Pharmacokinetic and pharmacodynamic evaluation of the atypical tetracyclines chelocardin and amidochelocardin in murine infection models

Abstract

ABSTRACT The quest for novel anti-infectives against drug-resistant pathogens of the so-called ESKAPE panel is accompanied by intensive research aiming to find treatment options for the future. In this study, we evaluated the pharmacokinetics and pharmacodynamics of the two atypical tetracyclines: chelocardin (CHD) and amidochelocardin (CDCHD). Although CHD was in phase II clinical trials in the 1970s against urinary tract infections (UTI), CDCHD is a novel derivative obtained by biosynthetic engineering. A pharmacokinetic evaluation in uninfected, non-neutropenic CD-1 outbred mice using intravenous, peroral, and subcutaneous routes showed that CHD had higher plasma exposure than CDCHD but underwent an epimerization that was not observed for CDCHD. CDCHD showed persistently high exposure levels in urine lasting for more than 24 hours, whereas CHD urine concentrations decreased faster over time. Pharmacodynamic characterization in the neutropenic thigh infection model with K. pneumoniae and E. coli as challenge pathogens in CD-1 outbred mice proved that CHD was more effective in reducing bacterial burden in the thigh, in particular against E. coli, whereas CDCHD effectively reduced bacterial burden in kidneys affected by hematogenous seeding from the primary inoculation site, that is, thigh. Assessment of both atypical tetracyclines in an ascending UTI model with bladder as the primary inoculation site against gentamicin as positive control revealed high effectiveness of CDCHD. In summary, CDCHD warrants further preclinical exploration for the indication of UTI. IMPORTANCE There is a strong need to find novel treatment options against urinary tract infections associated with antimicrobial resistance. This study evaluates two atypical tetracyclines, namely chelocardin (CHD) and amidochelocardin (CDCHD), with respect to their pharmacokinetics and pharmacodynamics. We show CHD and CDCHD are cleared at high concentrations in mouse urine. Especially, CDCHD is highly effective in an ascending urinary tract infection model, suggesting further preclinical evaluation.

Keywords

• tetracycline
• urinary tract infection
• Klebsiella pneumoniae
• Escherichia coli
• PK/PD
• chelocardin