Biomedical subjects
Publications and source records attributed to G Meinardi.
The isosteric CH----N substitution in the class of 2-arylpenems results in improved antibacterial activity, with retention of the favorable characteristic of stability towards renal dehydropeptidase. High therapeutic efficacy was demonstrated in experimental mice septicemias with the 2-(3-pyridyl) derivative 2b and its orally absorbed acetoxymethyl ester prodrug 4n.
The therapeutic activities of the parenterally administered penem FCE 22101, cefuroxime and ampicillin were compared in an experimental model of genital infections in progesterone-treated virgin rats and normal female mice. Treatment with FCE 22101 significantly inhibited the proliferation of Staphylococcus aureus ATCC 13709, Escherichia coli G and Enterobacter cloacae 1321 E, as compared with untreated controls. Against Staph. aureus ampicillin was slightly more active than cefuroxime, which showed equivalent activity to FCE 22101, while against Esch. coli and Ent. cloacae cefuroxime and ampicillin were less active than FCE 22101. The activity of the antibiotics against beta-lactamase-producing strains was also tested and here FCE 22101 exhibited the greatest inhibitory effect on bacterial growth.
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The combination of trimethoprim (TMP) and sulfamethopyrazine (SMP) has been successfully used to treat chronic urinary tract infections. Since parenchymal involvement associated with renal insufficiency of varying degree is not infrequent in these patients, it was considered important to study the pharmacokinetics of TMP and SMP in a fixed dose combination. Four groups of patients were studied: 1) 4 patients with endogenous creatinine clearance (CLcR) between 80 and 40 ml/min; 2) 3 patients with CLcR between 40 and 10 ml/min; 3) 3 patients on chronic peritoneal dialysis (CAPD); and 4) 3 patients on haemodialysis. A single oral dose of 250 mg TMP and 200 mg SMP was given to each patient. Multiple samples were collected over 9 days and the following pharmacokinetic parameters were calculated: total area under the plasma level curve, slow disposition rate constant beta and the corresponding t1/2 beta, plasma clearance and the apparent volume of distribution. The results show that the two moieties of the TMP-SMP combination behaved differently in uraemic patients as fas as elimination rate was concerned. TMP was eliminated more slowly both in patients with diminished renal function and in those subjected to haemo- or peritoneal dialysis. The reduction in the rate of elimination of TMP was significantly correlated with the degree of renal impairment. The elimination of SMP, however, was not significantly affected by the reduced renal function; indeed a tendency to increase was noted, at least in dialyzed patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Introduction of a hydroxyl group into the thiazole ring nitrogen of cephalosporins belonging to the cefotiam and cefotaxime families gave rise to products, better described by the tautomeric N-oxide form, which proved particularly active against Gram-negative bacteria. Cephems bearing a (Z)-alkoxyimino functionality are of special interest for broadness of spectrum; among them, 7 beta-[(Z)-2-(2-amino-4-thiazolyl-N-oxide)-2 -methoxyiminoacetamido]-3-(tetrazolo-[1,5-b] pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid (5c-7, FCE 20635), in other ways similar to cefotaxime, showed useful levels of activity against cephalosporinase-producing strains resistant to the reference drug. Preliminary in vivo studies demonstrated the therapeutic efficacy of the new compound in the treatment of experimental systemic, subcutaneous and urinary tract infections in mice.
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The synthesis and in vitro activity of 7 beta-[(Z)-2-alkoxyimino- 2-(2-aminothiazol-4-yl) acetamido]cephalosporins with a tetrazolo[1,5-b]pyridazine at the 3-position are described. These cephalosporins showed excellent activity against Gram-negative bacteria, including beta-lactamase producing strains. The most interesting compound of the series was 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetamido] -3-(8-carboxytetrazolo[1,5-b]pyridazin-6-yl)- thiomethyl-3-cephem-4-carboxylic acid (9, FCE 20485) because of its extraordinarily long half-life and marked in vivo activity.
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The synthesis and in vitro activity of 7 alpha-methoxy-7 beta-vinylenethioacetamido cephalosporins with various substituents at the 3-position are described. These cephalosporins showed good activity against beta-lactamase producing Gram-negative bacteria. 7 alpha-Methoxy-7-[(Z)-beta-cyano-vinylenethioacetamido]-3-[(1-methyl-1H-tetrazol -5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3) was several times more active in vitro than cefoxitin and comparable to cefmetazole.
