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At least 19 recordsLinked to original sources
PubMed1979

Development of sulphonamide-trimethoprim combinations for urinary tract infections. Part 3: Pharmacokinetic characterization of sulphadiazine and sulphamethoxazole given with trimethoprim.

Plasma levels and renal excretion of sulphonamide and trimethoprim following oral administration of co-trimazine (140 mg sulphadiazine + 90 mg trimethoprim) and co-trimoxazole (800 mg sulphamethoxazole + 180 mg trimethoprim) were monitored in healthy volunteers after a single dose and in the steady state after 12-hourly dosage. The plasma levels of free, non-protein bound components after co-trimazine were approximately half those after co-trimoxazole and thus correlated with the doses given. Urine recovery of trimethoprim was better after co-trimazine (70%) than after co-trimoxazole (58%). Sixty-six percent of the sulphadiazine was recovered as unchanged, active sulphonamide in the urine compared with only 13% of the sulphamethoxazole. Consequently, the sulphonamide levels of sulphadiazine were 2.5 times those of sulphamethoxazole. With respect to plasma half-life after the first dose, sulphadiazine with 8.0 hours was closer to trimethoprim with a half-life of 8.8 hours after cotrimazine and 9.6 hours after co-trimoxazole than to the half-life of sulphamethoxazole which was 7.7 hours. The distribution volume of sulphadiazine was closer to that of trimethoprim than was that of sulphamethoxazole. On the basis of these characteristics, it has been concluded that sulphadiazine is more suitable for a fixed combination tablet with trimethoprim than sulphamethoxazole, particularly for the treatment of urinary tract infections. Some renal tubular reabsorption occurs with both unchanged sulphonamides but is more pronounced with sulphamethoxazole. The solubilities of the sulphonamides and their acetylated metabolites at acid urinary pH indicate that therapy with co-trimazine is at least as safe as with co-trimoxazole. With the former drug, the result of scrutiny for crystals after dosage until the steady state was negative, whereas crystals of acetylated sulphamethoxazole were detected and verified chemically in two of eight subjects.

Drug Combinations↗
PubMed1978

Synergistic activity of gentamicin with trimethoprim or sulfamethoxazole-trimethoprim against Escherichia coli and Klebsiella pneumoniae.

The effect of combinations of gentamicin with trimethoprim or sulfamethoxazole-trimethoprim against clinical isolates of Escherichia coli (11 strains) and Klebsiella pneumoniae (12 strains) was examined by using a microdilution checkerboard technique. All isolates were susceptible to each antimicrobial agent. Synergism, defined as at least a 2-log(2)-dilution lowering of the minimal inhibitory concentration of either antibiotic in the combination compared with the minimal inhibitory concentration of the antibiotic alone, was observed with 15 of 23 (65%) isolates tested against trimethoprim and gentamicin and 14 of 23 (61%) isolates tested against sulfamethoxazole-trimethoprim and gentamicin. A 3-log(2)-dilution lowering of the minimal inhibitory concentration of either antibiotic was observed in 7 of 23 (30%) trimethoprim and gentamicin trials and 3 of 23 (13%) sulfamethoxazole-trimethoprim and gentamicin trials. Antagonism was observed in 3 of 46 combination trials and only with strains of K. pneumoniae.

Drug Synergism↗
PubMed1977

Sensitivity of Pseudomonas aeruginosa to sulphonamides and trimethoprim and the activity of the combination trimethoprim: sulphamethoxazole.

The activities of three sulphonamides and trimethoprim against strains of Pseudomonas aeruginosa have been studied. Sulphadiazine had most activity, sulphadimidine had little, and the activity of sulphamethoxazole was intermediate. According to their sensitivity to sulphamethoxazole, strains were divided into two groups: "highly resistant" (16%, MIC greater than 1000 microgram per ml) and "moderately resistant" (84%, MIC less than or equal to 1000 microgram per ml). The former were resistant on disk testing to Sulphatriad 300 microgram. Sulphamethoxazole and trimethoprim did not act in synergy against them. The moderately resistant strains were sensitive to Sulphatriad; trimethoprim and sulphamethoxazole showed marked synergy against them in agar-plate dilution tests. The concentrations of trimethoprim and sulphamethoxazole necessary for synergy lay for each drug within the range of concentrations at which they have been found in urine, and the ratio of their MICs when acting in synergy was similar to the ratio of their concentrations in urine. It is suggested that a disk containing trimethoprim and sulphamethoxazole in a ratio of 1 : 2 rather than 1 : 20 would be more appropriate when testing strains from urine for their sensitivity to co-trimoxazole.

