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Biomedical subjects

T Fekete

Publications and source records attributed to T Fekete.

At least 19 recordsLinked to original sources
PubMed1996

Comparative susceptibilities of Klebsiella species, Enterobacter species, and Pseudomonas aeruginosa to 11 antimicrobial agents in a tertiary-care university hospital.

The in vitro activity of cefepime was compared versus that of 10 antimicrobial agents commonly used in the treatment of serious infections caused by common aerobic gram-negative bacteria: aztreonam, cefoperazone, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, piperacillin, ticarcillin-clavulanic acid, and tobramycin. We tested 30 clinical isolates representing a cross section of Klebsiella and Enterobacter species and Pseudomonas aeruginosa collected at our tertiary-care university hospital. The most potent beta-lactams were imipenem and cefepime, which demonstrated significant activity against the majority of strains in all 3 genera of bacteria tested, as did ciprofloxacin and tobramycin. Ceftazidime was active against Pseudomonas aeruginosa but was less potent against Klebsiella and Enterobacter spp. Cefoperazone and ceftriaxone were less active than ceftazidime against Pseudomonas aeruginosa. Cefepime was found to be highly active against many resistant organisms that traditionally have been difficult to treat.

Anti-Bacterial Agents↗
PubMed1996

Dose-time response in mouse skin tumor induction by 7, 12-dimethylbenz[a]anthracene and 12-O-tetradecanoyl-phorbol-13-acetate.

The question was addressed whether the dose-response relationship derived from a carcinogenicity study can be used for mechanistic interpretation and to what extent the shape of the curve is dependent on the duration of the bioassay and the time of analysis. The mouse skin tumor model was used. It allows recording of the time of tumor appearance without interim sacrifice. Groups of 16 female NMRI mice were treated twice weekly by dermal administration with combinations of (a) 2.5 nmol 12-O-tetradecanoyl-phorbol-13-acetate (TPA) plus 0, 0.3, 1, 3, or 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA) or with (b) 2.5 nmol DMBA plus 0, 0.1, 0.3, 1, 3, or 10 nmol TPA. The appearance of the first papilloma was recorded for each animal and the cumulative incidence data were analyzed in two ways: (i) With the usual dose-prevalence representation at a fixed time point, the dose response for TPA was sigmoidal, while it was linear-superlinear for DMBA. This was observed at all time points, indicating that the dose-response information may be used for a distinction between DNA-reactive and tumor-promoting mechanisms of action. (ii) When time-to-tumor and loss of tumor-free lifetime was analyzed as a function of dose, there was again a marked difference between DMBA and TPA. The tumor-free lifetime increased with each step of dose reduction but the slope was about four times larger for TPA compared with that for DMBA. Further reduction of the TPA dose could result in a situation in which the natural life span sets a limit to an observable effect. Under the conditions of this bioassay for mouse skin papilloma induction by a combination treatment with DMBA plus TPA, the findings support the idea of a no-effect low-dose threshold for the tumor-promoting agent.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Endogenous and exogenous factors in carcinogenesis: limits to cancer prevention.

Organ-specific cancer incidence rates can vary dramatically between low- and high-incidence areas. Such differences are due to (1) heritable susceptibility determinants, (2) risk factors associated with the environmental and local living conditions (e.g., viruses, pollution), and (3) personal life-style factors. For organs showing large differences between cancer registries, exogenous factors might be most important, while for organs showing only small differences, endogenous and unavoidable factors are expected to be more important. In this paper, a working hypothesis based on descriptive cancer epidemiology is presented to estimate, in a quantitative manner, the unavoidable contribution to the process of carcinogenesis and to discuss limitations to individual cancer prevention. Cumulative cancer incidence rates for a 75-year period of life (CR74, in percent) were taken from IARC Scientific Publication No. 120 (1992). For each organ, values were ranked in ascending order, and the ratio between high-rate and low-rate registries (90th percentile/10th percentile) was determined. This measure of variability among registries differed strongly between organs. Largest ratios were seen for organs with well-known exogenous risk factors, such as pharynx, lip, tongue, mouth, liver, esophagus, and melanoma in males, and lung, esophagus, gallbladder, liver, and bladder in females. Small ratios were seen for rectum, brain, colon, and Hodgkin's disease in males, and breast, rectum, ovary, brain, and colon in females. It is concluded that the process of carcinogenesis in the latter organs has a stronger endogenous/unavoidable component, for some tissues possibly of hormonal type. A fictitious population was composed where, for each organ, the minimum reported cancer rate was taken. When based on all cancer registries world-wide, CR74 sums over all sites of 2.0% and 2.3% resulted in males and females, respectively. When only Central/Western European countries were included in the analysis in order to reduce differences in risk factors nos. 1 and 2, the sum of the minimum values was 10.4% and 8.7%. After correction of the data for smoking, 'minimum' cancer incidence rates in males and females were estimated to be 7.6% and 6.8%. Based on a median cancer incidence rate for nonsmoking males in Europe of about 21%, therefore, individual preventive measures taken by a nonsmoker can reduce the cancer risk, on average, 'only' by a factor of about 3. A considerable fraction of cases thus appears to be hardly avoidable.

