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At least 19 recordsLinked to original sources

PubMed1974

Trimethoprim-sulfamethoxazole compared with sulfamethoxazole in urinary tract infection.

Thirty-nine subjects with active non-obstructive urinary tract infection due to common pathogens were treated in a randomized fashion either with sulfamethoxazole alone (22 patients) or a combination of trimethoprim-sulfamethoxazole (17 patients) during four consecutive weeks in the course of a controlled study. The combination trimethoprim-sulfamethoxazole appeared more effective than sulfamethoxazole alone in eradicating infection. Complete disappearance of urinary tract infection was obtained in 82% of subjects treated with the combination versus 59% in those treated with sulfamethoxazole alone. Recurrence of infection averaged 43% in the group treated with the combination and 54% in those treated with sulfamethoxazole alone. The mean time interval between successful response and recurrence of infection was 17 weeks for the combination and 20 weeks for sulfamethoxazole alone. When the comparison of the results between sulfamethoxazole alone and the combination trimethoprim-sulfamethoxazole is restricted to the subjects with E. coli infection (69% of all cases), no important difference between the two groups can be demonstrated. A skin rash which sometimes disappeared spontaneously despite continued medication was the only side effect noted with the trimethoprim-sulfamethoxazole combination.

Adult↗

PubMed1973

Absorption and urinary execretion of trimethoprim, sulfamethoxazole, and trimethoprim-sulfamethoxazole: results with single doses in normal young adults and preliminary observations during therapy with trimethoprim-sulfamethoxazole.

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Administration, Oral↗

PubMed1993

Assay of the acetyl-CoA probe acetyl-sulfamethoxazole and of sulfamethoxazole by gas chromatography-mass spectrometry.

We present gas chromatographic-mass spectrometric assays for (i) the concentration of sulfamethoxazole and (ii) the concentration and molar percentage enrichment of acetyl-sulfamethoxazole in biological fluids. The compounds are extracted with ethyl acetate, derivatized with either diazomethane or pentafluorobenzyl bromide, and analyzed by gas chromatography-mass spectrometry. Quantitation is achieved using internal standards, [2H4]sulfamethoxazole and acetyl-[2H4]sulfamethoxazole. Limits of detection are 200 nmol for the methyl derivatives and 2 nmol for the pentafluorobenzyl derivatives. The high sensitivity of the assay with the pentafluorobenzyl derivatives allows measuring in plasma and urine (i) the pharmacokinetics of sulfamethoxazole and acetyl-sulfamethoxazole and (ii) the stable isotope enrichment of the acetyl moiety of acetyl-sulfamethoxazole. The latter is used as a probe for the noninvasive chemical biopsy of liver extramitochondrial acetyl-CoA.

Acetyl Coenzyme A↗

PubMed1978

Trimethoprim-sulfamethoxazole vs sulfamethoxazole for acute urinary tract infections in children.

A total of 118 children between 6 months and 10 years of age with acute urinary tract infection were treated in a random; double-blind manner with 12 mg/kg/day of trimethoprim-sulfamethoxazole (61 patients) or 50 mg/kg/day of sulfamethoxazole (57 patients) for ten days. Mean trimethoprim and sulfamethoxazole susceptibilities of Escherichia coli isolated from these patients were 1.2 and 0.6 microgram/ml, respectively. Mean serum concentrations of trimethoprim and sulfamethoxazole were 1.8 and 62 microgram/ml, respectively, one hour after the dose. Of the children who completed the ten days of prescribed medication, clinical and bacteriological cure was confirmed immediately after treatment for all but one patient in each group. Most patients in each treatment group with recurrent infections had underlying urological abnormalities. Severe hematological, renal, or hepatic toxicity requiring interruption of treatment was not encountered. No advantage of trimethoprim-sulfamethoxazole over sulfamethoxazole alone for acute urinary tract infection was demonstrated.

Acute Disease↗

PubMed2001

[Determination of sulfamethoxazole in compound sulfamethoxazole tablet by first derivative ratio spectrometry].

