Update on Candida Infection Nov PDF Free Download

Update on Candida Infection Nov. 2010 Gary Wong Pharmacy Clinical site leader University Health Network Course coordinator University of Toronto

Goals What is an yeast infection Risk factors for yeast infections Understand the mechanism of action, kinetics, and adverse affects of antifungal agents Understand the roles of various antifungal agents as define by the guidelines

Fungi Yeast like Candida albicans C. glabrata C. parapsilosis C. tropicalis C. krusei Pneumocyctis jirovecii Crytococcus neoformans Blastomyces dermatitidis Histoplama capsulatum Molds Aspergillus spp. mucormycosis

Oropharyngeal Candidiasis Esophageal Candidiasis Candidiasis (line, Gut) Candida Vaginitis

Nosocomial Bloodstream Infections in US Hospitals: 95-02 Rank Pathogen BSI per 10,000 admissions Total (n=20,978) % BSI % Crude Mortality ICU (n=10,515 ) Non-ICU (n=10,515) Total ICU 1. CoNS 15.8 31.3 35.9 26.6 20.7 25.7 13.8 2. S. aureus 10.3 20.2 16.8 23.7 25.4 34.4 18.9 3. Enterococcus spp. Non- ICU 4.8 9.4 9.8 9.0 33.9 43.0 24.0 4. Candida spp. 4.6 9.0 10.1 7.9 39.2 47.1 29.0 5. E. coli 2.8 5.6 3.7 7.6 22.4 33.9 16.9 6. Klebsiella spp. 2.4 4.8 4.0 5.5 27.6 37.4 20.3 BSI=blood stream infection; CoNS=coagulase-negative staphylococci Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) study Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317.

Risk Factors for Candida Multiple antibiotics- > 3 antibiotics High APACHE score - predictive of infection and mortality Burns- burn size > 50% Central venous lines- CV catheters, Hickman Renal failure- prior hemodialysis TPN, total parenteral nutrition Multiple Sites (>2) colonization Major surgery- abdominal, cardiothoracic Transplantation- Liver Neutropenia- depth and duration of neutropenia Duration of stay in ICU Pfaller, Epidemmiology Clin Micr Rev. 2007 20:133-163

Risk Factors Invasive Candidiasis High-risk patients Surgery Leukopenia Burns Premature infants Risk Factors ICU >7 days CVCs Antibiotics TPN Colonization If candidemia develops ~40% die ~60% survive Rex JH, et al. Adv Intern Med. 1998;43:321-369. Pappas PG, et al. Clin Infect Dis. 2003;37:634-643.

Antifungal therapy Cell membrane Polyene: Amphotericin B, Nystatin Azoles: Fluconazole, itraconazole, voriconazole, Posaconazole. Cell wall Echinocandins: Caspofungin, Micafungin, Anidulafungin Nucleoside analog: Flucytosine

Amphotericin B Nystatin

Amphotericin B A Polyene molecule which is not water soluble Comes from Streptomyces nodosus Binds to the ergosterol molecules in the membrane of the fungus. This binding makes the membrane dysfunctional and electrolyte imbalances occur. A broad spectrum activity Kills most Candida spp. and Aspergillosis.

Amphotericin B

Adverse effects Amphotericin B Infusion related side effects: fever, chills, rigors, aches, and hypoxia. Nephrotoxicity in 25% of patients Hypokalemia Hypomagnesemia Drug interactions Avoid other nephrotoxic agents

Lipid Amphotericin B products Abelcet lipid complex, AmBisome liposomal These products are Amphotericin which is combined with a lipid molecule which binds the amphotericin B. Prodrug.

phospholipid bilayer amphotericin B molecules Ref: Clin Infect Dis 1996; 22(Suppl2):S133-44.

amphotericin B - OH + OH OH + OH - Hydrophilic Region OH OH OH OH Hydrophobic Region OH OH OH OH - OH Schematic Representation + OH OH + OH cholesterol - Hydrophilic Region

Lipid Amphotericin B products AmBisome Less infusion related side effects Less renal toxicity Same efficacy Dose: 3mg/kg vs 5mg/kg Febrile Neutropenia: Wingard CID 2000:31:1155-63 Invasive Aspergillosis: Cornely CID 2007; 44:1289-97

