Pharmacogenomics of Cytauxzoon felis Cytochrome
            <i>b</i>
            : Implications for Atovaquone and Azithromycin Therapy in Domestic Cats with Cytauxzoonosis

Schreeg, Megan E.; Marr, Henry S.; Tarigo, Jaime L.; Cohn, Leah A.; Levy, Michael G.; Birkenheuer, Adam J.

doi:10.1128/jcm.01407-13

Cited by 19 publications

(21 citation statements)

References 23 publications

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“…Cytauxzoon felis cytb genotypes had been previously characterized using bidirectional sequencing. Any secondary nucleotide peaks present at a height of Ն30% of the primary nucleotide peak height on DNA sequence chromatograms were detected by a computer program and denoted using IUPAC ambiguity codes (Vector NTI; Invitrogen, Grand Island, NY) (22).…”

Section: Methodsmentioning

confidence: 99%

“…In related parasites, mutations in the putative atovaquone-binding site of cytb have been associated with responses to A&A treatment (19)(20)(21). A recent study identified a C. felis cytb genotype (cytb1) that was associated with increased survival rates in cats treated with A&A (22). Cats that were infected with this genotype (cytb1) and were treated with imidocarb dipropionate, which does not target cytb, did not have a significantly improved survival rate compared to imidocarb dipropionate-treated cats infected with non-cytb1 genotypes (22).…”

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confidence: 99%

“…A recent study identified a C. felis cytb genotype (cytb1) that was associated with increased survival rates in cats treated with A&A (22). Cats that were infected with this genotype (cytb1) and were treated with imidocarb dipropionate, which does not target cytb, did not have a significantly improved survival rate compared to imidocarb dipropionate-treated cats infected with non-cytb1 genotypes (22). Therefore, the improved survival rate of cats infected with C. felis cytb1 appears to be specifically associated with A&A treatment.…”

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confidence: 99%

“…Therefore, the improved survival rate of cats infected with C. felis cytb1 appears to be specifically associated with A&A treatment. It is not known whether this association is a direct result of the cytb1 nucleotide or amino acid sequence or whether cytb1 is simply a genetic marker of other mechanisms of susceptibility to A&A treatment (22). Identification of C. felis cytb1 in a clinical sample from a cat with cytauxzoonosis could provide useful prognostic information for a client deciding whether to pursue A&A therapy, which can cost thousands of dollars.…”

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confidence: 99%

“…While it is currently not known how many copies of the mitochondrial genome exist in C. felis organisms, up to 150 copies of the mitochondrial genome can exist within one nondividing haploid organism for related apicomplexan parasites (27). Characterization of C. felis cytb genotypes revealed heteroplasmic single-nucleotide polymorphisms (SNPs) in 16 of 30 C. felis cytb genotypes, representing 33% of total samples (23/69 samples) (22). Due to the rapid clinical course, high mortality rates, costs of treatment, and prevalence of heteroplasmy, an assay to detect C. felis cytb1 must be rapid, cost-effective, and sensitive enough to discriminate heteroplasmic SNPs.…”

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confidence: 99%

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Rapid High-Resolution Melt Analysis of Cytauxzoon felis CytochromebTo Aid in the Prognosis of Cytauxzoonosis

et al. 2015

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Cytauxzoon felis is a virulent, tick-transmitted, protozoan parasite that infects felines. Cytauxzoonosis was previously thought to be uniformly fatal in domestic cats. Treatment combining atovaquone and azithromycin (A&A) has been associated with survival rates of over 60%. Atovaquone, a ubiquinone analogue, targets C. felis cytochrome b (cytb), of which 30 unique genotypes have been identified. The C. felis cytb genotype cytb1 is associated with increased survival rates in cats treated with A&A. The purpose of this study was to design a PCR panel that could distinguish C. felis cytb1 from other cytochrome b genotypes. Primer pairs were designed to span five different nucleotide positions at which single-nucleotide polymorphisms in the C. felis cytb gene had been identified. Through the use of high-resolution melt analysis, this panel was predicted to distinguish cytb1 from other cytb genotypes. Assays were validated using samples from 69 cats with cytauxzoonosis for which the C. felis cytb genotypes had been characterized previously. The PCR panel identified C. felis cytb1 with 100% sensitivity and 98.2% specificity. High-resolution melt analysis can rapidly provide prognostic information for clients considering A&A treatment in cats with cytauxzoonosis. Cytauxzoonosis is an emerging disease in domestic and wild felids in North and South America, caused by the tick-transmitted apicomplexan parasite Cytauxzoon felis (1-8). Cytauxzoonosis was originally thought to be uniformly fatal in domestic cats (4, 5), but our understanding of the epidemiology of C. felis is evolving. Recent evidence indicates that some cats survive C. felis infections without any evidence of clinical disease and/or history of antiprotozoal therapy (9-13). Whether this change is due to increased recognition of subclinical infections, differences in infectious doses, alternative mechanisms of transmission, or differences in virulence between strains is unclear. For cats presented to veterinary hospitals with acute cytauxzoonosis, however, mortality rates remain high. Even with advances in treatment, mortality rates ranged from 40 to 74% in a prospective randomized clinical trial (14). In that study, atovaquone and azithromycin (A&A) treatment was associated with improved survival rates compared to imidocarb dipropionate treatment (14), which was previously considered the treatment of choice (15, 16). The majority of cats with acute cytauxzoonosis that die do so within 2 to 5 days after presentation (4,14). Given this rapid clinical course, it is critical to initiate A&A therapy as soon as possible.Azithromycin is thought to target the mitochondrial ribosomes of the parasite, while atovaquone is presumed to target protozoal cytochrome b (cytb), disrupting electron transport in the parasite mitochondria (17, 18). In related parasites, mutations in the putative atovaquone-binding site of cytb have been associated with responses to A&A treatment (19-21). A recent study identified a C. felis cytb genotype (cytb1) that was associated with increase...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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