Drug Interactions Between Antibiotics & Maintenance Meds PDF

CLINICAL REVIEW DRUG INTERACTIONS BETWEEN ANTIBIOTICS AND SELECT MAINTENANCE MEDICATIONS: SEEING MORE CLEARLY THROUGH THE NARROW Randolph E. Regal THERAPEUTIC WINDOW OF OPPORTUNITY...

CLINICAL REVIEW DRUG INTERACTIONS BETWEEN ANTIBIOTICS AND SELECT MAINTENANCE MEDICATIONS: SEEING MORE CLEARLY THROUGH THE NARROW Randolph E. Regal THERAPEUTIC WINDOW OF OPPORTUNITY Celina Ong Vue Objective: Infections often occur while treating patients with long-term medications for INTRODUCTION chronic illnesses. Treating these infections with systemic antibiotics often leads to pharma- Whether it is in the long-term care, inpa- cokinetic and pharmacodynamic interactions between the antimicrobials and one or more tient hospital, or ambulatory care settings, of the maintenance medications. Previously optimized long-term regimens may become the intermittent occurrence of infections either subtherapeutic or supertherapeutic, with deleterious consequences. This article dis- cusses some of the most significant and commonly encountered antibiotic drug interactions and the subsequent use of systemic antibi- that may occur with medications with “narrow therapeutic windows” including warfarin, otics is a relatively frequent event. As a phenytoin, carbamazepine, theophylline, and the two calcineurin inhibitors. Given the result, pharmacists may encounter transient logistics of many consultant pharmacists’ practices, it may not always be possible for them but clinically important drug interactions to react prospectively when these combinations are prescribed at their facilities. Therefore, with long-term maintenance medications. there are several things the pharmacist can do: provide regular and comprehensive inser- These interactions may be of special concern vice training on this topic, be available as needed to answer patient-specific questions, when patients are on medications with nar- and provide readily available charts and other educational materials that help identify and characterize these important interactions. row therapeutic windows. Antibiotics are Data sources: A Medline search of the English literature was performed in October/ usually added onto the long-term drug regi- November 2003, going back to 1980 for the commonly used antibiotics and drug inter- men for relatively fleeting periods of time. actions stated in this text. In some cases, cross referencing of articles reviewed also led to However, during this hiatus, drug-drug older publications. Textbooks dealing with drug interactions also were used as initial interactions may lead to anything from rela- sources. However, whenever possible, any data quoted within the text were verified from tively benign increases or decreases in phar- the original research paper. macologic action to overtly toxic side effects Study Selection: Pharmacokinetic studies, case reports, and general review articles pub- or therapeutic failures.When it is not possi- lished in the English medical literature were all selected for review. In cases where review articles were cited that summarize groups of data from previous original research papers, ble to choose noninteracting antibiotic alter- the authors made the best possible effort to verify the accuracy by referring to the original natives, it is crucial that the maintenance research papers. medication(s) be adjusted to mitigate or Data Synthesis: Because of the breadth of the topic in terms of all the antibiotics discussed, avoid the deleterious effects of the drug- the interacting medications that pertained to each antibiotic, and the lack of homogeneity drug interactions. In this paper, we will among the various types of papers (most of which were case reports), most analyses evaluate some of the most common and include broad-based summaries based on the aggregate findings of the authors. clinically significant drug-drug interactions Conclusion: The addition of antibiotics to a stabilized medical regimen can result in either potentiation or antagonism of the clinical effects of narrow-therapeutic-window medications that may occur between antibiotics and nar- such as warfarin, phenytoin, theophylline, calcineurin inhibitors, carbamazepine, and row therapeutic window medications such numerous other agents. As usual in the clinical arena, awareness is the first step in appro- as warfarin, phenytoin, theophylline, cal- priate management of these encounters. cineurin inhibitors, carbamazepine, and a Key Words: Antibiotics, Carbamazepine, Cyclosporine, Digoxin, Drug interactions, selected group of other potentially toxic Phenytoin, Rifampin, Tacrolimus, Warfarin. medications.This will facilitate the clinician’s Abbreviations: CBZ = carbamazepine, CSA = cyclosporine, CYP = cytochrome, DPH = ability to identify, assess, and monitor the phenytoin, INR = international normalized ratio, NAF = nafcillin, PT = prothrombin time, drug interactions to avert or minimize these RIF = rifampin. Consult Pharm 2004;19:1119–28. unwanted iatrogenic effects. WARFARIN POTENTIATION RANDOLPH E. REGAL, BS, PHARMD, is Clinical Pharmacist/Clinical Assistant Professor, University of Michigan Hospital and Health Centers, University of Michigan College of Pharmacy, Ann Arbor, Michigan. At the time Several antibiotics have been found to inter- of this writing, CELINA ONG VUE, PHARMD, was a student, University of Michigan Hospital and Health fere with warfarin