In VivoEfficacy and PK/PD Modeling of KBP-7072, An Aminomethylcycline Antibiotic, in Neutropenic Pneumonia and Thigh Infection Models

Abstract

ABSTRACTKBP-7072 is a novel aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative multidrug resistant bacterial isolates and strains.Antibacterial activity and the PK/PD relationship were assessed usingin vivoinfection models. Six to 8-week-old female CD-1 mice were randomized to oral KBP-7072, minocycline and vehicle in aKlebsiella pneumoniaemurine model, and KBP-7072, linezolid and vehicle for aStreptococcus pneumoniaemurine model. Each animal was inoculated withK. pneumoniaeorS. pneumoniaeplaced on the tip of the nares. KBP-7072 and antibiotics were started 3 hours post inoculation and continued for 3 days forK. pneumoniae, and were started 18 hours post inoculation and continued for 3 days forS. pneumoniae. Animals were euthanized at 0 (control group), 24, 48 or 72 hours post final dose.In vivoefficacy and PK/PD parameters were determined inStaphylococcus aureusisolate (6424MRSA-363),K. pneumoniaeisolate (6680kpn-522), andE. coliisolate (6691eco-558) murine thigh infection models.In vivoefficacy and PK/PD parameters (fAUC/MIC,fCmax/MIC and %T>MICfree) were calculated. Respiratory infection occurred in all inoculated mice. KBP-7072 produced a significant (p<0.05 to <0.001) dose-dependent decrease in colony forming units (CFUs) at all doses and a dose-dependent increase in survival rate (p<0.001 vs. vehicle). The median survival in all KBP-7072-treated groups was significantly greater vs. comparators (p<0.001). These results demonstrate potentin vivoefficacy for KBP-7072 and determined that the AUC/MIC parameter was optimal for assessing bacteriostatic and bactericidal effects of KBP-7072.