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

Abstract

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.

In vitro activity of antibiotic combinations against Pseudomonas aeruginosa biofilm and planktonic cultures

“…The ideal approach to conditions found in CF patients would be the use of in vivo models as already described [44,45]. Using mouse models of P. aeruginosa respiratory infections, a synergistic activity was reported with a 5-day oral administration of clarithromycin (100 mg/kg/day) + ceftazidime (1500 mg/kg/day) [44] and a 7-day oral administration of clarithromycin (10 mg/kg/day) + levofloxacin (10 mg/kg/day) [45].…”

“…Using mouse models of P. aeruginosa respiratory infections, a synergistic activity was reported with a 5-day oral administration of clarithromycin (100 mg/kg/day) + ceftazidime (1500 mg/kg/day) [44] and a 7-day oral administration of clarithromycin (10 mg/kg/day) + levofloxacin (10 mg/kg/day) [45]. The two studies showed that co-administration of antibiotics in these cases allowed improvement of biofilm destruction compared with single drug administration.…”

Antimicrobials as Potential Adjunctive Agents in the Treatment of Biofilm Infection with <i>Staphylococcus epidermidis</i>

“…It would be important to detect the minimal concentration showing significant killing in biofilms. Recently, it was shown that increasing concentrations (32 or 128 Ìg/ml) of clarithromycin had a synergistic or additive effect in timekill experiments for mucoid-producing P. aeruginosa [29]. However, it would be less applicable to clinical management of patients if any antibiotic had good bactericidal activity only at much higher concentrations than clinically achievable concentrations.…”

Suppression of Pseudomonas aeruginosa quorum-sensing systems by macrolides: a promising strategy or an oriental mystery?

“…Gram-negative bacteria attach primarily by means of proteinaceous appendages known as fi mbriae and pili, with other antibiotics. [53][54][55] In regard to the direct killing activity of macrolides against P. aeruginosa, we have reported reduction of the viability of this organism when the bacteria were incubated with macrolides for prolonged times. 14 Exposure to azithromycin for 48 h or more significantly decreased the viability of P. aeruginosa PAO1 in a concentration-dependent manner, whereas no effect on viability was observed with 24 h or less incubation with macrolide.…”