Gestione pratica delle infezioni fungine in terapia intensiva

Gestione pratica delle infezioni fungine in terapia intensiva

Matteo BassettiMatteo Bassetti

Clinica Malattie infettiveClinica Malattie infettive

A.O.U. San Martino A.O.U. San Martino

GenovaGenova

Relationship between hospital mortality and the timing of antifungal treatment

Ho

spit

al m

ort

alit

y (%

)

0

35

30

25

20

15

10

5

< 12

Delay in start of antifungal treatment (hours)

12–24 24–48 > 48

Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5

Mortality associated with Candida infections in ICU

Variable Mortality rate (%)*

Department

Medical

Surgical

58

37

Candida species

C. albicans

C. parapsilosis

C. glabrata

36

33

69

Overall 41

*Crude mortality.

Tortorano AM, et al. 3rd TIMM. Turin, Italy,28–31 Oct 2007; Oral communication O.07

p < 0.01 by log-rank test

0 7 14 21 28

0.1

0.2

0.3

0.4

0.5

0.6

Days

Pro

port

ion

in

fect

ed

Placebo

Fluconazole

260 surgical ICU patients (stay > 3days) randomizedto double-blind oral antifungal prophylaxis

Pelz Ann Surg 233:542-548, 2001

Fluco in High-risk SICU patients

Prophylaxis in the (S)ICU Pelz et al., Ann Surg 233:542-548, 2001

- Fluco vs. placebo in extremely high risk ICU- Placebo: 16% rate of invasive candidiasis

This rates equals that in BMT- Fluco 400/d: 8% rate- P < 0.01

A very unusual population- Median APACHE III = 60, lots of liver transplant- Applicability in most ICUs is unclear

Sandven CCM 2002

Sandven et al.: Low-risk surgical patientsDouble-blind single-dose antifungal prophylaxis in

109 patients with intra-abdominal perforation

10%

43%

7,5%10%

34%

14%

0

10

20

30

40

50

60 %

Emergence ofcolonization

Complications Death

NS

NS

NS

RESULTS OF CANDIDA PROPHYLAXIS IN ICU PATIENTS

RESULTS OF CANDIDA PROPHYLAXIS IN ICU PATIENTS

0

20

40

60

80

100 %

Successof

prophylaxis

Emergencecolonizationby Candida

Deathfrom

any cause

Invasivecandidosis

Candidemia

Fluconazole 100 mg/dPlacebo

53

78%

P<0.01

66

30%

P<0.001

39 41%

NS

3%7%

NS

06%

P=0.014

Garbino et al. Intensive Care Med 2002;28:1708-1717

Antifungals in critically ill and surgical patients: meta-analysis

NNT= 94 NNT in high-risk= 9 NNT in low risk= 188

Impact on Candidal infections Impact on mortality

Playford et al. JAC 2006; 57: 628–638

PROPHYLACTIC FLUCONAZOLE…..PROPHYLACTIC FLUCONAZOLE…..

• HAS ELIMINATED CANDIDA COLONISATION!

More patient comfort



……..BUT……..BUT



• DID NOT REDUCE MORTALITY

• HAS SELECTED RESISTANT CANDIDA SPECIES



• DID NOT REDUCE MORTALITY

• HAS SELECTED RESISTANT CANDIDA SPECIES

◊ incidence of candidemia episodes/10 000 patient-days/year;

■ DDD’s of fluconazole x 100 pts/days Figure 1.

