Objective: To measure azithromycin (AZM) concentrations in serum and bronchial secretions in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa pulmonary infection.
Patients and Methods: 10 CF patients (four male, six female; mean age 29 ± 10 years) with chronic P. aeruginosa pulmonary infection were randomised to receive either 500 or 1000mg of AZM (five patients per group) orally once daily for 5 days. Concentrations of AZM in serum and bronchial secretions (obtained after physiotherapy) were evaluated every 24 hours for the 5 days of administration and the following 6 days.
Main Outcome Measures and Results: High AZM concentrations were found in bronchial secretions, persisting after drug administration had ended. Mean concentrations were ≥4 mg/L for the 1000 mg/day dose from day 2 to 11 and >2 mg/L for the 500 mg/day dose from day 2 to day 10. Serum AZM concentrations were much lower (<0.4 mg/L for the 1000 mg/day, and <0.2 mg/L for the 500 mg/day, dosage).
Conclusions: These data appear to indicate the possibility of obtaining in vivo AZM concentrations previously shown to inhibit production of virulence factors in P. aeruginosa in vitro. We consider that clinical trials evaluating prolonged administration of AZM to CF patients would be both useful and justifiable.
Cystic Fibrosis Azithromycin Macrolides Cystic Fibrosis Patient Epithelial Line Fluid
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The authors thank Ms Lesley Cook for revising the English text.
Hoiby N. Cystic fibrosis and endobronchial pseudomonas infection. Curr Opin Pediatr 1993; 5: 247–54PubMedGoogle Scholar
Kobayashi H. Biofilm disease: its clinical manifestation and therapeutic possibilities of macrolides. Am J Med 1995; 99Suppl. 6A: 26s–30s.PubMedCrossRefGoogle Scholar
Periti P, Mazzei T, Mini E, et al. Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part I). Clin Pharmacokinet 1989; 16(2): 193–214PubMedCrossRefGoogle Scholar
Periti P, Mazzei T, Mini E, et al. Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part II). Clin Pharmacokinet 1989; 16(3): 261–82PubMedCrossRefGoogle Scholar
Tateda K, Ishii Y, Matsumoto T, et al. Direct evidence for anti-pseudomonal activity of macrolides: exposure-dependent bactericidal activity and inhibition of protein synthesis by erythromycin, clarithromycin, and azithromycin. Antimicrob Agents Chemother 1996; 40: 2271–5PubMedGoogle Scholar
Olsen KM, San Pedro GS, Gann LP, et al. Intrapulmonary pharmacokinetics of azithromycin in healthy volunteers given five oral doses. Antimicrob Agents Chemother 1996; 40(11): 2582–5PubMedGoogle Scholar
Koizumi F, Ohnishi A, Takemura H, et al. Effective monitoring of concentrations of ofloxacin in saliva of patients with chronic respiratory tract infections. Antimicrob Agents Chemother 1994; 38(5): 1140–3PubMedCrossRefGoogle Scholar
Shepard RM, Duthu GS, Ferraina RA, et al. High-performance liquid Chromatographic assay with electrochemical detection for azithromycin in serum and tissues. J Chromatogr 1991; 565(1-2): 321–7PubMedCrossRefGoogle Scholar
Karnes TH, March C. Precision, accuracy and data acceptance criteria biopharmaceutical analysis. Pharm Res 1993; 10: 1420–6PubMedCrossRefGoogle Scholar
Braggio S, Barnaby RJ, Grossi P, et al. A strategy for validation of bioanalytical methods. J Pharm Biomed Anal 1996; 14: 375–88PubMedCrossRefGoogle Scholar
