Warfarin (Coumadin; Jantoven) is an oral anticoagulant most commonly used for the prevention and treatment of thromboembolic events (blood clots) in patients with atrial fibrillation, prosthetic heart valves, venous thrombosis and/or pulmonary embolism.1 Trimethoprim/Sulfamethoxazole (TMP/SMX) is an oral antibiotic most commonly used to treat respiratory, urinary tract and skin infections.2-5  Because TMP/SMX is a frequently prescribed antibiotic, the opportunities for coadministration with warfarin are quite prevalent.6

The concern with concurrent therapy is the high incidence of clinically significant increases in INR when patients taking warfarin are prescribed TMP/SMX.  Warfarin is a racemic (equal) mixture of two enantiomers, S-warfarin and R-warfarin.  While both enantiomers are pharmacologically active, S-warfarin provides the majority of the clinical effect and toxicity of warfarin, as it is five times more potent than R-warfarin.  Both S-warfarin and R-warfarin are metabolized by cytochrome P450 (CYP) enzymes (a group of gut and liver enzymes responsible for drug metabolism).  More specifically, the S-warfarin is primarily metabolized by CYP2C9, while the R-warfarin is metabolized by CYP3A4.7  Due to S-warfarin's greater potency, any inhibition of CYP2C9 may cause dramatic increases in the degree of anticoagulation as manifested by an increase in the International Normalized Ratio (INR).  The problem with the coadministration of warfarin and SMX is that the metabolism of S-warfarin and SMX are both mediated by CYP2C9.8 More importantly, SMX has been shown to be an inhibitor of CYP2C9 at therapeutic concentrations thereby causing at least a 20% increase in S-warfarin concentrations.9,10  While TMP normally inhibits only CYP2C8 at most doses used in clinical practice, if the therapeutic concentrations exceed 100 microM, it can also inhibit both CYP2C9 and CYP3A4 and therefore also increase the levels of both warfarin enantiomers.9

It appears that both SMX and S-warfarin display the same stereoselectivity and regioselectivity for the binding site on CYP2C9.7,9  As such, SMX is competing for binding sites on the CYP2C9 with S-warfarin.  Since, the gene expression for CYP2C9 has not changed to allow for more or less CYP2C9 to be available, the S-warfarin and SMX have a limited number of binding sites available for their metabolism and elimination from the body.  Therefore, SMX is a competitive inhibitor of S-warfarin metabolism.7,9

Yes.  In fact, the adjusted relative risk (RR) for over anticoagulation (i.e., INR > 6) when starting TMP/SMX (Bactrim) in a patient on stable doses of warfarin has been reported to be 20.1 (95% CI; 10.7 to 37.9).11  This translates into a significantly likelihood for over anticoagulation to occur if no change in warfarin dose is made when starting TMP/SMX.  Recent data suggest a prophylactic, short term dose reduction of warfarin of at least 10 to 20% to be an effective strategy for maintaining a therapeutic level of anticoagulation in patients getting started on TMP/SMX.12  Therefore, it is important for clinicians to consider reductions of the warfarin dose and to initiate close monitoring for signs and symptoms of bleeding when initiating TMP/SMX for the treatment of an infection.

References:

1. Ansell J, Hirsh J, Hylek E et al.  Pharmacology and management of the vitamin K antagonists:  American College of Chest Physicians evidence-based clinical practice guidelines  Chest 2008;133(6 Suppl):160S-198S.
   
2. Anon JB, Jacobs MR, Poole MD et al.  Antimicrobial Treatment Guidelines for Acute Bacterial Rhinosinusitis.  Otolaryngol Head Neck Surg  2004;130(1 Suppl): 1-45.
3. Mandell LA, Wunderink RG, Anzueto A et al.  Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.  Clin Infect Dis   2007;44:S27-72.
4. Warren JW, Abrutyn E, Hebel JR et al.  Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women.  Clin Infect Dis  1999;29:745-58.
5. Stevens DL, Bisno AL, Chambers HF et al.  Practice guidelines for the diagnosis and management of skin and soft-tissue infections.  Clin Infect Dis  2005;41:1373-406.
6. Lamb E. Top 200 prescription drugs of 2007. Pharmacy Times. 2008;74:20-23.
7. Rettie AE, Korzekwa KR, Kunze KL et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions.  Chem Res Toxicol  1992;5:54-9.
8. Cribb AE, Spielberg SP, Griffin GP.  N4-hydroxylation of sulfamethoxazole by cytochorme P450 of the cytochorme P4502C subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes.  Drug Metab Dispos   1995;23:406-414.
9. Wen X, Wang JS, Backman JT et. al.  Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively.  Drug Metab Dispos   2002;30:631-635.
10. O'Reilly RA.  Stereoselective interaction of trimethoprim-sulfamethoxazole with the separated entiomorphs of racemic warfarin in man.  N Engl J Med  1980;302:33-5.
11. Visser LE, Penning-van Bees FJ, Kasbergen AA et al.  Overanticoagulation associated with combined use of antimicrobial drugs and acenocoumarol or phenprocoumon anticoagulants.  Thromb Haemost  2002;88:705-10
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;26:44-8.

Bactrim, Septra, Warfarin, Jantoven, Coumadin, Drug Interaction Warfarin and Bactrim