Skip to main content
Log in

Implications on Emergence of Antimicrobial Resistance as a Critical Aspect in the Design of Oral Sustained Release Delivery Systems of Antimicrobials

  • Short Communication
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To assess the effects of the unabsorbed fraction of an orally administered antimicrobial drug which enters the colon on the emergence of resistance among the natural microflora, a phenomenon largely overlooked so far despite its clinical importance, especially when sustained release formulations are used.

Methods

Effects of an orally administered model β-lactam antibiotic (amoxicillin) on emergence of resistant bacteria were assessed using a microbiological assay for qualitative and quantitative determination of resistant bacteria in fecal samples of rats following gastric administration of the drug to rats for 4 consecutive days. Time- and site-controlled administration of a β-lactamase to the rat colon was assessed as a potential strategy for prevention the emergence of resistant bacteria following oral administration of incompletely absorbed antimicrobials.

Results

Emergence of resistant bacteria was demonstrated following oral administration of amoxicillin to rats, whereas de-activation of the β-lactam prior to entering the colon, by infusion of a β-lactamase into the lower ileum, was shown to prevent the emergence of resistant colonic bacteria.

Conclusions

This study illustrates the need to consider the emergence of antimicrobial resistance as a goal equally important to microbiological and clinical cure, when designing oral sustained-release delivery systems of antimicrobial drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Abbreviations

ARB:

Ampicillin-resistant bacteria

References

  1. A. Hoffman. Pharmacodynamic aspects of sustained-release formulations. Adv. Drug Deliv. Rev. 33:185–199 (1998).

    Article  PubMed  CAS  Google Scholar 

  2. A. Hoffman, and D. Stepensky. Pharmacodynamic aspects of modes of drug administration for optimization of drug therapy. Crit. Rev. Ther. Drug Carr. Syst. 16:571–639 (1999).

    CAS  Google Scholar 

  3. A. Nolting and H. Derendorf. Pharmacokinetic/pharmacodynamic modeling of antibiotics. In H. Derendorf, and G. Hochhaus (eds.), Handbook of Pharmacokinetic/Pharmacodynamic Correlation. CRC, Boca Raton, FL, 1995, pp. 363–388.

  4. C. W. Wester, L. Durairaj, A. T. Evans, D. N. Schwartz, S. Husain, and E. Martinez. Antibiotic resistance—a survey of physician perceptions. Arch. Intern. Med. 162(19):2210–2216 (2002).

    Article  PubMed  Google Scholar 

  5. R. Chandra, P. Liu, J. D. Breen, J. Fisher, C. Xie, R. LaBadie, R. J. Benner, L. J. Benincosa, and A. Sharma. Clinical pharmacokinetics and gastrointestinal tolerability of a novel extended-release microsphere formulation of azithromycin. Clin. Pharmacokinet. 46(3):247–259 (2007).

    Article  PubMed  CAS  Google Scholar 

  6. A. Hoffman, H. D. Danenberg, I. Katzhendler, R. Shuval, D. Gilhar, and M. Friedman. Pharmacodynamic and pharmacokinetic rationales for the development of an oral controlled-release amoxicillin dosage form. J. Control. Release 54:29–37 (1998).

    Article  PubMed  CAS  Google Scholar 

  7. W. H. Barr, E. M. Zola, E. L. Candler, S. M. Hwang, A. V. Tendolkar, R. Shamburek, B. Parker, and M. D. Hilty. Differential absorption of amoxicillin from the human small and large intestine. Clin. Pharmacol. Ther. 56(3):279–285 (1994).

    Article  PubMed  CAS  Google Scholar 

  8. D. Zarowny, R. Ogilvie, D. Tamblyn, C. MacLeod, and J. Ruedy. Pharmacokinetics of amoxicillin. Clin. Pharmacol. Ther. 16(6):1045–1051 (1974).

    PubMed  CAS  Google Scholar 

  9. X. Cao, S. T. Gibbs, L. Fang, H. A. Miller, C. P. Landowski, H. C. Shin, H. Lennernas, Y. Zhong, G. L. Amidon, L. X. Yu, and D. Sun. Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm. Res. 23(8):1675–1686 (2006).

    Article  PubMed  CAS  Google Scholar 

  10. J. Harmoinen, S. Mentula, M. Heikkila, M. Van der Rest, P. J. Rajala-Schultz, C. J. Donskey, R. Frias, P. Kosi, N. Wickstrand, H. Jousimies-Somer, E. Westermarck, and K. Lindevall. Orally administered targeted recombinant beta lactamase prevents ampicillin-induced selective pressure on the gut microbiotica: a novel approach to reducing antimicrobial resistance. Antimicrob. Agents Chemother. 48:75–79 (2004).

    Article  PubMed  CAS  Google Scholar 

  11. U. Stiefel, J. Harmoinen, P. Koski, S. Kaariainen, N. Wickstrand, K. Lindevall, N. J. Pultz, R. A. Bonomo, M. S. Helfand, and C. J. Donskey. Orally administered recombinant metallo-β-lactamase preserves colonization resistance of piperacillin-tazobactam-treated mice. Antimicrob. Agents Chemother. 46(12):5190–5191 (2005).

    Article  CAS  Google Scholar 

  12. E. Torok, T. Somogyi, K. Rutkai, L. Iglesias, and I. Bielsa. Fusidic acid suspension twice daily: a new treatment schedule for ski and soft tissue infection in children, with improved tolerability. J. Derm. Treat. 15(3):15–63 (2004).

    Google Scholar 

  13. E. Bergogne-Bérézin, and A. Bryskier. The suppository form of antibiotic administration: pharmacokinetics and clinical application. J. Antimicrob. Chemother. 43:177–185 (1999).

