Fungal infections in critically ill patients

Dr Tim FeltonThe University of Manchester

Case study• 24 year old female• Psoriasis with arthropathy• Obesity (110kg)• Admitted to ICU • Methorexate 10mg weekly1. H1N1 pneumonitis2. ARDS3. Pancytopenia4. 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 CanadaC. 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%

JoHI (2002) 50:243-260

Risk factors (compared to C. albicans)C. glabrata (Fluconazole prophylaxis), BMT, Surgery, Solid organ cancer

C. tropicalis BMT, Solid tumours, Intravascular deviceC. krusei Neutropenia, Fluconazole prophylaxis, BMT

C. parapsilosis Intravascular device, TPN, BMT, NeonatesC. krusei Fluconazole prophylaxisC. lusitaniae Polyene use (inducible resistance)

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%• (13)-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 Flucytosin

eAmphotericin

BEchinocandin

sC. albicans S S S S SC. glabrata S – DD to R S – DD to R S S to I SC. tropicalis S S S S SC. parapsilosis S S S S S to RC. 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

• 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%)

AJRCCM. 2004;170: 621

• 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…………………

• 110 ICU admission, IPA by EORTC/MSG criteria• 1/3 hematological malignancy interpret with care• BAL GM probably useful; Serum GM probably not

AJRCCM . 2008;177: 27-34.

Beware: Piperacillin - ta

zobactam

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