Initial Antifungal Therapy for Critical Ill Patients When and Which ? 林口長庚 胸腔內科 林鴻銓 Lin, Horng-Chyuan Division of Pulmonary Infectious & Immunological Disease Department of Thoracic Medicine Chang Gung Memorial Hospital Chang Gung University

Fungal Infections in the ICU Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients, Critical Care 2008, 12:R5 Characteristics of fungal infection Aspergillus and Candida (75%)

Cause of infection (%) CoNSStaph Entero- coccus Candida Pseudo- monas Candida - the Third Most Common Cause of BSI in the ICU BSI=Blood stream infection. ICU=Intensive care unit. Wisplinghoff H et al. Clin Infect Dis. 2004;39: Cause of nosocomial BSI in the ICU (US; ) % 16.8% 9.8% 10.1% 4.7%

US ( ; N=3683) More than 50% of Systemic Candida Infection - Caused by Candida albicans Europe ( ; N=775) Pfaller MA et al. Clin Microbiol Infect. 2004;10(suppl 1): % C glabrata 18% 14% C parapsilosis 13% 8% C tropicalis 10% 5% Other spp 2% 3% C krusei 2% C albicans C albicans 58% C albicans C albicans 54%

Consensus Statement on the Management of Invasive Candidiasis in ICU in the Asia-Pacific Region Distribution of Candida spp. associated with candidaemia in selected Asian countries International Journal of Antimicrobial Agents 34 (2009) 205–209

Risk Factors for Invasive Candidiasis Use of antibacterials Neutropenia Colonization Damaged mucosa The catheter Underlying Diseases Host factors Medical interventions Candida colonization

Risk Factors for Invasive Candidiasis Host factors Medical interventions Candida colonization 1.Extremes of age 2.Neutropenia 3.Renal failure 4.Higher APACHE II score 5.Trauma/burns 6.Bowel perforation 1.Chemotherapy 2.Dialysis 3.Central venous catheters 4.Antibiotic use (risk increases with each additional antibiotic) 5.Parenteral nutrition 6.Prior surgery (especially abdominal) 7.Length of ICU stay of 7 days 8.Nasogastric tubes 9.Gastric acid suppression

Diagnostic Tests for Invasive CandidiasisCultureHistologyAntigenAntibody Enolase mannan PCR 1-3-β-D-glucan C-reactive protein (CRP) Procalcitonin (PCT) Interleukin-6 (IL-6) Colonization Infection Invasion

Early Antifungal Intervention Strategies in ICU Patients Risk factors without evidence for colonization Prophylaxis Risk factors and colonization with Candida in the absence of symptoms Preemptive therapy Symptoms suggesting sepsis and risk factors before the documentation of infection Empirical therapy Antifungal therapy Crit Care Med 2010; 38[Suppl.]:S380 –S387

1950~ 1970~ ~ 2002~ 2004 Early Azoles Clotrimazole Miconazole Ketoconazole Lipid Amphotericin B Ambisone Abelcet Amphocil 2 nd Tri-azole: Vfend Echinocandins: Cancidas Polyenes Nystatin Amphotericin B 1st Tri-azoles Fluconazole itraconazole Micafungin Posaconazole 1990~ Development of Anti-fungal Agents

Invasive Aspergillosis Chronic Necrotizing Aspergillosis Aspergillomas ABPA allergic sinusitis Diseases caused by Aspergillus infection Immune Response Preexisting Fibrocavitatory lung diseases Structural lung disease General debilitation Neutropenia Hematopoietic Stem Cell Transplantation Solid Organ Transplantation AIDS Chronic Granulomatous Disease Asthma Bronchiectasis Cystic fibrosis Patients in MICUs ?

“Halo Sign” Is an Early Indicator of Invasive Pulmonary Aspergillosis Halo Sign Greene RE, et al. Clin Infect Dis. 2007; 44: VFE-M

Invasive Pulmonary Aspergillosis in Non-neutropenic Critically Ill Patients Risk factor COPD in combination with prolonged corticosteroi d use High-dose systemic corticosteroids >3weeks (prednisone equivalent >20 mg/day) Chronic renal failure with renal replacement therapy Diabetes mellitus Near- drowning Liver cirrhosis/ acute hepatic failure Intensive Care Med (2007) 33:1694–1703

Antifungal Drugs for Invasive Pulmonary Aspergillosis in Critically Ill Patients in ICUAlternatives Liposomal amphotericin B 3-5 mg/kg/day i. v. Amphotericin B deoxycholate 1 mg/kg/day i. v. Caspofungin 70mg i.v. on day 1, then 50 mg/day i. v. First choice Voriconazole 6mg/kg q 12 h i.v. on day 1, then 4mg/kg q 12 h i.v. Voriconazole 400 mg q 12 h oral on day 1, then 200 mg q 12 h oral Primary therapy of IPA Intensive Care Med (2007) 33:1694–1703