Organism Comparative In Vitro Activity Against Candida MIC 90 (µg/ml) n POS FLZ ITZ VOR AMB All Candida spp 6965 1.0 16.0 1.0 0.5 1.0* C albicans 3535 0.063 2.0 0.25 0.063 1.0* C glabrata 1218 2.0 64.0 4.0 2.0 1.0* C parapsilosis 970 0.25 4.0 0.5 0.125 1.0 C tropicalis 719 0.25 4.0 0.5 0.5 1.0 C krusei 189 1.0 64.0 1.0 0.5 2.0 C lusitaniae 84 0.25 4.0 2.0 0.063 2.0 C guilliermondii 26 1.0 32.0 4.0 8.0 1.0 C dubliniensis 164 0.125 32.0 0.5 0.125 1.0 Candida spp 60 2.0 16.0 1.0 0.25 1.0 *Number of strains tested against AMB was slightly less for all Candida (n = 6921), C albicans (n = 3517), and C glabrata (n = 1192). Includes strains of C famata, C kefyr, C lipolytica, C pelliculosa, C pseudotropicalis, C rugosa, C sphaerica, C stellatoidea, and C zeylanoides. Sabatelli F et al. Antimicrob Agents Chemother. 2006:2009-2015.

Organism Comparative In Vitro Activity Against Molds and Other Fungi n MIC 90 (µg/ml) POS ITZ VOR AMB All molds 1702 1.0 2.0 2.0 2.0 Aspergillus spp 1423 0.5 2.0 0.5 1.0 Dimorphic fungi 151 0.25 0.25 ND 0.5 Fusarium spp 67 32.0 32.0 32.0 32.0 Zygomycetes 86 4.0 32.0 128.0 2.0 Agents of chromoblastomycosis, mycetoma, and phaeohyphomycosis 241 16.0 64.0 ND 32.0 Other molds* 58 0.5 1.0 0.5 2.0 *Includes strains of Acremonium, Basidiomycetes, Bjerkandera, Coprinus, Paecilomyces, Pseudallescheria, Schizophyllum, and Trichophyton. Sabatelli F et al. Antimicrob Agents Chemother. 2006:2009-2015.

Azoles Inhibit CYP450 enzyme lanosterol 14- demethylase prevent conversion of lanosterol to ergosterol significant drug interactions

Azoles

Triazoles Adverse effects Well-tolerated Rare instances of elevated liver enzymes Visual (Vori) QT (Vori and Posa) Resistance C. krusei, C. glabrata with fluconazole

Pharmacokinetics Fluconazole Voriconazole Posaconazole Dose 400 mg 200 mg 400 mg (800 mg empiric) absorption 90% 90% N/a Protien binding 11% 99.5% 80% C max (mg/l) 6.7 2.1-4.8 0.12-0.38 ½ Life (hr) 30 6 25.6-34 Elimination Renal 80% Hepatic Hepatic CID 2009: 48:1441-58 Tx Med Letter Jan 2008; 6 (65)

Pharmacokinetics Pearls Fluconazole Voriconazole Posaconazole Food None Decrease Increase Hepatic Weak CYP2C9 CYP CYP3A4 CYP2C19 CYP3A4 (400% fatty) CYP3A4 PPI None Omeprazole Increase 15-41% Place in Therapy Candida limited spectrum Aspergillosis SE Esomeprazole Derease 33% Prophylaxis BMT Limited indications CID 2009: 48:1441-58 Tx Med Letter Jan 2008; 6 (65) Vori vs AMB. NEJM 2002; 347:408-415, 2002 Cornely OA, N Engl J Med 2007; 356:348 59.

Echinocandins New class of agents -Caspofungin (Cancidas, Merck, 2001) -Micafungin (FK463, Fujisawa, 2007) -Anidulafungin (Pfizer, 2008)

Echinocandins

Echinocandin Echinocandin antifungal, amine polypeptide. Inhibits synthesis of ß-(1,3)-D-glucan Disrupts cell wall integrity & osmotic stability Causes cell lysis ß-(1,3)-D-glucan not present in mammalian cells

Echinocandins Mannoproteins -(1,6)-Glucan -(1,3)-Glucan GS Ergosterol Chitin -(1,3)- Glucan Synthesis

Echinocandins Pharmacokinetic Poor absorbed orally, only used IV Well distributed therapeutic concentrations in lung, liver, large intestine, spleen, kidney Minimal CSF & eye penetration. Elimination: Hepatic

Pharmacokinetics Caspofungin Micafungin Anidulafungin Dose 50 mg 50 mg 50 mg (target dose) (70/50) (100) 200/100 Protien binding 96.5% 99.5% 80% C max (mg/l) 10.5 4.4 2-3.5 ½ Life (hr) 9-11 13 25.6-34 Elimination Hepatic Hepatic Chem&Hepatic Hydrolysis, N-acetylation and spontaneous degratation Stone ACC 2002;46:739-745, Mukai ICAAC 2001 Thye ICAAC 2002, Abstracts A-34, 1391, 1392 Dowell et al. J Clin Pharmacol 2004;44:590-598 Hiemenz et al. AAC 2005;49:1331-1336 Primarily hepatic by arylsulfatase and COMT Slow non-enzymatic degradation to inactive metabolites