0,00

0,50

1,00

1,50

2,00

2,50

3,00

3,50

Y 1999 Y 2000 Y 2001 Y 2002 Y 2003

Years observed

Inci

denc

e of

can

dide

mia

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Fluc

onaz

ole

DD

D's

x 1

00 p

ts/d

ays

Shift from CA to CNA

Bassetti M et al. BMC Infect Dis 2006; 10: 621

Restriction of prophylactic fluconazole use Bassetti et al – JAC 2009; 64:625-629

Med-surg ICU (500 adm./an)

108 months (Jan 99-Dec 2007)

Overall prevention of NI unchanged

213 candidemia (1.42/10 000 patient-days)

albicans (46%), parapsillosis (22%), glabrata 13%

Intervention:

Janv 1999-Janv 2003: Extensive Prophylaxis

Janv 2003-Dec 2007:Incitation not to do

Statistical analysis:

Segmented linear regression

Incidence of Candidemia and fluconazole in ICU

Stop fluco

Stop fluco

Bassetti M et al. J Antimicrob Chemother 2009: 64:625-9.

Non-albicans candidaemia

C. albicans candidaemiaX

So what about pre-So what about pre-emptive therapy with emptive therapy with

predicitive rules?predicitive rules?

Candida Score

Leon C et al. Crit Care Med 2006; 34:730- 737

Candida score validation

León C et al Crit Care Med. 2009;37:1624-33

Other Predictive rules

The best performing predictive rule was:

Patients in the ICU >4 daysAND Any systemic antibiotic (days 1–3)OR Central venous catheter (days 1–3)AND at least two: Total parenteral nutrition (days 1–3) Any dialysis (days 1–3) Major surgery (days -7–0) Pancreatitis (days -7–0) Any use of steroids (days -7–3) Immunosuppressive agents (days -7–0)

Ostrosky-Zeichner et al. Eur J Clin Microbiol Infect Dis 2007

0

100

200

300

400

500

600

_____

_____

_____ _____

(13)-β-D-GLUCAN CONCENTRATIONS

CBSI: proven Candida BSI PCBSI: possible Candida BSI NCBSI: no Candida BSICONTROLS: healthy volunteers

Horizontal bars indicate median values

CBSI PCBSI NCBSI CONTROLS

BG valuesPg/ml

Del Bono V et al. 49th ICAAC, 2009

Criteria to start pre-emptive antifungal therapy

Pz. In ICU ≥ 4 days.

Abx in the last 7 daysO

CVC from 7 days

2 of the following:•Total parenteral nutrition (days 1–3)• Any dialysis (days 1–3)• Major surgery (days -7–0)• Pancreatitis (days -7–0)• Any use of steroids (days -7–3)• Immunosuppressive agents (days -7–0)

Candida colonization or (1-3)-ß-D-glucan

•Start antifungal

Different antifungal strategies

Bassetti M et al. Crit Care 2010 December 1

Bassetti M et al. Crit Care 2010 December 1

Empiric use of antifungals in the ICU setting

Still no good data clinical for empiric antifungal therapy in the non-neutropenic population

Follow fundamental principles for treating candidemia Utilize serologic markers, surveillance cultures, and/or

a ‘scoring system’ to determine most appropriate use Duration of therapy not specifically addressed,

although the implication is to curtail therapy in stable patients absent positive culture/serologic data

Pappas PG, et al. Clin Infect Dis 2009; 48: 503–35

15 July 2008

Fluconazol Placebo 95% CI / P-value

n (ITT) 133 137

Success 44 (36%) 48 (38%) 0.69–1.32; P = 0.78

Invasive mycosis 6 (5%) 11 (9%) RR 0.57; 0.22–1.49

30-Day mortality 29 (24%) 22 (17%) RR 1.36; 0.82–2.24

Schuster et al, Ann Intern Med 2008

Double-blind, placebo-controlled trial with fluconazol 800 mg (x 14d)in 270 adult IC-patients:

4 days of fever (>38.3°C) ICU stay > 96h APACHE II ≥ 16 Broad spectrum antibiotics Central line ≥ 24h

Susceptibility profile of Candida species

Dodds Ashely ES et al. Clin Infect Dis 2008 ; 43: S28–39

Distribution of the Candida spp. In vitro susceptibility to fluconazole

305 isolates identified, 210 isolates tested 17% fluconazole-R or S-DD (using validated susceptibility testing

methods)