Dose-Response Relationship, Drug↗
PubMed1979

Development of sulphonamide-trimethoprim combinations for urinary tract infections. Part I: Comparison of the antibacterial effect of sulphonamides alone and in combination with trimethoprim.

Plasma half life and in vitro activity were major criteria for selection of sulphonamides which are likely to give a strong synergistic action with trimethoprim in vivo. On the basis of literature data six sulphonamides, sulphadiazine, sulphachloropyridazine, sulphamethoxazole, sulphaisodimidine, sulphamerazine and sulphamethomidine appeared particularly suitable for combination with trimethoprim. An investigation of the activity in vitro of these compounds and their combinations with the latter against clinically isolated, sulphonamide-sensitive Klebsiella-Enterobacter and Escherichia coli strains showed optimal synergy at trimethoprim-sulphonamide ratios between 1:10 and 1:40, but that appreciable mutual potentiation occurred within a rather broad range of concentration ratios. Limited experiments indicated that synergy occurs less frequently and is less pronounced against sulphonamide resistant bacteria. The different sulphonamides behaved rather similarly in their combinations with trimethoprim, and in order to find the best sulphonamide, detailed comparisons of the pharmacokinetic properties of the different combinations are necessary.

Bacteria↗
PubMed1977

Studies on the in vitro development of drug resistance of Proteeae to sulfonamides, trimethoprim and combinations of a sulfonamide and trimethoprim.

A strain of Proteus mirabilis repeatedly subcultured in the presence of a combination of sulfisoxazole and 0.4 microgram/ml of trimethoprim and a strain of P. vulgaris subcultured in the presence of sulfamethoxazole and trimethoprim combined in a 5:1 ratio gradually developed resistance to the combinations. However, the level of resistance developed by the organisms exposed to the combination was always appreciably lower than the level of resistance developed by the same strains exposed to either the sulfonamide or trimethoprim alone.

Drug Combinations↗
PubMed1979

The effect of trimethoprim-sulphonamide, trimethoprim and sulphonamide on the occurrence of resistant enterobacteriaceae in human intestinal flora.

After the administration of various antimicrobial agents for chemotherapeutic purposes a general change in the intestinal flora of the patient is often observed. In contrast, the combination trimethoprim-sulphonamide causes in most cases a strong selective decrease in the number of Enterobacteriaceae organisms for treatment periods as long as four to 12 weeks. The results correspond to clinical experience with trimethoprim-sulphonamide therapy in urinary tract infection where reinfections with resistant organisms are the exception.

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↗
PubMed1979

Nuclear magnetic resonance studies of the binding of trimethoprim to dihydrofolate reductase.

The resonances of the aromatic protons of trimethoprim [2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine] in its complexes with dihydrofolate reductases from Lactobacillus casei and Escherichia coli cannot be directly observed. Their chemical shifts have been determined by transfer of saturation experiments and by difference spectroscopy using [2',6'-2H2]trimethoprim. The complex of 2,4-diamino-5-(3',4'-dimethoxy-5'-bromobenzyl)pyrimidine with the L. casei enzyme has also been examined. At room temperature, the 2',6'-proton resonance of bound trimethoprim is very broad (line width great than 30 Hz); with the E. coli enzyme, the resonance sharpens with increasing temperature so as to be clearly visible by difference spectroscopy at 45 degrees C. This line broadening is attributed to an exchange contribution, arising from the slow rate of "flipping" about the C7-C1' bond of bound trimethoprim. The transfer of saturation measurements were also used to determine the dissociation rate constants of the complexes. In the course of these experiments, a decrease in intensity of the resonance of the 2',6'-proton resonance of free trimethoprim on irradiation at the resonance of the 6 proton of free trimethoprim was observed, which only occurred in the presence of the enzyme. This is interpreted as a nuclear Overhauser effect between two protons of the bound ligand transferred to those of the free ligand by the exchange of the ligand between the two states. The chemical shift changes observed on the binding of trimethoprim to dihydrofolate reductase are interpreted in terms of the ring-current shift contributions from the two aromatic rings of trimethoprim and from that of phenylalanine-30. On the basis of this analysis of the chemical shifts, a model for the structure of the enzyme-trimethoprim complex is proposed. This model is consistent with the (indirect) observation of a nuclear Overhauser effect between the 2',6' and 6 protons of bound trimethoprim.

Binding Sites↗
PubMed1977

[Bacteriological study on the chemotherapeutic combination sulfametrole-trimethoprim/comparison with co-trimoxazole (author's transl)].