DNA Damage↗
PubMed1996

Lipoic acid impairs glycine conjugation of benzoic acid and renal excretion of benzoylglycine.

Glycine conjugation of benzoic acid is catalyzed by the mitochondrial enzymes benzoyl-coenzyme A(CoA) synthetase and benzoyl-CoA: glycine N-acyltransferase and requires ATP, CoA, and glycine as cosubstrates. Lipoic acid (LA), an important endogenous and also therapeutic compound, depletes hepatic CoA; therefore, it may interfere with glycine conjugation. To test this hypothesis, LA (0.5-1.5 mmol/kg ip) was given to anesthetized, glycine-loaded rats 1 hr before administration of benzoic acid (1 mmol/kg iv). LA inhibited glycine conjugation of benzoic acid in a dose-dependent manner as indicated by: 1) reduced clearance of benzoic acid from blood; 2) delayed appearance of benzoylglycine in blood; and 3) decreased excretion of benzoylglycine in urine. LA also decreased urinary excretion of injected benzoylglycine, indicating that reduced excretion of this metabolite after benzoic acid injection is caused by diminished formation and impaired renal transport of benzoylglycine. Urine formation was decreased by LA in a dose-dependent fashion, and acute renal failure was evident in rats receiving the highest dose. LA depleted hepatic CoA, carnitine, and glutathione, but not ATP, whereas it increased the hepatic concentration of glycine. In isolated and solubilized rat liver mitochondria, LA inhibited both benzoyl-CoA synthetase (IC50 approximately 1.5 mM) and benzoyl-CoA:glycine N-acyltransferase (IC50 approximately 0.3 mM). Thus, depletion of CoA and inhibition of the pertinent enzymes seem responsible for impairment of glycine conjugation of benzoic acid by LA. LA may also impair renal tubular cell function, compromising the tubular secretion of benzoylglycine and causing acute renal failure.

Acyltransferases↗
PubMed1996

Does hepatic ATP depletion impair glycine conjugation in vivo?

Conjugation with glycine, a reaction important in the elimination of carboxylic acids (e.g. benzoic and salicylic acids), takes place in hepatic mitochondria and uses ATP, coenzyme A, and glycine. Although normal ATP supply does not limit glycine conjugation in vivo (Gregus, Z., et al., Drug Metab. Dispos. 20, 234, 1992), ATP deficiency may impair it. This hypothesis was tested by examining the effect of ATP depletors (oligomycin, fructose, and ethionine) on glycine conjugation and elimination of benzoic acid in rats. Pretreatment with the mitochondrial ATP synthesis inhibitor oligomycin (0.5-2 mg/kg, intraportally) decreased glycine conjugation of benzoic acid markedly and in a dose-dependent manner, as indicated by the delayed elimination of benzoate and delayed appearance of benzoylglycine in blood. Oligomycin also dramatically diminished urinary excretion of benzoylglycine, because it inhibited not only formation of benzoylglycine from benzoate, but also the renal transport of benzoylglycine. Treatment with fructose (a consumer of both cytosolic and mitochondrial ATP) or ethionine (a consumer of cytosolic ATP) depleted hepatic ATP from approximately 2.5 micromol/g to levels comparable with those observed after administration of 1 mg/kg oligomycin (approximately 1.2 micromol/g). Despite this, elimination of benzoate and formation of benzoylglycine were decreased less by fructose than by oligomycin and only negligibly by ethionine. ATP depletors did not influence hepatic glycine levels, and only oligomycin lowered coenzyme A levels in liver. However, the oligomycin-induced decline of hepatic coenzyme A levels was delayed, contrary to impairment of glycine conjugation, which was almost immediate. In summary, impairment of benzoylglycine formation by ATP depletors apparently correlates with their capacity to diminish ATP levels in hepatic mitochondria (i.e. at the site of glycine conjugation). These observations suggest that limited availability of mitochondrial (but not cytosolic) ATP reduces glycine conjugation capacity. Therefore, mitochondrium toxic agents and pathological mitochondrial injuries acting in liver may compromise glycine conjugation by decreasing ATP supply.

Adenosine Triphosphate↗
PubMed1994

A comparison of serial plate agar dilution, Bauer-Kirby disk diffusion, and the Vitek AutoMicrobic system for the determination of susceptibilities of Klebsiella spp., Enterobacter spp., and Pseudomonas aeruginosa to ten antimicrobial agents.

