Fungal infections in
critically ill patients
Dr Tim Felton
The University of Manchester
Case study
•
•
•
•
•
24 year old female
Psoriasis with arthropathy
Obesity (110kg)
Admitted to ICU
Methorexate 10mg
weekly
1. H1N1 pneumonitis
2. ARDS
3. Pancytopenia
4. Severe sepsis
Day 6
• Persistent sepsis
• Respiratory failure (consider for ECMO)
• Treated with broad-spectrum antibiotics
• Identify Candida tropicalis from airways
Is the Candida culture relevant?
What would you do next?
Would you treat?
Day 7
• Identify Candida tropicalis from urine
Is two Candida cultures relevant?
What would you do next?
Would you treat (and if so with what)?
Treatment
• Day 7
– Fluconazole 400mg daily
• Day 14
– Caspofungin 70mg then
50mg
• Day 20
– Ambisome 3mg/kg
• Day 53
– RIP
Epidemiology
• 4th (9%) most common cause of blood
stream infection in the US (and
climbing…)
• 6-10th most common in Europe
• Incidence up to 10x higher in ICU
patients
• Attributable mortality 49-60%
Candida species in ICU
Bassetti
2006
Comert
2007
Laverdiere
2007
Italy
Turkey
Canada
C. albicans
40%
66%
72%
C. glabrata
15%
9%
16%
C. parapsilosis
23%
11%
C. tropicalis
9%
Non-albicans Candida species
• Increasingly reported as both colonisers and pathogens
• Mortality
– C. albicans ≈ 15 to 35%
– C. tropicalis and C. glabrata ≈ 40 to 70%
– C. parapsilosis ≈ 10 to15%
Risk factors (compared to C. albicans)
C. glabrata
(Fluconazole prophylaxis), BMT, Surgery, Solid organ cancer
C. tropicalis
BMT, Solid tumours, Intravascular device
C. krusei
Neutropenia, Fluconazole prophylaxis, BMT
C. parapsilosis Intravascular device, TPN, BMT, Neonates
C. krusei
Fluconazole prophylaxis
C. lusitaniae
Polyene use (inducible resistance)
JoHI (2002) 50:243-260
Risk factors for Candidemia
•
•
•
•
•
•
•
•
•
Older age
Diabetes mellitus
Central venous lines
Mechanical ventilation
Multiple antibiotics
Parenteral nutrition
Major surgery
Colonization
Candiduria
•
•
•
•
•
•
•
•
•
Immunosuppression
High APACHE II (>30)
Prolonged neutropenia
Uraemia
Haemodialysis
Low cardiac output
Diarrhoea
Extensive burns
Acute pancreatitis
JoHI (2007) 66: 201-206
Diagnostic tests
• Blood culture
– Sens 50%, spec 100%
• (13)-β-D-glucan
– Sens 70%, spec 87%
• PCR
– Sens 90%, spec 100%
Mycoses 2010 53:424-433
Predictive scores
•
•
•
•
Leon et al. 2006
1*(total parenteral nutrition)
+1*(surgery)
+1*(multifocal Candida species
colonization)
• +2*(severe sepsis)
• Score >2.5
• Sensitivity 81%
• Specificity 74%
• Ostrosky-Zeichner et al. 2007
• Any systemic antibiotic (days
1–3)
• OR CVC(days 1–3)
• AND at least 2 of the following
–
–
–
–
–
–
total parenteral nutrition (days 1–3)
any dialysis (days 1–3)
any major surgery (days −7–0)
pancreatitis (days −7–0)
any use of steroids (days −7–3)
or use of other
immunosuppressive agents (days
−7–0)
Colonisation scores
• Pittet et al. 1994
• Colonization index
• No. of non-blood body sites colonised
(heavy growth) by Candida spp./total no. of
sampled sites
• 100% sensitivity and specificity.
Treatment
•
•
•
•
•
•
Early and appropriate
Mortality (after +ve blood culture)
Day 0 – 15%
Day 1 – 24%
Day 2 – 37%
Later – 41%
Garey et al. 2006 CID 43:25–31
Antifungal susceptibility
Species
Fluconazole Voriconazole Flucytosine Amphotericin B Echinocandins
C. albicans
S
S
S
S
S
C. glabrata
S – DD to R
S – DD to R
S
S to I
S
C. tropicalis
S
S
S
S
S
C. parapsilosis
S
S
S
S
S to R
C. krusei
R
S
I to R
S to I
S
C. lusitaniae
S
S
S
S to R
S
CID (2009) 48:503–35
Prophylaxis
• Reduces rates of colonisation to candidemia
• May reduce mortality from candidemia
• Probably helpful if
– High levels of candidemia
– Other infection controls measures are enforced
– High risk individuals
Pfaller et al. 2007. Clin Microbiol Rev 20:133–163
Pre-emptive treatment
• Very few studies
• Piarroux et al. 2004
• Bases of colonisation index
• Reduced rates of invasive candidiasis
(compared to historial controls)
• Fluconazole
Piarroux et al. 2004 CCM 32:2443–2449
Treatment
Guery et al. 2009. ICM. 35;206-214
Treatment
Case study
•
•
•
•
•
•
27 year old female
Known asthmatic
3/7 increasing SOB, wheeze and cough
Symbicort 200 2 puff bd + Bricanyl 500 prn
No other PMHx (no DM)
Ex-smoker
In A+E
• Bronchospasm and
tachycopnea
• Mild tachycardia and
normotension
• CXR Hyper-expanded
but clear lung fields
• Responded to nebs
• Clarithromycin 500mg
BD (penicillin allergy)
• Prednisolone 40mg od
8 hours later….
