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 in the With these agents, there is no need for more warfarin dose reduction group did (P=.05). frequent INR testing or preemptive reduc- Although this secondary outcome was not tions in warfarin dose. In patients for whom statistically significant (most likely due to the the use of TMP/SMX or metronidazole can’t small sample population [N=20]), the impli- be avoided, consider reducing the patient’s cation is clinically significant. Two patients warfarin dose by 10% to 35% and recheck- who reduced their dose had a subtherapeutic ing the INR 5 days after starting the antibi- INR compared to none of the patients in the otic.9,11,12 When prescribing agents such as control group, which was also not a statisti- fluoroquinolones, macrolides, and tetracy- cally significant difference. clines, do not reduce the patient’s warfarin The authors concluded that a 30% dose preemptively and recheck INR 5 days to 35% reduction in mean daily warfarin after starting therapy.

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Do antibiotics decrease the erythromycin and azithromycin may interact 2 efficacy of oral contraceptives? with OCs, but the clinical significance of this It’s unlikely, but antibiotics may reduce the interaction is still unknown.16 efficacy of OCs. Short-courses of TMP/SMX are gener- There have been few, but well document- ally thought to be safe;16 a small study looked ed, reports of women using OCs who be- at cotrimoxazole 1 g twice daily in 9 women came pregnant after taking antimicrobials.14 taking long-term OC steroids and found that It is recognized that rifampin, an inducer short courses of the drug were unlikely to of enzymes that metabolize estrogens, de- cause any adverse effects on contraceptive creases the efficacy of OCs.15 Ketoconazole’s control.23 Tetracyclines and penicillins were interaction seems less well documented, but the antibiotics most frequently involved in combining the agent with low-estrogen (low- case reports of pregnancy from the United dose) OCs warrants caution.16 What is not Kingdom (TABLE 32).16 well understood is whether more common or It is hypothesized that some women may broad-spectrum antibiotics also increase the have a higher risk of OC failure than others risk of OC failure. due to how they metabolize ethinyl estradi- Three mechanisms have been proposed:16 ol.24 Another hypothesis is that some women • Antimicrobials affect hepatic enzyme have gut flora that is more susceptible to the induction, which increases metabo- antibiotic being used. And still another pos- lism of hormones. sibility is that lower doses of hormones are When prescribing • Broad-spectrum antibiotics reduce being used in OCs than were studied for fluoroquinolones, gut bacteria, which alters enterohe- this interaction.15 Anything that decreases macrolides, and patic circulation and reduces plasma the concentration of these lower-dose OCs tetracyclines, hormone concentrations. is concerning, especially in patients with a do not reduce • Antibiotics increase gastrointestinal higher body mass index (BMI). The few phar- the patient’s motility, which decreases absorption macokinetic studies that have been conduct- warfarin dose (and reabsorption) of OCs. ed show that it takes longer for OCs to reach preemptively. a steady state in obese women and that they A 2007 study found that when physicians have a lower area under the curve (AUC) and pharmacists were surveyed and asked and maximum estrogen concentration than if broad-spectrum antibiotics have a clini- women with a normal BMI.25 cally significant interaction with OCs, 83% of physicians and 89% of pharmacists answered u THE BOTTOM LINE Because the degree of “Yes;”17 however, a large epidemiologic study variability between patients is unknown and performed in the United States showed no obesity rates are increasing, concern that association between antibiotic use and OC low-dose OCs may lose efficacy when com- failure.18 bined with antibiotics is warranted. While After this report, investigators in the the absolute risk of breakthrough pregnancy Netherlands completed a similar cross-over seems small, the most conservative approach analysis and found that there was a rela- is to advise patients to use a back-up method tionship between the use of antibiotics and of contraception during times of antibiotic breakthrough pregnancy in a population- use. based prescription database, but that the results didn’t hold for broad-spectrum anti- biotics or in a sensitivity analysis.19 Pharma- Which drugs prolong QT cokinetic studies are also conflicting, as some 3 intervals? have shown an effect on serum hormone lev- Macrolides and fluoroquinolones are 2 class- els, while others have not.15,20-22 es of antibiotics associated with prolonged ❚ High- vs low-risk agents. Cipro- QT intervals, but other drugs and risk factors floxacin did not affect hormone levels in are important to consider, as well. 2 studies.20,21 Rifampin and voriconazole may Physicians often receive phone calls enhance systemic exposure to OCs.15,22 And from pharmacists warning about drug-drug

