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At least 19 recordsLinked to original sources
PubMed1980

Comparison of trimethoprim alone with trimethoprim sulphamethoxazole in the treatment of respiratory and urinary infections with particular reference to selection of trimethoprim resistance.

279 patients were treated with 100 mg trimethoprim or 100 mg trimethoprim combined with 500 mg sulphamethoxazole (co-trimoxazole) twice daily for 5 days in a prospective randomised double-blind trial. In chest infections in patients in general practice and in an acute geriatric assessment unit, the efficacy of each regimen was similar, but there were more side-effects with co-trimoxazole than with trimethoprim alone. In urinary-tract infections the two regimens also produced similar cure rates. Treatment with trimethoprim rarely selected resistant pathogens in the sputum or resistant Enterobacteriacae in the intestine, although the incidence of resistant coagulase-negative staphylococci on the skin increased with both regimens. Most chest and urinary infections hitherto treated with co-trimoxazole should be treated with trimethoprim alone.

Adult↗
PubMed1980

Plasma levels of trimethoprim and sulfonamide after administration of trimethoprim-sulfamethoxazole and trimethoprim-sulfamoxole.

In a cross-over study with ten healthy volunteers, the plasma levels of trimethoprim (TMP) and sulfonamides were compared using orally given trimethoprim-sulfamethoxazole (TMP-SMX: Septra) and trimethoprim-sulfamoxole (TMP-SMO: Supristol) in recommended doses. The dosage schedule for TMP-SMX was 2 tablets every 12 h for nine doses, and for TMP-SMO it was 2 tablets as in the first dose, followed by 1 tablet every 12 h for eight more doses. Serial plasma levels of TMP and sulfonamides after the first dose of each of the two products showed no significant differences. However, after the ninth dose of each product, the paired t test revealed significantly higher levels of TMP and sulfonamides after TMP-SMX as compared with TMP-SMO.

Adult↗
PubMed1982

Emergence of high-level trimethoprim resistance in fecal Escherichia coli during oral administration of trimethoprim or trimethoprim--sulfamethoxazole.

The effect of daily administration of trimethoprim (TMP), trimethoprim--sulfamethoxazole (TMP--SMX), or placebo on aerobically grown fecal gram-negative bacteria was monitored in 136 students from the United States during a two-week diarrhea-prevention study in Mexico. Unlike patients in other studies with these agents, who had urinary-tract infection or granulocytopenia, most persons in this study had no change in total fecal Enterobacteriaceae and had high-level TMP and SMX resistance in virtually all these strains. Escherichia coli was the predominant TMP-resistant organism isolated; 96 per cent of 165 TMP-resistant Esch. coli isolates were resistant to at least four antimicrobial agents, and 25 per cent were resistant to seven. TMP resistance was transferable in 40 ot 100 strains tested. Despite the lack of TMP resistance in other studies of prophylaxis, our results clearly demonstrate the remarkable capacity for emergence and dissemination of resistance to this agent.

Anti-Bacterial Agents↗
PubMed1990

Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone.

BACKGROUND: Antimicrobial drugs that can be taken orally are needed for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Preliminary data indicate that dapsone with trimethoprim may be an effective alternative to trimethoprim-sulfamethoxazole, which is frequently toxic. METHODS: In a double-blind trial, 60 patients with AIDS and mild-to-moderately-severe first episodes of P. carinii pneumonia (partial pressure of oxygen in arterial blood, greater than 60 mm Hg while breathing room air) were randomly assigned to 21 days of treatment with either trimethoprim-sulfamethoxazole (20 and 100 mg per kilogram of body weight per day, respectively) or trimethoprim-dapsone (20 mg per kilogram per day and 100 mg per day). RESULTS: The orally administered treatment failed because of progressive pneumonitis in 3 of the 30 patients assigned to trimethoprim-sulfamethoxazole and in 2 of the 30 assigned to trimethoprim-dapsone (P greater than 0.3). Major toxic effects required a switch to intravenous pentamidine for 17 patients (57 percent) in the trimethoprim-sulfamethoxazole group, as compared with 9 (30 percent) in the trimethoprim-dapsone group (P less than 0.025). With trimethoprim-sulfamethoxazole, there were more instances of severe chemical hepatitis (six, as compared with one in the trimethoprim-dapsone group) and marked neutropenia (five vs. one). Intolerable rash (three in each treatment group) and severe nausea and vomiting (two in each group) occurred with equal frequency with both drug combinations. Methemoglobinemia occurred in most of the patients treated with trimethoprim-dapsone, but it was asymptomatic and the level exceeded 20 percent in only one patient. Mild hyperkalemia (serum potassium level, 5.1 to 6.1 mmol per liter) also occurred in 53 percent of the patients treated with trimethoprim-dapsone. CONCLUSIONS: In patients with AIDS, oral therapy with trimethoprim-sulfamethoxazole and with trimethoprim-dapsone are equally effective for mild-to-moderate first episodes of P. carinii pneumonia, but with trimethoprim-dapsone there are fewer serious adverse reactions than with trimethoprim-sulfamethoxazole.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Prior trimethoprim use and trimethoprim-resistant urinary tract infection: a nested case-control study with multivariate analysis for other risk factors.