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A combination of trimethoprim (TMP) and sulfamethopyrazine (SMP) was administered to six healthy volunteers for 8 days, according to the proposed therapeutic repeated dose schedule. The weak base TMP (pKa = 7.3) and the weak acid SMP (pKa = 6.1) were measured simultaneously in serum and saliva, both under normal conditions and after stimulation of saliva flow. The flow of saliva was stimulated by chewing plastic material in order to obtain saliva at a pH close to the normal plasma pH of 7.4. This procedure excluded pH-dependent distribution effects. Under these experimental conditions a highly significant correlation was observed between the serum and saliva concentrations of both drugs, with very small inter- and intraindividual variations. Substantial agreement was found between the saliva:serum concentration ratio and the fractions of both drugs not bound to plasma protein. Some discrepancies were noted, probably due to minor shifts in saliva pH during the collection period.
The synthesis and in vitro activity of 7-vinylenethioacetamido cephalosporins with a tetrazolo-pyridazine at the 3-position are described. These cephalosporins showed good activity against Gram-positive and Gram-negative bacteria. 7-[(Z)-beta-carboxyvinylenethio-acetamido]-3-[(tetrazolo[1,5-b]pyridazin-8- amino-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid (K 13176, 21) was significantly more active in vitro and in vivo than cefazolin against Gram-negative bacteria.
The synthesis and in vitro structure-activity relationships of 7-vinylenethioacetamido and thioacrylamido cephalosporins with various substituents at the 3-position are described. 7(Z)-beta-Vinylenethioacetamido cephalosporins proved the most active against Gram-positive and Gram-negative bacteria. 7-[(Z)-beta-Cyanovinylenethioacetamido]-3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (K 13101, 40) was several times more active in vitro than cefazolin.
Bacterial resistance to beta-lactam antibiotics, as indicated on sensitivity tests, is not always directly proportional to their beta-lactamase synthesis capacity. From the epidemiological viewpoint, therefore, it would appear important to look specifically for the various beta-lactamases in bacteria. Chemical and biological methods for this purpose are reviewed, with particular attention to those including special steps which render them speedy, economical and feasible in any laboratory. Practical examples are offered.
A new apparatus is described which can be used to investigate the in vitro antibacterial activity of antibiotics as a function of different concentration-time curves. The apparatus can be adjusted to simulate the biexponential serum level curves observed in vivo after oral or intramuscular administration. Preliminary studies were carried out with cefazolin against an E. coli strain simulating initial concentrations of 5, 10 and 20 micrograms/ml that decreased exponentially with half-lives of 30, 60 and 120 min. In all the situations tested there was an initial phase of rapid bactericidal activity followed by a phase of bacteriostatic activity, whose length depended on the drug elimination rate but was relactively independent of the initial concentrations. Bacterial regrowth occurred when the antibiotic concentration fell below the minimum inhibitory concentration (MIC) of the drug. The antibacterial activity of cefazolin, cephacetrile, and cephradine against an E. coli strains was also investigated, in a medium containing 4% human albumin, simulating the serum level curves observed in humans after an intramuscular dose of 1 g. The results obtained confirm that, for cephalosporins, the dosage schedule should be adjusted taking into account the potency of the drug (MIC) and its rate of elimination.
A new apparatus is described which serves to investigate the in vitro antibacterial activity of antibiotics as a function of different concentration time curves. The apparatus can be adjusted to simulate the biexponential serum level curves observed in vivo after oral or intramuscular administration. Preliminary studies were carried out with a cephalosporin derivative, cefazolin, against Escherichia coli and Klebsiella sp. strains simulating initial concentrations of 5, 10, and 20 mug/ml that decreased exponentially with half-lives of 30, 60, and 120 min. Surviving cells were counted at 1-h intervals for 10 h. In all the situations tested there was an initial phase of rapid bactericidal activity followed by a phase of bacteriostatic activity, whose length depended on the drug elimination rate but was relatively independent of the initial concentrations. Bacterial regrowth occurred when the antibiotic concentration fell below the minimum inhibitory concentration of the drug against the strains tested. The antibacterial activity of cefazolin, cephacetrile, and cephradine against E. coli and Klebsiella strains was also investigated, in a medium containing 4% human albumin, simulating the serum level curves observed in humans after an intramuscular dose of 1 g. The results obtained suggest that, for cephalosporins, a longer half-life might be more useful than higher peak levels.