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PubMed2006

Tetramethylpyrazine attenuates adriamycin-induced apoptotic injury in rat renal tubular cells NRK-52E.

Tetramethylpyrazine (TMP), a compound purified from Rhizoma Ligustici, is a widely used active ingredient in Chinese herbal medicine to treat cardiovascular diseases on account of its vasodilatory actions and antiplatelet activity. Studies have shown that TMP can remove oxygen free radicals and protect rat kidney from ischemia-reperfusion injury. In addition, adriamycin-induced nephrosis in rats is commonly used in pharmacological studies of human chronic renal diseases. Apoptosis of renal tubular cells has been reported in adriamycin-treated rats. To examine the therapeutic potential of TMP on chronic progressive renal diseases, adriamycin-induced injury in rat renal tubular cells NRK-52E has been used to monitor its protective effect. In TUNEL staining, TMP showed a dose-dependent protective effect against adriamycin-induced apoptosis in NRK-52E cells. Pretreatment of the cells with 10 or 100 microM of TMP effectively decreased the reactive oxygen species (ROS) formation induced by adriamycin, as measured in fluorescent assays. TMP was found to reduce the adriamycin-stimulated activities of caspase-3, caspase-8 and caspase-9, inhibit adriamycin-induced release of cytochrome C, and elevate the expression of Bcl-x (L). TMP was also able to inhibit the death receptor signaling pathway and suppress the activation of transcription factor NF-kappaB in adriamycin-treated NRK-52E cells. Based on the results of this study, we suggest that TMP can attenuate adriamycin-induced oxidative stress and apoptotic injury in NRK-52E cells, and that it may have therapeutic potential for patients with renal diseases. TMP: tetramethylpyrazine LDH: lactate dehydrogenase ROS: reactive oxygen species DCF: 2',7'-dichlorofluorescein TNF-alpha: tumor necrosis factor-alpha TUNEL: terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling.

Animals↗
PubMed2001

Successful prophylaxis against Pneumocystis carinii pneumonia in HIV-infected children using smaller than recommended dosages of trimethoprim-sulfamethoxazole.

Prophylaxis against Pneumocystis carinii pneumonia (PCP) is an essential part of the management of children with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). No dose-ranging studies were ever performed; therefore, the amount of trimethoprim-sulfamethoxazole (TMP-SMX) needed to suppress PCP in children with HIV/AIDS is not known. The dose recommended by the Centers for Disease Control (CDC) has been thought to be just above the threshold needed for prevention, based on anecdotal breakthrough PCP in cancer patients who were improperly dosed. We have been giving prophylaxis based on body weight rather than surface area, and this, combined with growth of our children, has led to a large experience with dosages lower than the currently recommended 150 mg/m2. The medical records of children with HIV who met CDC guidelines for institution of PCP prophylaxis were reviewed. To ascertain the per square meter (m2) dosage each child was receiving, body surface area was calculated from height and weight measurements. Dosages were recalculated every 6 months and at each dosage change. Data regarding PCP infection, bacterial infections, and side effects of TMP-SMX were extracted. Data were compiled from 1,719.5 child-months of TMP-SMX prophylaxis, including 1,532.5 child-months below the currently recommended dose. Sixty-seven percent of our child-months were at or below two-thirds the CDC recommended dose. There were no cases of proven or suspected PCP. Incidence of other serious bacterial infections was low. Bacteremia and sepsis with Streptococcus pneumoniae was the most common proven bacterial infection, at a rate of 5.5 episodes per 100 child-years. The incidence of bacterial infection did not vary by the dose of TMP-SMX. TMP-SMX prophylaxis was well tolerated; most reactions were mild and self-limited and did not recur with re-institution of the drug. Only 6.1% of this cohort had TMP-SMX prophylaxis discontinued due to perceived toxicity. These data show that the currently recommended dose of TMP-SMX (150 mg/m2) may not be required to prevent PCP in children with HIV/AIDS. The drug is well tolerated at all dosage levels. The incidence of serious bacterial infection in this cohort of patients did not depend upon the amount of TMP-SMX prescribed. A prospective, controlled clinical trial of low-dose TMP-SMX for children with HIV infection is warranted.