    Article  PubMed  Google Scholar 

  14. I. Tamai, T. Nakanishi, K. Hayashi, T. Terao, Y. Sai, T. Shiraga, K. Miyamoto, E. Takeda, H. Higashida, and A. Tsuji. The predominant contribution of oligopeptide transporter PepT1 to intestinal absorption of β-lactam antibiotics in the rat small intestine. J. Pharm. Pharmacol. 49:796–801 (1997).

    PubMed  CAS  Google Scholar 

  15. A. H. Dantzig. Oral absorption of β-lactams by intestinal peptide transport proteins. Adv. Drug Deliv. Rev. 23(1–3):63–76 (1997).

    Article  CAS  Google Scholar 

  16. V. H. Lee. Membrane transporters. Eur. J. Pharm. Sci. 11(suppl.2):S41–S50 (2000).

    Article  PubMed  CAS  Google Scholar 

  17. E. J. Vollaard, and H. A. L. Classener. Colonization resistance. Antimicrob. Agents Chemother. 38:409–414 (1994).

    PubMed  CAS  Google Scholar 

  18. T. D. Luckey. Introduction to intestinal microecology. Am. J. Clin. Nutr. 25:1292–294 (1972).

    PubMed  CAS  Google Scholar 

  19. C. E. Nord, L. Kager, and A. Heimdahl. Impact of antimicrobial agents on the microflora and the risk of infections. Am. J. Med. 76:99–106 (1984).

    Article  PubMed  CAS  Google Scholar 

  20. K. D. Hooker, and J. T. DiPiro. Effect of antimicrobial therapy on bowel flora. Clin. Pharm. 12:878–888 (1988).

    Google Scholar 

  21. C. E. Nord, and C. Edlund. Impact of antimicrobial agents on human intestinal microflora. J. Chemother. 2:218–237 (1990).

    PubMed  CAS  Google Scholar 

  22. C. Edlund and C. E. Nord. Effect on the human normal microflora of oral antibiotics for treatment of urinary tract infections. J. Antimicrob. Chemother. 46(suppl. S1):41–48 (2000).

    Article  CAS  Google Scholar 

  23. L. B. Rice. Antimicrobial resistance in gram-positive bacteria. Am. J. Infect. Control 34(5 Suppl.1):S11–S19 (2006).

    Article  PubMed  Google Scholar 

  24. R. Patel. Clinical impact of vancomycin-resistant Enterococci. J. Antimicrob. Chemother. 51(suppl.3):iii13–iii21 (2003).

    PubMed  CAS  Google Scholar 

  25. S. E. Cosgrove. The relationship between antimicrobial resistance and patient outcomes: mortality length of hospital stay and health care costs. Clin. Infect. Dis. 42(suppl.2):S82–S89 (2006).

    Article  PubMed  Google Scholar 

  26. C. M. Kaye, A. Allen, S. Perry, M. McDonagh, M. Davy, K. Storm, N. Bird, and O. Dewit. The clinical pharmacokinetics of a new pharmacokinetically enhanced formulation of amoxicillin/Clavulanate. Clin. Ther. 23(4):578–584 (2001).

    Article  PubMed  CAS  Google Scholar 

  27. S. Sethi, J. Bretton, and B. Wynne. Efficacy and safety of pharmacokinetically enhanced amoxicillin-clavulanate at 2,000/125 milligrams twice daily for 5 Days versus amoxicillin-clavulanate at 875/125 milligrams twice daily for 7 days in the treatment of acute exacerbations of chronic bronchitis. Antimicrob. Agents Chemother. 49:153–160 (2005).

    Article  PubMed  CAS  Google Scholar 

  28. W. A. Craig. Overview of newer antimicrobial formulations for overcoming pneumococcal resistance. Am. J. Med. 117(Supp. 3A):S16–S22 (2004).

    Google Scholar 

  29. M. J. Darkes and G. M. Perry. Clarithromycin extended-release tablet: a review of its use in the management of respiratory tract infections. Am. J. Respir. Medicine 2(2):175–201 (2003).

    CAS  Google Scholar 

  30. M. A. Drehobl, M. C. De Salvo, D. E. Lewis, and J. D. Breen. Single-dose azithromycin microspheres vs. clarithromycin extended release for the treatment of mild-to-moderate community-acquired pneumonia in adults. Chest 128(4):2230–2237 (2005).

    Article  PubMed  CAS  Google Scholar 

  31. W. A. Craig. Postantibiotic effects and the dosing of macrolides, azalides, and streptogramins. In S. H. Zinner, L. S. Young, and J. F. Acar (eds.), Expanding Indications for the New Macrolides, Azalides and Streptogramins. Marcel Dekker, New York, 1997, pp. 27–38.

    Google Scholar 

  32. P. Cole. Pharmacologic and clinical comparison of cefaclor in immediate release capsule and extended-release tablet forms. Clin. Ther. 19:617–625 (1997).

    Article  PubMed  CAS  Google Scholar 

  33. Bayer Healthare, http://www.CiproXR.com (accessed 12/15/2006).

  34. A. Hoffman, D. Stepensky, E. Lavy, S. Eyal, E. Klausner, and M. Friedman. Pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms. Int. J. Pharm. 227(1–2):141–153 (2004).

    Article  CAS  Google Scholar 

Download references

Ackowledgement

This study was supported in part by the David R. Bloom Center for Pharmacy at the Hebrew University. A. Hoffman is affiliated with this center.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amnon Hoffman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoffman, A., Horwitz, E., Hess, S. et al. Implications on Emergence of Antimicrobial Resistance as a Critical Aspect in the Design of Oral Sustained Release Delivery Systems of Antimicrobials. Pharm Res 25, 667–671 (2008). https://doi.org/10.1007/s11095-007-9373-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-007-9373-6

Key words

Navigation