Fungal infections caused by Candida and Aspergillus species are increasingly common in critically ill patients. These infections are associated with high morbidity and mortality. Clinicians must have a high index of suspicion given the challenges of diagnosis in ICU patients. Treatment is complicated by potential adverse drug reactions and interactions.

1. Fungal infections in
critically ill patients
Dr Tim Felton
The University of Manchester

2. 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

3. Day 6
• Persistent sepsis
• Respiratory failure (consider for ECMO)
• Treated with broad-spectrum antibiotics
• Identify Candida tropicalis from airways

4. Is the Candida culture relevant?
What would you do next?
Would you treat?

5. Day 7
• Identify Candida tropicalis from urine

6. Is two Candida cultures relevant?
What would you do next?
Would you treat (and if so with what)?

7. Treatment
• Day 7
– Fluconazole 400mg daily
• Day 14
– Caspofungin 70mg then
50mg
• Day 20
– Ambisome 3mg/kg
• Day 53
– RIP

8. 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%

9. Candida species in ICU
Bassetti Comert Laverdiere
2006 2007 2007
Italy Turkey Canada
C. albicans 40% 66% 72%
C. glabrata 15% 9% 16%
C. parapsilosis 23% 11%
C. tropicalis 9%

10. 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

11. Risk factors for Candidemia
• Older age • Immunosuppression
• Diabetes mellitus • High APACHE II (>30)
• Central venous lines • Prolonged neutropenia
• Mechanical ventilation • Uraemia
• Multiple antibiotics • Haemodialysis
• Parenteral nutrition • Low cardiac output
• Major surgery • Diarrhoea
• Colonization • Extensive burns
• Candiduria • Acute pancreatitis
JoHI (2007) 66: 201-206

12. 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

13. Predictive scores
• Leon et al. 2006 • Ostrosky-Zeichner et al. 2007
• 1*(total parenteral nutrition) • Any systemic antibiotic (days
• +1*(surgery) 1–3)
• +1*(multifocal Candida species • OR CVC(days 1–3)
colonization) • AND at least 2 of the following
• +2*(severe sepsis) – total parenteral nutrition (days 1–3)
– any dialysis (days 1–3)
– any major surgery (days −7–0)
• Score >2.5 – pancreatitis (days −7–0)
• Sensitivity 81% – any use of steroids (days −7–3)
• Specificity 74% – or use of other
immunosuppressive agents (days
−7–0)

14. 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.

15. 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

16. 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

17. 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

18. 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

19. Treatment
Guery et al. 2009. ICM. 35;206-214

20. Treatment

22. 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

23. 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

24. 8 hours later….
• Decompensation
• ICU - Intubation and MV
• Resistant bronchospasm (sedation, muscle
paralysis, ketamine and Sevoflurane)
• Day 2 - persistent high grade fever (active
cooling)

25. Day 4
• Surveillance NBL
– Aspergillus fumigatus
• CXR
– widespread airspace
infiltrates (ALI)

26. Is the Aspergillus culture relevant?
What would you do next?
Would you treat?

27. Day 5
• Bronchoscopy and BAL
– Culture positive for Aspergillus fumigatus.
– No evidence of bacteria growth or acid-fast
bacilli.
• Serum Aspergillus PCR +ve.

28. Is the Aspergillus culture/PCR relevant?
What would you do next?
Would you treat (and if so with what)?

29. 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

30. 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

32. 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%)

33. • 36/1756 patients (2%)
• 20 IPA (defined as “pneumonia”)
• 14 colonised
• Mortality
– Colonisation 50%
– IPA 80%

34. 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

35. 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

36. 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

37. 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…………………

39. 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

40. 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

41. Other diagnostic tests
• PCR
– Not evaluated in critically ill patients
• Biopsy
– Gold standard
– Difficult!

42. 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

43. 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

44. Treatment in ICU
• Lipid preparations of Amphotericin B
– Less nephrotoxic than deoxycholate
• Eichinocandin
– Salvage therapy
• Combination

45. 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