AIDS-Related Opportunistic Infections↗
PubMed1997

Rapid disease progression in human immunodeficiency virus type 1-infected individuals with adverse reactions to trimethoprim-sulfamethoxazole prophylaxis.

We studied the relation between the occurrence of adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis and the subsequent course of human immunodeficiency virus (HIV) infection in a cohort of homosexual men. Adverse reactions to TMP-SMZ were associated with a more rapid progression to AIDS (P < .001) and death (P < .001) and with a more rapid decline in CD4+ cell counts (P = .001). The median time to progression to AIDS was 14.9 months in subjects with adverse reactions to TMP-SMZ and 32.5 months in those without adverse reactions. After exclusion of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis from the case definition of AIDS, the differences in the rate of progression to AIDS between subjects with and without adverse reactions to TMP-SMZ were still highly significant (P = .004). A low CD4+ cell count at baseline and the use of antiretroviral agents before the start of prophylaxis were predictors of adverse reactions to TMP-SMZ but did not account for the difference in progression to AIDS between subjects with and without adverse reactions to TMP-SMZ. In a univariate analysis, the relative hazard of adverse reactions to TMP-SMZ for progression to AIDS was 2.54 (95% confidence interval [CI], 1.50-4.28); in a multivariate analysis, it was 2.21 (95% CI, 1.29-3.81). The relative hazards of adverse reactions to TMP-SMZ for progression to AIDS with the exclusion of PCP and toxoplasmosis, CD4+ cell counts of <50/mm3, and death were 2.16 (95% CI, 1.25-3.72), 2.37 (95% CI, 1.36-4.12), and 3.21 (95% CI, 1.80-5.72), respectively. It is unclear whether adverse reactions to TMP-SMZ induce or merely predict progression of HIV disease.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Treatment of experimentally induced enterotoxigenic Escherichia coli diarrhea with trimethoprim, trimethoprim-sulfamethoxazole, or placebo.

In a double-blind study of the treatment of disease caused by enterotoxigenic Escherichia coli (ETEC), diarrhea was induced in volunteers with a trimethoprim (TMP)- and sulfamethoxazole (SMZ)-susceptible strain of E. coli that produces both heat-stable and heat-labile toxin. III volunteers were then treated with TMP, TMP-SMZ, or placebo. Volunteers treated with both TMP alone and the TMP-SMZ combination showed a substantial decrease in the duration and severity of the illness, as compared with the placebo-treated controls. TMP-resistant (MIC, 3.1-12.5 micrograms/ml) ETEC were isolated from stool cultures of five of 10 TMP-treated volunteers and none of 10 TMP-SMZ-treated volunteers after 48 hr of therapy, and in two volunteers the appearance of resistant organisms was associated with a clinical relapse. These data suggest that the TMP-SMZ combination should be evaluated in field trials to determine its usefulness as an adjunct to replacement of fluid and electrolytes in the therapy of ETEC diarrhea.

Adult↗
PubMedDate not supplied

Pharmacokinetics of intravenous trimethoprim-sulfamethoxazole in children and adults with normal and impaired renal function.

Thirty-seven children and adults aged 0.2-82 years were treated intravenously with 150 mg of trimethoprim (TMP) and 750 mg of sulfamethoxazole (SMZ)/m2 every 8 hr, usually for known or suspected pneumocystis pneumonia; when necessary dosage was adjusted to maintain peak TMP levels of 5-10 micrograms/ml. On day 2 of treatment, mean peak levels of TMP-SMZ were 7.02 and 148 micrograms/ml, respectively, and mean half-lives were 9.6 and 10.7 hr, respectively. All age groups achieved similar peak levels of TMP-SMZ, although dosages per weight were higher in children than in adults. Peak increments (peak levels minus levels before infusion) were higher and more reliable after iv than after oral dosage (P less than 0.001). The half-lives of TMP and SMZ increased with age (r = +0.73 and +0.39, respectively) and were correlated directly with the level of serum creatinine (r = +0.85 and +0.39, respectively). Serum concentrations of N4-acetyl-SMZ, the major hepatic metabolite of SMZ, increased in proportion to concentrations of creatinine in serum (r = +0.92; P less than 0.001). Adverse effects included fluid overload due to the large dilution volume and thrombocytopenia, which was associated with higher serum TMP levels and longer treatment as compared with nonthrombocytopenic patients. A loading dose of 250 mg of TMP and 1,250 mg of SMZ/m2 is recommended, followed by maintenance doses of 150 mg of TMP and 750 mg of SMZ/m2 every 8 hr for children aged 10 years or younger and every 12 hr for adults with normal renal function. In renal failure the dosage interval (hr) should be increased to 12 times the serum creatinine level (mg/dl) (maximum, 48 hr). Serum concentrations of TMP and perhaps of N4-acetyl-SMZ should be monitored in patients with severe renal failure.