The use of rapid, automated technologies for assessment of antimicrobial susceptibility and determination of minimum inhibitory concentrations has been evolving for over a decade. We compared the Vitek AutoMicrobic system and Bauer-Kirby disk diffusion with the National Committee for Clinical Laboratory Standards methods of serial plate agar dilution for qualitative and quantitative susceptibilities of 301 hospital isolates of Klebsiella spp., Enterobacter spp., and Pseudomonas aeruginosa. Antibiotics tested were aztreonam, cefoperazone, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, piperacillin, ticarcillin-clavulanic acid, and tobramycin. Agar dilution and Bauer-Kirby results were more strongly correlated for all three genera than were the results for agar dilution and Vitek. If agar dilution is presumed to be the "gold standard," Bauer-Kirby disk diffusion had only half the number of false susceptibles as did the Vitek. Thus, the Vitek AutoMicrobic system seems to be somewhat less reliable for both qualitative and quantitative measurement of susceptibility and resistance than is Bauer-Kirby disk diffusion.

Agar↗
PubMed1994

Investigation of a pseudo-outbreak of orthopedic infections caused by Pseudomonas aeruginosa.

OBJECTIVE: To report a pseudoepidemic of Pseudomonas aeruginosa infections discovered during an investigation of postoperative joint infections. DESIGN: A retrospective review of case patients' hospital charts, operative reports, and laboratory data, as well as environmental culturing, polymerase chain reaction (PCR) ribotyping of outbreak isolates, and in vitro analysis of P aeruginosa growth characteristics. SETTING: A 510-bed, university-affiliated adult tertiary care hospital. RESULTS: Between October 1 and December 1, 1992, seven postsurgical joint infections were diagnosed, including four caused by P aeruginosa. A bottle of "sterile" saline used to process tissue specimens was found to be contaminated with P aeruginosa. Further investigation revealed that P aeruginosa had grown from seven additional tissue cultures, all of which had been processed with the contaminated saline. PCR ribotypes of the contaminant matched those of the clinical isolates. In vitro, P aeruginosa strains were viable in commercial nonbacteriostatic saline, but never caused visible turbidity. Six patients received antibiotics for their presumed infections; four patients had peripherally inserted central catheters placed, and one experienced severe anaphylactic reactions to several antibiotics. CONCLUSIONS: Pseudoepidemics due to common organisms are often difficult to detect, and delayed recognition can result in substantial morbidity. This outbreak investigation illustrates the potential for contamination of diluents in the microbiology laboratory and emphasizes the need for meticulous quality control.

Adolescent↗
PubMed1993

Antimicrobial susceptibility testing of Neisseria gonorrhoeae and implications for epidemiology and therapy.

Antimicrobial susceptibility testing (AST) of Neisseria gonorrhoeae has been under development since the early days of antimicrobial agents. However, it is rarely applied to clinical isolates today. The history of the various in vitro tests to determine the susceptibility of N. gonorrhoeae to antibiotics is rich with evidence that these results predict response to therapy for almost all agents tested. Further, AST is a useful and important aspect of strain characterization and disease epidemiology in conjunction with the more specific but laborious techniques of auxotyping, serotyping, and plasmid analysis. Current technology has overcome many of the objections to AST for N. gonorrhoeae with standardization of test media and the development of an accurate disk diffusion AST method that is suited to most clinical laboratories regardless of volume or level of technical expertise. Ironically, the very low level of resistance to the current primary treatment strategy in the United States, ceftriaxone or another potent cephalosporin, makes the use of AST somewhat superfluous.

Anti-Bacterial Agents↗
PubMed1993

Dependence of glycine conjugation on availability of glycine: role of the glycine cleavage system.

1. Glycine conjugation of benzoic acid was investigated in anaesthetized rats by measuring the disappearance of benzoate from blood, and the appearance of benzoylglycine in blood and urine. 2. Administration of glycine (1-10 mmol/kg,i.v.) increased the capacity of benzoylglycine formation in a dose-dependent fashion, with a maximal rate (8.1 mumol/kg per min) occurring after administration of 5 mmol/kg glycine. The normal endogenous glycine supply (1.7 mM in liver) permits glycine conjugation only at an approximate half-maximal rate (4.5 mumol/kg/per min). 3. The increase in benzoylglycine formation in response to exogenous glycine supply is also a function of the benzoate dosage. Decreased responsiveness at high benzoate dosage indicates that the availability of coenzyme A is another factor that also limits the capacity of glycine conjugation. 4. Cysteamine (200 mg/kg, i.p.), a potent inhibitor of the mitochondrial glycine cleavage system, rapidly increased hepatic glycine concentration 2-3-fold without affecting the concentration of the other co-substrates (i.e. coenzyme A and ATP) of glycine conjugation. 5. Administration of cysteamine increased the blood clearance of benzoate by 50%, the appearance of benzoylglycine in blood, and the urinary excretion of benzoylglycine. 6. It is concluded that the activity of glycine cleavage system is an important determinant of glycine supply and, thereby, the capacity of glycine conjugation of xenobiotics.

