Mary Onysko, PharmD, BCPS; Nathan Holcomb, PharmD; Jaime Hornecker, Antibiotic interactions: PharmD, BCPS, CDE University of Wyoming, School of Pharmacy, Answers to 4 common questions Laramie [email protected] Which antibiotics should you consider when a patient is The authors reported no taking warfarin? Which ones are associated with drug- potential conflict of interest relevant to this article. induced, prolonged QT intervals? Read on. espite encouraging data that antibiotic prescribing PRACTICE is on the decline, patients are still prescribed antibi- RECOMMENDATIONS otics frequently, making these agents the 12th most ❯ Avoid preemptive warfarin D 1 frequently used drug class. At the same time, prescribers are dose reductions unless you are caring for patients with increasingly complex drug regimens prescribing trimethoprim/ sulfamethoxazole (TMP/SMX) that provide fertile ground for drug interactions with these an- or metronidazole. B tibiotics. And, of course, lifestyle factors such as alcohol con- sumption are a consideration when any prescription is written. ❯ Recommend a back-up As pharmacists, we find that certain questions about an- contraceptive method to a woman who is taking a tibiotic prescribing and interactions come up with frequency. broad-spectrum antibiotic These questions often pertain to the use of warfarin, oral con- and low-dose OCs— traceptives, drugs that prolong the QT interval, and alcohol. especially if the woman But conflicting reports about issues such as monitoring in- is overweight. C ternational normalized ratio (INR) in patients taking warfarin ❯ Consider using the macro- and antibiotics, and whether (or which) antibiotics decrease lide, clarithromycin, or the the efficacy of oral contraceptives (OCs) can make decision- fluoroquinolone, ciprofloxa- making challenging. cin, in patients taking medica- This review provides evidence-based answers to questions tions that prolong QT interval you may have. It also details some reliable sources of informa- or who are at higher risk for tion you can consult (TABLE 12-7) when discussing treatment torsades de pointes (TdP). B options with other members of the health care team. ❯ Refrain from cautioning patients taking metronidazole against Which antibiotics are preferable when a consuming alcohol. A 1 patient is taking warfarin, and are preemp- Strength of recommendation (SOR) tive warfarin dose reductions advisable? A Good-quality patient-oriented The simple answer is that agents with a lower likelihood of af- evidence fecting the INR, such as penicillin G, clindamycin, and 1st- and B Inconsistent or limited-quality 4th-generation cephalosporins, are a good place to start, and patient-oriented evidence whether to preemptively reduce the warfarin dose hinges on C Consensus, usual practice, opinion, disease-oriented the antibiotic being prescribed. evidence, case series ❚ 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. 442 THE JOURNAL OF FAMILY PRACTICE | JULY 2016 | VOL 65, NO 7 TABLE 1 A sampling of available resources for researching interactions2-7 Resource/App Description Availability & Pricing Clinical Pharmacology Drug reference library, drug-drug interactions, Computer, smartphone, tablet drug ID, IV compatibility, global drug name https://www. Core app: $199/year database, and formulary database for 3rd party clinicalpharmacology.com/ prescription plans Add-on modules: $39-$119/year each Epocrates Drug reference library, drug-drug Computer, smartphone, tablet interactions, drug ID, guidelines, ICD-10, http://www.epocrates.com/ Epocrates: Free diseases, and calculator Epocrates Plus: $174.99/year Facts and Comparisons Drug reference library, drug-drug interactions, Computer (Smartphone and tablet versions drug ID, IV compatibility, and calculator are made by Lexicomp. Refer to Lexicomp for http://www.wolterskluwercdi. pricing.) com/facts-comparisons-online/ GlobalRPh IV dilutions, calculator, drug reference Computer only database, infectious disease database, http://www.globalrph.com/ Free pathogenic bacteria, renal dosing, and oncology Lexicomp Drug reference library, drug-drug interactions, Computer, smartphone, tablet drug ID, Lexi-Calculator, and IV compatibility http://www.wolterskluwercdi. Four options with varying databases and com/lexicomp-online tools. Annual subscription: $175-$798 Medscape app Drug reference library, drug-drug interactions, Smartphone, tablet conditions database, procedures database, drug http://www.medscape.com/ Free full access to app ID, calculator, news and articles in medicine and public/applanding pharmacy Micromedex Drug reference library, drug comparisons, Computer, smartphone, tablet drug-drug interactions, IV compatibility, drug