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PubMed1990

Evidence for variable metal-radical spin coupling in oxoferrylporphyrin cation radical complexes.

Oxoferrylporphyrin cation radical complexes were generated by m-chloroperoxybenzoic acid oxidation of the chloro and trifluoromethanesulfonato complexes of tetramesitylporphyrinatoiron(III) [(TMP)Fe] and the trifluoromethanesulfonato complex of tetra(2,6-dichlorophenyl)porphyrinatoiron(III) [TPP(2,6-Cl)Fe]. Coupling between ferryl iron (S = 1) and porphyrin radical (S' = 1/2) spin systems was investigated by Mössbauer and EPR spectroscopy. The oxoferrylporphyrin cation radical systems generated from the TMP complexes show strong ferromagnetic coupling. Analysis of the magnetic Mössbauer spectra, using a spin Hamiltonian explicitly including a coupling tensor J, suggests an exchange-coupling constant J greater than 80 cm-1. The EPR spectra show non-zero rhombicity, the origin of which is discussed in terms of contributions from the usual zero-field effects of iron and from iron-radical spin-dipolar interaction. A consistent estimate of zero-field splitting parameter D approximately + 6 cm-1 was obtained by EPR and Mössbauer measurements. EPR and Mössbauer parameters are shown to be slightly dependent on solvent, but not on the axial ligand in the starting (TMP)Fe complex. In contrast to the TMP complex, the oxoferrylporphyrin cation radical system generated from [TPP(2,6-Cl)FeOSO2CF3] exhibits Mössbauer and EPR spectra consistent with weak iron-porphyrin radical coupling of magnitude of J approximately 1 cm-1.

Chemical Phenomena↗
PubMed1998

Pharmacokinetics of sulfonamides and trimethoprim in the donkey (Equus asinus).

The body disposition of sulfadimidine (SDM), sulfadiazine (SDZ), sulfamethoxypyridazine (SMPZ) and a trimethoprim-sulfadimethoxine combination (TMP-SDMX) was investigated in the donkey. The four sulfonamides and TMP were injected intravenously at doses of 20 mg/kg (SDM, SDZ, SMPZ), 12.5 mg/kg (SDMX) and 2.5 mg/kg (TMP). The body clearance (ClB) of SDZ (1.70 +/- 0.14 ml/min/kg) was significantly higher than those of SDM (1.13 +/- 0.18 ml/min/kg), SMPZ (1.10 +/- 0.09 ml/min/kg) and SDMX (0.75 +/- 0.04 ml/min/kg). In contrast, the volume of distribution at steady state (Vss) was similar for the four sulfonamides (0.68 +/- 0.08 L/kg, 0.63 +/- 0.07 L/kg, 0.47 +/- 0.06 L/kg, and 0.46 +/- 0.05 L/kg for SDM, SDZ, SMPZ and SDMX, respectively). Both ClB and Vss were significantly higher for TMP (4.36 +/- 0.60 ml/min/kg and 2.71 +/- 0.86 L/kg) than for sulfonamides. Antipyrine ClB (3.49 +/- 0.35 ml/min/kg) and Vss (0.66 +/- 0.16 L/kg), determined in order to assess hepatic oxidative function and total body water volume, respectively, were either different from (ClB), or similar to (Vss), values calculated for sulfonamides. The results obtained were compared to those reported in horses.

Animals↗
PubMed1997

Transmembrane potentials during high voltage shocks in ischemic cardiac tissue.

