No abstract

'8F-labeled fleroxacin was used to measure the pharmacokinetics of fieroxacin in healthy and infected animals by positron emission tomography (PET) and tissue radioactivity measurements. In all experiments, a pharmacological dose of unlabeled drug (10 mJkg) was coinjected with the tracer. The pharmacokinetics of [18FJfleroxacin was measured in groups of healthy mice (n = six per group) at 10, 30, 60, and 120 min after inijection and in groups of rats with Escherchia coli thigh infections (n = six per group) at 60 and 120 min after injection by radioactivity measurements in excised tissues. In healthy rabbits (n = 4) and in rabbits with E. coli thigh infections (n = 4), tissue concentrations of drug were determined by serial PET imaging over 2 h; after the final image was acquired, animals were sacrificed and concentrations measured by PET were compared with the results of tissue radioactivity measureinents. In all three species, there was rapid equilibration of[18F]fleroxacin to significant concentratiobs in most peripheral organs; low concentrations of drug were detected in the brain. Accumulations of radiolabeled drug in infected and healthy thigh muscles were similar. Peak concentrations of drug of more than three times the MIC for 90% of members of the family Enterobacteriaceae (>100-fold for most organisms) were achieved in all tissues except brain and remained above this level for more than 2 h. Especially high peak concentrations were achieved in the kidney (>75 ,ug/g), liver (>50 ,ug/g), blood (>25 ,g/g), and bone and lung (>10 Fg/g). Since the MICs for 90% of all Enterobacteriaceae are <2 ,ug/ml, fleroxacin should be particularly useful in treating gram-negative infections affecting these tissues. In contrast, the low concentration of drug delivered to the brain should limit the toxicity of the drug for the central nervous systens.

Positron emission tomography (PET) with [18Fjfleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with -20 mCi of[18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion.Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (>34), liver (>25), lung (>20), myocardium (>19), and spleen (>18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (>10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram ± standard error of the mean) of drug were as follows: brain, 0.

A hitherto undescribed Nocardia culture has been isolated from an Australian soil sample and found to produce novel polyether antibiotics X-14868A, X-14868B, X-14868C and X-14868D.

Ninety-two laboratories in the USA submitted isolates of Streptococcus pneumoniae to a single laboratory for susceptibility testing. Overall, 64% of 4489 isolates were susceptible to penicillin, 24% were intermediate and 13% were resistant to penicillin, although susceptibilities varied depending on geographical region. Macrolide/azalide resistance varied from 4 to 30%, with some regions having macrolide/azalide resistance higher than penicillin resistance. Children 12 years of age were significantly more likely to be infected with a penicillin-resistant pneumococcus than were adolescents or adults. Isolates from the respiratory tract were more likely to be penicillin resistant and >50% of pneumococci from the ear were resistant to penicillin. Almost 25% of penicillin-susceptible isolates had cefaclor MICs 2.0 mg/L and 15% of penicillin-susceptible isolates had loracarbef MICs 2.0 mg/L. These isolates would be erroneously reported as susceptible using NCCLS guidelines, and this finding may explain the lack of clinical response in patients treated with these antibiotics. The predicted plasma concentrations of all cephalosporins tested exceeded the geometric mean MIC for at least 40% of the dosing interval for penicillin-susceptible S. pneumoniae; for penicillin-intermediate S. pneumoniae, only cefprozil (56%), cefuroxime (64%) and cefpodoxime (63%) reached >40% of time above the geometric mean MIC in the dosing interval. None of the cephalosporins evaluated achieved a substantial time above the geometric mean MIC during its dosing interval for fully penicillin-resistant S. pneumoniae.