Dynamics of Clarithromycin and Azithromycin Efficacies against ExperimentalHaemophilus influenzaePulmonary Infection

Abstract

The dynamics of clarithromycin and azithromycin efficacy against pulmonary Haemophilus influenzae infection in rats were evaluated. Efficacy was measured by reduction in pulmonary H. influenzae burden on days 3 and 7 postinoculation. Clarithromycin therapy was effective on day 3 or 7 of therapy, while azithromycin was effective on day 7 but not on day 3 of therapy. Both macrolides produced marked efficacy against all six strains of H. influenzae tested, including four strains for which MICs were above the susceptible breakpoint (8 μg/ml) concentration of clarithromycin. The two macrolides demonstrated markedly different pharmacokinetic characteristics, with clarithromycin present in both blood and tissue, while azithromycin was concentrated primarily in tissue. During pulmonary infection in rats, H. influenzaewas found in both intracellular locations and an extracellular location in the lung. Blood concentrations of clarithromycin and azithromycin approximated human pharmacokinetics, and the blood concentrations for either macrolide rarely exceeded MICs for H. influenzae. At dosages producing blood concentrations similar to values achieved clinically, clarithromycin produced efficacy on day 3 of therapy, while both clarithromycin and azithromycin were equally effective on day 7. The different dynamics of clarithromycin and azithromycin suggest that length of therapy should be considered as a key parameter in evaluations of drug efficacy.

Exploring the role of antibiotics and steroids in managing respiratory diseases

“…Both antibiotics were equally effective against pulmonary infection caused by Haemophilus influenzae . [ 162 ] The efficacy of macrolides in treating Haemophilus influenzae airway infection was further assessed by Rutman et al [ 163 ] They reported that newer macrolides like dirithromycin possessed cytoprotective effect. Use of dirithromycin at concentrations of 0.125–1.0 μg/ml significantly reduced mucosal injury caused by Haemophilus influenzae .…”

Pharmacokinetics/pharmacodynamics of macrolides

“…The pharmacokinetic profiles of these newer drugs differ in many aspects from each other, as well as from erythromycin, however, both are excellent at reaching high concentrations intracellularly. Azithromycin is unique because of 1) its long serum half-life, enabling it to function effectively in oncedaily dosing, and 2) its extensive tissue distribution, reaching high concentrations in alveolar macrophages while low levels remain in the plasma [13][14][15]. Table 1 provides a summary of the pharmacokinetics of several macrolides.…”

“…Contrary to azithromycin, clarithromycin has high concentrations in the ELF of the lungs and plasma, as well as in alveolar macrophages (AM) [15,20]. Clarithromycin has greater acid stability, improved pharmacokinetics, better gastrointenstinal tolerance, and a broader spectrum of activity than erythromycin [13,14].…”

“…It is important to keep in mind, however, that although poor serum concentrations are observed, the high tissue penetration is the more important predictor of success for macrolides in treating infections at sites where the serum is not in equilibrium with the intracellular fluid. Efficacy was measured against H. injluenzae in one study by examining the reduction of pulmonary H. injluenzae burden on days 3 and 7 postinoculation [15]. Azithromycin was effective in reducing colony counts on day 7, although no effect was seen on day 3.…”

“…The quicker efficacy rate of clarithromycin, seen by day 3, is probably due to the drug's ability to concentrate in both intracellular and extracellular locations of the lung, thus ensuring a rapid response to H. inJluenzae in all pulmonary locations. Also, the extracellular concentration of azithromycin is usually low, accounting for the delayed response observed due to a potential need for the drug to diffuse out of the cell and into the extracellular locations [15].…”