Transmembrane, voltage sensitive fluorescent dye (TMF) recording techniques have shown that high voltage shocks (HVS), typically used in defibrillation, produce either hyper- or depolarization of the transmembrane potential (TMP) when delivered in the refractory period of an action potential (AP) in normal cardiac tissue (NT). Further, HVS produce an extension of the AP, which has been hypothesized as a potential mechanism for electrical defibrillation. We examined whether HVS modify TMP of ischemic tissue (IT) in a similar manner. In seven Langendorff rabbit hearts, recordings of APs were obtained in both NT and IT with TMF using di-4-ANEPPS, and diacetylmonoxime (23 microM) to avoid motion artifacts. Local ischemia was produced by occlusion of the LAD, HVS of either biphasic (5 + 5 ms) or (3 + 2 ms) or monophasic shapes (5 ms) were delivered at varying times (20%-90%) of the paced AP. Intracardiac ECG and TMF recordings of the TMP were each amplified, recorded, and digitized at a frequency of 1 kHz. The paced AP in IT was triangular in shape with no obvious phase 3 plateau, typically seen in NT. There was normally a reduced AP amplitude (expressed as fractional fluorescence) in IT (2.6% +/- 1.79%) compared to 3.8% +/- 0.66% in NT, and shortened AP duration (137 +/- 42 vs 171 +/- 11 ms). One hundred-Volt HVS delivered during the refractory period of paced AP in IT in five rabbits, elicited a depolarization response of the TMP with an amplitude up to three times greater than the paced AP. This is in contrast to NT where the 100-V HVS produced hyperpolarization in four hearts, and only a slight depolarization response in one heart. These results suggest that HVS, typically delivered by a defibrillation shock, modify TMPs in a significantly different manner for ischemic cells, which may influence success in defibrillation.

Action Potentials↗
PubMed2003

A cost-effectiveness analysis of treatment strategies for acute uncomplicated pyelonephritis in women.

UNLABELLED: At least 250,000 episodes of acute uncomplicated pyelonephritis are treated annually in the emergency department (ED). Trimethoprim-sulfamethoxazole (TMP-SMX) and norfloxacin have both been used as treatments for acute uncomplicated pyelonephritis. OBJECTIVES: To investigate the cost-effectiveness of two outpatient treatment strategies, TMP-SMX and norfloxacin, for acute uncomplicated pyelonephritis in adult women between the ages of 18 and 65 years. METHODS: Common principles of cost-effectiveness analysis were used for this evaluation. The authors developed a decision tree to estimate the costs and effectiveness of two different treatment strategies: TMP-SMX 160/800 mg twice per day for 10 days and norfloxacin 400 mg twice per day for 10 days. The time frame of the decision tree was 11 days. Outcomes were expressed in U.S. dollars, quality-adjusted life-days (QALDs), and dollars per QALD. Sensitivity analyses were performed on most variables. RESULTS: Norfloxacin is more effective and less costly than the alternative, TMP-SMX. Norfloxacin treatment will save $195.85 per patient, resulting in an aggregate saving of more than $40 million annually. Patients are expected to enjoy a better quality of life with an incremental 0.0601 QALD per patient, if they are treated with norfloxacin. These results are robust across a wide range of probabilities and costs. CONCLUSIONS: In this analysis, norfloxacin 400 mg twice a day was a more cost-effective treatment than TMP/SMX 160/800 mg twice a day for women with pyelonephritis.

Acute Disease↗
PubMed1990

Photoreaction of 4,5',8-trimethylpsoralen with adenosine.

The near-UV induced photoreaction of 4,5',8-trimethylpsoralen (TMP) with adenosine was investigated in a dry film state. Four major photoadducts were isolated and purified by reverse-phase liquid chromatography. The structures of the photoproducts were elucidated on the basis of spectroscopic methods, including UV, FT-IR, mass spectrometry (FAB and EI methods) and 1H-NMR analysis. These photoproducts were characterized to be TMP-adenosine 1:1 adducts, which resulted from the covalent bond formation between the carbon C(4) of TMP and ribose 1' or 5' carbon of adenosine. Of the photoadducts, one photoadduct (V) was the major product, reflecting some selectivity in the photoreaction of TMP with adenosine in the solid state.

Adenosine↗
PubMed1994

Regional fibre stress-fibre strain area as an estimate of regional blood flow and oxygen demand in the canine heart.