Trimethoprim resistance is increasingly prevalent in community-acquired urinary infections. The objective of this study was to evaluate the association between exposure to community-prescribed trimethoprim and other risk factors in subjects and subsequent trimethoprim-resistant urinary tract infection. The design was a nested case-control study using a record-linkage database. Study subjects submitted a urine sample to the Ninewells Hospital Laboratory between July 1993 and December 1995. Antibiotic exposure in subjects with trimethoprim-resistant isolates (cases) was compared with antibiotic exposure in subjects with trimethoprim-susceptible isolates (controls). Study subjects were drawn from the catchment area of a large teaching hospital in Tayside, Scotland. There were 13765 males and females aged 1-106 years who submitted their first urine sample for culture during the study period. After adjustment for significant risk factors and confounding variables, logistic regression analysis showed exposure to trimethoprim [odds ratio (OR) 4.35] or any antibiotic other than trimethoprim (OR 1.32) to be predictive of resistance. The growth of Proteus spp. (OR 115.14) and bacterial growth other than Escherichia coli and Proteus spp. (OR 2.83) were also predictor variables. Hospitalization in the previous 6 months was not independently associated with trimethoprim resistance. In conclusion, trimethoprim resistance was independently associated with exposure to trimethoprim and to antibiotics other than trimethoprim. Reduction in trimethoprim prescribing alone may not reduce the prevalence of trimethoprim resistance.

Anti-Infective Agents, Urinary↗
PubMed1999

Increased in vitro production of interleukin 6 in response to trimethoprim among persons with trimethoprim induced systemic adverse reactions.

OBJECTIVE: Trimethoprim occasionally triggers a systemic adverse reaction including fever, malaise, head and backache, and even overt meningeal irritation, particularly in women with an autoimmune rheumatic disease. To study the unknown pathogenesis of the reaction we measured the effect of trimethoprim upon the cytokine [interleukin (IL) 2, 6, 10, and tumor necrosis factor-alpha] production of trimethoprim reactive and tolerant persons' peripheral blood mononuclear cells in vitro. METHODS: Peripheral blood mononuclear cells from 12 women reactive to trimethoprim (3 with primary Sjögren's syndrome, 3 with systemic lupus erythematosus, 1 with systemic scleroderma, 5 with no rheumatic disease) were cultured in the presence of trimethoprim, and the cytokine production was measured. Eleven women who tolerated trimethoprim (6 with Sjögren's syndrome and 5 with no rheumatic disease) served as controls. RESULTS: Therapeutic trimethoprim concentration induced in the mononuclear cells of the trimethoprim reactive patients significantly higher IL-6 production [mean +/- SD (median), 2034+/-2965 (572) pg/ml] versus cells of the trimethoprim tolerant subjects [954+/-2552 (89) pg/ml; p = 0.036]. No significant differences in the production of other cytokines were detected. CONCLUSION: Trimethoprim induces IL-6 production in the peripheral blood mononuclear cells of trimethoprim reactive persons. We suggest that IL-6 production is the probable trigger leading to the clinical reaction.

Adult↗
PubMed1999

Characterization of dihydrofolate reductase genes from trimethoprim-susceptible and trimethoprim-resistant strains of Enterococcus faecalis.

