Invasive Aspergillosis Initial Antifungal Therapy for Critical Ill Patients 林口長庚 胸腔內科 林鴻銓 Lin, Horng-Chyuan Head of Department of Internal Medicine, Taoyuan Branch of Chang Gung Memorial Hospital Associate Professor, Department of Thoracic Medicine Chang Gung Memorial Hospital Chang Gung University, Taiwan

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%)

Pulmonary Aspergillosis CNS aspergillosis Sinonasal aspergillosis Endophthalmitis Renal abscessesEndocarditis Cutaneous Osteomyelitis Invasive Aspergillosis

Risk Factors for Invasive Aspergillosis

Risk Factors for Invasive Aspergillosis in ICU Prolonged neutropenia Hematologic malignancy Allogeneic HSCT High Risk Prolonged corticosteroid therapy COPD Autologous HSCT Cirrhosis with duration of stay >7 days Solid-organ cancer HIV infection Lung transplantation Systemic disease requiring prolonged immunosuppression Intermediate Risk Severe burn Other solid-organ transplantation Corticosteroid therapy <7 days Prolonged stay in ICU Malnutrition Cardiac surgery Low Risk

Diagnosis of Invasive Aspergillosis Predictive values of the galactomannan assay Clinical Infectious Diseases 2006; 42:1417–27

Colonization-Prophylaxis-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

Antifungal Drug Development

Targets for Antifungal Therapy

Lipid Formulations of Amphotericin B Ambisome ® L-AMB Abelcet ® ABLC Amphotec ® ABCD Phospholipid sheets/ribbons Cholesterol disksLiposomes

Targets for Antifungal Therapy

Azole Mechanism of Action

Pharmacology of Azole Antifungals

Echinocandins-Pharmacology Beauvais et al. J Bacteriology 2001; 183: Kurtz et al. Antimicrob Agents Chemother 1994; 38: 1480.

Initiation of Antifungal Therapy Morrell et al. Antimicrob Agents Chemother 2005; 49: Garey et al. Clin Infect Dis 2006; 43: 25.

No infection subclinical infection Onset of symptoms Diagnosis Death Prophylaxis Preemptive Empirical therapy Targeted therapy High risk patients Culture-dependent biomarkers (GM, BG, PCR,Combination of tests?) HRCT Histopathology/cultur e Aspergillus fungal burden Evolution of Aspergillus infection Probability of diagnosis of IA Antigenemia, DNAemia Angioinvasion, necrosis Increase fungal bburden, Dissemination Postmortem Antemortem

Immune Response to Inhaled Aspergillus Species N Engl J Med 2009;360: COPD and Severe asthma Clin. Microbiol. Rev. 2009, 22(4):535.

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 ? Clin. Microbiol. Rev. 2009, 22(4):535.

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

Invasive Pulmonary Aspergillosis in Non-neutropenic Critically Ill Patients Risk factors COPD in combination with prolonged corticosteroid 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 ICU Alternatives 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

AspergillosisCondition Primary Therapy Alternative Therapy Invasive pulmonary aspergillosis Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h) L-AMB (3–5 mg/kg/day IV), ABLC (5 mg/kg/day IV), caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter), micafungin (IV 100–150 mg/day; dose not establishedc), posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of diseased), itraconazole (dosage depends upon formulation) Invasive sinus aspergillosis Tracheobronchial aspergillosis Chronic necrotizing pulmonary aspergillosis (subacute invasive pulmonary aspergillosis) Chronic cavitary pulmonary aspergillosisg Aspergillosis of the CNS Aspergillus infections of the heart (endocarditis, pericarditis, and myocarditis) Aspergillus osteomyelitis and septic arthritis ABLC, AMB lipid complex; AMB, amphotericin B; L-AMB, liposomal AMB IDSA Guidelines for Aspergillosis CID 2008:46:327–60

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 ?

AspergillosisCondition Primary Therapy Alternative Therapy Chronic necrotizing pulmonary aspergillosis (subacute invasive pulmonary aspergillosis) Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h) L-AMB (3–5 mg/kg/day IV), ABLC (5 mg/kg/day IV), caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter), micafungin (IV 100–150 mg/day; dose not establishedc), posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of diseased), itraconazole (dosage depends upon formulation) Because chronic necrotizing pulmonary aspergillosis requires a protracted course of therapy measured in months, an orally administered triazole, such as voriconazole or itraconazole, would be preferred over a parenterally administered agent ABLC, AMB lipid complex; AMB, amphotericin B; L-AMB, liposomal AMB IDSA Guidelines for Aspergillosis CID 2008:46:327–60

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 ?

AspergillosisCondition Primary Therapy Alternative Therapy Chronic cavitary pulmonary aspergillosis Itraconazole or Voriconazole L-AMB (3–5 mg/kg/day IV), ABLC (5 mg/kg/day IV), caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter), micafungin (IV 100–150 mg/day; dose not establishedc), posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of diseased), itraconazole (dosage depends upon formulation) AspergillomaNo therapy or surgical resection Itraconazole or voriconazole; L-AMB (3–5 mg/kg/day IV), ABLC (5 mg/kg/day IV), caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter), micafungin (IV 100–150 mg/day; dose not establishedc), posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of diseased), itraconazole (dosage depends upon formulation) Innate immune defects demonstrated in most of these patients; long-term therapy may be needed. ABLC, AMB lipid complex; AMB, amphotericin B; L-AMB, liposomal AMB IDSA Guidelines for Aspergillosis CID 2008:46:327–60

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 ?

