Pharmaceutical Research

, Volume 28, Issue 9, pp 2059–2071 | Cite as

Interdisciplinary Science and the Design of a Single-Dose Antibiotic Therapy

  • William Curatolo
Expert Review


Azithromycin is a unique antibiotic due to its serum half-life of 69 h. This half-life is long enough to permit administration of an entire course of therapy in a single dose, if the gastrointestinal (GI) side effects of such a high dose can be minimized. A series of exploratory clinical pharmacology studies were carried out to understand the site-specific absorption and toleration constraints involved in delivering a 2 g oral single-dose regimen. These studies demonstrated that (a) GI side effects were locally mediated in the GI tract, (b) the duodenum was more sensitive than the ileocecal region, and (c) colonic absorption was limited. A novel controlled release suspension dosage form was designed to meet these constraints, and was shown to deliver the desired systemic dose with acceptable toleration. This dosage form, Zmax®, is an oral powder-for-constitution which possesses two major features: (a) 200 μm controlled release microspheres which release the drug as they transit down the small intestine, and (b) alkalizing agents which raise the pH of the gastric milieu for ∼20 min to minimize gastric release of the drug (which has high solubility at low pH), in order to minimize exposure of the drug to the sensitive duodenal region. The ability to provide a high single dose of azithromycin results in “front-loading” the mononuclear and polymorphonuclear leukocytes which concentrate the drug and carry it to sites of infection. This provides high drug concentrations early on at infection sites, when the bacterial burden is greatest, potentially improving efficacy and potentially overcoming resistant bacterial strains. Finally, this revolutionary single dose formulation gives 100% compliance, which maximizes the likelihood of therapeutic success.


antibiotic compliance azithromycin controlled release leukocyte targeting microspheres single dose therapy 



The assembly of this review was facilitated by many stimulating discussions with the authors of many of the publications quoted, in particular: Julian Lo, Timothy Hagen, Scott Herbig, Richard Korsmeyer, Steven LeMott, George Foulds, Ping Liu, Richa Chandra, David Luke, Hylar Friedman, Avinash Thombre, Michael Dunne, and Jeanne Breen of Pfizer; and Leah Appel, Joshua Shockey, David Lyon, Dwayne Friesen, Scott McCray, Rod Ray, and Marshall Crew of Bend Research Inc. I am indebted to Dwayne Friesen, Scott McCray, George Foulds, and Richard Korsmeyer for a critical reading of this review.


