703. Mechanisms of High-Level Ceftolozane/Tazobactam (CT) Resistance against Pseudomonas aeruginosa and Synergy between CT and tobramycin (TOB)
Session: Poster Abstract Session: Resistance Mechanisms: Gram-Negative
Thursday, October 4, 2018
Room: S Poster Hall
  • 2018 IDWeek MDR PSA poster 36x18 8 31 18.pdf (652.4 kB)
  • Background: Ceftolozane/tazobactam (CT) is a cephalosporin/β-lactamase inhibitor with excellent activity against multi-drug resistant (MDR) P. aeruginosa (PSA). Several cases of CT-resistance (CT-R) development after exposure have been reported. We recovered a PSA isolate with high-level CT-R from a bacteremic patient with severe, prolonged neutropenia and 5 weeks of CT exposure. Then, multiple mutational pathways and the role of combination therapy were evaluated.

    Methods: Minimum inhibitory concentrations (MIC) to CT were determined by Etest. Synergy tests between CT and tobramycin (TOB) were conducted and interpreted based on the fractional inhibitory concentration index (FICI). Furthermore, whole genome sequencing was performed. Paired-end reads were mapped and compared to reference strain PAO1. Variant analyses were conducted using CLC Genomics Workbench.

    Results: The MICs for CT and TOB were > 256 mg/L and 4 mg/L, respectively. The combination revealed synergistic effects (FICI < 0.5) with reduced CT and TOB MICs to 16 mg/L and 1 mg/L, respectively. Clinically, combination therapy of CT 3g q8h given over 4h and TOB 7 mg/kg q24h successfully cleared the bacteremia within 2 days. Genomic analysis revealed the CT-R isolate contained multiple variants in the ampC gene, including G183D associated with low level CT-R. Two additional variants in aminoacid position 79 (R79Q) and position 105 (T105A) were located inside or near helix-H2 which interacts with the Ω-loop through hydrogen-binding rendering the serine active site more pliable to accommodate larger molecules. Moreover, the CT-R isolate showed a truncated ampD and multiple mutations in mexD, mexT, mexI, and mexR, a primary regulator of mexAB-oprM. The isolate also contained the oprD mutation (Q142X) and an oprD-inactivating mutation (W417X). In addition to these chromosomal mutations, the isolate harbored OXA-50, blaPAO1, and aph(3’)-IIb.

    Conclusion: High-level CT-R was likely driven by multiple mutations in the ampC region causing structural changes. While resistance to CT is worrisome, our case of a severe neutropenic patient who rapidly cleared bacteremia on CT 3g qh8 given over 4h plus TOB emphasizes the importance of strategic combination and dosing in combating MDR PSA.

    Wonhee So, PharmD1, James Shurko, PharmD2, Ralph Galega, MS2, Rod E. Quilitz, PharmD1, John Greene, MD, FACP3 and Grace C. Lee, PharmD, PhD2, (1)Pharmacy, Moffitt Cancer Center, Tampa, FL, (2)The University of Texas at Austin, College of Pharmacy, Austin, Texas and the University of Texas Health San Antonio, San Antonio, Texas, San Antonio, TX, (3)Infectious Diseases, H. Lee Moffitt Cancer Center, Tampa, FL


    W. So, None

    J. Shurko, None

    R. Galega, None

    R. E. Quilitz, None

    J. Greene, None

    G. C. Lee, None

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