Noncompromised penicillin-resistant pneumococcal pneumonia CBA/J mouse model and comparative efficacies of antibiotics in this model

Abstract

The present study confirms that CBA/J mice are susceptible to several clinical isolates of Streptococcus pneumoniae, including four of five penicillin-susceptible and all five penicillin-resistant strains tested, thus providing the first noncompromised animal model for penicillin-resistant S. pneumoniae pneumonia. In this model, doses of penicillin G of 0.6 mg/kg of body weight given six times at 1-h intervals produced effective pulmonary clearance of a penicillin-susceptible strain (penicillin G MIC, 0.015 microgram/ml), while doses of 40 mg/kg given six times at 1-h intervals were required to clear a penicillin-resistant strain (penicillin G MIC, 1 microgram/ml). Imipenem (MIC, 0.25 microgram/ml) was the most active antibiotic tested against the penicillin-resistant strain, with a calculated dose of 0.42 mg/kg given six times at 1-h intervals, resulting in a 2-log decrease in the number of pulmonary bacteria. Comparable effects were seen with vancomycin (MIC, 0.5 microgram/ml), cefotaxime (MIC, 0.5 microgram/ml), and penicillin G at doses of 3.3, 5.5, and 31.0 mg/kg given six times at 1-h intervals, respectively. The pharmacokinetic profile of vancomycin in infected lungs was superior to those of the other antibiotics, especially in regard to the elimination half-life (215.4 min for vancomycin versus 15.0, 14.5, and 14.5 min for penicillin G, cefotaxime, and imipenem, respectively). Both imipenem and vancomycin allowed 90% survival when 40-mg/kg doses were administered twice a day beginning 5 days after infection. Survival rates with penicillin G (160-mg/kg doses) and cefotaxime (40-mg/kg doses) were 40 and 30%, respectively, while no saline-treated mice survived. The present study shows that the CBA/J mouse pneumonia model may be useful for evaluating antibiotic efficacies against penicillin-resistant pneumococcal pneumonia in immunocompetent individuals. Our data suggest that imipenem and vancomycin may be the most active agents against penicillin-resistant S. pneumoniae pneumonia.

Assessment of the efficacy of telithromycin simulating human exposures against S. pneumoniae with ribosomal mutations in a murine pneumonia model

“…injections of cyclophosphamide 150 mg/kg (Cytoxan ® , Bristol-Myers Squibb) on days four and one prior to the inoculation of the mice. In order to compare with an infection established in the presence of functional white blood cells CBA/J mice were utilized [3]. This strain of mice has been shown to succumb to pneumococcal infection in the presence of an immune system and thus does not require cyclophosphamide induced neutropenia to establish infection.…”

In Vitro and Animal PK/PD Models

“…Overall the efficacy in rats with various penicillins was similar to those obtained in mice (Woodnut and Berry 1999). Neutropenic mice or normal CBA/J mice were used in some studies to be able to determine accurate efficacy values for penicillin-resistant strains (Tateda et al 1996;Scoriano 1996). Experimental pneumococcal pneumonia could also be induced by the aerosol route using an exposure chamber and a small particle nebulizer.…”

“…Many organisms will not grow well or actually die in normal nonneutropenic mice. For example, penicillin-resistant pneumococci will not grow in normal ICR/Swiss or CD1 mice, but they do grow well in normal CBA/J mice (Tateda et al 1996). It is recommended that an untreated organism grows at least 1.5 log 10 CFU/thigh over 24 h when non-neutropenic mice are to be used.…”

Low-dose aerosol model of pneumococcal pneumonia in the mouse: utility for evaluation of antimicrobial efficacy

“…Under the conditions of such a fulminant infection, it is possible that the outcome of therapy is determined primarily by attainable drug concentrations in serum rather than concentrations achieved at the site of primary infection in the lung parenchyma. Intranasal instillation of a smaller infectious dose (10 5 -10 6 CFUs) has been used successfully to create a more indolent infection, although a number of pneumococcal strains tested still resulted in mortality rates of 50% or greater within 96 h [15,16]. All of the above models are also disadvantageous in that each animal must be infected individually by skilled personnel, making the infection step especially labour intensive.…”