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PubMed1989

New forms of multidrug therapy for the treatment of leprosy. First report for the practice on rifampicin + sulfamethoxazole-trimethoprim + protionamide and rifampicin + sulfamethoxazole-trimethoprim + isoniazid.

Since 1970, when the lifelong monotherapy with dapsone (DDS) in leprosy could be replaced by short-term combination therapy with rifampicin + isoniazid + protionamide + DDS (Isoprodian-RMP), chemotherapeutic research was faced with two problems: (1) to find alternative treatment regimens for cases of intolerance, and (2) to work out forms of therapy allowing a further reduction of the average treatment time of 2 years. The present paper describes the attempts made to find solutions to these problems. With two new combinations, alternatives have become available, and the average treatment time is shortened to 6 months. Both combinations are also effective in tuberculosis.

Drug Therapy, Combination↗
PubMed1992

Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial.

BACKGROUND: Prophylaxis with low-dose trimethoprim-sulfamethoxazole has been shown to be cost-effective in the prevention of urinary tract infections, pyelonephritis, urosepsis, and pneumocystis pneumonia in renal transplant recipients. Ciprofloxacin, effective against almost all urinary tract pathogens in this patient population, represents a promising alternative prophylactic agent for patients unable to tolerate trimethoprim-sulfamethoxazole due to toxicity. METHODS: We conducted a randomized, double-blind trial to compare low-dose trimethoprim-sulfamethoxazole with ciprofloxacin for the prevention of urinary tract infections in renal transplant recipients. Patients received either ciprofloxacin (250 mg) or trimethoprim-sulfamethoxazole (80 mg trimethoprim, 400 mg sulfamethoxazole) daily for 6 months following transplantation. Treatment was considered successful if patients completed the 6-month course and 3-month follow-up period without evidence of urinary tract infection or drug-related toxicities. RESULTS: Of 103 eligible patients, 51 received ciprofloxacin and 52 received trimethoprim-sulfamethoxazole. At 6 months, treatment was successful in 75% (38 of 51) receiving ciprofloxacin and 71% (37 of 52) treated with trimethoprim-sulfamethoxazole (P = 0.87, relative risk 1.04, 95% confidence limits 0.83 to 1.33). Thirteen patients (25%) receiving trimethoprim-sulfamethoxazole withdrew from the study-4 for resistant urinary tract infection and 9 for drug-related toxicity, while 3 (6%) of the patients receiving ciprofloxacin withdrew because of drug-related toxicity (P = 0.016, relative risk of urinary tract infection or adverse event 0.24, 95% confidence limits 0.07 to 0.78). At 9 months, all 38 patients who completed the 6-month course of ciprofloxacin remained free of urinary tract infection, while an additional 4 patients who had received trimethoprim-sulfamethoxazole prophylaxis (total of 8 patients over the 9 months) developed urinary tract infections (P = 0.006, Fisher's exact test for urinary tract infection alone). Pneumocystis pneumonia occurred in a total of 7 (14%) patients who were randomized to ciprofloxacin, but 2 of the 7 had withdrawn from the study at least 2 weeks prior to the diagnosis of pneumocystis pneumonia. There were no cases of pneumocystis pneumonia in patients receiving trimethoprim-sulfamethoxazole (P = 0.006). Following completion of the study, monthly aerosolized pentamidine administered in conjunction with ciprofloxacin has provided complete protection against urinary tract infection and pneumocystis pneumonia in 30 transplant recipients unable to tolerate trimethoprim-sulfamethoxazole therapy. CONCLUSIONS: Ciprofloxacin is at least as effective as trimethoprim-sulfamethoxazole in the prevention of urinary tract infection in renal transplant recipients, and is better tolerated. Ciprofloxacin prophylaxis is associated with a higher incidence of pneumocystis pneumonia than is trimethoprim-sulfamethoxazole therapy. An uncontrolled follow-up study suggests that ciprofloxacin prophylaxis combined with monthly aerosolized pentamidine may be efficacious in preventing both urinary tract infection and pneumocystis pneumonia in renal transplant recipients.

Adult↗
PubMed1994

The hydroxylamine of sulfamethoxazole and adverse reactions in patients with acquired immunodeficiency syndrome.