Enterococci are usually susceptible in vitro to trimethoprim; however, high-level resistance (HLR) (MICs, >1,024 microg/ml) has been reported. We studied Enterococcus faecalis DEL, for which the trimethoprim MIC was >1,024 microg/ml. No transfer of resistance was achieved by broth or filter matings. Two different genes that conferred trimethoprim resistance when they were cloned in Escherichia coli (MICs, 128 and >1,024 microg/ml) were studied. One gene that coded for a polypeptide of 165 amino acids (MIC, 128 microg/ml for E. coli) was identical to dfr homologs that we cloned from a trimethoprim-susceptible E. faecalis strain, and it is presumed to be the intrinsic E. faecalis dfr gene (which causes resistance in E. coli when cloned in multiple copies); this gene was designated dfrE. The nucleotide sequence 5' to this dfr gene showed similarity to thymidylate synthetase genes, suggesting that the dfr and thy genes from E. faecalis are located in tandem. The E. faecalis gene that conferred HLR to trimethoprim in E. coli, designated dfrF, codes for a predicted polypeptide of 165 amino acids with 38 to 64% similarity with other dihydrofolate reductases from gram-positive and gram-negative organisms. The nucleotide sequence 5' to dfrF did not show similarity to the thy sequences. A DNA probe for dfrF hybridized under high-stringency conditions only to colony lysates of enterococci for which the trimethoprim MIC was >1,024 microg/ml; there was no hybridization to plasmid DNA from the strain of origin. To confirm that this gene causes trimethoprim resistance in enterococci, we cloned it into the integrative vector pAT113 and electroporated it into RH110 (E. faecalis OG1RF::Tn916DeltaEm) (trimethoprim MIC, 0.5 microg/ml), which resulted in RH110 derivatives for which the trimethoprim MIC was >1, 024 microg/ml. These results indicate that dfrF is an acquired but probably chromosomally located gene which is responsible for in vitro HLR to trimethoprim in E. faecalis.

Amino Acid Sequence↗
PubMed1997

In vitro activity of trimethoprim alone compared with trimethoprim-sulfamethoxazole and other antimicrobials against bacterial species associated with upper respiratory tract infections.

Trimethoprim-sulfamethoxazole has been used to treat various respiratory tract infections. Nevertheless, for many patients, intolerance of the sulfonamide component precludes use of this combination. This study examined the activity of trimethoprim alone in comparison to that of trimethoprim-sulfamethoxazole and other antimicrobials against bacterial species implicated in respiratory tract infections. For Haemophilus influenzae, minimal inhibitory concentrations of trimethoprim were equal to or one dilution greater than those of trimethoprim-sulfamethoxazole, with 56 of 58 strains inhibited by the former at < or = 0.25 microgram/ml. All oxacillin-susceptible Staphylococcus aureus and 96.7% of Streptococcus pyogenes were inhibited by trimethoprim < or = 2 micrograms/ml. In contrast, only 50% of Streptococcus pneumoniae were inhibited by this concentration of trimethoprim, whereas 93.3% were susceptible to the combination at < or = 2/38 micrograms/ml. All oxacillin-resistant S. aureus and all Moraxella catarrhalis were resistant to trimethoprim, although many of the former and all of the latter were susceptible to trimethoprim-sulfamethoxazole.

Anti-Bacterial Agents↗
PubMedDate not supplied

Pharmacokinetics of sulphadoxine and trimethoprim and tissue irritation caused by two sulphadoxine-trimethoprim containing products after subcutaneous administration in pre-ruminant calves.

