Bioavailability and efficacy of levofloxacin against Francisella tularensis in the common marmoset (Callithrix jacchus).
Pharmacokinetic and efficacy studies with levofloxacin were performed in the common marmoset (Callithrix jacchus) model of inhalational tularemia. Plasma levofloxacin pharmacokinetics were determined in six animals in separate single-dose and multidose studies. Plasma drug concentrations were analyzed using liquid chromatography-tandem mass spectrometry-electrospray ionization. On day 7 of a twice-daily dosing regimen of 40 mg/kg, the levofloxacin half-life, maximum concentration, and area under the curve in marmoset plasma were 2.3 h, 20.9 microg/ml, and 81.4 microg/liter/h, respectively. An efficacy study was undertaken using eight treated and two untreated control animals. Marmosets were challenged with a mean of 1.5 x 10(2) CFU of Francisella tularensis by the airborne route. Treated animals were administered 16.5 mg/kg levofloxacin by mouth twice daily, based on the pharmacokinetic parameters, beginning 24 h after challenge. Control animals had a raised core body temperature by 57 h postchallenge and died from infection by day 5. All of the other animals survived, remained afebrile, and lacked overt clinical signs. No bacteria were recovered from the organs of these animals at postmortem after culling at day 24 postchallenge. In conclusion, postexposure prophylaxis with orally administered levofloxacin was efficacious against acute inhalational tularemia in the common marmoset. The marmoset appears to be an appropriate animal model for the evaluation of postexposure therapies.
Nelson
Michelle
M
Biomedical Sciences, Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom. mnelson@dstl.gov.uk
Lever
Mark S
MS
Dean
Rachel E
RE
Pearce
Peter C
PC
Stevens
Daniel J
DJ
Simpson
Andrew J H
AJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002144:Callithrix; D002853:Chromatography, Liquid; D004334:Drug Administration Schedule; D005260:Female; D005604:Francisella tularensis / Q000187:drug effects* / Q000472:pathogenicity*; D064704:Levofloxacin; D008297:Male; D015242:Ofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome; D014406:Tularemia / Q000188:drug therapy / Q000382:microbiology
D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D015242:Ofloxacin