We measured the urine concentrations of sulfamethoxazole, sulfamethoxazole hydroxylamine, and N-sulfamethoxazole on days 3 and 10 in 15 patients with acquired immunodeficiency syndrome treated with a combination product of trimethoprim (15 mg/kg/day) and sulfamethoxazole (75 mg/kg/day). The percentage of sulfamethoxazole and metabolites excreted on days 3 and 10, respectively, were sulfamethoxazole 17.2% +/- 11.3% versus 15.6% +/- 8.2%; sulfamethoxazole hydroxylamine 2.6% +/- 2.0% versus 5.0% +/- 5.2% (p < 0.05); N-acetylsulfamethoxazole 80.0% +/- 12.9% versus 79.8% +/- 11.8%. The percentage of sulfamethoxazole hydroxylamine excreted was similar between the eight patients who discontinued therapy because of toxicity and the seven patients who did not (2.9% +/- 2.3% versus 2.3% +/- 2.0%, p = 0.7). In two patients who had major liver toxicity the percentage of sulfamethoxazole hydroxylamine excreted was significantly lower than that of the 13 patients who did not (0.8% +/- 0.1% versus 2.9% +/- 2.0%, p < 0.05). This is the first report of the formation and excretion of sulfamethoxazole hydroxylamine in patients with acquired immunodeficiency syndrome. With 15 patients we were unable to show a significant correlation between the percentage of sulfamethoxazole hydroxylamine excreted and adverse reactions. However, patients with liver toxicity excreted less sulfamethoxazole hydroxylamine.

AIDS-Related Opportunistic Infections↗
PubMed1986

Penetration of trimethoprim and sulfamethoxazole into cysts in a patient with autosomal-dominant polycystic kidney disease.

This study examines the causes for the therapeutic failure of trimethoprim-sulfamethoxazole in a patient with infected cysts caused by a sensitive strain of Escherichia coli. We determined the concentration of trimethoprim and sulfamethoxazole in eight cysts (four proximal, four distal) following therapeutic nephrectomy in a patient treated eight days with trimethoprim-sulfamethoxazole in appropriate doses. In four proximal cysts, mean trimethoprim level was 16.1 +/- 0.8 micrograms/mL with mean sulfamethoxazole level of 94.7 +/- 13.0 micrograms/mL. In distal cysts, mean trimethoprim level was 227.8 +/- 16.8 micrograms/mL with mean sulfamethoxazole level of 9.7 +/- 3.6 micrograms/mL. Serum peak and trough trimethoprim concentrations were 9.8 micrograms/mL and 5.4 micrograms/mL with peak and trough sulfamethoxazole concentrations of 136.0 micrograms/mL and 65.0 micrograms/mL. Significant WBC counts were present in seven cysts, three proximal and four distal. All three proximal cysts were sterile; in contrast, the four distal cysts grew the same strain of E coli isolated from the blood and urine of this patient. The infection resolved following nephrectomy. We conclude that the failure of trimethoprim-sulfamethoxazole to eradicate the infection was caused by the inability of sulfamethoxazole to enter distal cysts in sufficient concentration for the synergistic effect commonly seen with trimethoprim and sulfamethoxazole in combination. Treatment of cyst infections with trimethoprim-sulfamethoxazole should probably be avoided in instances when the organism is resistant to trimethoprim alone.

Cysts↗
PubMed1988

Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study.

