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The role of moxifloxacin and levofloxacin pharmacokinetics (PK) in antimicrobial efficacy and in the selection of fluoroquinolone-resistant Streptococcus pneumoniae strains was investigated using the rabbit tissue cage abscess model. A rabbit tissue cage was created by insertion of sterile Wiffle balls in the dorsal cervical area. Animals orally received a range of moxifloxacin or levofloxacin doses that simulate human PK for 7 days 48 h after the Wiffle balls were inoculated with fluoroquinolone-sensitive S. pneumoniae ( Moxifloxacin has a greater bactericidal rate as determined by regression of log CFU versus time data. The AUC/MIC and peak/MIC ratios correlated with the efficacy of both drugs (P < 0.05). Resistance to either drug did not develop with any of the doses as assessed by a change in the MIC. In conclusion, data derived from this study show that moxifloxacin and levofloxacin exhibit rapid bactericidal activity against S. pneumoniae in vivo, and moxifloxacin exhibits enhanced bactericidal activity compared to levofloxacin, with AUC/MIC and peak/ MIC ratios correlated with antimicrobial efficacy for both drugs. The development of fluoroquinolone-resistant S. pneumoniae was not observed with either drug in this model.

Because patients with cystic fibrosis (CF) have pulmonary exacerbations secondary to multi-antibiotic-resistant Gram-negative bacilli, antibiotics, like meropenem, are often utilized. We studied the pharmacokinetics of meropenem (2 g i.v. administered every 8 h in clinically stable CF patients to determine if the recommended maximum doses could sustain adequate concentrations during the dosing interval. These pharmacokinetic data were similar to those obtained in non-CF populations. Using this regimen, concentrations of meropenem exceed the susceptibility breakpoint (4 µg/ml) for 50% of the dosing interval, and therefore provide optimization of the pharmacodynamic profile of the compound.

Recent in vitro and in vivo data have substantiated the beneficial effects of macrolides/ azalides for use against Pseudomonas aeruginosa. While macrolides/azalides are not very potent in vitro antimicrobial agents against this pathogen, they appear to have an adjunctive role by either altering the course of infection owing to their inhibition of biofilm production or modulation of the host anti-inflammatory response, or both. To determine the in vitro and in vivo effects of clarithromycin as adjunctive therapy with ceftazidime against a mucoidproducing strain of P. aeruginosa, we performed a standard time-kill experiment and a pneumonia model in mice, respectively. Time-kill studies were performed over a 24 h period with varying concentrations of clarithromycin and ceftazidime alone or in combination. Synergic activity was noted with the use of 0.5 x MIC of ceftazidime combined with either 0.5 or 2 x MIC of clarithromycin. Neutropenic mice were infected with 10(8) cfu of mucoid P. aeruginosa intranasally to produce pneumonia and subsequently treated with oral clarithromycin (100 mg/kg) and/or sc ceftazidime (1500 mg/kg) as monotherapy or in combination. The addition of 5 days of clarithromycin to the ceftazidime regimen significantly improved survival as compared with the beta-lactam alone (48% versus 32%, P = 0.04). While a statistically significant difference was not detected with the addition of 3 days of clarithromycin therapy, a trend towards improved survival was noted with this regimen (38% versus 32%). These data demonstrate the adjunctive potential of clarithromycin when administered in combination with an antipseudomonal agent for the treatment of mucoid-producing Pseudomonas in acute respiratory infection.

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