Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis

被引:0
作者
Stott, Katharine E. [1 ,2 ]
Beardsley, Justin [3 ]
Kolamunnage-Dona, Ruwanthi [4 ]
Castelazo, Anahi Santoyo [1 ]
Kibengo, Freddie Mukasa [5 ]
Nguyen Thi Hoang Mai [6 ]
Day, Jeremy [3 ,7 ]
Hope, William [1 ]
机构
[1] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Ctr Antimicrobial Pharmacodynam, Liverpool, Merseyside, England
[2] Malawi Liverpool Wellcome Trust Clin Res Programm, Blantyre, Malawi
[3] Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam
[4] Univ Liverpool, Inst Translat Med, Dept Biostat, Liverpool, Merseyside, England
[5] MRC UVRI Uganda Res Unit AIDS, Entebbe, Uganda
[6] Hosp Trop Dis, Ho Chi Minh City, Vietnam
[7] Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England
基金
英国医学研究理事会; 美国国家卫生研究院; 英国惠康基金;
关键词
cryptococcal meningitis; pharmacokinetics; pharmacodynamics; fluconazole; central nervous system pharmacokinetics; central nervous system infections; meta-analysis; HIGH-DOSE FLUCONAZOLE; ANTIFUNGAL THERAPY; AMPHOTERICIN-B; FLUCYTOSINE; MONOTHERAPY; PHARMACODYNAMICS; RESISTANCE; INFECTION; BURDEN; ACCESS;
D O I
10.1128/AAC.00885-18
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the central nervous system (CNS) is not known. A fluconazole PK study was conducted in 43 patients receiving oral fluconazole (usually 800 mg every 24 h [q24h]) in combination with amphotericin B deoxycholate (1 mg/kg q24h) for cryptococcal meningitis (CM). A four-compartment PK model was developed, and Monte Carlo simulations were performed for a range of fluconazole dosages. A meta-analysis of trials reporting outcomes of CM patients treated with fluconazole monotherapy was performed. Adjusted for bioavailability, the PK parameter means (standard deviation) were the following: clearance, 0.72 (0.24) liters/h; volume of the central compartment, 18.07 (6.31) liters; volume of the CNS compartment, 32.07 (17.60) liters; first-order rate constant from the central to peripheral compartment, 12.20 (11.17) h(-1), from the peripheral to central compartment, 18.10 (8.25) h(-1), from the central to CNS compartment, 35.43 (13.74) h(-1), and from the CNS to central the compartment, 28.63 (10.03) h(-1). Simulations of the area under concentration-time curve resulted in median (interquartile range) values of 1,143.2 (range, 988.4 to 1,378.0) mg . h/liter in plasma (AUC(plasma)) and 982.9 (range, 781.0 to 1,185.9) mg . h/liter in cerebrospinal fluid (AUC(CSF)) after a dosage of 1,200 mg q24h. The mean simulated ratio of AUC(CSF)/AUC(plasma) was 0.89 (standard deviation [SD], 0.44). The recommended dosage of fluconazole for CM induction therapy fails to attain the pharmacodynamic (PD) target in respect to the wild-type MIC distribution for C. neoformans. The meta-analysis suggested modest improvements in both CSF sterility and mortality outcomes with escalating dosage. This study provides the pharmacodynamic rationale for the long-recognized fact that fluconazole monotherapy is an inadequate induction regimen for CM.
引用
收藏
页数:14
相关论文
共 42 条
[1]   Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients [J].
Alobaid, Abdulaziz S. ;
Wallis, Steven C. ;
Jarrett, Paul ;
Starr, Therese ;
Stuart, Janine ;
Lassig-Smith, Melissa ;
Mejia, Jenny Lisette Ordonez ;
Roberts, Michael S. ;
Sinnollareddy, Mahipal G. ;
Roger, Claire ;
Lipman, Jeffrey ;
Roberts, Jason A. .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2016, 60 (11) :6550-6557
[2]   Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model [J].
Andes, D ;
van Ogtrop, H .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1999, 43 (09) :2116-2120
[3]   Population pharmacokinetics of fluconazole after administration of fosfluconazole and fluconazole in critically ill patients [J].
Aoyama, T. ;
Hirata, K. ;
Hirata, R. ;
Yamazaki, H. ;
Yamamoto, Y. ;
Hayashi, H. ;
Matsumoto, Y. .
JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS, 2012, 37 (03) :356-363
[4]   FLUCONAZOLE PENETRATION INTO CEREBROSPINAL-FLUID - IMPLICATIONS FOR TREATING FUNGAL-INFECTIONS OF THE CENTRAL NERVOUS-SYSTEM [J].
ARNDT, CAS ;
WALSH, TJ ;
MCCULLY, CL ;
BALIS, FM ;
PIZZO, PA ;
POPLACK, DG .
JOURNAL OF INFECTIOUS DISEASES, 1988, 157 (01) :178-180
[5]   Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis [J].
Beardsley, J. ;
Wolbers, M. ;
Kibengo, F. M. ;
Ggayi, A. -B. M. ;
Kamali, A. ;
Cuc, N. T. K. ;
Binh, T. Q. ;
Chau, N. V. V. ;
Farrar, J. ;
Merson, L. ;
Phuong, L. ;
Thwaites, G. ;
Van Kinh, N. ;
Thuy, P. T. ;
Chierakul, W. ;
Siriboon, S. ;
Thiansukhon, E. ;
Onsanit, S. ;
Supphamongkholchaikul, W. ;
Chan, A. K. ;
Heyderman, R. ;
Mwinjiwa, E. ;
van Oosterhout, J. J. ;
Imran, D. ;
Basri, H. ;
Mayxay, M. ;
Dance, D. ;
Phimmasone, P. ;
Rattanavong, S. ;
Lalloo, D. G. ;
Day, J. N. .
NEW ENGLAND JOURNAL OF MEDICINE, 2016, 374 (06) :542-554
[6]   Inadequacy of High-Dose Fluconazole Monotherapy Among Cerebrospinal Fluid Cryptococcal Antigen (CrAg)-Positive Human Immunodeficiency Virus-Infected Persons in an Ethiopian CrAg Screening Program [J].
Beyene, Tafese ;
Zewde, Anteneh G. ;
Balcha, Abera ;
Hirpo, Belda ;
Yitbarik, Tadele ;
Gebissa, Teshome ;
Rajasingham, Radha ;
Boulware, David R. .
CLINICAL INFECTIOUS DISEASES, 2017, 65 (12) :2126-2129
[7]   Antiretroviral roll-out, antifungal roll-back: access to treatment for cryptococcal meningitis [J].
Bicanic, T ;
Wood, R ;
Bekker, LG ;
Darder, M ;
Meintjes, G ;
Harrison, TS .
LANCET INFECTIOUS DISEASES, 2005, 5 (09) :530-531
[8]   Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole [J].
Bicanic, Tihana ;
Meintjes, Graeme ;
Wood, Robin ;
Hayes, Madeleine ;
Rebe, Kevin ;
Bekker, Linda-Gail ;
Harrison, Thomas .
CLINICAL INFECTIOUS DISEASES, 2007, 45 (01) :76-80
[9]   Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: The role of fluconazole resistance and immune reconstitution [J].
Bicanic, Tihana ;
Harrison, Thomas ;
Niepieklo, Alina ;
Dyakopu, Nontobeko ;
Meintjes, Graeme .
CLINICAL INFECTIOUS DISEASES, 2006, 43 (08) :1069-1073
[10]  
BRAMMER KW, 1990, REV INFECT DIS, V12, pS318