Administration, Oral↗
PubMed1990

The emergence and mechanisms of trimethoprim resistance in Escherichia coli isolated from outpatients in Finland.

Trimethoprim (TMP), either alone or in combination with sulphonamides, is commonly used for treating urinary tract infections. In Finland, TMP alone has been in clinical use since 1973. TMP resistance in the major outpatient urinary tract pathogen, Escherichia coli, increased during 1978-1988 from 5% to 16% in the Turku area, during 1980-1988 from 3% to 19% in the Helsinki area and also during 1980-1988 from 3% to 14% in the Rovaniemi area. The majority (91%) of TMP-resistant strains were highly-resistant to TMP (MIC greater than or equal to 1024 mg/l). The most common (57%) TMP resistance gene, detected by DNA hybridization, was the type I dihydrofolate (DHFR) gene. The type II DHFR genes were found in less than 3% of the strains studied. No positive hybridizations were detected with the type III DHFR probe, and only a few positive hybridizations were found with the type V DHFR probe. Forty percent of the isolates did not hybridize with any of the DHFR probes used, suggesting additional unknown resistance mechanisms responsible for the high-level TMP resistance. These unknown TMP resistance mechanisms, together with the type I DHFR-mediated resistance, were responsible for the increase of TMP resistance among the E. coli strains studied.

Escherichia coli↗
PubMed1992

Trimethoprim-sulphamethoxazole appears more effective than aerosolized pentamidine as secondary prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS.

OBJECTIVE: We compared the efficacies of low-dose trimethoprim-sulphamethoxazole (TMP-SMX; one tablet: TMP, 160 mg, SMX, 800 mg, twice daily, twice a week) and aerosolized pentamidine (300 mg every 4 weeks) as secondary prophylaxis against Pneumocystis carinii pneumonia (PCP) in patients with HIV infection. DESIGN: A retrospective controlled study. SETTING: The study was performed at St Vincent's Hospital, Sydney, Australia, which is a tertiary referral university hospital. PATIENTS, PARTICIPANTS: Over a 4-year period, following primary episodes of PCP, 60 patients received TMP-SMX and 73 aerosolized pentamidine. Thirty-eight patients who received no secondary prophylaxis served as historical controls. MAIN OUTCOME MEASURES: The rate of and time to PCP relapse was recorded for patients receiving low-dose TMP-SMX, aerosolized pentamidine, or no prophylaxis. RESULTS: Only one (1.7%) patient in the TMP-SMX-treated group relapsed, compared with 31 (42.5%) of those in the aerosolized pentamidine group and 21 (55.1%) of those in the control group (P less than 0.0001). Median PCP-free survival times were greater than 1153 days in the TMP-SMX group, 496 days in the pentamidine group, and 265 days in the control group (P less than 0.0001 between all groups). The rate of or time to relapse was not influenced by CD4+ lymphocyte count at the start of prophylaxis, primary therapy of PCP, history of allergy to TMP-SMX, or zidovudine therapy during the period of secondary prophylaxis in any patient group. Both therapies were well tolerated, with three (5%) of those receiving TMP-SMX and four (5%) of those receiving pentamidine discontinuing therapy as a result of side-effects. CONCLUSIONS: Low-dose TMP-SMX appears to be more effective compared with aerosolized pentamidine as secondary prophylaxis against PCP in HIV-infected patients. Zidovudine was well tolerated by both groups, but did not influence the rate of or time to relapse.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Trimethoprim-sulfamethoxazole versus pentamidine for Pneumocystis carinii pneumonia in AIDS patients: results of a large prospective randomized treatment trial.

