Antibiotic interactions: Answers to 4 common questions

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Applied Evidence

Antibiotic interactions: Answers to 4 common questions

J Fam Pract. 2016 July;65(7):442-448

By

Mary Onysko, PharmD, BCPS

Nathan Holcomb, PharmD

Which antibiotics should you consider when a patient is taking warfarin? Which ones are associated with drug-induced, prolonged QT intervals? Read on.

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References

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7. Epocrates. Available at: http://www.epocrates.com/. Accessed December 8, 2015.

8. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012;125:183-189.

9. PL Detail-Document #280806. Antimicrobial drug interactions with warfarin. Pharmacist’s Letter/Prescriber’s Letter. August 2012.

10. Lane M, Zeringue A, McDonald J. Serious bleeding events due to warfarin and antibiotic co-prescription in a cohort of veterans. Am J Med. 2014;127:657-663.e2.

11. Hale SF, Lesar TS. Interaction of vitamin K antagonists and trimethoprim-sulfamethoxazole: ignore at your patient’s risk. Drug Metab Drug Interact. 2014;29:53-60.

12. Ahmed A, Stephens JC, Kaus CA, et al. Impact of preemptive warfarin dose reduction on anticoagulation after initiation of trimethoprim-sulfamethoxazole or levofloxacin. J Thromb Thrombolysis. 2008;26:44-48.

13. Holt RK, Anderson EA, Cantrell MA, et al. Preemptive dose reduction of warfarin in patients initiating metronidazole. Drug Metabol Drug Interact. 2010;25:35-39.

14. Hughes BR, Cunliffe WJ. Interactions between the oral contraceptive pill and antibiotics. Br J Dermatol. 1990;122:717-718.

15. Bolt HM. Interactions between clinically used drugs and oral contraceptives. Environ Health Perspect. 1994;102:35-38.

16. Aronson JK. Meyler’s Side Effects of Drugs. 16th ed. The International Encyclopedia of Adverse Drug Reactions and Interactions. Amsterdam, Netherlands: Elsevier; 2016. Available at: http://ac.els-cdn.com/B978044453717101009X/3-s2.0-B978044453717101009X-main.pdf?_tid=b33f6564-9deb-11e5-a8f0-00000aab0f01&acdnat=1449607315_83f5068fc5105226fcc6d7279c083516. Accessed December 8, 2015.

17. Masters KP, Carr BM. Survey of pharmacists and physicians on drug interactions between combined oral contraceptives and broad-spectrum antibiotics. Pharm Pract (Granada). 2009;7:139-144.

18. Toh S, Mitchell AA, Anderka M, et al; National Birth Defects Prevention Study. Antibiotics and oral contraceptive failure—a case-crossover study. Contraception. 2011;83:418-425.

19. Koopmans PC, Bos JH, de Jong van den Berg LT. Are antibiotics related to oral combination contraceptive failures in the Netherlands? A case-crossover study. Pharmacoepidemiol Drug Saf. 2012;21:865-871.

20. Archer JS, Archer DF. Oral contraceptive efficacy and antibiotic interaction: A myth debunked. J Am Acad Dermatol. 2002;46:917–923.

21. Scholten PC, Droppert RM, Zwinkels MGJ, et al. No interaction between ciprofloxacin and an oral contraceptive. Antimicrob Agents Chemother. 1998;42:3266-3268.

22. Andrews E, Damle BD, Fang A, et al. Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects. Br J Clin Pharmacol. 2008;65:531-539.

23. Grimmer SF, Allen WL, Back DJ, et al. The effect of cotrimoxazole on oral contraceptive steroids in women. Contraception. 1983;28:53-59.

24. Dickinson BD, Altman RD, Nielsen NH, et al; Council on Scientific Affairs, American Medical Association. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol. 2001;98:853-860.

25. Edelman AB, Cherala G, Stanczyk FZ. Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review. Contraception. 2010;82:314-323.

