-
Microbiome Feb 2023Hospitalisation and antimicrobial treatment are common in horses and significantly impact the intestinal microbiota. Antimicrobial treatment might also increase levels...
BACKGROUND
Hospitalisation and antimicrobial treatment are common in horses and significantly impact the intestinal microbiota. Antimicrobial treatment might also increase levels of resistant bacteria in faeces, which could spread to other ecological compartments, such as the environment, other animals and humans. In this study, we aimed to characterise the short- and long-term effects of transportation, hospitalisation and trimethoprim-sulfadiazine (TMS) administration on the faecal microbiota and resistome of healthy equids.
METHODS
In a longitudinal experimental study design, in which the ponies served as their own control, faecal samples were collected from six healthy Welsh ponies at the farm (D0-D13-1), immediately following transportation to the hospital (D13-2), during 7 days of hospitalisation without treatment (D14-D21), during 5 days of oral TMS treatment (D22-D26) and after discharge from the hospital up to 6 months later (D27-D211). After DNA extraction, 16S rRNA gene sequencing was performed on all samples. For resistome analysis, shotgun metagenomic sequencing was performed on selected samples.
RESULTS
Hospitalisation without antimicrobial treatment did not significantly affect microbiota composition. Oral TMS treatment reduced alpha-diversity significantly. Kiritimatiellaeota, Fibrobacteres and Verrucomicrobia significantly decreased in relative abundance, whereas Firmicutes increased. The faecal microbiota composition gradually recovered after discontinuation of TMS treatment and discharge from the hospital and, after 2 weeks, was more similar to pre-treatment composition than to composition during TMS treatment. Six months later, however, microbiota composition still differed significantly from that at the start of the study and Spirochaetes and Verrucomicrobia were less abundant. TMS administration led to a significant (up to 32-fold) and rapid increase in the relative abundance of resistance genes sul2, tetQ, ant6-1a, and aph(3")-lb. lnuC significantly decreased directly after treatment. Resistance genes sul2 (15-fold) and tetQ (six-fold) remained significantly increased 6 months later.
CONCLUSIONS
Oral treatment with TMS has a rapid and long-lasting effect on faecal microbiota composition and resistome, making the equine hindgut a reservoir and potential source of resistant bacteria posing a risk to animal and human health through transmission. These findings support the judicious use of antimicrobials to minimise long-term faecal presence, excretion and the spread of antimicrobial resistance in the environment. Video Abstract.
Topics: Humans; Horses; Animals; Trimethoprim; Longitudinal Studies; RNA, Ribosomal, 16S; Hospitalization; Feces; Microbiota
PubMed: 36850017
DOI: 10.1186/s40168-023-01465-6 -
BMJ Clinical Evidence Jul 2008Cystitis is a bacterial infection of the lower urinary tract which causes pain when passing urine, and causes urgency, haematuria, and suprapubic pain not associated... (Review)
Review
INTRODUCTION
Cystitis is a bacterial infection of the lower urinary tract which causes pain when passing urine, and causes urgency, haematuria, and suprapubic pain not associated with passing urine. Recurrent cystitis is usually defined as three episodes of urinary tract infection in the previous 12 months, or two episodes in the previous 6 months.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical question: Which interventions prevent further recurrence of cystitis in women experiencing at least two infections per year? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: continuous antibiotic prophylaxis (trimethoprim, co-trimoxazole, nitrofurantoin, cefaclor, or a quinolone or cephalexin); continuous prophylaxis with methenamine hippurate; cranberry juice and cranberry products; oestrogen (topical) in postmenopausal women; passing urine after intercourse; postcoital antibiotic prophylaxis; single-dose self-administered antibiotic.
Topics: Acute Disease; Bacterial Infections; Cystitis; Female; Humans; Incidence; Nitrofurantoin; Prospective Studies; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections
PubMed: 19445741
DOI: No ID Found -
Molecular Systems Biology Sep 2022Dose-response relationships are a general concept for quantitatively describing biological systems across multiple scales, from the molecular to the whole-cell level. A...
Dose-response relationships are a general concept for quantitatively describing biological systems across multiple scales, from the molecular to the whole-cell level. A clinically relevant example is the bacterial growth response to antibiotics, which is routinely characterized by dose-response curves. The shape of the dose-response curve varies drastically between antibiotics and plays a key role in treatment, drug interactions, and resistance evolution. However, the mechanisms shaping the dose-response curve remain largely unclear. Here, we show in Escherichia coli that the distinctively shallow dose-response curve of the antibiotic trimethoprim is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth, which in turn weakens the effect of this antibiotic. At the molecular level, this feedback is caused by the upregulation of the drug target dihydrofolate reductase (FolA/DHFR). We show that this upregulation is not a specific response to trimethoprim but follows a universal trend line that depends primarily on the growth rate, irrespective of its cause. Rewiring the feedback loop alters the dose-response curve in a predictable manner, which we corroborate using a mathematical model of cellular resource allocation and growth. Our results indicate that growth-mediated feedback loops may shape drug responses more generally and could be exploited to design evolutionary traps that enable selection against drug resistance.