STUDY OBJECTIVE: To ascertain the efficacy and toxicity of trimethoprim-sulfamethoxazole or pentamidine when either is given alone during the entire treatment period for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Prospective, randomized, noncrossover comparison of trimethoprim-sulfamethoxazole with pentamidine. Trimethoprim-sulfamethoxazole dosage was adjusted to maintain serum trimethoprim at 5 to 8 micrograms/mL. Pentamidine dosage was reduced by 30% to 50% for an absolute rise in serum creatinine of more than 88 mumol/L (1 mg/dL). SETTING: Tertiary care hospital and AIDS clinic. PATIENTS: Thirty-six patients were treated with trimethoprim-sulfamethoxazole and 34 with pentamidine. Pretreatment clinical features and laboratory test results were similar in the two groups. MEASUREMENTS AND MAIN RESULTS: Thirty-six recipients of trimethoprim-sulfamethoxazole and 33 recipients of pentamidine completed therapy without crossover. Trimethoprim-sulfamethoxazole caused a rash (44%) and anemia (39%) more frequently (P less than or equal to 0.03, whereas pentamidine caused nephrotoxicity (64%), hypotension (27%), or hypoglycemia (21%) more frequently (P less than or equal to 0.01). The (A - a)DO2 improved by greater than 1.3 kPa (10 mmHg) 8 days earlier for trimethoprim-sulfamethoxazole recipients (95% CI for the difference in response, -1 to 17; P = 0.04). Thirty-one (86%) patients treated with trimethoprim-sulfamethoxazole and 20 (61%) with pentamidine survived and were without respiratory support at completion of treatment (95% CI for the difference in response, 5% to 45%; P = 0.03). CONCLUSIONS: For most patients with AIDS and P. carinii pneumonia, successful treatment with a single agent is possible. Toxicity associated with the two standard treatments is rarely life-threatening and may be diminished if the trimethoprim-sulfamethoxazole dosage is modified by pharmacokinetic monitoring and the pentamidine dosage is reduced for nephrotoxicity. Oxygenation improved more quickly and survival was better with trimethoprim-sulfamethoxazole.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones.

T cells can recognize small molecular compounds like drugs. It is thought that covalent binding to MHC bound peptides is required for such a hapten stimulation. Sulfamethoxazole, like most drugs, is not chemically reactive per se, but is thought to gain the ability to covalently bind to proteins after intracellular drug metabolism. The purpose of this study was to investigate how sulfamethoxazole is presented in an immunogenic form to sulfamethoxazole-specific T cell clones. The stimulation of four CD4(+) and two CD8(+) sulfamethoxazole-specific T cell clones by different antigen-presenting cells (APC) was measured both by proliferation and cytolytic assays. The MHC restriction was evaluated, first, by inhibition using anti-class I and anti-class II mAb, and second, by the degree of sulfamethoxazole-induced stimulation by partially matched APC. Fixation of APC was performed with glutaraldehyde 0.05%. The clones were specific for sulfamethoxazole without cross-reaction to other sulfonamides. The continuous presence of sulfamethoxazole was required during the assay period since pulsing of the APC was not sufficient to induce proliferation or cytotoxicity. Stimulation of clones required the addition of MHC compatible APC. The APC could be fixed without impairing their ability to present sulfamethoxazole. Sulfamethoxazole can be presented in an unstable, but MHC-restricted fashion, which is independent of processing. These features are best explained by a direct, noncovalent binding of sulfamethoxazole to the MHC-peptide complex.

Antigen-Presenting Cells↗
PubMed2006

Trimethoprim-sulfamethoxazole versus norfloxacin in the prophylaxis of spontaneous bacterial peritonitis in cirrhosis.

BACKGROUND: The prognosis of patients with chronic liver disease and spontaneous bacterial peritonitis is poor, being of great importance its prevention. AIM: To compare the effectiveness of trimethoprim-sulfamethoxazole versus norfloxacin for prevention of spontaneous bacterial peritonitis in patients with cirrhosis and ascites. PATIENTS AND METHODS: Fifty seven patients with cirrhosis and ascites were evaluated between March 1999 and March 2001. All of them had a previous episode of spontaneous bacterial peritonitis or had ascitic fluid protein concentration < or = 1 g/dL and/or serum bilirubin > or = 2.5 mg/dL. The patients were randomly assigned to receive either 800/160 mg/day of trimethoprim-sulfamethoxazole 5 days a week or 400 mg of norfloxacin daily. The mean time of observation was 163 days for the norfloxacin group and 182 days for the trimethoprim-sulfamethoxazole group. In the statistical analysis, differences were considered significant at the level of 0.05. RESULTS: According to the inclusion criteria, 32 patients (56%) were treated with norfloxacin and 25 (44%) with trimethoprim-sulfamethoxazole. Spontaneous bacterial peritonitis occurred in three patients receiving norfloxacin (9.4%) and in four patients receiving trimethoprim-sulfamethoxazole (16.0%). Extraperitoneal infections occurred in 10 patients receiving norfloxacin (31.3%) and in 6 patients receiving trimethoprim-sulfamethoxazole (24.0%). Death occurred in seven patients (21.9%) who received norfloxacin and in five (20.0%) who received trimethoprim-sulfamethoxazole. Side effects occurred only in the trimethoprim-sulfamethoxazole group. CONCLUSION: In spite of the reduced number of patients and time of observation, trimethoprim-sulfamethoxazole and norfloxacin were equally effective in spontaneous bacterial peritonitis prophylaxis, suggesting that trimethoprim-sulfamethoxazole is a valid alternative to norfloxacin.

