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

Autor:	Stott KE; Antimicrobial Pharmacodynamics and Therapeutics Group, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom.; Malawi Liverpool Wellcome Clinical Research Programme, Blantyre, Malawi., Mohabir JT; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Bowers K; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Tenor JL; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Toffaletti DL; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Unsworth J; Antimicrobial Pharmacodynamics and Therapeutics Group, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom., Jimenez-Valverde A; Antimicrobial Pharmacodynamics and Therapeutics Group, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom., Ahmadu A; Malawi Liverpool Wellcome Clinical Research Programme, Blantyre, Malawi., Moyo M; Malawi Liverpool Wellcome Clinical Research Programme, Blantyre, Malawi.; Department of Medicine, Kamuzu University of Health Sciences, Blantyre, Malawi., Gondwe E; Malawi Liverpool Wellcome Clinical Research Programme, Blantyre, Malawi., Chimang'anga W; Malawi Liverpool Wellcome Clinical Research Programme, Blantyre, Malawi., Chasweka M; Malawi Liverpool Wellcome Clinical Research Programme, Blantyre, Malawi., Lawrence DS; Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Tropical Medicine, London, United Kingdom.; Botswana Harvard Health Partnership, Gaborone, Botswana.; Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Jarvis JN; Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Tropical Medicine, London, United Kingdom.; Botswana Harvard Health Partnership, Gaborone, Botswana., Harrison T; Institute of Infection and Immunity, St George's University London, London, United Kingdom., Hope W; Antimicrobial Pharmacodynamics and Therapeutics Group, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom., Lalloo DG; Liverpool School of Tropical Medicine, Liverpool, United Kingdom., Mwandumba HC; Malawi Liverpool Wellcome Clinical Research Programme, Blantyre, Malawi., Perfect JR; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Cuomo CA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	MBio [mBio] 2024 Oct 16; Vol. 15 (10), pp. e0159224. Date of Electronic Publication: 2024 Aug 27.
DOI:	10.1128/mbio.01592-24
Abstrakt:	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. Importance: HIV-associated cryptococcal meningitis is associated with a high burden of mortality. Research into the different strain types causing this disease has yielded inconsistent findings in terms of which strains are associated with worse clinical outcomes. Our study suggests that the exposure of patients to potent anti-cryptococcal drugs has a more significant impact on clinical outcomes than the strain type of the infecting organism. Future research should focus on optimizing drug exposure, particularly in the context of novel anticryptococcal drugs coming into clinical use. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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