Animals↗
PubMed1993

Effect of valproic acid on glycine conjugation of benzoic acid.

Conjugation with glycine proceeds through ATP-dependent coupling of carboxylic acids with coenzyme A (CoA). Therefore, chemicals that form CoA esters may interfere with glycine conjugation. We tested the hypothesis that valproic acid (VPA), which is esterified with CoA in the first step of its mitochondrial beta-oxidation, may compromise glycine conjugation of aromatic carboxylic acids, by investigating the effect of acute VPA administration on glycine conjugation of benzoic acid in rats. VPA administered 1 hr before injection of benzoate only decreased the blood clearance of benzoate and the urinary excretion of benzoylglycine slightly in normal rats. However, in rats loaded with glycine, 2 and 3 mmol/kg of VPA reduced the blood clearance of benzoate by 34 and 59%, diminished the peak blood level of the glycine conjugate and depressed the maximal urinary excretion rate of benzoylglycine by 28 and 66%, respectively. To elucidate the mechanism of VPA-induced inhibition of benzoylglycine formation, the effects of VPA on hepatic levels of cosubstrates and the activities of enzymes involved in glycine conjugation were also determined. One hour after administration of VPA, hepatic ATP levels remained unchanged, whereas the concentration of CoA was reduced by 67 to 73% and that of glycine was increased by 58 to 67%. Activities of the enzymes of glycine conjugation were not influenced by VPA. However, 2-n-propyl-4-pentenoic acid, a metabolite of VPA, inhibited benzoyl-CoA synthetase. In summary, VPA minimally influenced the capacity of glycine conjugation of benzoic acid in normal rats, but decreased it markedly in glycine-loaded rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Susceptibility of Neisseria gonorrhoeae to cefpodoxime: determination of MICs and disk diffusion zone diameters.

We studied the susceptibilities of 77 strains of Neisseria gonorrhoeae to four antibiotics: cefpodoxime, ceftriaxone, penicillin, and tetracycline. All strains were susceptible to ceftriaxone. Cefpodoxime MICs (range, 0.001 to 0.125 micrograms/ml) were parallel to and approximately four times those of ceftriaxone, and all strains will probably be considered susceptible to cefpodoxime. Disk diffusion zone diameters for cefpodoxime ranged from 35 to 57 mm. Of the strains, 32% were penicillin resistant and 51% were tetracycline resistant (MIC, greater than or equal to 2 micrograms/ml). Susceptibility measurements were consistent for disk diffusion zone diameter and MIC, with an overall agreement of 215 of 225 (96%) for ceftriaxone, penicillin, and tetracycline combined. On the basis of these in vitro data, cefpodoxime should be evaluated in the treatment of gonorrhea.

Ceftizoxime↗
PubMed1990

Controversies in the prevention of infective endocarditis related to dental procedures.

There is a long historical relationship between dental procedures and infective endocarditis. Yet despite the availability and wide use over the past three decades of inexpensive, relatively safe antibiotics before dental work, the incidence of endocarditis has not decreased. Can any conclusion be drawn about the merits of antibiotic prophylaxis around the time of dental procedures? If so, is there a preferred regimen? This article outlines the historical developments that have led to current recommendations and presents a critique of current opinion on the advisability of specific programs to prevent cardiac infections related to professional dental work.

Animals↗
PubMed1989

Susceptibility to cephalosporins of penicillin-susceptible and penicillin-resistant strains of Neisseria gonorrhoeae from Philadelphia.

Using agar dilution, we determined MICs of penicillin, cefoxitin, ceftriaxone, cefmetazole, tetracycline, and spectinomycin for 129 strains of Neisseria gonorrhoeae. All strains were susceptible to ceftriaxone (MIC range, less than or equal to 0.008 to 0.06 micrograms/ml) and spectinomycin (16 to 32 micrograms/ml). The MICs for 50, 90, and 100% of strains tested were 1.0, 2.0, and greater than 8.0 micrograms/ml; 0.12, 1.0, and greater than 8.0 micrograms/ml; 0.5, 1.0, and 2.0 micrograms/ml; and 1.0, 2.0, and greater than 8.0 micrograms/ml for cefmetazole, penicillin, cefoxitin, and tetracycline, respectively. Seven strains were beta-lactamase producers; eight were chromosomally resistant to penicillin. There was a log-linear relation for non-beta-lactamase-producing strains between the MICs of cefmetazole, cefoxitin, and tetracycline and the MIC of penicillin (Pearson r = 0.787, 0.544, and 0.358, respectively).

Cephalosporins↗