The first derivative ratio spectrometry is used for the determination of sulfamethoxazole in compound sulfamethoxazole tablet. According to the first derivative ratio spectrum of sulfamethoxazole, peak-zero method is applied for the determination at 251 nm. There is a good linear correlation between the first derivative ratio spectrum value and concentration (1-15 micrograms.mL-1) for the method that can eliminate the disturbance of trimethoprim, and no difference while comparing the method with pharmacopoeia method (P > 0.05).

Spectrophotometry, Ultraviolet↗

PubMed2001

Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+ T-cells.

1. Hypersensitivity to the drug sulfamethoxazole (SMX) is thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX-NHOH) and further oxidation to the ultimate reactive metabolite, nitroso-sulfamethoxazole (SMX-NO). SMX-NO covalently modifies self proteins which in turn might be recognized as neo-antigens by T-cells. The antioxidant glutathione (GSH) is known to protect cells from reactive metabolites by conjugation and subsequent dissociation to SMX-NHOH and/or SMX. 2. To study the reactivity of T-cells to SMX metabolites and their respective role in the generation of drug-specific T-cells, we analysed the effect of GSH on the response of PBMC to SMX and its metabolites SMX-NHOH and SMX-NO. Furthermore, we monitored the proliferative response of drug-specific T-cell clones in the presence or absence of GSH. 3. We found that addition of GSH to peripheral blood mononuclear cells had no effect on the SMX-specific response but enhanced the proliferation to SMX-metabolites. The response of SMX-NO-specific T-cell clones was abrogated when GSH was present during the covalent haptenation of antigen presenting cells (APC). Conversely, SMX-specific T-cell clones gained reactivity through the conversion of SMX-NO to the parent drug by GSH. While GSH had no effect on the initial activation of T-cell clones, it prevented covalent binding to APCs, reduced toxicity and thereby led to proliferation of drug-specific T-cells to non-reactive drug metabolites. 4. Our data support the concept that in allergic individuals T-cells recognize the non-covalently bound parent drug rather than APC covalently modified by SMX-NO.

Adult↗

PubMed2026

Genome-wide identification of conditionally essential genes for growth in the presence of sulfamethoxazole and trimethoprim in sulfamethoxazole- and trimethoprim-resistant Escherichia coli.

UNLABELLED: Resistance to sulfonamides (SULs) and trimethoprim (TMP) in Escherichia coli threatens their clinical relevance. Beyond known resistance mechanisms, little is understood about the cellular responses that enable resistant E. coli to grow under these antibiotic stresses. This study aimed to identify genes that support bacterial growth under SUL and TMP stress. Two saturated transposon mutant libraries were constructed in resistant E. coli MG1655 harboring either dfrA1 or sul2. They were grown with and without 1/2 and 1/4 minimum inhibitory concentration (MIC) of sulfamethoxazole (SMX) or TMP, and mutant depletion was assessed via transposon-directed insertion-site sequencing. At 1/2 MIC, 36 and 89 genes were identified as conditionally essential during SMX and TMP exposure, while 5 and 2 genes were classified as conditionally essential at 1/4 MIC. Genes identified as conditionally essential at 1/4 MIC were also important at 1/2 MIC. Conditionally essential genes belonged to lipopolysaccharide biosynthesis, peptidoglycan metabolism, energy production, membrane integrity, phosphate metabolism, and stress responses, highlighting the role of these factors in maintaining cell stability under SMX and TMP stress. Validation with 10 conditionally essential genes (apaH, mtn, surA, waaO, nlpI, prc, wzxE, fadR, degP, and tpiA) showed that deletion mutants indeed exhibited growth defects and two- to eightfold reductions in MIC under antibiotic stresses compared to their parent strains. This study highlights cellular responses to SMX and TMP under antibiotic stress, and it has identified a list of genes whose products may serve as potential helper drug targets to resensitize resistant E. coli to SMX and TMP treatments. IMPORTANCE: Sulfonamides (SULs) and trimethoprim (TMP) are broad-spectrum antimicrobials. They are commonly used to treat infections in both humans and animals. Resistance against SUL and TMP is widespread in pathogenic bacteria, and there is a need to overcome this problem. One possibility is to target the cellular mechanism by which the resistant bacteria adapt to growth in the presence of the antimicrobials. In this study, we identify the genes, besides the resistance genes, which enable resistant Escherichia coli to grow in the presence of SUL and TMP. We further show that knocking out many of these genes attenuates the resistant E. coli for growth during SUL and/or TMP stress, irrespective of which SUL- or TMP-resistant gene the bacteria carry. The gene products of these genes may serve as potential helper drug targets to resensitize resistant E. coli to sulfamethoxazole and TMP treatments.

