Exposure to potential drug-antimicrobial agent interactions in primary health care

Božana Nikolić; Jovan Popović; Mirjana Bećarević; Dušica Rakić

doi:10.2298/VSP160930383N

Božana Nikolić University of Novi Sad, Faculty of Medicine, Department of Pharmacy
Jovan Popović University of Novi Sad, Faculty of Medicine, Department of Pharmacology and Toxicology
Mirjana Bećarević University of Novi Sad, Faculty of Medicine, Department of Pharmacy
Dušica Rakić University of Novi Sad, Faculty of Medicine, Department of General Education Subjects

DOI: https://doi.org/10.2298/VSP160930383N

Keywords: drug therapy;, anti-bacterial agents;, drug interactions;, outpatients;, adverse drug reaction reporting systems;, pharmacovigilance.

Abstract

Background/Aim. Drug-drug interactions involving antimicrobials present important and often unrecognized complications of pharmacotherapy which can be prevented. The aim of the present study was to identify the frequency and type of potential drug-antimicrobial agent interactions among outpatients and to define recommendations for their management. Methods. Cross-sectional prescription database study was conducted. The analysis randomly included 823 patients who visited Health Center Novi Sad over 1-month period (November 1–30, 2011) and had prescribed ≥ 2 drugs where at least one drug was antimicrobial agent for systemic use. All interacting drug combinations involving antimicrobials were identified according to Drug Interaction Facts. Additionally, based on the compendium, potential interactions were classified into categories: pharmacological mechanisms, potential clinical outcomes and management advice. Results. Overall, 88 potential clinically significant drug-antimicrobial agent interactions were identified among 69 (8.4%) exposed outpatients [the mean age 61.7 years (SD ± 15.4); the mean number of prescribed drugs 7.5 (SD ± 2.9); 56.5% females]. The most common identified potential interacting pairs were benzodiazepines undergoing oxidative metabolism and clarithromycin or erythromycin, and aminophylline and ciprofloxacin. In 83.0% of all cases underlying mechanism was pharmacokinetic involving primary inhibition of metabolic pathways mediated by CYP3A4 and CYP1A2 isoenzymes. Excessive sedation (22.7%), cardiotoxicity (20.5%), miscellaneous aminophylline adverse effects (13.6%), and bleeding (10.2%) were the most frequently implicated potential clinical outcomes. Risk for adverse interactions could be managed by close monitoring of simultaneous administration of drugs (37.5%), different risk-modifyng strategies (31.8%), and avoiding combinations (30.7%). Conclusion. Among outpatients, there was common potential for clinically significant interactions involving antimicrobials. Information based on the results of the present study could be integrated in existing computerized physician order entry system in the Health Center as a form of clinical support.

References

REFERENCES

Strandell J, Wahlin S. Pharmacodynamic and pharmacoki¬netic drug interactions reported to VigiBase, the WHO global indi-vidual case safety report database. Eur J Clin Pharmacol 2011; 67(6): 633‒41.

Molden E, Andersson KS. Simvastatin-associated rhabdo-myolysis after coadministration of macrolide antibiotics in two patients. Pharmacotherapy 2007; 27(4): 603‒7.

Flockhart DA, Drici MD, Kerbusch T, Soukhova N, Richard E, Pearle PL, et al. Studies on the mechanism of a fatal clarithro-mycin-pimozide interaction in a patient with Tourette syn-drome. J Clin Psychopharmacol 2000; 20(3): 317‒24.

Magro L, Moretti U, Leone R. Epidemiology and characteris¬tics of adverse drug reactions caused by drug-drug interactions. Expert Opin Drug Saf 2012; 11(1): 83‒94.

Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS, Brandt JT, et al. Cytochrome P450 3A inhibition by keto¬conazole affects prasugrel and clopidogrel pharmacokinet¬ics and pharmacodynamics differently. Clin Pharmacol Ther 2007; 81(5): 735‒41.

Gugler R, Allgayer H. Effects of antacids on the clinical phar-macokinetics of drugs. An update. Clin Pharmacoki¬net 1990; 18(3): 210‒9.

Kays MB, Overholser BR, Mueller BA, Moe SM, Sowinski KM. Effects of sevelamer hydrochloride and calcium acetate on the oral bioavailability of ciprofloxacin. Am J Kidney Dis 2003; 42(6): 1253‒9.

Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospi¬talized for drug toxicity. JAMA 2003; 289(13): 1652‒8.

Wright J, Paauw DS. Complications of antibiotic therapy. Med Clin North Am 2013; 97(4): 667‒79, xi.

Pai MP, Momary KM, Rodvold KA. Antibiotic drug interac¬tions. Med Clin North Am 2006; 90(6): 1223‒55.

Spriet I, Meersseman W, de Hoon J, von Winckelmann S, Wil¬mer A, Willems L. Mini-series: II. clinical aspects. clini¬cally relevant CYP450-mediated drug interactions in the ICU. Intensive Care Med 2009; 35(4): 603‒12.

Becker DE. Adverse drug interactions. Anesth Prog 2011; 58(1): 31‒41.

Becker DE. Antimicrobial drugs. Anesth Prog 2013; 60(3): 111‒22.

Tey HL, Tian EL, Tan AW. Drug interactions in derma-tological practice. Clin Exp Dermatol 2008; 33(5): 541‒50.

