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

Invasive AspergillosisInitial 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 HospitalChang Gung University, Taiwan

2012-02-20

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 abscesses Endocarditis

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~ 1970~80 1997~ 2002~ 2004

Early Azoles ClotrimazoleMiconazole

Ketoconazole

Lipid Amphotericin BAmbisone

AbelcetAmphocil

2nd Tri-azole: VfendEchinocandins: Cancidas

PolyenesNystatin

Amphotericin B

1st Tri-azolesFluconazoleitraconazole

Micafungin

Posaconazole

1990~

Development of Anti-fungal Agents

Antifungal Drug Development

Targets for Antifungal Therapy

Lipid Formulations of Amphotericin B

Ambisome ® L-AMBAbelcet ® ABLC Amphotec ® ABCD

Phospholipidsheets/ribbons Cholesterol disks Liposomes

Targets for Antifungal Therapy

Azole Mechanism of Action

Pharmacology of Azole Antifungals

Echinocandins-Pharmacology

Beauvais et al. J Bacteriology 2001; 183: 2273.Kurtz et al. Antimicrob Agents Chemother 1994; 38: 1480.

Initiation of Antifungal Therapy

Morrell et al. Antimicrob Agents Chemother 2005; 49: 3640.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/culture

Aspergillus fungal burden

Evolution of Aspergillus infection

Probability of diagnosis of IAAntigenemia, DNAemia Angioinvasion, necrosis

Increase fu

ngal bburden, D

issemination

Postmortem

Antemortem

Immune Response to Inhaled Aspergillus Species

N Engl J Med 2009;360:1870-84.

COPD and Severe asthmaClin. Microbiol. Rev. 2009, 22(4):535.

Invasive AspergillosisChronic

NecrotizingAspergillosis

AspergillomasABPA

allergicsinusitis

Diseases caused by Aspergillus infection

Immune Response

PreexistingFibrocavitatory lung diseases

Structural lung diseaseGeneral debilitation

NeutropeniaHematopoietic Stem Cell TransplantationSolid Organ TransplantationAIDSChronic Granulomatous Disease

AsthmaBronchiectasisCystic fibrosis

Patients in MICUs ?

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

“Halo Sign” Is an Early Indicator of Invasive Pulmonary Aspergillosis

Halo SignHalo Sign

Greene RE, et al. Clin Infect Dis. 2007; 44:373-379.Greene RE, et al. Clin Infect Dis. 2007; 44:373-379.

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 1day, followed by 4 mg/kg IV every 12h; 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 aspergillosisTracheobronchial aspergillosisChronic necrotizing pulmonary aspergillosis (subacute invasive pulmonary aspergillosis)Chronic cavitary pulmonary aspergillosisgAspergillosis of the CNSAspergillus 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



AspergillomasABPA

allergicsinusitis


Immune Response





Patients in MICUs ?

Aspergillosis

Condition Primary Therapy Alternative Therapy

Chronic necrotizing pulmonaryaspergillosis (subacute invasivepulmonary aspergillosis)

Voriconazole (6 mg/kg IV every 12 h for 1day, followed by 4 mg/kg IV every 12h; oral dosage is 200 mg every 12 h)


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





AspergillomasABPA

allergicsinusitis


Immune Response





Patients in MICUs ?


Chronic cavitary pulmonaryaspergillosis

Itraconazole or Voriconazole


Aspergilloma No 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.





AspergillomasABPA

allergicsinusitis


Immune Response





Patients in MICUs ?

Aspergillosis


Allergic bronchopulmonaryaspergillosis

Itraconazole Oral 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



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 invasiveaspergillosis

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)


Surg

ery

in in

vasi

ve

aspe

rgill

osis

Pulmonary lesion in proximity togreat vessels or pericardium

Invasion of chest wall from contiguouspulmonary lesion

Aspergillus empyema

Persistent hemoptysis from asingle cavitary lesion

Infected vascular catheters andprosthetic devices

Sinusitis

Resection of pulmonary lesion

Resection of pulmonary lesion

Placement of chest tube

Resection of cavity

Removal of catheters and

devices

Resection of infected tissues

Voriconazole

Genus

Aspergillus Candida Fusarium Scedosporium

Species

• 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

PulmonaryEpithelial Lining Cells3

11 x Plasma

PulmonaryEpithelial Lining Cells3

11 x Plasma

Brain1

2–3 x Plasma

Brain1

2–3 x Plasma

Cerebrospinal Fluid2

0.5 x plasma

Cerebrospinal Fluid2

0.5 x plasma

Sources: 1. Elter T, et al. Int J Antimicrob Agents. 2006;28:262–265. 2. Lutsar I, et al. Clin Infect Dis. 2003;37:728–732. 3. Capitano B, et al. Antimicrob Agents Chemother. 2006;50:1878–1880.Sources: 1. Elter T, et al. Int J Antimicrob Agents. 2006;28:262–265. 2. Lutsar I, et al. Clin Infect Dis. 2003;37:728–732. 3. 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-0804007

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 Tipsof Aspergillus Hyphae

Control - NoCaspofungin exposure

Minimum EffectiveConcentration (MEC)

Allergic Bronchopulmonary Aspergillosis

1. A complex hypersensitivity reaction2. Asthmatics 3. Bronchi become colonized by Aspergillus4. Repeated episodes of bronchial obstruction,

inflammation, and mucoid impaction bronchiectasis, fibrosis

Clinical features• 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)

BilateralPulmonary infiltrates

Proximal bronchiectasis

Asthma, persistentHyphi in mucus plug

Viscid mucus plug

Cutaneous reactionSerum IgE and IgGTo A fumigatus

Indoor allergens(CGMH)

CAP- A

d1 (D

. pte

rony

ssim

us)

d2 (D

. far

inae)

i6 (C

ockr

oach

)

e1 (C

at d

ande

r)

e5 (D

og d

ande

r)

m5

(Can

dida)

0

10

20

30

40

50

60

70

80

90

100

Per

cen

tag

e(%

) 49.2% 49.8%

20.0%

7.2%11.3%

19.6%

Outdoor allergens(CGMH)

CAP- B

m1

(Pen

icillin

um)

m2

(Clad

ospo

rium

)

m3

(Asp

ergil

lus)

w1 (R

agwee

d)

g2 (B

erm

uda

gras

s)

t18

(Euc

alypt

us)

0

10

20

30

40

50 P

erce

nta

ge

(%)

11.5%

2.1%

8.4% 8.4% 8.4%

2.1%

Aspergillosis


Allergic bronchopulmonaryaspergillosis

Itraconazole Oral 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


Pathogenesis of ABPA

Aspergillus fumigatusLactophenol cotton blue

Magnification x 1000

Scanning electron micrograph of the fruiting heads of Aspergillus fumigatus

Initial Anidulafungin Therapy for Critical Ill Patients in MICU

2011-01 ~ 2011-04


2011-01 ~ 2011-04


2011-01 ~ 2011-04


2011-01 ~ 2011-04

Acinetobacter baumannii

MDR-AB

Extended Spectrum -lactamase (ESBL)

MRSA

VRE

Pseudomonas aeruginosa

Stenotrophomonas maltophilia

Tigecycline

CarbapenemImipenem Meropenem

Anti-pseudomonas antibiotics

Tazocin, Cefepem

Anti-pseudomonas Fluroquinolone

VancomycinLinezolid

Teicoplanin

FungusCandida

Aspergillus

Documents

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

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