Broad Antimicrobial Resistance in a Case of Relapsing Babesiosis Successfully Treated With Tafenoquine

Rogers, Ralph; Krause, Peter J.; Norris, Ashlyn M.; Ting, Michelle H.; Nagami, Ellen H.; Cilley, Brian; Vannier, Edouard

doi:10.1093/cid/ciac473

Cited by 18 publications

(14 citation statements)

References 11 publications

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“…Additionally, there is evidence that mutations in the equivalent residue (Y268) confer resistance to atovaquone in the related malarial parasite, Plasmodium falciparum (Figure 1D) [14][15][16] . We also identified a V141A substitution, which has been previously reported in a relapsing B. microti infection and has been suggested to confer resistance 7 . Two distinct nucleotide mutations led to the amino acid substitution M134I; at a lower allele frequency, one variant also produced M134T, which has been identified in another case 17 .…”

Section: Resultssupporting

confidence: 59%

“…Within the apicoplast genome, we found one variant, S121G, at high allele frequency in rpl4. This variant has been recently reported 7 , though its effect on azithromycin resistance is not clear, as it is not within the section of RPL4 that interacts with azithromycin in malarial models 7,18 .…”

Section: Resultsmentioning

confidence: 98%

“…Genetic variation in B. microti may also be associated with clinical relapse 6 . Several previously described variants include the molecular targets of atovaquone (cytochrome b; cytb) and azithromycin (ribosomal protein L4; rpl4) that potentially confer resistance to these drugs in B. microti 4,[6][7][8][9][10][11] . Atovaquone is known to hinder electron transport in the mitochondria of Plasmodium parasites at the cytochrome b site 12 , which is also the drug's target in other apicomplexan parasites 13 .…”

Section: Introductionmentioning

confidence: 99%

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Babesia microti with multiple resistance mutations detected in an immunocompromised patient receiving atovaquone prophylaxis

Holbrook

Klontz

Adams

et al. 2022

Preprint

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Section: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Babesia microti with multiple resistance mutations detected in an immunocompromised patient receiving atovaquone prophylaxis

Holbrook

Klontz

Adams

et al. 2022

Preprint

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“…Identifying the mechanisms of RBC blood type risk factors for the development of Babesia infection and severe babesiosis may help improve the treatment and prevention of babesiosis. Current antibiotic therapy is effective in most cases but inducible antibiotic resistance can develop in B. microti during prolonged duration with standard antibiotic regimens in immunocompromised hosts [36][37][38][39]. A better understanding of the mechanism of Babesia entrance into RBCs might help in the development of antibiotics that impair parasite invasion.…”

Section: Discussionmentioning

confidence: 99%

The impact of ABO and RhD blood types on Babesia microti infection

et al. 2023

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Background Babesiosis is an emerging infectious disease caused by intraerythrocytic Babesia parasites that can cause severe disease and death. While blood type is known to affect the mortality of Plasmodium falciparum malaria patients, associations between red blood cell (RBC) antigens and Babesia microti infection and disease severity are lacking. Methods We evaluated RhD and ABO blood types of Babesia-infected (18S rRNA reactive) blood donors in 10 endemic states in the Northeastern and northern Midwestern United States. We also assessed possible associations between RhD and ABO blood types and disease severity among hospitalized babesiosis patients in Connecticut. Results A total of 768 Babesia-infected blood donors were analyzed, of which 750 (97.7%) had detectable B. microti-specific antibodies. B. microti-infected blood donors were more likely to be RhD- (OR of 1.22, p-value 0.024) than RhD+ donors. Hospitalized RhD- babesiosis patients were more likely than RhD+ patients to have high peak parasitemia (p-value 0.017), which is a marker for disease severity. No differences in RhD+ blood type were noted between residents of the Northeast (OR of 0.82, p-value 0.033) and the Midwest (OR of 0.74, p-value 0.23). Overall, ABO blood type was not associated with blood donor B. microti infection, however, B. microti-infected donors in Maine and New Jersey were more likely to be blood type B compared to non-type B (OR 2.49 [p = 0.008] and 2.07 [p = 0.009], respectively), while infected donors from Pennsylvania were less likely to be type B compared to non-type B (OR 0.32 [p = 0.02]). Conclusions People expressing RhD antigen may have a decreased risk of B. microti infection and babesiosis severity. The association of B antigen with B. microti infection is less clear because the antigen appeared to be less prevalent in infected Pennsylvania blood donors but more prevalent in Maine and New Jersey infected donors. Future studies should quantify associations between B. microti genotypes, RBC antigens, and the frequency and severity of B. microti infection to increase our understanding of human Babesia pathogenesis and improve antibody, vaccine, and RBC exchange transfusion strategies.

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“…In SCID mice, tafenoquine showed strong inhibition against B. microti infection, evident from the single dose requirement (Mordue and Wormser, 2019;Liu et al, 2021). Tafenoquine treatment in cases of relapsing babesiosis caused by drug-resistant B. microti is followed by resolution of parasitemia and symptoms in the patient, demonstrating tafenoquine's excellent effectivity in clinical settings (Marcos et al, 2022;Rogers et al, 2022). However, the use of tafenoquine entails the risk of inducing severe hemolytic anemia in G6PD-deficient patients (Peters and Van Noorden, 2009).…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts

Galon

Amer

et al. 2022

Front. Cell. Infect. Microbiol.

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Human babesiosis is a global emerging tick-borne disease caused by infection with intra-erythrocytic parasites of the genus Babesia. With the rise in human babesiosis cases, the discovery and development of new anti-Babesia drugs are essential. Phosphatidylinositol 4-kinase (PI4K) is a widely present eukaryotic enzyme that phosphorylates lipids to regulate intracellular signaling and trafficking. Previously, we have shown that MMV390048, an inhibitor of PI4K, showed potent inhibition against Babesia species, revealing PI4K as a druggable target for babesiosis. However, twice-administered, 7-day regimens failed to clear Babesia microti parasites from the immunocompromised host. Hence, in this study, we wanted to clarify whether targeting PI4K has the potential for the radical cure of babesiosis. In a B. microti-infected SCID mouse model, a 64-day-consecutive treatment with MMV390048 resulted in the clearance of parasites. Meanwhile, an atovaquone (ATO) resistant parasite line was isolated from the group treated with ATO plus azithromycin. A nonsynonymous variant in the Y272C of the cytochrome b gene was confirmed by sequencing. Likewise, MMV390048 showed potent inhibition against ATO-resistant parasites. These results provide evidence of PI4K as a viable drug target for the radical cure of babesiosis, which will contribute to designing new compounds that can eradicate parasites.

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Broad Antimicrobial Resistance in a Case of Relapsing Babesiosis Successfully Treated With Tafenoquine

Cited by 18 publications

References 11 publications

Babesia microti with multiple resistance mutations detected in an immunocompromised patient receiving atovaquone prophylaxis

Babesia microti with multiple resistance mutations detected in an immunocompromised patient receiving atovaquone prophylaxis

The impact of ABO and RhD blood types on Babesia microti infection

Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts

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