metabolism through the Centers, University of Michigan College of Pharmacy, Ann Arbor, Michigan. cytochrome P450 system.Warfarin is a FOR CORRESPONDENCE: Randolph E. Regal, PharmD, University of Michigan Hospital and Health Centers, racemic mixture that is extensively metabo- Department of Pharmacy Services, UH/ B2D301 Box 0008, 1500 E. Medical Center Drive, Ann Arbor, MI lized by these isozymes (Figure 1). Although 48109-0008. Phone: 734-647-4717; fax 734-936-7027; e-mail: [email protected]. this article will not discuss the gestalt of the Copyright © 2004, American Society of Consultant Pharmacists, Inc. All rights reserved. cytochrome P450 system, other articles are VOL. 19, NO. 12 DECEMBER 2004 THE CONSULTANT PHARMACIST 1119 Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications FIGURE 1. METABOLIC PATHWAYS OF THE S AND R ENANTIOMERS OF available that give excellent overviews WARFARIN, AND MEDICATIONS THAT INHIBIT EACH ENANTIOMER on this topic.1,2 The more potent S-isomer is metabolized primarily by CYP2C9. Meanwhile, the less potent R-isomer is Warfarin biotransformed by CYP1A2, 2C19, and 3A4. Inhibition of these isozymes results in decreased warfarin clearance, an increased antithrombotic effect, and a subsequently T1/2 = T1/2 = S isomer R isomer supratherapeutic INR.3,4 Antibiotics that are 1–2days 1.5–4days known to inhibit the metabolism of warfarin include ciprofloxacin5 (1A2), metronidazole6 (2C9), sulfamethoxazole/trimethoprim7,8 (2C9), erythromycin and clarithromycin9 Metabolized by Metabolized by (1A2, 3A4), and the azole antifungals10-13 CYP450 CYP 2C9 CYP450 3A4, 1A2, 2C19 (1A2, 2C9, 3A4), including voriconazole, its most recently marketed member.14 Case reports regarding the potentiation of S-Warfarin Inhibitors R-Warfarin Inhibitors warfarin by the fluoroquinolones, including antiretrovirals (numerous) antiretrovirals—numerous(2C19,3A4) ofloxacin,15 norfloxacin,16 and ciprofloxacin,17 amiodarone amiodarone (1A2, 3A4) began to be published shortly after the azole antifungals azole antifungals (1A2, 2C19, 3A4) marketing of these antibiotics in mid-1980s. disulfiram CCBs (3A4) Soon after the marketing of ciprofloxacin in fluoxetine ciprofloxacin (1A2, 3A4) 1987, several case reports inspired investiga- fluvoxamine clarithro/erythromycin (1A2, 3A4) tors to conduct prospective studies concern- INH fluoxetine (2C19, 3A4) metronidazole fluvoxamine (2C19, 3A4) ing this interaction. However, because many TMP/SMX grapefruit juice (3A4) of the studies were nonrandomized, of small zafirlukast INH (1A2, 3A4) sample size, and involved healthy and young metronidazole (3A4) volunteers, they collectively failed to demon- S-Warfarin Inducers rifampin and related oral contraceptives (1A2) strate a consistent and significant potentia- anticonvulsants omeprazole (2C19) tion of warfarin by these antibiotics. Indeed, carbamazepine zafirlukast (3A4) based upon a review done by Ellis et al.,18 it phenytoin zileuton (1A2, 3A4) appears as if the interactions manifest more phenobarbital/primidone R-Warfarin Inducers often in the elderly with multiple medical anticonvulsants (1A2, 2C19, 3A4) problems on numerous medications. Looking carbamazepine at a compilation of 66 cases reported ana- phenytoin phenobarbital/primidone lyzed by this article, the median age of the glucocorticoids (3A4) coagulopathic patients was 72 years, with griseofulvin(3A4) patients taking a mean of 6.5 medications. nafcillin and related (3A4) The average time to detection of the coagu- rifampin and related (1A2, 2C19, 3A4) lopathy was 5.5 days after quinolone initia- St. John’s wort (1A2, 3A4) tion, with median PT/INRs of 38 sec and smoking (1A2) 10 sec, respectively. In total, there was The S form is presumed to be 2–5 times more potent than the R form. bleeding in 25, resultant hospitalization in Abbreviations: INH=isoniazid, CCB=calcium channel blockers,TMP/SMX= trimethoprim/sulfamethoxazole. 15, and one incident-related death.18 1120 THE CONSULTANT PHARMACIST DECEMBER 2004 VOL. 19, NO. 12  Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications Currently, the literature contains a few TABLE 1. VITAMIN K DEPENDENT CLOTTING FACTORS anecdotal case reports that imply that lev- INHIBITED BY WARFARIN ofloxacin may also potentiate warfarin.19,20 However, one study in healthy male subjects Factor Name Factor Function Factor Half-life found no evidence of a significant pharma- cokinetic interaction between these two Protein C Anticoagulant 8 hours agents.21 Again, until more data are available, Protein S Anticoagulant 30 hours we must learn our lesson from the cipro- floxacin experience and reserve judgement Factor VII Procoagulant 7 hours about the nature and severity of the warfarin- Factor IX Procoagulant 24 hours levofloxacin interaction in the older, less Factor X Procoagulant 36 hours healthy patient population.Thus far, there is Factor II Procoagulant 50 hours no evidence to suggest that either moxi- floxacin, gatifloxacin, or some of the other Source: Refs. 1, 2. newer quinolones will pharmacokinetically potentiate warfarin’s effects.22,23 proteins it affects, the onset of hypopro- Of course, concurrent use of the above- thrombinemia is gradual, and the problem is listed antibiotics and warfarin may result in easily reversed or prevented with the use of an increased risk of bleeding. It is important vitamin K supplementation.26,27 to note that because of the long half-lives of