Anti-Infective Agents↗
PubMedDate not supplied

Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial.

CONTEXT: The optimal antimicrobial regimen and treatment duration for acute uncomplicated pyelonephritis are unknown. OBJECTIVE: To compare the efficacy and safety of a 7-day ciprofloxacin regimen and a 14-day trimethoprim-sulfamethoxazole regimen for the treatment of acute pyelonephritis in women. DESIGN: Randomized, double-blind comparative trial conducted from October 1994 through January 1997. SETTING: Twenty-five outpatient centers in the United States. PATIENTS: Of 378 enrolled premenopausal women aged at least 18 years with clinical diagnosis of acute uncomplicated pyelonephritis, 255 were included in the analysis. Other individuals were excluded for no baseline causative organism, inadequate receipt of study drug, loss to follow-up, no appropriate cultures, and other reasons. INTERVENTIONS: Patients were randomized to oral ciprofloxacin, 500 mg twice per day for 7 days (with or without an initial 400-mg intravenous dose) followed by placebo for 7 days (n = 128 included in analysis) vs trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without intravenous ceftriaxone, 1 g) (n = 127 included in the analysis). MAIN OUTCOME MEASURE: Continued bacteriologic and clinical cure, such that alternative antimicrobial drugs were not required, among evaluable patients through the 4- to 11-day posttherapy visit, compared by treatment group. RESULTS: At 4 to 11 days posttherapy, bacteriologic cure rates were 99% (112 of 113) for the ciprofloxacin regimen and 89% (90 of 101) for the trimethoprim-sulfamethoxazole regimen (95% confidence interval [CI] for difference, 0.04-0.16; P = .004). Clinical cure rates were 96% (109 of 113) for the ciprofloxacin regimen and 83% (92 of 111) for the trimethoprim-sulfamethoxazole regimen (95% CI, 0.06-0.22; P = .002). Escherichia coli, which caused more than 90% of infections, was more frequently resistant to trimethoprim-sulfamethoxazole (18%) than to ciprofloxacin (0%; P<.001). Among trimethoprim-sulfamethoxazole-treated patients, drug resistance was associated with greater bacteriologic and clinical failure rates (P<.001 for both). Drug-related adverse events occurred in 24% of 191 ciprofloxacin-treated patients and in 33% of 187 trimethoprim-sulfamethoxazole-treated patients, respectively (95% CI, -0.001 to 0.2). CONCLUSIONS: In our study of outpatient treatment of acute uncomplicated pyelonephritis in women, a 7-day ciprofloxacin regimen was associated with greater bacteriologic and clinical cure rates than a 14-day trimethoprim-sulfamethoxazole regimen, especially in patients infected with trimethoprim-sulfamethoxazole-resistant strains.

Acute Disease↗
PubMed1996

Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole.

OBJECTIVE: To determine the effect of multiple dosing of combined sulfamethoxazole and trimethoprim on the single-dose pharmacokinetics of lamivudine. METHODS: Fourteen subjects with human immunodeficiency virus who had CD4+ cells > or = 200/mm3 received two single doses of 300 mg lamivudine, separated by 7 to 14 days, in a randomized two-day crossover study. Treatment consisted of lamivudine alone versus trimethoprim-sulfamethoxazole (160/180 mg) daily on days 1 through 4 followed by lamivudine plus trimethoprim-sulfamethoxazole on day 5. Blood and urine were collected over 24 to 32 hours to determine lamivudine, trimethoprim, sulfamethoxazole, and N-4-acetylsulfamethoxazole concentrations. RESULTS: Coadministration of a single dose of lamivudine and trimethoprim-sulfamethoxazole after daily dosing for 5 days altered the pharmacokinetics of lamivudine. A 43% increase in area under the concentration-time curve (AUC infinity) and a 35% decrease in renal clearance (CLR) were observed when lamivudine was coadministered with trimethoprim-sulfamethoxazole compared with lamivudine alone. The geometric least-squares trimethoprim-sulfamethoxazole were as follows: AUC infinity, 10,124 (9,432-10,866) and 14,448 (13,461-15,508) ng . hr/ml, respectively; CLR, 16.6 (14.1-19.4) and 10.8 (9.5-12.6) L/hr, respectively. Coadministration did not significantly alter the pharmacokinetics of trimethoprim or sulfamethoxazole. CONCLUSIONS: Coadministration of lamivudine with trimethoprim-sulfamethoxazole resulted in an increased AUC infinity and a decreased CLR of lamivudine. However, given the favorable safety profile of lamivudine, it is unlikely that this interaction will result in a significant increase in concentration-related toxicity at the doses studied.

