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At least 19 recordsLinked to original sources
PubMed1979

[Bactericidal activity "in vitro" of sulfamethoxazol-tri-methoprime (SMZ-TMP) alone and in combination with various antibiotics on bacterial strains isolated from urinary tract infections (author's transl)].

The authors study "in vitro" effects of sulfamethoxazol-trimethroprime (SMZ-TMP) on 1 078 bacterial strains isolated from urinary-tract infections during january 1974, the second trimester 1974 and january 1975. Study involves two parts : comparison between bacteriostatic activity of SMZ-TMP, ampicillin and nalidixic acid; evaluation of bactericidal activity of antibiotic associations including SMZ-TMP. MIC study included all strains. On Gram- negative bacilli the bacteriostatic activity of SMZ-TMP (74,6 percent of sensitive strains) was comparable with nalidixic acid (79,6 percent of sensitive strains) and better than ampicillin 31,4 percent of sensitive strains). On staphylococcus strains the bacteriostatic activity of SMZ-TMP (84,6 percent of sensitive strains) is better than ampicillin (36,4 percent of sensitive strains); on streptococcus strains the bacteriostatic activity of ampicillin (71 percent of sensitive strains) is better than SMZ-TMP (5l percent of sensitive strains). 473 associations including SMZ-TMP were studied upon 44 strains of Gram- negative bacilli by bactericidal test. ("Cross disposition" method, derive from "cellophane transfer method".

Ampicillin↗
PubMed1979

Differentiation of rapidly growing mycobacteria with trimethoprim (Tmp).

Inhibition of Mycobacterium smegmatis, M. vaccae, and M. diernhoferi by Trimethoprim (Tmp) in both liquid and solid media is described. Other mycobacteria were not inhibited by the same concentrations. The selective inhibition of the above strains, particularly M. smegmatis, by Tmp could be used for differentiation of these species from other fast-growing acid-fast bacteria.

Culture Media↗
PubMed1978

Effect of TMP-SMX on nasopharyngeal carriage of ampicillin-sensitive and ampicillin-resistant hemophilus influenzae type B.

The carriage rate of ampicillin-resistant Hemophilus influenzae type B in a chronic care facility was investigated. Up to 48% of the children carried this strain. Of interest was the finding of simulaneous carriage of ampicillin-resistant and ampicillin-sensitive HITB, a phenomenon which was detected by using both chocolate agar and chocolate agar containing 2 microgram/ml of ampicillin. A trial of sulfamethoxazole-trimethoprin successfully eradicated the ampicillin-sensitive HITB, but had no effect on the ampicillin-resistant HITB.

Ampicillin↗
PubMed1977

Treatment of gonorrhea with trimethoprim-sulfamethoxazole.

The following regimens were randomly administered to 271 men with gonococcal urethritis: 4.8 X 10(6) units of aqueous procaine penicillin G intramuscularly plus 1 g of probenecid orally (APPG); nine tablets of trimethoprim-sulfamethoxazole (TMP-SMZ; 720 mg of TMP and 3,600 mg of SMZ), orally as a single dose (TMP-SMZ-9); and 12 tablets of TMP-SMZ (960 mg of TMP and 4,800 mg of SMZ) orally as two doses of six tablets taken at a 6-hr interval (TMP-SMZ-12). The failure rates of the APPG, TMP-SMZ-9, and TMP-SMZ-12 regimens were 4%, 23%, and 19%, respectively. APPG was significantly more effective (P less than 0.05) than TMP-SMZ-9 or TMP-SMZ-12. Isolates of Neisseria gonorrhoeae from treatment failures as compared to those from treatment successes were significantly more resistant to SMZ (P less than 0.01) and to the TMP-SMZ combination in a ratio of 19 parts SMZ to one part TMP (P less than 0.05). Minimal inhibitory concentrations of SMZ, TMP, TMP-SMZ, and penicillin G showed positive correlation coefficients.

Administration, Oral↗
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

The effect of trimethoprim and sulfamethoxazole on Toxoplasma gondii in vitro and in vivo.

