Trimethoprim-sulfamethoxazole with methotrexate

Ferrazzini G, Klein J, Sulh H et al. Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with evksm ai. J Pediatr 1990 17 823-826. 

Several drugs (e.g., sulfasalazine, trimethoprim-sulfamethoxazole, and methotrexate) have been reported to cause a fohc acid deficiency megaloblastic anemia. These drugs either interfere with folate absorption or inhibit the dihydrofolate reductase enzyme necessary for conversion of dihydrofolate to its active tetrahydrofolate form (see Chap. 102, on drug-induced blood dyscrasias). 

The starting dose as well as dose adjustment in therapy are made according to guidelines fixed in the treatment protocols. For pneumocystis carinii pneumonia prophylaxis, trimethoprim-sulfamethoxazole is administered on three consecutive days per week, with the largest possible interval in reference to the weekly methotrexate application. This is done to account for the theoretical enhancement of the antifolic activity of methotrexate by co-administered trimethoprim-sulfamethoxazole (72,73). Because several reports have suggested an improved outcome with bedtime administration, 6-MP is commonly administered in the evening hours (74,75). Also, 6-MP should not be given in combination with milk because the xanthine oxidase (XO) activity contained in milk decreases the bioavailability of 6-MP (76,77,78). 

Jeurissen ME, Boerbooms AM, van de Putte LB. Pancytopenia and methotrexate with trimethoprim-sulfamethoxazole. Ann Intern Med 1989 111(3) 261. 

Several other agents have been used to prevent recurrence of ANCA-associated diseases. Mycophenolate mofetU has been used anecdotally with favorable results for remission maintenance. Methotrexate has also been used however, it should not be given when the creatinine clearance is <50 mL/min. Trimethoprim-sulfamethoxazole was found to reduce ANCA-associated vasculitis, especially in the upper respiratory tract. 

The mechanism differs from that underlying the sulfamethoxazole/trimethoprim interaction. Sulphonamides such as co-trimoxazole and sulfadiazine are known to cause renal dysfunction - interstitial nephritis and renal failure, which may -L excretion of methotrexate. Sulphonamides are also known to compete with methotrexate for renal elimination. Displacement from protein-binding sites of methotrexate is a minor contribution to the interaction... 

Cardiovascular An 8-year-old weighing 48 kg presented to an emergency department 1 h after intentionally ingesting 15 ondansetron 4-mg oral tablets (1.25 mg/kg). He was on oral treatment with mercaptopurine (50 mg, daily), methotrexate (12.5 mg, once weekly), sulfamethoxazole/trimethoprim (80 mg, twice daily), in addition to oral ondansetron (8 mg, three times daily as needed), for precursor B-cell lymphoblastic lymphoma. Approximately 6 h after ondansetron ingestion, the patient developed hypotension, but without heart rate or electrocardiogram alterations. Blood pressure lowering was managed with a 2-L bolus of normal saline followed by intravenous noradrenaline infused until symptoms resolved. The symptoms resolved in approximately 12 h [24 ]. 

---