In vitro and in vivo influence of adjunct clarithromycin on the treatment of mucoid Pseudomonas aeruginosa

Recent in vitro and in vivo data have substantiated the beneficial effects of macrolides/azalides for use against Pseudomonas aeruginosa. While macrol ides/azalides are not very potent in vitro antimicrobial agents against thi s pathogen, they appear to have an adjunctive role by either altering the c ourse of infection owing to their inhibition of biofilm production or modul ation of the host anti-inflammatory response, or both. To determine the in vitro and in vivo effects of clarithromycin as adjunctive therapy with ceft azidime against a mucoid-producing 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 concentrat ions of clarithromycin and ceftazidime alone or in combination. Synergic ac tivity was noted with the use of 0.5 x MIC of ceftazidime combined with eit her 0.5 or 2 x MIC of clarithromycin. Neutropenic mice were infected with 1 0(8) cfu of mucoid P. aeruginosa intranasally to produce pneumonia and subs equently 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 c larithromycin to the ceftazidime regimen significantly improved survival as compared with the beta-lactam alone (48% versus 32%, P = 0.04). While a st atistically 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 antips eudomonal agent for the treatment of mucoid-producing Pseudomonas in acute respiratory infection.