26. Owens RC Jr, Ambrose PG. Torsades de pointes associated with fluoroquinolones. Pharmacotherapy. 2002;22:663-668.

27. Letsas KP, Efremidis M, Kounas SP, et al. Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. Clin Res Cardiol. 2009;98:208-212.

28. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89:1363-1372.

29. Shaffer D, Singer S, Korvick J, et al. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration adverse event reporting system. Clin Infect Dis. 2002;35:197-200.

30. FDA Briefing Document. Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. November 5, 2015. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM467383.pdf. Accessed June 11, 2016.

31. Chou HW, Wang JL, Chang CH, et al. Risks of cardiac arrhythmia and mortality among patients using new-generation macrolides, fluoroquinolones, and β-lactam/β-lactamase inhibitors: a Taiwanese nationwide study. Clin Infect Dis. 2015;60:566-577.

32. Wong AY, Root A, Douglas IJ, et al. Cardiovascular outcomes associated with use of clarithromycin: population based study. BMJ. 2016;352:h6926.

33. Inghammar M, Svanström H, Melbye M, et al. Oral fluoroquinolone use and serious arrhythmia: bi-national cohort study. BMJ. 2016;352:i843.

34. Visapää JP, Tillonen JS, Kaihovaara PS, et al. Lack of disulfiram-like reaction with metronidazole and ethanol. Ann Pharmacother. 2002;36:971-974. 35. Fjeld H, Raknes G. Is combining metronidazole and alcohol really hazardous? Tidsskr Nor Laegeforen. 2014;134:1661-1663.

PRACTICE RECOMMENDATIONS

› Avoid preemptive warfarin dose reductions unless you are prescribing trimethoprim/sulfamethoxazole (TMP/SMX) or metronidazole. B
› Recommend a back-up contraceptive method to a woman who is taking a broad-spectrum antibiotic and low-dose OCs—especially if the woman is overweight. C
› Consider using the macrolide, clarithromycin, or the fluoroquinolone, ciprofloxacin, in patients taking medications that prolong QT interval or who are at higher risk for torsades de pointes (TdP). B
› Refrain from cautioning patients taking metronidazole against consuming alcohol. A

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

Despite encouraging data that antibiotic prescribing is on the decline, patients are still prescribed antibiotics frequently, making these agents the 12th most frequently used drug class.¹ At the same time, prescribers are caring for patients with increasingly complex drug regimens that provide fertile ground for drug interactions with these antibiotics. And, of course, lifestyle factors such as alcohol consumption are a consideration when any prescription is written.

As pharmacists, we find that certain questions about antibiotic prescribing and interactions come up with frequency. These questions often pertain to the use of warfarin, oral contraceptives, drugs that prolong the QT interval, and alcohol. But conflicting reports about issues such as monitoring international normalized ratio (INR) in patients taking warfarin and antibiotics, and whether (or which) antibiotics decrease the efficacy of oral contraceptives (OCs) can make decision-making challenging.

This review provides evidence-based answers to questions you may have. It also details some reliable sources of information you can consult (TABLE 1^2-7) when discussing treatment options with other members of the health care team.

1. Which antibiotics are preferable when a patient is taking warfarin, and are preemptive warfarin dose reductions advisable?

The simple answer is that agents with a lower likelihood of affecting the INR, such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins, are a good place to start, and whether to preemptively reduce the warfarin dose hinges on the antibiotic being prescribed.

The more detailed answer. The fundamental mechanisms of interaction between warfarin and antibiotics are two-fold:⁸

Antimicrobial agents disrupt gastrointestinal flora that synthesize vitamin K.
Antimicrobials inhibit cytochrome p450 (CYP450) enzymes (primarily CYP2C9 and 3A4), which are responsible for the metabolism of warfarin.