JFPONLINE.COM VOL 65, NO 7 | JULY 2016 | THE JOURNAL OF FAMILY PRACTICE 445 TABLE 3 Antimicrobials more (and less) likely to interfere with OCs, especially low-dose varieties2

More likely to decrease OC effectiveness Less likely to decrease OC effectiveness Azithromycin Ciprofloxacin Erythromycin Trimethoprim/sulfamethoxazole Ketoconazole Penicillins Rifampin Tetracyclines

OC, oral contraceptives.

interactions when they prescribe macrolides An analysis of 2 studies by the US Food or fluoroquinolones for patients already tak- and Drug Administration estimated an oc- ing medications known to prolong QT inter- currence rate of serious cardiac arrhythmias Anything that vals or inhibit cytochrome P450 enzymes. of 46 to 85 per 100,000 users with cardio- decreases the Long QT syndrome increases the risk of TdP, vascular disease, compared to 5 to 44 per concentration of a life-threatening arrhythmia. While TdP is 100,000 users without cardiovascular dis- lower-dose OCs rare, its severity warrants a discussion of risk ease.30 And this may underestimate the actual is concerning, factors and the likelihood of occurrence. incidence because spontaneous reporting especially in Two QT interval prolonging medications of adverse effects declines the longer a drug patients with used together in healthy individuals does is on the market. Ciprofloxacin is associated a higher body not warrant a change in therapy. TdP is most with less risk than levofloxacin and gatifloxa- mass index. likely to occur when 2 or more QT interval cin (the latter of which is no longer available prolonging medications are used in a patient in the United States).26 who is already at high risk for arrhythmia be- A recent population-based study using cause of risk factors such as prolonged QT in- data on over 10.6 million people from the terval at baseline, family history of prolonged Taiwan National Health Insurance Database QT intervals, female gender, age >60 years, examined the risk of cardiovascular death electrolyte abnormalities (hypokalemia, hy- among patients using new-generation mac- pomagnesemia, hypocalcemia), underlying rolides, fluoroquinolones, andβ -lactam/ comorbid diseases (eg, chronic heart failure, β-lactamase inhibitors.31 The absolute risk left ventricular hypertrophy, atrial fibrilla- of cardiovascular death per 1000 individu- tion), hypertension, bradycardia, and genetic als was 0.06 for clarithromycin, 0.12 for cip- (ion channel) polymorphisms.26,27 rofloxacin, 0.13 for amoxicillin-clavulanate, ❚ Antiarrhythmics and antipsychotics 0.36 for azithromycin, 0.39 for levofloxacin, are most commonly associated with drug- and 0.46 for moxifloxacin. The mean interval induced prolonged QT interval, with most between first antibiotic use and the adverse case reports and research being linked to cardiac event was <4 days. Not surprisingly, antiarrhythmics (TABLE 42).28 But macrolide the highest risk was seen in patients with un- and fluoroquinolone antibiotics also have derlying cardiovascular disease. been associated with TdP, although to a lesser Another population-based study, this extent. In a retrospective analysis of case re- time conducted in Hong Kong, evaluated ports of TdP involving macrolides, erythro- the cardiovascular safety of clarithromycin mycin was present (with or without other compared to that of amoxicillin. Clarithro- medications thought to prolong QT) in 53% mycin was found to increase the incidence of the cases and clarithromycin was involved of myocardial infarction, arrhythmia, and in 36% of the reports.29 cardiac mortality in the short term, with the

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TABLE 4 Commonly prescribed medications/medication classes reported to prolong the QT interval2

Analgesics • Formoterol • Ziprasidone • Celecoxib • Levalbuterol Quinolones • Methadone • Salmeterol • Ciprofloxacin • Oxycodone Corticosteroids • Gemifloxacin Antiarrhythmics • Prednisolone • Levofloxacin Anticholinergics • Prednisone • Moxifloxacin • Fesoterodine Diuretics • Ofloxacin • Solifenacin • Furosemide • Trimethoprim/ sulfamethoxazole • Tolterodine • Indapamide SSRIs/SNRIs Antiemetics Gastrointestinal agents • Citalopram • Ondansetron • Famotidine • Escitalopram Antihistamines Macrolides/related antibiotics • Fluoxetine • Diphenhydramine • Azithromycin • Paroxetine Using 2 drugs • Fexofenadine • Clarithromycin • Sertraline that may • Hydroxyzine • Clindamycin increase the • Trazodone Antineoplastics • Erythromycin QT interval • Venlafaxine Antiretrovirals Psychotropics is likely safe Serotonin 5-HT agonists Azole antifungal agents • Atomoxetine in the absence • Sumatriptan • Fluconazole • Haloperidol of certain • Zolmitriptan • Itraconazole • Lithium risk factors. Tricyclic antidepressants • Ketoconazole • Mirtazapine • Voriconazole • Paliperidone Bronchodilators • Quetiapine • Albuterol • Risperidone