The synergism of the compounds Nd-(4-methoxy-1,2,5-thiadiazol-3-yl)-sulfanilamide (sulfametrole; SOL) and 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine (trimethoprim; TMP) contained in the preparation Lidaprim was proved in vitro in the agar dilution test, the disc agar diffusion method as well as a crossover test against various grampositive and gramnegative bacteria. Sulfametrole enhanced the activity of trimethoprim or its activity was intensified by trimethoprim, respectively. The increase in efficiency depends on the primary sensitivity or resistance of the bacteria against trimethoprim and/or the sulfonamide. The combination of trimethoprim + sulfametrole (1 + 20) had the same antibacterial activity as the combination co-trimoxazole = trimethoprim + Nd-(5-methyl-3-isoxazolyl)-sulfanilamide (sulfamethoxazole; SMZ). The bactericidal efficiency was shown against a strain of E. coli. Using the combination experimental development of resistance against various bacteria could not be obtained (10 times repeated contact with subbacteriostatic concentrations). Chemotherapeutical experiments in the mouse have confirmed the enhancement indicated in vitro of the combination trimethoprim-sulfonamide, irrespective of the sulfonamides chosen. Determinations of the intestinal flora before, during and after oral administration of 2 X 2 tablets SOL-TMP (Lidaprim) over a period of 10 days showed that the absolute number of bacteria in samples of faeces had not been reduced. Enterobacteria and anaerobic lactobacilli (L. bifidus), which could not be identified during the period of administration, reappeared after the end of therapy.

Animals↗
PubMed1978

Therapy of gonorrhea. Comparison of trimethoprim-sulfamethoxazole and ampicillin.

Eighty-nine men with gonococcal urethritis were randomly treated with trimethoprim-sulfamethoxazole, four tablets (trimethoprin, 320 mg, and sulfamethoxazole, 1,600 mg) twice daily for two days, or ampicillin, 3.5 g, plus probenecid, 1 g, in a single dose. Forty-one (95.3%) of 43 patients who received trimethoprin-sulfamethosazole and 41 (97.6%) of 42 given ampicillin were cured. Neither drug caused major side effects. All isolates of Neisseria gonorrhoeae were susceptible in vitro to trimethoprim-sulfame-thoxazole, and all but one were inhibited by ampicillin. The ampicillin-resistant strain (minimum inhibitory concentration, 4 micrograms/ml) produced penicillinase and was reovered from a patient who responded to treatment with trimethoprim-sulfamethoxazole. There was no significant correlation between the minimum inhibitory concentrations of trimethoprim-sulfamethoxazole and ampicillin. It is concluded that trimethoprim-sulfamethoxazole is as efficacious and safe as ampicillin in the therapy of gonococcal urethritis.

Ampicillin↗
PubMed1977

Prophylactic efficacy of nitrofurantoin macrocrystals and trimethoprim-sulfamethoxazole in urinary infections. Biologic effects on the vaginal and rectal flora.

We examined bacterial persistence and resistance in the vaginal and fecal flora of 28 women who received a total of 253 months of daily low-dosage prophylaxis with nitrofurantoin macrocystals (100 mg per day) or trimethoprim-sulfamethoxazole (40 and 200 mg respectively). During trimethoprim-sulfamehtoxazole prophylaxis, 8.5% of monthly vaginal and 27% of monthly fecal cultures grew Escherichia coli, as compared to 36 and 96%, respectively for nitrofurantoin macrocrystals. Esch. coli resistant to nitrofurantoin occurred in two of 95 fecal cultures during therapy, and Esch. coli resistant to trimethoprim-sulfamethoxazole in 16 of 182 (8.8%) fecal cultures. In the 12 months before treatment, 92 episodes of recurrent urinary infection occurred, as compared to six during treatment (none occurred on trimethoprim-sulfamethoxazole). These results confirm the value of trimethoprim-sulfamethoxazole prophylaxis for high-risk patient with recurrent urinary infections. Prophylaxis with nitrofurantoin macrocrystals seems adequate for less severe problems of reinfection.

Adult↗
PubMed1978

In vitro susceptibility of Haemophilus influenzae to sulfamethoxazole-trimethoprim and cefaclor, cephalexin, and cephradine.

