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PubMedDate not supplied

Trimethoprim-sulfamethoxazole in treatment of severe infections.

A retrospective comparison between clinical experience with trimethoprim-sulfamethoxazole (TMP-SMZ) and predictive laboratory investigations demonstrates that the most accurate predictions concern antibacterial activity of the drug against individual organisms. With regard to therapy for some relatively severe infections, clinical experience is limited and further research is needed. Some such studies that were not feasible in the past are now possible as a result of the availability of trimethoprim (TMP) as a single agent and of parenteral forms of both TMP and TMP-SMZ. The infections reviewed in this light herein include septicemia, endocarditis, meningitis, neonatal sepsis, anaerobic infections, ophthalmic infections, and infections due to "higher" bacteria and fungi. Based on current knowledge of in vitro drug activity, the clinical picture in such serious infections, and the experience with TMP-SMZ so far, it is predicted that TMP will be used either alone or in combination with other antibacterial agents (such as the polymyxins, metronidazole, and various sulfonamides in different ratios) for treatment of some of these infections.

Anaerobiosis↗
PubMedDate not supplied

Laboratory surveillance of synergy between and resistance to trimethoprim and sulfonamides.

Results of susceptibility tests of Enterobacteriaceae isolated at 14 different centers demonstrate synergy between trimethoprim (TMP) and sulfamethoxazole (SMZ) against sulfonamide-susceptible isolates, which account for between less than 50% and greater than 75% of the isolates at different centers. Only 1%-4% of the isolates of Escherichia coli or Proteus mirabilis from the five centers in the United States were found to be resistant when tested with a disk containing both TMP and SMZ, but greater than 8% of such isolates from five of the other centers were resistant to the combination disk. A larger percentage of isolates of Klebsiella pneumoniae or Serratia marcescens were resistant, but the number varied from center to center. In the United States, resistance of human and animal isolates of Salmonella to the TMP-SMZ combination was almost completely absent, although greater than 50% of the animal isolates were resistant to sulfonamides. At a center that tested TMP and SMZ resistance with separate disks, resistance to TMP was found to be 30 times more common in sulfonamide-resistant than in sulfonamide-susceptible E. coli. This ratio may be useful as a monitor as treatment with TMP alone increases.

Bacteria↗
PubMedDate not supplied

Oral or intravenous trimethoprim-sulfamethoxazole therapy for shigellosis.

A review of the literature concerning shigellosis treated with trimethoprim-sulfamethoxazole (TMP-SMZ) revealed comparative studies of 149 cases and noncomparative studies of 147 cases. Bacteriologic and clinical success rates were greater than or equal to 90% and TMP-SMZ compared favorably with alternative drug therapy. In the present study TMP-SMZ was given intravenously as initial therapy to 11 children hospitalized for severe shigella colitis. Bacteriologic and clinical responses were comparable to those observed with oral TMP-SMZ therapy. Pharmacokinetic studies revealed substantial differences between the responses of these children and those reported for adult patients; a higher ratio of SMZ to TMP (50:1) was found in children. It is concluded that TMP-SMZ is effective therapy for shigellosis and is the drug of choice in areas where ampicillin resistance is prevalent.

Administration, Oral↗
PubMedDate not supplied

Use of trimethoprim-sulfamethoxazole singly and in combination with other antibiotics in immunocompromised patients.

Experience with trimethoprim-sulfamethoxazole (TMP-SMZ) alone or in combination with other agents in the treatment of immunocompromised patients other than those with Pneumocystis carinii pneumonitis and the acquired immunodeficiency syndrome is reviewed. A comparative study involving 126 episodes of fever showed a higher rate of response to a TMP-SMZ-carbenicillin regimen than to a gentamicin-carbenicillin combination (85% vs. 69%, respectively, P less than or equal to .04). In another study TMP-SMZ was used after unsuccessful therapy with the combination of an antipseudomonal penicillin and an aminoglycoside; 54% of the 35 patients treated orally and 49% of 86 treated intravenously responded to TMP-SMZ regimens. Other studies document successful results with TMP-SMZ used in combination with either an aminoglycoside or an antipseudomonal penicillin. TMP-SMZ has a role in the treatment of infections due to gram-negative bacilli in immunocompromised hosts, particularly when the infecting agent is not Pseudomonas aeruginosa and is resistant to moxalactam but susceptible to gentamicin.

