tomopenem and Bacterial-Infections

The objective of this study was to assess the impact of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite in humans. Thirty-two subjects were enrolled in an open-label, two-center study. Subjects were evenly assigned to one of four groups, based on creatinine clearance ranges of > or =80, 50 to 79, 30 to 49, and <30 ml/min. The drug was given as a single 1,500-mg constant-rate intravenous infusion over 60 min. There were no safety concerns with increasing renal dysfunction. Renal impairment had a significant impact on exposure of both tomopenem and its metabolite. Mean (+/- standard deviation) areas under the curve for tomopenem increased with decreasing renal function, from 191 +/- 35.2 to 1,037 +/- 238 microg.h/ml. The maximum concentration of drug in plasma (C(max)) increased with a maximum difference of 44% between the severe and normal groups. In contrast, the corresponding increase in C(max) of the metabolite was much higher, at 174%. Total body clearance was linearly correlated with creatinine clearance (R(2) = 0.97; P < 0.0001). Renal clearance for tomopenem decreased with increasing severity of disease, with mean values decreasing from 4.63 +/- 0.89 to 0.59 +/- 0.19 liters/h. The results of this study indicated a strong correlation between the creatinine clearance and total clearance of tomopenem. While renal impairment appeared to have a significant effect on the pharmacokinetics of tomopenem, an even greater effect was seen on the elimination of the inactive metabolite.

Topics: Adult; Aged; Bacterial Infections; Carbapenems; Creatinine; Female; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Renal Insufficiency

To compare the in vitro activities of the carbapenem, CS-023, four representative beta-lactam antibiotics and levofloxacin, against 970 Gram-positive or Gram-negative US clinical isolates.. Susceptibilities of bacteria chosen for their varying levels of resistance to the comparator agents were determined by NCCLS microdilution methodology.. CS-023 exhibited activity comparable to that of imipenem against most Gram-positive isolates, but was approximately 8-fold more potent against oxacillin-resistant staphylococci. It was comparable to meropenem against most Gram-negative isolates, but was 4- to 8-fold more potent against five isolates of meropenem-resistant Pseudomonas aeruginosa.. If tissue and body fluid concentrations >8 mg/L can safely be achieved, further studies of CS-023 are warranted to determine its clinical efficacy.

Topics: Anti-Infective Agents; Bacterial Infections; Carbapenems; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Oxacillin; Penicillin Resistance; Penicillins; Pseudomonas aeruginosa; Staphylococcus; United States