fungal infections in icumsic.org.my/filedownloader.asp?filename=asmic2015_tangs... · epidemiology...

Fungal infections in ICU

Tang Swee Fong

Department of Paediatrics

Universiti Kebangsaan Malaysia

Epidemiology of invasive fungal infections - US

Martin GS, et al. N Engl J Med 2003;348:1546-1554

+300%

Fungal ‘players’

• Opportunistic

– Normal flora

• Candida spp.

– Ubiquitous in our

environment

• Aspergillus spp.

• Cryptococcus spp.

• Mucor spp.

• Newly emerging fungi • Fusarium spp.

• Scedosporidium spp.

• Trichosporin spp.

• Penicillium spp.

• Zygomycetes

• Endemic geographically restricted • Blastomyces sp.

• Coccidiodes sp.

• Histoplasmosis sp.

Species distribution

0

10

20

30

40

50

60

C. albicans C. parapsilopsis C. glabrata

Perc

en

t

Pappas, 2003

Zaoulis, 2005

Abelson, 2005

Pappas PG, et al. Clin Infect Dis 2003; 37:634-43

Zaoulis TE, et al. Microbiol Infect Dis 2005;52:295-8

Abelson JA, et al. Pediatrics 2005; 116:61-7

Candidaemia in a paediatric intensive care unit

4.3% had candidaemia

Overall mortality 28.1%

Predictors of mortality

• Severity of illness

• Isolation of C. tropicalis

Singhi SC, et al. Pediatr Crit Care Med 2004;5:369-74

Trends in mortality by type of blood stream infection

• Crude in-hospital mortality:

candidaemia, 28.3% vs bacterial bloodstream infection, 15.0% (p<0.0001)

Shorr AF, et al. Crit Care Med 2009;37:2519-26

Adjusted length of stay and total costs by type of

blood stream infection

Candida Gram-

positive

Gram-

negative

Anaerobe Mixed

bacteria

LOS, days

(95% CI)

4.8*

(4.1, 5.5)

2.4

(2.3, 2.6)

Reference

group

3.3

(2.8, 3.8)

1.8

(1.5, 2.2)

Total cost, $

(95% CI)

12,617*

(10755, 14479)

4,473

(4,062,

4,885)

Reference

group

6,871

(5,472,

8,269)

3,693

(2,629,

4,758)

Shorr AF, et al. Crit Care Med 2009;37:2519-26

*p<0.0001)

Outcomes attributable to candidaemia, US

Paediatric Adult

Variable With

candidaemia

(n=1118)

Without

candidaemia

(n=2062)

Attributable

increase

(95% CI)

With

candidaemia

Without

candidaemia

Attributable

increase

(95% CI)

Mortality, %

15.8 5.9 10

(6.2-13.8)

30.6 16.1 14.5 (12.1-

16.9)

Length of stay,

mean no. of days

per patient

44.8 23.7 21.1

(14.4-27.8)

18.6 8.5 10.1

(8.9-11.3)

Total charges,

mean USD per

patient

183,645 91,379 92, 266

(65,058-

119,474)

66,154 26,823 39,331

(3,360-

45,602)

Zaoutis TE, et al. Clin Infect Dis 2005;41:1232-9

Risk factors for invasive candidiasis in the intensive

care setting

Environmental factors

• Endotracheal intubation

• Central venous and arterial lines

• Urinary catheterisation

• Parenteral nutrition

• Prolonged ICU stay

• Broad-spectrum antibiotics

• Bacterial infections

• Immunosuppressive drugs

• Cancer and chemotherapy

• Blood transfusions

• Dialysis

• Recent surgery (especially GIT)

• Transplantation

Host factors

• Immunodeficiency

• Neutropaenia

• Malignancies

• Bone marrow transplantation

• Critical illness

• Preterm birth

• Low Apgar score

• Congenital abnormalities

• Prior colonisation with Candida

spp.

v


care setting












• Dialysis


• Transplantation

Host factors


• Neutropaenia

• Malignancies



• Preterm birth



spp.


care setting












• Dialysis


• Transplantation

Host factors


• Neutropaenia

• Malignancies



• Preterm birth



spp.

incidence of colonisation and invasive candidiasis after 8 days

Peak incidence around day 10 of ICU stay

Candida colonisation index (CCI)

Eggimann P, 2006

Snydman DR, 2003

number of distinct body sites positive for Candida spp.