Anti-Bacterial Agents↗
PubMedDate not supplied

Use of trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency syndrome.

This report reviews the use of trimethoprim-sulfamethoxazole (TMP-SMZ) in individuals with Pneumocystis carinii pneumonitis (PCP) and the acquired immunodeficiency syndrome (AIDS). Before AIDS, TMP-SMZ was at least as effective as pentamidine in pediatric and adult populations and was notably less toxic. In a study prospectively comparing TMP-SMZ with pentamidine in patients with AIDS, the toxicity associated with either therapy was very high, a problem suggesting a need for the development of additional types of therapy. There was no difference in the clinical responses to the different therapeutic regimens; the majority of patients showed some improvement. The rates of both major and minor toxic reactions were similar in the two groups, although the reactions differed qualitatively. In patients with AIDS rash was frequently associated with TMP-SMZ therapy and was almost never associated with pentamidine therapy. Neutropenia was common with both drugs. Pentamidine may produce hypoglycemia, which, though infrequent, may be life threatening. Neutropenia and rash are two adverse effects of TMP-SMZ therapy being described with great frequency in patients with AIDS. Mild neutropenia is common in patients with AIDS, even when therapy is not being administered. The high rate of toxic reactions limits the usefulness of TMP-SMZ for routine prophylaxis.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Use of trimethoprim-sulfamethoxazole in a glucose-6-phosphate dehydrogenase-deficient population.

Trimethoprim-sulfamethoxazole (TMP-SMZ) has been associated with hemolytic anemia in patients deficient in glucose-6-phosphate dehydrogenase (G-6-PD). The effect of a daily dose of SMZ of 50 mg/kg was evaluated in a double-blinded study that compared vancomycin with TMP-SMZ given intravenously for treatment of serious Staphylococcus aureus infections. Levels of G-6-PD were determined when patients entered the trial. Most patients were black Americans. G-6-PD-deficient patients were followed serially, with determinations of hemoglobin, haptoglobin, and bilirubin levels, reticulocyte count, and urinalysis. Pretherapy hemoglobin levels were compared with levels during and after therapy. One hundred patients were divided into four groups: group A comprised G-6-PD-deficient patients receiving TMP-SMZ (n = 20); group B, G-6-PD-deficient patients receiving vancomycin (n = 25); and groups C and D, patients with normal G-6-PD levels receiving TMP-SMZ (n = 24) and vancomycin (n = 31), respectively. Groups were comparable in terms of age of patients and duration of therapy. Hemolysis did not occur in any patient receiving TMP-SMZ and occurred in only one patient receiving vancomycin. Both this study and published reports indicate that TMP-SMZ rarely causes hemolysis in a G-6-PD-deficient population.

Adult↗
PubMed1984

Trimethoprim-sulfamethoxazole in the prevention of infection in neutropenic patients. EORTC International Antimicrobial Therapy Project Group.

