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.
Abbreviations
- ARB:
-
Ampicillin-resistant bacteria
References
A. Hoffman. Pharmacodynamic aspects of sustained-release formulations. Adv. Drug Deliv. Rev. 33:185–199 (1998).
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).
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.
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).
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).
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).
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).
D. Zarowny, R. Ogilvie, D. Tamblyn, C. MacLeod, and J. Ruedy. Pharmacokinetics of amoxicillin. Clin. Pharmacol. Ther. 16(6):1045–1051 (1974).
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).
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).
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).
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).
E. Bergogne-Bérézin, and A. Bryskier. The suppository form of antibiotic administration: pharmacokinetics and clinical application. J. Antimicrob. Chemother. 43:177–185 (1999).
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).
A. H. Dantzig. Oral absorption of β-lactams by intestinal peptide transport proteins. Adv. Drug Deliv. Rev. 23(1–3):63–76 (1997).
V. H. Lee. Membrane transporters. Eur. J. Pharm. Sci. 11(suppl.2):S41–S50 (2000).
E. J. Vollaard, and H. A. L. Classener. Colonization resistance. Antimicrob. Agents Chemother. 38:409–414 (1994).
T. D. Luckey. Introduction to intestinal microecology. Am. J. Clin. Nutr. 25:1292–294 (1972).
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).
K. D. Hooker, and J. T. DiPiro. Effect of antimicrobial therapy on bowel flora. Clin. Pharm. 12:878–888 (1988).
C. E. Nord, and C. Edlund. Impact of antimicrobial agents on human intestinal microflora. J. Chemother. 2:218–237 (1990).
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).
L. B. Rice. Antimicrobial resistance in gram-positive bacteria. Am. J. Infect. Control 34(5 Suppl.1):S11–S19 (2006).
R. Patel. Clinical impact of vancomycin-resistant Enterococci. J. Antimicrob. Chemother. 51(suppl.3):iii13–iii21 (2003).
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).
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).
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).
W. A. Craig. Overview of newer antimicrobial formulations for overcoming pneumococcal resistance. Am. J. Med. 117(Supp. 3A):S16–S22 (2004).
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).
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).
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.
P. Cole. Pharmacologic and clinical comparison of cefaclor in immediate release capsule and extended-release tablet forms. Clin. Ther. 19:617–625 (1997).
Bayer Healthare, http://www.CiproXR.com (accessed 12/15/2006).
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).
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
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-007-9373-6