Pharmacokinetics/pharmacodynamics of macrolides

  • Holly M. Mattoes
  • Charles H. Nightingale
Part of the Milestones in Drug Therapy MDT book series (MDT)


The macrolides are a class of antibiotics used to treat many different infections, and, in light of their excellent intracellular activity, they are especially important in the treatment of respiratory tract infections [1]. The pharmacokinetics and pharmacodynamics of macrolides differ dramatically from other antimicrobial agents [2]. Pharmacokinetics deals with the action of the drug in the body over a period of time, encompassing issues of absorption, distribution, metabolism, and elimination. Pharmacodynamics of antimicrobials is the study of the concentration of drug to which the bacteria is exposed as a function of time indexed to serum measurements of the drug’s microbiological activity (minimum inhibitory concentration [MIC] or minimum bactericidal concentration [MBC]). The macrolide class began with erythromycin; however, its high side-effect profile, frequent dosing, and drug interactions make it a difficult drug to use clinically [1, 3, 4]. As a result, newer macrolides have been developed, and the newer macrolide/azalide drugs, azithromycin and clarithromycin, will be the focus of this chapter. Data on roxithromycin as well as the macrolides josamycin and spiramycin, which are more popular in Europe, also will be discussed.


Alveolar Macrophage Antimicrob Agent Minimum Bactericidal Concentration Macrolide Antibiotic Immediate Release 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gunasekara NS, Barman Balfour JA (1999) Management of community-acquired pneumonia:defining the role of azithromycin. Dis Manage Health Outcomes 5: 41–54CrossRefGoogle Scholar
  2. 2.
    Nightingale CH (1997) Pharmacokinetics and pharmacodynamics of newer macrolides. PediatrInfect Dis J 16: 438–443CrossRefGoogle Scholar
  3. 3.
    Ludden TM (1985) Pharmacokinetic interactions of the macrolide antibiotics. Clin Pharmaco-kinet 10: 63–79CrossRefGoogle Scholar
  4. 4.
    Perth P, Mazzei T, Mini E, Novelli A (1992) Pharmacokinetic drug interactions of macrolides.Clin Pharmacokinet 23: 106–131CrossRefGoogle Scholar
  5. 5.
    Quintiliani R, Nightingale CH, Freeman CD (1994) Pharmacokinetic and pharmacodynamic considerations in antibiotic selection, with particular attention to oral cephalosporins. Infect Dis Clin Pract 3: 1–7CrossRefGoogle Scholar
  6. 6.
    Bauernfeind A, Jungwirth R, Eberlein E (1995) Comparative pharmacodynamics of clarithro-mycin and azithromycin against respiratory pathogens. Infection 23: 316–321PubMedCrossRefGoogle Scholar
  7. 7.
    Dunn CJ, Barradell LB (1996) Azithromycin: A review of its pharmacological properties and useas 3-day therapy in respiratory tract infections. Drugs 51: 483–505PubMedCrossRefGoogle Scholar
  8. 8.
    Owens RC, Nicolau DP, Quintiliani R, Nightingale CH (1997) Bactericidal activity of clari-thromycin, azithromycin and cefuroxime against penicillin-susceptible, Intermediate, and -resistant pneumococci. In: Abstracts of 20th International Congress of Chemotherapy (Sydney, Australia), June 29-July 3Google Scholar
  9. 9.
    Den Hollander JG, Knudsen JD, Mouton JW, Fuursted F, Frimodt-Moller N, Verbrugh HA, Espersen F (1998) Comparison of pharmacodynamics of azithromycin and erythromycin in vitro and in vivo. Antimicrob Agents Chemother 42: 377–382Google Scholar
  10. 10.
    Craig WA (1995) Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbial Infect Dis 22: 8996CrossRefGoogle Scholar
  11. 11.
    Vogelman B, Gudmundson G, Leggett J, Turnidge J, Ebert S, Craig WA (1998) Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in animal model. J Infect Dis 158: 831–847CrossRefGoogle Scholar
  12. 12.
    Mazzei T, Novelli A, Fallani S, Cassetta MI, Conti S. Bacterial killing by macrolides: concentration-dependent or time-dependent? In: Abstracts of 5th International Conference on the Macrolides, Azolides, Streptogramins, Ketolides and Oxazolidinones (Seville, Spain), January 26–28,2000Google Scholar
