Pharmacokinetics and adverse effects of 20-mg/kg/day trimethoprim and 100-mg/kg/day sulfamethoxazole in healthy adult subjects

Abstract

The pharmacokinetics of trimethoprim-sulfamet-hoxazole 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 cannii pneumonia (PCP). Daily doses were evenly divided and orally administered every 6 h for 3 days. Trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole concentrations in serum and urine were measured by high-performance liquid chromatography. Five subjects withdrew from the study because of intolerable gastrointestinal and central nervous system toxicities. In the seven subjects that completed the study, the mean maximum serum drug concentrations after the last dose were 13.6 ± 2.0, 372 + 64, and 50.1 10.9 ,ig/ml for trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole, respectively. The mean half-lives were 13.6 3.5, 14.0 2.3, and 18.6 4.3 h, respectively. Changes in absolute neutrophil count were significantly correlated with the minimum concentrations of trimethoprim and sulfamethoxazole in serum and trimethoprim area under the concentration-time curve (for all three parameters, r2 = 0.6 and P < 0.05). Our findings add to the evidence that serum drug concentrations in adults following the conventional dose of trimethoprim-sulfamethoxazole for PCP are excessive and contribute to certain adverse reactions. Further studies are indicated in patients to optimize the dosing regimen of trimethoprim-sulfamethoxazole in the treatment of PCP.Pneumocystis carinii pneumonia (PCP) is the most prevalent opportunistic infection in patients infected with human immunodeficiency virus type 1 (HIV), with over 80,000 cases reported since 1981 (3). This pneumonia accounts for 60% of the index diagnoses of AIDS, and approximately 80% of patients will develop an episode of PCP during their course of HIV infection (2). About 90% of patients with mild to moderate disease will respond with early initiation of therapy; however, in nearly 25% of patients, this pneumonia has been a major cause of mortality (13). Although widespread use of anti-pneumocystis pneumonia chemoprophylaxis will potentially reduce the incidence of PCP in HIVinfected patients, efforts focused on optimizing the acute management of this life-threatening infection nonetheless are warranted.Trimethoprim-sulfamethoxazole in a daily dose of 20 and 100 mg/kg of body weight, respectively, is a standard therapeutic modality for the treatment of PCP in AIDS patients, despite a greater than 60% incidence of adverse reactions during treatment (1,9,12,17,23 methoprim concentrations at 5 to 8 ,ug/ml decreased toxicity without an apparent diminution in efficacy. In addition, preliminary data indicate that maintaining the peak serum sulfamethoxazole concentration below 200 ,ug/ml may decrease the incidence of leukopenia (5).The current dosing recommendation of 20-mg/kg/day trimethoprim and 100-mg/kg/day sulfamethoxazole for treatment of PCP originated from studies in pediatric cancer patients (10,11). This repre...

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

“…It is likely that this represents rapid elimination of this compound in mice as we have determined (unpublished) that in Balb/c mice, the genetic background of the scid mice used in the present study, trimethoprim has a T l/2 of approximately 2 h in serum or lung lavage fluid following im or po administration of 100/500 mg/kg/day trimethoprim/sulphamethoxazole, whereas sulphamethoxazole has a T ip of about 20 h in serum and about 10 h in lung lavage fluid. Although the Ti n of sulphamethoxazole in Balb/c mice is similar to that in humans (8-6 h (Grose, Bodey & Loo, 1979); 11 h (Kaplan et al, 1973); 14 h (Stevens et al, 1991)), the T l/2 of trimethoprim in mice is considerably shorter than the Tip. of trimethoprim in humans (7-6 h (Grose et al, 1979); 11 h (Kaplan et al, 1973); 13-6 h (Stevens et al, 1991)).…”

“…Although the Ti n of sulphamethoxazole in Balb/c mice is similar to that in humans (8-6 h (Grose, Bodey & Loo, 1979); 11 h (Kaplan et al, 1973); 14 h (Stevens et al, 1991)), the T l/2 of trimethoprim in mice is considerably shorter than the Tip. of trimethoprim in humans (7-6 h (Grose et al, 1979); 11 h (Kaplan et al, 1973); 13-6 h (Stevens et al, 1991)). This confirms previous observations of rapid elimination of trimethoprim in rodents (Walzer et al, 1992a).…”

Multiple-dose pharmacokinetics of 12 milligrams of trimethoprim and 60 milligrams of sulfamethoxazole per kilogram of body weight per day in healthy volunteers

“…As a result, excessive concentrations of trimethoprim-sulfamethoxazole in serum in adults caused by disparities in drug disposition compared with that of children occurred when the pediatric dose was extrapolated to adult AIDS patients. This could be a contributing factor in the increased incidence of concentration-dependent toxicities observed for the former population.We have recently reported the pharmacokinetics of 20-mg/ kg/day trimethoprim and 100-mg/kg/day sulfamethoxazole in the 7 of 12 healthy adult volunteer subjects who completed the study (20). The concentrations of trimethoprim and sulfamethoxazole in serum were excessive and resulted in toxicity related to systemic drug exposure (i.e., high area under the concentration-time curves and high trough serum drug concentrations).…”

“…Therefore, this study was designed to characterize the pharmacokinetic parameters of 12-mg/kg/day trimethoprim and 60-mg/kg/day sulfamethoxazole in healthy volunteer subjects. Both clinical and laboratory assessments of drug toxicity were evaluated because of the low tolerability of co-trimoxazole in our previous trial (20). …”

A changing pattern of susceptibility of Xanthomonas maltophilia to antimicrobial agents: implications for therapy

“…Hence, it would be tempting to use high doses of these agents (at or close to the maximum tolerated doses), preferably in combination, in the treatment of serious X. maltophilia infections. As an example, administration of trimethoprim at 12 to 15 mg/kg of body weight per day and sulfamethoxazole at 60 to 75 mg/kg/day will maintain maximum serum trimethoprim concentrations of 5 to 10 ,ug/ml (34,35,38); administration of even higher doses, 20 mg of trimethoprim per kg per day and 100 mg of sulfamethoxazole per kg per day, will result in even higher maximum serum drug concentrations of 13.6 and 372 ,ug/ml, respectively (36). Most X maltophilia isolates would be inhibited at those drug concentrations.…”