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 Director of Clinical Research Oregon Health & Sciences University
Disclosures Pfizer- Honorarium/Grant Astella- Honorarium/Grant Novartis- Honorarium/Grant
We Must Remember That the Absence of Evidence Is Not otthe Evidence ceof Absence 3
Mortality Due to Invasive Candidiasis 70 Between 1 July 1997 and 30 61 June 2001 60 % Mort tality 50 40 N=108 matched pairs There were no statistically significant differences in 30 age, sex, underlying 20 disease(s), time at risk, 12 10 0 Candidiais Control surgical procedure, or vital signs at admission between cases and controls. Nosocomial candidemia is still associated with an extremely high crude 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. N=245 In the hospital cohort, 72 (29.4%) patients died during hospitalization ti and 40 (36.0%) patients t died in the intensive care unit cohort. 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% 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 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 Hospital Mor rtality (%) Hospital Mortality Associated with Delayed Antifungal Therapy for Candidemia 35 30 25 20 15 10 157 patients with candidemia Initiation of antifungal therapy after blood culture <12 hours: 9 (5.7%) 12 to 24 hours: 10 (6.4%) 24 to 48 hours: 86 (54.8%) 48 hours: 52 (33.1%) 5 0 (n=9) (n=10) (n=86) (n=52) <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 % Graft Su urvival 60 50 40 30 20 10 0 1 2 Yr Post-RTx Wassner et. J of Ped 1976;88:134
Optimizing Antifungal Therapy Antifungal PK Concentration at Infection Site Fungal MIC/Resistant Host Factors PD Fungal Killing Clinical Cure
PATH Alliance The Prospective Antifungal Therapy (PATH) Alliance: A comprehensive registry 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: 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 University it 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 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 Miami Morris University of Pennsylvania Schuster University of Alabama at Birmingham Pappas Emory University Lyon 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 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%) Drug-Drug interactions None Tacrolimus (20%), Cyclosporine increases caspofungin levels (35%), Caspofungin levels may be decreased by inducers Rifampin, phenytoin, dexamethasone,,.. Hepatotoxicity (2 4%) Anemia (2 4%) None 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 higherh steady-state t t blood concentrations. ti Indication 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 M ean Fluco onazole [s serum] 1.4 1.2 1 0.8 06 0.6 0.4 0.2 0 0 1 2 3 4 5 6 Dose Loading Dose No Loading Dose
Voriconazole Dosage and Administration Intravenous Oral Patients 40 kg and above Loading Dose Regimen (first 24 hours) Maintenance Dose (after first 24 hours) Serious Candida infections Empirical Therapy Invasive aspergillosis/ Scedosporium and Fusarium infections/ Other serious mould infections Two doses of 6 mg/kg 12 hours apart 4 mg/kg every 12 hours 4 mg/kg every 12 hours Two doses of 400 mg 12 hours apart 200 mg every 12 hours 200 mg every 12 hours If patient response is inadequate, increase dose to 4 mg/kg IV or 300 mg oral
Voriconazole Non-linear Pharmacokinetics 8 State n (μg/ml) Due to saturation of metabolism (Michaelis- 6 Menten kinetics) 5 Greater than proportional 4 increase in exposure with 3 increasing dose 2 On average, 1.5-fold oral dose escalation from 200 1 mg q 12 h to 300 mg q 12 0 h will lead to a 2.5-fold increase in exposure e Steady S centration Average sma Conc Pla 7 0 100 200 300 400 Twice Daily Dose (mg)
