Francisella tularensis Susceptibility toAntibiotics: A Comprehensive Review of the Data Obtained In vitro and in Animal Models

The antibiotic classes that are recommended for tularaemia treatment are the aminoglycosides, the fluoroquinolones and the tetracyclines. However, cure rates vary between 60 and 100% depending on the antibiotic used, the time to appropriate antibiotic therapy setup and its duration, and the presence of complications, such as lymph node suppuration. Thus, antibiotic susceptibility testing (AST) of F. tularensis strains remains of primary importance for detection of the emergence of antibiotic resistances to first-line drugs, and to test new therapeutic alternatives. However, the AST methods reported in the literature were poorly standardized between studies and AST data have not been previously evaluated in a comprehensive and comparative way. The aim of the present review was to summarize experimental data on antibiotic susceptibilities of F. tularensis obtained in acellular media, cell models and animal models since the introduction of fluoroquinolones in the treatment of tularaemia in 1989. We compiled MIC data of 33 antibiotics (including aminoglycosides, fluoroquinolones, tetracyclines, macrolides, beta-lactams, chloramphenicol, rifampicin, and linezolid) against 900 F. tularensis strains (504 human strains), including 107 subsp. tularensis (type A), 789 subsp. holarctica (type B) and four subsp. mediasiatica strains, using various AST methods. Specific culture media were identified or confirmed as unsuitable for AST of F. tularensis. Overall, MICs were the lowest for ciprofloxacin (<= 0.002- 0.125mg/L) and levofloxacin, and ranged from <= 0.016 to 2 mg/L for gentamicin, and 0.064 to 4 mg/L for doxycycline. No resistant strain to any of these antibioticswas reported. Fluoroquinolones also exhibited a bactericidal activity against intracellular F. tularensis and lower relapse rates in animal models when compared with the bacteriostatic compound doxycycline. As expected, lower MIC values were found for macrolides against type A and biovar I type B strains, compared to biovar II type B strains. The macrolides were more effective against F. tularensis grown in phagocytic cells than in acellular media.