Pharmacodynamics of liposomal amphotericin B and flucytosine for cryptococcal meningoencephalitis: safe and effective regimens for immunocompromised patients.
Background: Cryptococcal meningoencephalitis is a lethal infection with relatively few therapeutic options. The optimal dosage of liposomal amphotericin B (LAmB) alone or in combination with flucytosine is not known.Methods: A murine model of cryptococcal meningoencephalitis was used. The fungal den...
| Published in: | Journal of Infectious Diseases Vol. 208; no. 2; pp. 351 - 362 |
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| Main Authors: | , , , , , , , , , , , |
| Format: | research Journal Article |
| Published: |
Oxford University Press / USA
Jul2013
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104181694&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104181694 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00221899 1YU jtl: Journal of Infectious Diseases issn: 00221899 maglogo: N pubinfo: dt: Jul2013 vid: 208 iid: 2 pid: 622 pub: Oxford University Press / USA artinfo: ui: 104181694 NLM23599314 2012160001 10.1093/infdis/jit164 NLM23599314 PMC3685229 104181694 ppf: 351 ppct: 11 formats: tig: atl: Pharmacodynamics of liposomal amphotericin B and flucytosine for cryptococcal meningoencephalitis: safe and effective regimens for immunocompromised patients. aug: au: O'Connor, Lucy Livermore, Joanne Sharp, Andrew D Goodwin, Joanne Gregson, Lea Howard, Susan J Felton, Timothy W Schwartz, Julie A Neely, Michael N Harrison, Thomas S Perfect, John R Hope, William W affil: School of Translational Medicine, The University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust. sug: subj: Amphotericin B Pharmacodynamics Antifungal Agents Pharmacodynamics Cryptococcus Drug Effects Heterocyclic Compounds Pharmacodynamics Meningitis, Cryptococcal Drug Therapy Meningoencephalitis Drug Therapy Amphotericin B Pharmacokinetics Animals Antifungal Agents Pharmacokinetics Brain Drug Effects Brain Microbiology Cryptococcus Drug Therapy, Combination Heterocyclic Compounds Pharmacokinetics Immunocompromised Host Male Meningitis, Cryptococcal Immunology Meningitis, Cryptococcal Metabolism Meningitis, Cryptococcal Microbiology Meningoencephalitis Microbiology Mice Microbial Culture and Sensitivity Tests Models, Biological Male ab: Background: Cryptococcal meningoencephalitis is a lethal infection with relatively few therapeutic options. The optimal dosage of liposomal amphotericin B (LAmB) alone or in combination with flucytosine is not known.Methods: A murine model of cryptococcal meningoencephalitis was used. The fungal density in the brain was determined using quantitative cultures. Pharmacokinetic-pharmacodynamic relationships were determined for LAmB and flucytosine administered alone. The effect of the combination was described using the Greco model and a mathematical model. The results were bridged to humans.Results: Inoculation resulted in hematogenous dissemination and logarithmic growth within the central nervous system. There was histological evidence of multifocal infection throughout the brain. Both LAmB and flucytosine produced a dose-dependent reduction in fungal burden. The effect of the combination of agents in the brain was additive. Bridging studies suggested that a human dosage of LAmB 3 mg/kg/d resulted in a submaximal antifungal effect. Regimens of LAmB 6 mg/kg/d alone, LAmB 3 mg/kg/d plus flucytosine 50 mg/kg/d, and LAmB 3 mg/kg/d plus flucytosine 100 mg/kg/d all resulted in near-maximal antifungal activity.Conclusions: Potential regimens for further study in clinical trials include LAmB 6 mg/kg/d alone, LAmB 3 mg/kg/d plus flucytosine 50 mg/kg/d, and LAmB 3 mg/kg/d plus flucytosine 100 mg/kg/d. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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