Relapsing Babesiosis With Molecular Evidence of Resistance to Certain Antimicrobials Commonly Used to Treat <i>Babesia microti</i> Infections

Marcos, Luis A.; Wormser, Gary P.

doi:10.1093/ofid/ofad391

Cited by 7 publications

(6 citation statements)

References 34 publications

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“…Moreover, the Rpl4 G76V mutation generated here in P. falciparum has been previously reported to confer azithromycin resistance in P. falciparum (Sidhu et al, 2007), as well as in the bacteria causing gonorrhea and pneumococcal disease (Canu et al, 2002; Ma et al, 2020)(Figure 1F). In zoonotic infections of Babesia microti, three different Rpl4 mutations in the same region are associated with azithromycin resistance (Marcos & Wormser, 2023).…”

Section: Resultsmentioning

confidence: 99%

“…Our four azithromycin selection regimens, across two Plasmodium species, all retrieved parasites with point mutations in the apicoplast-encoded ribosomal protein Rpl4. Mutations in Rpl4 are also associated with azithromycin resistance in other strains of P. falciparum (Goodman et al, 2013; Sidhu et al, 2007; Wilson et al, 2015), zoonotic infections of people with Babesia microti (Marcos & Wormser, 2023) in the plastid of the green alga Chlamydomonas reinhardtii (Bowers et al, 2003), and in various bacteria related to the ancestor of plastids (Canu et al, 2002; Ma et al, 2020). Mutations in Rpl4 thus seem to be a universal mechanism of resistance to azithromycin and closely related macrolides.…”

Section: Discussionmentioning

confidence: 99%

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Malaria parasite resistance to azithromycin is not readily transmitted by mosquitoes

Buchanan,

McConville,

Yeoh

et al. 2023

Preprint

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Drug resistance in malaria parasites severely erodes our ability to control disease. Combination therapies—where multiple compounds are combined to reduce the probability of resistance emerging to two or more compounds simultaneously—are the favoured solution to stemming antimalarial resistance. Thus, identifying suitable partner compounds for combinations is a priority. We sought potential partner compounds with inherent refractoriness to the spread of resistance that might better protect the primary antimalarial. We focused on azithromycin, a cheap, safe antibacterial that kills malaria parasites by blocking protein synthesis in the apicoplast—a relict plastid in malaria parasites. Selection for azithromycin resistance in rodent (Plasmodium berghei) and human (P. falciparum) malaria parasites yielded various mutations in the apicoplast-encoded gene for the 50S large ribosomal subunit protein L4 (Rpl4).P. bergheiRpl4 mutant parasites developed poorly in mosquitoes, producing aberrant oocysts and low numbers of sporozoites.P. falciparumRpl4 mutants developed normally in mosquitoes. The azithromycin resistant mutants of bothP. bergheiandP. falciparumparasites could establish liver stage infections, but both species developed aberrantly, andP. bergheifailed to progress to blood stage infections without massive mechanical intervention. The mutations in the apicoplast-encoded ribosomal protein Rpl4 apparently confer azithromycin resistance in the vertebrate blood phase, but the mutations confer a fitness deficit—likely reduced efficiency of apicoplast protein synthesis—that becomes a severe problem for the parasites in the highly-replicative mosquito stage (forP. berghei) and liver stage (for bothP. bergheiandP. falciparum). The apicoplast is more active metabolically in mosquito and liver stages than blood stage, and we hypothesise that the mutations in apicoplast Rpl4 render it less able to deliver on these metabolic needs, thus retarding parasite development. Azithromycin resistance will therefore be less likely to spread geographically, making it an attractive option as a perennial partner compound to protect appropriate frontline antimalarials from resistance spread.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Malaria parasite resistance to azithromycin is not readily transmitted by mosquitoes

Buchanan,

McConville,

Yeoh

et al. 2023

Preprint

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“…Our study also suggests that antibody might play an important role in protection against secondary challenge while playing a more limited role in the primary immune response. These data reopen a debate into the importance of B cells and antibody in the control of B. microti infection, especially given the susceptibility of individuals treated with Rituximib and other agents that impair B cell function to persistent babesiosis as well as babesiosis refractory to current therapies [ 12 , 13 , 33 , 34 ]. Although an important function of CD4 T cells is the production of IFN-γ, the absence of IFN-γR did not compromise protection against secondary challenge with the parasite in our model.…”

