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Antimicrobial Agents and Chemotherapy, April 2008, p. 1401-1406, Vol. 52, No. 4
0066-4804/08/$08.00+0 doi:10.1128/AAC.01153-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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
Alasdair P. MacGowan,*
Karen E. Bowker, and
Alan R. Noel
Bristol Centre for Antimicrobial Research & Evaluation, Department of Medical Microbiology, Southmead Hospital, Bristol, United Kingdom
Received 31 August 2007/ Returned for modification 8 November 2007/ Accepted 23 January 2008
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; methicillin-sensitive 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 106 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, 108 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 108 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 (AUBKC24) 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 AUBKC24 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 2x and 4x 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.
* Corresponding author. Mailing address: Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol & North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom. Phone: 44(0)117 959 5651. Fax: 44(0)117 959 3154. E-mail: alasdair.macgowan{at}nbt.nhs.uk
Published ahead of print on 28 January 2008.
Antimicrobial Agents and Chemotherapy, April 2008, p. 1401-1406, Vol. 52, No. 4
0066-4804/08/$08.00+0 doi:10.1128/AAC.01153-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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