Integration of genomic and pharmacokinetic data to predict clinical outcomes in HIV-associated cryptococcal meningitis

Stott, Katherine, Mohabir, Jason T, Bowers, Katharine, Tenor, Jennifer L, Toffaletti, Dena L, Unsworth, Jennifer, Jimenez-Valverde, Ana, Ahmadu, Ajisa, Moyo, Melanie, Gondwe, Ebbie, Chimang'anga, Wezi, Chasweka, Madalitso, Lawrence, David S, Jarvis, Joseph N, Harrison, Tom, Hope, Wiliam, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, Mwandumba, Henry, Perfect, John R and Cuomo, Christina A (2024) 'Integration of genomic and pharmacokinetic data to predict clinical outcomes in HIV-associated cryptococcal meningitis'. mBio, Vol 15, Issue 10, e01592.

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Abstract

Cryptococcal meningitis causes an estimated 112,000 global deaths per annum. Genomic and phenotypic features of the infecting strain of Cryptococcus spp. have been associated with outcomes from cryptococcal meningitis. Additionally, population-level pharmacokinetic variability is well documented in these patient cohorts. The relative contribution of these factors to clinical outcomes is unknown. Based in Malawi, we conducted a sub-study of the phase 3 Ambition-CM trial (ISRCTN72509687), collecting plasma and cerebrospinal fluid at serial time points during the first 14 days of antifungal therapy. We explored the relative contribution of pathogen genotype, drug resistance phenotype, and pharmacokinetics on clinical outcomes including lumbar opening pressure, pharmacodynamic effect, and mortality. We report remarkable genomic homogeneity among infecting strains of Cryptococcus spp., within and between patients. There was no evidence of acquisition of antifungal resistance in our isolates. Genotypic features of the infecting strain were not consistently associated with adverse or favorable clinical outcomes. However, baseline fungal burden and early fungicidal activity (EFA) were associated with mortality. The strongest predictor of EFA was the level of exposure to amphotericin B. Our analysis suggests the most effective means of improving clinical outcomes from HIV-associated cryptococcal meningitis is to optimize exposure to potent antifungal therapy.

Item Type:	Article
Subjects:	QS Anatomy > QS 20.5 Research (General) WL Nervous System > WL 200 Meninges. Blood-brain barrier
Faculty: Department:	Clinical Sciences & International Health > Malawi-Liverpool-Wellcome Programme (MLW)
Digital Object Identifer (DOI):	https://doi.org/10.1128/mbio.01592-24
Depositing User:	Debbie Jenkins
Date Deposited:	23 Sep 2024 10:57
Last Modified:	06 Nov 2024 14:51
URI:	https://archive.lstmed.ac.uk/id/eprint/25266

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