EMBARGOED UNTIL: Thursday, September 12, 11:00 AM MDT
(Session 143, Paper B-1058)
LRRI, Albuquerque, NM, United States
Scientists report that plazomicin, a novel antibiotic designed to overcome multidrug resistance, is able to cure lethal tularemia in a primate model of the disease. These results were presented to support the development of plazomicin as a potential treatment for pneumonic tularemia under the FDA’s Animal Rule, the path for introducing new antibacterial agents against potential bioterrorism threats like tularemia.
The studies were performed by the developer of plazomicin, Achaogen, Inc. (South San Francisco), in collaboration with Lovelace Respiratory Research Institute, and conducted at Lovelace’s specialized biosafety level 3 research facility located near Albuquerque, New Mexico. The project was funded by the Biomedical Advanced Research and Development Authority (BARDA), an office under the Assistant Secretary for Public Health and Emergency Preparedness at the U.S. Department of Health and Human Services. The results were presented on September 12th at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy in Denver, Colorado.
Pneumonic tularemia is a serious, often fatal disease caused by inhalation of the bacterium Francisella tularensis. The pathogen is widespread in our environment, including in animal vectors and soil and water, and can cause skin infections due contact with contaminated soil or animal and tick bites. The bacterium was first identified in 1912 following reports of a plague like illness in ground squirrels in Tulare County, California, its namesake. About 100-200 cases of tularemia (rabbit fever) are reported each year in people, with a fatality rate of around 5-10%. However, the pneumonic form of the disease, caused by inhalation of the bacteria into the lungs, occurs only rarely but is a more deadly form of the disease, resulting in >50% mortality if left untreated. A very small number of bacteria (10 or fewer) are enough to cause disease if inhaled into the lungs. Thus, the potential for aerosolized F. tularensis to be used as a bioweapon has been recognized by the U.S. government and led to heightened interest in the development of new treatments. The current recommended treatments for tularemia are streptomycin and gentamicin, both members of the aminoglycoside class of antibiotics. Plazomicin is also an aminoglycoside antibiotic, but was designed by Achaogen to defeat bacterial resistance mechanisms that inactivate existing members of this class. While plazomicin is currently under clinical development for treatment for serious multi-drug resistant infections in hospitalized patients, tularemia, and in particular pneumonic tularemia, is too rare to study clinically. Thus studies must be conducted in non-human primate animal models that mimic the human form of the disease in order to demonstrate effectiveness.
These studies were the first time plazomicin has been assessed in a non-human primate model of tularemia. Since the most effective therapy course was unknown, the researchers varied both the amount of drug from 1/6 to 2/3 of the human dose of plazomicin proposed for other serious bacterial infections, and the duration of the therapy, for as few as 5 days to as long as 10 days (10-14 days is the proposed duration of plazomicin treatment for other serious bacterial infections). After the animals were exposed to the bacteria into their lungs, they were watched for the onset of a fever, a sign of active infection, prior to the start of antibiotic treatment. In addition, a set of animals was left untreated to confirm the lethality of the infection. While all of these untreated animals died of pneumonic tularemia within 10 days, no plazomicin treated animals succumbed to the disease. Survival occurred regardless of doses or durations of the plazomicin therapy tested. To push the limits of plazomicin’s effectiveness one step further, the researchers also held back treatment of plazomicin in one set of animals for a full 24 hours after the start of fever, in order to assess the drug’s ability to treat more advanced disease. Even after this delay of treatment, all of the plazomicin treated animals survived. This new result is very encouraging, and suggests that plazomicin could be an important treatment in the event of a bioterror attack by weaponized Francisella tularensis. Because plazomicin was designed to overcome multi-drug resistance, it could be particularly important if the weaponized strain were resistant to older antibiotics.