Of 545 patients expected to develop prolonged neutropenia and randomized to received trimethoprim-sulfamethoxazole (TMP-SMZ) or placebo, 342 were evaluable for occurrence of infection or bacteremia. Some centers used oral nonabsorbable antibiotics in addition. Infection occurred in 64 (39%) of 165 placebo recipients and 46 (26%) of 177 TMP-SMZ recipients (P = .016), whereas bacteremia occurred in 32 (19%) and 22 (12%), respectively (P = .106, difference not significant [NS]). In the 139 patients with acute nonlymphocytic leukemia (ANLL), infection occurred in 35 (55%) of 64 placebo-treated patients and 31 (41%) of 75 TMP-SMZ-treated patients (P = .162, NS), whereas bacteremia occurred in 15 (23%) and 18 (24%; NS), respectively. Excluding patients with ANLL, infection occurred in 29 (29%) of 101 placebo-treated patients and 15 (15%) of 102 TMP-SMZ recipients (P = .038), whereas bacteremia occurred in 17 (17%) and four (4%; P = .005), respectively. Gram-positive cocci were isolated less frequently from TMP-SMZ-treated, bacteremic patients, but more of their isolates were resistant to TMP-SMZ than were those from placebo recipients.

Agranulocytosis↗
PubMed1984

Incidence of trimethoprim-sulfamethoxazole-resistant enterobacteriaceae among transplant recipients.

Of 114 recipients of pancreatic, renal, and bone marrow transplants who were given trimethoprim-sulfamethoxazole (TMP-SMZ) for antimicrobial prophylaxis, 44 (39%) had a total of 52 fecal isolates of TMP-SMZ-resistant gram-negative bacilli. In most of these 44 patients, the resistant isolate was found at a concentration of greater than or equal to 10(6) organisms/ml of feces. Escherichia coli was the most frequent of the isolates, and Citrobacter freundii was the next most frequent. Eight of the 114 transplant recipients had gram-negative bacteremia; in six of these eight patients, a TMP-SMZ-resistant gram-negative bacillus was the etiologic agent of bacteremia. Four of the latter six patients had stool cultures analyzed prior to the detection of bacteremia; all four had high concentrations (greater than or equal to 10(8)/ml) of fecal TMP-SMZ-resistant E. coli one to 20 days before they were found to have E. coli bacteremia. In each of these instances, the E. coli isolates from the stool and the blood had similar antibiograms. These findings indicated that resistance to TMP-SMZ is becoming more prevalent and that the screening of patients for the presence of fecal TMP-SMZ-resistant Enterobacteriaceae prior to initiation of long-term therapy with this antimicrobial agent may be worthwhile.

Bone Marrow Transplantation↗
PubMed1994

Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031.

Trimetrexate is a powerful inhibitor of the dihydrofolate reductase of Pneumocystis carinii. AIDS patients (n = 215) with moderate to severe P. carinii pneumonia were enrolled in a double-blind study of trimetrexate plus leucovorin versus trimethoprim-sulfamethoxazole (TMP-SMZ) for 21 days. By study day 10, study therapy failed because of lack of efficacy in 16% of patients assigned to TMP-SMZ and 27% assigned to trimetrexate (P = .064), and the PAO2-PaO2 improved significantly faster with TMP-SMZ. By study day 21, failure rates were 20% with TMP-SMZ and 38% with trimetrexate (P = .008), with respective mortality rates of 12% and 20% (P = .088). By study day 49, the difference in mortality (16% vs. 31%) was significant (P = .028). The cumulative incidence of serious and treatment-terminating adverse events including hematologic toxicities was less with trimetrexate (P < .001). Thus, trimetrexate plus leucovorin was effective, albeit inferior to TMP-SMZ, for moderately severe P. carinii pneumonia but was better tolerated than TMP-SMZ.

AIDS-Related Opportunistic Infections↗
PubMed1983

Cerebral cortical extracellular fluid H+ and K+ activities during hypotension in cats.

