title: 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.
abstract: 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 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 (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.
authors.affiliation: Bristol Centre for Antimicrobial Research & Evaluation, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom. alasdair.macgowan@nbt.nhs.uk
authors.forename: Alasdair P
authors.initials: AP
authors.lastname: MacGowan
authors.forename: Karen E
authors.initials: KE
authors.lastname: Bowker
authors.forename: Alan R
authors.initials: AR
authors.lastname: Noel
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial; D006801:Humans; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests / Q000379:methods / Q000592:standards; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development*; D014640:Vancomycin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; C492232:tomopenem; D014640:Vancomycin; D008712:Methicillin