Potent In Vitro Activity of Tomopenem (CS-023) against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa

Abstract

Tomopenem (formerly CS-023) is a novel 1␤-methylcarbapenem with broad-spectrum coverage of grampositive 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 g/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 ␤-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 g/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.

Synergistic effect of emodin in combination with ampicillin or oxacillin against methicillin-resistantStaphylococcus aureus

“…First, positive detection of the mecA gene for MRSA, or methicillin-resistant gene product, namely penicillin binding protein PBP2a, is an advance preparation for demonstration of MRSA (Witte et al, 2007). Second, the treatment guidelines for these infections recommend combinations of antibiotics against these pathogenic organisms (Koga et al, 2008). To meet this need, various natural products were screened (Shuangsuo et al, 2006;Yan et al, 2009).…”

In Vivo Pharmacodynamic Activity of Tomopenem (formerly CS-023) against Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus in a Murine Thigh Infection Model

“…Tomopenem (formerly CS-023) is a novel parenteral carbapenem with broad-spectrum activities against diverse hospital pathogens, including P. aeruginosa and MRSA. Tomopenem has been reported to show potent activities against clinical isolates of P. aeruginosa and MRSA due to its strong activities against the various mutants of P. aeruginosa, such as OprDdeficient P. aeruginosa, its high level of expression of efflux pumps, and its high level of affinity for MRSA PBP2a (14).…”

In vitro activity of beta-lactam antibiotics to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)

“…However, the presence of the mecA gene per se does not always result in high MIC values against all beta-lactam antimicrobial agents, which has been shown by the development of the fifth generation of cephalosporins. As for the different cephalosporins, the affinity to PBP2a varies between the various carbapenems [15].…”