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Definition of wildtype MIC distributions for targeted species for determination of optimal dosing for zabofloxacin, a novel fluoronaphthyridone

Abstract number: P553

Jones R., Ambrose P., Wikler M.

Objectives: Zabofloxacin (formerly DW-224a) is a new quinolone-like agent with potent activity against pathogens responsible for respiratory tract and uncomplicated skin and skin structure infections (S. pneumoniae [SPN], H. influenzae [HI], M. catarrhalis [MCAT] and S. aureus [SA]). Zabofloxacin was evaluated by CLSI MIC methods for subsequent PK/PD target attainment (TA) analysis to optimise doses used in various clinical trials.

Methods: Recent (2006) wildtype clinical isolates from worldwide locations (Europe, Asia, North and South America) were susceptibility (S) tested by CLSI methods: SPN (225; 200 wildtype, 25 levofloxacin-resistant [LEVO-R]); SA (200 wildtype, 200 MRSA and LEVO-R; 25 CA-MRSA); HI (55 wildtype); MCAT (10 wildtype) and CoNS (40 wildtype with 20 LEVO-R). Zabofloxacin was compared to LEVO, gemifloxacin [GEMI] and moxifloxacin [MOXI]. PK/PD studies of TA were calculated by Monte Carlo simulation from this MIC distribution for doses 50–800 mg daily (protein binding at 77%).

Results: Wildtype SPN and SA (MIC90, 0.03 mg/L); and HI and MCAT (MIC90, 0.015 mg/L were very zabofloxacin-S. In contrast, LEVO-R SPN (MIC90, 1 mg/L) and MRSA (MIC90, >8 mg/L) had higher zabofloxacin MIC values. CA-MRSA were zabofloxacin-S (also LEVO-S). Beta-lactamases and PBP-mediated resistances did not adversely influence zabofloxacin potency. Zabofloxacin (MIC50, 0.015 mg/L) was two- and eight-fold more potent than GEMI and MOXI versus wildtype penicillin-R SPN. 90% TA was achieved against SPN, HI, and MCAT wildtype pathogens (MIC, leqslant R: less-than-or-eq, slant0.06 mg/L; geqslant R: gt-or-equal, slanted300 mg/day) and many LEVO-R SPN.

Conclusions: Zabofloxacin was two- to 16- and two- to >64-fold more active than MOXI or LEVO, respectively; equal to GEMI versus RTI pathogens and wildtype MSSA. Optimal dosing appears to be achievable due to high zabofloxacin potency versus these 755 contemporary clinical strains. Clinical trial designs and PK/PD-based dosing regimens will be optimised for this promising, new orally administered agent.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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