Eravacycline (TP-434) is efficacious in animal models of infection

Abstract

Eravacycline is a novel broad-spectrum fluorocycline antibiotic being developed for a wide range of serious infections. Eravacycline was efficacious in mouse septicemia models, demonstrating 50% protective dose (PD50) values of ≤ 1 mg/kg of body weight once a day (q.d.) against Staphylococcus aureus, including tetracycline-resistant isolates of methicillin-resistant S. aureus (MRSA), and Streptococcus pyogenes. The PD50 values against Escherichia coli isolates were 1.2 to 4.4 mg/kg q.d. In neutropenic mouse thigh infection models with methicillin-sensitive S. aureus (MSSA) and S. pyogenes, eravacycline produced 2 log10 reductions in CFU at single intravenous (i.v.) doses ranging from 0.2 to 9.5 mg/kg. In a neutropenic mouse lung infection model, eravacycline administered i.v. at 10 mg/kg twice a day (b.i.d.) reduced the level of tetracycline-resistant MRSA in the lung equivalent to that of linezolid given orally (p.o.) at 30 mg/kg b.i.d. At i.v. doses of 3 to 12 mg/kg b.i.d., eravacycline was more efficacious against tetracycline-resistant Streptococcus pneumoniae in a neutropenic lung infection model than linezolid p.o. at 30 mg/kg b.i.d. Eravacycline showed good efficacy at 2 to 10 mg/kg i.v. b.i.d., producing up to a 4.6 log10 CFU reduction in kidney bacterial burden in a model challenged with a uropathogenic E. coli isolate. Eravacycline was active in multiple murine models of infection against clinically important Gram-positive and Gram-negative pathogens.

FIG 1

Efficacy of eravacycline and comparators in murine lung infection models. Lung infection models were conducted as described in Materials and Methods. Each symbol represents an individual mouse, horizontal lines indicate the mean, and error bars indicate the standard error of the mean. (A) SP160 model. Closed circles, untreated controls at 0 and 24 h, relative to the start of treatment; light gray diamonds, 3 mg/kg i.v. eravacycline (ERV); medium gray diamonds, 6 mg/kg i.v. ERV; black diamonds, 12 mg/kg i.v. ERV; open diamonds, 30 mg/kg oral (p.o.) linezolid (LZD). (B) SA191 model. Closed circles, untreated controls at 0 and 24 h, relative to the start of treatment; light gray diamonds, 10 mg/kg i.v. ERV; dark gray squares, 50 mg/kg i.v. vancomycin (VAN); open diamonds, 30 mg/kg p.o. LZD.; **, statistically significant reduction versus 24 h untreated control, P < 0.01.

FIG 2

Efficacy of eravacycline and comparators in a mouse pyelonephritis model with uropathogenic, tet(B) tetracycline-resistant E. coli EC200. The pyelonephritis infection model was conducted as described in Materials and Methods. Each symbol represents an individual mouse, and the horizontal line indicates the mean. Error bars indicate the standard error of the mean. Closed circles, untreated controls at 0 and 24 h, relative to the start of treatment; light gray diamonds, 2 mg/kg i.v. ERV; medium gray diamonds, 5 mg/kg i.v. ERV; black diamonds, 10 mg/kg i.v. ERV; open diamonds, 2 mg/kg i.v. levofloxacin (LVX). Statistically significant reduction versus 24 h untreated control: *, P < 0.05; **, P < 0.01.