スルファメトキサゾール·トリメトプリム

A high incidence (up to 80%) of adverse reactions to trimethoprim/sulfamethoxazole occurs in AIDS patients receiving this combination for the treatment or prophylaxis of Pneumocystis carinii pneumonia. These adverse reactions have included nausea and vomiting, fever, cutaneous reactions (erythroderma, morbilliform rash, toxic epidermal necrolysis, Stevens-Johnson syndrome), peripheral cytopenias (neutropenia, thrombocytopenia, anemia), hepatitis, and azotemia. Some of these are believed to be hypersensitivity reactions because they recur with drug rechallenge. However, some of the serious toxic reactions associated with trimethoprim/sulfamethoxazole, such as myelosuppression, appear to be dose related. Concomitant zidovudine may exacerbate the myelosusppression.

Skin rashes are among the most common adverse effects caused by trimethoprim/sulfamethoxazole and are most often due to hypersensitivity to the sulfonamide component. These are usually mild, diffuse, maculopapular rashes that are reversible upon discontinuation of the drug. Serious skin reactions, including toxic epidermal necrolysis, erythema multitome, exfoliative dermatitis, and the Stevens-Johnson syndrome, have occurred rarely.

There is no evidence that trimethoprim-sulfamethoxazole, when given in the recommended doses, induces folate deficiency in normal persons. However, the margin between toxicity for bacteria and that for man may be relatively narrow when the cells of the patient are deficient in folate. In such cases, trimethoprim-sulfamethoxazole may cause or precipitate megaloblastosis, leukopenia, or thrombocytopenia. In routine use, the combination appears to exert little toxicity. About 75% of the untoward effects involve the skin. These are typical of those known to be produced by sulfonamides. However, trimethoprim-sulfamethoxazole has been reported to cause up to three times as many dermatological reactions as does sulfisoxazole when given alone.

Patients with AIDS frequently react adversely when trimethoprim-sulfamethoxazole is administered to treat infection due to Pneumocystis carinii. Fever, malaise, rash, and/or pancytopenia were noted in 8 of 18 patients in one series; the incidence was 90% in another. It may be possible to continue therapy if the dose of the combination is lowered and concentrations of trimethoprim in plasma are monitored. Renal allograft recipients may suffer from severe hematological toxicity.

For more Human Toxicity Excerpts (Complete) data for TRIMETHOPRIM/SULFAMETHOXAZOLE (13 total), please visit the HSDB record page.

Teratogenic in rats. /From table/

Studies in rabbits given doses of 150 to 350 mg of sulfamethoxazole causes increased maternal mortality but has no adverse effects on the fetus. Studies in rabbits given doses of trimethoprim 6 times the usual human therapeutic dose have shown that trimethoprim causes an increase in the number of dead, resorbed, and malformed fetuses.

Studies in rats given oral doses of 200 mg of trimethoprim and 533 mg of sulfamethoxazole per kg of body weight have shown that sulfamethoxazole causes teratogenic effects (primarily cleft palates). However, doses of 192 mg of trimethoprim per kg of body weight and 512 mg of sulfamethoxazole per kg of body weight, when administered separately, did not cause cleft palates in rats. Doses of 88 mg of trimethoprim per kg of body weight and 355 mg of sulfamethoxazole per kg of body weight have been shown to causes cleft palates when administered concurrently.

Studies in rats, given oral doses as high as 70 mg of trimethoprim per kg of body weight and 350 mg of sulfamethoxazole per kg of body weight daily, have not shown that sulfamethoxazole or trimethoprim causes any adverse effects on fertility or general reproductive performance.

Bacterial mutagenicity studies with sulfamethoxazole and trimethoprim combination have not been done. Trimethoprim has not been shown to be mutagenic in the Ames assay.

