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Title: Theileria equi isolates vary in susceptibility to imidocarb dipropionate but demonstrate uniform in vitro susceptibility to a bumped kinase inhibitor

item HINES, SIDDRA - Washington State University
item RAMSAY, JOSHUA - Washington State University
item Kappmeyer, Lowell
item LAU, AUDREY - Washington State University
item OJO, KAYODE - University Of Washington
item VANVOORHIS, WESLEY - University Of Washington
item Knowles Jr, Donald
item MEALEY, ROBERT - Washington State University

Submitted to: Parasites & Vectors
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/17/2014
Publication Date: 1/20/2015
Citation: Hines, S.A., Ramsay, J.D., Kappmeyer, L.S., Lau, A.O., Ojo, K.K., Vanvoorhis, W., Knowles Jr, D.P., Mealey, R.H. 2015. Theileria equi isolates vary in susceptibility to imidocarb dipropionate but demonstrate uniform in vitro susceptibility to a bumped kinase inhibitor. Parasites & Vectors. doi: 10.1186/s13071-014-0611-6.

Interpretive Summary: Theileria causes a persistent infection of equine erythrocytes. Infection of horses with T. equi is exotic to the United States. Occasionally U. S. horses are found to be infected with T. equi. One important option to owners of infected horses is treatment that eliminates T. equi infection and therefore transmission risk. Data in this report show that some T. equi infections are resistant to current treatment with imidocarb dipropionate and explore the possibilities of bumped kinase inhibitors in the treatment of imidocarb dipropionate resistant T. equi.

Technical Abstract: The apicomplexan hemoparasite Theileria equi is a causative agent of equine piroplasmosis, eradicated from the United States in 1988. However, recent outbreaks have sparked renewed interest in treatment options for infected horses. Imidocarb dipropionate is the current drug of choice, however variation in clinical response to therapy has been observed. Herein, we quantified the invitro susceptibility of multiple T. equi isolates to both imidocarb dipropionate and a bumped kinase inhibitor compound 1294. We also evaluated the capacity of in vitro imidocarb dipropionate exposure to decrease susceptibility to that drug. The efficacy of imidocarb dipropionate for clearing infection in four T. equi infected ponies was also assessed. We observed an almost four-fold difference in imidocarb dipropionate susceptibility between two distinct isolates of T. equi. Four ponies infected with the less susceptible USDA Florida strain failed to clear the parasite despite two rounds of treatment. Importantly, a further 15-fold decrease in susceptibility was produced in this strain by continuous in vitro imidocarb dipropionate exposure. Despite a demonstrated difference in imidocarb dipropionate susceptibility, there was no difference in the susceptibility of two T. equi isolates to bumped kinase inhibitor 1294. The observed variation in imidocarb dipropionate susceptibility, further reduction in susceptibility caused by drug exposure in vitro, and failure to clear T. equi infection in vivo, raises concern for the emergence of drug resistance in clinical cases undergoing treatment. Bumped kinase inhibitors may be effective as alternative drugs for the treatment of resistant T. equi parasites.