Trimethoprim (TMP) and sulfamethoxazole (SMZ) were studied alone and in combination to determine their effect in vitro on intracellular Toxoplasma gondii and in vivo against murine toxoplasmosis. In the in vitro experiments, whereas 1 and 2 microgram/ml TMP had no demonstrable effect on intracellular T. gondii, 10-20 microgram/ml TMP resulted in death of the intracellular organisms; concentrations as high as 100 microgram/ml SMZ had no demonstrable effect against the intracellular organisms. When used in combination, a significant synergistic effect was noted with 2 microgram/ml TMP-50 microgram/ml SMZ. Studies on the kinetics of inhibition and/or killing of Toxoplasma revealed that 18 hours of treatment with 2 microgram/ml TMP-50 microgram/ml SMZ resulted in irreversible inhibition of the intracellular organisms. When used in vivo against a 50,000 LD100 dose of Toxoplasma, TMP fed by gavage or mixed in the diet had no effect in murine toxoplasmosis at doses as high as 200 mg/kg a day. SMZ administered by gavage had no effect at doses up to 200 mg/kg a day; but at 300 and 400 mg/kg SMZ, protection was 47% and 83%, respectively. Treatment of infected mice was continued for 14 consecutive days, whether the drugs were administered alone or in combination. The combination 200 mg/kg TMP-200 mg/kg SMZ, when administered by gavage, protected 87% of mice. Survival after 14 days of SMZ mixed in the diet was 0% at 100 mg/kg, 47% at 200 mg/kg, and 100% at 300 mg/kg. Survival with the combination was 40% for 200 mg/kg TMP-100 mg/kg SMZ and 100% for 100 mg/kg TMP-200 mg/kg SMZ. The half-life of TMP in serum of Swiss Webster mice was calculated to be 24 min. The results obtained in vivo were inferior to those obtainable with the combination of pyrimethamine plus sulfadiazine. The problems of interpretation of results obtained in the murine model using TMP-SMZ and in their extrapolation to the treatment of the infection in man are discussed.

Administration, Oral↗
PubMed1976

Pathway of thiamine pyrophosphate synthesis in Micrococcus denitrificans.

The pathway of thiamine pyrophosphate (TPP) biosynthesis, which is formed either from exogeneously added thiamine or from the pyrimidine and thiazole moieties of thiamine, in Micrococcus denitrificans was investigated. The following indirect evidence shows that thiamine pyrophosphokinase (EC 2.7.6.2) catalyzes the synthesis of TPP from thiamine: (i) [35S]thiamine incubated with cells of this microorganism was detected in the form of [35S]thiamine; (ii) thiamine gave a much faster rate of TPP synthesis than thiamine monophosphate (TMP) when determined with the extracts; and (iii) a partially purified preparation of the extracts can use thiamine, but not TMP, as the substrate. The activities of the four enzymes involved in TMP synthesis from pyrimidine and thiazole moieties of thiamine were detected in the extracts of M. denitrificans. The extracts contained a high activity of the phosphatase, probably specific for TMP. After M. denitrificans cells were grown on a minimal medium containing 3 mM adenosine, which causes derepression of de novo thiamine biosynthesis in Escherichia coli, the activities of the four enzymes involved with TMP synthesis, the TMP phosphatase, and the thiamine pyrophosphokinase were enhanced two- to threefold. These results indicate that TPP is synthesized directly from thiamine without forming TMP as an intermediate and that de novo synthesis of TPP from the pyrimidine and thiazole moieties involves the formation of TMP, followed by hydrolysis to thiamine, which is then converted to TPP directly. Thus, the pathway of TPP synthesis from TMP synthesized de novo in M. denitrificans is different from that found in E. coli, in which TMP synthesized de novo is converted directly to TPP without producing thiamine.

Adenosine↗
PubMed1979

Double-blind comparison of sulphonamide-trimethoprim combinations in acute uncomplicated urinary tract infections.

The effects of a twice daily dosage of a combination of 410 mg sulphadiazine + 90 mg trimethoprim (SD + TMP) and 800 mg sulphamethoxazole + 160 mg trimethoprim (SMZ + TMP) were compared in uncomplicated urinary tract infections. All but one patient in each treatment group, i.e. 36 SD + TMP treated and 42 SMZ + TMP treated patients respectively, were cured. The percentage of side-effects related to therapy in the patients receiving the combination with sulphadiazine was 15.1% and in those with sulphamethoxazole 23.7%. Due to the small number tested, however, differences were not statistically different. It is noteworthy that only one of the SD + TMP patients had to stop therapy because of a rash, whereas therapy was stopped for this reason in three of the SMZ + TMP patients. SD + TMP represents a good alternative to SMZ + TMP in the treatment of urinary tract infections.

Adolescent↗
PubMed1979

Biochemical determinants of tumor sensitivity to 5-fluorouracil: ultrasensitive methods for the determination of 5-fluoro-2'-deoxyuridylate, 2'-deoxyuridylate, and thymidylate synthetase.

