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 4 th (9%) most common cause of blood stream infection in the US (and climbing…) 6-10 th 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 ItalyTurkeyCanada 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% JoHI (2002) 50: Risk factors (compared to C. albicans) C. glabrata(Fluconazole prophylaxis), BMT, Surgery, Solid organ cancer C. tropicalisBMT, Solid tumours, Intravascular device C. kruseiNeutropenia, Fluconazole prophylaxis, BMT C. parapsilosisIntravascular device, TPN, BMT, Neonates C. kruseiFluconazole prophylaxis C. lusitaniaePolyene 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:
Predictive scores Leon et al *(total parenteral nutrition) +1*(surgery) +1*(multifocal Candida species colonization) +2*(severe sepsis) Score >2.5 Sensitivity 81% Specificity 74% Ostrosky-Zeichner et al 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 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 CID 43:25–31
Antifungal susceptibility Species FluconazoleVoriconazoleFlucytosineAmphotericin BEchinocandins C. albicans SSSSS C. glabrata S – DD to R SS to IS C. tropicalis SSSSS C. parapsilosis SSSSS to R C. krusei RSI to RS to IS C. lusitaniae SSSS to RS 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 Clin Microbiol Rev 20:133–163
Pre-emptive treatment Very few studies Piarroux et al Bases of colonisation index Reduced rates of invasive candidiasis (compared to historial controls) Fluconazole Piarroux et al CCM 32:2443–2449
Treatment Guery et al ICM. 35;
Case study 27 year old female Known asthmatic 3/7 increasing SOB, wheeze and cough Symbicort 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)
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
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
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: Beware: Piperacillin - tazobactam
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 :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