PATH Alliance Registry: Identification of Inappropriate Drug Dosing - - PowerPoint PPT Presentation
PATH Alliance Registry: Identification of Inappropriate Drug Dosing of Antifungal Agents in Patients with Chronic Kidney Disease Review of 6000 Patients with Fungal Infections Ali J. Olyaei, PharmD, BCPS Associate Professor of Medicine &
Ali J. Olyaei, PharmD, BCPS Associate Professor of Medicine & Surgery Associate Professor of Medicine & Surgery Director of Clinical Research Oregon Health & Sciences University
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Between 1 July 1997 and 30 June 2001
June 2001 N=108 matched pairs
There were no statistically significant differences in age, sex, underlying disease(s), time at risk,
d sease(s), t e at s , surgical procedure, or vital signs at admission between cases and controls.
and attributable mortality--much higher than that expected from
and attributable mortality--much higher than that expected from underlying disease alone.
Gudlaugsson O Clin Infect Dis. 2003 Nov 1;37(9):1172-7.
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157 patients with candidemia Initiation of antifungal therapy after blood culture <12 hours: 9 (5 7%)
20 25 30
rtality (%)
<12 hours: 9 (5.7%) 12 to 24 hours: 10 (6.4%) 24 to 48 hours: 86 (54.8%) 48 hours: 52 (33.1%)
10 15 20
Hospital Mor
(n=9) (n=10) (n=86) (n=52)
5 <12 12 to 24 24 to 48 >48
Morrell M, et al. Antimicrob Agents Chemother 2005;49:3640-5
n=20 Hx of Seizure and n=92 control 70 80 40 50 60 70 urvival 20 30 40 % Graft Su 10 1 2
Thomas Jefferson University Hospital Horn U i it f Pitt b h M di l C t P t University of Pittsburgh Medical Center Paterson Massachusetts General Hospital Fishman University of Arkansas for Medical Sciences Anaissie Duke University Steinbach University of Washington Marr University of Washington Marr University of Wisconsin Medical School Andes University of Michigan Health System Kauffman Washington Hospital Center Shoham University of Iowa Health Care Diekema Oregon Health & Science University Olyaei Hamilton Health Sciences Rotstein Mount Sinai School of Medicine Huprikar University of Nebraska Freifeld University of Minnesota Young University of Minnesota Young University of Miami Morris University of Pennsylvania Schuster University of Alabama at Birmingham Pappas Emory University Lyon y y y Hopital Maisonneuve-Rosemont Laverdiere City of Hope National Medical Center Ito
Anidulafungin Caspofungin Micafungin Oral Absorption
poor < 2% poor
Distribution (Vd)
30-50 L 9.67 L 4.95 L
Dosing (MTD)
200 mg LD then 100 mg daily 70 mg LD then 35 – 50 mg (100 mg) 50 – 150 mg
Major metabolic
Degradation Peptide hydrolysis, slow N-acetylation Catechol-O-methyltransferase enzyme
pathway
system (COMT)
t 1/2
24-36 hours 9-11 hours 14.7 hours after single infusion 14.6 hours after multiple doses
CNS penetration
Probably poor Probably poor Rat study: levels in brain approximately 2% plasma
Dosage adjustment
None for renal or hepatic impairment Moderate hepatic insufficiency (Child Pugh 7- 9) Children < 8 years of age None for renal or hepatic impairment
Common ADR
LFTS (2%) Hepatotoxicity (1.9 – 10.3%) Anemia (0.9 – 10%) Hepatotoxicity (2 – 4%) Anemia (2 – 4%)
Drug-Drug interactions
caspofungin levels (35%), Caspofungin levels may be decreased by inducers
Cost
?? ?? ??
Guidelines for Treatment of Candidiasis Clinical Infectious Diseases 2004;38:161-89
Patients 40 kg and above Loading Dose Regimen (first 24 hours) Two doses of 6 /k Two doses of 400 6 mg/kg 12 hours apart 400 mg 12 hours apart Maintenance Dose (after first 24 hours) (after first 24 hours) Serious Candida infections Empirical Therapy 4 mg/kg every 12 hours 200 mg every 12 hours Invasive aspergillosis/ Scedosporium and Fusarium infections/ Other serious mould infections 4 mg/kg every 12 hours 200 mg every 12 hours
If patient response is inadequate, increase dose to 4 mg/kg IV or 300 mg oral
Serum concentration (mcg/ml)
Smith J et al. Antimicrob Agents Chemother 2006;50:1570-2
Serum concentration (mcg/ml)
2.00 (n=8)
T t t ti 1 / L 1.75 1.50 1.25
Target concentration: 1 μg/mL 0.50 1.00 0.75
6 8 10 14 2 4 12 0.50 0.25
6 8
*In men receiving caspofungin 50 mg daily with a 70-mg loading dose on day 1. MIC = minimum inhibitory concentration Adapted from Stone JA et al. Antimicrob Agents Chemother. 2002;46:739–745.
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Edwards JE et al Clin Infect Dis 1997:25;43
Edwards JE et al Clin Infect Dis 1997:25;43
60 % of patients 45 50 40 50 30 40 5 10 20 5 < 400 mg >400 mg Unknown
54 60 % of patients 43 54 40 50 30 40 10 20 3 < 400 mg >400 mg Unknown
53 60 43 53 40 50 30 40 4 10 20 4 < 400 mg >400 mg Unknown
Yagasaki et al, Intensive Care Med 2003a; 29:1844-1848
Caspofungina Micafungin Anidulafungin
Treatment of esophageal candidiasis* See footnote below* 150 mg QD 100 mg load; 50 mg QD (higher relapse rates after anidulafungin therapy: 53.3% anidulafungin vs 19.3% fluconazole) Treatment of candidemia and the following 70 mg load; 50 mg QD 200 mg load; 100 mg QD g Candida infectionsb: intra-abdominal abscesses, peritonitis g ; g Q g ; g Q Not studied in sufficient number
determine efficacy in that group Empirical therapy for presumed fungal infections in febrile neutropenic patients 70 mg load; 50 mg QD infections in febrile neutropenic patients Treatment of invasive aspergillosis in patients who are refractory to or intolerant
formulations of amphotericin B, and/or itraconazole) 70 mg load; 50 mg QD Not studied as initial therapy for invasive aspergillosis
aDosage adjustment to 35 mg QD after 70-mg loading dose recommended for moderate hepatic insufficiency.
itraconazole) aspergillosis Prophylaxis of Candida infections in HSCT patients 50 mg QD
bNot studied in endocarditis, osteomyelitis, and meningitis due to Candida.
HSCT = hematopoietic stem cell transplant; QD = once daily. Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information. * Approved Indication by the Food and Drug Administration (FDA) and not approved indication in Saudi Arabia.
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