Escherichia coli↗

PubMed1975

Comparison of trimethoprim-sulfamethoxazole with sulfamethoxazole in urinary tract infections of children.

The effect of trimethorpim-sulfamethoxazole was compared with that of sulfamethoxazole alone in 26 children with urinary tract infection, randomly assigned according to a double-blind procedure to two equally sized groups. TMX-SMX was found to be superior in rendering the urine culture negative for the 3 months after the start of treatment. Also, over 12-month follow-up period there were fewer recurrences in the patients who received TMP-SMX but here the difference between the two groups did not reach statistical significance.

Administration, Oral↗

PubMed1975

A comparison of trimethorprim-sulfamethoxazole with sulfamethoxazole alone in infections localized to the kidneys.

Ninety patients with urinary tract infections were treated in a randomized double-blind study with either a combination of trimethoprim and sulfamethoxazole (TMP-SMX) or sulfamethoxazole alone (SMX). Thirty of 42 patients treated with TMP-SMX were cured by the time of follow-up compared with 26 of 48 treated with SMX alone. Of the 29 patients infected with SMX-resistent organisms, the combination TMP-SMX cured 12 of 17, whereas SMX alone cured 2 of 12. Of the 61 patients infected with SMX-sensitive organisms, TMP-SMX cured 18 of 25; SMX alone cured 24 of 36. In 50 women the infection was found localized to The upper urinary tract by the use of the Fairley bladder washout technique. TMPsmx cured 16 or 24 of these patients with proved upper tract infections and SMX alone cured 11 of 26. Although none of these differences were significant, TMP-SMX appears to be an effective drug combination for the therapy of proved upper tract infection and is also effective in eradicating sulfonamide-resistant organisms.

Administration, Oral↗

PubMed1995

Sulfamethoxazole-trimethoprim double-blind, placebo-controlled, crossover trial in Machado-Joseph disease: sulfamethoxazole-trimethoprim increases cerebrospinal fluid level of biopterin.

We performed a double-blind, placebo-controlled, crossover trial of sulfamethoxazole-trimethoprim (S-T) in 8 patients with Machado-Joseph disease (MJD), and measured the blood and cerebrospinal fluid levels of biopterins, biogenic amines or metabolites, and folate. The clinical results were as follows; mild improvements of hyperreflexia of knee jerks and of rigospasticity of the legs during S-T treatment period. In addition, S-T significantly reduced the times of 8 motor activities on the timed tests. The biochemical results showed that basal levels of all biopterins and homovanillic acid in the cerebrospinal fluid (CSF) were reduced to less than half the levels of those of controls with other neurological diseases. After S-T treatment, total and oxidized form of biopterins in the CSF increased significantly. Therefore, S-T may be effective to neurologic deficits through its mechanism of increasing the level of brain biopterins.

Adult↗

PubMed1990

A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora, and the cost-benefit of prophylaxis.

