Therapy With Macrolides in Patients With Cystic Fibrosis

Allyson S. Gaylor, Pharm.D., Joan C. Reilly, Pharm.D.

Pharmacotherapy. 2002;22(2) 

In This Article

Macrolide Antibiotics

Erythromycin was the first drug of this class, discovered in 1952.[7] Its popularity increased in 1976 during an outbreak of pneumonia caused by Legionella pneumophila.[8] Although it was beneficial, its gastrointestinal side effect profile made it intolerable for many patients. Thus the search for better-tolerated macrolides began.

The term macrolide refers to the lactone ring structure to which different sugars are attached. Clarithromycin has a 14-member ring like erythromycin but contains a methylated hydroxyl group at position 6. Azithromycin is a 15-member ring that adds a methyl substituted nitrogen (Figure 1). Modification of the ring structure and attached sugars results in different pharmacokinetic and pharmacodynamic properties (Table 1).[9,10,11,12,13] These properties allow for once-daily dosing with azithromycin versus multiple daily doses of erythromycin and clarithromycin.

Structural formulas of erythromycin, clarithromycin, and azithromycin.

Major problems with drug interactions were overcome with structural modifications. Erythromycin and clarithromycin are both metabolized by the cytochrome P450 enzyme system and thus can inhibit the metabolism of other drugs significantly. The major route of elimination for azithromycin is biliary excretion of unchanged drug, thus causing reduced potential for significant drug interactions.[14] Structural modifications also resulted in different side effect profiles. Gastrointestinal side effects with erythromycin are thought to be due to its 14-member ring acting as a motilin receptor stimulant.[15] Clarithromycin and azithromycin appear to be better tolerated with regard to gastrointestinal effects.[16,17]

Postmarketing surveillance showed increases in liver enzymes in a small number of patients taking azithromycin and clarithromycin.[10,18] Rare cases of hearing impairment were reported with azithromycin.[10,19] These symptoms appear to be dose related, as most occurred in patients receiving high dosages of azithromycin for mycobacterial lung disease and were reversible.[20,21]

All macrolides readily cross cell membranes, a characteristic that allows for high intracellular concentrations. These high concentrations allow the drug to accompany phagocytic cells to the site of infection where the drug is slowly released. Clarithromycin is released from cells more rapidly than azithromycin. Slow release of azithromycin allows for continuous drug exposure, sustained tissue concentrations, and long half-life.[22] This is the reason macrolides have a much higher concentration at the site of infection than in serum.[8]

Concentrations of erythromycin in bronchial secretions, bronchial mucosa, and epithelial lining fluid were 0.82, 1.75, and 0.97 µg/ml, respectively, after administration of 250 mg 4 times/day, whereas serum concentrations were less than 2 µg/ml.[23] Tissue concentrations of clarithromycin and azithromycin are reported to be 2- to 6-fold and greater than 100-fold higher than serum concentrations, respectively.[9,10] Lung tissue concentrations of clarithromycin reached a peak of 17.47 mg/L with a peak serum concentration of 2.82 mg/L, whereas concentrations of azithromycin were 4 µg/ml and 0.012 µg/ml in lungs and serum, respectively.[10,24]

The bronchopulmonary kinetics of azithromycin and clarithromycin were compared in healthy volunteers.[25] Plasma and alveolar macrophage concentrations were higher for clarithromycin than for azithromycin, but the alveolar macrophage:plasma concentration ratio was significantly higher for azithromycin. Other studies showed that azithromycin continues to accumulate in alveolar macrophages and reaches a peak concentration in macrophages 120 hours after a single 500-mg dose; it can be detected more than 15 days after completing a 5-day course of therapy.[26,27] Accumulation in macrophages is important since it greatly increases the intracellular half-life and serves as a delivery vehicle to transport drug to sites of infection. Several studies reported higher drug concentrations at sites of infection than at noninfected sites.[28,29,30]

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