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British Medical Journal (Clinical... Feb 1983
Topics: Animals; Drug Combinations; Female; Humans; Infant; Male; Pentamidine; Pneumonia, Pneumocystis; Rats; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 6402123
DOI: 10.1136/bmj.286.6364.499 -
Journal of the Pediatric Infectious... Aug 2018With the continued high prevalence of chlamydia worldwide and high risk of transfer from mothers to their infant during delivery, a need for safe and effective therapies... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
With the continued high prevalence of chlamydia worldwide and high risk of transfer from mothers to their infant during delivery, a need for safe and effective therapies for infants who acquire a chlamydial infection remains. We conducted a systematic review and meta-analysis of antibiotic treatments, including oral erythromycin, azithromycin, and trimethoprim, for neonatal chlamydial conjunctivitis.
METHODS
We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from their inception to July 14, 2017. We included randomized and nonrandomized studies that evaluated the effects of erythromycin, azithromycin, or trimethoprim in neonates with chlamydial conjunctivitis. A meta-analysis using a random-effects generic inverse-variance method was performed, and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.
RESULTS
We found 12 studies (n = 292 neonates) and were able to meta-analyze 7 studies that used erythromycin at a dose of 50 mg/kg body weight per day for 14 days. The clinical and microbiological cure were 96% (95% confidence interval [CI], 94%-100%) and 97% (95% CI, 95%-99%), respectively, and adverse gastrointestinal effects occurred in 14% (95% CI, 1%-28%) of the neonates. The microbiological cure in the study that assessed azithromycin at 20 mg/kg per day were 60% (95% CI, 27%-93%) when it was given in a single dose and 86% (95% CI, 61%-100%) when given in a 3-day course. Two studies reported compliance with treatments, and 1 study reported no pyloric stenosis events. Because of the risk of bias and the few neonates included across the studies, the certainty of evidence is low to very low. No studies assessed trimethoprim.
CONCLUSIONS
Although evidence suggests that erythromycin at 50 mg/kg per day for 14 days results in higher numbers of cure than does azithromycin, compliance and risk of pyloric stenosis related to their use for other infections in neonates will factor into treatment recommendations. More data are needed to compare these treatments directly.
Topics: Anti-Bacterial Agents; Azithromycin; Bias; Chlamydia Infections; Chlamydia trachomatis; Conjunctivitis, Bacterial; Drug Administration Schedule; Erythromycin; Female; Gastrointestinal Diseases; Humans; Infant, Newborn; Male; Pyloric Stenosis; Risk Factors; Trimethoprim
PubMed: 30007329
DOI: 10.1093/jpids/piy060 -
The Journal of Antibiotics Jan 2020The development of new mechanisms of resistance among pathogens, the occurrence and transmission of genes responsible for antibiotic insensitivity, as well as cancer... (Review)
Review
The development of new mechanisms of resistance among pathogens, the occurrence and transmission of genes responsible for antibiotic insensitivity, as well as cancer diseases have been a serious clinical problem around the world for over 50 years. Therefore, intense searching of new leading structures and active substances, which may be used as new drugs, especially against strain resistant to all available therapeutics, is very important. Dihydrofolate reductase (DHFR) has attracted a lot of attention as a molecular target for bacterial resistance over several decades, resulting in a number of useful agents. Trimethoprim (TMP), (2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine) is the well-known dihydrofolate reductase inhibitor and one of the standard antibiotics used in urinary tract infections (UTIs). This review highlights advances in design, synthesis, and biological evaluations in structural modifications of TMP as DHFR inhibitors. In addition, this report presents the differences in the active site of human and pathogen DHFR. Moreover, an excellent review of DHFR inhibition and their relevance to antimicrobial and parasitic chemotherapy was presented.
Topics: Anti-Bacterial Agents; Drug Design; Drug Development; Drug Discovery; Folic Acid Antagonists; Humans; Tetrahydrofolate Dehydrogenase; Trimethoprim
PubMed: 31578455
DOI: 10.1038/s41429-019-0240-6 -
Poultry Science Jan 2022One hundred and twenty chicken samples from feces (n = 80), the carcass surface at slaughter at 2 meat chicken farms (n = 20), and retail chicken meat from 5 markets...