Through yet another mechanism of war- both warfarin isomers and three of the four farin potentiation, broad-spectrum antibiotics affected clotting factors (where the half lives of virtually any class may eradicate intestinal of factors IX, X, and II average about 20, 40, microbes that synthesize absorbable mena- and 60 hours, respectively, see Table 1), the quinones within the intestinal tract. Mena- onset and the offset of the drug-drug interac- quinones are vitamin K precursors that usual- tion may take several days to weeks to fully ly are reabsorbed in the ileum and thus pro- manifest.3,4 Thus, it should be suggested that vide an endogenous source of vitamin K.28 the INR be monitored closely during antibi- Once the stores of vitamin K are depleted, otic therapy and up to at least two weeks even in the absence of coexisting warfarin after its discontinuation. therapy, hypoprothrombinemia may gradually Other mechanisms exist for warfarin appear.This mechanism of potentiation is the potentiation. Certain broad spectrum most plausible explanation for a recent case cephalosporins contain the N-methylthiote- report that showed hypoprothrombinemia trazole side chain, a moiety that chemically (INR to 6.2) and hematuria in a 58-year-old opposes vitamin K by inhibiting hepatic vita- patient on the same dose of warfarin but 2.5 min K epoxide reductase.24 Of these agents, weeks post a seven-day course of amoxicillin- only cefotetan still remains in general use. In clavulanate for a suspected ear infection. Of the absence of concomitant warfarin, clinical- note, the patient did experience a few loose ly significant hypoprothrombinemia with bowel movements during the antibiotic ther- cefotetan is usually only seen in cases where apy, but never reported profuse diarrhea.29 renal dosing is not implemented and patients Finally, irrespective of the antibiotics chosen also have some degree of debility and/or to treat the patient, infections themselves malnutrition.25 As one might expect from the may potentiate warfarin and a number of long half-lives of warfarin and the clotting other P450 substrates.The mechanism pro- VOL. 19, NO. 12 DECEMBER 2004 THE CONSULTANT PHARMACIST 1121 Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications posed is that interferons released during concentration was found to be 95 mcg/mL septic episodes may inhibit several of the (24 mcg/mL).The DPH was then restarted CYP P450 systems.30 at a dose of 300 mg qd while the fluconazole was continued.Two weeks later, his DPH INHIBITION OF PHENYTOIN level was found to be 48 mcg/mL (12 METABOLISM mcg/mL). Phenytoin is an anticonvulsant used for the In another case presented in the same treatment of generalized tonic-clonic seiz- paper, a 42-year-old male with AIDS was ures, simple partial seizures, and complex taking oral DPH 300 mg qhs for five months partial seizures.Total phenytoin (DPH) and oral fluconazole 200 mg/d po for serum levels at about 10 mcg/mL to 20 oropharyngeal candidiasis for two months. mcg/mL (40 to 80 mcg/mL): or, even better This patient did not develop signs of DPH physiologically, free levels at 1 to 2 mcg/mL toxicity until two months after initiation of (4 to 8 mcg/mL), are usually desired to fluconazole therapy.The patient presented achieve optimal control while minimizing with a two-day history of dizziness, ataxia, clinical signs of toxicity. DPH is metabolized vertigo, nausea and vomiting, abdominal mainly by the CYP P450 2C8/2C9 and pain, and ocular difficulties. His total DPH 2C19 isozymes. Antibiotics that have been concentration was 202 mcg/mL (51 shown to inhibit the metabolism and potenti- mcg/mL). DPH was held, and the levels ate the effects of DPH include metronida- dropped to 105 mcg/mL and 84 mcg/mL zole31 (2C8/9), sulfamethoxazole/trimetho- (26 mcg/mL and 21 mcg/mL) on hospital prim (2C8/9), and the azole antifungals10, 32 days 2 and 3, respectively. His symptoms (2C8/9, 2C19). Naturally, concurrent use resolved. Fluconazole was changed to clotri- of these antibiotics and DPH may result in mazole troches, and his DPH dose was an increased risk of hydantoin toxicity, which changed to 200 mg qd. Over the next five usually manifests as confusion, dizziness, weeks, his DPH levels ranged from 28 to 47 weakness, ataxia, hyperreflexia, nystagmus, mcg/mL (7 to 12 mcg/mL).32 These reports and tremors. suggest that complications may occur beyond Because of the Michaelis-Menten kinetics the first few weeks of concurrent therapy of DPH, the effects of these drug-drug inter- with DPH.Thus, regular monitoring of DPH actions are extremely unpredictable.The serum concentration should persist through- peak effects of these interactions may be out the combination therapy. delayed by several days to weeks. For exam- ple, in one case report,32 a 60-year-old male INHIBITION OF THEOPHYLLINE with AIDS was taking oral DPH 300 mg q METABOLISM am and 400 mg q pm for longer than one Theophylline is a methylxanthine bron- year prior to admission, with levels reported- chodilator that is commonly used for the ly held steady at about 35 mcg/mL (9 treatment of symptoms and reversible airway mcg/mL). Six days after initiation of flucona- obstruction resulting from chronic asthma, zole (600 mg qd po for three days followed chronic bronchitis, or chronic obstructive by 400 mg qd po for three days) for pre- pulmonary disease (COPD).Theophylline sumed cryptococcal pneumonia, the patient serum level measurements, which are usually complained of dizziness, weakness, slurred now desired to be in the range of 5 to 15 speech, and double vision.The total DPH mg/L, must be drawn to optimize therapy 1122 THE CONSULTANT PHARMACIST DECEMBER 2004 VOL. 19, NO. 12  Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications and avoid overt toxicity.Theophylline is pri- In addition, even if the patient remains within REFERENCES 1. Michalets EL. Update: clinically significant marily metabolized by the CYP P450 1A2 the therapeutic range, a sudden increase in cytochrome p-450 drug interactions. and 2E1 isozymes. Antibiotics that have been theophylline concentration may produce Pharmacotherapy 1998;8:84-112. shown to significantly inhibit the metabolism intolerable adverse effects in some patients. 