http://micromedex.com/ Subscription: $2.99/year/app ID, and Red Book online academic Each component is its own app • Antimicrobials inhibit cytochrome supratherapeutic INRs in patients being p450 (CYP450) enzymes (primarily prescribed antibiotics. But the evidence CYP2C9 and 3A4), which are respon- suggests that this step should be consid- sible for the metabolism of warfarin. ered only in the presence of the antibiotics TMP/SMX and metronidazole.9,11 The antibiotics most likely to interfere A 2008 study investigated the antico- with warfarin are TMP/SMX, ciprofloxacin, agulation effects of a 10% to 20% preemptive levofloxacin, metronidazole, fluconazole, warfarin dose reduction vs no dosing change azithromycin, and clarithromycin (TABLE 2).9,10 in patients taking TMP/SMX or levofloxacin. Low-risk agents include clindamycin, cepha- The investigators found that the preemptive lexin, and penicillin G. When prescribing an warfarin dose reduction (intervention) signif- antibiotic for a patient taking warfarin, it is icantly decreased the number of suprathera- important not only to be aware of the agents peutic INR values above 4 when compared to that should be avoided, but also the agents controls (2 of 8 vs 8 of 9).12 that do not require more frequent monitoring In the dose-reduction group, no patients of INR. receiving TMP/SMX developed a subthera- ❚ Preemptive warfarin dose reductions? peutic INR, whereas 40% (4 of 10 patients) Some physicians make preemptive warfa- who received levofloxacin developed a sub- rin dose reductions in an attempt to avoid therapeutic INR.12 The authors of the study JFPONLINE.COM VOL 65, NO 7 | JULY 2016 | THE JOURNAL OF FAMILY PRACTICE 443 TABLE 2 dose is effective in maintaining therapeu- Antimicrobials likely tic anticoagulation in patients started on metronidazole. to increase INR when ❚ Significant bleeding events.A retro- 9 used with warfarin spective cohort study of slightly more than 22,000 veterans who were prescribed war- Azithromycin farin for ≥30 uninterrupted days and given Ciprofloxacin antibiotics with either a high or low risk for Clarithromycin interaction with warfarin were studied for 10 Fluconazole and other azole antifungals significant bleeding events for one month. Ninety-three significant bleeding events oc- Levofloxacin curred in the high-risk group and 36 occurred Metronidazole* in the low-risk group over the course of the Trimethoprim/sulfamethoxazole* study. The agent associated with the great- INR, international normalized ratio. est increased risk of bleeding was TMP/SMX *Preemptive warfarin dose reduction recommended. (hazard ratio [HR]=2.09; 95% CI, 1.45-3.02). Of note, metronidazole was not included in this study endpoint. The study’s secondary endpoint of INR concluded that a prophylactic warfarin >4 found that 10% of patients taking metro- When TMP/SMX dose reduction of 10% to 20% is effective in nidazole and 8% of patients taking TMP/SMX or metronidazole maintaining therapeutic anticoagulation in in addition to warfarin had INRs >4. Almost can’t be avoided, patients receiving TMP/SMX. They added 10% (9.7%) of patients prescribed fluconazole consider that while no change in warfarin dosing is had a peak INR value >6. Patients taking low- reducing necessary with levofloxacin, short-term INR risk antibiotics (clindamycin or cephalexin) the patient’s follow-up is a prudent approach to prevent had no increased risk of bleeding. Monitor- warfarin dose subtherapeutic INRs. Others recommend ing INR within 3 to 14 days of starting patients by 10% to 35% INR monitoring when antibiotic therapy is on antibiotics was found to decrease the risk and rechecking started and stopped and whenever the dose of serious bleeding events (HR=0.61; 95% CI, the INR 5 days is changed.9 0.42-0.88). More frequent INR monitoring by after starting A 2010 retrospective, single-center, co- itself (without preemptive warfarin dose re- the antibiotic. hort study looked at patients who were tak- ductions) is appropriate for other antibiotics, ing metronidazole and warfarin. Researchers including macrolides, tetracyclines, and some compared those who received a preemptive cephalosporins (2nd and 3rd generation).9 dose reduction of warfarin (mean reduction was 34.6% ± 13.4%) to those who did not and u THE BOTTOM LINE When prescribing an- found a statistically significant mean differ- tibiotics for patients taking warfarin, try to ence in INR of 1.28 (P=.01). 13 choose agents with a lower likelihood of af- Almost half (46%) of the patients who did fecting INR such as penicillin G, clindamycin, not receive a warfarin dose reduction had an and 1st- and 4th-generation cephalosporins. INR >4, whereas none of the patients