Evaluation of moxifloxacin, a new 8-methoxyquinolone, for treatment of meningitis caused by a penicillin-resistant pneumococcus in rabbits

Abstract

Moxifloxacin is a new 8-methoxyquinolone with high activity against gram-positive bacteria, including penicillin-resistant pneumococci. In an experimental meningitis model, we studied the pharmacokinetics of moxifloxacin in infected and uninfected rabbits and evaluated the antibiotic efficacies of moxifloxacin, ceftriaxone, and vancomycin against a penicillin-resistant Streptococcus pneumoniae strain (penicillin, ceftriaxone, vancomycin, and moxifloxacin MICs were 1, 0.5, 0.5, and 0.125 microgram/ml, respectively). Moxifloxacin entered cerebrospinal fluid (CSF) readily, with peak values within 15 to 30 min after bolus intravenous infusion and with a mean percent penetration into normal and purulent CSF of approximately 50 and 80%, respectively. The bactericidal effect of moxifloxacin was concentration dependent, and regrowth was seen only when the concentration of moxifloxacin in CSF was below the minimal bactericidal concentration. All antibiotic-treated groups (moxifloxacin given in two doses of 40 mg/kg of body weight, moxifloxacin in two 20-mg/kg doses, ceftriaxone in one 125-mg/kg dose, and vancomycin in two 20-mg/kg doses) had significantly higher reductions in CSF bacterial concentration than the untreated group (P < 0.05). Moxifloxacin was as effective as vancomycin and ceftriaxone in reducing bacterial counts at all time points tested (3, 5, 10, and 24 h). Moreover, moxifloxacin given in two 40-mg/kg doses resulted in a significantly higher reduction in CSF bacterial concentration (in log10 CFU per milliliter) than vancomycin within 3 h after the start of antibiotic treatment (3.49 [2.94 to 4.78] versus 2.50 [0.30 to 3.05]; P < 0.05). These results indicate that moxifloxacin could be useful in the treatment of meningitis, including penicillin-resistant pneumococcal meningitis.

FIG. 1

In vitro time-kill curves with a penicillin-resistant S. pneumoniae strain. Antibiotic concentrations are shown as multiples of the MIC for the strain. The lower limit of detection of bacteria was 1.7 log₁₀ CFU/ml.

FIG. 2

Median concentrations of bacteria in CSF and mean concentrations of antibiotics in CSF after the start of antibiotic therapy for experimental meningitis caused by a penicillin-resistant S. pneumoniae strain. Antibiotics were given as intravenous bolus infusions. The following differences were significant (P < 0.05): two 40-mg/kg doses of moxifloxacin versus vancomycin at 3 h; two 40-mg/kg doses of moxifloxacin versus two 20-mg/kg doses of moxifloxacin at 3, 5, and 10 h; all antibiotic groups versus the untreated control group. The lower limit of detection of bacteria was 1.7 log₁₀ CFU/ml.

FIG. 3

Median concentration of bacteria and mean concentration of moxifloxacin in CSF in a model of experimental meningitis (n = 3) caused by a penicillin-susceptible S. pneumoniae strain. The lower limit of detection of bacteria was 1.7 log₁₀ CFU/ml.