Co-trimoxazole is metabolized in the liver. Trimethoprim is metabolized to oxide and hydroxylated metabolites and sulfamethoxazole is principally N-acetylated and also conjugated with glucuronic acid. Both drugs are rapidly excreted in urine via glomerular filtration and tubular secretion. In adults with normal renal function, approximately 50-60% of a trimethoprim and 45-70% of a sulfamethoxazole oral dose are excreted in urine within 24 hours. Approximately 80% of the amount of trimethoprim and 20% of the amount of sulfamethoxazole recovered in urine are unchanged drug. In adults with normal renal function, urinary concentrations of active trimethoprim are approximately equal to those of active sulfamethoxazole. Urinary concentrations of both active drugs are decreased in patients with impaired renal function.

Co-trimoxazole is widely distributed into body tissues and fluids, including sputum, aqueous humor, middle ear fluid, prostatic fluid, vaginal fluid, bile, and cerebrospinal fluid; trimethoprim also distributes into bronchial secretions. Trimethoprim has a larger volume of distribution than does sulfamethoxazole. In adults, apparent volume of distribution of 100-120 and 12-18 l have been reported for trimethoprim and sulfamethoxazole, respectively. In patients with uninflamed meninges, trimethoprim and sulfamethoxazole concentrations in cerebrospinal fluid are about 50 and 40%, respectively, of concurrent serum concentrations of the drugs. Trimethoprim and sulfamethoxazole concentrations in middle ear fluid are approximately 75 and 20%, respectively, and in prostatic fluid are approximately 200 and 35%, respectively, of concurrent serum concentrations of the drugs.

After a single oral dose of the combined preparation, trimethoprim is absorbed more rapidly than sulfamethoxazole. The concurrent administration of the drugs appears to slow the absorption of sulfamethoxazole. Peak blood concentrations of trimethoprim ususally occur by 2 hours in most patients, while peak concentrations of sulfamethoxazole occur by 4 hours after a single oral dose.

Trimethoprim is rapidly distributed and concentrated in tissues, and about 40% is bound to plasma protein in the presence of sulfamethoxazole. The volume of distribution of trimethoprim is almost nine times that of sulfamethoxazole. The drug readily enters cerebrospinal fluid and sputum. High concentrations of each component of the mixture are also found in bile.

The pharmacokinetics of trimethoprim-sulfamethoxazole were studied in 12 healthy adult subjects receiving trimethoprim at 20 mg/kg of body weight per day and sulfamethoxazole at 100 mg/kg/day, which is the conventional dose for treating Pneumocystis carinii pneumonia. Daily doses were evenly divided and orally administered every 6 h for 3 days. Trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole concn in serum and urine were measured by HPLC. Five subjects withdrew from the study because of intolerable GI and CNS toxicities. In the seven subjects that completed the study, the mean maximum serum drug concn after the last dose were 13.6 + or - 2.0, 372 + or - 64, and 50.1 + or - 10.9 ug/ml for trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole, respectively. The mean half-lives were 13.6 + or - 3.5, 14.0 + or - 2.3, and 18.6 + or - 4.3 hr, respectively. Changes in absolute neutrophil count were significantly correlated with the minimum concn of trimethoprim and sulfamethoxazole in serum and trimethoprim area under the concn-time curve (for all three parameters, r2 = 0.6 and p < 0.05). These findings add to the evidence that serum drug concn in adults following the conventional dose of trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia are excessive and contribute to certain adverse reactions.

This article reviews the pharmacokinetics, clinical use, and adverse effects of trimethoprim/sulfamethoxazole in renally impaired patients. Renal dysfunction changes the pharmacokinetics of both component drugs. Trimethoprim and sulfamethoxazole disposition are not significantly altered until creatinine clearance is less than 30 ml/min, when sulfamethoxazole metabolites and trimethoprim accumulate and may lead to toxicity. Renal dysfunction, however, does not preclude the use of trimethoprim/sulfamethoxazole to treat susceptible infections, even when creatinine clearance is less than 15 ml/min. Adverse effects may occur more frequently in renally impaired patients but are not clearly related to increased serum concentrations of either drug. Guidelines for appropriate dosing and monitoring of trimethoprim/sulfamethoxazole therapy in these patients are presented.