Efficacy of Co-Trimoxazole against Experimental Melioidosis Acquired by Different Routes of Infection

Abstract

Burkholderia pseudomallei is the causative agent of melioidosis and presents with diverse clinical manifestations. Naturally occurring infection occurs following contamination of cuts or skin abrasions, or ingestion of contaminated water, and occasionally through inhalational of infected soil or water particles.

Marmosets as models of infectious diseases

“…Taken together, these findings provide additional evidence to support the use of the marmoset model of melioidosis for assessing medical countermeasures. Encouragingly, these findings regarding HLA-DR, CD54 and CD16 were also observed in a more recent, related study with B. pseudomallei (Nelson et al, 2022a).…”

“…Two studies (model development and characterization and therapeutic efficacy) Mouse, Guinea pigs, Rabbits, Cynomolgus monkey (Lever et al, 2008;Nelson et al, 2011b;Ben-Shmuel et al, 2018;Perry et al, 2020;Stratilo et al, 2020 Mouse, Goats, African green monkey, Rhesus monkey, Invertebrates (Woods, 2002;Nelson et al, 2011a;Rowland et al, 2012a;Soffler et al, 2012;Laws et al, 2013;Nelson et al, 2015;Ganesan et al, 2020;Nelson et al, 2021;Trevino et al, 2021;Nelson et al, 2022a;Ngugi et al, 2022)…”

“…Work from our research group has led to the development of a marmoset model of experimental melioidosis caused by three natural routes of exposure to B. pseudomallei, i.e., through broken skin, inhalation and ingestion (Nelson et al, 2011a;Nelson et al, 2015;Nelson et al, 2021;Nelson et al, 2022a;Ngugi et al, 2022). Clinically, this is important as the route of exposure, whilst often difficult to determine at disease presentation, is likely to impact on the efficacy of medical countermeasures.…”

“…Biocontainment concerns Tendency to develop chronic disease with granulomatous lesions (Nicholls, 1930;Stanton and Fletcher, 1932;Cottew et al, 1952;Laws and Hall, 1963;Narita et al, 1982;Thomas et al, 1990;Vesselinova et al, 1996;Najdenski et al, 2004;Warawa, 2010;Soffler et al, 2012;Soffler et al, 2014;Amemiya et al, 2017) Invertebrates Likely natural disease vectors Susceptible to infection; can infect naïve guinea pigs Limited number of studies High prevalence of B. pseudomallei in the environment makes it difficult to prove role of invertebrates as disease vectors (Kharbov et al, 1981;Sulaiman et al, 2000;O'quinn et al, 2001;Schell et al, 2008;Hasselbring et al, 2011;Fisher et al, 2012;Amemiya et al, 2017) (particularly) aerosol challenge and this may be due to the tendency for a decline in the proportion of neutrophils in the lung during the early stages of infection (Nelson et al, 2022a;Ngugi et al, 2022). Alternative explanations should not be disregarded.…”

“…Additional evidence implicating neutrophils as key players in early melioidosis include the association between excessively high or low neutrophil counts and poorer outcomes in humans, and the increased susceptibility of individuals with certain conditions (e.g., diabetes) associated with suboptimal neutrophil function (Chanchamroen et al, 2009;Saengmuang et al, 2014;Jenjaroen et al, 2015). With a marmoset-specific candidate biomarker indicative of infection (a reduction in neutrophil HLA-DR expression), our research group recently evaluated the efficacy of co-trimoxazole using the marmoset model of experimental melioidosis (Nelson et al, 2022a). In this study, animals were challenged by one of three exposure routes: inhalational, ingestion or subcutaneous.…”