meropenem and tomopenem

Tomopenem (formerly CS-023), a novel 1beta-methylcarbapenem, exhibited high affinity for penicillin-binding protein (PBP) 2 in Staphylococcus aureus, PBP 2 in Escherichia coli, and PBPs 2 and 3 in Pseudomonas aeruginosa, which are considered major lethal targets. Morphologically, tomopenem induced spherical forms in E. coli and short filamentation with bulges in P. aeruginosa, which correlated with the drug's PBP profiles. The potential of resistance of these bacteria to tomopenem was comparable to that to imipenem.

Topics: Carbapenems; Escherichia coli; Microbial Sensitivity Tests; Mutation; Penicillin-Binding Proteins; Pseudomonas aeruginosa; Staphylococcus aureus

Tomopenem (formerly CS-023) is a novel 1beta-methylcarbapenem with broad-spectrum coverage of gram-positive and gram-negative pathogens. Its antibacterial activity against European clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa was compared with those of imipenem and meropenem. The MICs of tomopenem against MRSA and P. aeruginosa at which 90% of the isolates tested were inhibited were 8 and 4 microg/ml, respectively, and were equal to or more than fourfold lower than those of imipenem and meropenem. The antibacterial activity of tomopenem against MRSA was correlated with a higher affinity for the penicillin-binding protein (PBP) 2a. Its activity against laboratory mutants of P. aeruginosa with (i) overproduction of chromosomally coded AmpC beta-lactamase; (ii) overproduction of the multidrug efflux pumps MexAB-OprM, MexCD-OprJ, and MexEF-OprN; (iii) deficiency in OprD; and (iv) various combinations of AmpC overproduction, MexAB-OprM overproduction, and OprD deficiency were tested. The increases in the MIC of tomopenem against each single mutant compared with that against its parent strain were within a fourfold range. Tomopenem exhibited antibacterial activity against all mutants, with an observed MIC range of 0.5 to 8 microg/ml. These results suggest that the antibacterial activity of tomopenem against the clinical isolates of MRSA and P. aeruginosa should be ascribed to its high affinity for PBP 2a and its activity against the mutants of P. aeruginosa, respectively.

Topics: Carbapenems; Imipenem; Meropenem; Methicillin Resistance; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Staphylococcus aureus; Thienamycins

Tomopenem (CS-023) is a novel parenteral carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria, as well as potent activity against drug-resistant pathogens, including penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. We compared the in vivo activity of tomopenem and that of meropenem in a chronic lower respiratory infection mouse model of P. aeruginosa.. Mice with chronic airway infection by P. aeruginosa were treated with saline (as the control, twice daily), tomopenem (100 mg/kg, twice daily) or meropenem (100 mg/kg, twice daily) for 7 days. After treatment, the number of viable bacteria in lungs and histopathological findings were analysed. The pharmacokinetics of tomopenem and meropenem were also analysed after initial treatment.. The number of viable bacteria in lungs treated with saline, tomopenem or meropenem was 4.21 +/- 1.28, 2.91 +/- 0.87 and 3.01 +/- 1.00 log(10) cfu/lung (mean +/- SEM), respectively (P < 0.05, control versus tomopenem- or meropenem-treated groups). In the histopathological examination of lung specimens, the control group had the features of chronic bronchial infection; however, tomopenem- and meropenem-treated groups had fewer inflammatory cells compared with the control group. The pharmacokinetic parameter of % time above MIC for tomopenem and meropenem was 16% and 17% in sera and 15% and 18% in lungs, respectively.. Tomopenem significantly reduced the number of viable bacteria in a murine model of chronic airway infection by P. aeruginosa, compared with the control. Considering the longer half-life of tomopenem in humans compared with most other carbapenems, tomopenem treatment of chronic airway infection with P. aeruginosa is expected to be efficacious.

Topics: Animals; Anti-Bacterial Agents; Carbapenems; Colony Count, Microbial; Humans; Lung; Male; Meropenem; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Serum; Thienamycins

To characterize the renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, and meropenem in humans, we examined their affinities as substrates to human renal transporters. In vitro studies on the uptake of [14C]CS-023 and [14C]meropenem were conducted using HEK293 cells expressing human organic anion transporters (hOAT) 1, hOAT3, hOAT4, and the human organic cation transporters (hOCT) 1 and hOCT2. CS-023 did not serve as the substrate for any of the transporters tested. On the other hand, meropenem was transported by hOAT1 and hOAT3. The Km value of the hOAT3-mediated transport was 847 microM, and the uptake was inhibited by probenecid, p-aminohippurate and benzylpenicillin with Ki values of 3.76, 712, and 202 microM, respectively. One of the reasons why CS-023 is not a substrate of hOATs, and vice versa for meropenem, would be that a very small proportion of CS-023 exists as the anionic form at the physiological pH, whereas 50% of meropenem exists as the anionic form. These findings indicate that the lack of recognition of CS-023 by renal transporters is one of the reasons for its long plasma half-life in humans compared with meropenem which undergoes renal tubular secretion mediated by hOAT1 and hOAT3.

Topics: Algorithms; Anti-Bacterial Agents; Biological Transport, Active; Carbapenems; Carrier Proteins; Cationic Amino Acid Transporter 2; Cell Line; Humans; Kidney; Kinetics; Meropenem; Organic Anion Transport Protein 1; Organic Anion Transporters, Sodium-Independent; Organic Cation Transporter 1; Thienamycins

The plasma half-life of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, is longer than that of meropenem in animals and humans. To address this issue, renal clearance studies were conducted in rabbits. A constant rate infusion of CS-023 and meropenem was conducted in male Japanese White rabbits. Concentrations in the plasma, urine and renal cortex were measured to evaluate renal clearance and renal tissue uptake. CS-023 showed a clearance ratio (renal clearance/glomerular filtration rate) of around 1, which was not affected by co-administration of probenecid or p-aminohippurate. On the other hand, meropenem exhibited a clearance ratio of around 3, which was significantly decreased to 1 by co-administration of probenecid. p-Aminohippurate, in contrast, had no effect. The renal cortex/plasma concentration ratio of CS-023 was around 0.6 with or without probenecid co-administration. This ratio of meropenem was around 3, which was decreased significantly by co-administration of probenecid to around 0.6. These data suggest that meropenem is secreted in the renal tubules via organic anion transporters, but CS-023 is not. The present findings in rabbits would indicate that a lack of renal tubular secretion of CS-023 is a reason for the long plasma half-life compared with meropenem.

Topics: Animals; Carbapenems; In Vitro Techniques; Kidney; Kidney Cortex; Kidney Tubules; Male; Meropenem; Metabolic Clearance Rate; Microsomes; Models, Animal; Rabbits; Thienamycins