Section: Discussionmentioning

confidence: 99%

Immune Mediators Important for a Protective Secondary Response to Babesia microti

Conti,

Gagliardi,

Arnaboldi

et al. 2024

Pathogens

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Babesia microti (B. microti) is a tick-transmitted protozoan parasite that invades red blood cells. It is the primary cause of human babesiosis in the US. The severity of babesiosis caused by B. microti infection can range from asymptomatic to fatal. Risk factors for severe disease include general immune suppression, advanced age (>50) and lack of a spleen. However, severe disease can occur in the absence of any known risk factors. The degree to which tick-transmitted B. microti infection confers protection from subsequent exposure is largely unexplored. This is an important question as both the prevalence and geographic range of tick-transmitted B. microti infection continues to increase and individuals in endemic regions may have multiple exposures over their lifetime. In the current study we used a mouse model to evaluate the degree to which primary infection with B. microti protected against secondary challenge with the same parasite strain. We show that CD4 T cells, and to a lesser extent B cells, contribute to protection. However, mice exhibited significant protection from secondary parasite challenge even in the absence of either CD4 T cells or B cells. The protection mediated by CD4 T cells did not depend on their production of IFN-γ as mice with a targeted gene deletion for the IFN-γ receptor remained fully protected against secondary challenge. Other factors including inducible nitric oxide synthase (iNOS) and the adaptor protein MyD88, important for toll-like receptors, IL-18 and IL-1 signaling, were not important for protection against primary or secondary challenge with B. microti. Thus, our study shows that resolution of primary infection with B. microti results in robust protection against secondary challenge with parasites, at least in the short term. Further studies are needed to evaluate the length of protection and the degree to which protection is impacted by parasite heterogeneity. Although we show an important role for CD4 T cells in protection against secondary challenge, our results suggest that no single aspect of the immune system is solely responsible for adequate protection against secondary challenge with B. microti.

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“…She had already followed a course of atovaquone and azithromycin for babesiosis, which was ineffective in relieving her sweats and malarial-type symptoms. Babesia had now become resistant to standard antibiotic/antimalarial regimens, including clindamycin, azithromycin, and atovaquone [188,189]; so, other antimalarial protocols were tried. Her first regimen, therefore, included minocycline and rifampin, gradual increases in the dose of dapsone, atovaquone/proguanil (Malarone), and multiple 3-day pulses of lumefantrine/artemether (Coartem) with Cryptolepis sanguinolenta and artemisinin for her ongoing, resistant night sweats secondary to Babesia, which eventually improved [190].…”

Section: Discussionmentioning

confidence: 99%

Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review

Horowitz,

Fallon,

Freeman

2024

Microorganisms

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Three patients with relapsing and remitting borreliosis, babesiosis, and bartonellosis, despite extended anti-infective therapy, were prescribed double-dose dapsone combination therapy (DDDCT) for 8 weeks, followed by one or several two-week courses of pulsed high-dose dapsone combination therapy (HDDCT). We discuss these patients’ cases to illustrate three important variables required for long-term remission. First, diagnosing and treating active co-infections, including Babesia and Bartonella were important. Babesia required rotations of multiple anti-malarial drug combinations and herbal therapies, and Bartonella required one or several 6-day HDDCT pulses to achieve clinical remission. Second, all prior oral, intramuscular (IM), and/or intravenous (IV) antibiotics used for chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDS), irrespective of the length of administration, were inferior in efficacy to short-term pulsed biofilm/persister drug combination therapy i.e., dapsone, rifampin, methylene blue, and pyrazinamide, which improved resistant fatigue, pain, headaches, insomnia, and neuropsychiatric symptoms. Lastly, addressing multiple factors on the 16-point multiple systemic infectious disease syndrome (MSIDS) model was important in achieving remission. In conclusion, DDDCT with one or several 6–7-day pulses of HDDCT, while addressing abnormalities on the 16-point MSIDS map, could represent a novel effective clinical and anti-infective strategy in CLD/PTLDS and associated co-infections including Bartonella.

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Relapsing Babesiosis With Molecular Evidence of Resistance to Certain Antimicrobials Commonly Used to Treat Babesia microti Infections

Cited by 7 publications

References 34 publications

Malaria parasite resistance to azithromycin is not readily transmitted by mosquitoes

Malaria parasite resistance to azithromycin is not readily transmitted by mosquitoes

Immune Mediators Important for a Protective Secondary Response to Babesia microti

Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review

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