OBJECTIVE: To compare the clinical efficacy and safety of trimethoprim-sulfamethoxazole (TMP-SMX) with pentamidine in the therapy of Pneumocystis carinii pneumonia (PCP) in patients with AIDS. PATIENTS, PARTICIPANTS: TMP-SMX (TMP, 20 mg/kg/day plus SMX, 100 mg/kg/day) was compared with pentamidine (4 mg/kg/day), both administered intravenously for 21 days in a prospective randomized treatment trial of 163 patients diagnosed with PCP between November 1984 and May 1988. RESULTS: Ninety-two evaluable patients received TMP-SMX as initial therapy; 68 received pentamidine. Failure to complete therapy was common. Of those receiving TMP-SMX, 39 (42%) required change in therapy because of failure to respond, and an additional 31 (34%) because of drug toxicity. This compared with 27 (40%; P = 0.733) and 17 (25%; P = 0.235), respectively, in the pentamidine-treated group. The overall survival rates were similar in the two groups, 62 out of 92 (67%) initially administered TMP-SMX versus 50 out of 68 (74%) initially administered pentamidine (P = 0.402). The survival rates for patients requiring a change in therapy because of failure to respond was 46% (18 out of 39) for the TMP-SMX group compared with 56% (15 out of 27) for the pentamidine group. When a change in therapy was made because of toxicity, survival rates were 97% (30 out of 31) for those receiving TMP-SMX versus 94% (16 out of 17) for those receiving pentamidine. CONCLUSION: TMP-SMX and pentamidine are of equivalent efficacy as initial therapies for PCP in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Use of trimethoprim-sulfamethoxazole to prevent bacterial infections in children with acute lymphoblastic leukemia.

We assessed the efficacy of prophylactic antibiotics in children receiving intensive chemotherapy for acute lymphoblastic leukemia. The patients were randomized to receive either trimethoprim-sulfamethoxazole (TMP-SMX) or placebo in a double-blind trial. Thirty patients were evaluated in each group. Children receiving TMP-SMX had fewer episodes of bacteremia (0 vs. 5) and otitis media (3 vs. 18). The geometric mean of the neutrophil nadir was 172 in the TMP-SMX group and 287 in controls. However, no increased delay or dose reduction of chemotherapy was observed in the TMP-SMX treated patients. Five patients who received TMP-SMX developed Gram-negative rods resistant to TMP-SMX on surveillance stool cultures. We conclude that TMP-SMX prophylaxis decreased certain bacterial infections in children with acute lymphoblastic leukemia without causing clinically significant toxicity. The emergence of Gram-negative rods resistant to TMP-SMX in treated patients suggests that TMP-SMX prophylaxis should be restricted to patients who are at high risk for developing a bacterial infection or Pneumocystis carinii pneumonia.

Administration, Oral↗
PubMed1990

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.

Absorption↗
PubMed2005

Inhibition of cyclic strain-induced endothelin-1 secretion by tetramethylpyrazine.

1. Chuanxiong is a Chinese herb that has been used widely in China to treat vascular disorders. 2,3,5,6-Tetramethylpyrazine (TMP) is one of the major components purified from chuanxiong. Many studies have demonstrated that TMP is effective in the treatment of cardiovascular diseases. However, the mechanism of action by which TMP exerts relaxation in vascular vessels remains unclear. 2. Endothelin (ET)-1 is a potent vasopressor synthesised by endothelial cells both in culture and in vivo. The aims of the present study were to test the hypothesis that TMP may alter strain-induced ET-1 secretion and to identify the putative underlying signalling pathways in endothelial cells. 3. We showed that TMP inhibits strain-induced ET-1 secretion. 2,3,5,6-Tetramethylpyrazine also inhibits the strain-induced formation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. Furthermore, pretreating cells with TMP or the anti-oxidant N-acetyl-cysteine decreased strain-induced increases in ET-1 secretion and ERK1/2 phosphorylation. Using a reporter gene assay, TMP and N-acetyl-cysteine were demonstrated to also attenuate the strain-induced activity of the activator protein-1 reporter. 4. In summary, we have demonstrated, for the first time, that TMP inhibits strain-induced ET-1 gene expression, in part by interfering with the ERK1/2 pathway via attenuation of ROS formation. Thus, the present study provides important new insights into the molecular pathways that may contribute to the proposed beneficial effects of TMP in the vascular system.

