A systematic review and meta‐analysis of the relative efficacy and safety of treatment regimens for <scp>HIV</scp>‐associated cerebral toxoplasmosis: is trimethoprim‐sulfamethoxazole a real option?

Hernandez, Adrián V.; Thota, Priyaleela; Pellegrino, D; Pasupuleti, Vinay; Benítes-Zapata, Vicente A.; Deshpande, Abhishek; Oliveira, AC Penalva de; Vidal, José E.

doi:10.1111/hiv.12402

Cited by 74 publications

(61 citation statements)

References 27 publications

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“…First line drug combinations are pyrimethamine+sulfadiazine, which target two independent steps of the folic acid synthesis pathway, depriving the parasites of purines. While effective against acute toxoplasmosis, allergies or adverse effects to sulfa drugs force a switch to another therapeutic (23). The second line drug combination is pyrimethamine+clindamycin, the latter of which targets translation in the parasite-specific plastid-like organelle called the apicoplast (24).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Guanabenz Combination Therapy Against Chronic Toxoplasmosis Across Multiple Mouse Strains

Martynowicz¹,

Doggett²,

Sullivan³

2020

Preprint

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21Toxoplasma gondii, an obligate intracellular parasite that can cause life-threatening 22 acute disease, differentiates into a quiescent cyst stage to establish lifelong chronic infections in 23 animal hosts, including humans. This tissue cyst reservoir, which can reactivate into an acute 24 infection, is currently refractory to clinically available therapeutics. Recently, we and others have 25 discovered drugs capable of significantly reducing brain cyst burden in latently infected mice, 26 but not to undetectable levels. In this study, we examined the use of novel combination 27 therapies possessing multiple mechanisms of action in mouse models of latent toxoplasmosis. 28Our drug regimens included combinations of pyrimethamine, clindamycin, guanabenz, and 29 endochin-like quinolones (ELQs), and were administered to two different mouse strains in an 30 attempt to eradicate brain tissue cysts. We observed mouse strain-dependent effects with these 31 drug treatments: pyrimethamine + guanabenz showed synergistic efficacy in C57BL/6 mice, yet 32 did not improve upon guanabenz monotherapy in BALB/c mice. Contrary to promising in vitro 33 results demonstrating toxicity to bradyzoites, we observed an antagonistic effect between 34 guanabenz + ELQ-334 in vivo. While we were unable to completely eliminate brain cyst burden, 35we found that a combination treatment of ELQ-334 + pyrimethamine impressively reduced brain 36 cysts to 95% in C57BL/6 mice, which approaches the limit of detection. These analyses 37 highlight the importance of evaluating anti-infective drugs in multiple mouse strains and will help 38 inform further preclinical cocktail therapy studies designed to treat chronic toxoplasmosis. 39 40

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Section: Discussionmentioning

confidence: 99%

Efficacy of Guanabenz Combination Therapy Against Chronic Toxoplasmosis Across Multiple Mouse Strains

Martynowicz¹,

Doggett²,

Sullivan³

2020

Preprint

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“…8.9H–J). The introduction of highly active antiretroviral therapy (HAART) has caused a remarkable decline in incidence and prevalence of Toxoplasma gondii brain infection in patients with HIV/AIDS (Antinori et al, 2004; Riveiro-Barciela et al, 2013; Hernandez et al, 2017), but the benefit also relates to the prompt therapy with specific anti-Toxoplasma drugs (Hernandez et al, 2017). Similarly, the incidence of cytomegalovirus and other herpetic infections declined after the introduction of HAART for the control of AIDS/HIV (Schwarcz et al, 2013).…”

Section: Infections Of the Cerebellummentioning

confidence: 99%

The neuropathology of the adult cerebellum

Koeppen

2018

Handbook of Clinical Neurology

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This chapter summarizes the neuropathologic features of nonneoplastic disorders of the adult cerebellum. Gait ataxia and extremity dysmetria are clinical manifestations of diseases that interrupt the complex cerebellar circuitry between the neurons of the cerebellar cortex, the cerebellar nuclei (especially the dentate nuclei), and the inferior olivary nuclei. The cerebellum is a prominent target of several sporadic and hereditary neurodegenerative diseases, including multiple system atrophy, spinocerebellar ataxia, and Friedreich ataxia. Purkinje cells display selective vulnerability to hypoxia but a surprising resistance to hypoglycemia. A classic toxin that damages the cerebellar cortex is methylmercury, but the most common injurious agent to Purkinje cells is ethanol. Many drugs cause ataxia, but doubts continue about phenytoin. Ischemic lesions of the cerebellum due to arterial thrombosis or embolism cause a spectrum of symptoms and signs, depending on the territory involved. Large hemorrhages have an unfavorable prognosis because they displace critical brainstem structures or penetrate into the fourth ventricle. Fungal infections and toxoplasmosis of the cerebellum, and cerebellar progressive multifocal leukoencephalopathy, have become rarer because of improved control of the acquired immunodeficiency syndrome. Ataxia is a prominent feature of prion disease. Adult-onset Niemann-Pick type C1 disease and Kufs disease may have a predominantly ataxic clinical phenotype. The adult cerebellum is also vulnerable to several leukodystrophies. A rare but widely recognized complication of cancer is paraneoplastic cerebellar degeneration.

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“…Reactivation of latent infection in immunodeficiency, such as people living with HIV and without combination antiretroviral therapy, results, in cerebral toxoplasmosis. In rare cases, due to failure of Th1 immune response disseminated toxoplasmosis might occur, which involves at least two organs [5,[11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Human extracellular vesicles and correlation with two clinical forms of toxoplasmosis

et al. 2020

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A systematic review and meta‐analysis of the relative efficacy and safety of treatment regimens for HIV‐associated cerebral toxoplasmosis: is trimethoprim‐sulfamethoxazole a real option?

Cited by 74 publications

References 27 publications

Efficacy of Guanabenz Combination Therapy Against Chronic Toxoplasmosis Across Multiple Mouse Strains

Efficacy of Guanabenz Combination Therapy Against Chronic Toxoplasmosis Across Multiple Mouse Strains

The neuropathology of the adult cerebellum

Human extracellular vesicles and correlation with two clinical forms of toxoplasmosis

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