2. Omiecinski CJ, Remmel RP, Hosagrahara VP. Concise review of the cytochrome p450s of theophylline are primarily CYP 1A2 Unlike erythromycin and clarithromycin, and their roles in toxicology.Toxicological inhibitors, and include ciprofloxacin, ery- azithromycin does not appear to have a signif- Sciences 1999;48:151-6. thromycin, and clarithromycin. icant effect upon theophylline pharmacoki- 3. Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991;324:1865-75. Concurrent administration of ciprofloxacin netics.The explanation for this appears to be 4. Hirsh J, Dalen JE, Anderson DR et al. Oral with theophylline was shown to cause a mean azithromycin’s inability to bind to the CYP anticoagulants: mechanism of action, clinical increase in theophylline AUC of 45% in one P450 3A isozymes.37 effectiveness, and optimal therapeutic range. study,33 and theophylline clearance reductions The usual manifestations of theophylline Chest 2001;119:s8-s21. 5. Ellis RJ, Mayo MS, Bodensteiner DM. of 30% to 113% have been found in several toxicity include agitation, tremors, tachycar- Ciprofloxacin-warfarin coagulopathy: a case others.22 Although enoxacin also has been dia, nausea/vomiting, abdominal pain and, series. Am J Hematol 2000;63:28-31. found to have a significant effect on theo- in more severe cases, metabolic acidosis, 6. O’Reilly RA.The stereoselective interac- tion of warfarin and metronidazole in man. phylline disposition,23 no such interaction has seizures, hypotension, and fatal tachyarrhyth- N Engl J Med 1976;295:354-7. been found with levofloxacin and the other mias.Therefore, careful clinical and pharma- 7. Kaufman JM, Fauver HE Jr. Potentiation of newer quinolones.22 cokinetic monitoring of theophylline is warfarin by trimethoprim-sulfamethoxazole. Urology 1980;16:601-3. Studies addressing the interaction between required when these agents are added to 8. O’Reilly RA. Stereoselective interaction of erythromycin and theophylline have demon- theophylline therapy. trimethoprim-sulfamethoxazole with the sep- strated that this antibiotic decreases theo- arated enantiomorphs of racemic warfarin in man. N Engl J Med 1980;302:33-5. phylline clearance, thereby resulting in an INHIBITION OF CALCINEURIN INHIBITOR 9. Pai MP, Graci DM, Amsden GW. average elevation of 20% to 25% in serum METABOLISM (CYCLOSPORINE AND Macrolide drug interactions: an update. theophylline concentrations.34,35 This interac- TACROLIMUS) Ann Pharmacother 2000;34:495-513. 10. Piscitelli SC, Rodvold KA. eds. Drug tion is thought to be most important in Cyclosporine (CSA) is an immunosuppres- Interactions in Infectious Diseases.Totowa, patients who receive concomitant therapy for sive agent indicated for the prophylaxis of NJ:. Humana Press;2000. at least seven days and/or have a relatively organ rejection in kidney, liver, and heart 11. Baciewicz AM, Menke JJ, Bokar JA et al. Fluconazole-warfarin interaction. Ann high baseline theophylline concentration transplants, as well as for rheumatoid arthri- Pharmacother 1994;28:1111. (≥12 mg/L).9 Clarithromycin is another tis and psoriasis. CSA toxicities (as listed in 12. Black DJ, Kunze KL,Wienkers LC et al. macrolide antibiotic that has been shown to Table 2) are generally dose-related, and the Warfarin-fluconazole. II.: a metabolically based drug interaction: in vivo studies. Drug inhibit the metabolism of theophylline via systemic exposure of CSA directly correlates Metab Dispos 1996;24:422-8. CYP 1A2. In two unpublished Phase I studies with drug efficacy. CSA is extensively metab- 13. Albengres E, Le Louet H,Tillement J-P. cited in the manufacturer’s package insert,36 olized by CYP450 3A4.Tacrolimus is another Systemic antifungal agents: drug interactions of clinical significance. Drug Safety 1998; extended-release theophylline 6.5 or 12 potent immunosuppressive drug used in liver 18:83-97. mg/kg was administered concomitantly with or kidney transplant recipients.Tacrolimus, 14. Purkins L,Wood N, Kleinermans D et al. oral clarithromycin 250 or 500 mg every 12 like CSA, is extensively metabolized by Voriconazole potentiates warfarin induced prothrombin time prolongation. J Clin hours. An approximate 20% increase in theo- CYP450 3A4 and consequently shows a simi- Pharmacol 2003;56:24-9. phylline steady-state values of Cmax, Cmin, lar drug interaction profile. Antibiotics that 15. Leor J, Matetzki S. Ofloxacin and war- and area under the curve (AUC) were noted have been shown to inhibit the metabolism of farin (letter). Ann Intern Med 1988;109:761. when theophylline was given with clar- CSA and tacrolimus include the azole anti- 16. Linville T, Matanin