In vitro susceptibility to fluconazole Species Distribution

n tested S S-DD or R Candida albicans 174 (57%) 113 96% 4% Candida glabrata 51 (17%) 38 50% 50% Candida parapsilosis 23 (7.5%) 19 90% 10% Candida krusei 16 (5.2%) 6 17% 83% Candida tropicalis 15 (4.9%) 14 86% 14% Candida kefyr 11 (3.6%) 9 100% 0 Candida guilliermondii 5 (1.6%) 5 80% 20% Candida lusitaniae 2 (0.7%) 2 100% 0 Other Candida species 8 (2.6%) 4 50% 50% Total 305 210 83% 17%

Leroy et al. Crit Care Med 2009; 37:1612–1618

In vitro susceptibility to fluconazole in patients naïve and previously exposed to azoles in ICU


Initial empiric antifungal treatment

(n=271) Fluconazole

Caspofungin

Voriconazole

Caspofungin + Fluconazole

Liposomal amphotericin B

Amphotericin B deoxycholate

Itraconazole

Caspofungin + Voriconazole

Amphotericin B lipid complex

Amphotericin B deoxycholate + Fluconazole

Amphotericin B deoxycholate + Flucytosine

Amphotericin B deoxycholate + Voriconazole

Liposomal amphotericin B + Caspofungin

Liposomal amphotericin B + Flucytosine

65,7%

18,1%

5,5%

3,0%

2,2%

1,1%

1,1%

1,1%

0,4%

0,4%

0,4%

0,4%

0,4%

0,4%


Risk factors for fluconazole resistance

Odds ratio 95 percent confidence Limits

P - value

Neoplasia 2.9 1.4 – 5.9 ≤ 0.005

Prior fluconazole use 3.8 1.7 – 8.2 ≤ 0.001

Cisterna R et al. J Clin Microbiol 2010; doi:10.1128/JCM.00920-10

IDSA- Candidemia in non-neutropenic

If species is unknown, either fluconazole (800mg loading dose, 400 mg daily) or an echinocandin is appropriate initial therapy for most adult patients (AI)

An echinocandin is favored if- Moderately severe to severe illness,- Recent azole use for treatment or prophylaxis (AIII), or- Isolate is known to be C. glabrata or C. krusei (BIII)

Fluconazole for patients who are- less critically ill and - who have no recent azole exposure (AIII).

Move from candin to fluconazole when isolates likely susceptible to fluconazole (e.g., C. albicans) and patient is clinically stable (AIII)

Remove or exchange intravenous catheters

Treat for two weeks after clearance of bloodstream

Treatment in ICU

Empirical treatment(IA)

yes (A-III)No (A-III)

fluconazole echinocandin

Azole exposure

High risk of C. glabrata or krusei ? Or severe (A-III)

yesNo

Clinical Infectious Diseases 2009; 48:503–35

NoYes

fluconazole echinocandin

Clinicaly stable

Known fungi

Sensitive to fluconazole

C. parapsilosis

C. Glabrata (B-III)

C krusei (A-I)

Yes (B-III) No

Secondary adapted to results. Invasive candidiasis - IDSA 2009Clinical Infectious Diseases 2009; 48:503–35

AmB-L

Major changes from the previous IDSA Guidelines (2004)

Emphasis on fluconazole and echinocandins as the ‘preferred choices’ for proven/suspected IC

De-emphasis on AmB and LFAmB under most circumstances

Concept of step down therapy is strongly encouraged

There is little distinction made between the echinocandins

Fluconazole

AMBPhillips, 1995

P=.04

FluAMB + FluRex, 2003

Antifungal drug studies candidaemia

MITT - Investigator-Assessed Response at End of Treatment (%)

VoriconazoleAMB->Flu

Kullberg, 2005

P=.82

CaspofunginMicafunginPappas, 2007

MicafunginLiposomal AMB

Kuse, 2007

P=.27

AMBCaspofungin

Mora-Duarte, 2002

P=.09

Adapted from Kullberg BJ, et al. Lancet. 2005

P=.64

AnidulafunginFluconazoleReboli, 2007

P=.009

Flu

con

azo

l (8

00)