CCI =

total sites tested

* CCI > 0.5: identified infected patients

Corr

ecte

d c

olo

nis

ation index Corrected Colonisation Index

= CCI x number of sites with heavy candida growth

Pathophysiology of invasive candidiasis

Adhesion Colonisation

Diabetes

Neutropenia

Burns

Antibiotics

Exogenous

Antibiotics

Vascular access

Parenteral nutrition

ICU stay > 7 days

Candida colonisation

Renal failure

Major abdominal surgery

Invasion

Candidaemia

0.5-1/1000 admissions

(10% of bacteraemia)

Dissemination 35% die

from candidaemia

35% survival

35% die

from underlying disease

Endogenous

Modified from Eggimann P, et al. Lancet Infect Dis 2003;3:685-702

Diagnosis

• Difficult to diagnose

• 20% have no fever

• 20-30% diagnosed at post-

mortem autopsy

Diagnosis

• Positive blood culture from a normally sterile site

• Positive only in 50-60% cases (even with

disseminated infection)

• Histologically positive biopsy specimen

• Not routinely carried out

Surface colonisation vs invasive disease

• Positive

endotracheal tube

secretions

• Immune status?

• Lung opacities?

• Candiduria

• Immune status?

• Remove urinary

catheter

• Repeat urine

culture

• Ultrasound

kidneys

• Blood culture

Diagnosis

Candida

• Fungal wall elements (β-D glucan, mannan, β 1-3 glucan)

• PCR assays

Aspergillus

• High resolution CT scan

• Serological and molecular techniques

Jones BL, et al. Curr Opin Infect Dis 2003;16:521-6

Diagnosis

When to treat?

• Septic patients

• Profound immunosuppression

• Specimens positive for Candida

• Asymptomatic

• Non-neutropaenic

Time to starting antifungal therapy and mortality

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

Garey KW, et al. Clin Infect Dis 2006;43:25-31

Antifungal therapies in critical care settings

Prophylactic Pre-emptive Empirical Curative

Proof of

infection

Sign of sepsis


Risk factors

Targeted

prophylaxis

Targeted

empirical

No colonisation

data needed

Prophylaxis

Administration of antifungals to patients at high

risk

• Organ-transplanted patients

• Immunocompromised with expected long-term

neutropaenia

• Non-immunocompromised patients

• High risk of invasive candidiasis (frequency of candidiasis

>10%)

• Expected long ICU stay

• Prolonged mechanical ventilation

Eggimann P, et al. Lancet Infect Dis 2003;3:772-85

Pappas PG, et al. Clin Infect Dis 2009;38:161-89

Antifungal agents for preventing fungal infections in

non-neutropenic critically ill patients

Playford GE, et al. J Antimicrob Chemother 2006;57:628-38

Reduce fungal infections by one-half

Reduce mortality by one-quarter



Proof of

infection

Sign of sepsis


Risk factors

Targeted

prophylaxis

Targeted

empirical

No colonisation

data needed

Pre-emptive therapy

Early administration of antifungal treatment

• Evidence of substantial colonisation

• Presence of multiple risk factors



“Candida score” – bedside scoring system

Predictors of proven Candida infection

• Multifocal Candida colonisation (1 pt)

• Total parenteral nutrition (1 pt)

• Surgery upon ICU admission (1pt)

• Severe sepsis (2 points)

Cut-off score > 2.5

- 7.75-fold increased likelihood of

IC (95% CI, 4.74-12.66)

