Administration Of Trimethoprim Research Articles

In Vivo Validation of a Reversible Small Molecule-Based Switch for Synthetic Self-Amplifying mRNA Regulation

Synthetic mRNA therapeutics have the potential to revolutionize healthcare, as they enable patients to produce therapeutic proteins inside their own bodies. However, convenient methods that allow external control over the timing and magnitude of protein production after invivo delivery of synthetic mRNA are lacking. In this study, we validate the invivo utility of a synthetic self-amplifying mRNA (RNA replicon) whose expression can be turned off using a genetic switch that responds to oral administration of trimethoprim (TMP), a US Food and Drug Administration (FDA)-approved small-molecule drug. After intramuscular electroporation, the engineered RNA replicon exhibited dose-dependent and reversible expression of its encoded protein upon TMP administration. The TMP serum level needed for maximal downregulation of protein translation was approximately 45-fold below that used in humans for therapeutic purposes. To demonstrate the therapeutic potential of the technology, we injected mice with a TMP-responsive RNA replicon encoding erythropoietin (EPO) and successfully controlled the timing and magnitude of EPO production as well as changes in hematocrit. This work demonstrates the feasibility of controlling mRNA kinetics invivo, thereby broadly expanding the clinical versatility of mRNA therapeutics.

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization.

Gene therapies that chronically suppress vascular endothelial growth factor (VEGF) represent a new approach for managing retinal vascular leakage and neovascularization. However, constitutive suppression of VEGF in the eye may have deleterious side effects. Here, we developed a novel strategy to introduce Flt23k, a decoy receptor that binds intracellular VEGF, fused to the destabilizing domain (DD) of Escherichia coli dihydrofolate reductase (DHFR) into the retina. The expressed DHFR(DD)-Flt23k fusion protein is degraded unless "switched on" by administering a stabilizer; in this case, the antibiotic trimethoprim (TMP). Cells transfected with the DHFR(DD)-Flt23k construct expressed the fusion protein at levels correlated with the TMP dose. Stabilization of the DHFR(DD)-Flt23k fusion protein by TMP was able to inhibit intracellular VEGF in hypoxic cells. Intravitreal injection of self-complementary adeno-associated viral vector (scAAV)-DHFR(DD)-Flt23k and subsequent administration of TMP resulted in tunable suppression of ischemia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy (OIR). Hence, our study suggests a promising novel approach for the treatment of retinal neovascularization. Schematic diagram of the tunable system utilizing the DHFR(DD)-Flt23k approach to reduce VEGF secretion. a The schematic shows normal VEGF secretion. b Without the ligand TMP, the DHFR(DD)-Flt23k protein is destabilized and degraded by the proteasome. c In the presence of the ligand TMP, DHFR(DD)-Flt23k is stabilized and sequestered in the ER, thereby conditionally inhibiting VEGF. Green lines indicate the intracellular and extracellular distributions of VEGF. Blue lines indicate proteasomal degradation of the DHFR(DD)-Flt23k protein. Orange lines indicate the uptake of cell-permeable TMP. TMP, trimethoprim; VEGF, vascular endothelial growth factor;ER, endoplasmic reticulum.

Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model

Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CLcre), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters.

Refractory hyperkalaemia associated with trimethoprim-sulfamethoxazole therapy in neutropaenic sepsis

Hyperkalaemia is a potentially life threatening electrolyte disorder commonly seen in critically ill patients secondary to renal impairment. Herein, we report a case of severe hyperkalaemia, which was disproportionate to the degree of renal impairment, associated with neutropaenic sepsis, in a critically ill middle aged gentleman. Hyperkalaemia was refractory to medical treatment necessitating haemodialysis in the background of recent administration of trimethoprim- sulfamethoxazole (TMX-SMX) for presumed pneumocystis jiroveci pneumonia. It is important for clinicians to be aware of this complication as TMX-SMX is a popular antibiotic in immunocompromised populations.

Safety and efficacy of upfront graded administration of trimethoprim–sulfamethoxazole in systemic lupus erythematosus: A retrospective cohort study