Topics: Anti-Bacterial Agents; Escherichia coli; Feedback; Tetrahydrofolate Dehydrogenase; Trimethoprim
PubMed: 36124745
DOI: 10.15252/msb.202110490 -
Antimicrobial Agents and Chemotherapy Jan 1985The in vitro activities of trimethoprim (TMP), alone and in combination with sulfamethoxazole (SMX), against 131 clinical isolates of enterococci, 126 Streptococcus...
The in vitro activities of trimethoprim (TMP), alone and in combination with sulfamethoxazole (SMX), against 131 clinical isolates of enterococci, 126 Streptococcus faecalis isolates, and 5 Streptococcus faecium isolates were determined by a broth microdilution method with Mueller-Hinton broth that was substantially free of inhibitory substances. The geometric mean MIC of TMP for strains of S. faecalis was 0.164 micrograms/ml (range, 0.03 to 8 micrograms/ml), with a geometric mean MBC of 0.298 micrograms/ml (range, 0.063 to 8 micrograms/ml). Although all strains were resistant to the sulfonamide alone, the inhibitory and bactericidal activities of TMP against strains of S. faecalis were markedly potentiated when TMP was combined in a fixed ratio of 1:19 with SMX; the geometric mean MIC of TMP was reduced to 0.016 micrograms/ml (range, 0.002 to 0.25 micrograms/ml), with a geometric mean MBC of 0.031 micrograms/ml (range, 0.004 to 0.25 micrograms/ml). The combination had no synergistic effect against strains of S. faecium; the geometric mean MICs and MBCs of both agents were ca. 0.06 micrograms/ml. The MBC/MIC ratios for TMP and TMP-SMX were less than or equal to 16 for all 131 strains. MICs and MBCs for TMP-SMX were unchanged, and for TMP they decreased when performed in broth supplemented with 50% heat-inactivated pooled human serum. For TMP and TMP-SMX, the susceptibilities of isolates with high-level resistance to gentamicin or streptomycin were the same as those of isolates susceptible to less than or equal to 2,000 micrograms of aminoglycoside per ml. These results suggest that TMP-SMX and TMP alone could prove useful in the treatment of serious enterococcal infections, including infections by strains with high-level resistance to aminoglycosides.
Topics: Aminoglycosides; Anti-Bacterial Agents; Culture Media; Drug Combinations; Drug Resistance, Microbial; Enterococcus faecalis; Microbial Sensitivity Tests; Streptococcus; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 3920958
DOI: 10.1128/AAC.27.1.71 -
Current Protocols in Chemical Biology 2013Over the past decade, chemical tags have been developed to complement the use of fluorescent proteins in live-cell imaging. Chemical tags retain the specificity of...
Over the past decade, chemical tags have been developed to complement the use of fluorescent proteins in live-cell imaging. Chemical tags retain the specificity of protein labeling achieved with fluorescent proteins through genetic encoding, but provide smaller, more robust tags and modular use of organic fluorophores with high photon output and tailored functionalities. The trimethoprim-based chemical tag (TMP-tag) was initially developed based on the high affinity interaction between E. coli dihydrofolate reductase and the antibiotic trimethoprim and was subsequently rendered covalent and fluorogenic via proximity-induced protein labeling reactions. To date, the TMP-tag is one of the few chemical tags that enable intracellular protein labeling and high-resolution live-cell imaging. Here we describe the general design, chemical synthesis, and application of TMP-tag for live-cell imaging. Alternate protocols for synthesizing and using the covalent and the fluorogenic TMP-tags are also included.
Topics: Anti-Bacterial Agents; Cell Line; Drug Design; Fluorescent Dyes; Humans; Molecular Imaging; Recombinant Fusion Proteins; Transfection; Trimethoprim
PubMed: 23839994
DOI: 10.1002/9780470559277.ch130019 -
Canadian Medical Association Journal Jun 1975The fate of trimethoprim and sulfamethoxazole and the combination of both these agents was studied in a group of healthy pregnant women who were undergoing therapeutic...
