Harumi Araki

Application of muscle microdialysis to evaluate the concentrations of the fluoroquinolones pazufloxacin and ofloxacin in the tissue interstitial fluids of rats

Muscle microdialysis has been used to determine the unbound concentrations of the fluoroquinolones, pazufloxacin and ofloxacin, in tissue interstitial fluids (Cisf, u) of rats under steady state conditions.

In vitro antibacterial properties of T-5575 and T-5578 novel parenteral 2-carboxypenams.

T-5575 and T-5578, novel 2-carboxypenams in which a carboxyl group has been introduced into the C-2 beta position of the nucleus, were evaluated for their in vitro antibacterial properties. The spectrum of activity of T-5575 was similar to that of aztreonam. However, it showed stronger activities than those of aztreonam against most gram-negative bacteria. T-5575 also showed potent activities against isolates of Enterobacter cloacae, Citrobacter freundii, and Pseudomonas aeruginosa resistant to ceftazidime, with MICs at which 90% of the isolates were inhibited of 0.39, 0.39, and 3.13 microgram/ml, respectively. T-5578 showed moderate levels of activity against gram-negative bacteria, compared with those of T-5575. Its activity against P. aeruginosa, however, was superior to those of T-5575 and the reference drugs tested. The most characteristic feature of T-5578 was its potent activities against ceftazidime-, imipenem-, and gentamicin-resistant P. aeruginosa isolates, with MICs at which 90% of the isolates were inhibited at 0.39, 3.13, and 3.13 microgram/ml, respectively. These two compounds were unfortunately poorly active against gram-positive bacteria, such as Staphylococcus aureus and streptococci. Both compounds were found to be stable for hydrolysis by various kinds of beta-lactamases and to have low affinities for these enzymes, with Ki values of > 100 microM. These novel penams bound most tightly to penicillin-binding protein 3 of Escherichia coli and P. aeruginosa. These results indicate that T-5575 and T-5578 can be regarded as promising 2-carboxypenams specially targeted against gram-negative pathogens.

Significance of inducible cephalosporinase remaining in the experimentally infected rat granuloma pouch after beta-lactam therapy.

We studied the influence of inducible cephalosporinase on levels of secondarily administered beta-lactam antibiotics in exudates using experimentally infected rat granuloma pouches. Cefoperazone or cefmetazole was administered intramuscularly at a dose of 100 mg/kg of body weight to rats at 2 and 8 h after infection of rat pouches with Serratia marcescens W-24, which possesses an inducible type I beta-lactamase (cephalosporinase). Subsequently, cefotaxime or cefbuperazone was administered at an intravenous dose of 100 mg/kg to rats at 24 h postinfection. Levels of cefotaxime in the pouch exudates of the cefmetazole-pretreated group were lower than those in the control group, which was infected but not pretreated with antibiotics. This was due to the inactivation of cefotaxime by extracellular cephalosporinase which was induced by cefmetazole and which remained in the rat pouches. However, cefotaxime concentrations were not reduced in the cefoperazone-pretreated group because of the low inducibility of cefoperazone against cephalosporinase production. On the other hand, cefbuperazone concentrations were similar in all groups (control, cefoperazone pretreated, and cefmetazole pretreated), because cefbuperazone is more stable against this enzyme than cefotaxime is. In conclusion, concentrations of secondarily administered beta-lactam antibiotics are affected by inducibly produced cephalosporinase at the infection site when a good inducer like cefmetazole is administered beforehand.