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 & Surgery Associate Professor of Medicine & Surgery Director of Clinical Research Oregon Health & Sciences University

Disclosures • Pfizer- Honorarium/Grant • A t ll Astella- Honorarium/Grant H i /G t • Novartis- Honorarium/Grant

We Must Remember That the Absence of Evidence Is Not the Evidence of Absence de ce s ot t e de ce o bse ce 3

Mortality Due to Invasive Candidiasis 70 Between 1 July 1997 and 30 61 61 June 2001 June 2001 60 tality N=108 matched pairs 50 % Mort 40 40 There were no statistically significant differences in 30 age, sex, underlying d sease(s), t disease(s), time at risk, e at s , 20 20 12 surgical procedure, or 10 vital signs at admission between cases and 0 controls. Candidiais Control • Nosocomial candidemia is still associated with an extremely high crude 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.

Treatment-related risk Factors for Hospital Mortality in Candida Bloodstream Infections. Mortality in Candida Bloodstream Infections. � N=245 � In the hospital cohort, 72 (29.4%) patients died during hospitalization and 40 (36.0%) patients d i h it li ti d 40 (36 0%) ti t died in the intensive care unit cohort. � Independent determinants of hospital mortality Independent determinants of hospital mortality � Inadequate initial fluconazole dosing (AOR, 9.22; 95% CI, 2.15-19.79; p = 0.004 � Retention of a central vein catheter (AOR 6 21; 95% � Retention of a central vein catheter (AOR, 6.21; 95% CI, 3.02-12.77; p = 0.011) Crit Care Med. 2008 Nov;36(11):2967-72.

Time to Initiation of Fluconazole Therapy Impacts Mortality in Patients with Candidemia Mortality in Patients with Candidemia N=230 Clin Infect Dis. 2006 Jul 1;43(1):25-31

Delaying Antifungal Therapy Until Blood Cultures are Positive: A Risk for Hospital Mortality Positive: A Risk for Hospital Mortality Hospital Mortality Associated with Hospital Mortality Associated with Delayed Antifungal Therapy for Candidemia 35 157 patients with candidemia 30 rtality (%) Initiation of antifungal therapy after 25 blood culture <12 hours: 9 (5 7%) <12 hours: 9 (5.7%) 20 20 Hospital Mor 12 to 24 hours: 10 (6.4%) 15 24 to 48 hours: 86 (54.8%) 48 hours: 52 (33.1%) 10 5 (n=86) (n=9) (n=10) (n=52) 0 <12 12 to 24 24 to 48 >48 Morrell M, et al. Antimicrob Agents Chemother 2005;49:3640-5

Anticonvulsants and Allograft Survival n=20 Hx of Seizure and n=92 control 80 70 70 60 urvival 50 % Graft Su 40 40 30 20 10 0 1 2 Y P Yr Post-RTx t RT Wassner et. J of Ped 1976;88:134

Optimizing Antifungal Therapy Host Factors Concentration at Infection at Infection Site PK PD Fungal g A tif Antifungal l Killing Fungal MIC/Resistant MIC/Resistant Clinical Cure

PATH Alliance The Prospective Antifungal Therapy (PATH) Alliance: • A comprehensive registry • • Data collection and monitoring trends in patients with Data collection and monitoring trends in patients with invasive fungal infections (IFIs) • Diagnosis • Treatment • Outcomes of patients • A descriptive paper describing the PATH Alliance will A descriptive paper describing the PATH Alliance will appear in the December edition of Diagnostic Microbiology and Infectious Disease

PATH Alliance • • 2008: 2008: • 3699 patients enrolled with proven or probable IFI • 3106 patients completed • 24 sites (22 US, 2 Canada)

21 Sites Contributing to this Study Site Investigator Thomas Jefferson University Hospital Horn U i University of Pittsburgh Medical Center it f Pitt b h M di l C t P t Paterson Massachusetts General Hospital Fishman University of Arkansas for Medical Sciences Anaissie Duke University Steinbach University of Washington University of Washington Marr 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 University of Minnesota Young Young University of Miami Morris University of Pennsylvania Schuster University of Alabama at Birmingham Pappas Emory University y y Lyon y Hopital Maisonneuve-Rosemont Laverdiere City of Hope National Medical Center Ito

