The new quinolones.
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Biomedical subjects
Publications and source records attributed to R Wise.
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Two hundred and fifty patients were admitted to a prospective randomized trial to compare the efficacy of Augmentin with metronidazole in the prevention of sepsis after appendicectomy. Pre-operatively they received either 500 mg metronidazole or 1.2g Augmentin intravenously. Those patients with gangrenous or perforated appendices received eight additional doses of the trial drug at 8 hourly intervals. Overall there were 13 wound infections in the Augmentin group (11 per cent) and 21 in the metronidazole group (18 per cent). The 90 per cent confidence limits for the overall 7 per cent difference in infection rates were +/- 8.5 per cent. There were high rates of wound infection in the gangrenous group (Augmentin 8 per cent versus metronidazole 19 per cent) and especially in the perforated group (Augmentin 33 per cent versus metronidazole 63 per cent). There was no statistically significant difference between the infection rates with the two antibiotics but our study suggests that Augmentin, which is active against both aerobes and anaerobes, may be more effective than metronidazole in reducing wound sepsis after appendicectomy.
The pharmacokinetics of cefotaxime, its desacetyl metabolite and ceftriaxone were studied in 72 patients with various degrees of renal and hepatic failure. Patients with severe renal failure (creatinine clearance 3 to 10 ml/min) had a cefotaxime serum half-life of 2.6 h, a desacetyl cefotaxime serum half-life of 10 h and ceftriaxone serum half-life of 17 h. In the case of ceftriaxone, this serum half-life could be very variable--increasing to over 50 h, possibly due to co-existing hepatic dysfunction. Increases in serum half-life were found for cefotaxime in the presence of liver disease.
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The susceptibility of 554 recent clinical isolates and known resistant bacterial strains to the new monocyclic beta-lactam Ro 17-2301 were studied and compared to that to other beta-lactams (including aztreonam and temocillin) and gentamicin. Ro 17-2301 had a high degree of activity against the Enterobacteriaceae (MIC90 less than or equal to 0.25 mg/l) being similar or slightly more active than aztreonam and ceftazidime. Strains of Acinetobacter spp. (MIC90 16 mg/l). Haemophilus influenzae strains (including beta-lactamase producers) were more susceptible (MIC90 0.5 mg/l) than those of Neisseria gonorrhoeae (MIC90 4 mg/l); against these latter two groups of isolates aztreonam was more active (MIC90 0.12 mg/l). Both aztreonam and Ro 17-2301 had little activity against Gram-positive cocci with the exception of Streptococcus pneumoniae for which the MIC90 of RO 17-2301 was 16 mg/l. Ro 17-2301 had modest activity against Bacteroides fragilis. The MBC of Ro 17-2301 was very similar to the MIC and the addition of human serum had little effect on the amount of the compound. The mean serum protein binding was 26.3%. A study of the penicillin binding protein affinity of Ro 17-2301 in a strain of Escherichia coli showed PBP 3 to be the primary target. The morphological response to exposure to Ro 17-2301 was filamentation followed by lysis after prolonged exposure.
The activity of the extended spectrum cephalosporin cefpirome (HR 810) was compared with that of other beta-lactams and gentamicin. A total of 524 clinical isolates and strains known to be resistant to certain agents were studied. Against the Enterobacteriaceae, Haemophilus influenzae and Neisseria spp. cefpirome was highly active (MIC90 less than or equal to 0.5 mg/l), generally being as active or slightly more active than ceftazidime and cefotaxime, and 8 to 32 times more active than cefuroxime. Against Pseudomonas aeruginosa cefpirome (MIC90 8 mg/l) was four-fold less active than ceftazidime. Staphylococcus aureus was susceptible to cefpirome (MIC90 2 mg/l) and cefpirome was the only cephalosporin tested with significant activity against Lancefield Group D streptococci. Bacteroides spp. (with the exception of Bact. ureolyticus) were resistant to cefpirome. The compound was bactericidal to all the susceptible strains studied with the exception of Lancefield Group D streptococci. The major target site for cefpirome was PBP 3 and the protein binding was low.
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The competition of the new penem antibiotic, Sch 34343, for the penicillin-binding-proteins (PBPs) of Escherichia coli and Bacteroides fragilis was studied. Sch 34343 caused rounding of cells, and then sphaeroplast formation and lysis in both organisms. The primary target in both organisms was PBP 2, and at higher concentrations PBP 1a and 1b (and 1c in Bact. fragilis). These targets were inhibited at well below therapeutically achievable concentrations. The results indicate that in E. coli and Bact. fragilis, the bactericidal activity of Sch 34343 is related to inhibition of two out of three 'essential' PBPs.
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The pharmacokinetics of teicoplanin were studied following a 440 mg intravenous dose in six male volunteers. The levels of the compound were measured in serum, blister fluid and urine. The mean serum level 0.5 h after injection was 44.6 mg/l falling to 3.6 mg/l at 49 h. The elimination half-life of teicoplanin from serum was 34.2 h and the apparent distribution half-life 1.5 h. Penetration into blister fluid was moderately fast, the mean maximum concentration (14.8 mg/l) occurring at 2.7 h, and the mean percentage penetration being 77.4%. Urinary recovery of the drug was 48.3% by 96 h.
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The pharmacokinetics of the monobactam carumonam (Ro 17-2301) as derived from serial measurement of the concentrations of this agent in serum, blister fluid, and urine were studied in six male volunteers subsequent to intravenous infusion of a single 2-g dose. Drug levels in serum in excess of 75 micrograms/ml were achieved 0.5 h after the end of infusion, declining to 2.9 micrograms/ml at 8 h. The mean serum and blister fluid elimination half-lives were 1.68 and 1.7 h, respectively. The urinary recovery of the drug by 24 h was 80.6% (range, 68.3 to 91.1%). Carumonam penetrated blister fluid well, the mean percentage penetration (as measured by the ratio of areas under curves) being 101.6%.