Efficacy of SCH27899 in an animal model of Legionnaires' disease using immunocompromised A/J mice

Abstract

The efficacy of SCH27899, a new everninomicin antibiotic, against replicative Legionella pneumophila lung infections in an immunocompromised host was evaluated using a murine model of Legionnaires' disease. A/J mice were immunocompromised with cortisone acetate and inoculated intratracheally with L. pneumophila serogroup 1 (10(5) CFU per mouse). At 24 h postinoculation, mice were administered either SCH27899 (6 to 60 mg/kg [MPK] intravenously) or a placebo once daily for 5 days, and mortality and intrapulmonary growth of L. pneumophila were assessed. In the absence of SCH27899, there was 100% mortality in L. pneumophila-infected mice, with exponential intrapulmonary growth of the bacteria. In contrast, administration of SCH27899 at a dose of > or =30 MPK resulted in > or =90% survival of infected mice, which was associated with inhibition of intrapulmonary growth of L. pneumophila. In subsequent studies, the efficacy of SCH27899 was compared to ofloxacin (OFX) and azithromycin (AZI). Administration of SCH27899, OFX, or AZI at a dose of > or =30 MPK once daily for 5 days resulted in > or =85% survival of infected mice and inhibition of intrapulmonary growth of the bacteria. However, L. pneumophila CFU were recovered in lung homogenates following cessation of therapy with all three antibiotics. These studies demonstrate that SCH27899 effectively prevents fatal replicative L. pneumophila lung infection in immunocompromised A/J mice by inhibition of intrapulmonary growth of the bacteria. However, in this murine model of pulmonary legionellosis, SCH27899, like OFX and AZI, was bacteriostatic.

FIG. 1

Intrapulmonary growth of L. pneumophila in immunocompetent and immunocompromised A/J mice. A/J mice were administered CA (100 MPK) or an equivalent volume of saline subcutaneously and inoculated IT with L. pneumophila (10⁵ CFU/mouse). At specific time points p.i. mice were humanely euthanized, lungs were excised, and intrapulmonary L. pneumophila was quantified by culture of lung homogenates. Results represent the mean of bacteria in the lungs of 4 to 6 mice per time point. ∗, significantly enhanced growth compared to similarly infected competent mice.

FIG. 2

Effect of SCH27899 (30 or 60 MPK OD for 5 days) on intrapulmonary growth of L. pneumophila. A/J mice were administered CA (100 MPK) subcutaneously and inoculated IT with L. pneumophila (10⁵ CFU/mouse). At 24 h p.i., immunocompromised infected mice were administered SCH27899 (30 or 60 MPK i.v. OD) for 5 days or an equivalent volume of placebo for 5 days. Mice were subsequently humanely euthanized at 6 or 10 days p.i., lungs were excised and homogenized, and intrapulmonary L. pneumophila was quantified by culture of lung homogenates. Results represent the mean of bacteria in the lungs of 6 to 8 mice per time point. ∗, significantly less growth compared to similarly infected compromised untreated mice.

FIG. 3

Effect of SCH27899, AZI, or OFX on intrapulmonary growth of L. pneumophila. A/J mice were administered CA (100 MPK) subcutaneously and inoculated IT with L. pneumophila (10⁵ CFU/mouse). At 24 h p.i., infected mice were administered either SCH27899 (30 MPK i.v.), OFX (30 MPK p.o.), or AZI (30 MPK p.o.) for 5 days or an equivalent volume of placebo for 5 days. Mice were subsequently humanely euthanized at 7 or 10 days p.i., lungs were excised and homogenized, and intrapulmonary L. pneumophila was quantified by culture of lung homogenates. Results represent the mean of bacteria in the lung of 7 to 8 mice per time point. ∗, significantly less growth compared to similarly infected mice administered placebo; t, significantly enhanced growth compared to AZI.