  13. 13.
    Bergman KL, Olsen KM, Peddicord TE, Fey PD, Rupp ME (1999) Antimicrobial activities and postantibiotic effects of clarithromycin, 14-hydroxy-clarithromycin, and azithromycin in epithelial cell lining fluid against clinical isolates of Haemophilus influenzae and Streptococcus pneumoniae. Antimicrob Agents Chemother 43: 1291–1293Google Scholar
  14. 14.
    Girard AE, Girard D, English AR, Gootz TD, Cimochowski CR, Faiella JA, Haskell SL, Retsema JA (1987) Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half life and excellent tissue distribution. Antimicrob Agents Chemother 31: 1948–1954PubMedCrossRefGoogle Scholar
  15. 15.
    Alder JD, Ewing RI, Nilius AM, Mitten M, Tovcimak A, Oleksijew A, Jarvis K, Paige L, Tanaka SKT (1998) Dynamics of clarithromycin and azithromycin efficacies against experimental Haemophilus influenzae pulmonary infection. Antimicrob Agents Chemother 42: 2385–2390PubMedGoogle Scholar
  16. 16.
    Kirst HA, Sides GD (1989) New directions for macrolide antibiotics: pharmacokintics and clinical efficacy. Antimicrob Agents Chemother 33: 1419–1422PubMedCrossRefGoogle Scholar
  17. 17.
    Cooper MA, Nye K, Andrews JM, Wise R (1990) The pharmacokinetics and inflammatory fluid penetration of orally administered azithromycin. J Antimicrob Chemother 26: 533–538PubMedCrossRefGoogle Scholar
  18. 18.
    Retsema JA, Girard AE, Girard D, Milisen WB (1990) Relationship of high tissue concentrations of azithromycin to bactericidal activity and efficacy in vivo. J Antimicrob Chemother 25: 83–89Google Scholar
  19. 19.
    Data on file. Pfizer Inc, New York, NY.Google Scholar
  20. 20.
    Patel KB, Xuan D, Tessier PR, Russomanno JH, Quintiliani R, Nightingale CH (1996) Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin. Antimicrob Agents Chemother 40: 2375–2379PubMedGoogle Scholar
  21. 21.
    Fish DN, Gotfried MH, Danziger LH, Rodvold KA (1994) Penetration of clarithromycin into lung tissues from patients undergoing lung resection. Antimicrob Agents Chemother 38: 876–878PubMedCrossRefGoogle Scholar
  22. 22.
    Rodvold KA, Gotfried MH, Danziger LH, Servi RJ (1997) Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers. Antimicrob Agents Chemother 41: 1399–1402PubMedGoogle Scholar
  23. 23.
    Gustayson LE, Cao GX, Semia SJ, Palmer RN. Pharmacokinetics of a new extended release clarithromycin tablet at doses of 500 and 1000 mg daily. In: Abstracts of 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco, California), September 26–29,1999Google Scholar
  24. 24.
    Shortridge D, Flamm RK. In vitro susceptibility testing of Streptococcus pneumoniae isolates from a Multi-Center European Clinical Treatment Trial: claritrohmycin modified release treatment of the acute exacerbation of chronic bronchitis. In: Abstracts of 21st International Congress of Chemotherapy (Birmingham, England), July 5–9,1999Google Scholar
  25. 25.
    Fraschini F, Scaglione F, Demartini G, Dugnani S. In vitro comparative dynamics of clarithromycin modified release and azithromycin. In: Abstracts of 21“ International ZZCongress of Chemotherapy (Birmingham, England), July 5–9,1999Google Scholar
  26. 26.
    Hutton J, Ryan J, Conway D. Cost-effectiveness of once-daily clarithromycin compared to amoxycillin/clavulanic acid in the treatment of acute exacerbation of chronic bronchitis. In: Abstracts of 21“ International Congress of Chemotherapy (Birmingham, England), July 5–9,1999Google Scholar
  27. 27.
    Adam D. Short-course therapy of lower respiratory tract infection with a 500mg total daily dosage of clarithromycin: once daily vs. twice daily administration. In: Abstracts of 2P International Congress of Chemotherapy (Birmingham, England), July 5–9,1999Google Scholar
  28. 28.
    Markham A, Faulds D (1994) Azithromycin: an update. Drugs 48: 297–321PubMedCrossRefGoogle Scholar
