Isordil

Warfarin (Coumadin) is associated with numerous clinically significant drug and food interactions.1,2 Additionally, several disease states may alter the response to warfarin.3 Some 20 years have passed since it was reported that the effect of trimethoprim/ sulfamethoxazole (Septra, Bactrim, Cotrim) on response to warfarin is caused by stereoselective inhibition of the more active S-warfarin.4

Although the interaction is well documented with trimethoprim/ sulfamethoxazole (TMP-SMX)4-8 and other sulfonamides,9-12 most reports occurred at least 20 years ago. Today, clinicians may not be as vigilant regarding this interaction. This concern was heightened by a recent case of a hospital admission due to bleeding and high International Normalized Ratio (INR), most likely caused by the effect of TMP-SMX on response to warfarin.

The Case

A 79-year-old man was admitted to the hospital in November 1999, secondary to complaints of maroon-colored stool. According to the patient's daughter, two days prior to admission, the patient had approximately three episodes of maroon- to black-colored stool that appeared to contain blood clots.

The patient's medical history was significant for hypertension, chronic obstructive pulmonary disease, Type 2 diabetes, prostate cancer, two transient ischemic attacks, and a questionable history of Crohn's disease. The patient also had documented allergies to penicillin and ciprofloxacin.

In March 1999, the patient was hospitalized following a cerebrovascular accident while on aspirin therapy. Warfarin was started and the patient was discharged on a dose of 7 mg/day with an INR of 2.3. Other medications at discharge were albuterol MDI (Proventil, Ventolin) two puffs every 4 hours, docusate sodium 200 mg daily, flunisolide MDI (AeroBid) two puffs twice daily, guaifenesin with phenylpropanolamine (Entex LA) 1 tablet every 12 hours, isosorbide dinitrate (Isordil) 40 mg three times daily, metoclopramide (Reglan) 10 mg four times daily, theophylline 300 mg twice daily, insulin, meclizine (Antivert) 25 mg every 6 hours as needed, and acetylcysteine (Mucomyst) every 6 hours as needed.

Eight days prior to the November admission, the patient was prescribed TMP-SMX double-strength tablets for a urinary tract infection (UTI). The dosage prescribed was two tablets twice a day for 10 days. The only prothrombin time (PT) and INR recorded between the March and November admissions was in June and showed a PT of 17.3 and INR of 1.8. Dosage changes to warfarin were not made, nor was closer monitoring of the PT/INR performed. From March to November, medication changes included the addition of tolbutamide (Orinase) 500 mg two tablets three times daily with meals, clonidine (Catapres) 0.1 mg every 4 hours as needed, and quinapril (Accupril) 20 mg daily, which were all started in the spring of 1999.

At admission, the patient was hemodynamically stable, with no complaints of hematemesis, abdominal pain, or diarrhea. The patient had a hematocrit of 30.4%, a PT of 60.6, an IN of 4.6, and a platelet count of 224 x 10^sup 3^/mm^sup 3^.

Warfarin therapy was discontinued due to toxicity. The patient was aggressively treated with intravenous (I.V.) fluids to correct a suspected fluid loss. Six hours after admission, the patient's hematocrit was 26.2%, at which time he received 2 units of packed red blood cells.

On the second hospital day, the patient's hematocrit ranged from 24% to 27% and the INR dropped to 2.4. Prior to esophagogastroduodenoscopy (EGD), the patient received 1 mg vitamin K intravenously. The examination showed no source of bleeding, and a colonoscopy was scheduled for the next day. The patient's INR fell to 1.2, and enoxaparin (Lovenox) was started for CVA prophylaxis. No source of bleeding was found via colonoscopy. The TMP-SMX was finally discontinued.

The patients condition normalized over the next 5 days with a resolution of melena and the hematocrit stabilized at 35.4%. The patient was discharged to the nursing home on all prior medications except TMP-SMX and warfarin. The patient's maintenance anticoagulation remained enoxaparin 30 mg every 12 hours. The patient was continued on this dose for 4 months.

N Discussion

In the extremely busy and complex dinical arena, important drug interactions maybe overlooked. TMP-SMX is frequently and routinely prescribed for several indications, and concomitant warfarin therapy is indicated in many of these patients. Metabolism inhibition of the warfarin S-stereoisomer is most likely caused by the sulfonamide component of TMP-SMX: sulfonamides alone are documented to enhance response to warfarin.9-12 Because warfarin interaction with TMP-SMX has not been reported in the literature in many years, it is possible that some clinicians are not as cognizant of it as they were 10 to 20 years ago. Only one case report of warfarin interaction with TMP-SMX has been in the literature since 1980.(13)

UTIs occur in about 10% of men and 20% of women over the age of 65,14 and this rises to 30% to 50% in the institutionalized elderly.15 The most frequent infecting organism is Escherichia coli; however, other common pathogens include Proteus, Pseudomonas, Klebsiella, Enterobacter, enterococci, and staphylococci. E. coli is more common in the outpatient population, and the latter are more often found in hospitalized patients.14

UTIs in the elderly generally do not present with the typical manifestations. Instead, patients may present with acute mental status changes, dizziness, nausea, or general deterioration without any of the common genitourinary symptoms. If a readily identifiable cause cannot be determined when a patient presents in this manner, the clinician should keep UTI high on the differential diagnosis list.

