Pharmacodynamic Assessment of Clarithromycin in a Murine Model of Pneumococcal Pneumonia

Abstract

The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 10 8 -CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored. The bacterial density in lung tissues was examined after 24 h of CLR treatment and in control groups. Pharmacokinetic analysis of CLR in mice demonstrated that the regimen of 150 mg/kg twice a day was representative of human pharmacokinetics and was used to compare the efficacy of CLR against sensitive and resistant S. pneumoniae strains. Immunocompetent CBA/J mice were also infected and treated as described above and evaluated for bacterial density and survival to assess the effect of the presence of leukocytes. All three pharmacodynamic parameters, the duration (percent) of the time that serum CLR concentrations remain above the MIC (%T>MIC), the ratio of the area under the concentrationtime curve from 0 to 24 h (AUC 0-24 ) to the MIC, and the ratio of the maximum concentration of drug in serum to the MIC, were found to be closely correlated to CLR bacterial efficacy (P < 0.001). Furthermore, all parameters had close correlation to bacterial density (r 2 ‫؍‬ 0.72 to 0.82), median survival (r 2 ‫؍‬ 0.93 to 0.94), and total percent survival (r 2 ‫؍‬ 0.91 to 0.92). These in vivo data suggest that the bacterial activity of CLR is closely correlated with all three parameters over a wide range of exposures and, as a consequence of parameter interdependency, AUC 0-24 /MIC is the most reasonable predictor of antibiotic efficacy. In this neutropenic pneumonia model, CLR was less efficacious against S. pneumoniae strains for which MICs were >4 g/ml. However, the presence of leukocytes in the immunocompetent mice resulted in improved bactericidal activity, relative to that in the neutropenic animals, despite an MIC of 4 g/ml.

Comparison of clarithromycin and ciprofloxacin therapy for Bacillus anthracis Sterne infection in mice with or without 60Co gamma-photon irradiation

“…2 ml of diluent, twice daily for 21 days. A previous study showed that this regimen provides human-simulated exposures in the murine pneumonia model for the parent compound CLR (Tessier et al, 2002). For administration per os, special feeding cannulas were used with small ball tips, and then cleaned and sterilized in self-sealing pouches.…”

“…Plasma samples were stored frozen at À70 8C until assayed using a validated HPLC methodology at the Center for Anti-Infective Research and Development, Hartford Hospital (Tessier et al, 2002).…”

Bactericidal Efficacy of ABI-0043, a Novel Rifamycin, in a Murine Pneumococcal Pneumonia Model

“…All isolates were maintained in skim milk medium (BD Biosciences, Sparks, Md.) at Ϫ80°C and subcultured twice on trypticase soy agar with 5% sheep blood (BD Biosciences) before use in in vitro and in vivo experiments [8]. MICs of NCEs and rifampin were determined against S. pneumoniae strains SPN 21, SPN 95, and SPN 100 in triplicate using standard CLSI (previously NCCLS) methods [11].…”

“…Mice were rendered neutropenic by IP injection of cyclophosphamide (Cytoxan; Bristol-Myers Squibb, Princeton, N.J.) 150 mg/kg at four days and 100 mg/kg at 1 day prior to inoculation [13,14]. Pneumonia was induced via oropharyngeal inoculation of a 0.05 ml suspension of SPN 100 prepared from an inoculum adjusted to approximately 10 8 CFU/ml as described previously [8]. By 8 to 16 hours post inoculation, all animals showed signs of infection including rough coat appearance and limited mobility.…”

“…A group of 6 control mice was sacrificed just prior to initiation of dosing and at the time of lung harvest (at 6 hours for the single dose groups and at 24 hours for groups receiving 3 doses) for each treatment regimen. Lungs were aseptically removed and individually homogenized in 1.0 ml of normal saline as described previously [8]. Serial dilutions of homogenate were plated on trypticase soy agar with 5.0% sheep blood and subsequently incubated at 35°C for 24 In the untreated control groups, both the 0 and 6 hours CFU levels in lung tissue were consistent between runs, starting at 10 6 to 10 7 CFU with an increase by about 1 log 24 hours post inoculation.…”