Administration, Oral↗
PubMed1991

Disposition of drugs in cystic fibrosis. I. Sulfamethoxazole and trimethoprim.

The disposition of sulfamethoxazole and trimethoprim, after constant rate intravenous administration (10 mg/kg/hr sulfamethoxazole and 2 mg/kg/hr trimethoprim for 1 hour), was investigated in adult patients with cystic fibrosis (n = 7) and in age-matched healthy subjects (control subjects, n = 8). The total plasma clearance of sulfamethoxazole was found to be increased in cystic fibrosis (0.0262 +/- 0.0064 L/hr/kg) when compared with that found in control subjects (0.0188 +/- 0.0043 L/hr/kg). This increase in clearance was found to be primarily attributable to an increase in the metabolic clearance of sulfamethoxazole to N4-acetylsulfamethoxazole (0.00903 +/- 0.00247 versus 0.00355 +/- 0.00049 L/hr/kg) with the renal clearance of sulfamethoxazole remaining unchanged. These conclusions were not altered when the pharmacokinetic parameters were computed for the unbound drug or when they were normalized with respect to body surface area. These data indicate that, in cystic fibrosis, the enzymes mediating the metabolism of sulfamethoxazole to N4-acetylsulfamethoxazole, N-acetyltransferase(s), may be induced, activated, or both, or that the uptake of sulfamethoxazole by cells that metabolize sulfamethoxazole to N4-acetylsulfamethoxazole is enhanced. The total plasma clearance of trimethoprim was also found to be increased in cystic fibrosis (0.1808 +/- 0.0440 L/hr/kg) when compared with that found in control subjects (0.1139 +/- 0.0193 L/hr/kg). In contrast to sulfamethoxazole, this increase in clearance was found to be primarily attributable to an increase in the renal clearance of trimethoprim (0.1240 +/- 0.0299 versus 0.0720 +/- 0.0166 L/hr/kg). These data indicate that the tubular secretion of trimethoprim may be enhanced in cystic fibrosis.

Adult↗
PubMed1992

A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. The Dutch AIDS Treatment Group.

BACKGROUND: Primary prophylaxis against Pneumocystis carinii pneumonia (PCP) is recommended for patients with human immunodeficiency virus (HIV) infection if their CD4 cell counts are below 200 per cubic millimeter (0.2 x 10(9) per liter). Either aerosolized pentamidine or trimethoprim-sulfamethoxazole (co-trimoxazole) is commonly prescribed for prophylaxis, but the relative efficacy and toxicity of these agents are unknown. METHODS: We conducted a multicenter trial involving 215 HIV-infected patients with no history of PCP but with CD4 cell counts below 200 per cubic millimeter. The patients were randomly assigned to one of three regimens: aerosolized pentamidine once a month, 480 mg of trimethoprim-sulfamethoxazole once a day (80 mg of trimethoprim and 400 mg of sulfamethoxazole), or 960 mg of trimethoprim-sulfamethoxazole once a day (160 mg and 800 mg, respectively). The cumulative incidence of PCP was estimated by Kaplan-Meier survival analysis. RESULTS: After a mean follow-up of 264 days, 6 of the 71 patients in the pentamidine group had a confirmed first episode of PCP (11 percent), whereas none of the 142 patients in the two trimethoprim-sulfamethoxazole groups had PCP (P = 0.002). However, adverse events that required discontinuation of the medication were much more frequent in the trimethoprim-sulfamethoxazole groups (17 and 18 patients) than in the pentamidine group (2 patients). The adverse reactions occurred significantly sooner in the group given 960 mg of trimethoprim-sulfamethoxazole than in the group given 480 mg (mean time, 16 vs. 57 days; P = 0.02). CONCLUSIONS: For patients with HIV infection, trimethoprim-sulfamethoxazole taken once a day is more effective as primary prophylaxis against PCP than aerosolized pentamidine administered once a month, although adverse drug reactions are more frequent with trimethoprim-sulfamethoxazole.