Echinocandin S/E Neutropenia (Micafungin 1.2%, Anidulafungin 1%) thrombocytopenia (Caspofungin <4%) Nausea and vomiting 3% Elevated AST/ALT: (Caspofungin 11-24%). Hypokalemia: (Caspofungin <4%). Phlebitis: (Caspofungin, Anidulafungin) Eschenauer G et al. Ther Clin Risk Man 2007;3:71-97 Pappas P, Rotstein C, Betts RF et al. CID 2007;45:883-893

In Vitro Activity of Echinocandins Against Bloodstream Isolates of Candida Species Species No. of isolates tested Results for: ANID CASP MICA MIC 90 % 2 g/ml MIC 90 % 2 g/ml MIC 90 % 2 g/ml C. albicans 2,869 0.06 100 0.06 100 0.03 100 C. glabrata 747 0.12 99.9 0.06 99.9 0.015 100 C. tropicalis 625 0.06 100 0.06 99.8 0.06 100 C. krusei 136 0.06 100 0.25 100 0.12 100 C. parapsilosis 759 2 92.5 1 99.9 2 100 C. guilliermondii 61 2 90.2 1 95.1 1 100 All Candida spp. 5,346 2 98.8 0.25 99.9 1 100 Pfaller MA et al. J Clin Microbiol 2008;46:2620-2629

In Vitro Activity Antifungal Agents Against Aspergillus fumigatus Antifungal drug MIC 50 µg/ml MIC 90 µg/ml Anidulafungin 0.03 0.03 Amphotericin B 0.5 1 Caspofungin a 0.06 0.25 Itraconazole 0.06 0.12 Voriconazole < 0.03 0.12 a Expressed as minimal effective concentration (MEC) Vazquez JA, Sobel JD. Clin Infect Dis 2006;43:215-222

Case 1 HS 45 yrs male present with oral thrush and Rx Nystatin 5mL S and S, then fluconazole. Present to General surgery floor with Intra abd infection, Day 3 goes to OR to have a collection drained, and now day 4 ICU being consulted. Patient temp 39.0 C and WBC is 12.0 PHM: Liver Tx August 2010 for Hepatitis B Recent thrush 3 weeks ago Hepatitis B in 1990 from blood transfusion SBP 2009 (E.coli) Tx Cipro Gi bleed 2008, Ascities, Jaundice, Allergies: None Current medication Tacrolimus 4mg bid, Prednisone 20 mg daily Lamivudine 100 mg daily Ceftriaxone 1g iv daily Metronidazole 500mg iv q12h. Morphine 2-4mg q4h PRN

Risk level Temperature Prophylaxis Treatment Theories Empiric/Pre emptive Specific 40 39 38 37 36 Colonization Ag test: 1,3 glucan Blood and sterile site positive 10 5 2.5 00 Immunosuppressive Rx Antibiotics Central lines TPN Surgery 0 1 2 3 4 5 6 7 8 9 Days in ICU Remote Probable disease Proven

Antifungal Prophylaxis High risk SICU Meta-analysis 45 RCT trials review used only 6 RCT trials Development of Candidemia and nonbloodstream IFI Konstantinos CCM 2006 34:1216-1224

Antifungal Prophylaxis High risk SICU Meta-analysis Mortality Konstantinos CCM 2006 34:1216-1224

Empiric Therapy Double blinded, RCT, 26 us hospital 95-00 18 yrs older, > than 96 hours ICU, and fever (38.3c) three occassions APACHE II >16 Broad spectrum antibiotic Central venous catheter Exclusion LFTS 5 times the upper limit neutropenia, HIV, organ or bone marrow transplantation, burns Schuster, Ann Intern Med. 2008; 149:83-90.

Therapy Empiric Therapy Fluconazole 800 mg for 14 days Placebo for 14 days Outcome at 4 days 38.3C, fungal infection, use of antifungal, D/C therapy from S/E Secondary: Discharge, mortality at 30 days Assessment by committee of 6 members Schuster, Ann Intern Med. 2008; 149:83-90.

Results Fluconazole (133) Placebo(137) Success: 44 (36%) 48 (38%) (RR, 0.95 [CI, 0.69 to 1.32]; P 0.78) Mortality: 29 (24%) 22 (17%) (RR, 1.36 [CI, 0.82to 2.24]; P 0.23) Schuster, Ann Intern Med. 2008; 149:83-90.