Objectives: Trimethoprim–sulfamethoxazole (TMP/SMX) is effective as prophylaxis against many infections in immunocompromised patients. However, it is not commonly prescribed for patients with systemic lupus erythematous (SLE) due to the risk of adverse reactions (ADRs). An upfront graded administration protocol for TMP/SMX was adopted, and its safety and efficacy were assessed.Methods: Data from 59 patients with SLE patients who received prophylactic TMP/SMX were retrospectively analyzed. The incidence and risk factors for ADRs in patients who received TMP/SMX before and after the introduction of graded administration were assessed.Results: The incidence of ADRs was 41.9% in the non-graded administration group, vs. 10.7% in the graded administration group (p = 0.009). The rate of high fever, liver function test (LFT) abnormality, shortness of breath, and hospitalization were reduced in upfront graded administration group. In addition, a higher rate of anti-Ro/SS-A positivity was found in patients experienced ADRs (46.2% in reactors vs. 5.6% in non-reactors; p = 0.012) in the non-graded administration group.Conclusions: Upfront graded administration of TMP/SMX reduces the incidence and severity of ADRs in SLE patients. The high incidence of TMP/SMX ADRs in SLE patients was also confirmed, especially when anti-Ro/SS-A antibody is present.

Application of in vivo microdialysis for investigation of unbound drug concentrations of intravenously administered sulfadimidine in the paranasal sinus mucosa of horses.

To monitor concentrations of sulfadimidine in the paranasal sinus mucosa (PSM) of unsedated horses following IV administration of trimethoprim-sulfadimidine via in vivo microdialysis. 10 healthy adult horses. Concentric microdialysis probes were implanted into the subepithelial layers of the frontal sinus mucosa of standing sedated horses. Four hours after implantation, trimethoprim-sulfadimidine (30 mg/kg) was administered IV every 24 hours for 2 days; dialysate and plasma samples were collected at intervals during that 48-hour period and analyzed for concentrations of sulfadimidine. The dialysate concentration and relative loss of sulfadimidine from the perfusate were used to calculate the PSM concentration. Microdialysis probe implantation and subsequent in vivo microdialysis were successfully performed for all 10 horses. Following the first and second administration of trimethoprim-sulfadimidine, mean ± SD peak concentrations of sulfadimidine were 55.3 ± 10.3 μg/mL and 51.5 ± 8.7 μg/mL, respectively, in plasma and 9.6 ± 4.5 μg/mL and 7.0 ± 3.3 μg/mL, respectively, in the PSM. Peak sulfadimidine concentrations in the PSM were detected at 5.9 ± 2.7 hours and 5.4 ± 2.3 hours following the first and second drug administrations, respectively. For 12 hours, mean PSM sulfadimidine concentration remained greater than the minimum inhibitory concentration indicative of sulfonamide susceptibility of equine bacterial isolates (4.75 μg/mL). In vivo microdialysis for continuous monitoring of PSM sulfadimidine concentrations in unsedated horses was feasible. Intravenous administration of trimethoprim (5 mg/kg) and sulfadimidine (25 mg/kg) proved likely to be efficient for treating sinusitis caused by highly susceptible pathogens, providing that the dosing interval is 12 hours.

Pancytopenia in two horses following administration of potentiated sulfonamide antimicrobials

SummaryAdverse drug reactions to potentiated sulfonamide antimicrobial drug combinations have been reported in many species, including horses. This report describes the occurrence of pancytopenia in 2 horses, one subsequent to an immune mediated reaction and the other bone marrow aplasia following the administration of trimethoprim and sulfadimidine. These cases highlight the importance of judicious use of antimicrobial agents and describe adverse drug reactions in horses receiving potentiated sulfonamide antimicrobials.

Gibel carp Carassius auratus gut microbiota after oral administration of trimethoprim/ sulfamethoxazole

Trimethoprim/sulfamethoxazole is widely used in the treatment of infectious diseases caused by bacterial pathogens in aquaculture. However, the practice of antibiotic administration can promote the emergence of resistant strains of bacteria and result in a wane in efficacy over time. The objective of this study was to assess the effect of oral treatment with trimethoprim/sulfamethoxazole on the gastrointestinal (GI) microbiota of healthy gibel carp and those affected with bacterial enteritis. By using denaturing gradient gel electrophoresis (DGGE), the changes in the predominant bacterial communities were directly depicted for the first time. The main findings were (1) Actinobacteria, Firmicutes and Proteobacteria were the predominant phyla in the healthy gibel carp intestine; (2) administration of antibiotics had a more profound impact on the intestinal microflora of healthy fish than of the diseased ones; and (3) Enterobacteriaceae might be one of the major drug-resistant bacteria in the gibel carp intestine. This study provides an insight into the effect of antibiotic treatment on the establishment and colonization of fish GI microbiota and speculates on some possible drug-resistant bacteria.

Salivary Gland Nocardiosis in an Immunocompetent Patient

We report a case of nocardiosis in an immunocompetent patient who presented with pain and multiple swellings in the face. Nocardia asteroides was isolated from the parotid and submandibular salivary glands. The patient was successfully treated by surgical drainage and oral administration of trimethoprim and sulfamethoxazole. To the best of our knowledge, this is the first reported case from India on N. asteroides affecting the salivary gland.

