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Antimicrobial Agents and Chemotherapy, January 2009, p. 319-322, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.00595-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Tomopenem (CS-023/RO4908463) against Anaerobic Bacteria{triangledown}

Kaori Tanaka,1* Hiroshige Mikamo,2 Kenichi Nakao,1 Taku Ichiishi,1 Takatsugu Goto,1 Yuka Yamagishi,2 and Kunitomo Watanabe1

Division of Anaerobe Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan,1 Department of Infection Control and Prevention, Aichi Medical University, 21 Karimata, Yazako, Nagakute-cho, Aichi-gun, Aichi 480-1195, Japan2

Received 7 May 2008/ Returned for modification 7 June 2008/ Accepted 17 October 2008


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ABSTRACT
 
The antianaerobic activity of tomopenem, a new longer-half-life parenteral carbapenem, was compared with other carbapenems. Tomopenem showed broad activity against 63 reference species. The activity of tomopenem against 293 clinical isolates was potent (MIC90, 0.06 to 4 µg/ml) and comparable to those of meropenem and doripenem and more potent than that of panipenem.


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INTRODUCTION
 
Tomopenem (CS-023/RO4908463) is a new parenteral carbapenem with a long half-life. It is a 2-substituted 1-β-methyl carbapenem with a unique guanidine-pyrrolidine side chain. Pharmacokinetic studies indicate that tomopenem has a longer half-life (about 2 h) than those of launched carbapenem (about an hour), such as imipenem-cilastatin and meropenem (6, 9, 11). Ertapenem, one of the new parenteral carbapenems, also has a prolonged plasma half-life of about 5 h, largely due to its high protein binding of >95% (13). As for tomopenem, it is reported that its low affinity to renal transporters is one of the reasons for its long plasma half-life in humans (10). Tomopenem has a broad spectrum of activity against gram-positive and gram- negative aerobic organisms, including methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae, and Pseudomonas aeruginosa (5, 6, 14). Tomopenem was also reported to be active against Bacteroides fragilis, but its activity against other anaerobic bacteria is unknown. We evaluated the in vitro activity of tomopenem against anaerobic gram-positive and gram-negative species.

For the investigation of the anaerobic antibacterial spectrum, a total of 69 gram-positive and gram-negative reference strains (63 species in 24 genera) of anaerobic bacteria and some fastidious microaerophilic anaerobes were examined. Those reference strains include strains obtained from ATCC, DSM, JCM (Japan Collection of Microorganisms), NCTC, and VPI (Virginia Polytechnic Institute and State University, Blacksburg), and some characteristic clinical strains belong to GAI, the culture collection of our laboratory. A total of 293 clinical strains isolated from various sources (including intra-abdominal infection, head and neck space infection, pleuropulmonary infection, and skin and soft tissue infection) between 2000 and 2006 were also studied. Isolates were identified by standard criteria (3, 4, 12).

The antimicrobial agents used in this study were obtained as powders of known potency from their respective manufacturers and are as follows: tomopenem and panipenem (Daiichi Sankyo Co., Ltd., Tokyo, Japan), meropenem (Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan), and doripenem and metronidazole (Shionogi & Co., Ltd., Osaka, Japan).

The MICs were determined by an agar dilution method in accordance with NCCLS document M11-A6 (8). Brucella HK agar (Kyokuto Pharmaceutical Industrial Co., Ltd., Tokyo, Japan) supplemented with 5% laked sheep blood was used as the test medium. Brucella HK agar contains hemin (10 µg/ml) and vitamin K1 (10 µg/ml) in its formula to support growth of fastidious anaerobes. A total of 105 CFU/spot of test strains was inoculated and incubated at 35°C in an anaerobic chamber (82% N2, 10% CO2, 8% H2). B. fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29741, and Eggerthella lenta ATCC 43055 were used as quality control strains.

The results of the susceptibility test on the reference strains are listed in Table 1. Overall, tomopenem showed broad and potent activities against various reference species, comparable to those of other carbapenems, and was more potent than metronidazole. Tomopenem inhibited most of the reference strains at or below the concentration of 1 µg/ml, while it was not active against carbapenemase-producing B. fragilis (strains GAI 30079 and GAI 30144).


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  		TABLE 1. Antimicrobial activities of tomopenem and other reference compounds against anaerobic bacteria and facultative anaerobic bacteria

Table 2 shows the in vitro activities of tomopenem and reference agents against clinical strains frequently isolated in anaerobic infections. These results are expressed as MIC range, MIC50s, and MIC90s. Among the clinical isolates, tomopenem showed potent activity against anaerobic gram-negative species. Tomopenem showed potent activity against species of the Bacteroides fragilis group that are often found in surgical infections. The MIC50s and MIC90s of tomopenem against B. fragilis and other B. fragilis group strains were 0.25 to 0.5 µg/ml and 1 to 4 µg/ml, respectively. Tomopenem inhibited all other investigated gram-negative strains at or below 1 µg/ml. Its activity against gram-negative species was comparable to those of meropenem and doripenem and more potent than that of panipenem. The investigated agents showed similar activities against anaerobic gram-positive cocci. MIC50 and MIC90 against Finegoldia magna, Parvimonas micra, and Peptoniphilus asaccharolyticus were ≤0.015 to 0.25 and 0.06 to 0.5 µg/ml, respectively. Although carbapenems are not used against Clostridium difficile infections, tomopenem showed the most potent activity among the carbapenems tested, with MIC50s and MIC90s of 1 and 2 µg/ml. The most potent agent against C. difficile was metronidazole, with MIC50s and MIC90s of 0.5 and 1 µg/ml, respectively.


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  		TABLE 2. In vitro activity of tomopenem and other reference compounds against clinical isolates of anaerobic bacteria

The reported antianaerobic activities of ertapenem (1, 2, 7, 15) were comparable to those of tomopenem measured in this study. This study demonstrates that tomopenem has potent activity that is comparable to other carbapenems against clinically important gram-positive and gram-negative anaerobic bacteria. Most anaerobic infections are polymicrobial and involve both aerobes and anaerobes. It has been reported that tomopenem is the agent with broad and potent activities against aerobic bacteria (5, 6, 14) and with the longer half-life (9). These reports and our in vitro data indicate the potential role of tomopenem in those polymicrobial infections. Further in vivo studies are necessary to demonstrate this point.


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FOOTNOTES
 
* Corresponding author. Mailing address: Division of Anaerobe Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan. Phone: 81-58-230-6555. Fax: 81-58-230-6551. E-mail: kktb{at}gifu-u.ac.jp Back

{triangledown} Published ahead of print on 27 October 2008. Back


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Antimicrobial Agents and Chemotherapy, January 2009, p. 319-322, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.00595-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.




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