PT - JOURNAL ARTICLE AU - Xiaojuan Tan AU - Min Zhang AU - Qingmei Liu AU - Ping Wang AU - Tian Zhou AU - Vincent Benn AU - Fred Yang TI - <em>In Vivo</em> Efficacy and PK/PD Modeling of KBP-7072, An Aminomethylcycline Antibiotic, in Neutropenic Pneumonia and Thigh Infection Models AID - 10.1101/2020.03.18.998112 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.03.18.998112 4099 - http://biorxiv.org/content/early/2020/03/20/2020.03.18.998112.short 4100 - http://biorxiv.org/content/early/2020/03/20/2020.03.18.998112.full AB - KBP-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 using in vivo infection models. Six to 8-week-old female CD-1 mice were randomized to oral KBP-7072, minocycline and vehicle in a Klebsiella pneumoniae murine model, and KBP-7072, linezolid and vehicle for a Streptococcus pneumoniae murine model. Each animal was inoculated with K. pneumoniae or S. pneumoniae placed on the tip of the nares. KBP-7072 and antibiotics were started 3 hours post inoculation and continued for 3 days for K. pneumoniae, and were started 18 hours post inoculation and continued for 3 days for S. pneumoniae. Animals were euthanized at 0 (control group), 24, 48 or 72 hours post final dose. In vivo efficacy and PK/PD parameters were determined in Staphylococcus aureus isolate (6424MRSA-363), K. pneumoniae isolate (6680kpn-522), and E. coli isolate (6691eco-558) murine thigh infection models. In vivo efficacy and PK/PD parameters (fAUC/MIC, fCmax/MIC and %T&gt;MICfree) were calculated. Respiratory infection occurred in all inoculated mice. KBP-7072 produced a significant (p&lt;0.05 to &lt;0.001) dose-dependent decrease in colony forming units (CFUs) at all doses and a dose-dependent increase in survival rate (p&lt;0.001 vs. vehicle). The median survival in all KBP-7072-treated groups was significantly greater vs. comparators (p&lt;0.001). These results demonstrate potent in vivo efficacy for KBP-7072 and determined that the AUC/MIC parameter was optimal for assessing bacteriostatic and bactericidal effects of KBP-7072.