Cells, Cultured↗
PubMed2006

Origin of class 1 and 2 integrons and gene cassettes in a population-based sample of uropathogenic Escherichia coli.

The prevalence of urinary tract infections (UTI) caused by trimethoprim-sulfamethoxazole (TMP-SMX)-resistant Escherichia coli is increasing and varies geographically in the United States. Recent community-based UTI studies have demonstrated geographic clustering of an Escherichia coli clonal group, suggesting occurrence of a community outbreak of UTI. A large proportion of this clonal group (designated CgA) isolated from women in a California college community was found to be resistant to TMP-SMX. We wished to determine if the acquisition of TMP-SMX resistance by CgA occurred before or after the CgA strains were introduced into this community. Between October 1999 and January 2000 and between October 2000 and January 2001, 482 E. coli isolates were consecutively collected from the urine samples of women with UTI at a student health clinic and analyzed for determinants of TMP-SMX resistance. In particular, the distribution of integrons harboring resistance cassettes for TMP-SMX (dfr) was examined. Among 95 TMP-SMX-resistant isolates, 68 and 27 isolates carried class 1 and class 2 integrons, respectively. A class 1 integron was found in 25 (93%) of 27 TMP-SMX-resistant CgA isolates but in only 43 (63%) of 68 TMP-SMX-resistant non-CgA isolates (P < 0.001) and in none of 44 TMP-SMX-susceptible E. coli isolates (P < 0.0001). CgA strains carried only a single arrangement of class 1 gene cassettes (dfrA17-aadA5), while the non-clonal group strains carried nine different cassette arrangements. These results support the idea that CgA strains acquired their resistance at a common site prior to their spread to the college community.

Escherichia coli↗
PubMed1987

Pharmacokinetics of intravenous trimethoprim-sulfamethoxazole during hemodialysis.

The pharmacokinetics of intravenous trimethoprim-sulfamethoxazole (TMP-SMZ) were studied in patients receiving hemodialysis. 16 stable end-stage renal disease patients received a single ampul of TMP-SMZ (160 mg TMP, 800 mg SMZ) with 250 ml 5% dextrose and water over 45 min just prior to beginning hemodialysis. All patients were dialyzed for 4 h with a 1.0 m2 cuprophane hollow-fiber dialyzer at a blood flow of 200 ml/min. Mean arterial TMP concentration peaked at 1.93 micrograms/ml following infusion and fell to 1.03 micrograms/ml by the end of dialysis (p less than 0.001). Mean arterial SMZ concentration peaked at 41.8 micrograms/ml at the end of the infusion and fell to 16.4 micrograms/ml by the end of dialysis (p less than 0.005). The extraction ratio averaged 19% for TMP and 21% for SMZ. The elimination half-life during dialysis for TMP was 6.0 h and for SMZ was 3.1 h. Dialysis clearance averaged 38 ml/min for TMP and 42 ml/min for SMZ. 44% of the administered TMP and 57% of the administered SMZ were removed during dialysis. Therefore, 50% of the maintenance dose of TMP-SMZ should be supplemented after each dialysis session.

Adult↗
PubMed1986

Pharmacokinetics of oral co-trimazine and the penetration of its components sulfadiazine and trimethoprim into peripheral human lymph.