The pharmacokinetics of sulphadoxine-trimethoprim was studied in 6 pre-ruminant calves using two different products. Product A, which contained 200 mg sulphadoxine and 40 mg trimethoprim per mL, was administered intravenously or subcutaneously at a dosage of 25 mg sulphadoxine and 5 mg trimethoprim.kg-1 bodyweight. Product B, containing 62.5 mg sulphadoxine and 12.5 mg trimethoprim per mL plus lidocaine (1 mg.mL-1), was given subcutaneously at the same dosage. After intravenous administration of product A the mean time of half-life of elimination phase (t1/2) for sulphadoxine was 12.9 h, steady-state volume of distribution (Vd(ss)) was 0.44 L.kg-1 and clearance was 0.024 L.kg-1.h-1. Respective values for trimethoprim were 1.9 h, 2.0 L.kg-1 and 0.9 L.kg-1.h-1. After subcutaneous administration, the bioavailability of sulphadoxine was 96% and 98% and the time to reach a maximum concentration was 6.3 and 8.0 h for products A and B, respectively. The Cmax for trimethoprim was higher for product A (0.49 microgram.mL-1) than for product B (0.32 microgram.mL-1) (p = 0.014). Slow absorption from the injection site appeared to delay the elimination of trimethoprim after subcutaneous administration when compared to that after intravenous administration: apparent elimination t1/2 for trimethoprim after intravenous administration of product A was 1.9 h compared to 3.9 h and 3.6 h after subcutaneous administration of products A and B, respectively. The difference between intravenous and subcutaneous administrations was statistically significant (p < 0.05). Also the mean residence time was significantly shorter (p < 0.05) after intravenous administration (2.4 h) than that after subcutaneous administration of product A (6.9 h) and B (7.1 h). The bioavailability of trimethoprim was lower than that of sulphadoxine: 76% and 74% for products A and B, respectively. All 6 calves showed pain after subcutaneous administration of product A and the injection sites were warm and showed soft oedematous reactions 5-8 cm in diameter. Three of the calves also showed some pain after subcutaneous administration of product B; the local reactions were less severe. A marked increase was seen in creatine kinase activity after subcutaneous administration of both products. Product A caused a more pronounced increase but the difference was not statistically significant. We suggest 30 mg.kg-1 at 24-h intervals or alternatively 15 mg.kg-1 at 12-h intervals as the minimum dosage of sulphadoxine-trimethoprim combination for pre-ruminant calves. Extravascular routes of administration should be avoided due to marked tissue irritation at the injection site.

Animals↗
PubMed2006

Crystal engineering of analogous and homologous organic compounds: hydrogen bonding patterns in trimethoprim hydrogen phthalate and trimethoprim hydrogen adipate.

BACKGROUND: Trimethoprim [2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine] is an antifolate drug. It selectively inhibits the bacterial dihydrofolate reductase (DHFR) enzyme. RESULTS: In the crystal structures of trimethoprim (TMP)-hydrogen phthalate (1) and trimethoprim-hydrogen adipate (2), one of the N atoms of the pyrimidine ring is protonated and it interacts with the deprotonated carboxylate oxygens through a pair of nearly parallel N-H...O hydrogen bonds to form a fork-like interaction. In the compound 1, the pyrimidine moieties of the TMP cations are centrosymmetrically paired through a pair of N-H...N hydrogen bonds involving 4-amino group and the N (N3) atom of the pyrimidine rings to form a 8-membered hydrogen bonded ring [R2(2)(8)]. The 4-amino group of one TMP moiety and 2-amino group of another TMP moiety (both moieties are members of a base pair) are bridged by the carbonyl oxygen of the phthalate moiety through N-H...O hydrogen bonds forming 8-membered hydrogen-bonded ring [R2(2)(8)]. The characteristic hydrogen-bonded rings observed in the structure aggregate into a supramolecular ladder consisting of a pair of chains, each of which is built up of alternate TMP and hydrogen phthalate ions. In the compound 2, two TMP cations and two hydrogen adipate anions are arranged about an inversion center so that the complementary DDAA (D = donor, A = acceptor) arrays of quadruple hydrogen-bonding patterns are formed. The head-to-tail arrangement of the hydrogen adipate ions leads to a hydrogen-bonded supramolecular chain. From crystal engineering point of view, it is interesting to note that the compound 1 has a hydrogen-bonded network remarkably identical with its aliphatic analogue, trimethoprim hydrogen maleate. Similarly the compound 2, resembles its homolog trimethoprim hydrogen glutarate. CONCLUSION: In the crystal structure of trimethoprim hydrogen phthalate, the hydrogen-bonded network is remarkably identical with its aliphatic analogue, trimethoprim hydrogen maleate. Similarly in the crystal structure of trimethoprim hydrogen adipate the hydrogen bonded network resembles its homolog trimethoprim hydrogen glutarate.

Journal Article↗
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↗
PubMed1994

Trimethoprim resistance in urinary pathogens in northern Scotland: epidemic spread of a resistance plasmid encoding the type Ib trimethoprim-resistant dihydrofolate reductase.

