Pharmacodynamic assessment of ertapenem (MK-0826) against Streptococcus pneumoniae in a murine neutropenic thigh infection model

Abstract

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.

FIG. 1.

Population predicted concentrations versus concentrations observed by NONMEM analysis.

FIG. 2.

Goodness of fit between the NONMEM simulated ertapenem concentration-time profile after 50-mg/kg dosing and the mean observed serum ertapenem concentration-versus-time profile in the murine thigh infection model.

FIG. 3.

Densities of S. pneumoniae in the thighs of infected animals at the start of therapy. Each value represents 1 of 16 isolates and is the mean ± standard deviation for 8 thighs.

FIG. 4.

Growth in density of S. pneumoniae in the thighs of infected control animals over 24 h. Each value represents 1 of 16 isolates and is the mean ± standard deviation for 8 thighs.

FIG. 5.

Changes in density of S. pneumoniae in the thighs of infected animals after 24 h of ertapenem therapy. Each value represents 1 of 16 isolates and is the mean ± standard deviation for 8 thighs.

FIG. 6.

Sigmoid E_max evaluation of the correlation between T>MIC_free and the bactericidal activity of ertapenem. r² = 0.88.

FIG. 7.

Growth in density of S. pneumoniae (SP-129) in the thighs of infected immunocompromised (ICR) and immunocompetent (CBA/J) control animals over 24 h. Values are means ± standard deviations for 8 thighs.

FIG. 8.

Changes in density of S. pneumoniae (SP-129) in the thighs of infected immunocompromised (ICR) and immunocompetent (CBA/J) animals after 24 h of ertapenem therapy. Values are means ± standard deviations for 8 thighs.

FIG. 9.

Percentage of survival of pneumococcus-infected animals after 4 days of ertapenem treatment and 3 days posttreatment (n = 15). Each set of bars represents one S. pneumoniae isolate.