title: Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens.
abstract: TP-271 is a novel, fully synthetic fluorocycline antibiotic in clinical development for the treatment of respiratory infections caused by susceptible and multidrug-resistant pathogens. TP-271 was active in MIC assays against key community respiratory Gram-positive and Gram-negative pathogens, includingStreptococcus pneumoniae(MIC90= 0.03 µg/ml), methicillin-sensitiveStaphylococcus aureus(MSSA; MIC90= 0.25 µg/ml), methicillin-resistantS. aureus(MRSA; MIC90= 0.12 µg/ml),Streptococcus pyogenes(MIC90= 0.03 µg/ml),Haemophilus influenzae(MIC90= 0.12 µg/ml), andMoraxella catarrhalis(MIC90≤0.016 µg/ml). TP-271 showed activity (MIC90= 0.12 µg/ml) against community-acquired MRSA expressing Panton-Valentine leukocidin (PVL). MIC90values againstMycoplasma pneumoniae,Legionella pneumophila, andChlamydia pneumoniaewere 0.004, 1, and 4 µg/ml, respectively. TP-271 was efficacious in neutropenic and immunocompetent animal pneumonia models, generally showing, compared to the burden at the start of dosing, ~2 to 5 log10CFU reductions against MRSA,S. pneumoniae, andH. influenzaeinfections when given intravenously (i.v.) and ~1 to 4 log10CFU reductions when given orally (p.o.). TP-271 was potent against key community-acquired bacterial pneumonia (CABP) pathogens and was minimally affected, or unaffected, by tetracycline-specific resistance mechanisms and fluoroquinolone or macrolide drug resistance phenotypes.IMPORTANCERising resistance rates for macrolides, fluoroquinolones, and β-lactams in the most common pathogens associated with community-acquired bacterial pneumonia (CABP) are of concern, especially for cases of moderate to severe infections in vulnerable populations such as the very young and the elderly. New antibiotics that are active against multidrug-resistantStreptococcus pneumoniaeandStaphylococcus aureusare needed for use in the empirical treatment of the most severe forms of this disease. TP-271 is a promising new fluorocycline antibiotic demonstratingin vitropotency and nonclinical efficacy by intravenous and oral administration against the major pathogens associated with moderate to severe CABP.
authors.affiliation: Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA.
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.affiliation: Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Fyfe
authors.affiliation: Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA.
authors.forename: William
authors.initials: W
authors.lastname: O'Brien
authors.affiliation: International Health Management Associates, Inc., Schaumburg, Illinois, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Hackel
authors.affiliation: Southern Research Institute, Birmingham, Alabama, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Minyard
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Ken B
authors.initials: KB
authors.lastname: Waites
authors.affiliation: M360, Sherbrooke, Quebec, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Dubois
authors.affiliation: Vivisource Laboratories, Waltham, Massachusetts, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Murphy
authors.affiliation: Vivisource Laboratories, Waltham, Massachusetts, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Slee
authors.affiliation: University of North Texas Health Science Center, Fort Worth, Texas, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.affiliation: Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA.
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Sutcliffe
keywords: TP-271; community-acquired bacterial pneumonia; fluorocycline