PURPOSE: To determine the efficacy of long-term prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) for prevention of bacterial infection following renal transplantation, the absorption of TMP-SMZ in transplant patients, the effects of prophylaxis on the microflora, and the cost-benefit of prophylaxis. PATIENTS AND METHODS: One hundred thirty-two adult patients selected to undergo renal transplantation participated in a randomized, double-blind, placebo-controlled trial. RESULTS: Patients randomized to receive TMP-SMZ experienced fewer hospital days with fever (3.3% versus 7.7%, p less than 0.001) and significantly fewer bacterial infections during the transplant hospitalization after removal of a urethral catheter (0.76 versus 1.88 per 100 days, p less than 0.005) and following discharge from the hospital (0.08 versus 0.30 per 100 days, p less than 0.001). During the transplant hospitalization, a daily dose of 320/1,600 mg was highly effective for prophylaxis whereas 160/800 mg daily gave unexpectedly low blood levels and was effective only for prevention of urinary tract infections after catheter removal. Prophylaxis was most effective in prevention of infections of the urinary tract (24 versus 54, p less than 0.005) and bloodstream (one versus nine, p less than 0.01) and infections caused by enteric gram-negative bacilli (four versus 46, p less than 0.001), enterococci (six versus 22, p = 0.006), or Staphylococcus aureus (one versus nine, p = 0.01). Prophylaxis did not prevent urinary tract infection associated with urethral catheters in the early posttransplant period, but after catheter removal, reduced the risk of urinary tract infection threefold (p less than 0.001). No significant differences in colonization by TMP-SMZ-resistant gram-negative bacilli were identified between the two groups; patients given TMP-SMZ were, paradoxically, less likely to become colonized by candida, probably because of less exposure to antibiotics for treatment of infection. Recipients of prophylaxis did not have a higher rate of infection caused by TMP-SMZ-resistant bacteria or Candida; however, their infections were more likely to be caused by resistant bacteria than infections in patients in the placebo group (62% versus 18%, p less than 0.001). CONCLUSIONS: Prophylaxis with TMP-SMZ, which is well tolerated, significantly reduces the incidence of bacterial infection following renal transplantation, especially infection of the urinary tract and bloodstream, can provide protection against Pneumocystis carinii pneumonia, and is cost-beneficial. Subnormal absorption of TMP-SMZ in the early posttransplant period mandates 320/1,600 mg daily for optimal benefit. Prophylaxis has little discernible effect on the microflora.

Absorption↗

PubMed2004

Sulfamethoxazole-imprinted polymer for selective determination of sulfamethoxazole in tablets.

A sulfamethoxazole (SMO)-imprinted polymer (MIP) was prepared in acetonitrile using the mixture of acrylamide and 4-vinylpyridine as functional monomers. The molecular recognition properties of the polymer was evaluated in both acetonitrile and aqueous acetonitrile mobile phases. SMO contents in two kinds of tablets were determined satisfactorily using the MIP packed HPLC column with aqueous mobile phase.

Anti-Infective Agents↗

PubMed1984

Excretion rates of sulfamethoxazole and N4-acetyl-sulfamethoxazole by fresh water turtles Pseudemys scripta elegans.

Sulfamethoxazole and N4-acetylsulfamethoxazole are excreted by fresh water turtles Pseudemys scripta elegans in a biphasic mode, characterized half-lives of 5 and 100 min. Acetylation and deacetylation reactions cannot be detected below a dose of 50 mg/kg. The mass balance of the dose administered is incomplete, only 30 per cent of the dose can be recovered as parent compound and metabolite. The sulfonamides must be mainly excreted by the faeces and may be metabolized in the gastro-intestinal tract.

Acetylation↗

PubMed2003

Characterization of sulfamethoxazole and sulfamethoxazole metabolite-specific T-cell responses in animals and humans.

Sulfamethoxazole (SMX) is associated with hypersensitivity reactions. Identification of drug-specific lymphocytes from hypersensitive patients suggests involvement of the immune system. Lymphocytes from humans recognize SMX and nitroso-SMX (SMX-NO), whereas cells from sensitized rats recognize only SMX-NO. In this investigation, we study the nature of SMX-specific T cells in four species. Male rats, mice, and rabbits were immunized with SMX (50 mg kg-1) or SMX-NO (1 mg kg-1). Lymphocytes and/or splenocytes were isolated and incubated with SMX, SMX-hydroxylamine or SMX-NO and proliferation were measured. Lymphocytes were also isolated from SMX-hypersensitive patients (n = 3) and drug-specific proliferation was measured. In addition, rabbits were bled fortnightly for 4 months to determine whether SMX-NO-specific T cells cross-react with SMX. To confirm that SMX-NO responses were due to covalent binding and not cross-reactivity, cells were pulsed with SMX-NO and/or coincubated with glutathione. Splenocytes from mice, rats, and rabbits proliferated when stimulated with SMX-NO, but not SMX. A 2-h pulse with SMX-NO was sufficient for proliferation, whereas cells coincubated with SMX-NO and glutathione did not proliferate. Rabbit lymphocytes proliferated in the presence of SMX-NO and SMX-hydroxylamine, but not SMX. SMX-hydroxylamine was converted to SMX-NO in culture. The SMXNO-specific response of rabbit lymphocytes was maintained for at least 4 months and the cells did not cross-react with SMX. Human lymphocytes from hypersensitive patients proliferated in the presence of SMX and both metabolites. These results highlight important differences in T-cell recognition of drug (metabolite) antigens in animals that have been sensitized against a drug metabolite and patients with hypersensitivity to the drug.