  1. 1.
    Retsema J, Girard A, Schelkly W, Manousos M, Anderson M, Bright G, et al. Spectrum and mode of action of azithromycin (CP-62, 993), a new 15-membered-ring macrolide with improved potency against Gram-negative organisms. Antimicrob Agents Chemother. 1987;31:1939–47.PubMedGoogle Scholar
  2. 2.
    Neu H. Clinical microbiology of azithromycin. Am J Med. 1991;91(Suppl 3A):12S–8S.PubMedCrossRefGoogle Scholar
  3. 3.
    Gardner M, Ronfeld R. Interpretation and characterization of the pharmacokinetics of azithromycin in man. In “Program and Abstracts of the Eighth Mediterranean Congress of Chemotherapy 1992”; Athens, Greece; Abstract 407, p. 302.Google Scholar
  4. 4.
    Luke D, Foulds G, Cohen S, Levy B. Safety, toleration, and pharmacokinetics of intravenous azithromycin. Antimicrob Agents Chemother. 1996;40:2577–81.PubMedGoogle Scholar
  5. 5.
    Foulds G, Shepard R, Johnson R. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother. 1990;25(Suppl A):73–82.PubMedGoogle Scholar
  6. 6.
    Gladue R, Bright G, Isaacson R, Newborg M. In vitro and in vivo uptake of azithromycin (CP-62, 993) by phagocytic cells: possible mechanism of delivery and release at site of infection. Antimicrob Agents Chemother. 1989;33:277–82.PubMedGoogle Scholar
  7. 7.
    Shentag J, Ballow C. Tissue-directed pharmacokinetics. Am J Med. 1991;91(Suppl 3A):5S–11S.CrossRefGoogle Scholar
  8. 8.
    McDonald P, Pruul H. Phagocytic uptake and transport of azithromycin. Eur J Clin Microbiol Infect Dis. 1991;10:828–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Girard A, Cimochowski C, Faiella J. Correlation of increased azithromycin concentrations with phagocyte infiltration into sites of localized infection. J Antimicrob Chemother. 1996;37(Suppl C):9–19.PubMedGoogle Scholar
  10. 10.
    Foulds G, Johnson R. Selection of dose regimens of azithromycin. J Antimicrob Chemother. 1993;31(Suppl E):39–50.PubMedGoogle Scholar
  11. 11.
    Curatolo W. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm Sci Tech Today. 1998;1:387–93.CrossRefGoogle Scholar
  12. 12.
    Hagen T, Lo JB, Thombre A, Herbig S, Appel L, Crew M, et al. Azithromycin dosage forms with reduced side effects. US Patent 6,984,403B2. European Patent EP-1537859B1. European Patent Application published 2005.Google Scholar
  13. 13.
    Yuhas L, Fuerst J, Timpano J, Fiese E. pKa values of CP-62,993, azithromycin, assigned using 1H-NMR spectroscopy. The AAPS Journal 2003;5(S1), Abstract 001468. Available from
  14. 14.
    Fiese EF, Steffen S. Comparison of the acid stability of azithromycin and erythromycin A. J Antimicrob Chemother. 1990;25(Suppl A):39–47.PubMedGoogle Scholar
  15. 15.
    Foulds G, Curatolo W. Unpublished.Google Scholar
  16. 16.
    Foulds G, Connolly A, Fortner J, Fletcher A. Separation of presystemic and post-absorptive influences on the bioavailability of azithromycin in cynomolgous monkeys. In: Zinner SH, editor. Expanding Indications for the new Macrolides, Azalides, and Spectrogramins. New York: Marcel Dekker Inc; 1997. p. 460–3.Google Scholar
  17. 17.
    Foulds G, Shepard R, Allen R, Ferraina R, Fletcher A. Transintestinal elimination of azithromycin in dogs. 5th European Congress of Clinical Microbiology and Infectious Diseases, Oslo, Norway. Sept. 9–11, 1991; Abstract 220.Google Scholar
  18. 18.
    Sugie M, Asakura E, Zhao Y, Torita S, Nadai M, Baba K, et al. Possible involvement of the drug transporters P glycoprotein and multidrug resistance-associated protein Mrp2 in disposition of azithromycin. Antimicrob Agents Chemother. 2004;48:809–14.PubMedCrossRefGoogle Scholar
  19. 19.
    Bennett J, Horspool K. Unpublished, personal communication.Google Scholar
  20. 20.
    Amsden G, Nafziger A, Foulds G, Cabelus L. A study of the pharmacokinetics of azithromycin and nelfinavir when coadministered in healthy volunteers. J Clin Pharmacol. 2000;40:1522–7.PubMedGoogle Scholar
  21. 21.
