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Pre-clinical studies of a new quinolone (UB-8902) against Acinetobacter baumannii resistant to ciprofloxacin

Abstract number: P551

López-Rojas R., Sánchez-Céspedes J., Docobo-Pérez F., Vila J., Pachón J.

Objectives: To evaluate the in vitro and in vivo activity of a new derivative of ciprofloxacin (UB-8902) against Acinetobacter baumannii.

Methods: We used two A. baumannii strains (Ab58 and Ab661). The antibiotics of the study were ciprofloxacin, moxifloxacin, and the new generated quinolone UB-8902. Animals used were immunocompetent C57BL/6 female mice.

In vitro tests: MIC (microdilution method) and bactericidal activity (time-kill curves) were performed following CLSI recomendations.

In vivo assays: we studied the toxicity parameters of the UB-8902 [lethal dose 0 (LD0), lethal dose 50 (LD50), and lethal dose 100 (LD100)] inoculating groups of 6 animals with rising concentrations in base 2 of UB-8902, from 0.5 mg/kg/ip to reach a 100% of mortality (Reed and Muench method). To ascertain the bacterial minimum lethal dose (MLD) and the bacterial lethal dose 50 (BLD50) of the strains Ab58 and Ab661, groups of 10 animals were inoculated (using a murine model of peritoneal sepsis) with a potentially lethal concentration (8 log cfu/mL), and decreasing in base 10 until reaching the minimum which caused a 100% of mortality. To study the effective dose 50 (ED50) of UB-8902, we used a model of peritoneal sepsis with groups of 10 animals with an inoculum similar to the MLD of the strains, and treated with a dose of UB-8902 from 0.5 mg/kg, increasing in base 2, to LD0 or until a 50% of survival was reached.

Results: MICs (mg/L): Ab58, CIP = 0.25, MOX=0.016, UB-8902=0.03; Ab661, CIP=8, MOX=1, UB-8902=0.5. In time-kill curves for Ab58, bactericidal activity was observed from 4 h with 4xCMI of UB-8902, from 8 h with 4xCMI of CIP, and there was no bactericidal activity with MOX. For Ab661, bactericidal activity was observed from 4 h with 4xCMI of UB-8902, from 4 h with 4xCMI and from 8 h with 2xCMI of CIP, and from 8 h with 2xCMI and 4xCMI of MOX. The toxicity parameters of UB-8902 (mg/kg) were: LD0=512, LD50=608.5, LD100=2048. The MLD was 7.5 log cfu/mL for both strains, being BLD50 of Ab58 6.11 log cfu/mL and 7 log cfu/mL for Ab661. The ED50 of UB-8902 for Ab58 was 16 mg/kg, and for Ab661 was 128 mg/kg.

Conclusions: The new quinolone UB-8902 presents bactericidal activity against A. baumannii resistant to ciprofloxacin and is effective in reducing the mortality in a model of murine peritoneal sepsis, with a dose lower than the toxic one, which warrants the future assessment of its efficacy in other in vivo experiments, such as a discriminative murine model of pneumonia.

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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