The fate of trimethoprim and sulfamethoxazole and the combination of both these agents was studied in a group of healthy pregnant women who were undergoing therapeutic abortion. Assays were performed on samples of blood, urine, amniotic fluid and fetal tissues, using a standardized protocol for the selection of patients, dose administration, sample collection and assay techniques. A comparative evaluation of kinetics to assess the maternal handling and the distribution of trimethoprim throughout the fetoplacental unit disclosed no significant difference in the concentration within fetal fluids and tissue compartments. On the other hand, the concentration of sulfamethoxazole was lower in fetal tissues than in fetal fluids when relative ratios to trimethoprim were compared. The implications of the difference in behaviour of pharmacokinetic and clinical points of view.
Topics: Administration, Oral; Adult; Amniotic Fluid; Biological Assay; Colorimetry; Drug Combinations; Female; Fetal Blood; Fetus; Humans; Kinetics; Liver; Lung; Maternal-Fetal Exchange; Placenta; Pregnancy; Sulfamethoxazole; Trimethoprim; Urine
PubMed: 1137830
DOI: No ID Found -
Nature Communications May 2021The antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant...
The antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant bacteria. Previous laboratory evolution experiments have identified resistance-conferring mutations in the gene encoding the TMP target, bacterial dihydrofolate reductase (DHFR), in particular mutation L28R. Here, we show that 4'-desmethyltrimethoprim (4'-DTMP) inhibits both DHFR and its L28R variant, and selects against the emergence of TMP-resistant bacteria that carry the L28R mutation in laboratory experiments. Furthermore, antibiotic-sensitive E. coli populations acquire antibiotic resistance at a substantially slower rate when grown in the presence of 4'-DTMP than in the presence of TMP. We find that 4'-DTMP impedes evolution of resistance by selecting against resistant genotypes with the L28R mutation and diverting genetic trajectories to other resistance-conferring DHFR mutations with catalytic deficiencies. Our results demonstrate how a detailed characterization of resistance-conferring mutations in a target enzyme can help identify potential drugs against antibiotic-resistant bacteria, which may ultimately increase long-term efficacy of antimicrobial therapies by modulating evolutionary trajectories that lead to resistance.
Topics: Amino Acid Substitution; Anti-Bacterial Agents; Crystallography, X-Ray; Directed Molecular Evolution; Drug Design; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Folic Acid Antagonists; Genes, Bacterial; Genotype; Humans; Models, Molecular; Mutation; Tetrahydrofolate Dehydrogenase; Trimethoprim; Trimethoprim Resistance
PubMed: 34011959
DOI: 10.1038/s41467-021-23191-z -
British Medical Journal (Clinical... Aug 1985
Topics: Drug Combinations; Humans; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 3926242
DOI: 10.1136/bmj.291.6493.481 -
Veterinary Research 2000The pharmacokinetics of sulphadoxine-trimethoprim was studied in 6 pre-ruminant calves using two different products. Product A, which contained 200 mg sulphadoxine and... (Comparative Study)
Comparative Study
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.
Topics: Animals; Anti-Infective Agents; Biological Availability; Cattle; Creatine Kinase; Cross-Over Studies; Drug Combinations; Injections, Intravenous; Injections, Subcutaneous; Skin; Sulfadoxine; Time Factors; Trimethoprim
PubMed: 11050747
DOI: 10.1051/vetres:2000137 -
Bulletin of the World Health... 1974For the treatment of malaria, combinations of drugs with antifolic action have the great advantage, compared with other drug associations, of synergic action, which... (Review)
Review
For the treatment of malaria, combinations of drugs with antifolic action have the great advantage, compared with other drug associations, of synergic action, which increases the effectiveness of the preparation, limits its toxicity, and reduces the risk of resistance. The associations of a sulfonamide (sulfalene, S) with a diaminopyrimidine derivative (pyrimethamine, P, or trimethoprim, T) have given good immediate clinical results. An analysis of the pharmacodynamic and pharmacokinetic characteristics of the three components explains the relative ease with which relapse is encountered with the association ST. The association SP is, from this point of view, more logical and effective and its importance in prophylaxis is surveyed in the light of a critical discussion of the arguments that are at present throwing doubt on the usefulness of its wider employment.
Topics: Adolescent; Adult; Child; Child, Preschool; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Erythrocytes; Folic Acid Antagonists; Humans; Immunity; Infant; Infant, Newborn; Malaria; Middle Aged; Oxidoreductases; Plasmodium falciparum; Pyrimethamine; Sulfonamides; Trimethoprim
PubMed: 4613504
DOI: No ID Found