    Luke D, Foulds G. Disposition of oral azithromycin in humans. Clin Pharmacol Ther. 1997;61:641–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Garey K, Peloquin C, Godo P, Nafziger A, Amsden G. Lack of effect of zafirlukast on the pharmacokinetics of azithromycin, clarithromycin, and 14-hydroxyclarithromycin in healthy volunteers. Antimicrob Agents Chemother. 1999;43:1152–5.PubMedGoogle Scholar
  23. 23.
    Hopkins S. Clinical toleration and safety of azithromycin. Amer J Med. 1991;91(suppl 3A):40S–5S.PubMedCrossRefGoogle Scholar
  24. 24.
    Foulds G, Luke DR, Willavize SA, Curatolo W, Friedman H, Gardner MJ, et al. Effect of food and formulation on bioavailability of azithromycin. In: Zinner SH, editor. Expanding indications for the New Macrolides, Azalides, and Spectrogramins. New York: Marcel Dekker Inc; 1997. p. 469–73.Google Scholar
  25. 25.
    Curatolo W, Foulds G, Friedman H. Method of dosing azithromycin. U.S. Patent 5,605,899. European Patent EP-0679400B1. European Patent Application published 1995.Google Scholar
  26. 26.
    Foulds G, Luke DR, Teng R, Willavize SA, Friedman H, Curatolo W. The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension. J Antimicrob Chemother. 1996;37(Suppl C):37–44.PubMedGoogle Scholar
  27. 27.
    Curatolo W, Foulds G, LaBadie R. Mechanistic study of the azithromycin dosage form-dependent food effect. Pharm Res. 2010;27:1361–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Curatolo W, Liu P, Johnson BA, Hausberger A, Quan E, Vendola T, et al. Effects of food on a gastrically-degraded drug: Azithromycin fast-dissolving gelatin capsules and HPMC capsules. Pharm. Res. doi: 10.1007/s11095-011-0386-9.
  29. 29.
    Curatolo W, Friedman H, Korsmeyer R, LeMott S. Controlled-release dosage forms of azithromycin. US Patent 6,068,859. European Patent EP-0758244B1. European Patent Application published 1997.Google Scholar
  30. 30.
    Curatolo W, Luke D, Foulds G, Friedman H. Site-specific absorption and toleration of azithromycin. Proc. Intl. Symp. Control. Rel. Bioactive Material 1996;23:57–58.Google Scholar
  31. 31.
    Luke D, Foulds G, Friedman H, Curatolo W, Scavone J. Clinical pharmacology of azithromycin given at various sites along the gastrointestinal tract in healthy subjects. In: Zinner SH, editor. Expanding indications for the New Macrolides, Azalides, and Streptogramins. New York: Marcel Dekker; 1997. p. 464–8.Google Scholar
  32. 32.
    Sutton S, Evans L, Fortner J, McCarthy J, Sweeney K. Dog colonoscopy model for predicting human colon absorption. Pharm Res. 2006;23:1554–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Luke D, Foulds G, Going P, Melnik G, Lawrence V. Rectal azithromycin in healthy subjects. In: Zinner SH, editor. Expanding indications for the New Macrolides, Azalides, and Streptogramins. New York: Marcel Dekker; 1997. p. 474–7.Google Scholar
  34. 34.
    Physicians’ Desk Reference, 56th Edition. Zithromax®. Medical Economics, Montvale, NJ, USA, publ. 2002; p.2739.Google Scholar
  35. 35.
    Lo JB, Appel L, Herbig S, McCray S, Thombre A. Formulation design and pharmaceutical development of a novel controlled release form of azithromycin for single-dose therapy. Drug Dev Ind Pharm. 2009;35:1522–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Appel L, Ray R, Newbold D, Friesen D, McCray S, West JB, et al. Azithromycin multiparticulate dosage forms by melt-congeal processes. US Patent Application 2005/0158391A1; published 2005.Google Scholar
  37. 37.
    Appel L, Ray R, Lyon D, West JB, McCray S, Crew M, et al. Multiparticulate crystalline drug compositions having controlled release profiles. US Patent Application 2005/0181062A1; published 2005.Google Scholar
  38. 38.
    Appel L, Crew M, Friesen D, Ray R. Method for making pharmaceutical microspheres. European Patent EP-1,691,787B1; published 2006.Google Scholar
  39. 39.
    Ray R, Appel L, Friesen D, Crew M, Newbold M. Controlled release dosage forms of azithromycin. US Patent Application 2005/0123615A1; published 2005.Google Scholar
  40. 40.
    Hunt J, MacDonald I. The influence of volume on gastric emptying. J Physiol. 1954;126:459–74.PubMedGoogle Scholar
  41. 41.