Müller F, Dormann H, Pfistermeister B, Sonst A, Patapovas A, Vogler R, et al. Application of the Pareto principle to identify and address drug-therapy safety issues. Eur J Clin Pharmacol 2014; 70(6): 727‒36.

Nikolic B, Jankovic S, Stojanov O, Popovic J. Prevalence and pre-dictors of potential drug-drug interactions. Cent Eur J Med 2004; 9(2): 348–56.

WHO Collaborating Center for Drug Statistics Methodol¬ogy. ATC/DDD Index. [cited 2015 Jan 30]. Available from: http://www.whocc.no/atc_ddd_index/

Geerts AF, de Koning FH, de Smet PA, van Solinge WW, Eg¬berts TC. Laboratory tests in the clinical risk management of poten-tial drug-drug interactions: A cross-sectional study using drug-dispensing data from 100 Dutch community pharmacies. Drug Saf 2009; 32(12): 1189‒97.

Pergolizzi JV, Labhsetwar SA, Puenpatom RA, Joo S, Ben-Jo¬seph R, Summers KH. Exposure to potential CYP450 pharma-cokinetic drug-drug interactions among ostearthri¬tis patients: Incremental risk of multiple prescriptions. Pain Pract 2011; 11(4): 325‒36.

Tatro DS. Drug Interaction Facts 2012: The Authority on Drug Interactions. St Louis MO (USA): Wolters Kluwer Health; 2011.

Strom BL. Sample size considerations for pharmacoepidemi-ology studies. In: Strom BL, Kimmel SE, editors. Textbook of Pharmacoepidemiology. Chichester: John Wiley & Sons; 2006. p. 25‒33.

Denneboom W, Dautzenberg MG, Grol R, de Smet PA. Analy¬sis of polypharmacy in older patients in primary care using a multidisciplinary expert panel. Br J Gen Pract 2006; 56(528): 504‒10.

Mino-León D, Galván-Plata ME, Doubova SV, Flores-Hernan¬dez S, Reyes-Morales H. A pharmacoepidemiological study of potential drug interactions and their determinant factors in hospitalized patients. Rev Invest Clin 2011; 63(2): 170‒8. (Spanish)

Reason B, Terner M, Moses Mckeag A, Tipper B, Webster G. The impact of polypharmacy on the health of Canadian seniors. Fam Pract 2012; 29(4): 427‒32.

Doan J, Zakrzewski-Jakubiak H, Roy J, Turgeon J, Tan¬nenbaum C. Prevalence and risk of potential cytochrome P450-mediated drug-drug interactions in older hospitalized patients with poly-pharmacy. Ann Pharmacother 2013; 47(3): 324‒32.

Reis AM, Cassiani SH. Adverse drug events in an intensive care unit of a university hospital. Eur J Clin Pharmacol 2011; 67(6): 625‒32.

Yeates RA, Laufen H, Zimmermann T. Interaction between midazolam and clarithromycin: Comparison with azithromycin. Int J Clin Pharmacol Ther 1996; 34(9): 400‒5.

Zakrzewski-Jakubiak H, Doan J, Lamoureux P, Singh D, Tur¬geon J, Tannenbaum C. Detection and prevention of drug-drug interactions in the hospitalized elderly: Utility of new cytochrome p450-based software. Am J Geriatr Pharmacother 2011; 9(6): 461‒70.

Edwards DJ, Bowles SK, Svensson CK, Rybak MJ. Inhibition of drug metabolism by quinolone antibiotics. Clin Phar-macokinet 1988; 15(3): 194‒204.

Gisclon LG, Curtin CR, Fowler CL, Williams RR, Hafkin B, Natarajan J. Absence of a pharmacokinetic interaction be-tween intravenous theophylline and orally administered levofloxacin. J Clin Pharmacol 1997; 37(8): 744‒50.

Hocaoğlu N, Yıldıztepe E, Bayram B, Aydın B, Tunçok Y, Kal¬kan Ş. Demographic and Clinical Characteristics of Theophylline Exposures between 1993 and 2011. Balkan Med J 2014; 31(4): 322‒7.

Guthrie B, Mccowan C, Davey P, Simpson CR, Dreischulte T, Barnett K. High risk prescribing in primary care patients particularly vulnerable to adverse drug events: Cross sec¬tional population database analysis in Scottish general practice. BMJ 2011; 342: d3514.

Davydov L, Yermolnik M, Cuni LJ. Warfarin and amoxicil-lin/clavulanate drug interaction. Ann Pharmacother 2003; 37(3): 367‒70.

Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: Clinical relevance. Clin Pharmacokinet 2000; 38(2): 111‒80.

Dreischulte T, Guthrie B. High-risk prescribing and monitor¬ing in primary care: How common is it, and how can it be im-proved?. Ther Adv Drug Saf 2012; 3(4): 175‒84.

Gandhi TK, Weingart SN, Borus J, Seger AC, Peterson J, Bur¬dick E, et al. Adverse drug events in ambulatory care. N Engl J Med 2003; 348 (16): 1556‒64.

Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of fer-rous sulfate and multivitamins with zinc on absorption of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother 1989; 33(11): 1841‒4.

Campbell NR, Kara M, Hasinoff BB, Haddara WM, McKay DW. Norfloxacin interaction with antacids and minerals. Br J Clin Pharmacol 1992; 33(1): 115‒6.

Hines LE, Murphy JE. Potentially harmful drug-drug interac-tions in the elderly: A review. Am J Geriatr Phar¬macother 2011; 9(6): 364‒77.