Key Characteristics of the Echinocandin Antifungals 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 Degradation Peptide hydrolysis, slow N-acetylation Catechol-O-methyltransferase enzyme Major metabolic system (COMT) pathway 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- Children < 8 years of age 9) None for renal or hepatic impairment Common ADR LFTS (2%) Hepatotoxicity (1.9 – 10.3%) Hepatotoxicity (2 – 4%) Anemia (0.9 – 10%) Anemia (2 – 4%) • None • Tacrolimus (20%), Cyclosporine increases • None Drug-Drug caspofungin levels (35%), Caspofungin levels interactions may be decreased by inducers • Rifampin, phenytoin, dexamethasone, ,….. ?? ?? ?? Cost

Fluconazole

Fluconazole Dosage Although trials to date have not used this method, (??) administration of twice the usual daily dose of fluconazole as a loading dose is a pharmacologically rational way to more rapidly achieve higher steady-state blood concentrations. ti l t idl hi hi h t d t t bl d t ti Indication Indication Systemic Infection Systemic Infection (disseminated candidiasis, pneumonia) Loading Dose (day 1) 400 mg x 2 daily dose Daily Dose 400 to 800 mg Guidelines for Treatment of Candidiasis Clinical Infectious Diseases 2004;38:161-89

Serum Concentration of Fluconazole with & without Loading Dose serum] 1.4 1.2 onazole [s 1 0.8 ean Fluco 0 6 0.6 0.4 0.2 M 0 0 1 2 3 4 5 6 Dose Dose Loading Dose No Loading Dose

Voriconazole Dosage and Administration Intravenous Oral Patients 40 kg and above Loading Dose Regimen (first 24 hours) Two doses of Two doses of 6 mg/kg 6 /k 400 400 mg 12 hours apart 12 hours apart Maintenance Dose (after first 24 hours) (after first 24 hours) Serious Candida infections 4 mg/kg every 12 200 mg every Empirical Therapy hours 12 hours Invasive aspergillosis/ Scedosporium and 4 mg/kg every 12 200 mg every Fusarium infections/ Other serious mould hours 12 hours infections If patient response is inadequate, increase dose to 4 mg/kg IV or 300 mg oral

Voriconazole Non-linear Pharmacokinetics 8 n ( μ g/ml) 7 • Due to saturation of State 6 metabolism (Michaelis- centration e Steady S Menten kinetics) 5 • Greater than proportional 4 increase in exposure with p sma Conc 3 3 Average increasing dose 2 • On average, 1.5-fold oral 1 dose escalation from 200 dose escalation from 200 Pla mg q 12 h to 300 mg q 12 0 h will lead to a 2.5-fold 0 100 200 300 400 increase in exposure p Twice Daily Dose (mg) Twice Daily Dose (mg)

Therapeutic Drug Monitoring: Voriconazole Serum Concentration and Response o co a o e Se u Co ce t at o a d espo se Reponse to Voriconazole p 100% 100 Better responses in patients with higher patients with higher 80 80 levels cess (%) 60 44% Improved outcomes p Succ 40 with dose escalation in patients with 20 levels < 2 mcg/ml 0 <2.05 (n=18) > 2.05 (n=10) Serum concentration (mcg/ml) Serum concentration (mcg/ml) Smith J et al. Antimicrob Agents Chemother 2006;50:1570-2

Pharmacology: Mean Trough Concentrations of Caspofungin Concentrations of Caspofungin* 2.00 (n=8) 1.75 ntration, 1.50 1.25 mL T Target concentration: 1 μ g/mL t t ti 1 / L μ g/m ugh Conce 1.00 0.75 0.50 0.50 Trou 0.25 0 0 2 4 12 6 6 8 8 10 0 14 Time, days • Mean plasma drug concentrations maintained above 1.0 μ g/mL, a target chosen to exceed the MIC at which 90% of most clinically relevant Candida isolates were i hibit d inhibited *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 .

Percentage of Patients with a Loading Dose for Fluconazole, Voriconazole and Caspofungin (n=2552) 65 80% 65.80% 70% 60% 50% 50% 40% 30% 19.10% 19.10% 11.60% 20% 10% 0 0 Fluconazole Voriconazole Caspofungin

International Conference for the Development of Consensus on the Management and of Consensus on the Management and Prevention of Severe Candidal Infections Edwards JE et al Clin Infect Dis 1997:25;43 23