Prevalence of qnrS-positive Escherichia coli from chicken in Thailand and possible co-selection of isolates with plasmids carrying qnrS and trimethoprim-resistance genes under farm use of trimethoprim.
One hundred and twenty chicken samples from feces (n = 80), the carcass surface at slaughter at 2 meat chicken farms (n = 20), and retail chicken meat from 5 markets (n = 20) collected during 2018 and 2019 were examined for the prevalence of plasmid-mediated quinolone resistance (PMQR) in Escherichia coli. We detected qnrS-positive E. coli in a total of 74 samples from feces (n = 59), the carcass surface (n = 7), and retail meat (n = 8). These 74 qnrS-positive isolates were tested for antimicrobial susceptibility to determine the minimum inhibitory concentrations (MICs) of certain antimicrobials and genetically characterized. Ampicillin-resistance accounted for 71 of the 74 isolates (96%), followed by resistance to oxytetracycline (57/74; 77%), enrofloxacin (ERFX) (56/74; 76%), sulfisoxazole (SUL) (56/74; 76%), trimethoprim (TMP) (49/74; 66%), and dihydrostreptomycin (48/74; 65%). All farm-borne SUL- and TMP-resistant isolates except one were obtained from samples from farm A where a combination of sulfadiazine and TMP was administered to the chickens. Concentrations of ERFX at which 50 and 90% of isolates were inhibited were 2 μg/mL and 32 μg/mL, respectively. Diverse pulsed-field gel electrophoresis (PFGE) patterns of XbaI-digested genomic DNA were observed in the qnrS-positive isolates from fecal samples. Several isolates from feces and the carcass surface had identical XbaI-digested PFGE patterns. S1-nuclease PFGE and Southern blot analysis demonstrated that 7 of 11 dfrA13-positive fecal isolates carried both the qnrS and dfrA13 genes on the same plasmid, and 2 of 3 dfrA1-positive isolates similarly carried both qnrS and dfrA1 on the same plasmid, although the PFGE patterns of XbaI-digested genomic DNA of the isolates were different. These results suggest that the qnrS gene is prevalent in chicken farms via horizontal transfer of plasmids and may partly be co-selected under the use of TMP.
Topics: Animals; Chickens; Escherichia coli; Escherichia coli Proteins; Farms; Plasmids; Prevalence; Thailand; Trimethoprim
PubMed: 34788713
DOI: 10.1016/j.psj.2021.101538 -
Acta Veterinaria Scandinavica 1974DAVITIYANANDA, DANIS and FOLKE RASMUSSEN: Acta vet. scand. 1974, , 340–355. — In 21 experiments on 5 healthy, nonpregnant cows are sulphadoxine and trimethoprim...
DAVITIYANANDA, DANIS and FOLKE RASMUSSEN: Acta vet. scand. 1974, , 340–355. — In 21 experiments on 5 healthy, nonpregnant cows are sulphadoxine and trimethoprim infused intravenously for maintenance of constant levels of the drugs through the experimental periods. The experiments show that both sulphadoxine and trimethoprim are bound to the proteins in blood plasma and milk. Further it is demonstrated that sulphadoxine (an acid) is excreted into milk in concentrations lower than in blood plasma while trimethoprim (a base) is excreted into milk in concentrations higher than in blood plasma. Both results are consistent with the theory that drugs are excreted through the mammary gland by passive diffusion. Glomerular filtration and back-diffusion are both involved in the renal handling of sulphadoxine and trimethoprim. For trimethoprim active tubular secretion is also demonstrated. Both the mammary and renal handling of sulphadoxine as well as trimethoprim are influenced by the pH of milk and urine, respectively. The experiments underline that it is the unionized, non-protein-bound fraction of the drugs which diffuses through biological membranes. sulphadoxine; trimethoprim; mammary excretion; renal excretion; cow.