Cerebral cortical blood flow, electrical activity, and extracellular fluid (ECF) pH and K+ ion activities were measured in anesthetized cats (0.7% halothane 65% N2O in O2) subjected to hypotension (mean BP 30-32 and 26-28 mmHg), induced by either practolol and trimetaphan (TMP) or practolol and nitroprusside (NTP). Limited blood withdrawal was also necessary to achieve these blood pressure (BP) levels. Cerebral cortical blood flow during hypotension was greater with NTP than with TMP, and hyperemia occurred in the recovery phase after NTP but not TMP. Electrical activity also was maintained better with NTP. ECF K+ increased in five of six TMP experiments but in only one of six NTP experiments. Values of K+ greater than 15 mM were only seen in the TMP group. Release of K+ into the ECF space occurred at values of cerebral cortical oxygen delivery below 3 ml 100 g-1 min-1. ECF K+ partially recovered after the end of hypotension in all except the experiment with the highest value. A progressive and severe cerebral acidosis was seen in all experiments during induced hypotension, and values below pH 6.50 were present at the stage of K+ increase in the ECF space. It is concluded that the ability of cell membranes in the cat's cortex to maintain normal ionic gradients is depressed by hypotension to these levels with TMP, but not with NTP, and that this difference is related to better-maintained oxygen supply values during NTP hypotension.

Animals↗
PubMed1983

Blood-brain barrier function following drug-induced hypotension in the dog.

To examine the effects of hypotension induced either with trimethaphan (TMP) or nitroprusside (NTP) on blood-brain barrier (BBB), penetration of Evans blue (EB) was observed in dogs anesthetized with halothane. Dogs given TMP were divided into two groups: Group 1, seven dogs rendered hypotensive to mean cerebral perfusion pressure (CPP) of 45 mmHg for 45 min and then of 30 mmHg for 45 min; Group 2, three dogs examined 3 days after arterial hypotension identical to that in Group 1. Dogs given NTP were divided into four groups: Group 1, seven dogs rendered hypotensive with NTP (at dose less than 1 mg/kg) identical to the TMP-Group 1; Group 2, three dogs examined as the TMP-Group 2; Group 3, seven dogs rendered hypotensive to CPP 45 mmHg for 45 min; Group 4, seven dogs rendered hypotensive with NTP (at dose greater than 1 mg/kg) identical to the NTP-Group 1. In all dogs, the dorsal cortical surface and standardized serial coronal sections were examined for evidence of EB penetration. The mean EB penetration score (+/- SEM) for TMP-Groups 1 and 2 was 12 +/- 6, 0 +/- 0, respectively, and for NTP-Groups 1, 2, 3, and 4 was 105 +/- 14, 30 +/- 7, 6 +/- 6, and 125 +/- 26, respectively. These results suggest that dysfunction of the BBB in the NTP group was more pronounced than in the TMP group.

Anesthesia↗
PubMed1998

Effects of tetramethylpyrazine, a Chinese medicine, on plasma endothelin-1 levels during acute pulmonary hypoxia in anesthetized dogs.

Our study was designed to elucidate the effects of tetramethylpyrazine (TMP), a Chinese medicine, on plasma endothelin-1 (ET-1) levels in dogs with acute pulmonary alveolar hypoxia. Anesthetized dogs were used under artificial ventilation with room air or a hypoxic gas mixture (10% O2 and 90% N2) (n = 10) for 60 min. Effects of TMP (80 mg/kg) were studied by i.v. injection of TMP before exposure to hypoxia (n = 8). Mean pulmonary arterial pressure (PAPm), systemic arterial pressure (SAPm), right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and heart rate (HR) were measured. The pulmonary vascular resistance (PVR) was calculated by the equation of (PAPm-PCWP) x 8/CO. Plasma ET-1 levels were determined in the abdominal aorta and pulmonary artery by RIA. The effects of TMP on PAP and plasma ET-1 level were evaluated by using percent increase in PAPm and the change of Da-pET (delta ET) before and after hypoxia. Both PAPm and PVR were significantly elevated 5 min after acute hypoxia over a period of 60 min, whereas CO and PCWP did not change. Plasma ET-1 levels in the abdominal aorta and Da-pET showed a significant increase. Administration of TMP significantly decreased the hypoxia-induced increase in the PAPm, PVR, and delta ET. These results suggest that TMP could be a useful therapeutic agent in the treatment of pulmonary hypertension induced by acute hypoxia through decrease of plasma ET-1 levels.