Candida score Non neutropenic Critically Ill Patients. Prospective observational Multi-center (70 hosp) study in Spain 1699 patients >18 yrs, 7 to 73 days ICU, May 1988 to Jan 1999 Neutropenic patients excluded Surveillance: Stats Weekly: ET, GI aspirate, Urine On discretion: Blood, Lines, feces, wound, drainage patients with sepsis had Ophthalmic exams 65% of the data was used to calculate odds ratio, logistic regression and Form the score 35% of the data was used to validate the model Power of the score was evaluated receiver operating characteristic Leon CCM 2006 34:730-737

Candida score Non neutropenic Critically ill Patients. Number (%) APACHE II Mortality Odds Ratio 95% Non-Colonized 719 (43%) 18 33.3% 1 Colonized Unifocal Multi-focal 103 (26.5%) 252 (50.9%) 18 26.5% 50.9% 1.04 (0.8-1.4) 1.54 (1.2-1.9) Proven Candida infection 97 (5.8%) 17 57.7% 3.2(2.0-5.0) Candidemia 58, Endophthalmitis 6 Peritonitis 30, Peritonitis and blood 3 Leon CCM 2006 34:730-737

Candida score Non neutropenic Critical ill Patients. Leon CCM 2006 34:730-737

Candida score Variable Coefficient Values TPN 0.908 1 Surgery 0.997 1 Multi-focal colonization 1.112 1 Severe Sepsis 2.038 2 Total =Score Value of 2.5= sensitivity of 81%, specific 74% Risk ratio=7.75 95% CI proven fungal infection Leon CCM 2006 34:730-737

Antifungal vs Time 192 patients in 4 US Hosp (2002-05) Mortality % 45 40 35 30 25 20 15 10 5 0 Day <1 Clin Inf Dis 2006; 43:25-31 Day 1 Day 2 Time to therapy Day >3 All Pts Appropriate P<0.0009

Clinical Infectious Diseases 2009; 48:503 35

Therapeutic concepts Prophylaxis ICU For ICU patients, fluconazole at a dosage of 400 mg (6 mg/kg) daily is recommended for high-risk patients in adult units with a high incidence of invasive candidiasis (B-I). Clinical Infectious Diseases 2009; 48:503 35

Invasive Candidiasis RCT Fluconazole vs others 3 RCT of Amphotericin vs Fluconazole Rex, J N Engl J Med 1994;331:1325-30 Phillips, P Eur J Clin Micr ID 1997:16:337-45 Anaissie E; CID 1996;23:964-72 Anidulafungin vs Fluconazole Anidul 200/100mg vs Fluconazole 800/400mg Annette C; NEJM 2007; 356:2472-2482

Invasive Candidiasis RCT Echinocandins vs others Caspofungin vs AmB Caspo 70/50 vs AmB 0.6 mg/kg Mora-Duarte J N Engl J Med 2002 347:2020-9 Micafungin vs other Mica vs Lipid AmB 3mg/kg Kuse, ER, et al. Lancet 2007;362(9330):1519-27 Mica 100mg, Mica 150mg vs Caspo 70/50mg Pappas PG, Clin Infect Dis 2007; 45:883-93.

Invasive Candidiasis RCT Voriconazole vs others Voriconazole vs Lipid Amb Vori 6mg/kg then 3mg/kg vs Lipid AmB 0.3 mg/kg Bj Kullberg, Lancet 2005 366:1435-1442

HS: Blood gram stain grows Yeast What agent would you choose? Fluconazole or Enchinocandin (A-I) When would you prefer Enchinocandin? Echinocandin for (A-III) Unstable patients Patient With previous azole exposure Clinical Infectious Diseases 2009; 48:503 35

Cultures non abicans Germ tube test Negative non albicans

Clinical Infectious Diseases 2009; 48:503 35

HS: Blood gram stain grows C. krusei What agent would you choose? Step down therapy Enchinocandin IV therapy Voriconazole oral therapy Clinical Infectious Diseases 2009; 48:503 35

Vori Mic J CLINICAL MICRO Mar. 2006, 44: 819 826

HS: Blood gram stain grows C. glabrata What agent would you choose? Step down therapy Enhinocandin continue Azole clinically improving, and follow-up culture negative (B- III) MIC (14 days) Clinical Infectious Diseases 2009; 48:503 35

Fluc and Vori vs C. glabrata Pfaller, Clin Micr Rev. 2007 20:133-163

HS: Blood gram stain grows C. parapsilosis What agent would you choose? Step down therapy Candida parapsilosis Fluconazole Enchinocandin if Clinically improving and follow-up culture negative (B-III) Clinical Infectious Diseases 2009; 48:503 35

Canadian Approvals? flucytosine 1994 fluconazole 1996 itraconazole 1995 ketoconazole 1997 ABLC (Abelcet) 2000 liposomal amphotericin B (AmBisome) 2001 amphotericin B 2001 caspofungin 2004 voriconazole 2007 micafungin 2007 posaconazole 2008 Anidulafungin

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