Leon C, et al. Crit Care Med 2006;34:730-7

Hollenbach E. Mycoses 2008;51:25-45

Sensitivity – 81%

Specificity – 76%

Pre-emptive therapy

Early administration of antifungal treatment

• Evidence of substantial colonisation

• Presence of multiple risk factors

Risk of severe candidiasis outweighs potential

side-effects and emergence of resistant strains





Proof of

infection

Sign of sepsis


Risk factors

Targeted

prophylaxis

Targeted

empirical

No colonisation

data needed

Empiric therapy

Treatment of high risk patients who

• exhibit signs and symptoms of disease

• even in the absence of positive cultures or

evidence of disease

For critically ill patients with

• risk factors for invasive candidiasis

• persistent fever with no other known cause found

• multiple organ dysfunction



Empiric therapy

Should be based on

• clinical assessment of risk factors

• serologic markers for invasive candidiasis

• culture data from nonsterile sites



Empiric therapy

Fluconazole

Echinocandins

• Moderate to severe disease

• Recent exposure to azole

• At high risk of infection with C. glabrata or C. krusei

Amphotericin B

• Intolerance to or limited availability of other

antifungals



Treatment of candidaemia in non-neutropaenic

patients

Selection of agents

• History of recent azole exposure

• History of intolerance to an antifungal agent

• Dominant Candida species

• Current susceptibility data in clinical location

• Severity of illness

• Relevant comorbidities

• Evidence of CNS, cardiac valves and/or visceral

involvement


Antifungal choices

Polyenes

• Amphotericin B

• ABLC, ABCD,

AmBisome

• Liposomal nystatin

Azoles

• Fluconazole

• Itraconazole

• Voriconazole

• Posaconazole

• Ravuconazole

Echinocandins

• Caspofungin

• Micafungin

• Anidulafungin

• Aminocandin

Fluconazole

First line therapy

• mild to moderate illness (ie haemodynamically stable)

• no previous exposure to azoles

• do not belong in a group at high risk of C. glabrata

Not for patients with candidaemia and suspected

concomitant endocardial or CNS involvement

Step-down therapy for infections with organisms

likely to be susceptible


Echinocandins

Significant fungicidal activity

Favourable safety profile

Few drug interactions

Initial therapy

• recent exposure to an azole

• moderately severe to severe disease

• allergy or intolerance to azoles or AmB

• high risk of infection with C. krusei and C. glabrata


Amphotericin

Initial therapy

• alternative therapy unavailable or unaffordable

• history of intolerance to echinocandins or azoles

• infection refractory to other therapy

• organism is resistant to other agents

• suspected infection with non-Candida yeast eg

Cryptococcus neoformans


Treatment of Non-Candida albicans

candidaemia

C. parasilopsis

• Fluconazole

• ? Less responsive to echinocandin

C. glabrata

• Echinocandin


Other measures

• Dilated fundoscopic

examination

• Removal of vascular

lines

Duration of therapy

14 days

• after resolution of symptoms

• clearance of Candida species from bloodstream

• pertains to all systemic antifungal therapy (including

sequential therapy with AmB or echinocandin

followed by an azole)


Prevention

Hand washing

Optimal placement of central venous

catheter and care

Strict control of antimicrobial use

Summary – invasive candidiasis

Cause of substantial morbidity and mortality

Trend towards increasing numbers of infections

caused by non-albicans Candida species

Prophylaxis vs preemptive vs empirical therapy

Choice of antifungal agent depends on local

epidemiologic and patient factors

Conclusion

• Past

• Fungal infections rare

• Difficult to diagnose

• Limited treatment

options

• Present

• Fungal infections

more common

• Still difficult to

diagnose

• More treatments

available Future

• Diagnostics

• Risk identification

• Assessment of management strategies

Thank you

fungal infections in icumsic.org.my/filedownloader.asp?filename=asmic2015_tangs... · epidemiology...

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