Anesthesia, General↗
PubMed1998

Trimethoprim-sulfamethoxazole for the prevention of methicillin-resistant Staphylococcus aureus pneumonia in severely burned patients.

BACKGROUND: Patients with severe burns are at increased risk of developing methicillin-resistant Staphylococcus aureus (MRSA) ventilator-associated pneumonia. This study was designed to determine whether MRSA pneumonia can be prevented by prophylactic administration of trimethoprim-sulfamethoxazole (TMP-SMX). METHODS: We conducted a prospective, randomized, placebo-controlled study in patients with severe burns (> or = 20%), who required ventilator support. Prophylaxis was done with oral TMP-SMX (80 mg/400 mg) three times daily for 10 days from 4 to 6 days after burn injury. The incidence of MRSA pneumonia and the side effects were evaluated during the administration period. RESULTS: Twenty-one patients were assigned to receive TMP-SMX, and 19 patients to receive placebo. The incidence of MRSA pneumonia was 4.8% in the TMP-SMX group and 36.8% in the placebo group, showing a significant difference (p = 0.017). No major side effects of therapy were seen in the TMP-SMX group. CONCLUSION: Prophylactic treatment with TMP-SMX can prevent MRSA pneumonia in severely burned patients.

Administration, Oral↗
PubMedDate not supplied

Treatment of uncomplicated gonococcal infection with trimethoprim-sulfamethoxazole.

The efficacy of trimethoprim-sulfamethoxazole (TMP-SMZ; 80 mg of TMP and 400 mg of SMZ per tablet; nine tablets taken once daily for three days; total, 27 tablets) was compared with the U.S. Public Health Service recommended regimen of 2 g of tetracycline daily for five days for the treatment of uncomplicated genital gonorrhea. Fourteen (3%) of the 461 patients treated with tetracycline and 24 (5%) of the 477 patients treated with TMP-SMZ failed to be cured; the difference between the two groups was not significant. Treatment of patients with TMP-SMZ was more likely to fail if the isolates of Neisseria gonorrhoeae had MICs of > or = 0.5 microgram of TMP/ml and > or = 9.5 micrograms of SMZ/ml. Adverse effects were more often reported by patients receiving TMP-SMZ. The results show that TMP-SMZ is an effective therapy for uncomplicated gonococcal infections in men and women and may also eliminate agents causing postgonococcal urethritis. The utility of this drug combination may be limited by the adverse effects that are associated with the large dose used.

Anti-Bacterial Agents↗
PubMed2002

Monitoring adverse drug reactions to sulfonamide antibiotics in human immunodeficiency virus-infected individuals.

Patients infected with the human immunodeficiency virus (HIV) are at higher risk for adverse drug reactions from trimethoprim-sulfamethoxazole (TMP-SMX) than the HIV-negative population. Studying the HIV-positive population the authors aimed to validate the predictive and diagnostic value of the lymphocyte toxicity assay (LTA) for adverse drug reactions. Patient lymphocytes were analyzed for toxicity to SMX and TMP. Of 35 enrolled HIV patients, 18 had TMP-SMX hypersensitivity syndrome reaction (HSR); 10 tolerated the drug; and 5 had never received the drug. When cases with HSR were compared with controls that tolerated the drugs, cytotoxicity was higher for cases: 29.5% +/- 10.1% versus 19.3% +/- 11.2% for SMX (P < 0.022) and 25.0% +/- 11.9% versus 16.3% +/- 11.0% for TMP (P < 0.04). The authors' proposed threshold value for assigning positive results for TMP and SMX hypersensitivities was 22.5%. The LTA has a strong potential for use as a diagnostic tool to assess TMP-SMX hypersensitivity in HIV-infected individuals. Larger patient populations, as well as in vitro studies are needed to further address the reasons for elevated results in immunocompromised patients and to validate the usefulness of the test.

