Cytauxzoon felis is an emerging tick-transmitted protozoan parasite of domestic and wild felids. Cytauxzoonosis is typically fatal in clinical cases without aggressive treatment. Combination treatment with atovaquone and azithromycin (A&A) along with supportive care has improved survival rates to over 60%; in contrast, survival rates with imidocarb dipropionate are 26%. Parasite resistance to atovaquone via a cytochrome b parasite gene (cytb) mutation has been identified in other protozoans and is a concern for C. felis. Specifically, mutations at the M128 amino acid position of the putative atovaquone binding site on cytb have been associated with resistance.

We aimed to characterize the atovaquone binding region of cytb in samples from a C. felis-infected domestic cat that remained parasitemic despite treatment with atovaquone and azithromycin. An approximately nine-year-old, female spayed domestic shorthair was presented for adoption assessment; the cat was anemic, which persisted despite fenbendazole and doxycycline treatment. Comprehensive infectious disease testing detected C. felis via microscopy and polymerase chain reaction (PCR). Atovaquone (15 mg/kg PO q 8 h x 10 days) and azithromycin (10 mg/kg PO q 24 h x 10 days) treatment were administered, and the PCV improved, but the cat remained persistently infected with C. felis. Sequencing of the atovaquone binding region of cytb over the course of infection (pre- and post-treatment samples) would reveal a transition from wild-type (M128) to isoleucine and valine (M128I and M128V) at 2 and 4 months post-treatment. A repeat treatment course with A&A using an increased atovaquone dose (25 mg/kg PO q 8 h x 10 days) would fail to clear the C. felis infection and M128I and M128V mutations persisted. The wild-type M128 cytb was not detected in post-treatment samples up to 210 days.

This is the first documentation of resistance of C. felis to atovaquone associated with M128 cytb mutations. Additionally, this carrier cat appears to be the first chronically C. felis-infected felid with persistent anemia. This case suggests that parasites with mutations of cytb M128 can be selected and impart resistance to A&A treatment even in the face of increased atovaquone dosing.

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