SSRIs/SNRIs, selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors.

risk returning to baseline after treatment con- Should patients avoid alcohol cluded.32 A binational cohort study of Danish 4 while taking metronidazole? and Swedish adults confirmed that fluoro- Probably not. quinolones (especially ciprofloxacin) do not Warning patients against drinking alco- increase the risk of a serious arrhythmia com- hol while taking metronidazole has been a pared to penicillins.33 common practice for years. The mechanism for this theorized interaction was thought u THE BOTTOM LINE For patients taking other to be similar to the interaction between di- QT interval prolonging medications or who sulfiram and ethanol.34 Disulfiram inhibits are at a higher risk for TdP, consider using hepatic aldehyde dehydrogenase (ALDH) clarithromycin over erythromycin or azithro- when combined with alcohol, which leads to mycin for a macrolide antibiotic or cipro- increased levels of acetaldehyde in the blood floxacin over levofloxacin or moxifloxacin if a and symptoms of flushing, palpitations, nau- fluoroquinolone is warranted. Using 2 drugs sea, vomiting, headache, and visual distur- that may increase the QT interval is likely safe bances.35 However, multiple studies using in the absence of certain risk factors. rats have found that metronidazole does not

JFPONLINE.COM VOL 65, NO 7 | JULY 2016 | THE JOURNAL OF FAMILY PRACTICE 447 inhibit ALDH or increase acetaldehyde con- 13. Holt RK, Anderson EA, Cantrell MA, et al. Preemptive dose re- duction of warfarin in patients initiating metronidazole. Drug 34 centrations like disulfiram does. Metabol Drug Interact. 2010;25:35-39. A 2000 review article discussed 6 cases 14. Hughes BR, Cunliffe WJ. Interactions between the oral contracep- tive pill and antibiotics. Br J Dermatol. 1990;122:717-718. involving serious metronidazole-ethanol 15. Bolt HM. Interactions between clinically used drugs and oral con- interactions. Ethanol alone was found to ex- traceptives. Environ Health Perspect. 1994;102:35-38. 16. Aronson JK. Meyler’s Side Effects of Drugs. 16th ed. The International plain the reaction in 2 of the cases, and the re- Encyclopedia of Adverse Drug Reactions and Interactions. Amster- maining 4 could be linked to the use of other dam, Netherlands: Elsevier; 2016. Available at: http://ac.els-cdn. com/B978044453717101009X/3-s2.0-B978044453717101009X- 35 drugs or disease states. A 2002 Finnish study main.pdf?_tid=b33f6564-9deb-11e5-a8f0-00000aab0f01&acdnat =1449607315_83f5068fc5105226fcc6d7279c083516. Accessed De- found no statistically significant differences cember 8, 2015. in objective or subjective signs of a disulfi- 17. Masters KP, Carr BM. Survey of pharmacists and physicians on 34 drug interactions between combined oral contraceptives and ram-like interaction. When considering the broad-spectrum antibiotics. Pharm Pract (Granada). 2009;7:139- symptoms associated with the interaction, it 144. 18. Toh S, Mitchell AA, Anderka M, et al; National Birth Defects Pre- is important to remember that many of the vention Study. Antibiotics and oral contraceptive failure—a case- symptoms can result from metronidazole crossover study. Contraception. 2011;83:418-425. 19. Koopmans PC, Bos JH, de Jong van den Berg LT. Are antibiotics therapy alone, regardless of whether other related to oral combination contraceptive failures in the Neth- medications or alcohol are used.35 erlands? A case-crossover study. Pharmacoepidemiol Drug Saf. 2012;21:865-871. 20. Archer JS, Archer DF. Oral contraceptive efficacy and antibiotic u THE BOTTOM LINE Researchers have failed interaction: A myth debunked. J Am Acad Dermatol. 2002;46:917– 923. to identify a clinically significant interaction 21. Scholten PC, Droppert RM, Zwinkels MGJ, et al. No interaction Patients don't between metronidazole and alcohol. Avoid- between ciprofloxacin and an oral contraceptive.Antimicrob Agents Chemother. 1998;42:3266-3268. need to avoid ing alcohol while taking metronidazole does 22. Andrews E, Damle BD, Fang A, et al. Pharmacokinetics and tol- alcohol not appear to be necessary. JFP erability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects. 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