    Chandra R, Liu P, Breen J, Fisher J, Xie C, LaBadie R, et al. Clinical pharmacokinetics and gastrointestinal tolerability of a novel extended-release microsphere formulation of azithromycin. Clin Pharmacokinet. 2007;46:247–59.PubMedCrossRefGoogle Scholar
  42. 42.
    D’Ignazio J, Camere M, Lewis D, Jorgenson D, Breen J. Novel, single-dose microsphere formulation of azithromycin versus 7-day levofloxacin therapy for treatment of mild to moderate community-acquired pneumonia in adults. Antimicrob Agents Chemother. 2005;49:4035–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Drehobl M, De Salvo M, Lewis D, Breen J. Single-dose azithromycin microspheres vs clarithromycin extended release for the treatment of community-acquired pneumonia in adults. Chest. 2005;128:2230–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Zervos M, Breen J, Jorgenson D, Goodrich J. Novel, single-dose microsphere formulation of azithromycin versus levofloxacin for the treatment of acute exacerbation of chronic bronchitis. Infect Dis Clin Pract. 2005;13:115–21.CrossRefGoogle Scholar
  45. 45.
    Blasi F, Aliberti S, Tarsia P. Clinical applications of azithromycin microspheres in respiratory tract infections. Intl J Nanomed. 2007;2:551–9.Google Scholar
  46. 46.
    Harrison T, Keam S. Azithromycin extended release. A review of its use in the treatment of acute bacterial sinusitis and community-acquired pneumonia in the US. Drugs. 2007;67:773–92.CrossRefGoogle Scholar
  47. 47.
    Liu P, Allaudeen H, Chandra R, Phillips K, Jungnik A, Breen J, et al. Comparative pharmacokinetics of azithromycin in serum and white blood cells of healthy subjects receiving a single-dose extended-release regimen versus a 3-day immediate-release regimen. Antimicrob Agents Chemother. 2007;51:103–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Girard D, Finegan S, Dunne M, Lame M. Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models. J Antimicrob Chemother. 2005;56:365–71.PubMedCrossRefGoogle Scholar
  49. 49.
    Blumer J. Evolution of a new drug formulation: the rationale for high-dose, short-course therapy with azithromycin. Intl J Antimicrob Agents. 2005;26 Suppl 3:S143–7.CrossRefGoogle Scholar
  50. 50.
    Greenberg R. Overview of patient compliance with medical dosing: a literature review. Clin Ther. 1984;6:592–9.PubMedGoogle Scholar
  51. 51.
    Bond W, Hussar D. Detection methods and strategies for improving medication compliance. Amer J Hosp Pharm. 1991;48:1978–88.Google Scholar
  52. 52.
    Sclar D, Tartaglione T, Fine M. Overview of issues related to medical compliance with implications for the outpatient management of infectious diseases. Infect Agents Dis. 1994;3:266–73.PubMedGoogle Scholar
  53. 53.
    Bergman A, Werner R. Failure of children to receive penicillin by mouth. New EnglJMed. 1963;268:1334–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Sutton S. The use of gastrointestinal intubation studies for controlled release development. Br J Clin Pharmacol. 2009;68:342–54.PubMedCrossRefGoogle Scholar
  55. 55.
    Nellans H, Peterson A, Peeters T. Gastrointestinal side effects: clarithromycin superior to azithromycin in reduced smooth muscle contraction and binding. Abstracts of the 1991 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); Abstract 518; pg.185.Google Scholar
  56. 56.
    Bortolotti M, Annese V, Mari C, Lopilato C, Porrazzo G, Miglioli M. Dose-related stimulatory effect of clarithromycin on interdigestive gastroduodenal motility. Digestion. 2000;62:31–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Weber F, Richards R, McCallum R. Erythromycin: a motilin agonist and gastrointestinal prokinetic agent. Amer J Gastroenterol. 1993;88:485–90.Google Scholar
  58. 58.
    Feighner S, Tan C, McKee K, Palyha O, Hreniuk D, Pong S-S, et al. Receptor for motilin identified in the human gastrointestinal system. Science. 1999;284:2184–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Takeshita E, Matsuura B, Dong M, Miller L, Matsui H, Onji M. Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J Gastroenterol. 2006;41:223–30.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.The Bayberry InstituteNianticUSA

Personalised recommendations