AspergillosisCondition Primary Therapy Alternative Therapy Allergic bronchopulmonary aspergillosis ItraconazoleOral voriconazole (200 mg PO every 12 h) or posaconazole (400 mg PO BID) Corticosteroids are a cornerstone of therapy; itraconazole has a demonstrable corticosteroid-sparing effect IDSA Guidelines for Aspergillosis CID 2008:46:327–60

AspergillosisCondition Primary Therapy Alternative Therapy Empirical and preemptive antifungal therapy For empirical antifungal therapy, 1.L-AMB (3 mg/kg/day IV), 2.Caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter), 3.Itraconazole (200 mg every day IV or 200 mg BID), 4.Voriconazole (6 mg/kg IV every 12h for 1 day, followed by 3 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h) Prophylaxis against invasive aspergillosis Posaconazole (200 mg every 8h) Itraconazole (200 mg every 12 h IV for 2 days, then 200 mg every 24 h IV) or itraconazole (200 mg PO every 12 h); micafungin (50 mg/day ) IDSA Guidelines for Aspergillosis CID 2008:46:327–60

Surgery in invasive aspergillosis Pulmonary lesion in proximity to great vessels or pericardium Invasion of chest wall from contiguous pulmonary lesion Aspergillus empyema Persistent hemoptysis from a single cavitary lesion Infected vascular catheters and prosthetic devices Sinusitis Resection of pulmonary lesion Placement of chest tube Resection of cavity Removal of catheters and devices Resection of infected tissues

VoriconazoleGenus AspergillusCandidaFusariumScedosporiumSpecies A flavus A fumigatus A terreus A niger A nidulans C albicans C glabrata C krusei C parapsilosis C tropicalis C dubliniensis C inconspicua C guilliermondii Fusarium spp S apiospermum (asexual form of Pseudallescheria boydii) S prolificans

Voriconazole (VFEND ® ) Achieves High Drug Concentrations in Clinically Relevant Tissues Pulmonary Epithelial Lining Cells 3 11 x Plasma Pulmonary Epithelial Lining Cells 3 11 x Plasma Brain 1 2–3 x Plasma Brain 1 2–3 x Plasma Cerebrospinal Fluid x plasma Cerebrospinal Fluid x plasma Sources: 1. Elter T, et al. Int J Antimicrob Agents. 2006;28:262– Lutsar I, et al. Clin Infect Dis. 2003;37:728– Capitano B, et al. Antimicrob Agents Chemother. 2006;50:1878–1880. VFEND volume of distribution at steady state is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues VFE-M

Voriconazole - Invasive Aspergillosis Complete or Partial Response at 12 weeks (%) Herbrecht et al. N Engl J Med 2002; 347: 408.

Voriconazole Fungicidal Activity Lewis et al. Antimicrob Agents Chemother 2005; 49: 945.

Echinocandins Act at the Apical Tips of Aspergillus Hyphae Control - No Caspofungin exposure Control - No Caspofungin exposure Minimum Effective Concentration (MEC) Minimum Effective Concentration (MEC)

Allergic Bronchopulmonary Aspergillosis 1.A complex hypersensitivity reaction 2.Asthmatics 3.Bronchi become colonized by Aspergillus 4.Repeated episodes of bronchial obstruction, inflammation, and mucoid impaction  bronchiectasis, fibrosis 1.A complex hypersensitivity reaction 2.Asthmatics 3.Bronchi become colonized by Aspergillus 4.Repeated episodes of bronchial obstruction, inflammation, and mucoid impaction  bronchiectasis, fibrosis

Clinical features Asthma complicated by Asthma complicated by – Recurrent episodes of bronchial obstruction – Fever – Malaise – Expectoration of brownish mucous plugs – Peripheral blood eosinophilia – Hemoptysis – Wheezing not always evident – Some with asymptomatic pulmonary consolidation Asthma complicated by Asthma complicated by – Recurrent episodes of bronchial obstruction – Fever – Malaise – Expectoration of brownish mucous plugs – Peripheral blood eosinophilia – Hemoptysis – Wheezing not always evident – Some with asymptomatic pulmonary consolidation

Allergic Bronchopulmonary Aspergillosis (ABPA) Bilateral Pulmonary infiltrates Proximal bronchiectasis Asthma, persistent Hyphi in mucus plug Viscid mucus plug Cutaneous reaction Serum IgE and IgG To A fumigatus

Indoor allergens (CGMH) 49.2%49.8% 20.0% 7.2% 11.3% 19.6%

Outdoor allergens (CGMH) 11.5% 2.1% 8.4% 2.1%

AspergillosisCondition Primary Therapy Alternative Therapy Allergic bronchopulmonary aspergillosis ItraconazoleOral voriconazole (200 mg PO every 12 h) or posaconazole (400 mg PO BID) Corticosteroids are a cornerstone of therapy; itraconazole has a demonstrable corticosteroid-sparing effect IDSA Guidelines for Aspergillosis CID 2008:46:327–60

Pathogenesis of ABPA

Aspergillus fumigatus Lactophenol cotton blue Magnification x 1000 Scanning electron micrograph of the fruiting heads of Aspergillus fumigatus

Initial Anidulafungin Therapy for Critical Ill Patients in MICU ~

Initial Anidulafungin Therapy for Critical Ill Patients in MICU ~

Initial Anidulafungin Therapy for Critical Ill Patients in MICU ~

Initial Anidulafungin Therapy for Critical Ill Patients in MICU ~

Acinetobacter baumannii MDR-ABMDR-AB Extended Spectrum  -lactamase (ESBL) MRSAMRSA VREVRE Pseudomonas aeruginosa Stenotrophomonas maltophilia Tigecycline Carbapenem Imipenem Meropenem Anti-pseudomonas antibiotics Tazocin, Cefepem Anti-pseudomonas Fluroquinolone Vancomycin Linezolid Teicoplanin FungusCandidaAspergillusFungusCandidaAspergillus