1. In the present study the relation between regional left ventricular contractile work, regional myocardial blood flow and oxygen uptake was assessed during asynchronous electrical activation. 2. In analogy to the use of the pressure-volume area for the estimation of global oxygen demand, the fibre stress-fibre strain area, as assessed regionally, was used to estimate regional oxygen demand. The more often used relation between the pressure-sarcomere length area and regional oxygen demand was also assessed. 3. Experiments were performed in six anaesthetized dogs with open chests. Regional differences in mechanical work were generated by asynchronous electrical activation of the myocardial wall. The ventricles were paced from the right atrium, the left ventricular free wall, the left ventricular apex or the right ventricular outflow tract. Regional fibre strain was measured at the epicardial anterior left ventricular free wall with a two-dimensional video technique. 4. Regional fibre stress was estimated from left ventricular pressure, the ratio of left ventricular cavity volume to wall volume, and regional deformation. Total mechanical power (TMP) was calculated from the fibre stress-fibre strain area (SSA) and the duration of the cardiac cycle (tcycle) using the equation: TMP = SSA/tcycle. Regional myocardial blood flow was measured with radioactive microspheres. Regional oxygen uptake was estimated from regional myocardial blood flow values and arteriovenous differences in oxygen content. 5. During asynchronous electrical activation, total mechanical power, pressure-sarcomere length area, myocardial blood flow and oxygen uptake were significantly lower in early than in late activated regions (P < 0.05). 6. Within the experiments, the correlation between the pressure-sarcomere length area and regional oxygen uptake was not significantly lower than the one between total mechanical power (TMP) and regional oxygen uptake (VO2,reg). However, variability of this relation between the experiments was less for total mechanical power. Pooling all experimental data revealed: VO2,reg = k1 TMP+k2, with k1 = 4.94 +/- 0.31 mol J-1 k2 = 24.2 +/- 1.9 mmol m-3 s-1 (means +/- standard error of the estimate). 7. This relation is in quantitative agreement with previously reported relations between the pressure-volume area and global oxygen demand. The results indicate that asynchronous electrical activation causes a redistribution of mechanical work and oxygen demand and that regional total mechanical power is a better and more general estimate of regional oxygen demand than the regional pressure-sarcomere length area.

Animals↗
PubMed1981

Trimethoprim-rifampin, a new combination agent: efficacy in localized urinary infection and influence on microflora.

Twenty women with recurrent or persistent urinary tract infections were treated with a fixed combination of trimethoprim-rifampin (TMP-RAM). The site of infection was established by the antibody-coated bacteria test. Sixteen women had upper tract infections (antibody-coated bacteria tests positive); eight were cured, three failed, and five relapsed. All four women with lower tract infections (antibody-coated bacteria tests negative) were cured. Three of five patients with structural abnormalities failed. The 12 cures and 5 relapses were associated with organisms susceptible to either TMP (minimal inhibitory concentration, less than or = to 7 micrograms/ml) or RAM (minimal inhibitory concentration, less than or = to 32 micrograms/ml). In contrast, two of the three failures were associated with organisms resistant to both TMP and RAM. In one patient, RAM resistance emerged during treatment. During therapy, urinary strains were eradicated from the periurethral and anal-canal areas in all but 3 fo 16 patients. Adverse reactions, noted in 16 women, included nausea (10), dizziness (6), headaches (2), rash (1), an blurred vision (1). Antimicrobial susceptibility data on 246 isolated from urinary, periurethral, and anal-canal specimens are included. Our findings suggest that TMP-RAM is effective in urinary infections and may prevent the emergence of RAM-resistant strains.

Drug Combinations↗
PubMed1982

Comparative tolerability of ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole suspensions in children with otitis media.

The tolerabilities of ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole (TMP-SMX) suspensions were evaluated in 263 children with otitis media. Because of watery stools, therapy was discontinued in 6 of 83 patients treated with ampicillin, in none of 89 patients treated with amoxicillin (P less than 0.01), and in 1 of 91 patients treated with TMP-SMX (P less than 0.03). Of the patients who completed the treatment courses, 13 recipients of ampicillin suffered loose or watery stools for 4 or more days, compared with 6 of the amoxicillin recipients (P less than 0.04) and 5 of the TMP-SMX recipients (P less than 0.02). Thus, ampicillin was clearly less well tolerated than either amoxicillin or TMP-SMX.

Amoxicillin↗
PubMed1985

Emergence of trimethoprim resistance in fecal flora.