D. Norfloxacin and warfarin (letter). Ann Intern Med 1989; ithromycin. Although these percent differ- fungals,38-40 clarithromycin, erythromycin,41,42 110:751-2. ences may keep the theophylline concentra- and quinupristin/dalfopristin.43 17. Kamada AK. Possible interaction between tions in the therapeutic range in some In a study of six renal transplant recipi- ciprofloxacin and warfarin. Ann Pharmaco- ther 1990;24:27-8. patients, other patients maintained on the ents,38 fluconazole 200 mg/d orally resulted high end of the range may develop toxicity. in a 1.5-fold increase in the bioavailability of VOL. 19, NO. 12 DECEMBER 2004 THE CONSULTANT PHARMACIST 1123 Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications TABLE 2: IMPORTANT ANTIBIOTIC-MAINTENANCE MEDICATION DRUG INTERACTIONS ANTIBIOTIC POTENTIATION OF MAINTENANCE MEDICATIONS Interacting Drug Antibiotic Mechanism Effect(s) Comments/Management Warfarin Ciprofloxacin ↓ warfarin metabolism ↑ risk of bleeding; Decrease in warfarin dosage may be required via CYP 1A2 hypoprothrombinemia Metronidazole ↓ warfarin metabolism Due to the long T1/2 of both warfarin isomers via CYP 2C9 (R-warfarin: 20-89 hrs, S-warfarin:1/2 18-43 Sulfamethoxazole/ ↓ warfarin metabolism hrs) and the clotting factors, the onset and the Trimethoprim via CYP 2C9 offset of the drug-drug interaction may take several days to weeks to occur Erythromycin ↓ warfarin metabolism via CYP 1A2, 3A4 Monitor PT/INR closely during and up to Clarithromycin ↓ warfarin metabolism two weeks after the discontinuation of the via CYP 1A2, 3A4 antibiotic therapy Azole antifungals ↓ warfarin metabolism (i.e., fluconazole, via CYP 1A2, 2C9, itraconazole, 2C19, 3A4 ketoconazole, voriconazole) Phenytoin Metronidazole ↓ phenytoin metabolism ↑ risk of phenytoin Decrease in phenytoin dosage may be required via CYP 2C8/9 toxicity (i.e., confusion dizziness, weakness, Because of the Michaelis-Menton kinetics Sulfamethoxazole/ ↓ phenytoin metabolism ataxia, hyperreflexia, of phenytoin, the effects of the drug-drug Trimethoprim via CYP 2C8/9 nystagmus, and interactions are even more unpredictable tremors) Azole antifungals ↓ phenytoin metabolism The peak effects of the interaction may be (i.e., fluconazole, via CYP 2C8/9, 2C19 delayed by 10-14 days or longer itraconazole, ketoconazole, Monitoring of phenytoin serum voriconazole) concentrations should persist throughout the combination therapy Theophylline Erythromycin All ↓ theophylline ↑ risk of theophylline Decrease in theophylline dosage may be metabolism via toxicity (i.e., agitation, required Clarithromycin CYP 1A2 tremors, tachycardia, N/V, abdominal pain; Careful clinical and pharmacokinetic Ciprofloxacin and, in more severe monitoring of theophylline are required cases, metabolic acidosis, seizures, hypotension, and fatal dysryhthmias) Cyclosporine Azole antifungals All ↓ cyclosporine and ↑ risk of cyclosporine Decrease in cyclosporine and tacrolimus and (i.e., fluconazole, tacrolimus metabolism and tacrolimus toxicity dosages may be required Tacrolimus itraconazole via CYP 3A4 (i.e., acute tubular ketoconazole, necrosis, hypo- or Peak effects of the drug interaction may take voriconazole) hyperkalemia, 5–7 days hypomagnesemia, HTN Clarithromycin tremors, seizures, and Monitoring of circulating cyclosporine GI side effects) and tacrolimus serum concentrations and Erythromycin appropriate dosage adjustments are essential when these drugs are used concomitantly Quinupristin/ with the interacting antibiotic(s) Dalfopristin Abbreviations: HTN = hypertension, INR = international normalized ratio, N/V = nausea/vomiting. 1124 THE CONSULTANT PHARMACIST DECEMBER 2004 VOL. 19, NO. 12  Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications TABLE 2: IMPORTANT ANTIBIOTIC-MAINTENANCE MEDICATION DRUG INTERACTIONS (CONTINUED) ANTIBIOTIC POTENTIATION OF MAINTENANCE MEDICATIONS Interacting Drug Antibiotic Mechanism Effect(s) Comments/Management Carbamazepine Clarithromycin All ↓ carbamazepine ↑ risk of carbamazepine Decrease in carbamazepine dosage may be metabolism via toxicity (i.e., ataxia, required CYP 3A4 nystagmus, diplopia, Erythromycin headache,vomiting, The onset of the interaction is thought to apnea, seizures, coma) be within several days of initiation of erythromycin, clarithromycin and the azole Fluconazole antifungals and subsides several days after discontinuation of the antibiotic therapy Rifampin Cyclosporine ↑ cyclosporine metabolism ↓ serum cyclosporine Monitor serum cyclosporine concentrations; via CYP 3A4 concentration;may lead increase dosage may be required to graft rejection Calcium channel ↑ CCBs metabolism via ↓ serum CCBs Use alternative agent since large oral CCBs blockers CYP 1A2, 2C8/9, 3A4 concentration; may lead doses may not be adequate; monitor patient (i.e., diltiazem to therapeutic failure for clinical response verapamil, nifedipine) Digoxin ↑ Digoxin metabolism ↓ serum digoxin Monitor arrhythmia control; signs and via CYP 3A4 concentration; may lead symptoms of heart failure; and serum to therapeutic failure digoxin concentrations Theophylline ↑ theophylline metabolism ↓ serum theophylline Monitor serum theophylline concentrations; via CYP 1A2 concentration; may lead may increase dosage if needed to therapeutic failure Warfarin ↑ warfarin metabolism ↓ serum warfarin Monitor INR; may increase dosage if needed via CYP 2C9, 1A2, 3A4 concentration Phenytoin ↑ phenytoin metabolism via CYP 