Flu

con

azo

l (8

00)

Am

fote

rici

ne

B +

Flu

Am

fote

rici

ne

B +

Flu

Cas

po

fun

gin

Cas

po

fun

gin

Mic

afu

ng

inM

icaf

un

gin

L-A

mfo

teri

cin

e B

L-A

mfo

teri

cin

e B

Mic

afun

gin

Mic

afun

gin

Cas

po

fun

gin

Cas

po

fun

gin

Am

fote

rici

ne

BA

mfo

teri

cin

e B

Am

fote

rici

ne

B

F

luco

naz

ol

Am

fote

rici

ne

B

F

luco

naz

ol

Vo

rico

naz

ole

Vo

rico

naz

ole

Flu

con

azo

leF

luco

naz

ole

An

idu

lafu

ng

inA

nid

ula

fun

gin

Am

fote

rici

ne

BA

mfo

teri

cin

e B

Flu

con

azo

lF

luco

naz

ol

56%

69%71% 72% 74%

70% 62%

73% 72%72%

60%

76%

53%50%

P=.39

AnidulafunginCaspofungin MicafunginGlarea lozoyensis Aspergillus nidulansColeophoma empetri

Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Debono M, Gordee RS. Annu Rev Microbiol. 1994;48:471–497; Debono M et al. J Med Chem. 1995;38:3271–3281.

Chemical Structures

NO

O

O

NH

O

H

H

H HO

HCH3

O

O

H2N

OH

NHHO

H2N

HO NH

HN

OH

OH

HN OH

NH

HO

H3C

CH3 CH3

O

O

O

N

O

O

HN

N

O

O

O

O

O

N

O

H3C

SO

O

HO

OH

HO

HO

OH

HN

NH

NHH3C

H2N

HO

HO

OH

NH

OH

OH

CH3

O

O

N

H3C

O

N

O

O

O

O

O

HO

HO

HO

OH

HN

NH

OH

HO

HO OH

NH

HN

CH3

OH

NH

H3C

H3C

Side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity

Attività in vitro delle echinocandinenei confronti di Candida spp.

Organismo

MIC90 (µg/ml)

Numero di isolati

Micafungina Caspofungina Anidulafungina

C. albicans 2.869 0.03 0.06 0.06

C. parapsilosis 759 2 1 2

C. glabrata 747 0.015 0.06 0.12

C. tropicalis 625 0.06 0.06 0.06

C. krusei 136 0.12 0.25 0.06

C. guilliermondii 61 1 1 2

C. lusitaniae 58 0.25 0.5 0.5

C. kefyr 37 0.06 0.015 0.12

C. famata 24 1 1 2

Candida spp. 30 0.5 0.25 1

Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6

Pharmacology: Metabolism, Elimination,

Bioavailability, and Protein Binding

Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis. 2006;43:S28–S39.