The emergence of trimethoprim (TMP) resistance in fecal flora was compared in patients with urinary tract infection treated with TMP or TMP-sulfamethoxazole. No significant differences were found in the occurrence of TMP-resistant fecal aerobic bacteria in the two treatment groups before and after treatment.

Adolescent↗
PubMed1986

In vitro activities of Ro 19-5247 and Ro 15-8074, new oral cephalosporins.

The in vitro activities of two new oral cephalosporins, Ro 19-5247 and Ro 15-8074, were compared with the in vitro activities of cefuroxime, cefaclor, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole (TMP-SMZ), and doxycycline against a variety of bacterial species. MIC50s (MICs required to inhibit 50% of strains) of Ro 19-5247 were less than or equal to 0.13 micrograms/ml for streptococci (except Streptococcus faecalis) and Haemophilus influenzae; 0.25 to 2 micrograms/ml for most strains of Enterobacteriaceae, Aeromonas hydrophila, Branhamella catarrhalis, and gram-positive anaerobic bacteria; and 1 to 8 micrograms/ml for methicillin-susceptible staphylococci. MIC50s of Ro 15-8074 were similar to those of Ro 19-5247, except that gram-positive aerobes and anaerobes were less susceptible. Both Ro 19-5247 and Ro 15-8074 had greater in vitro activity against strains of Enterobacteriaceae than did comparative beta-lactams and doxycycline; TMP-SMZ had the broadest spectrum of activity against these organisms. None of the cephalosporins were active against methicillin-resistant staphylococci, S. faecalis, most nonfermenters, or Bacteroides sp. Inoculum size variations affected MICs in a species-dependent manner for beta-lactams and unpredictably for TMP-SMZ but had little effect for doxycycline. Bactericidal activity was consistent with beta-lactams, inconsistent with TMP-SMZ, and uncommon with doxycycline.

Anti-Bacterial Agents↗
PubMed1987

Selective gut decontamination with nalidixic acid or trimethoprim-sulfamethoxazole for infection prophylaxis in neutropenic cancer patients: relationship of efficacy to antimicrobial spectrum and timing of administration.

Eighty-four cancer patients at risk of infection because of neutropenia were randomized to receive nalidixic acid as an alternative to trimethoprim-sulfamethoxazole (TMP-SMX) for infection prophylaxis. Infections were documented significantly earlier and more often among patients who entered the trial with neutrophil counts of less than 0.1 X 10(9)/liter. TMP-SMX recipients experienced fewer microbiologically documented infections and bacteremias and were free of infection for a higher proportion of days with severe neutropenia (less than 0.1 X 10(9)/liter) than nalidixic acid recipients. Gram-negative bacillary and Staphylococcus aureus infections accounted for the major differences. Although the majority of aerobic gram-negative bacilli were eliminated from the feces after 1 week of prophylaxis with either agent, TMP-SMX was proved superior to nalidixic acid in this regard and was associated with acquired drug resistance by gram-negative bacilli less frequently. Both agents selected for colonization and subsequent infection by gram-positive cocci. Our data suggest that prophylaxis is most likely to be effective if administered to patients for at least 1 week before they become severely neutropenic. Nalidixic acid used as a single agent in doses of 4 g daily, however, cannot be recommended as an alternative to TMP-SMX for infection prophylaxis in neutropenic cancer patients.

Agranulocytosis↗
PubMed1990

Emergence of resistant fecal Escherichia coli in travelers not taking prophylactic antimicrobial agents.

Fecal specimens from individuals traveling to Mexico were examined before, during, and after travel for the presence of Escherichia coli resistant to ampicillin, chloramphenicol, gentamicin, kanamycin, streptomycin, sulfonamides, trimethoprim (TMP), and TMP-sulfamethoxazole (TMP-SMX). None of these individuals took prophylactic antibiotics, although 4 of 13 took short courses of an antimicrobial agent for therapy of traveler's diarrhea. With an average of 9.3 E. coli per sample, resistance to all agents tested except gentamicin was shown to increase during the time in Mexico (P less than 0.001 to P less than 0.05). For example, no TMP-resistant (Tmpr) E. coli isolates were found by this method before travel, whereas 57% of the individuals had Tmpr and Tmpr-Smxr E. coli by the final week in Mexico. This increase in resistance occurred regardless of whether an individual took a short course of antimicrobial therapy. This study shows that travel itself, even without the use of prophylactic or therapeutic antimicrobial agents, is associated with the acquisition of resistant E. coli. Travel to developing nations may rival other sources of resistant organisms.