The choice of antimicrobial therapy should be based on the suspected organism and the patient's clinical status. Asymptomatic bacteriuria should not be treated. Patients who are ambulatory or stable should be treated empirically with one of the following drugs: TMPSMX double strength twice daily, amoxicillin/clavulanic acid (Augmentin) 875 mg twice daily, an oral cephalosporin twice daily, or an oral fluoroquinolone (levofloxacin [Levaquin] 250 mg once daily or ciprofloxacin [Cipro] 250 mg twice daily). Hospitalized or unstable patients should be given IN. antibiotics, such as a third-generation cephalosporin, a penicillin with a beta-lactamase inhibitor, a fluoroquinolone, piperacillin, or an aminoglycoside. However, in patients receiving warfarin (because there are documented interactions with TMP-SMX, ciprofloxacin, and other fluoroquinolones),16 beta-lactams or aminoglycosides are better choices.

The patient in this case had only one PT/INR measured over an 8-month period. Patients who are receiving warfarin should have their PT/INR monitored frequently, preferably every 4 weeks once a stable measurement is achieved.2 If the patient requires a dosage adjustment or is placed on a drug that can interact with warfarin (or an interacting drug is discontinued), more frequent monitoring should be done until a stable response is seen.

A low molecular weight heparin, such as enoxaparin, should only be used for prophylaxis until warfarin can be restarted and a therapeutic INR obtained. This patient was subjected to 4 months of unnecessary injections and higher drug costs.

Despite the lack of monitoring, this case is suggestive of an interaction between warfarin and TMP-SMX because the TMP-SMX was the only obvious variable to change in this patient. No other disease states or concomitant drugs in this patient have been reported to affect response to warfarin.

This case report is a timely reminder to circumvent interaction with other appropriate antimicrobials that do not affect response to warfarin or to initiate careful monitoring of the INR when antimicrobial therapy cannot be changed. Although drug interactions are generally manageable, the effect of TMP-SMX is so well documented to be associated with high risk, avoidance of the combination is prudent.

REFERENCES

1. Wells PS, Holbrook AM, Crowther NR, et al.: The interaction of warfarin with drugs and food. Ann Intern Med 1994;121:676-83.

2. Hirsh J, Dalen JE, Anderson DR et al.: Oral anticoagulants. Chest 1998; 114:4455-4695.

3. Demirkan K, Stephens M, Newman K, et al.: Effect of disease states on response to warfarin and other oral anticoagulants. South Med J 2000; 93:448-54.

4. O'Reilly RA: Stereoselective interaction of trimethoprim-sulfamethoxazole with the separated enantiomorphs of racemic warfarin in man. N Engl J Med 1980;302:33-35.

5. O'Reilly RA, Motley CH: Racemic warfarin and trimethoprim-sulfamethoxazole interaction in humans. Ann Intern Med 1979;91:34-36.

6. Kaufman JM, Fauver HE: Potentiation of warfarin by trimethoprim-sulfamethoxazole. Urology 1980;16:601-03.

7. Greenlaw CW: Drug interaction between cotrimoxazole and warfarin. Am J Hosp Pharm 1979;36:1155-56.

8. Errick JK, Keys PW: Co-trimoxazole and warfarin: Case report of an interaction. Am J Hosp Pharm 1978;35:1399.

9. Tilstone WJ, Gray JM, Nimmo-Smith RH, et al.: Interaction between warfarin and sulfamethoxazole. Postgrad Med 1977;53:388-90.

10. Self TH, Evans W, Ferguson T: Interaction of sufisoxazole and warfarin. Circulation 1975; 52:528. 11. Sioris LJ, Weibert RT, Pentel PR: Potentiation of

warfarin anticoagulation by sulfisoxazole. Arch Intern Med 1980;140:546-47.

12. Lumholtz B, Siersbaek-Nielsen K, Skovsted L, et al.: Sufamethizole-induced Inhibition of diphenylhydantoin, tolbutamide, and warfarin metabolism. Clin Pharmacol Ther 1975;17:731-34.

13. Cook DE, Ponte CD: Suspected trimethoprim/ sulfamethoxazole-induced hypoprothrombinemia. J Earn Pract 1994;39:589-91.

14. Sobel JD, Kaye D: Urinary tract infections. In: Principles and practice of infectious disease. Mandel GL, Bennett JE, Dolin R, eds. Philadelphia Pa.: Churchill Livingstone, 2000;773-805.

15. Ernst ME, Ernst EJ: Effectively treating common infections in residents of long-term care facilities. Pharmacotherapy 1999;19:1026-35.

16. Jolson HM, Tanner LA, Green L, et al.: Adverse reaction reporting of interaction between warfarin and fluoroquinolones. Arch Intern Med 1991;151:1003-04.

Cheryl Cummings Stegbauer, CFNP, PhD

Clinical Case Report Editor

Carol C. Chafin, MAEd, PharmD Britt A. Ritter, PharmD Alan James, MD Timothy H. Self, PharmD

ABOUT THE AUTHORS

Carol C. Chafin, MAEd, PharmD, is a clinical pharmacy resident, University of Tennessee, Memphis. Britt A. Ritter, PharmD, is a clinical pharmacy resident, Baptist Memorial Hospital, Memphis.

Alan James, MD, is instructor of medicine, University of Tennessee, Memphis.

Timothy H. Self, PharmD, is professor of clinical pharmacy, University of Tennessee, Memphis.

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