The antibiotics most likely to interfere with warfarin are TMP/SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin (TABLE 2).^9,10 Low-risk agents include clindamycin, cephalexin, and penicillin G. When prescribing an antibiotic for a patient taking warfarin, it is important not only to be aware of the agents that should be avoided, but also the agents that do not require more frequent monitoring of INR.

Preemptive warfarin dose reductions? Some physicians make preemptive warfarin dose reductions in an attempt to avoid supratherapeutic INRs in patients being prescribed antibiotics. But the evidence suggests that this step should be considered only in the presence of the antibiotics TMP/SMX and metronidazole.^9,11

A 2008 study investigated the anticoagulation effects of a 10% to 20% preemptive warfarin dose reduction vs no dosing change in patients taking TMP/SMX or levofloxacin. The investigators found that the preemptive warfarin dose reduction (intervention) significantly decreased the number of supratherapeutic INR values above 4 when compared to controls (2 of 8 vs 8 of 9).¹²

In the dose-reduction group, no patients receiving TMP/SMX developed a subtherapeutic INR, whereas 40% (4 of 10 patients) who received levofloxacin developed a subtherapeutic INR.¹²The authors of the study concluded that a prophylactic warfarin dose reduction of 10% to 20% is effective in maintaining therapeutic anticoagulation in patients receiving TMP/SMX. They added that while no change in warfarin dosing is necessary with levofloxacin, short-term INR follow-up is a prudent approach to prevent subtherapeutic INRs. Others recommend INR monitoring when antibiotic therapy is started and stopped and whenever the dose is changed.⁹

A 2010 retrospective, single-center, cohort study looked at patients who were taking metronidazole and warfarin. Researchers compared those who received a preemptive dose reduction of warfarin (mean reduction was 34.6% ± 13.4%) to those who did not and found a statistically significant mean difference in INR of 1.28 (P=.01).¹³

Almost half (46%) of the patients who did not receive a warfarin dose reduction had an INR >4, whereas none of the patients in the warfarin dose reduction group did (P=.05). Although this secondary outcome was not statistically significant (most likely due to the small sample population [N=20]), the implication is clinically significant. Two patients who reduced their dose had a subtherapeutic INR compared to none of the patients in the control group, which was also not a statistically significant difference.

The authors concluded that a 30% to 35% reduction in mean daily warfarin dose is effective in maintaining therapeutic anticoagulation in patients started on metronidazole.

Significant bleeding events. A retrospective cohort study of slightly more than 22,000 veterans who were prescribed warfarin for ≥30 uninterrupted days and given antibiotics with either a high or low risk for interaction with warfarin were studied for significant bleeding events for one month.¹⁰ Ninety-three significant bleeding events occurred in the high-risk group and 36 occurred in the low-risk group over the course of the study. The agent associated with the greatest increased risk of bleeding was TMP/SMX (hazard ratio [HR]=2.09; 95% CI, 1.45-3.02). Of note, metronidazole was not included in this study endpoint.

When TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.

The study’s secondary endpoint of INR >4 found that 10% of patients taking metronidazole and 8% of patients taking TMP/SMX in addition to warfarin had INRs >4. Almost 10% (9.7%) of patients prescribed fluconazole had a peak INR value >6. Patients taking low-risk antibiotics (clindamycin or cephalexin) had no increased risk of bleeding. Monitoring INR within 3 to 14 days of starting patients on antibiotics was found to decrease the risk of serious bleeding events (HR=0.61; 95% CI, 0.42-0.88). More frequent INR monitoring by itself (without preemptive warfarin dose reductions) is appropriate for other antibiotics, including macrolides, tetracyclines, and some cephalosporins (2nd and 3rd generation).⁹

THE BOTTOM LINE When prescribing antibiotics for patients taking warfarin, try to choose agents with a lower likelihood of affecting INR such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins. With these agents, there is no need for more frequent INR testing or preemptive reductions in warfarin dose. In patients for whom the use of TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.^9,11,12 When prescribing agents such as fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient’s warfarin dose preemptively and recheck INR 5 days after starting therapy.