Adult↗
PubMed1996

Altered trimethoprim-sulfamethoxazole ratios for prophylaxis and treatment of Toxoplasma gondii and Pneumocystis carinii dual infections in rat model.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line drug for prophylaxis and treatment of Pneumocystis carinii pneumonia (PCP) and for prophylaxis of toxoplasmosis in HIV-infected patients. Evidence indicating intolerance related to the dose of SMX led us to examine the efficacy of altered TMP-SMX ratios in a corticosteroid-treated rat model. Infections were assessed by counting P. carinii cysts in lung and by titration of Toxoplasma gondii burdens in tissue culture. For prophylaxis, the reference regimen of 20 mg/kg TMP plus 100 mg/kg SMX was effective. Reduced doses of SMX (5 and 20 mg/kg) effective against PCP were effective against toxoplasmosis, provided the TMP dose was increased to 100 mg/kg. For curative treatment, the reversed ratio of 100 mg/kg TMP plus 20 mg/kg SMX was not effective. These results may provide a basis for altering the TMP-SMX ratios in setting of prophylaxis for both infections, especially in HIV infected patients who often poorly tolerate sulfonamides.

Animals↗
PubMed1998

A randomized trial of N-acetylcysteine for prevention of trimethoprim-sulfamethoxazole hypersensitivity reactions in Pneumocystis carinii pneumonia prophylaxis (CTN 057). Canadian HIV Trials Network 057 Study Group.

Hydroxylamine derivatives of sulfamethoxazole may be the reactive metabolites that cause adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMX). The increased frequency of reactions observed in HIV-positive individuals is hypothesized to be due to systemic glutathione deficiency and a decreased ability to scavenge these metabolites. Two hundred and thirty-eight patients were randomized to receive or not receive N-acetylcysteine (3 g of the 20% liquid solution) 1 hour before each dose of TMP-SMX (trimethoprim 80 mg, sulfamethoxazole 400 mg) twice daily, which was initiated as primary Pneumocystis carinii pneumonia prophylaxis. Forty-five patients had to discontinue TMP-SMX within 2 months because of fever, rash, or pruritus including 25 of 102 patients (25%) who were receiving TMP-SMX alone and 20 of 96 patients (21%) who were randomized to TMP-SMX and N-acetylcysteine. The difference between treatment groups is 4% (95% confidence interval [CI]: -16%, +9%). No independent association was found with the hypersensitivity reaction and age, gender, race, HIV risk factor, prior AIDS, concurrent use of fluconazole, or baseline CD4. N-acetylcysteine at a dose of 3 g twice daily could not be shown to prevent TMP-SMX hypersensitivity reactions in patients with HIV infection.

Acetylcysteine↗
PubMed2002

Dependence of induced transmembrane potential on cell density, arrangement, and cell position inside a cell system.

A nonuniform transmembrane potential (TMP) is induced on a cell membrane exposed to external electric field. If the induced TMP is above the threshold value, cell membrane becomes permeabilized in a reversible process called electropermeabilization. Studying electric potential distribution on the cell membrane gives us an insight into the effects of the electric field on cells and tissues. Since cells are always surrounded by other cells, we studied how their interactions influence the induced TMP. In the first part of our study, we studied dependence of potential distribution on cell arrangement and density in infinite cell suspensions where cells were organized into simple-cubic, body-centered cubic, and face-centered cubic lattice. In the second part of the study, we examined how induced TMP on a cell membrane is dependent on its position inside a three-dimensional cell cluster. Finally, the results for cells inside the cluster were compared to those in infinite lattice. We used numerical analysis for the study, specifically the finite-element method (FEM). The results for infinite cell suspensions show that the induced TMP depends on both: cell volume fraction and cell arrangement. We established from the results for finite volume cell clusters and layers, that there is no radial dependence of induced TMP for cells inside the cluster.

Cell Count↗