Isamu Saikawa

In vitro and in vivo antibacterial activities of T-3262, a new fluoroquinolone.

T-3262, a new fluoroquinolone, showed a broad spectrum of activity against gram-positive and gram-negative bacteria. T-3262 had most potent activity against gram-positive cocci, such as Staphylococcus, Streptococcus, and Enterococcus spp. The MICs of T-3262 for 90% of strains tested were between 0.05 and 1.56 micrograms/ml. Against members of the family Enterobacteriaceae and Pseudomonas aeruginosa, the activities of T-3262 were almost equal to those of ciprofloxacin. Obligate anaerobes were also susceptible to T-3262. T-3262 was bactericidal for one strain each of Staphylococcus aureus, Escherichia coli, and P. aeruginosa at concentrations near its MIC; and fluoroquinolones, including T-3262, inhibited DNA gyrase activity at low concentrations. The 50% effective dose of T-3262 after oral administration against systemic infections with S. aureus in mice was about 6 times lower than that of ofloxacin and about 20 times lower than that of norfloxacin.

Protective effect of piperacillin against nephrotoxicity of cephaloridine and gentamicin in animals.

The protective effect of piperacillin against the nephrotoxicity of cephaloridine and gentamicin was examined in experimental animals. In rabbits, piperacillin was infused at a dose of 1 mg/kg (body weight) per min over 225 min and cephaloridine (300 mg/kg) was intravenously administered as a bolus 45 min after the start of a drip infusion. Blood urea nitrogen, serum creatinine, and N-acetyl-beta-D-glucosaminidase (NAG) in urine were measured as the renal toxicological parameters before and 24 h after cephaloridine dosing. Although the single administration of cephaloridine significantly elevated these parameters, the elevation was prevented by the concomitant administration of piperacillin. The protective effect of piperacillin was superior to those of cephalothin and fosfomycin. In rats, piperacillin (1,000 mg/kg) was intravenously administered and immediately followed by the intramuscular administration of gentamicin (100 mg/kg) every 24 h for 5 days. When piperacillin was concomitantly administered with gentamicin, the elevations of blood urea nitrogen, serum creatinine, and urinary NAG were significantly lower than when gentamicin was given alone. The concomitant administration of piperacillin resulted in a significant protective effect against the nephrotoxicity of cephaloridine in rabbits and of gentamicin in rats. Histopathological observation also supported the protective effect of piperacillin. The protective mechanism of piperacillin might be the inhibition of transport from the peritubular side to tubular cells for cephaloridine and from both the peritubular and luminal sides for gentamicin. Images

Mechanism of action of cephalosporins and resistance caused by decreased affinity for penicillin-binding proteins in Bacteroides fragilis.

The susceptibilities of 52 clinical isolates of Bacteroides fragilis to five monoanionic cephalosporins were examined. Cefoperazone showed the highest antibacterial activity, followed by ceftezole, cefazolin, cefamandole, and cephalothin. There were two groups of resistant strains: one group (ca. 15%), of which B. fragilis G-232 was a typical sample, was resistant to ceftezole (MIC, 100 micrograms/ml), cefazolin (MIC, 100 micrograms/ml), and cephalothin (MIC, 200 micrograms/ml) but not cefoperazone (MIC, 6.25 micrograms/ml) or cefamandole (MIC, 25 micrograms/ml). On the basis of studies of stability to beta-lactamase, outer membrane permeation, and affinity for penicillin-binding proteins (PBPs), we conclude that decreased affinity for PBP 3 may play an important role in the resistance to ceftezole, cefazolin, and cephalothin in B. fragilis G-232. Another group (also ca. 15%), of which B. fragilis G-242 was a representative, was resistant to all five cephalosporins (MIC, 100 to 400 micrograms/ml) and produced a high amount of beta-lactamase. Similar broad-spectrum resistance was seen in a mutant of strain G-232 that had a greater-than-30-fold increase in beta-lactamase production. Images

Protective effect of piperacillin against the nephrotoxicity of cisplatin in rats

The protective effect of piperacillin against the nephrotoxicity of cisplatin was compared with that of fosfomycin in Fischer 344 rats. Blood urea nitrogen, serum creatinine, and morphological changes were evaluated as the renal toxicological parameters. Rats receiving 2 mg of cisplatin per kg of body weight for 5 days showed significant (P less than 0.01 by multiple-comparison test) elevation of blood urea nitrogen and serum creatinine concentrations compared with rats receiving saline alone and also exhibited development of cell lesions in the pars recta of the tubules in the outer stripe of the outer medulla. However, piperacillin (250 and 1,000 mg/kg) significantly (P less than 0.01 by multiple-comparison test) reduced these toxicological parameters in comparison with results for cisplatin alone. The protective effect of piperacillin was superior to that of fosfomycin, although platinum levels in the kidney were higher with the combination of cisplatin and piperacillin than with cisplatin plus fosfomycin. Although the nephrotoxicity of cisplatin was also reduced when cisplatin was administered concomitantly with sodium chloride in mole-equivalents to 250 and 1,000 mg of piperacillin per kg, its protective effect was less than that of the corresponding piperacillin dose. These results suggest that piperacillin may have a role as a protective agent against the nephrotoxicity of cisplatin. Images

Outer membrane permeation of Bacteroides fragilis by cephalosporins.

Outer membrane permeation of Bacteroides fragilis by cephalosporins was examined by a previously described method. The permeation parameters of cephalosporins in B. fragilis were close to 10(-5) cm3/min per microgram of cell dry weight. These values were about an order of magnitude lower than those in Escherichia coli. In B. fragilis, the permeation was not directly proportional to the hydrophilicity of cephalosporins, and the ion selectivity was weak.