Five healthy informed male volunteers received oral doses of 820 mg sulfadiazine (SDZ) plus 180 mg trimethoprim (TMP) (co-trimazine) every 24 h. Concentrations in serum, peripheral lymph from the leg and urine were determined after the first dose, and on the 4th day to reflect approximate steady-state conditions. TMP was assayed microbiologically and unchanged SDZ by high-pressure liquid chromatography. There was a rise in concentrations from the first dose to the 4th day. The rise for SDZ was by a factor of 1.6 in both serum and lymph; the rise for TMP was also 1.6 in serum, but 1.5 in lymph. The peak concentrations at steady state were 27.7 mg/l (SD) +/- 4.3 SDZ, and 1.6 +/- 0.68 mg/l TMP. The serum values at that time were 31.7 +/- 5.8 mg/l SDZ and 2.3 +/- 0.51 mg/l TMP. The simultaneous concentrations of both SDZ and TMP were always somewhat lower in lymph than in serum, also at the end of the observation periods, i.e. 12 h after the first dose and 72 h after the final one. But the serum concentrations of both SDZ and TMP were only slightly higher than in lymph. After the final dose, the ratio between the 12-hour areas under the concentration curves of lymph and serum was 0.68 +/- 0.12 for SDZ and 0.59 +/- 0.14 for TMP. The values after the first dose were similar, 0.63 +/- 0.17 and 0.57 +/- 0.05, respectively. The elimination half-life in serum during steady state was 16.5 h for SDZ, 8.6 h for acetylated SDZ and 9.4 h for TMP. In lymph the corresponding values were 19.2, 19.2 and 8.9 h.

Adult↗
PubMedDate not supplied

Trimethoprim-sulfamethoxazole in the treatment of otitis media secondary to ampicillin-resistant strains of Haemophilus influenzae.

Between August 1977 and January 1979, 16 children (7 males and 9 females) ranging in age from 5 to 38 months (mean age 18 months) were treated with trimethoprim-sulfamethoxazole (TMP-SMX) (40 mg/kg SMX per 24 hours) for otitis media caused by beta-lactamase strains of ampicillin-resistant Haemophilus influenzae. Fourteen patients had failed after antecedent ten-day courses of ampicillin (9 patients) or amoxicillin (5 patients) therapy. The remaining two patients received only five days of ampicillin before changing to TMP-SMX. Six of the isolates were nontypable, 3 were type B, 5 isolates were Haemophilus parainfluenzae, and 2 strains were unavailable for typing. Of 13 strains tested, 10 had a minimal inhibitory concentration (MIC) in excess of 3.12 microgram/ml of ampicillin; the remaining 3 had an MIC of < 3.12 microgram/ml. All 13 isolates were susceptible to 0.19 microgram/ml TMP-SMX. Five of 16 children were symptomatic (irritable; fever of > 38.2 C); within three days of starting TMP-SMX treatment, they became asymptomatic. Fifteen of 16 patients (93%) responded favorably after ten days of TMP-SMX. Only one patient had H influenzae resistant to ampicillin (12.5 microgram/ml) and sensitive to TMP-SMX (0.19 microgram/ml) isolated from the middle ear at the end of ten days of TMP-SMX. At the end of TMP-SMX therapy, middle ear effusions were noted in ten patients; the fluid was sterile in the four patients who had a second tympanocentesis. There were two recurrences within one month of TMP-SMX therapy. No adverse clinical reactions were noted.

Ampicillin↗
PubMed2005

Trimethoprim-sulfamethoxazole as a viable treatment option for infections caused by methicillin-resistant Staphylococcus aureus.

OBJECTIVE: To review available data regarding the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). DATA SOURCES: A MEDLINE search was performed (January 1966-December 2003) using the search terms Staphylococcus aureus , sulfamethoxazole, trimethoprim, co-trimoxazole, and methicillin resistance. Abstracts from infectious diseases meetings also were reviewed. DATA SYNTHESIS: The reported rate of TMP-SMX resistance in S. aureus is highly variable. From a mechanistic standpoint, TMP-SMX resistance among MRSA appears to be distinct from multidrug resistance, although some anecdotal reports suggest otherwise. Clonal outbreaks of MRSA resistant to TMP-SMX have been described; of these, the Brazilian clone has more often been resistant to TMP-SMX than the Iberian clone. Rates of TMP-SMX resistance are particularly high in institutions serving large numbers of patients infected by the human immunodeficiency virus, due to increased exposure for Pneumocystis prophylaxis. Limited studies and case reports have found TMP-SMX useful against infections caused by MRSA. CONCLUSIONS: A large body of anecdotal data, but only one randomized clinical trial, indicates the effectiveness of TMP-SMX as a treatment for MRSA infections. Double-blind, randomized controlled trials are needed to compare the two available oral agents-TMP-SMX and linezolid-against MRSA.