• Decompensation
• ICU - Intubation and MV
• Resistant bronchospasm (sedation, muscle
paralysis, ketamine and Sevoflurane)
• Day 2 - persistent high grade fever (active
cooling)
Day 4
• Surveillance NBL
– Aspergillus fumigatus
• CXR
– widespread airspace
infiltrates (ALI)
Is the Aspergillus culture relevant?
What would you do next?
Would you treat?
Day 5
• Bronchoscopy and BAL
– Culture positive for Aspergillus fumigatus.
– No evidence of bacteria growth or acid-fast
bacilli.
• Serum Aspergillus PCR +ve.
Is the Aspergillus culture/PCR relevant?
What would you do next?
Would you treat (and if so with what)?
Treatment
• Voriconazole (loaded then 4mg/Kg bd) then
to PO
• Continued for 6 months (Asp IgG 26)
• TDM
with
• Caspofungin 70mg then 50mg for 30 days
Follow up
•
•
•
•
Retrospective Day 0 IgG + IgE to Asp –ve
Day 8 Aspergillus IgG 148 mgA (0-40)
Extubated on day 25
CT (day 31) widespread cavities, ground
glass opacity and bronchiectasis
• Environmental cultures –ve
• No immune defect found
AJRCCM. 2004;170: 621
• 127 of 1850 (6.9%) consecutive medical ICU
admissions with IA or colonisation (micro/histol).
• 89/127 (70%) did not have haematological
malignancy
• 67/89 proven/probable IA
• 33 of 67 (50%) COPD
• Mortality 80% (Predicted 48%)
• 36/1756 patients (2%)
• 20 IPA (defined as “pneumonia”)
• 14 colonised
• Mortality
– Colonisation 50%
– IPA 80%
Risk factors in critical illness
• Steroids (odds ratio = 4.5)
– Prolonged corticosteroids treatment prior to ICU
– Steroid treatment with a duration of 7 days
•
•
•
•
•
•
•
•
•
Immunosuppressive therapy
Chronic obstructive pulmonary disease (odds ratio = 2.9)
Liver cirrhosis
Solid-organ cancer
HIV
Severe burns
Prolonged stay in the ICU (>21 days)
Malnutrition
Post–cardiac surgery status
Meersseman et al. CID. 2007;45: 205–16
Critical illness – risk factor?
• Compensatory anti-inflammatory response
syndrome
– Monocyte/macrophage deactivation
– Neutrophil deactivation
–  HLA-DR antigen expression
– Loss of antigen-presenting capacity
–  synthesis of pro-inflammatory cytokines
Environment
• Pulmonary colonisation prior to ICU
– Lobectomy, PM for unexpected cardiac death
– 30/74 (41%) patients with Aspergillus species
• Environmental contamination
– High concentration of air-bourne spores
Lass-Florl et al. BJH. 1999; 104:745-7
Respiratory tract samples
• Colonisation or IPA?
• 172 patients, Belgium ICUs, 7 years
– 89 colonisation
– 83 IPA (EORTC/MSG criteria)
• Poor positive predicative value for IPA
• But…………………
AJRCCM . 2008;177: 27-34.
• 110 ICU admission, IPA by EORTC/MSG criteria
• 1/3 hematological malignancy interpret with care
• BAL GM probably useful; Serum GM probably not
Imaging
• CT
– Frequently absent
– Halo sign, air
crescent sign and
nodules much more
common in
neutropenic patients
– Difficult to interpret
with ARDS
Calliot et al. J Clin Oncol. 1997. 15:139-47
Other diagnostic tests
• PCR
– Not evaluated in critically ill patients
• Biopsy
– Gold standard
– Difficult!
Diagnosis in critical illness
• High risk patients
• Pulmonary infiltrates and fever, not
responding to appropriate antibacterial
agents
• ± some concern that Aspergillus may be a
diagnostic possibility
– Recent unidentified case which died
– Isolation of Aspergillus from respiratory tract
Treatment in ICU
• IDSA recommendations but little evidence in
critically ill
• Voriconazole
– Hepatotoxicity and nephrotoxicity
– IV formulation – cyclodextran
– Substrate and inhibitor CYP2C19, 2C9 and 3A4
–  bioavailabity with fat – requires empty stomach
– TDM
Treatment in ICU
• Lipid preparations of Amphotericin B
– Less nephrotoxic than deoxycholate
• Eichinocandin
– Salvage therapy
• Combination
Summary
• Candida and Aspergillus increasingly
recognised as ICU pathogens
• Increased morbidity and mortality
• High index of suspicion
• Diagnostic strategy (clinical, radiology, lab)
• Treatment is complicated
– ADR, interactions