None

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