Trimethoprim versus Gentamicin for the Prevention of Bacteriuria following Transrectal Biopsy of the Prostate – Do Patients Need Additional Anaerobic Cover?

Objectives: To study the incidence of aerobic and anaerobic bacteriuria in patients undergoing transrectal ultrasound-guided biopsies of the prostate. A comparative assessment of efficacy of trimethoprim with gentamicin for the prevention of bacteriuria following the transrectal biopsy of the prostate. To assess the need for additional prophylaxis against anaerobes for patients undergoing transrectal biopsies of the prostate gland. Patients and Methods: In a pilot study during 1995–1997, all the patients undergoing transrectal ultrasound-guided biopsy of the prostate were randomised to receive either trimethoprim or gentamicin prophylaxis prior to the procedure. Midstream urine (MSU) samples were taken just prior to biopsy and 72 h later. A patient questionnaire to determine the symptoms of urinary tract infection (UTI) accompanied the 72-hour MSU request form. Urine samples were cultured aerobically, using a semiquantitative technique if dipstick analysis revealed the presence of blood, pus cell or nitrite. In addition to the routine aerobic culture, post-biopsy samples were also cultured for anaerobes by direct and enrichment methods. Bacteriuria was defined as a pure or mixed growth of 10⁵ colony-forming units/ml. Fisher’s test of exact probability was used for statistical analysis. Results: 115 patients were available for final analysis. 53 had received gentamicin and 62 trimethoprim. Four patients had pre-existing bacteriuria (3.5%), 3 in the trimethoprim group and 1 in the gentamicin group. Post-operative bacteriuria developed in 5 patients given gentamicin (9.4%) and 1 given trimethoprim (1.6%). This difference was not statistically significant (p = 0.085). Post-procedure bacteriuria was asymptomatic in all but 1 case. Anaerobes were detected in only 5 MSUs (4.3%) post-biopsy. Conclusion: Though there was no statistical significant difference in the rates of bacteriuria following administration of trimethoprim and gentamicin, data appear to favour trimethoprim prophylaxis. Further studies are warranted. Transrectal biopsy of the prostate is associated with a low incidence of anaerobic UTI. In view of the very low incidence of anaerobic bacteriuria, routine antibacterial prophylaxis against anaerobes does not appear to be justified.

Oral bioavailability of sulphadiazine and trimethoprim in fed and fasted pigs

The disposition of sulphadiazine ( SDZ) and trimethoprim ( TMP) was measured after intravenous and oral administration. Six healthy pigs weighing 17 to 34 kg received 20 mg kg −1 SDZ plus 4 mg kg −1 TMP intravenously, and 40 mg kg −1 SDZ plus 8 mg kg −1 TMP orally in both a fed and a fasted condition in a three-way cross-over design. After intravenous administration, SDZ and TMP were present in plasma for 30 and 12 hours, respectively. The volume of distribution was 0·5 litre kg −1 bodyweight for SDZ and 1·8 litre kg −1 bodyweight for TMP. The oral bioavailabilities for SDZ and TMP in the fed pigs were 85 per cent and 92 per cent, and in the fasted pigs 89 per cent and 90 per cent, respectively. Although the presence of food did not affect the almost complete absorption of both drugs, it did prolong the absorption phase. Mean absorption time was nearly twice as long in the fed as in the fasted pig. Based on bioavailability and the resulting plasma concentrations it is concluded that the oral administration of SDZ and TMP was efficient in both the fed and fasted pigs.

Trimethoprim potentiates valproic acid-induced Neural Tube Defects (NTDs) in mice

The antiepileptic drug valproic acid (VPA) may produce NTDs because of interference with folate metabolism. Therefore, the possible interactions of VPA with the dihydrofolate reductase inhibitor trimethoprim (TM) was investigated. The combination of TM with sulfamethoxazol is used for treatment of urinary infections, the most common complications of pregnancy. TM (80 and 160 mg/kg) was given i.p. and orally, 0.5 and 1 h, respectively, prior to valproic acid (VPA, 300 and 400 mg/kg, s.c.) in day 8 pregnant NMRI mice. Fetuses were examined for exencephaly, resorptions, and fetal weight retardation on day 18 of gestation. TM (160 mg/kg, i.p.) produced no exencephaly or embryolethality, but increased fetal weight. Administration of TM (80 mg/kg, i.p.) increased VPA-induced exencephaly and fetal weight retardation but not embryolethality. Exencephaly rates induced by VPA (300 and 400 mg/kg) were 4% and 12.9% and were increased by coadministration of TM to 22.7% and 42.5%, respectively ( P < 0.01). Oral TM also increased VPA-induced exencephaly and fetal weight retardation but with lower potency than i.p. injection. The observed effects were not due to altered VPA pharmacokinetics. These results support the view that VPA-induced neural tube defects may be mediated via an interaction with folate metabolism, and advise against TM-use in VPA-treated epileptics during pregnancy.

