Project leader: Michelle Nelson, PhD
Contract value: $4,288,600
Project dates: September 2015 - September 2019
Unless you’ve traveled in southeast Asia or northern Australia, you may not be familiar with melioidosis. Caused by the bacterium Burkholderia pseudomallei, melioidosis is widespread in these tropical areas, where people become infected by contact with contaminated soil or water. Up to 40% of infected patients die.1
Also called Whitmore’s disease, melioidosis can be tricky to diagnose, as it can cause a variety of diverse symptoms, which may appear from one day to many years after exposure.2 Patients may have lung infections from mild bronchitis to severe pneumonia, mimicking tuberculosis, or other bacterial pneumonias or infections. Clinical symptoms may depend on how the person was exposed to B. pseudomallei.3
Though not spread through human or animal contact, melioidosis is considered a high-priority potential biological threat agent;4 its close relative Burkholderia mallei was used as a bioweapon during World War I.5 Research on this pathogen requires high-containment laboratories (biosafety level 3, or BSL-3). There is no vaccine, and treatment with antibiotics is lengthy and difficult because of the bacterium’s inherent antibiotic resistance—it is "impervious to all but a few antibiotics."6
In this Medical Countermeasures Initiative (MCMi) regulatory science project, the Defence Science and Technology Laboratory (Dstl), which is part of the United Kingdom’s Ministry of Defence, will compare how effective different antibiotics are against melioidosis acquired by different routes of exposure—inhaled vs. swallowed, for example.
Dstl will test three antibiotics that are generally recommended for use against naturally occurring melioidosis: co-trimoxazole (a combination of trimethoprim and sulfamethoxazole), co-amoxiclav (a combination of amoxicillin and clavulanic acid), and meropenem. A pioneer in nonclinical testing and aerosol exposure, Dstl has more than 50 years of experience with threat agents requiring special handling, such as BSL-3 and -4 high containment.
This nonclinical testing may provide data that could be used in human clinical trials, such as informing whether a treatment that is effective against melioidosis in a naturally exposed population, such as rice farmers in southeast Asia, would also be an effective medical countermeasure in a melioidosis biological attack situation.
This project will examine a previously unstudied route of melioidosis infection (ingestion), and assess the pharmacokinetics (PK)—how drugs move within the body—of selected antibiotics. Tasks include:
- Developing an ingestion model of melioidosis, and comparing this model to other routes of infection
- Determining the PK profile of three antibiotics, and assessing efficacy of these antibiotics for different routes of exposure to melioidosis
- Analyzing data from previous U.S. government-funded studies, and comparing to human data
This work builds on previous studies funded by agencies including the Biomedical Advanced Research and Development Authority (BARDA) and the National Institutes of Health (NIH) in the Department of Health and Human Services (HHS), and the Defense Threat Reduction Agency (DTRA) and the Joint Project Management Office-Medical Countermeasure Systems (JPM-MCS) in the Department of Defense. FDA and other agencies coordinate federal medical countermeasure efforts as part of the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE).
This project was funded through the MCMi Regulatory Science Extramural Research program.
Michelle Nelson, Alejandro Nunez, et al. The lymphatic system as a potential mechanism of spread of melioidosis following ingestion of Burkholderia pseudomallei. PLOS Neglected Tropical Diseases. 2021 Feb 22. DOI: https://doi.org/10.1371/journal.pntd.0009016
Dance, D. Treatment and prophylaxis of melioidosis. Int J Antimicrob Agents. 2014 Feb 03;43:310-318. DOI: 10.1016/j.ijantimicag.2014.01.005
Limmathurotsakul D, Golding N,Dance D, Messina J, Pigott D, Moyes C, et al. Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis. Nat Microbiol. 2016 Jan 11 [cited 2016 Jan 12];1. DOI: 10.1038/nmicrobiol.2015.8 Available from: http://www.nature.com/articles/nmicrobiol20158
Lipsitz R, Garges S, Aurigemma R, et al. Workshop on Treatment and Postexposure Prophylaxis for Burkholderia pseudomallei and B. mallei Infection. Emerg Infect Dis. Epub 2012 Dec;18(12). Available from: http://wwwnc.cdc.gov/eid/article/18/12/12-0638_article
Nelson M, Salguero FJ,Dean RE, et al. Comparative experimental subcutaneous glanders and melioidosis in the common marmoset (Callithrix jacchus). Int J Exp Pathol. 2014 Dec;95(6):378-91. DOI: 10.1111/iep.12105
Nelson M, Dean RE, Salguero FJ, et al. Development of an acute model of inhalational melioidosis in the common marmoset (Callithrix jacchus). Int J Exp Pathol. 2011;92:428-35. DOI: 10.1111/j.1365-2613.2011.00791.x
Sivalingham SP, Sim SH, Jasper LC, et al. Pre- and post-exposure prophylaxis of experimental Burkholderia psuedomallei infection with doxycycline, amoxicillin/clavulanic acid and co-trimoxazole. J Antimicrob Chemother. 2008 Mar;61(3):674-8. DOI: 10.1093/jac/dkm527
2 CDC: Melioidosis [Internet]. Atlanta: Centers for Disease Control and Prevention (US). Health Care Workers, Diagnosis. 2012 Jan 6 [cited 2015 Aug 27]. Available from: http://www.cdc.gov/melioidosis/health-care-workers.html
3 Poe RH, Vassallo CL, Domm BM. Meliodosis: The remarkable imitator. Am Rev Respir Dis. 1971;104:427-31. Available from: http://www.atsjournals.org/doi/pdf/10.1164/arrd.19184.108.40.2067 (PDF, 539 KB)
42014 Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan [Internet]. [Washington]: Department of Health and Human Services (US); 2014 [cited 2015 Aug 27]; p. 9. Available from: http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf (PDF, 3.1 MB)
6 Stone R.