Therapeutic Drug Monitoring: Voriconazole o Serum Concentration o and Response se Succ cess (%) 100 80 60 40 20 0 Reponse to Voriconazole 100% Better responses in patients with higher levels 44% Improved outcomes with dose escalation in patients with levels < 2 mcg/ml <2.05 (n=18) > 2.05 (n=10) Serum concentration (mcg/ml) Smith J et al. Antimicrob Agents Chemother 2006;50:1570-2
Pharmacology: Mean Trough Concentrations of Caspofungin* Trou ugh Conce ntration, μg/m ml 2.00 1.75 1.50 1.25 1.00 0.75 0.50 0.25 (n=8) Target concentration: ti 1 μg/ml/ L 0 0 2 4 6 8 10 12 14 Time, days Mean plasma drug concentrations maintained above 1.0 μg/ml, a target chosen to exceed the MIC at which 90% of most clinically relevant Candida isolates were 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) 70% 60% 50% 40% 30% 20% 10% 0 11.60% 19.10% 65.80% Fluconazole Voriconazole Caspofungin
International Conference for the Development of Consensus on the Management and Prevention of Severe Candidal Infections Edwards JE et al Clin Infect Dis 1997:25;43 23
What Dose of Fluconazole Should be Used for the Treatment of Candidiasis Stable Patients 20 18 16 14 12 10 8 6 4 2 0 18 1 1 <400 mg 400 mg 800 mg > 800 mg 0 Edwards JE et al Clin Infect Dis 1997:25;43
What Dose of Fluconazole Should be Used for the Treatment of Candidiasis Deteriorating Patients 20 18 16 14 12 10 8 6 4 2 0 0 18 1 1 < 400 mg 400 mg 800 mg > 800 mg Edwards JE et al Clin Infect Dis 1997:25;43
Fluconazole Dosing in Candidiasis C. albicans (Normal Renal Function) % of patients 60 50 40 45 50 30 20 10 0 < 400 mg >400 mg Unknown 5
Fluconazole Dosing in Candidiasis C. glabrata (Normal Renal Function) % of patients 60 54 50 40 43 30 20 10 0 < 400 mg >400 mg Unknown 3
Fluconazole Dosing in Candidiasis C. Parapsilosis (Normal Renal Function) 60 50 40 43 53 30 20 10 0 < 400 mg >400 mg Unknown 4
Percentage of Patients on RRTx Hemodialysis (IHD) Dependent (n=420; 14%)
Percentage of Patients on RRTx with Candidiasis and Others Others Candidiasis (84%)
Distribution of Candida species for all Patients on Dialysis, and Patients on HD N=420 IFIs (from 365 patients on hemodialysis with Candida) C. albicans 218 (53%) C. glabrata 135 (32%) C. tropicalis 41 (10% C. kruseii 38 (10%) C. parapsilosis 45 (11%) C. lusitaniae 7 C. guillermondii 1 C. dubliniensis 3 Other Candida 5
Distribution of Candida species for Patients on Peritoneal dialysis, and Patients on CVVHD N=21 IFIs (from 21 patients on Peritoneal Dialysis with Candida) C. albicans 6 (28%) C. glabrata 6 (28%) C. parapsilosis 5 C. tropicalis 4 N=104 IFIs (from 93 patients on CVVRTx with Candida) C. albicans 65 (62%) C. glabrata 20 (21%) C. kruseii 9 C. Parapsilosis 9 C. tropicalis 9 C. lusitaniae 1 Other Candida 3
Overall 12 Week Mortality Rate (%) 100% 80% 60% 40% 50.30% 72.80% 38.10% 27.60% 20% 0 HD CVVRTx Peritoneal Not Dialysis i Dependent
12 Week Mortality Rate for Candidiasis Patients (%) 80% 70% 60% 50% 40% 30% 20% 10% 0 46.60% 69.90% 38.10% 27.90% HD CVVRTx Peritoneal Not Dialysis Dependent
12 Week Mortality Rate for Patients with Other Infections (%) 100% 80% 93.33% 60% 40% 20% 0 37.25% 28.09% HD CVVRTx Peritoneal Not Dialysis Dependent
Pharmacokinetic of Fluconazole in CVVRtx Pharmacokinetic study of critically ill patients undergoing hemodiafiltration (with a cellulose triacetate filter--high-flux, high ultrafiltration, surface 1.5 square meters), the average T1/2 is 9 hours trough plasma concentrations of fluconazole should be kept at or above 10 micrograms/milliliter for an effective concentration to inhibit most fungi. the recommended dosing regimen for fluconazole should be 500 or 600 milligrams every 12 hours for patients undergoing hemodiafiltration Yagasaki et al, Intensive Care Med 2003a; 29:1844-1848