Hypersensitivity to trimethoprim

We present two patients who experienced life-threatening immediate reactions and one patient who developed generalized urticaria following oral administration of trimethoprim (TMP) and sulfamethoxazole (SMX) combination. Skin prick tests with TMP were positive in the three patients. No patients reacted to skin prick tests with SMX. No significant levels of IgE antibodies to TMP were found by RAST in the serum of the patients. Normal subjects used as controls did not react to any of these tests. Single-blind, placebo-controlled oral challenges were positive with TMP and negative with SMX in all patients. These results suggest that the three patients developed type I hypersensitivity reactions to TMP. In our patients skin prick tests with TMP were useful in TMP hypersensitivity diagnosis.

Drug plasma levels following administration of trimethoprim and sulphonamide combinations to broilers

Trimethoprim (TMP) was administered in combination with either sulphadiazine or sulphadimidine to broilers, and plasma concentrations were determined simultaneously by newly developed thin-layer and/or high-performance liquid-chromatographic procedures, which also allowed quantification of the N4-acetyl metabolites of the sulphonamides. After i.v. injection of TMP (20 mg/kg body wt) and sulphadiazine (100 mg/kg body wt), both compounds were rapidly eliminated from plasma with half-lives of 1 and 2.7 h, respectively. Apparent volumes of distribution (3.3 and 0.96 l/kg, respectively) indicated that the tissue distribution of TMP was more extensive than that of the sulphonamide. After oral administration of the same dosages, elimination appeared to be slower compared to the i.v. injection, but this was obviously related to delayed absorption. Bioavailability after oral administration was approximately 100% of sulphadiazine, but only about 60% for TMP. Oral dosing of TMP in combination with sulphadimidine yielded similar maximum plasma concentrations of both compounds to those obtained with the combination of TMP with sulphadiazine, but the plasma concentration decline of sulphadimidine appeared to be more rapid than that of sulphadiazine after oral administration. During prolonged administration of different dosages of TMP-sulphadiazine combinations via drinking water, only low plasma concentrations were attained by the recommended dosage of the combination. Up to 10-fold higher dosages were tolerated by the animals without side-effects. In view of the fact that the sensitivity of bacterial strains to TMP-sulphonamide combinations differs widely, the plasma concentrations determined in the present study during prolonged drinking-water medication with different dosages of a TMP-sulphadiazine combination can be used to select effective doses for treatment of different poultry diseases.

Aseptic Meningitis Associated With Administration of Trimethoprim and Sulfamethoxazole

Sir .—Aseptic meningitis is common and is usually caused by a viral infection. However, other infectious and noninfectious causes of aseptic meningitis are legion. 1 Aseptic meningitis apparently induced by trimethoprim and sulfamethoxazole has been reported in at least five adult patients, 2-6 but to my knowledge it has not yet been reported in children. I present a child in whom recurring aseptic meningitis appeared to have been caused by trimethoprim and sulfamethoxazole. Patient Report .—A 6-year-old boy was admitted with fever, vomiting, and nuchal rigidity. He had a history of otitis media 2 weeks prior to admission that had been treated with amoxicillin; 1 day prior to admission the amoxicillin therapy was discontinued, and administration of trimethoprim and sulfamethoxazole was begun. Several hours after the first dose of trimethoprim and sulfamethoxazole, vomiting developed, followed by fever and stiff neck. At that time, the patient appeared acutely ill with nuchal

Absorption of two trimethoprim/sulphonamide combinations from the uterus of pony mares.

Plasma drug concentrations were measured after two commercially available potentiated sulphonamides, trimethoprim and sulfadoxine and trimethoprim and sulphadiazine, were infused daily for 2 and 3 days, respectively, into the uteri of pony mares which had been mated before ovulation. Intravenous administration of trimethoprim and sulfadoxine allowed uterine absorption of trimethoprim (23-43%) and sulfadoxine (29-34%) to be calculated. After intra-uterine administration trimethoprim and sulphadiazine were detected in the milk of a lactating mare. In order to maintain plasma concentrations likely to be required for clinical efficacy of both drugs they should be administered every 12 h. However, infusions of both preparations caused endometrial inflammation as assessed by cytological and histological examination and this may have been responsible for the low pregnancy rate.