AIDS-Related Opportunistic Infections↗
PubMed1993

Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS.

BACKGROUND: Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. METHODS: We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). RESULTS: Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P < 0.001), and death (P < 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. CONCLUSIONS: For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.

AIDS-Related Opportunistic Infections↗
PubMed1995

Pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients.

Current dosage regimens of trimethoprim-sulfamethoxazole used to treat Pneumocystis carinii pneumonia in AIDS patients have been based on data from healthy subjects or patients without AIDS. The clearance and absorption characteristics of the drugs may potentially be different between patients with and without AIDS. This study was conducted to assess the pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients treated for P. carinii pneumonia. Patients received trimethoprim at 15 mg/kg of body weight and sulfamethoxazole at 75 mg/kg of body weight daily intravenously in three to four divided doses and were switched to the oral route when the regimen was tolerated. Serum samples for determination of drug concentrations were obtained over 12 h after intravenous and oral dosing. The pharmacokinetics of trimethoprim and sulfamethoxazole were compared in eight critically ill versus nine non-critically ill male patients and were as follows, respectively: clearance, 1.88 +/- 0.44 versus 1.73 +/- 0.64 ml/min/kg for trimethoprim and 0.40 +/- 0.12 versus 0.34 +/- 0.11 ml/min/kg for sulfamethoxazole; volume of distribution, 1.6 +/- 0.5 versus 1.5 +/- 0.5 liters/kg for trimethoprim and 0.5 +/- 0.3 versus 0.4 +/- 0.1 liters/kg for sulfamethoxazole; and half-life, 10.9 +/- 7.4 versus 11.3 +/- 4.0 h for trimethoprim, and 15.5 +/- 9.5 versus 14.3 +/- 4.7 h for sulfamethoxazole. No significant differences (P > 0.05) were observed between patient groups, although there was wide intersubject variability. Absorption appeared to be similar between the critically ill and non-critically patients: bioavailability was 97.5% +/- 22.4% versus 101.8% +/- 22.7% for trimethoprim and 86.2% +/- 17.9% versus 99.1% +/- 20.5% for sulfamethoxazole, respectively. Because of the similar pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients, the two groups of patients may receive similar dosages. Dosage adjustment does not appear to be required when switching from the intravenous to the oral route.

AIDS-Related Opportunistic Infections↗
PubMed2002

Pharmacokinetics of sulfamethoxazole and trimethoprim in donkeys, mules, and horses.

OBJECTIVE: To compare serum disposition of sulfamethoxazole and trimethoprim after IV administration to donkeys, mules, and horses. ANIMALS: 5 donkeys, 5 mules, and 3 horses. PROCEDURE: Blood samples were collected before (time 0) and 5, 15, 30, and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, and 24 hours after IV administration of sulfamethoxazole (12.5 mg/kg) and trimethoprim (2.5 mg/kg). Serum was analyzed in triplicate with high-performance liquid chromatography for determination of sulfamethoxazole and trimethoprim concentrations. Serum concentration-time curve for each animal was analyzed separately to estimate noncompartmental pharmacokinetic variables. RESULTS: Clearance of trimethoprim and sulfamethoxazole in donkeys was significantly faster than in mules or horses. In donkeys, mean residence time (MRT) of sulfamethoxazole (2.5 hours) was less than half the MRT in mules (6.2 hours); MRT of trimethoprim in donkeys (0.8 hours) was half that in horses (1.5 hours). Volume of distribution at steady state (Vdss) for sulfamethoxazole did not differ, but Vdss of trimethoprim was significantly greater in horses than mules or donkeys. Area under the curve for sulfamethoxazole and trimethoprim was higher in mules than in horses or donkeys. CONCLUSIONS AND CLINICAL RELEVANCE: Dosing intervals for IV administration of trimethoprim-sulfamethoxazole in horses may not be appropriate for use in donkeys or mules. Donkeys eliminate the drugs rapidly, compared with horses. Ratios of trimethoprim and sulfamethoxazole optimum for antibacterial activity are maintained for only a short duration in horses, donkeys, and mules.

Animals↗