Comparison of 2 Antibiotics That Inhibit Protein Synthesis for the Treatment of Infection with<i>Yersinia pestis</i>Delivered by Aerosol in a Mouse Model of Pneumonic Plague

Heine, Henry S.; Louie, Arnold; Sörgel, Fritz; Bassett, Jennifer; Miller, Loren M.; Sullivan, Lawrence J.; Kinzig‐Schippers, Martina; Drusano, George L.

doi:10.1086/520547

Cited by 27 publications

(30 citation statements)

References 15 publications

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“…in uninfected mice (not shown). The pharmacokinetics of doxycycline have been previously reported; 40 mg/kg administered twice a day (24-h total of 80 mg/kg) yielded an approximate 24-h AUC of 107 g · h/ml and was predicted to be efficacious based on successful outcomes in other infection models (18).…”

Section: Resultsmentioning

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

Antimicrob Agents Chemother

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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

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Section: Resultsmentioning

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

Antimicrob Agents Chemother

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“…The calculated inhaled dose for each mouse was 1.02 ϫ 10 6 CFU or 15 LD 50 . Doses in this range have been used previously for successful aerosol Y. pestis challenge (3,36,75).…”

Section: Resultsmentioning

confidence: 99%

Effective Plague Vaccination via Oral Delivery of Plant Cells Expressing F1-V Antigens in Chloroplasts

et al. 2008

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“…Using controlled conditions, we showed that a subtherapeutic antimicrobial regimen in conjunction with AGPs provided nearly 100 % protection against a challenge with 200 LD 50 Y. pestis CO92. Currently, only streptomycin, tetracycline or doxycycline are approved by the United States Food and Drug Administration for treatment of plague, although it has been shown that gentamicin and levofloxacin are equally effective when given early to infected mice (Heine et al, 2007;Inglesby et al, 2000). Previous results demonstrate that aggressive gentamicin treatment at 12 mg (kg body weight)…”

Section: Discussionmentioning

confidence: 99%

Induction of innate immunity by lipid A mimetics increases survival from pneumonic plague

et al. 2008

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This study analysed the effect of priming the innate immune system using synthetic lipid A mimetics in a Yersinia pestis murine pulmonary infection model. Two aminoalkyl glucosaminide 4-phosphate (AGP) Toll-like receptor 4 (TLR4) ligands, delivered intranasally, extended time to death or protected against a lethal Y. pestis CO92 challenge. The level of protection was dependent upon the challenge dose of Y. pestis and the timing of AGP therapy. Protection correlated with cytokine induction and a decreased bacterial burden in lung tissue. AGP protection was TLR4-dependent and was not evidenced in transgenic TLR4-deficient mice. AGP therapy augmented with subtherapeutic doses of gentamicin produced dramatically enhanced survival. Combined, these results indicated that AGPs may be useful in protection of immunologically naive individuals against plague and potentially other infectious agents, and that AGP therapy may be used synergistically with other therapies.

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Comparison of 2 Antibiotics That Inhibit Protein Synthesis for the Treatment of Infection withYersinia pestisDelivered by Aerosol in a Mouse Model of Pneumonic Plague

Abstract: Doxycycline behaves in vivo as a bacteriostatic drug, requiring an intact immune system for clearance of the infection after aerosol challenge with Y. pestis. Gentamicin is bactericidal, even when given on a daily schedule. Neutropenia did not significantly affect survivorship.

Cited by 27 publications

References 15 publications

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

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

Effective Plague Vaccination via Oral Delivery of Plant Cells Expressing F1-V Antigens in Chloroplasts

Induction of innate immunity by lipid A mimetics increases survival from pneumonic plague

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