In Vitro and In Vivo Activity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis.

PHARMACOLOGY crossm In Vitro and In Vivo Activity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis Judith Steenbergen,a S. Ken Tanaka,a Lynda L. Miller,b Stephanie A. Halasohoris,b Jeremy R. Hershfieldb Paratek Pharmaceuticals, King of Prussia, Pennsylvania, USAa; Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAb ABSTRACT The in vitro activity and in vivo efficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague, Bacillus anthracis and Yersinia pestis, respectively. MICs of OMC were determined by broth microdilution according to CLSI guidelines for 30 isolates each of Y. pestis and B. anthracis. The in vivo efficacy of omadacycline was studied at a range of dosages in both a postexposure prophylaxis (PEP) murine model of anthrax and plague as well as in a delayed treatment model of inhalational anthrax. Omadacycline was active in vitro against Y. pestis (MIC90 of 1 ␮g/ml) and B. anthracis (MIC90 of 0.06 ␮g/ml). Omadacycline was less active in vitro than ciprofloxacin (CIP) against Y. pestis (CIP MIC90 of 0.03 ␮g/ml) but was more potent in vitro against B. anthracis (CIP MIC90 of 0.12 ␮g/ ml). In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control (P ⫽ 0.004). The median survival for the vehicle-treated controls was 6 days postchallenge, while all antibiotic-treated mice survived the entire study. Omadacycline treatment with 5, 10, or 20 mg/kg of body weight twice daily for 14 days had significant efficacy over the vehicle control in the treatment of aerosolized B. anthracis. Additionally, for postexposure prophylaxis treatment of mice infected with Y. pestis, the survival curves for omadacycline (40 mg/kg twice daily), ciprofloxacin, and doxycycline cohorts differed significantly from the vehicle control (P ⬍ 0.0001). Omadacycline is potent and demonstrates efficacy against both B. anthracis and Y. pestis. The well-characterized oral and intravenous pharmacokinetics, safety, and tolerability warrant further assessment of the potential utility of omadacycline in combating these serious biothreat organisms. Received 14 November 2016 Returned for modification 10 December 2016 Accepted 5 February 2017 Accepted manuscript posted online 21 February 2017 Citation Steenbergen J, Tanaka SK, Miller LL, Halasohoris SA, Hershfield JR. 2017. In vitro and in vivo activity of omadacycline against two biothreat pathogens, Bacillus anthracis and Yersinia pestis. Antimicrob Agents Chemother 61:e02434-16. https://doi.org/10.1128/ AAC.02434-16. Copyright © 2017 Steenbergen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to Judith Steenbergen, . KEYWORDS anthrax, biothreat, omadacycline I n the past 15 to 20 years, the threat of bioterrorism has increased as a result of increasing political and economic unrest in many parts of the world (1, 2). The Centers for Disease Control and Prevention (CDC) has classified bioterrorism agents into three categories, based on their potential to cause severe disease that results in high rates of mortality and according to how readily these agents can be disseminated in the general population (3). Among the bioterrorism agents that pose the highest threat are Bacillus anthracis and Yersinia pestis, which are the causative pathogens for anthrax and plague, respectively. Current antibiotic treatment options against these category A biothreat pathogens are limited, and the potential for engineered antibiotic resistance is high; thus, new therapeutic options are needed for prophylaxis and treatment of the diseases caused by these pathogens (4–8). Few new oral antibiotics are in development for the treatment of biothreat pathogens, and those older agents that have been approved are facing increasing resistance problems and could face engineered resistance. May 2017 Volume 61 Issue 5 e02434-16 Antimicrobial Agents and Chemotherapy aac.asm.org 1 Steenbergen et al. Antimicrobial Agents and Chemotherapy TABLE 1 MIC values for 30 strains of B. anthracis and Y. pestis for omadacycline and comparators MIC (␮g/ml) Strain and parameter B. anthracis (30 strains) MIC range MIC50 MIC90 Y. pestis (30 strains) MIC range MIC50 MIC90 Omadacycline Ciprofloxacin Tetracycline Doxycycline ⬍0.03–0.06 0.03 0.06 0.03–0.25 0.06 0.12 ⬍0.03–1 ⬍0.03 0.12 0.03–0.06 0.03 0.06 0.12–2 1 1 0.004–0.06 0.015 0.03 0.25–2 0.5 2 0.06–2 0.5 1 As a class, tetracyclines have been used for over 60 years and have proven effective and well tolerated for the treatment of a variety of bacterial infections, including those caused by many of the bacterial pathogens considered to be high-priority biologic threats (plague and anthrax). However, reports of resistance to tetracyclines, including doxycycline, and to fluoroquinolones and beta-lactams have appeared in the literature, and these reports highlight the need for new treatment options for these biothreat agents (4). In addition, recent safety concerns for the fluoroquinolones potentially limits their utility (9). Omadacycline is a novel aminomethylcycline of the tetracycline family that is designed to overcome mechanisms of resistance to the tetracycline class (10–12). The extensive preclinical and clinical development program for omadacycline is based on its demonstrated potent activity against key pathogens for serious community-acquired infections, including methicillin-resistant Staphylococcus aureus, multidrug-resistant Streptococcus pneumoniae, Gram-negative aerobes, and atypical pathogens, and its lack of cross-resistance to older-generation tetracyclines and other antibiotic classes (13– 17). Omadacycline is currently in clinical development for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP) as oral and intravenous (i.v.) monotherapy. Because of its broad in vitro spectrum of activity, clinical profile, and oral bioavailability, omadacycline could be well suited for use in the treatment or postexposure prophylaxis (PEP) of infections of concern in both the biodefense and public health settings. This study evaluated the in vitro and in vivo activity of omadacycline against B. anthracis and Y. pestis. (This study was previously presented at the ASM Biodefense and Emerging Diseases Research Meeting, Washington, DC, 25 to 27 February 2013.) RESULTS In vitro findings. Omadacycline was active against B. anthracis (MIC90 of 0.06 ␮g/ml) and Y. pestis (MIC90 of 1 ␮g/ml). Omadacycline was less potent than ciprofloxacin against Y. pestis (MIC90 of 0.03 ␮g/ml) but slightly more active against B. anthracis (MIC90 of 0.12 ␮g/ml) (Table 1). In vitro activity of omadacycline was generally comparable to that of tetracycline and doxycycline. The distribution of MICs for B. anthrac (...truncated)