Sulfamethoxazole-trimethoprim and three oral cephalosporins, cefaclor, cephalexin, and cephradine, were evaluated in vitro as possible alternatives to chloramphenicol in the treatment of non-central nervous system infections due to ampicillin-resistant Haemophilus influenzae. Sixty-four isolates of H. influenzae, including 31 beta-lactamase-positive strains, were tested by the agar dilution method. All strains were inhibited by 0.78/0.039 mug sulfamethoxazole-trimethoprim per ml and by 0.78 mug of chloramphenicol per ml. At 6.25 mug/ml, 100, 11, and 3% of all strains were inhibited by cefaclor, cephalexin, and cephradine, respectively. Thus, on the basis of drug concentrations presumably achievable in serum, 100% of strains were susceptible to sulfamethoxazole-trimethoprim, chloramphenicol, and cefaclor. However, a considerable inoculum effect was noted with both beta-lactamase-positive and -negative strains, when tested with sulfamethoxazole-trimethoprim; the minimal inhibitory concentrations of cefaclor were only slightly affected. Also, synergistic effects of sulfamethoxazole-trimethoprim, sulfamethoxazole-erythromycin, and sulfamethoxazole-cefaclor were seen when combinations were tested against both beta-lactamase-positive and -negative strains, as determined by minimal inhibitory concentrations measured by the broth dilution method and by killing curve analyses. These results support further evaluation of these combinations and of cefaclor alone for the treatment of non-central nervous system infections due to H. influenzae.

Cephalosporins↗
PubMed1979

Limited effect of trimethoprim-sulfamethoxazole prophylaxis on Pneumocystis carinii.

Trimethoprim-sulfamethoxazole has been proven effective in the treatment and prevention of Pneumocystis carinii pneumonitis in lower animals and humans. How effective the drug combination is in eradicating P. carinii from the host is not known. The immunosuppressed rat model was used to determine whether or not trimethoprim-sulfamethoxazole effectively eradicated the organism. Animals treated with trimethoprim-sulfamethoxazole for as long as 6 weeks were then placed in individual isolator cages, immunosuppressed with prednisone for 12 weeks, and sacrificed. P. carinii was found in the lungs of at least 90% of the drug-treated as well as untreated control groups. The data indicate that trimethoprim-sulfamethoxazole has a limited rather than a lethal effect on P. carinii and that protection is afforded only during the period of trimethoprim-sulfamethoxazole administration.

Animals↗
PubMed1979

Rapid assay for determination of trimethoprim and sulfamethoxazole levels in serum by spectrofluorometry.

A rapid spectrofluorometric method for determining the levels of both trimethoprim and sulfamethoxazole from the same specimen of serum is described. The method involves stepwise extraction of the specimen first with chloroform at an alkaline pH (pH 9.0) for trimethoprim followed by n-butyl chloride at an acidic pH (pH 2.0) for sulfamethoxazole. To quantitate trimethoprim, the chloroform layer was subjected to fluorometry by exciting the specimen at 295 nm and measuring the relative intensity at 330 nm. To determine sulfamethoxazole levels, the n-butyl chloride layer was subjected to fluorometry by exciting the specimen at 285 nm and measuring the relative intensity at 330 nm. Relative intensities were linear (r greater than 0.99) over the concentration ranges of 0.5 to 40 microgram/ml for trimethoprim and 1 to 400 microgram/ml for sulfamethoxazole. Values obtained by this spectrofluorometric procedure were in excellent agreement with those obtained by a conventional fluorometric assay for trimethoprim and a colorimetric assay for sulfamethoxazole. Elevated levels of endogenous metabolic products and numerous other drugs, including a number of antimicrobial agents, did not interfere with the method. Although salicylates interfere with the determination of sulfamethoxazole, an appropriate correction can be made. This method can also be used to determine the drug levels in cerebrospinal fluid.

Humans↗
PubMed1979

Drug therapy reviews: trimethoprim-sulfamethoxazole.

The mechanism of action, antimicrobial spectrum, pharmacokinetic properties, drug interactions, adverse reactions and therapeutic uses of trimethoprim-sulfamethoxazole, a combination enzyme-specific inhibitor of bacterial folate synthesis, are reviewed. Trimethoprim-sulfamethoxazole currently is approved by the FDA for the therapy of established recurrent bacterial urinary tract infections, pneumocystosis, otitis media in children and shigellosis. Claimed advantages of the drug are synergistic activity, bactericidal activity and ability to decrease the rate of emergence of resistance to the individual components. Trimethoprim-sulfamethoxazole is the drug of choice for treatment of pneumocystosis and an acceptable oral therapy for recurrent urinary tract infections caused by susceptible bacteria. In children with otitis media, it is used as an alternative to ampicillin and amoxicillin and is preferred when these patients are penicillin-sensitive or when the infection is caused by beta-lactamase-producing Haemophilus influenzae. Hematologic reactions (anemia, thrombocytopenia, granulocytopenia, agranulocytosis) to trimethoprim-sulfamethoxazole occur rarely. Gastrointestinal intolerance and skin eruptions are the most prevalent adverse reactions. Most untoward reactions to trimethoprim-sulfamethoxazole develop within two weeks of onset of therapy, and their incidence compares favorably with that of standard agents administered for the same indications.

Acute Disease↗