2C8/9, 2C19 Glucocorticoids ↑ glucocorticoids Monitor for decrease therapeutic effect and metabolism via CYP 3A4 ↓ serum drug titrate per response and tolerance Quinidine ↑ quinidine metabolism concentration; may lead via CYP 3A4 to therapeutic failure Monitor phenytoin and quinidine levels Methadone ↑ methadone metabolism via CYP 3A4 Triazolam/ ↑ triazolam metabolism via CYP 3A4 Midazolam ↑ midazolam metabolism via CYP 3A4 Alprazolam ↑ alprazolam metabolism via CYP 3A4 Diazepam ↑ diazepam metabolism via CYP 2C19, 3A4 Sulfonylureas ↑ sulfonylureas metabolism via CYP2C8/9 Losartan ↑ losartan metabolism via CYP 2C8/9, 3A4 TCAs ↑ parent and metabolite metabolism via 2C9 and others Nafcillin Cyclosporine ↑ cyclosporine metabolism ↓ serum cyclosporine Monitor serum cyclosporine concentrations; (& related) via CYP 3A4 concentration; may lead increase dosage may be required to graft rejection Warfarin ↑ warfarin metabolism ↓ serum warfarin Monitor INR; may increase dosage if needed via CYP 3A4 concentration; increase risk of clotting VOL. 19, NO. 12 DECEMBER 2004 THE CONSULTANT PHARMACIST 1125 Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications 18. Ellis RJ, Mayo MS, Bodensteiner DM. CSA, which peaked about day 4 of therapy. metabolized by cytochrome P450 3A4, Ciprofloxacin-warfarin coagulopathy: a case series. Am J Hematol 2000;63:28-31 Most likely through reducing CSA’s first-pass with only approximately 2% of the dose 19. Gheno G, Cinetto L. Levofloxacin- metabolism, erythromycin may increase CSA excreted unchanged in the urine. Clinically warfarin interaction. Eur J Clin Pharmacol concentration by two- to threefold after as meaningful drug interactions have occurred 2001;57:427. few as three days of erythromycin adminis- with concomitant administration of CBZ 20. Jones CB, Fugate SE. Levofloxacin and warfarin interaction. Ann Pharmacotherapy tration.41,42 In one published case of an inter- with erythromycin and clarithromycin. 2002;36:1554-7. action between CSA and quinupristin/dalfo- Erythromycin and clarithromycin decrease 21. Liao S, Palmer M, Fowler C et al. pristin, a patient who had undergone a the hepatic clearance of CBZ, thereby Absence of an effect of levofloxacin on warfarin pharmacokinetics and anticoagula- kidney transplant had baseline trough CSA elevating CBZ serum concentrations. In a tion in male volunteers. J Clin Phar 1996;36: concentrations of 80 to 105 ng/mL.43 At two-way, crossover design study with a 1072-7. two and three days after initiation of quin- four-week washout, eight healthy subjects 22. Aminimanizani A, Beringer P, Jeliffe R. Comparative pharmacokinetics and pharma- upristin/dalfopristin therapy, trough CSA received erythromycin 250 mg every six codynamics of the newer fluoroquinolone concentrations increased to 261 ng/mL and hours for five days before and three days antibacterials. Clin Pharmacokinet 2001; 291 ng/mL, respectively. A one-third reduc- after a 400-mg single dose of CBZ.There 40:169-87. 23. Radandt JM, Marchbanks CR, Dudley tion in the CSA dosage was required. was a decrease in CBZ clearance ranging MN. Interactions of fluoroquinolones with Tacrolimus dosage requirement after initia- from 5% to 41% in seven of the eight sub- other drugs: mechanisms, variability, clinical tion of azole antifungal therapy (fluconazole jects after concurrent administration with significance, and management. Clin Infect Dis 1992;14:272-84 5.3 mg/kg/d ± 2.5 mg/kg/d or itracona- erythromycin.45 The onset of the interaction 24. Shearer MJ, Bechtold H, Andrassy K et zole 5.6 mg/kg/d ± 2.3 mg/kg/d) in pedi- is thought to be within several days of initia- al. Mechanism of cephalosporin-induced atric heart/lung transplant patients (median tion of erythromycin or clarithromycin and hypo-prothrombinemia: relation to cephalosporin side chain, vitamin K metabo- age 15 years old), decreased by 68% within subsides several days after discontinuation lism, and vitamin K status. J Clin Pharmacol the first month of therapy.40 Azole antifungals of the antibiotics. 1988;28:88-95. markedly decrease tacrolimus requirements Case reports also indicate a potentiation 25. Conjura A, Bell W, Lipsky JJ. Cefotetan and hypoprothrombinemia. Ann Intern Med within the first few days of therapy. Based of CBZ by the azole antifungal fluconazole 1988;108:643. upon their findings, the authors recommend (FCZ).46,47 FCZ is known to be a fairly 26. Cohen H, Mackie IJ,Walshe K et al.The an empiric calcineurin inhibitor-dose reduc- potent inhibitor of the 2C isozymes, but is effects of cefotetan disodium on haemostasis. J Hosp Infect 1987;10:51-57. tion of at least 50% upon azole initiation.40 also a weaker inhibitor of the 3A4 isozyme. 27.Ward A, Richards DM. Cefotetan: a According to these reports, the effects of Thus, the 3A4 interactions are though to review of its antibacterial activity, pharmaco- these drug interactions upon CSA and only regularly occur at higher doses of FCZ. kinetic properties, and therapeutic use. Drugs 1985;30:382-426. tacrolimus may take about five to seven days Indeed, one case showed that a baseline 28. Conly J, Stein K. Reduction of vitamin to plateau. Monitoring of CSA and tacro- CBZ level of 6 mcg/mL increased to 18 K-2 concentrations in human liver associated limus serum concentrations and appropriate mcg/mL after 10 full days of concomitant with the use of broad spectrum antimicro- dosage adjustments are essential when these FCZ 400 mg qd.46 Another report showed bials. Clin Invest Med 1994;17:531-9. 