Mazzei T, Surrenti C, Novelli A, et al. Pharmacokinetics of azithromycin in patients with impaired hepatic function. J Antimicrob Chemother 1993; 31Suppl. E: 57–63PubMedCrossRefGoogle Scholar
Molinari G, Paglia P, Schito GC. Inhibition of motility of Pseudomonas aeruginosa and Proteus mirabilis by sub-inhibitory concentrations of azithromycin. Eur J Clin Microbiol Infect Dis 1992; 11: 469–71PubMedCrossRefGoogle Scholar
Molinari G, Guzman CA, Pesce A, et al. Inhibition of Pseudomonas aeruginosa virulence factors by subinhibitory concentrations of azithromycin and other macrolide antibiotics. J Antimicrob Chemother 1993; 31: 681–8PubMedCrossRefGoogle Scholar
Sakata K, Yajima H, Tanaka K, et al. Erythromycin inhibits the production of elastase by Pseudomonas aeruginosa without affecting its proliferation in vitro. Am Rev Respir Dis 1993; 148: 1061–5PubMedCrossRefGoogle Scholar
Mizukane R, Hirakata Y, Kaku M, et al. Comparative in vitro exoenzyme-suppressing activities of azithromycin and other macrolide antibiotics against Pseudomonas aeruginosa. Antimicrob Agents Chemother 1994; 38: 528–33PubMedCrossRefGoogle Scholar
Tanaka E, Kanthakumar K, Cundell DR, et al. The effect of erythromycin on Pseudomonas aeruginosa and neutrophil mediated epithelial damage. J Antimicrob Chemother 1994; 33: 765–5PubMedCrossRefGoogle Scholar
Nicolau DP, Banevicius MA, Nightingale CH, et al. Beneficial effect of adjunctive azithromycin in treatment of mucoid Pseudomonas aeruginosa pneumonia in the murine model. Antimicrob Agents Chemother 1999; 43: 3033–5PubMedGoogle Scholar
Bui KQ, Banevicius MA, Nightingale CH, et al. In vitro and in vivo influence of adjunct clarithromycin on the treatment of mucoid Pseudomonas aeruginosa. J Antimicrob Chemother 2000; 45: 57–62PubMedCrossRefGoogle Scholar
Kudoh S, Azuma A, Yamamoto M, et al. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med 1998; 157: 1829–32PubMedGoogle Scholar
Jaffe’ A, Francis J, Rosenthal M, et al. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998; 351: 420CrossRefGoogle Scholar
Schentag JJ, Ballow CH. Tissue-directed pharmacokinetics. Am J Med 1991; 12(91) Suppl. 3A: 5S–11SCrossRefGoogle Scholar
Freeman CD, Nightingale CH, Nicolau DP, et al. Intracellular and extracellular penetration of azithromycin into inflammatory and noninflammatory blister fluid. Antimicrob Agents Chemother 1994; 38: 2449–51PubMedCrossRefGoogle Scholar
Wise R. The pharmacokinetics of azithromycin. Rev Contemp Pharmacotherap 1994; 5: 329–40Google Scholar
Neumann M. Vademecum degli antibiotici ed agenti chemoterapici antiinfettivi, 5th ed. Sigma-Tau, Salerno 1994; 315–6Google Scholar
Doring G. Polymorphonuclear leukocyte elastase: its effect on the pathogenesis of Pseudomonas aeruginosa infection. In Hoiby N, Pedersen SS, Shand GH, et al., editors. Pseudomonas aeruginosa infection. Antibiotic Chemotherapy. Karger, Basel 1989: 169–76Google Scholar
Baldwin DR, Honeybourne D, Wise R. Pulmonary disposition of antimicrobial agents: methodological considerations. Antimicrob Agents Chemother 1992; 36(6): 1171–5PubMedCrossRefGoogle Scholar
Baldwin DR, Wise R, Andrews JM, et al. Azithromycin concentrations at the sites of pulmonary infection. Eur Resp J 1990; 3(8): 886–90Google Scholar
Retsema JA, Bergeron JM, Girard D, et al. Preferential concentration of azithromycin in an infected mouse thigh model. J Antimicrob Chemother 1993; 31Suppl. E: 5–16PubMedCrossRefGoogle Scholar