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Abstract
The facultative intracellular bacterium Rhodococcus equi, commonly causes pneumonia in foals. Mortality is 30% despite recommended combination antimicrobial therapy with a macrolide and rifampin. Over the past decade, the incidence of macrolide resistant R. equi in foals has increased. The aminoglycoside antibiotic gentamicin is highly active against R. equi but has limited clinical efficacy due to poor cellular penetration. Encapsulation of drugs in liposomes can enhance their cellular uptake. The broad objectives of this work were to 1) Assess the genotypic variation of macrolide resistance in R. equi isolates originating from a single farm, 2) compare the cellular uptake and efficacies of liposomal gentamicin (LG) and free gentamicin (FG) against R.equi in vitro and in vivo, and 3) to compare the pharmacokinetics and tolerability of LG and FG in healthy foals. Culture, sensitivity and genotyping by rep-PCR on tracheobronchial aspirates from foals and air samples indicated emergence of widespread macrolide and rifampin resistance in R. equi within one equine breeding farm. Resistant isolates formed 2 distinct genotypic clusters whereas there was more heterogeneity among susceptible isolates. Percentage of cultured equine alveolar macrophages containing intracellular LG was over 90% significantly greater than the % containing FG after 4, 24 and 48 hours incubation. Athymic nude mice infected with R. equi 103S and treated with LG had significantly lower concentrations of bacteria in the spleen and liver compared to mice treated with FG or placebo. In healthy foals, after IV administration, LG had a significantly greater plasma half-life and volume of distribution compared with FG. Peak gentamicin concentrations in BAL cells were significantly higher for LG compared with FG when administered by either intravenous (5.27 2.67 vs. 2.98 1.67 g/ml) or nebulized (4.47 2.66 vs. 1.49 0.57 g/ml) routes. LG was well tolerated and indices of renal injury were not significantly different from those of foals administered FG. Liposomal encapsulation enables higher intracellular gentamicin concentrations to be achieved and as such, LG warrants further investigation for the treatment of infections in foals caused by intracellular pathogens such as R. equi.