Animals↗

PubMed2005

Open-label randomized trial of oral trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol compared with trimethoprim-sulfamethoxazole and doxycycline for maintenance therapy of melioidosis.

Melioidosis (infection caused by Burkholderia pseudomallei) requires a prolonged course of oral antibiotics following initial intravenous therapy to reduce the risk of relapse after cessation of treatment. The current recommendation is a four-drug regimen (trimethoprim [TMP], sulfamethoxazole [SMX], doxycycline, and chloramphenicol) and a total treatment time of 12 to 20 weeks. Drug side effects are common; the aim of this study was to compare the efficacy and tolerance of the four-drug regimen with a three-drug regimen (TMP-SMX and doxycycline). An open-label, randomized trial was conducted in northeast Thailand. A total of 180 adult Thai patients were enrolled, of which 91 were allocated to the four-drug regimen and 89 to the three-drug regimen. The trial was terminated early due to poor drug tolerance, particularly of the four-drug regimen. The culture-confirmed relapse rates at 1 year were 6.6% and 5.6% for the four- and three-drug regimens, respectively (P = 0.79). The three-drug regimen was better tolerated than the four-drug regimen; 36% of patients receiving four drugs and 19% of patients receiving three drugs required a switch in therapy due to side effects (P = 0.01). The duration of oral therapy was significantly associated with relapse; after adjustment for confounders, patients receiving less than 12 weeks of oral therapy had a 5.7-fold increase of relapse or death. A combination of TMP-SMX and doxycycline is as effective as and better tolerated than the conventional four-drug regimen for the oral treatment phase of melioidosis.

Adolescent↗

PubMed1992

A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation. Side effects of trimethoprim-sulfamethoxazole, interaction with cyclosporine.

Questions have been raised regarding the safety of trimethoprim-sulfamethoxazole (TMP-SMZ) in organ transplantation, particularly adverse interactions with azathioprine and cyclosporine. In a prospective randomized, double-blind, trial in 132 patients that encompassed 33,876 patient-days, long-term prophylaxis with TMP-SMZ was found to significantly reduce the incidence of bacterial infection after renal transplantation. Prophylaxis was very well tolerated; none of the 66 recipients of TMP-SMZ, who took the drug for an average of 8.9 months, was withdrawn from the study because of hypersensitivity or toxic side effects. Serial measurements of hematologic parameters and liver function tests after transplantation in the two groups showed no significant differences. Recipients of cadaveric transplants, who were all given cyclosporine, randomized to receive TMP-SMZ had serum creatinine levels approximately 15% higher than those in control patients receiving cyclosporine (p less than 0.01); comparison of renal function by 24-hour endogenous creatinine clearances and technetium 99m-labeled diethylenetriamine-penta-acetic acid glomerular filtration rates in 17 patients crossed over to the alternate treatment group for 7 weeks, however, shows that the observed differences are reversible and represent inhibition of tubular excretion of creatinine by TMP in the presence of cyclosporine. Prophylaxis with TMP-SMZ had no discernable effect on cyclosporine pharmacokinetics: recipients of TMP-SMZ had blood levels of cyclosporine similar to those in patients in the placebo group. Episodes of graft rejection occurred at a similar frequency in the two groups (placebo, 50; TMP-SMZ, 44). We conclude that long-term prophylaxis with TMP-SMZ does not produce discernable hematologic, renal, or hepatic toxicity in renal transplant recipients nor does it augment nephrotoxicity with cyclosporine or increase the risk of rejection. TMP-SMZ may be used safely and is highly cost-beneficial for prophylaxis of infection in renal transplantation.