  29. 29.
    Chastre J, Brun P, Fourtillan JB, Soler P, Basset G, Manuel C, Trouillet JL, Gibert C (1987) Pulmonary disposition of roxithromycin (RU 28965), a new macrolide antibiotic. Antimicrob Agents Chemother 31: 1312–1316PubMedCrossRefGoogle Scholar
  30. 30.
    Fraschini F, Scaglione F, Pintucci G, Maccarinelli G, Dugnani S, Demartini G (1991) The diffusion of clarithromycin and roxithromycin into nasal mucosa, tonsil and lung in humans. J Antimicrob Chemother 27(Suppl A): 61–65PubMedCrossRefGoogle Scholar
  31. 31.
    Panteix G, Harf R, de Montclos H, Verdier MF, Gaspar A, Leclercq M (1988) Josamycin pulmonary penetration determined by broncho-alveolar lavage in man. J Antimicrob Chemother 22: 917–921PubMedCrossRefGoogle Scholar
  32. 32.
    Frydman AM, Le Roux Y, Desnottes JF, Kaplan, Debbar F, Cournot A, Duchier J, Gaillot J (1998) Pharmacokinetics of spiramycin in man. J Antimicrob Chemother 22(Suppl B): 93–103Google Scholar
  33. 33.
    Bergogne-Berezin E (1988) Spiramycin concentrations in the human respiratory tract: a review. J Antimicrob Chemother 22(Suppl B): 117–122PubMedGoogle Scholar
  34. 34.
    Bonnet M, Van der Auwera P (1992) In vitro and in vivo intraleukocyte accumulation of azithromycin (CP-62,993) and its influence on ex vivo leukocyte chemiluminescence. Antimicrob Agents Chemother 36: 1302–1309PubMedCrossRefGoogle Scholar
  35. 35.
    Gladue RP, Bright GM, Isaacson RE, Newborg MF (1989) In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrob Agents Chemother 33: 277–282PubMedCrossRefGoogle Scholar
  36. 36.
    Harf R, Panteix G, Desnottes JF, Diallo N, Leclercq M (1988) Spiramycin uptake by alveolar macrophages. J Antimicrob Chemother 22(Suppl B): 135–140PubMedGoogle Scholar
  37. 37.
    Hardy DJ, Swanson RN, Rode RA, Marsh K, Shipkowitz NL, Clement JJ (1990) Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14- hydroxy-clarithromycin, its major metabolite in humans. Antimicrob Agents Chemother 34: 1407–1413PubMedCrossRefGoogle Scholar
  38. 38.
    Ishida K, Kaku M, Irifune K, Mizukane R, Takemura H, Yoshida R, Tanaka H, Usui T, Suyama N, Tomono K et al (1994) In vitro and in vivo activities of macrolides against Mycoplasma pneumoniae. Antimicrob Agents Chemother 38: 790–798CrossRefGoogle Scholar
  39. 39.
    Foulds G, Shepard RM, Johnson RB (1990) The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 25: 73–82PubMedCrossRefGoogle Scholar
  40. 40.
    Bauernfeind A, Jungwirth R, Eberlein E (1995) Comparative pharmacodynamics of clarithromycin and azithromycin against respiratory pathogens. Infection 23: 316–321PubMedCrossRefGoogle Scholar
  41. 41.
    Ednie LM, Visalli MA, Jacobs MR, Appelbaum PC (1996) Comparative activities of clarithromycin, erythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci. Antimicrob Agents Chemother 40: 1950–1952PubMedGoogle Scholar
  42. 42.
    Hammerschlag MR, Qumei KK, Roblin PM (1992) In vitro activities of azithromycin, clarithromycin, L-ofloxacin, and other antibiotics against Chlamydia pneumoniae. Antimicrob Agents Chemother 36: 1573–1574PubMedCrossRefGoogle Scholar
  43. 43.
    Alvarez-Elcoro S, Enzler MJ (1999) The macrolides: erythromycin, clarithromycin and azithromycin. Mayo Clin Proc 74: 613–634PubMedCrossRefGoogle Scholar
  44. 44.
    Mazzel TA, Surrenti C, Novelli A, Biagini MR, Fallani S, Cassetta MI, Conti S, Surrenti E (1999) Pharmacokinetics of dirithomycin in patients with mild or moderate cirrhosis. Antimicrob Agents Chemother 43: 1556–1559Google Scholar

Copyright information

© Springer Basel AG 2002

Authors and Affiliations

  • Holly M. Mattoes
    • 1
  • Charles H. Nightingale
    • 1
    • 2
  1. 1.Department of Pharmacy ResearchHartford Hospital, University of ConnecticutHartfordUSA
  2. 2.Office of Research AdministrationHartford Hospital, University of ConnecticutHartfordUSA

Personalised recommendations