Anti-Bacterial Agents↗
PubMed1992

Low-dose trimethoprim-sulfamethoxazole alone and in association with zidovudine for prevention and treatment of murine Pneumocystis carinii pneumonia.

Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) alone was found to be as effective as low-dose TMP-SMX plus zidovudine and standard-dose TMP-SMX alone in preventing and treating Pneumocystis carinii pneumonia (PCP) in an immunosuppressed-rat model. Zidovudine alone had no preventive or curative effect on PCP. We conclude that the initially reported reduced incidence of PCP in human immunodeficiency virus-infected patients treated with zidovudine alone is not due to anti-P. carinii activity of zidovudine. Furthermore, the clinical efficacy of low-dose TMP-SMX for the prevention and treatment of PCP should be further investigated.

Animals↗
PubMed1992

Optimal dosing of trimethoprim-sulfamethoxazole when used with loperamide to treat traveler's diarrhea.

To explore the optimal dosing regimen for trimethoprim-sulfamethoxazole (TMP-SMX) when used in combination with loperamide to treat traveler's diarrhea, 190 U.S. adults with acute diarrhea were enrolled in a double-blind, randomized trial in Guadalajara, Mexico. All patients received loperamide (4-mg loading dose; 2 mg after each loose stool, not to exceed 16 mg/day for 3 days) and were randomized to receive a 3-day course of TMP-SMX (160:800 mg twice daily for six doses) (group A), a single large dose of TMP-SMX (320:1,600 mg) (group B), or a large loading dose (320:1,600 mg) followed by standard doses for 3 days (160:800 mg twice daily for five doses) (group C). Patients in group C responded best (P < 0.01), with 75% of subjects recovered from diarrhea in 12 h compared with 34 h (group A) and 33 h (group B). Similar differences in favor of group C were noted in the subset of patients who presented with moderate to severe diarrhea. On average, patients in group C took significantly (P < 0.05) less loperamide (1.2 mg) after the 4-mg loading dose compared with patients in group A (2.4 mg) or group B (2.0 mg). We conclude that the most efficacious treatment of traveler's diarrhea in the interior of Mexico is to take loperamide in usual doses to control symptoms in combination with a single large dose of TMP-SMX, which should then be continued for 3 days in standard doses.

Acute Disease↗
PubMed1992

Therapy of experimental meningitis due to Salmonella enteritidis.

In many areas of the developing world, Salmonella spp. account for greater than 50% of the gram-negative enteric organisms isolated from cerebrospinal fluid (CSF). The response of Salmonella meningitis to conventional therapy (chloramphenicol and/or ampicillin) is slow, complications arise frequently, and mortality rates of 60 to 80% are common. Two newer agents, ceftriaxone and imipenem, were compared with ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (TMP-SMX) in the therapy of experimental Salmonella meningitis beginning 14 h after intracisternal inoculation and continued by constant intravenous infusion for 8 h. Drug concentrations in serum and CSF closely approximated those achieved in the sera and CSF of humans receiving standard parenteral regimens. Penetration into purulent CSF [(concentration of drug in CSF/concentration of drug in serum) x 100] ranged from 18 to 41%. The rate of bacterial killing in CSF was significantly (P less than 0.001) more rapid during therapy with ceftriaxone and imipenem than it was during therapy with chloramphenicol or TMP-SMX. Ceftriaxone and imipenem sterilized the CSF of six of seven animals at 8 h, whereas it sterilized the CSF of three of eight animals treated with ampicillin (P = 0.18), one of eight animals treated with chloramphenicol, and none of seven animals treated with TMP-SMX (P less than or equal to 0.01; ceftriaxone or imipenem versus chloramphenicol or TMP-SMX). New beta-lactams, including ceftriaxone and imipenem, appear to be effective therapy against Salmonella spp. in this animal model and deserve further evaluation in humans.