Topics: Animals; Blood; Cattle; Creatinine; Female; Hydrogen-Ion Concentration; Infusions, Parenteral; Kidney; Mammary Glands, Animal; Milk; Protein Binding; Sulfanilamides; Trimethoprim; Urine
PubMed: 4414560
DOI: 10.1186/BF03547463 -
Bioconjugate Chemistry May 2018Trimethoprim is one of the most widely used antibiotics in the world. However, its efficacy is frequently limited by its poor water solubility and dose limiting...
Trimethoprim is one of the most widely used antibiotics in the world. However, its efficacy is frequently limited by its poor water solubility and dose limiting toxicity. Prodrug strategies based on conjugation of oligosaccharides to trimethoprim have great potential for increasing the solubility of trimethoprim and lowering its toxicity, but they have been challenging to develop due to the sensitivity of trimethoprim to chemical modifications, and the rapid degradation of oligosaccharides in serum. In this report, we present a trimethoprim conjugate of maltodextrin termed TM-TMP, which increased the water solubility of trimethoprim by over 100 times, was stable to serum enzymes, and was active against urinary tract infections in mice. TM-TMP is composed of thiomaltose conjugated to trimethoprim, via a self-immolative disulfide linkage, and releases 4'-OH-trimethoprim (TMP-OH) after disulfide cleavage, which is a known metabolic product of trimethoprim and is as potent as trimethoprim. TM-TMP also contains a new maltodextrin targeting ligand composed of thiomaltose, which is stable to hydrolysis by serum amylases and therefore has the metabolic stability needed for in vivo use. TM-TMP has the potential to significantly improve the treatment of a wide number of infections given its high water solubility and the widespread use of trimethoprim.
Topics: Animals; Anti-Bacterial Agents; Escherichia coli; Escherichia coli Infections; Female; Maltose; Mice; Polysaccharides; Trimethoprim; Urinary Tract Infections
PubMed: 29660287
DOI: 10.1021/acs.bioconjchem.8b00177 -
Virology Journal Jun 2021Respiratory RNA viruses including influenza virus have been a cause of health and economic hardships. These viruses depend on its host for replication and infection....
BACKGROUND
Respiratory RNA viruses including influenza virus have been a cause of health and economic hardships. These viruses depend on its host for replication and infection. Influenza virus infection is lethal to the chick embryo. We examined whether a combination of trimethoprim and zinc (Tri-Z), that acts on the host, can reduce the lethal effect of influenza A virus in chick embryo model.
METHOD
Influenza virus was isolated from patients and propagated in eggs. We determined viral load that infects 50% of eggs (50% egg lethal dose, ELD). We introduced 10 ELD into embryonated eggs and repeated the experiments using 100 ELD. A mixture of zinc oxide (Zn) and trimethoprim (TMP) (weight/weight ratios ranged from 0.01 to 0.3, Zn/TMP with increment of 0.1) was tested for embryo survival of the infection (n = 12 per ratio, in triplicates). Embryo survival was determined by candling eggs daily for 7 days. Controls of Zn, TMP, saline or convalescent serum were conducted in parallel. The effect of Tri-Z on virus binding to its cell surface receptor was evaluated in a hemagglutination inhibition (HAI) assay using chicken red cells. Tri-Z was prepared to concentration of 10 mg TMP and 1.8 mg Zn per ml, then serial dilutions were made. HAI effect was expressed as scores where ++++ = no effect; 0 = complete HAI effect.
RESULTS
TMP, Zn or saline separately had no effect on embryo survival, none of the embryos survived influenza virus infection. All embryos treated with convalescent serum survived. Tri-Z, at ratio range of 0.15-0.2 (optimal ratio of 0.18) Zn/TMP, enabled embryos to survive influenza virus despite increasing viral load (> 80% survival at optimal ratio). At concentration of 15 µg/ml of optimal ratio, Tri-Z had total HAI effect (scored 0). However, at clinical concentration of 5 µg/ml, Tri-Z had partial HAI effect (+ +).
CONCLUSION
Acting on host cells, Tri-Z at optimal ratio can reduce the lethal effect of influenza A virus in chick embryo. Tri-Z has HAI effect. These findings suggest that combination of trimethoprim and zinc at optimal ratio can be provided as treatment for influenza and possibly other respiratory RNA viruses infection in man.
