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Antimicrobial Agents and Chemotherapy, March 2000, p. 489-495, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vitro Activities of Novel trans-3,5-Disubstituted Pyrrolidinylthio-1beta -Methylcarbapenems with Potent Activities against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa

Rie Nagano, Kaneyoshi Shibata, Yuka Adachi, Hideaki Imamura, Terutaka Hashizume,* and Hajime Morishima

Banyu Tsukuba Research Institute, Okubo 3, Tsukuba 300-2611, Japan

Received 29 June 1999/Returned for modification 14 October 1999/Accepted 27 November 1999

The in vitro activities of the novel 1beta -methylcarbapenems J-111,225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a trans-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 µg/ml (MICs at which 90% of isolates are inhibited [MIC90s]), respectively, indicating that these agents were 32- to 64-fold more potent than imipenem, which has an MIC90 of 128 µg/ml. Although these drugs were less active in vitro than vancomycin, which had MIC90s of 1 and 2 µg/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Clostridium difficile, as well as MRSA, the novel carbapenems are worthy of further evaluation.

* Corresponding author. Mailing address: Banyu Tsukuba Research Institute, Okubo 3, Tsukuba 300-2611, Japan. Phone: 81-298-77-2000. Fax: 81-298-77-2029. E-mail: haszmett{at}banyu.co.jp.

Antimicrobial Agents and Chemotherapy, March 2000, p. 489-495, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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