Caspofungin Micafungin Anidulafungin

Metabolism Hepatic metabolism

by hydrolysis and N-acetylation

Spontaneous nonhepatic chemical

degeneration

Hepatic metabolism

by arylsulfatase and catechol-O-

methyltransferase

Nonhepatic chemical

degradation

Elimination/excretion

Urine 41%

Feces 34%

Urine + feces 82.5%

Feces 71%

Urine <1%

Feces ≈30%

Protein Binding 97% >99% >99%

Oral Bioavailability

<5% <5% <5%

Dialyzable No No No

Echinocandin studies

Mora-Duarte Kuse Reboli

Caspo AMB Mica L-AMB Anidu Fluco

Apache <20 80,7 80 72 76 80 83

Apache > 20 19,3 20 28 24 21 17

Prior antifungal therapy 56 67 NA NA NA NA

C. albicans 35 54 42,6 44,2 64 59

C. parapsilosis 19,8 18,3 18,3 15,8 10 14

C. glabrata 12,8 9,2 11,4 7,9 16 25

C. krusei 4 0,9 3 3,7 Excl.. Excl.

Neutropenia (< 500) 12,8 8,7 12 7,9 2 3

Fav. response (EOT) 80,7 64,9 89,6 89,5 75,6 60.2

Mortality 34,2 30,4 NA NA 22,8 31,4

Echinocandins Approved IndicationsEMEA

Empirical Therapy in Febrile

Neutropenic Pts

Therapy in Proven Infections

Therapy of Oesophageal Candidiasis

Prophylaxis of Candida-

Infections in HSCT Patients

Candida spp.Aspergillus spp.

Caspofungin

Children Yes YesYes

(Salvage therapy)

No No

Adults Yes YesYes

(Salvage Therapy)

No No

Anidulafungin

Adults No Yes No No No

Micafungin*

Children No Yes No Yesa Yes

Adults No Yes No Yes Yes

* The decision to use micafungin should take into account a potential risk for the development of liver tumours. Micafungin should therefore only be used if other antifungals are not appropriate

Candida colonization

Is frequent in ICU patients The gut is the main portal of entry in

neutropenic patients The skin is an important source of

candidemia in non-neutropenic patients Tracheal colonization reflect oropharyngeal

colonization and is not associated with candidal pneumonia in non- neutropenic ICU patients

1587 admissions

301 (19%) died

232 autopsies

135 (58%) with

pneumonia

97 (42%) without

pneumonia

77 patients with Candida in LRT

0 Candida pneumonia


0 Candida pneumonia

1587 admissions

301 (19%) died

232 autopsies

135 (58%) with

pneumonia

97 (42%) without

pneumonia


0 Candida pneumonia


0 Candida pneumonia

Is Candida colonization of CVC in non-

candidemic an indication for antifungals?

58 pts ( 91% in ICU) Independent predictors for outcome:

- ultimately fatal underlying disease (P = 0.02)- severe sepsis, septic shock or multiorgan

failure (P = 0.05).

Antifungal therapy does not seem to have a significant influence on clinical outcome

Perez-Parra A et al. Intensive Care Med 2009; 35:707–712

OUTCOME OF CANDIDEMIA IN THE UK 1997-99IMPACT OF CATHETER MANAGEMENT

OUTCOME OF CANDIDEMIA IN THE UK 1997-99IMPACT OF CATHETER MANAGEMENT

No line removal + antifungal (n=29) 31%

Line removal + antifungal (n=91) 14%

No treatment (n=31)58%

26%Day 30 mortality overall (n = 163)

Kibbler et al. J Hosp Infect 2003; 54:18-24

Early removal of central venous catheter in patients with

candidemia does not improve outcome

Nucci M et al. Clin Infect Dis 2010; 51:295–303

Early removal of central venous catheter in patients

with candidemia does not improve outcome

Nucci M et al. Clin Infect Dis 2010; 51:295–303

Candidemia in cancer patients: Impact of early removal of catheter

Liu CY et al. J Infect 2009; 58:154-160

OR (95% CI)OR (95% CI) PP

Inadequate antifungal therapy

2.35 (1.09-5.10)2.35 (1.09-5.10) 0.030.03

Infection biofilm-forming Candida species

2.33 (1.26-4.30)2.33 (1.26-4.30) 0.0070.007

APACHE score 1.03 (1.01-1.15)1.03 (1.01-1.15) 0.0010.001

Tumbarello et al JCM 2007

Biofilm Production by Candida spp

0

10

20

30

40

50

60

70

80

90

100 P = 0,04

0102030405060708090

100

Biofilm-positive Biofilm-negative

Mo

rtal

ity

(%)

P<0,001

P=0,003

Mortality by Biofilm-Producing Isolates

Activity against Candida biofilms

Kuhn et al AAC 2002 46:1773

L-AMB

L-AMB

Gestione pratica delle infezioni fungine in terapia intensiva

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