Pharmacokinetics of Trimethoprim in the Rat

The pharmacokinetics of trimethoprim was studied in male Sprague—Dawley rats following the intravenous administration of trimethoprim at a dose of 25 mg/kg. Plasma and tissue levels of trimethoprim, as a function of time, were determined by reversed-phase high-performance liquid chromatography. The disposition of trimethoprim was described by both a two-compartment open model with elimination from a central compartment and a noncompartmental method. For the compartmental analysis, the terminal elimination rate constant, elimination half-life, apparent volume of distribution in the central compartment, apparent volume of distribution in the central compartment based on the area under the plasma concentration—time curve, and volume of distribution at steady state, were determined to be 0.007min−1, 99min, 2059 mL/kg, 5729 mL/kg, and 2473 mL/kg, respectively. Noncompartmental pharmacokinetic parameters were obtained by the statistical moment theory. The estimates for mean residence time, clearance, and volume of distribution at steady state of trimethoprim were calculated to be 52min, 40mL min−1kg−1, and 2097 mL, respectively. Tissue distribution of trimethoprim followed a biphasic phenomenon with a maximum concentration at 30min for heart, lung, spleen, liver, kidney, seminal vesicles, and muscle, and at 45min for testicles, 20min for prostate gland, and <10min for brain. The data show that compared with the plasma concentration, higher levels of trimethoprim were found in heart, lung, spleen, liver, kidney, prostate gland, and seminal vesicles; a similar concentration was found for muscle, but lower levels of trimethoprim were found for brain and testicles.

Emergence of High-Level Trimethoprim Resistance in Fecal Escherichia Coli During Oral Administration of Trimethoprim or Trimethoprim-Sulfamethoxazole

Abstract 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 of 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. (N Engl J Med. 1982; 306:...

Synergism of trimethoprim combined with aminoglycosides in vitro and in serum of volunteers.

In vitro synergism of trimethoprim plus amikacin and trimethoprim plus sisomicin against 66 gram-negative bacilli was studied by microtiter checkerboard dilution. Synergism was defined as an FIC or FBC index equal to or less than 0.5. Fifty-two percent of strains were inhibited and 65% killed synergistically by the former combination, and 27% and 36% respectively by the latter combination (p less than 0.01). Serum bactericidal activity against 16 strains resistant to ampicillin and/or cephalothin was studied using serum from five volunteers one and six hours after intravenous administration of trimethoprim (160 mg), amikacin (250 mg) or the combination, and from six volunteers after administration of trimethoprim, tobramycin (1 mg/kg) or the combination. With trimethoprim and amikacin serum bactericidal titers greater than or equal to 1:8 were found more frequently with the combination (77 of 80 samples) than with either drug alone (trimethoprim 19 of 80 samples, amikacin 60 of 80 samples, p less than 0.01). Trimethoprim plus amikacin may be useful in the treatment of infections with gram-negative rods resistant to cephalothin and ampicillin.

Trimethoprim: mechanisms of action, antimicrobial activity, bacterial resistance, pharmacokinetics, adverse reactions, and therapeutic indications.

Trimethoprim has recently been marketed as a single-entity product for the treatment of initial episodes of uncomplicated symptomatic urinary tract infections; it was previously available only in combination with sulfamethoxazole. Trimethoprim exerts antimicrobial activity by blocking the reduction of dihydrofolate to tetrahydrofolate, the active form of folic acid, by susceptible organisms. It has inhibitory activity for most gram-positive aerobic cocci and some gram-negative aerobic bacilli. Resistance to trimethoprim may be either intrinsic or acquired. Acquired resistance most commonly stems from a chromosomal mutation that results in the production of a dihydrofolate reductase enzyme which is less vulnerable to trimethoprim inhibition. Gastrointestinal intolerance and skin eruptions are the most common untoward reactions resulting from the administration of trimethoprim. Trimethoprim constitutes very effective therapy for women with acute symptomatic urinary tract infections caused by E. coli, and the compound compares favorably with alternative standard agents, such as ampicillin and cephalexin. The safety of trimethoprim in the pregnant woman has not been established. Since indiscriminate use of trimethoprim could foster the emergence of trimethoprim resistance, thereby negating the value of both trimethoprim and trimethoprim-sulfamethoxazole, trimethoprim should only be prescribed for well defined indications. Trimethoprim is currently being investigated as definitive therapy for a wide range of infections, including bacterial exacerbations of chronic bronchitis, bacterial pneumonia, and typhoid fever. Initial reports are encouraging.