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

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 μg/ml) and B. anthracis (MIC90 of 0.06 μg/ml). Omadacycline was less active in vitro than ciprofloxacin (CIP) against Y. pestis (CIP MIC90 of 0.03 μg/ml) but was more potent in vitro against B. anthracis (CIP MIC90 of 0.12 μg/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.

[1]  M. Albert,et al.  High prevalence of ciprofloxacin resistance amongst strains of Neisseria gonorrhoeae isolated from commercial sex workers in Bangladesh. , 1998, The Journal of antimicrobial chemotherapy.

[2]  J. Hartings,et al.  The automated bioaerosol exposure system: preclinical platform development and a respiratory dosimetry application with nonhuman primates. , 2004, Journal of pharmacological and toxicological methods.

[3]  Tanja Popovic,et al.  Investigation of Bioterrorism-Related Anthrax, United States, 2001: Epidemiologic Findings , 2002, Emerging infectious diseases.

[4]  P. Worsham,et al.  In Vitro Antibiotic Susceptibilities of Yersinia pestis Determined by Broth Microdilution following CLSI Methods , 2015, Antimicrobial Agents and Chemotherapy.

[5]  Shay Weiss,et al.  Lessons to be Learned from Recent Biosafety Incidents in the United States. , 2015, The Israel Medical Association journal : IMAJ.

[6]  S. Levy,et al.  Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline , 2015, Antimicrobial Agents and Chemotherapy.

[7]  X. Cui,et al.  Anthrax infection. , 2011, American journal of respiratory and critical care medicine.

[8]  H. Schweizer Mechanisms of antibiotic resistance in Burkholderia pseudomallei: implications for treatment of melioidosis. , 2012, Future microbiology.

[9]  S. Levy,et al.  In Vitro and In Vivo Antibacterial Activities of Omadacycline, a Novel Aminomethylcycline , 2013, Antimicrobial Agents and Chemotherapy.

[10]  F. Romesberg,et al.  Origins of Yersinia pestis Sensitivity to the Arylomycin Antibiotics and the Inhibition of Type I Signal Peptidase , 2015, Antimicrobial Agents and Chemotherapy.

[11]  K. R. May The collison nebulizer: Description, performance and application , 1973 .

[12]  J. Kaur,et al.  Forensic Odontology in the Management of Bioterrorism , 2013 .

[13]  M. Huband,et al.  Activity of omadacycline tested against Streptococcus pneumoniae from a global surveillance program (2014). , 2018, Diagnostic microbiology and infectious disease.

[14]  S. Levy,et al.  Mechanism of Action of the Novel Aminomethylcycline Antibiotic Omadacycline , 2013, Antimicrobial Agents and Chemotherapy.

[15]  J. Petersen,et al.  Comparative review of Francisella tularensis and Francisella novicida , 2014, Front. Cell. Infect. Microbiol..

[16]  A. Goel Anthrax: A disease of biowarfare and public health importance. , 2015, World journal of clinical cases.

[17]  Theresa L. Smith,et al.  Centers for Disease Control and Prevention Expert Panel Meetings on Prevention and Treatment of Anthrax in Adults , 2014, Emerging infectious diseases.

[18]  M. Huband,et al.  Activity of omadacycline tested against Enterobacteriaceae causing urinary tract infections from a global surveillance program (2014). , 2018, Diagnostic microbiology and infectious disease.

[19]  Philip K. Russell,et al.  Tularemia as a biological weapon: medical and public health management. , 2001, JAMA.

[20]  Philip K. Russell,et al.  Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. , 2000, JAMA.

[21]  Gina Pugliese,et al.  Anthrax as a Biological Weapon: Medical and Public Health Management , 1999 .

[22]  Laura A. Muruato,et al.  Recent Advances in Burkholderia mallei and B. pseudomallei Research , 2015, Current Tropical Medicine Reports.

[23]  Mary Jane Ferraro,et al.  Performance standards for antimicrobial susceptibility testing : twelfth informational supplement , 2002 .

[24]  J. Ezzell,et al.  Antibiotic Treatment of Experimental Pneumonic Plague in Mice , 1998, Antimicrobial Agents and Chemotherapy.

[25]  R. Doi,et al.  The stability of messenger ribonucleic acid during sporulation in Bacillus subtilis. , 1971, The Journal of biological chemistry.

[26]  Mary Jane Ferraro,et al.  Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically : approved standard , 2000 .

[27]  B. Currie Melioidosis: Evolving Concepts in Epidemiology, Pathogenesis, and Treatment , 2015, Seminars in Respiratory and Critical Care Medicine.

[28]  P. Wayne PERFORMANCE STANDARDS FOR ANTIMICROBIAL SUSCEPTIBILITY TESTING, NINTH INFORMATIONAL SUPPLEMENT , 2008 .

[29]  A. C. Guyton,et al.  Measurement of the respiratory volumes of laboratory animals. , 1947, The American journal of physiology.

[30]  Douglas K Owens,et al.  Systematic Review: A Century of Inhalational Anthrax Cases from 1900 to 2005 , 2006, Annals of Internal Medicine.

[31]  W. J. Novick Development of in vitro susceptibility testing criteria and quality control parameters , 1989 .

[32]  Scott R. Lillibridge,et al.  Public Health Assessment of Potential Biological Terrorism Agents , 2002, Emerging infectious diseases.

[33]  B. Ivins,et al.  Determination of Antibiotic Efficacy against Bacillus anthracis in a Mouse Aerosol Challenge Model , 2007, Antimicrobial Agents and Chemotherapy.

[34]  Philip K. Russell,et al.  Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. , 1999, JAMA.