Creatinine↗

PubMed1995

In vitro formation, disposition and toxicity of N-acetoxy-sulfamethoxazole, a potential mediator of sulfamethoxazole toxicity.

Variation in the formation and disposition of the hydroxylamine of (SMX-HA) is thought to play an important role in the pathogenesis of sulfamethoxazole (SMX)-induced idiosyncratic adverse drug reactions. We hypothesized that, in analogy to carcinogenic arylamines, SMX-HA might be further converted to an electrophilic N-acetoxy metabolite which could play a role in mediating SMX toxicity. Accordingly, we chemically synthesized N-acetoxy-SMX, and examined the characteristics of its formation, metabolism, cytotoxicity and mutagenicity in human and bacterial test systems. The human arylamine N-acetyl-transferases, (NAT)1 and NAT2, were capable of converting SMX-HA to N-acetoxy-SMX. NAT1 and NAT2 possessed similar affinities for SMX-HA (apparent Km values of 650 and 520 microM, respectively), but the apparent maximal velocity of the NAT1-mediated acetylation was higher than that of NAT2. (1332 vs. 37 nmol/min/U of immunoreactive NAT protein). Human peripheral blood mononuclear cells 12,000 x g supernatant fractions converted N-acetoxy-SMX mainly back to SMX-HA, and also to a lesser extent to SMX, at clinically relevant concentrations. Similar pathways were observed in human hepatic cytosolic fractions. In a cytotoxicity assay, N-acetoxy-SMX was significantly more toxic to human peripheral blood mononuclear cells than SMX-HA (16.6 vs. 11.5% dead cells at a concentration of 300 microM). N-acetoxy-SMX was weakly mutagenic to the Salmonella typhimurium TA100 strain in the Ames test. These data suggest that the N-acetoxy metabolites of sulfonamides could potentially play a role in mediating sulfonamide idiosyncratic adverse drug reactions.

Acetyltransferases↗

PubMed1995

N4-hydroxylation of sulfamethoxazole by cytochrome P450 of the cytochrome P4502C subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes.

The N4-hydroxylation of sulfamethoxazole (SMX) to its hydroxylamine (SMX-HA) metabolite is the first step in the formation of reactive metabolites responsible for mediating hypersensitivity reactions associated with this compound. In rat hepatic microsomes, the NADPH-dependent oxidation of SMX to SMX-HA was increased 3-fold by pretreatment of rats with phenobarbital. Other cytochrome P450 (CYP) inducers were ineffective. The constitutive and induced SMX N-hydroxylation activities were inhibited by tolbutamide, and induction of SMX-HA activity paralleled the induction of progesterone 21-hydroxylase activity, a marker for CYP2C6. SMX N-hydroxylation in phenobarbital-treated rat hepatic microsomes was inhibited 70% by anti-CYP2C6 antisera. Thus, the N4-hydroxylation of SMX by rat hepatic microsomes was mediated by members of the CYP2C subfamily, probably CYP2C6. In a panel of human microsomes, SMX-HA formation correlated with tolbutamide hydroxylase activity (r = 0.75; p = 0.01); CYP2C9 content (r = 0.79; p < 0.01) and was inhibited 70% by 500 microM tolbutamide and 90% by 100 microM sulfaphenazole. Recombinant CYP2C9 catalyzed the N-hydroxylation of SMX. SMX-HA formation in human hepatic microsomes was therefore mediated predominantly by CYP2C9. CYP-mediated reduction of SMX-HA to SMX was markedly induced in dexamethasone and phenobarbital-treated rat hepatic microsomes, and was attributed to CYP3A and CYP2B forms. In uninduced rat and human hepatic microsomes, SMX-HA reduction was mediated predominantly by an NADH-dependent microsomal hydroxylamine reductase under aerobic conditions. Under anaerobic conditions, troleandomycin at > or = 1 microM inhibited the reduction of SMX-HA in human hepatic microsomes by 45%, whereas sulfaphenazole had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