The prevalence of trimethoprim resistance in enterobacterial urinary pathogens from hospitalised patients in the Angus district of northern Scotland (22.8%) was twice that found in similar isolates from patients attending general practitioners (11.2%). Thirty-three of the 143 trimethoprim-resistant strains were shown to harbour transferable plasmids conferring high-level trimethoprim resistance. In total, 17 different plasmid types were distinguished. Two plasmids, pUK1184 and pUK1185, accounted for 36% of the trimethoprim resistance plasmids and were shown by restriction endonuclease digestion fingerprints to be closely related to plasmid pUK28, previously demonstrated to be endemic in urinary pathogens in the Edinburgh area. Only 21% of the plasmids were shown to encode the type Ia trimethoprim-resistant dihydrofolate reductase, whereas 70% of the trimethoprim resistance plasmids were found to encode the type Ib dihydrofolate reductase. Hybridisation of the trimethoprim resistance plasmids identified in this study with gene probes specific for the integrase genes of transposons Tn7 and Tn21 indicates that the dhfrIa is rarely present within Tn7 or related transposons in these plasmids and may be more prevalent within Tn21-like transposons. In contrast, with the exception of the two endemic plasmids that harboured the dhfrIb gene within a Tn7-like transposon, the majority of dhfrIb genes were not found to be associated with either Tn7- or Tn21-like structures.

Bacteriuria↗
PubMed1985

Effect of a new sulfa-trimethoprim combination (trimethoprim-sulfamethopyrazine) in typhoid fever. A double-blind study on 72 adult patients.

A double-blind study on 72 adult patients affected by typhoid fever was done utilizing a new sulfa-trimethoprim combination (trimethoprim-sulfamethopyrazine) versus the well-known combination trimethoprim-sulfamethoxazole. The dosage used for the new drug was 2 capsules (250 mg trimethoprim + 200 mg sulfamethopyrazine per capsule) the 1st day and 1 capsule for the following 14 days or 2 capsules (trimethoprim 80 mg + sulfamethoxazole 400 mg per capsule) twice daily for 15 days. Both drugs proved to be very effective according to the parameters considered. No complications (intestinal bleeding, perforation, etc.) occurred in any of the patients, and untoward effects were not observed. It is therefore our opinion that treatment of typhoid fever with a sulfa-trimethoprim combination is both effective and safe.

Adolescent↗
PubMed1986

Trimethoprim binding to Lactobacillus casei dihydrofolate reductase: a 13C NMR study using selectively 13C-enriched trimethoprim.

We have measured the 13C chemical shifts for trimethoprim molecules selectively enriched with 13C at the 2-, 4-, 5-, 6-, and 7-positions and the p-OCH3 position in their complexes with Lactobacillus casei dihydrofolate reductase in the presence and absence of coenzyme analogues. The C2 carbon shifts indicate that the pyrimidine ring is protonated at N1 in all the complexes of trimethoprim with the enzyme and coenzymes and in each case the pyrimidine ring is binding in a similar way to that of the corresponding part of methotrexate in the enzyme-methotrexate complex. The C6 carbon of trimethoprim shows a large upfield shift in all complexes (3.51 to 4.70 ppm) but no shift in the complex of 2,4-diaminopyrimidine with the enzyme: these shifts probably arise from steric interactions between the C1' and C2' carbons and the H6 proton, which approach van der Waals contact in the folded conformation adopted by trimethoprim when bound to the enzyme. The large shift observed for C6 in all complexes indicates that the basic folded conformation is present in all of them. A comparison of the 13C shifts in the enzyme-trimethoprim-NADPH complex with those in the enzyme-trimethoprim binary complex shows substantial changes even for carbons such as C6 and p-OCH3 (0.46 and -0.36 ppm, respectively), which are remote from the coenzyme: these are caused by ligand-induced conformational changes that may involve displacement of the helix containing residues 42-49.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed2005

Molecular imprinting-chemiluminescence determination of trimethoprim using trimethoprim-imprinted polymer as recognition material.

A new molecular imprinting-chemiluminescence method for the determination of trimethoprim was developed, in which trimethoprim-imprinted polymer was used as the molecular recognition material and the CL reaction of trimethoprim with potassium permanganate in acidic medium was used as the detection system. The CL intensity responds linearly to the concentration of trimethoprim within the 5.0 x 10(-8)-5.0 x 10(-6) g mL(-1) range (r= 0.9983) with a detection limit of 2 x 10(-8) g mL(-1). The relative standard deviation for the determination of 1.0 x 10(-7) g mL(-1) trimethoprim solutions is 4.8% (n= 9). The method has been applied to the determination of trimethoprim in pharmaceutical preparations and body fluids, and satisfactory results were obtained.

Adsorption↗