Anti-Infective Agents↗
PubMed1985

Trimethoprim and methenamine hippurate. A new theoretical combination for the treatment of urinary tract infections.

The antibacterial interaction of methenamine hippurate (MH) and trimethoprim (TMP) was tested in vitro in 3 different media: urine, brain-heart broth and Mueller-Hinton broth. MH and TMP were found to have a synergistic interaction in chequer-board titration against 11/11 bacteria in urine. Low concentrations of MH (1/2 MIC) had an additive or synergistic effect with TMP against 14/14 bacteria in brain-heart broth and 20/26 bacteria in Mueller-Hinton broth. In addition, the growth of bacteria in urine from healthy subjects treated with TMP (200 mg), MH (1000 mg) or a combination of TMP + MH (200 + 1000 mg) twice a day for 5 days was compared. A synergistic or additive effect of TMP and MH was found against 14/16 strains. Antagonistic interaction was not found in any of the tests. Preliminary pharmacokinetic studies with TMP and MH showed no marked interaction between the drugs. The hydrolysis of MH to formaldehyde was inversely related to urinary pH, and at pH 5 most of the formaldehyde released from MH in urine was generated within 3 h. The results suggest that the combination of TMP and MH may be more efficient than TMP alone in the treatment of urinary tract infections.

Adult↗
PubMed2004

Differential Cl- and HCO3- mediated anion secretion by different colonic cell types in response to tetromethylpyrazine.

AIM: Colonic epithelium is known to secrete both Cl(-) and HCO(3)(-), but the secretory mechanisms of different colonic cell types are not fully understood. The present study aimed to investigate the differential activation of Cl(-) and HCO(3)(-) secretion by tetramethylpyrazine (TMP) in human crypt-like cell line, T84, and villus-like cell line, Caco-2, in comparison to the TMP-induced secretory response in freshly isolated rat colonic mucosa. METHODS: Colonic epithelial anion secretion was studied by using the short circuit current (I(SC)) technique. RT-PCR was used to examine the expression of Na(+)-HCO(3)(-)-cotranspoter in different epithelial cell types. RESULTS: TMP produced a concentration-dependent I(SC) which was increase in both T84 and Caco-2 cells. When extracellular Cl(-) was removed, TMP-induced I(SC) was abolished by 76.6% in T84 cells, but not in Caco-2 cells. However, after both Cl(-) and HCO(3)(-) were removed, TMP-induced I(SC) in Caco-2 cells was reduced to 10%. Bumetanide, an inhibitor of Na(+)-K(+)-Cl(-)-cotranspoter, inhibited the TMP-induced I(SC) by 96.7% in T84 cells, but only 47.9% in Caco-2 cells. In the presence of bumetanide and 4, 4'-diisothiocyanostilbene-2, 2'-disulfonic acid, an inhibitor of Na(+)-HCO(3)(-) cotransporter, inhibited the TMP-induced current in Caco-2 cells by 93.3%. In freshly isolated rat colonic mucosa, TMP stimulated distinct I(SC) responses similar to that observed in T84 and Caco-2 cells depending on the concentration used. RT-PCR revealed that the expression of Na(+)-HCO(3)(-) cotransporter in Caco-2 cells was 4-fold more greater than that in T84 cells. CONCLUSION: TMP exerts concentration-dependent differential effects on different colonic cell types with stimulation of predominant Cl(-) secretion by crypt cells at a lower concentration, but predominant HCO(3)(-) secretion by villus cells at a higher concentration, suggesting different roles of these cells in colonic Cl(-) and HCO(3)(-) secretion.

Animals↗