Topics: Animals; Chick Embryo; Humans; Influenza A virus; Orthomyxoviridae Infections; Trimethoprim; Zinc
PubMed: 34082750
DOI: 10.1186/s12985-021-01585-1 -
Acta Poloniae Pharmaceutica 2015The objective of this study was to evaluate and compare the effect of four superdisintegrants such as croscarmellose sodium (Ac-Di-Sol), crospovidone (Kollidon CL and...
The objective of this study was to evaluate and compare the effect of four superdisintegrants such as croscarmellose sodium (Ac-Di-Sol), crospovidone (Kollidon CL and with smaller particle sizes Kollidon CL-F), sodium starch glycolate (Explotab) in combination with β-lactose and microcrystalline cellulose (Avicel PH-102) as base excipients exhibiting properties of directly compressed tablets and increasing the disintegration and the dissolution rate of sulfadimidine sodium (SDD-Na) and trimethoprim (TMP). All tablets were prepared by direct compression method and superdisintegrants were used at 2% for all formulations. The tablets were evaluated with regard to uniformity of weight, hardness, friability, drug content, disintegration time and dissolution properties. Dissolution properties such as t50% and t80% (time to release 50 and 80% of drug), DP3045 (percent of drug dissolved in 30 and 45 min) and the dissolution rate constant value (K) were considered in comparing the dissolution results. The results showed that crospovidone (Kollidon CL) provides the shortest disintegration time and the fastest rate of dissolution for both TMP and SDD-Na. The kinetic study of the dissolution data reveals that in vitro release profiles of TMP and SDD-Na can be best explained by first order model or by Higuchi model. The obtained data were plotted into Korsmeyer-Peppas equation to find out the confirmed diffusion mechanism. For TMP release, the values of the release exponent are beyond the limits of Korsmeyer model, so-called, power law. For SDD-Na release, exponent values are characteristic for anomalous transport (non-Fickian) or the value of the release exponent is beyond the limits of Korsmeyer model.
Topics: Kinetics; Solubility; Sulfamethazine; Tablets; Trimethoprim
PubMed: 26642686
DOI: No ID Found -
Toxicological Sciences : An Official... Feb 2021Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, 1 possible...
Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, 1 possible reactive metabolite is the sulfate conjugate of α-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that α-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, α-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, α-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be 1 factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general.
Topics: Animals; Exanthema; Humans; Liver; Mice; Nevirapine; Rats; Skin; Trimethoprim
PubMed: 33394045
DOI: 10.1093/toxsci/kfaa182 -
Photodegradation of Ciprofloxacin, Clarithromycin and Trimethoprim: Influence of pH and Humic Acids.Molecules (Basel, Switzerland) May 2021In view of the rising relevance of emerging pollutants in the environment, this work studies the photodegradation of three antibiotics, evaluating the effects of the pH...
In view of the rising relevance of emerging pollutants in the environment, this work studies the photodegradation of three antibiotics, evaluating the effects of the pH of the medium and the concentration of dissolved organic matter. Simulated light (with a spectrum similar to that of natural sunlight) was applied to the antibiotics Ciprofloxacin (Cip), Clarithromycin (Cla) and Trimethoprim (Tri), at three different pH, and in the presence of different concentrations of humic acids. The sensitivity to light followed the sequence: Cip > Cla > Tri, which was inverse for the half-life (Tri > Cla > Cip). As the pH increased, the half-life generally decreased, except for Cla. Regarding the kinetic constant k, in the case of Cip and Tri it increased with the rise of pH, while decreased for Cla. The results corresponding to total organic carbon (TOC) indicate that the complete mineralization of the antibiotics was not achieved. The effect of humic acids was not marked, slightly increasing the degradation of Cip, and slightly decreasing it for Tri, while no effect was detected for Cla. These results may be relevant in terms of understanding the evolution of these antibiotics, especially when they reach different environmental compartments and receive sunlight radiation.
Topics: Anti-Bacterial Agents; Ciprofloxacin; Clarithromycin; Darkness; Half-Life; Humic Substances; Hydrogen-Ion Concentration; Kinetics; Light; Trimethoprim
PubMed: 34064068
DOI: 10.3390/molecules26113080