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
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
• Congenital abnormalities
• Prior colonisation with Candida
spp.
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
• Congenital abnormalities
• Prior colonisation with Candida
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
Candida colonisation
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
Antifungal therapies in critical care settings
Prophylactic Pre-emptive Empirical Curative
Proof of
infection
Sign of sepsis
Candida colonisation
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
Eggimann P, et al. Lancet Infect Dis 2003;3:772-85
Pappas PG, et al. Clin Infect Dis 2009;38:161-89
“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
Eggimann P, et al. Lancet Infect Dis 2003;3:772-85
Pappas PG, et al. Clin Infect Dis 2009;38:161-89
Antifungal therapies in critical care settings
Prophylactic Pre-emptive Empirical Curative
Proof of
infection
Sign of sepsis
Candida colonisation
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
Eggimann P, et al. Lancet Infect Dis 2003;3:772-85
Pappas PG, et al. Clin Infect Dis 2009;38:161-89
Empiric therapy
Should be based on
• clinical assessment of risk factors
• serologic markers for invasive candidiasis
• culture data from nonsterile sites
Eggimann P, et al. Lancet Infect Dis 2003;3:772-85
Pappas PG, et al. Clin Infect Dis 2009;38:161-89
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
Eggimann P, et al. Lancet Infect Dis 2003;3:772-85
Pappas PG, et al. Clin Infect Dis 2009;38:161-89
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
Pappas PG, et al. Clin Infect Dis 2009;48:503-35
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
Pappas PG, et al. Clin Infect Dis 2009;48:503-35
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
Pappas PG, et al. Clin Infect Dis 2009;48:503-35
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
Pappas PG, et al. Clin Infect Dis 2009;48:503-35
Treatment of Non-Candida albicans
candidaemia
C. parasilopsis
• Fluconazole
• ? Less responsive to echinocandin
C. glabrata
• Echinocandin
Pappas PG, et al. Clin Infect Dis 2009;48:503-35
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)
Pappas PG, et al. Clin Infect Dis 2009;48:503-35
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