331. Molecular Characterization of Fluoroquinolone Resistance Mechanisms in Isolates from the Delafloxacin Acute Bacterial Skin and Skin Structure Infections Clinical Trials
Session: Poster Abstract Session: Emerging Resistance - Epidemiology and Mechanisms
Thursday, October 5, 2017
Room: Poster Hall CD
Posters
  • IDWeek2017-delafloxacin-ABSSSI-trials.pdf (755.7 kB)
  • Background: Delafloxacin (DLX) is a broad-spectrum fluoroquinolone (FQ) antibacterial that has completed a clinical trial for treatment of acute bacterial skin and skin structure infections (ABSSSI). DLX is undergoing phase 3 trials for community-acquired bacterial pneumonia. This study characterized FQ resistance mechanisms among Gram-negative ABSSSI clinical trial isolates and correlated with microbiologic response.

    Methods: Isolates selected were 19 Enterobacteriaceae (ENT) and 11 P. aeruginosa (PSA) baseline isolates showing DLX MIC of ≥0.12 µg/mL recovered from the DLX arm. Isolates had the whole genome sequenced and screened for plasmid-mediated FQ resistance genes (oqx, qepA, qnr and aac(6’)-Ib-cr) and for the presence of QRDR mutations. 5 PSA isolates with DLX MIC of 0.5–4 µg/mL had expression of efflux-pumps (MexA, MexC, MexE, MexX) determined. Microbiological response for patients in the ME and MITT analysis sets were based on results of baseline and post-baseline cultures (FU and LFU Visits) and susceptibility testing, together with the investigator assigned clinical response.

    Results: DLX demonstrated high eradication rates for ENT and PSA (62/63, 98.4%). ENT isolates exhibiting DLX MIC values of 0.12–0.5 µg/mL did not show any of the investigated FQ resistance mechanisms. Enterobacter cloacae isolates (DLX MIC, 2–4 µg/mL) harbored a GyrA alteration (S83T) or qnrB6, while Escherichia coli (DLX MIC, 1–2 µg/mL) had multiple mutations in GyrA, ParE, and ParC or qnrS1 (Table). All Klebsiella pneumoniae and Proteus mirabilis (DLX MIC, 1–>8 µg/mL) had mutations in GyrA and ParC, and 1 P. mirabilis also carried qnrA1. PSA with DLX MIC of 0.12–0.5 µg/mL did not show any of the investigated FQ resistance mechanisms. PSA displaying DLX MIC of 1 µg/mL had a GyrA alteration (D87N), while those with a DLX MIC of 4 µg/mL had overexpression of MexA. All isolates included in this study were eradicated in the MEFUI, except for 1 E. cloacae (DLX MIC, 2 µg/mL) harboring S83T in GyrA.

     

    Conclusion:  Several FQ resistance mechanisms were detected, which were associated with DLX MICs of ≥1 µg/mL; however, the presence of these resistance determinants do not appear to affect microbiological response.

     

    Rodrigo E. Mendes, Ph.D.1, Dee Shortridge, Ph.D.1, Sandra P. McCurdy, M.S.2, Sue K. Cammarata, MD3, Michael D. Huband, BS1 and Robert K. Flamm, PhD4, (1)JMI Laboratories, Inc., North Liberty, IA, (2)Melinta Therapeutics, Lincolnshire, IL, (3)Melinta Therapeutics, Inc., New Haven, CT, (4)United States Committee on Antimicrobial Susceptibility Testing, Silverton, OR

    Disclosures:

    R. E. Mendes, Melinta Therapeutics: Research Contractor , Research grant

    D. Shortridge, Melinta Therapeutics: Research Contractor , Research grant

    S. P. McCurdy, Melinta Therapeutics: Employee , Salary

    S. K. Cammarata, Melinta Therapeutics: Employee , Salary

    M. D. Huband, Melinta Therapeutics: Research Contractor , Research grant

    R. K. Flamm, Melinta Therapeutics: Research Contractor , Research grant

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.