In Vitro and In Vivo Antibacterial Activities of CS-023 (RO4908463), a Novel Parenteral Carbapenem

Koga, Tetsufumi; Abe, Tomomi; Inoue, Harumi; Takenouchi, Takashi; Kitayama, Akiko; Yoshida, Tadao; Masuda, Nobuhisa; Sugihara, Chika; Kakuta, Masayo; Nakagawa, Miyuki; Shibayama, Takahiro; Matsushita, Yasuyuki; Hirota, Takashi; Ohya, Satoshi; Utsui, Yukio; Fukuoka, Takashi; Kuwahara, Syogo

doi:10.1128/aac.49.8.3239-3250.2005

Cited by 48 publications

(40 citation statements)

References 16 publications

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“…Treatment guidelines for these infections recommend specific antibiotics or combinations of antibiotics against these pathogens (1,28). Of all the ␤-lactams, carbapenems have the broadest spectra of antibacterial activity; tomopenem (formerly CS-023), a novel 1␤-methylcarbapenem, exhibits activity against diverse hospital pathogens, including MRSA and P. aeruginosa isolated in the United States and Japan (9,33). In a previous clinical trial in healthy volunteers, tomopenem (27) showed a longer half-life (1.7 h) than imipenem (IPM)-cilastatin (1.0 h) (22) and meropenem (MEM) (0.9 h) (26).…”

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

Koga

Masuda

Kakuta

et al. 2008

Antimicrob Agents Chemother

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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.

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

Koga

Masuda

Kakuta

et al. 2008

Antimicrob Agents Chemother

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“…The MIC 50 and MIC 90 against methicillin-sensitive S. aureus (MSSA) are 0.12 and 0.12 to 0.25 mg/liter (17,19,32). For methicillin-resistant S. aureus (MRSA), the MIC 50 and MIC 90 are 2 and 4 to 16 mg/liter (17,19,32). This contrasts to imipenem and meropenem, which have MRSA MIC 90 values of 32 and 16 to 32 mg/liter.…”

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“…Tomopenem retains in vitro potency against extended-spectrum ␤-lactamase-producing Escherichia coli and Klebsiella spp. as well as Pseudomonas aeruginosa (8,17,19,33).The pharmacokinetics studies with male healthy volunteers indicate relatively typical carbapenem pharmacokinetics except for a prolonged serum half-life of about 2 h, which is related to a lack of renal tubular secretion (29). Tomopenem is stable to digestion by human renal DHP-1 (18) and produces peak serum concentrations of about 44 mg/liter after a 700-mg dose and 100 mg/liter after a 1,400-mg dose in humans (29).…”

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“…It has a guanidine-pyrrolidine side chain and binds with high affinity to penicillin binding protein 1 (PBP1), PBP2, and PBP4 from Staphylococcus aureus. The MIC 50 and MIC 90 against methicillin-sensitive S. aureus (MSSA) are 0.12 and 0.12 to 0.25 mg/liter (17,19,32). For methicillin-resistant S. aureus (MRSA), the MIC 50 and MIC 90 are 2 and 4 to 16 mg/liter (17,19,32).…”

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confidence: 99%

“…Tomopenem retains in vitro potency against extended-spectrum ␤-lactamase-producing Escherichia coli and Klebsiella spp. as well as Pseudomonas aeruginosa (8,17,19,33).…”

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Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of Staphylococcus aureus Infection

MacGowan

Bowker

Noel

2008

Antimicrob Agents Chemother

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The antibacterial effects (ABE) of tomopenem (formerly RO4908463/CS-023) against seven Staphylococcus aureus strains (methicillin-resistant S. aureus [MRSA] strain tomopenem MICs, 0.5 to 16 mg/liter; methicillinsensitive S. aureus [MSSA] strain tomopenem MIC, 0.06 mg/liter) were studied in an in vitro pharmacokinetic model. Initially, two human doses were simulated, 750 mg every 8 hours (8hly) and 1,500 mg 8hly intravenously, using S. aureus at a standard inoculum of 10 6 CFU/ml. There was a rapid clearance of bacteria from the model by 12 h after drug exposure with most strains. Clearance was not related to the tomopenem MIC. The ABE of these two tomopenem dose regimens were also tested at a high inoculum, 10 8 CFU/ml; in all simulations, there was a >4-log drop in viable count at 24 h. Strains were not cleared from the model at 10 8 CFU/ml, in contrast to what was seen for the standard inoculum. When the ABE of tomopenem at 750 mg 8hly was compared to those of vancomycin, tomopenem was seen to have a superior effect, as measured by the area under the bacterial kill curve at 24 h (AUBKC 24 ) and 48 h (P < 0.05). Dose ranging studies were performed to provide time-above-MIC (T>MIC) drug exposures of 0 to 100% (8 to 10 doses per strain) with five MRSA/MSSA strains. The T>MIC for a 24-h bacteriostatic effect was 8% ؎ 5% (range, 1.3% to 15.4%); the T>MIC for a 4-log drop in viable count was 32% ؎ 18% (range, 12.8% to 36.2%). The T>MIC for a 90% maximum response using AUBKC 24 as ABE was 24.9% ؎ 15.7%. Inoculum had little impact on T>MIC exposures for ABE. There was emergence of resistance to tomopenem in the dose ranging studies, with increased growth of subpopulations on plates containing tomopenem at 2؋ and 4؋ the MIC compared to what was seen for preexposure population analysis at T>MICs of <20%. The pharmacodynamics of tomopenem against S. aureus is similar to those of other members of the carbapenem class, with the exception that MRSA is included. These data indicate that tomopenem will have clinically useful activity against MRSA at T>MICs achievable in humans.Tomopenem (formerly RO4908463/CS-023) is an injectable 2-substituted 1-␤-methyl carbapenem. It has a guanidine-pyrrolidine side chain and binds with high affinity to penicillin binding protein 1 (PBP1), PBP2, and PBP4 from Staphylococcus aureus. The MIC 50 and MIC 90 against methicillin-sensitive S. aureus (MSSA) are 0.12 and 0.12 to 0.25 mg/liter (17,19,32). For methicillin-resistant S. aureus (MRSA), the MIC 50 and MIC 90 are 2 and 4 to 16 mg/liter (17,19,32). This contrasts to imipenem and meropenem, which have MRSA MIC 90 values of 32 and 16 to 32 mg/liter. Tomopenem retains in vitro potency against extended-spectrum ␤-lactamase-producing Escherichia coli and Klebsiella spp. as well as Pseudomonas aeruginosa (8,17,19,33).The pharmacokinetics studies with male healthy volunteers indicate relatively typical carbapenem pharmacokinetics except for a prolonged serum half-life of about 2 h, which is related to a lack of renal tubular secretion (29). Tomop...

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β‐Lactam Antibiotics

Testero

Fisher

Mobashery

2010

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β‐lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β‐lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β‐lactam resistance, alterations to the molecular targets of the β‐lactams (the penicillin binding proteins) and the use of enzymes (the β‐lactamases) capable of the hydrolytic deactivation of the β‐lactams are paramount. This review traces the historical development of β‐lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β‐lactams leading to the discovery of new generation β‐lactam antibacterials effective against the Gram‐negative and ‐positive bacterial pathogens of current medical concern.

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In Vitro and In Vivo Antibacterial Activities of CS-023 (RO4908463), a Novel Parenteral Carbapenem

Cited by 48 publications

References 16 publications

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

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

Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of Staphylococcus aureus Infection

β‐Lactam Antibiotics

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