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 0.54 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 0.120.5 µg/mL did not show any of the investigated FQ resistance mechanisms. Enterobacter cloacae isolates (DLX MIC, 24 µg/mL) harbored a GyrA alteration (S83T) or qnrB6, while Escherichia coli (DLX MIC, 12 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 0.120.5 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.
R. E. Mendes,
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