Animals↗
PubMed1995

Increasing antimicrobial resistance of Shigella isolates in Israel during the period 1984 to 1992.

Recent (1984 to 1992) trends in the antimicrobial resistance of Shigella isolates in Israel were studied by analyzing the results of 106,000 stool cultures, 3,511 of which yielded Shigella spp. Over the study period, resistance to trimethoprim-sulfamethoxazole (TMP-SMX) increased from 59 to 92% (P = 0.0038) and that to ampicillin increased from 13 to 86% (P < 0.0001). Resistances to nalidixic acid, chloramphenicol, and broad-spectrum cephalosporins remained low. Shigella sonnei, which currently accounts for 90% of Shigella infections, was more resistant than S. flexneri to TMP-SMX (81 versus 57%, P < 10(-6)), ampicillin (42 versus 32%, P < 10(-5)), and tetracycline (38 versus 28%, P < 10(-5)). S. boydii and S. dysenteriae were relatively rare. Seasonality in antimicrobial resistance was found, with summer isolates being less resistant to TMP-SMX, ampicillin, or both than isolates obtained over the rest of the year (P < 10(-5)). We conclude that the resistance of shigellae, especially S. sonnei, to TMP-SMX and ampicillin is increasing to approximately 90%. Resistance should be recorded locally, and empiric therapy for suspected shigellosis should be changed accordingly.

Ampicillin↗
PubMed1995

Cloning and characterization of a novel, plasmid-encoded trimethoprim-resistant dihydrofolate reductase from Staphylococcus haemolyticus MUR313.

In recent years resistance to the antibacterial agent trimethoprim (Tmp) has become more widespread, and several trimethoprim-resistant (Tmpr) dihydrofolate reductases (DHFRs) have been described from gram-negative bacteria. In staphylococci, only one Tmpr DHFR has been described, the type S1 DHFR, which is encoded by the dfrA gene found on transposon Tn4003. In order to investigate the coincidence of high-level Tmp resistance and the presence of dfrA, we analyzed the DNAs from various Tmpr staphylococci for the presence of dfrA sequences by PCR with primers specific for the thyE-dfrA genes from Tn4003. We found that 30 or 33 isolates highly resistant to Tmp (MICs, > or = 512 micrograms/ml) contained dfrA sequences, whereas among the Tmpr (MICs, < or = 256 micrograms/ml) and Tmps isolates only the Staphylococcus epidermidis isolates (both Tmpr and Tmps) seemed to contain the dfrA gene. Furthermore, we have cloned and characterized a novel, plasmid-encoded Tmpr DHFR from Staphylococcus haemolyticus MUR313. The dfrD gene of plasmid pABU17 is preceded by two putative Shine-Dalgarno sequences potentially allowing for the start of translation at two triplets separated by nine nucleotides. The predicted protein of 166 amino acids, designated S2DHFR, encoded by the longer open reading frame was overproduced in Escherichia coli, purified, and characterized. The molecular size of the recombinant S2DHFR was determined by ion spray mass spectrometry to be 19,821.2 +/- 2 Da, which is in agreement with the theoretical value of 19,822 Da. In addition, the recombinant S2DHFR was shown to exhibit DHFR activity and to be highly resistant to Tmp.

Amino Acid Sequence↗
PubMed1996

Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa.

Pseudomonas aeruginosa possesses at least two multiple drug efflux systems which are defined by the outer membrane proteins OprM and OprJ. We have found that mutants overexpressing OprM were two- and eightfold more resistant than their wild-type parent to sulfamethoxazole (SMX) and trimethoprim (TMP), respectively. For OprJ-overproducing strains, MICs of TMP increased fourfold but those of SMX were unchanged. Strains overexpressing OprM, but not those overexpressing OprJ, became hypersusceptible to TMP and SMX when oprM was inactivated. The wild-type antibiotic profile could be restored in an oprM mutant by transcomplementation with the cloned oprM gene. These results demonstrate that the mexABoprM multidrug efflux system is mainly responsible for the intrinsic resistance of P. aeruginosa to TMP and SMX.

Anti-Bacterial Agents↗