29. Davydov L,Yermolnik M , Cuni LJ. drugs are used concomitantly with the a halving of CBZ’s clearance—and an Warfarin and amoxicillin/clavulanate drug aforementioned antibiotics. increase in CBZ levels from 12.4 to 24.5 interaction. Ann Pharmacother 2003;37: mcg/mL—on just 150 mg FCZ qd for 367-9. 30. Morgan ET. Regulation of cytochromes INHIBITION OF CARBAMAZEPINE three days.47 Given the pharmacology of the P450 during inflammation and infection. METABOLISM other azole antifungals and their known Drug Metab Rev 1997;29:1129-88. Carbamazepine (CBZ) is indicated for use as ability to inhibit the 3A4 isozyme, there is 31. Jensen JC, Gugler R. Interaction between metronidazole and drugs eliminated by oxida- an anticonvulsant for the treatment of reason to suspect that they too could elicit tive metabolism. Clin Pharmacol Ther 1985; epilepsy and pain associated with trigeminal a similar interaction when combined with 37:407-10. neuralgia. It is also used as a “mood stabiliz- CBZ. However, more data are needed to er” for anxiety, manic depression, and other further evaluate the significance of these psychological disorders.44 CBZ primarily is interactions. 1126 THE CONSULTANT PHARMACIST DECEMBER 2004 VOL. 19, NO. 12  Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications ANTIBIOTICS AS P450 INDUCERS attain a therapeutic INR during long-term 32. Cadle RM, Zenon III GJ, Rodriguez- Barradas MC et al. Fluconazole-induced Antibiotics may also induce the metabolism RIF therapy (reaching an INR of only 1.90). symptomatic phenytoin toxicity. Ann of some medications, thus producing sub- In addition, a 70% reduction in warfarin Pharmacother 1994;28:191-4. therapeutic serum concentrations and poten- dosage over four to five weeks was necessary 33. Gillum JG, Israel DS, Scott RB et al. to maintain a therapeutic INR after RIF dis- Effect of combination therapy with tiating therapeutic failure. One such antibiot- ciprofloxacin and clarithromycin on theo- ic is rifampin (RIF), which induces CYP1A2, continuation, demonstrating the clinically sig- phylline pharmacokinetics in healthy volun- 2C8/9, 2C19, and 3A4. RIF has been report- nificant offset of this drug interaction. Of teers. Antimicrob Agents Chemother course, RIF is well known to induce the 1996;40:1715-6. ed to consistently accelerate the metabolism 34.Wiggins J, Arbab O, Ayres JG et al. of calcium channel blockers,48,49 (1A2, metabolism of a plethora of other medica- Elevated serum theophylline concentration 2C8/9, 3A4), digoxin48,50 (3A4), CSA48,51 tions. Once RIF is added to a stabilized regi- following cessation of erythromycin treat- men, it generally takes about 2 to 4 days for ment. Eur J Resp Dis 1986;68:298-300. (3A4), theophylline48 (1A2), and warfarin48,52 35. Paulsen O, Hoglund P, Nilsson LG et al. (2C9, 1A2, 3A4). Other medications where the onset, 6 to 10 days for maximum effect, The interaction of erythromycin with theo- additional level monitoring and dose adjust- and two to three weeks for the offset of the phylline. Eur Clin Pharmacol 1987;32:493-8. ment may be necessary include DPH and RIF induction effect.To maintain optimum 36. Package insert. Biaxin (clarithromycin). North Chicago, IL: Abbott Laboratories; quinidine.48 A comprehensive review of RIF- therapeutic blood levels, dosages of these June 2002. related induction reactions also included glu- drugs may require adjustment when starting 37. Nahata M. Drug interactions with cocorticoids, methadone, benzodiazepines or stopping concomitantly administered azithromycin and the macrolides: an overview. J Antimicrob Chemother 1996;37:s133-s142. dependent upon oxidative metabolism (such RIF.48,52 38. Sud K, Singh B, Krishna VS et al. as diazepam, triazolam, midazolam and alpra- Nafcillin (NAF) and other penicillinase- Unpredictable cyclosporine-fluconazole inter- zolam), tricyclic antidepressants, sulfony- resistant penicillins such as cloxacillin, action in renal transplant recipients. Nephrol Dialysis Transplant 1999;4:1698-703. lureas, and losartan on the list of medications dicloxacillin, and oxacillin also have been 39. Macias MO, Salvador P, Jurtado J et al. where reduced therapeutic efficacy should be shown to significantly induce CYP3A4 and Tacrolimus-itraconazole interaction in a kid- anticipated and monitored accordingly. For may increase the metabolism of warfarin53,54 ney transplant patient (letter). Ann Pharma- cother 2000;34:536. instance, in the case of glucocorticoids, the and CSA.55 In one case report,53 NAF 2 g 40. Mahnke CB, Sutton RM,Venkataramanan authors recommended that the glucocorti- every four hours IVPB was added to warfarin R et al.Tacrolimus dosage requirements after coid dose be increased as much as two-to therapy 12.5 mg qd. Despite an increase in initiation of azole antifungal therapy in pedi- atric thoracic organ transplantation. Pediatr threefold to maintain comparable corticos- warfarin dosage to 25 mg daily, the result Transplant 2003;7:474-8. teroid activity.48 was a decreased PT from baseline.The elimi- 41. Freeman DJ, Martell R, Carruthers SG In one case report, a 60-year-old heart nation half-life of warfarin was 11 hours dur- et al. Cyclosporine-erythromycin interaction in normal subjects. Br J Clin Pharmacol transplant patient was stabilized on CSA 175 ing NAF treatment compared with 44 hours 1987; 23:776-8. mg daily with a trough