Average Daily Dose of Fluconazole in patients on CVVRTx 60% 50% 40% 30% 20% 10% 0 50.94% 33.96% 13.21% 1.89% 100-199 200-299 300-400 others Dosage Range (mg)
Number of Patients Received Daily Dose of Fluconazole (All Patients) 80% 60% 40% 20% 0 57.25% 19.48% 0.84% 25.26% <6 6-12 >12 u/k Daily Dose (mg/kg)
Number of Patients Received Daily Dose of Fluconazole ( Normal Renal Function) nts Number of Patie 500 400 300 200 100 0 Daily Dose (mg/kg)
Average Dose of Fluconazole for Patient with CrCl Between 30-50 ml/min 50% 40% 30% 20% 10% 0 43.41% 43.41% 8.78% 2.93% 2.44% <200 200-299 300-400 400-800 u/k Dosage Range (mg)
Average Daily Dose of Fluconazole in Patients on RRTx 50% 40% 30% 20% 10% 0 20.38% 45.86% 5.73% 24.20% 4.46% <200 200-300 300-400 400-600 u/k Dosage Range (mg)
Number of Patients Received Daily Dose of Voriconazole Patients # of 200 180 160 140 120 100 80 60 40 20 0 30% 25% 35% 10% 2- <4 4- <6 6-<8 8-<10 >10 U/K Dosage Range (mg/kg/day)
Percentage of Patients on Low Dose of Caspofungin (avg. Daily Dose <50mg) Receiving i Caspofungin <50mg Daily Receiving Caspofungin Receiving Caspofungin >50mg Daily
Clinical use of Flucytosine Approximately 80 to 90 percent of 5-FC is absorbed b following oral administration i ti. Peak serum levels of 30 to 45 mcg/ml occur one to two hours after a single oral dose of 150 mg/kg we generally recommend that a total dose of 100 mg/kg per day be given orally in four equally divided doses at six hour intervals for adult and pediatric patients with normal renal function
Clinical use of Flucytosine 20-50 ml/min: 1/2 normal dose (12.5 mg/kg Q6h or 25 mg/kg Q12h) <20 ml/min: 1/4 (25 mg/kg once daily) Hemodialysis: 1/2 normal dose as supplement at end of dialysis Continuous ambulatory peritoneal dialysis in adults: 0.5 to 1.0 gm Q24h
Echinocandins: Indications and Dosing Caspofungin a 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 Candida infections b : intra-abdominal abscesses, peritonitis Not studied in sufficient number of neutropenic patients to determine efficacy in that group Empirical therapy for presumed fungal infections in febrile neutropenic patients Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (ie, amphotericin B, lipid formulations of amphotericin B, and/or itraconazole) Prophylaxis of Candida infections in HSCT patients 70 mg load; 50 mg QD 70 mg load; 50 mg QD Not studied as initial therapy for invasive aspergillosis 50 mg QD a Dosage adjustment to 35 mg QD after 70-mg loading dose recommended for moderate hepatic insufficiency. b * Not Approved studied Indication in endocarditis, by the osteomyelitis, Food and Drug and Administration meningitis due (FDA) to Candida. not approved indication in Saudi Arabia. HSCT = hematopoietic stem cell transplant; QD = once daily. Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information.
Conclusions A strong evidence of high prevalence of inappropriate prescribing Less than optimal dosing of fluconazole and voriconazole when given for the treatment t tof fcandida and mold ldinfections was noted Health care Providers should be more diligent for monitoring for inappropriate antifungal dosing schedule Future studies are needed to quantify the adverse health outcomes resulting from inappropriate drug use in this critical ill populations
High Expectations!
Estimated Annual Costs to US Economy Candida $3 billion Aspergillus $1 billion
Remember that a lot we do is based on: Obvious ideas TTWWADI (That is The Way We Always done It) Still lots of room for EMB
There are no facts, Just Interpretations 51