Pharmacodynamic assessment of ertapenem (MK-0826) against Streptococcus pneumoniae in a murine neutropenic thigh infection model.
The objective of this study was to determine the susceptibility breakpoint of a new carbapenem, ertapenem (MK-0826), against Streptococcus pneumoniae strains based on bacterial density and survival studies in a murine thigh infection model. Sixteen S. pneumoniae isolates for which MICs ranged from 0.015 to 4.0 mg/liter were tested with neutropenic ICR mice. Animals were infected with bacteria at 10(5) to 10(6) CFU per thigh and were treated with ertapenem starting at 2 h postinfection for 4 days. Ertapenem was given subcutaneously at 50 mg/kg of body weight every 6 h, which simulates the human pharmacodynamic profile (in particular, the duration of time that the concentration of free drug remains above the MIC of 2 mg/liter). At 0 and 24 h postinfection, thighs were harvested for bacterial density determination. Survival was assessed during 4 days of therapy and 3 days after the therapy. A protein binding study was conducted with mice by use of the ultrafiltration method. Protein binding in mice was approximately 95%, which is comparable to that in humans. The average change in bacterial density ranged from -0.22 to -4.4 log CFU per thigh over 24 h compared to 0-h controls. The extent of microbial eradication was dependent on the MIC for the S. pneumoniae isolate. Substantial bactericidal activities (i.e., killing of approximately 2 log CFU per thigh) were consistently observed against isolates for which MICs were <or=2 mg/liter, which also resulted in nearly 100% survival during the 4 days of drug dosing and 3 days after the therapy. Less-pronounced and highly variable bactericidal activities were detected against isolates for which the MIC was 4 mg/liter. Substantial enhancement in bactericidal activity was observed for CBA/J mice and is attributed to the contribution of the host defenses in the immunocompetent species. Assessment of the effectiveness of ertapenem by bacterial-density reduction over 24 h and by survival over 4 days of therapy in the murine thigh infection model reveals that the drug maintains maximal efficacy against S. pneumoniae isolates for which the MIC of this agent is <or=2 mg/liter.
Xuan
Dawei
D
Department of Pharmacy Research, Hartford Hospital, Hartford, Connecticut 06102, USA.
Banevicius
Maryanne
M
Capitano
Blair
B
Kim
Myo-Kyoung
MK
Nightingale
Charles
C
Nicolau
David
D
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077727:Ertapenem; D005260:Female; D007769:Lactams; D051379:Mice; D008813:Mice, Inbred ICR; D009135:Muscular Diseases / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D009503:Neutropenia / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D011485:Protein Binding; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D016019:Survival Analysis; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D007769:Lactams; D047090:beta-Lactams; D000077727:Ertapenem