Fluorocyclines. 1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: A Potent, Broad Spectrum Antibacterial Agent

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TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitro against a panel of 29 Francisella tularensis isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.5 g/ml, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 50% lethal doses (LD 50 )/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing with TP-271 at 3, 6, 12, and 18 mg/kg of body weight/day, initiating at 24 h postchallenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 h postchallenge, survival was 89%, 100%, 100%, and 100% in the 3-, 6-, 12-, and 18-mg/kg/day TP-271 groups, respectively. No mice treated with the vehicle control survived. Surviving mice treated with TP-271 showed little to no relapse during 14 days posttreatment. In a nonhuman primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1,144 CFU of F. tularensis SCHU S4. Once-daily intravenous infusion with 1 or 3 mg/kg TP-271, or vehicle control, for 21 days was initiated within 6 h of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days after the last treatment, whereas no vehicle control-treated animals survived. The protection and low relapse afforded by TP-271 treatment in these studies support continued investigation of TP-271 for use in the event of aerosolized exposure to F. tularensis.KEYWORDS TP-271, fluorocycline, tularemia, Francisella tularensis F rancisella tularensis, the causative agent of tularemia, is a small aerobic nonmotile Gram-negative coccobacillus capable of causing the zoonotic disease tularemia, naturally spread among mammals by ticks, flies, and mosquitoes (1, 2). Humans can become infected with F. tularensis by insect bites, handling infectious animal materials, direct contact with or ingestion of contaminated water, food, or soil, and inhalation of infective aerosols. Inhalation of as few as 10 organisms can cause disease, making F. tularensis subsp. tularensis (type A subspecies) one of the most infectious pathogenic bacteria known and a likely agent for a bioterrorist attack (3). Accordingly, this pathogen is categorized as a priority category A (tier 1) threat agent by the Centers for Disease Control and Prevention (CDC) because of the high likelihood that F. tularensis will be used as a bioweapon (2).Inhalation of F. tularensis bacteria causes pneumonia, respiratory failure, shock, and a high incidence of mortality (2, 4). Aerosol dispersion of F. tularensis is predicted to be

Section: Methodsmentioning

confidence: 99%

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques

Grossman

Anderson

Christ³

et al. 2017

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“…Eravacycline (formerly TP-434) is a novel, fully synthetic antibiotic of the tetracycline class (8). Eravacycline was designed to be active against the two main acquired tetracycline-specific resistance mechanisms, ribosomal protection and active drug efflux (9,10).…”

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confidence: 99%

“…In in vitro studies, the compound has shown potent activity against a broad spectrum of susceptible and multidrug-resistant bacteria, including Gram-negative, Gram-positive, and anaerobic bacteria (11). Eravacycline has a potency profile similar to that of carbapenems except that it more broadly covers Gram-positive pathogens, like methicillin-resistant Staphylococcus aureus and enterococci, is active against carbapenem-resistant Gram-negative bacteria, but is not active against Pseudomonas aeruginosa (8).…”

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confidence: 99%

Phase 2, Randomized, Double-Blind Study of the Efficacy and Safety of Two Dose Regimens of Eravacycline versus Ertapenem for Adult Community-Acquired Complicated Intra-Abdominal Infections

Solomkin

Ramesh

Česnauskas³

et al. 2014

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107

f Eravacycline is a novel fluorocycline, highly active against Gram-positive and Gram-negative pathogens in vitro, including those with tetracycline and multidrug resistance. This phase 2, randomized, double-blind study was conducted to evaluate the efficacy and safety of two dose regimens of eravacycline compared with ertapenem in adult hospitalized patients with complicated intraabdominal infections (cIAIs). Patients with confirmed cIAI requiring surgical or percutaneous intervention and antibacterial therapy were randomized (2:2:1) to receive eravacycline at 1.5 mg/kg of body weight every 24 h (q24h), eravacycline at 1.0 mg/kg every 12 h (q12h), or ertapenem at 1 g (q24h) for a minimum of 4 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 10 to 14 days after the last dose of study drug therapy. Overall, 53 patients received eravacycline at 1.5 mg/kg q24h, 56 received eravacycline at 1.0 mg/kg q12h, and 30 received ertapenem. For the ME population, the clinical success rate at the TOC visit was 92.9% (39/42) in the group receiving eravacycline at 1.5 mg/kg q24h, 100% (41/41) in the group receiving eravacycline at 1.0 mg/kg q12h, and 92.3% (24/26) in the ertapenem group. The incidences of treatment-emergent adverse events were 35.8%, 28.6%, and 26.7%, respectively. Incidence rates of nausea and vomiting were low in both eravacycline groups. Both dose regimens of eravacycline were as efficacious as the comparator, ertapenem, in patients with cIAI and were well tolerated. These results support the continued development of eravacycline for the treatment of serious infections, including those caused by drug-resistant Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01265784.)

“…Antibiotics and media. Eravacycline was synthesized at Tetraphase Pharmaceuticals as described in Xiao et al (11). Tigecycline for injection (Pfizer, Groton, CT) was purchased from Skenderian Apothecary, Cambridge, MA.…”

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confidence: 99%

Eravacycline (TP-434) Is Efficacious in Animal Models of Infection

Grossman

Murphy²,

Slee³

et al. 2015

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