concentration about without NAF.The onset of the NAF-warfarin 42.. Murray BM, Edwards L, Morse GD 100 ng/mL.Treatment with RIF 600 mg interaction may take several days to occur et al. Clinically important interaction of and, once the NAF is stopped, it may take cyclosporine and erythromycin.Transplant- twice daily for two days resulted in a CSA ation 1987;43:602-4. concentration of 61 ng/mL, despite a CSA several days to weeks for the induction effect 43. Stamatakis MK, Richards JG. Interaction dose increase to 200 mg daily. Possibly to subside. between quinupristin/dalfopristin and NAF apparently also can cause a lowering cyclosporine. Ann Pharmacother 1997; because of close pharmacokinetic monitoring 31:576-8. and proactively increasing the dose of CSA, of CSA levels. In one case report, CSA 44. Elphick M.The clinical uses and pharma- this patient did not experience any signs of trough levels fell from 229 to 68 ng/mL and cology of carbamazepine in psychiatry. Int 272 to 42 ng/mL on two separate occasions Clin Psychopharmacol 1988;3:185-203. rejection.51 45.Wong YY, Ludden TM, Bell RD. Effect of The literature also helps impart some in the same renal transplant patient when erythromycin on carbamazepine kinetics. Clin understanding on the interaction between NAF was administered concomitantly with Pharmacol Ther 1983;33:460-4. CSA. Upon discontinuation of NAF, CSA 46.Finch CK, Green CA, Self TH. RIF and warfarin. In one case report,52 a Fluconazole-carbamazepine interaction. South dosage increase from 7.5 to 25 mg of war- trough levels rose to 205 and 296 ng/mL on Med J 2002;95:1099-100. farin over four months proved insufficient to the sixth and 14th day after NAF discontinua- VOL. 19, NO. 12 DECEMBER 2004 THE CONSULTANT PHARMACIST 1127 Clinical Review: Drug Interactions Between Antibiotics and Select Maintenance Medications 47. Nair DR, Morris HH. Potential flucona- tion, respectively.55 Of course, this lowering not in the population that actually requires zole-induced carbamazepine toxicity. Ann Pharmacother 1999;33:790-2. of CSA levels could result in acute allograft these medications, pharmacokinetic studies 48. Strayhorn VA, Baciewicz AM, Self TH. rejection. Not unlike warfarin, the onset and are helpful.Well-documented, postmarketing Update on rifampin drug interactions, III. offset of the NAF-CSA interaction may take surveillance case reports are another impor- Arch Intern Med 1997;157:2453-8. 49. Barbarash RA, Bauman JL, Fischer JH several days to weeks to fully manifest, so tant means to help pharmacists study and et al. Near-total reduction in verapamil vigilant CSA monitoring may be necessary better understand these interactions. bioavailability by rifampin. Electrocardio- before, during, and for at least a couple of It is important that clinicians be able to graphic correlates. Chest 1988;94:954-9. 50. Gault H, Longerich L, Dawe M et al. weeks after the NAF has been discontinued. recognize these clinically significant interac- Digoxin-rifampin interaction. Clin Pharmacol As could be imagined, the induction effect of tions. Awareness will help to avoid both Ther 1984;35:750-4. this group of penicillins may also alter the adverse drug effects and therapeutic failures. 51. Freitag VL, Skifton RD, Lake KD. Effect metabolism of other P450 3A4 substrates Most consultant pharmacists only are able to of short-term rifampin on stable cyclosporine concentrations. Ann Pharmacother 1999;33: such as nifedipine,56 but more data are need- physically visit their facilities once to a few 871-2. ed to better qualify and quantify the signifi- times a month.Therefore, it is usually not 52. Lee CR,Thrasher KA. Difficulties in anti- cance and predictability of these interactions. logistically possible for them to be “in the coagulation management during coadminis- tration of warfarin and rifampin. Pharma- know” at the point of order to facilitate a cotherapy 2001;21:1240-6. CONCLUSION timely prospective intervention. Conse- 53. Qureshi GD, Reinders TP, Somori GJ This article discusses some of the clinically quently, in addition to providing inservice et al.Warfarin resistance with nafcillin thera- py. Ann Intern Med 1984;100:527-9. relevant and significant drug interactions training and other ongoing educational 54.Taylor AT, Pritchard DC, Goldstein AO between antibiotics and certain maintenance processes, one helpful service is to use refer- et al. Continuation of warfarin-nafcillin inter- medications with narrow therapeutic win- ence tables (see Table 2) to remind physicians action during dicloxacillin therapy. J Fam Pract 1994;39:182-5. dows. Because large, controlled, prospective and nurses of the most important of the 55.Veremis SA, Maddux MS, Pollak R et al. clinical trials on drug interactions are impending interactions. Finally, the facility Subtherapeutic cyclosporine concentrations impractical and ethically questionable, the should have the consultant pharmacist’s during nafcillin therapy.Transplantation 1987;43:913-4. true significance and characteristics of these phone or pager number readily available so 56. MICROMEDEX® Healthcare Series Vol. interactions often are difficult to put into that nurses or physicians could reach the 120. 2004. clinical perspective. Although they are usually consultant for further information or case- fairly small, done in healthy volunteers, and specific advice. 1128 THE CONSULTANT PHARMACIST DECEMBER 2004 VOL. 19, NO. 12