Techniques have been developed to measure FdUMP, the active metabolite of 5-FUra; thymidylate synthetase (TMP synthase; 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45), the target enzyme for this antimetabolite; and dUMP, the substrate that competes with FdUMP for binding to TMP synthetase. As little as 0.02 pmol of FdUMP can be quantitated with a competitive ligand binding assay by using homogeneous Lactobacillus casei/MTX TMP synthetase as a binding protein. A new binding assay for TMP synthetase allows detection of 0.005 pmol of enzyme. The quantitative enzymatic conversion of dUMP to [methyl-(14)C]-TMP using 5,10-methylene[(14)C]tetrahydrofolate by pure L. casei TMP synthetase is used as an assay for dUMP with a sensitivity of 10 pmol. Cultured CCRF-CEM human lymphoblastic leukemia cells formed high levels of FdUMP (2.6 nmol per 10(9) cells) within 11 hr after exposure to 30 muM 5-FUra. Tumor cell TMP synthetase levels dropped, and then free FdUMP appeared. The intracellular dUMP pool was low (2-5 nmol per 10(9) cells) in logarithmically growing cultures of several tumor cell lines but expanded rapidly in CCRF-CEM cells on exposure to 5-FUra after enzyme levels decreased. The levels of dUMP found after exposure to 5-FUra are sufficient to severely retard inhibition of TMP synthetase by FdUMP.The methods described are sufficiently sensitive to allow these biochemical parameters of 5-FUra action to be measured in cell culture or in needle biopsy samples of human tumors.

Cell Line↗
PubMed1979

Pharmacokinetics of sulphadiazine, sulphamethoxazole and trimethoprim in patients with varying renal function.

The pharmacokinetics of tablets containing combinations of sulphadiazine (SDZ) and trimethoprim (TMP) (cotrimazine) and tablets with sulphamethoxazole (SMZ) and TMP (co-trimoxazole) were compared in patients with different renal functions. In normal renal function, SMZ is more similar to TMP than in renal impairment. In renal impairment although the serum half-life (t1/2) of both active and total SDZ remains similar to that of TMP, the t1/2 of total SMZ becomes several times higher than the t1/2 of TMP. The unchanged SMZ maintains approximately the same elimination velocity in reduced as in normal renal function. Consequently, for co-trimoxazole there is a buildup of SMZ metabolites which can only contribute to toxicity for co-trimoxazole, whereas the co-trimazine components have t1/2 values of the same order, also in renal dysfunction. The distribution volumes of SDZ, SMZ or TMP are the same regardless of renal function. However, the distribution volume of SDZ is closer to that of TMP, i.e. higher than the SMZ values. More active SDZ is excreted in the urine than SMZ both in normal and in reduced renal function. Thus co-trimazine, in addition to having some advantages in the normal individual, is in many respects distinctly more suitable in patients with renal functional impairment. On the basis of the patients with renal functional impairment. On the basis of the pharmacokinetic properties, dosage schedules are suggested that will give approximately the same plasma levels regardless of renal function.

Drug Combinations↗
PubMed1979

Low trimethoprim susceptibility of anaerobic bacteria due to insensitive dihydrofolate reductases.

All the 28 Bacteroides fragilis strains investigated were susceptible to sulfamethoxazole (minimal inhibitory concentration < 16 mug/ml) and resistant to trimethoprim (TMP; minimal inhibitory concentration > 4 mug/ml). Synergism between sulfamethoxazole and TMP was present in all strains at a ratio of 1:1. The few clostridia investigated proved more resistant to both compounds. Dihydrofolate reductases from B. fragilis, C. perfringens, and some other anaerobic species were isolated. Inhibition profiles with six structurally different inhibitors revealed major differences in all enzymes. For 50% inhibition, the enzyme from B. fragilis and all clostridia required concentrations of TMP which were between several hundredfold and 1,000-fold higher than those required for the enzyme of Escherichia coli, whereas the enzyme from Propionibacterium acnes only needed a threefold higher concentration. In vitro activities of TMP were seen to correspond to the activity at the enzymatic level in B. fragilis and P. acnes, but correspond to a much lesser extent to the activity at the enzymatic level in clostridia, where a poor penetration is assumed to be involved. Dihydrofolate reductase inhibitors other than TMP were found to be as active as TMP both at the enzyme and in vitro. In B. fragilis, higher concentrations of exogenous thymidine were required for increasing the minimal inhibitory concentration of TMP than in E. coli and probably also in C. perfringens.

Anaerobiosis↗
PubMed1979

Rifampin plus trimethoprim: bactericidal activity and suppression of resistance in human urine in vitro.

The bactericidal effect of a combination of rifampin (Ramp) and trimethoprim (Tmp) was studied using dense cultures of test organisms, including some urinary pathogens, growing in human urine. Drug concentrations used were similar to those attainable in human urine. The combination was more effective than the individual drugs and than a combination of Tmp plus sulfamethoxazole (Smx). Tmp was bactericidal in urine and blocked the emergence of Ramp-resistant bacteria. Ramp was responsible for most of the bactericidal action of the combination but also potentiated the bactericidal activity of Tmp. Ramp suppressed the selection of thy- (Tmp-resistant) bacteria. Under the experimental conditions, Smx+Tmp was not more bactericidal than Tmp alone for most of the test organisms, despite strong synergy between the two at subinhibitory concentrations.

Bacteria↗