Fungal infections in ICU. Tang Swee Fong Department of Paediatrics Universiti Kebangsaan Malaysia

Fungal infections in ICU Tang Swee Fong Department of Paediatrics Universiti Kebangsaan Malaysia

Epidemiology of invasive fungal infections - US +300% Martin GS, et al. N Engl J Med 2003;348:1546-1554

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.

Percent Species distribution 60 50 40 Pappas, 2003 Zaoulis, 2005 Abelson, 2005 30 20 10 0 C. albicans C. parapsilopsis C. glabrata 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 Grampositive Gramnegative 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) *p<0.0001) Shorr AF, et al. Crit Care Med 2009;37:2519-26

Outcomes attributable to candidaemia, US Paediatric Adult Variable With candidaemia Without candidaemia Attributable increase With candidaemia Without candidaemia Attributable increase (n=1118) (n=2062) (95% CI) (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 v 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.

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 Host 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 Transplantation 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 Recent surgery (especially GIT) Peak incidence around day 10 of ICU stay

Corrected colonisation index Candida colonisation index (CCI) CCI = number of distinct body sites positive for Candida spp. total sites tested * CCI > 0.5: identified infected patients Corrected Colonisation Index = CCI x number of sites with heavy candida growth Eggimann P, 2006 Snydman DR, 2003

Pathophysiology of invasive candidiasis Adhesion Colonisation Exogenous Diabetes Neutropenia Burns Antibiotics Invasion Antibiotics Vascular access Parenteral nutrition ICU stay > 7 days Candida colonisation Renal failure Major abdominal surgery Endogenous Candidaemia 0.5-1/1000 admissions (10% of bacteraemia) 35% survival Dissemination 35% die from candidaemia 35% die from underlying disease 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 postmortem 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 Targeted prophylaxis Targeted empirical No colonisation data needed Proof of infection Sign of sepsis Candida colonisation Risk factors

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 Reduce fungal infections by one-half Reduce mortality by one-quarter Playford GE, et al. J Antimicrob Chemother 2006;57:628-38

Antifungal therapies in critical care settings Prophylactic Pre-emptive Empirical Curative Targeted prophylaxis Targeted empirical No colonisation data needed Proof of infection Sign of sepsis Candida colonisation Risk factors

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) Sensitivity 81% Specificity 76% 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

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 Targeted prophylaxis Targeted empirical No colonisation data needed Proof of infection Sign of sepsis Candida colonisation Risk factors

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 Echinocandins Caspofungin Micafungin Anidulafungin Aminocandin Azoles Fluconazole Itraconazole Voriconazole Posaconazole Ravuconazole

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 Removal of vascular lines Dilated fundoscopic examination

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 Optimal placement of central venous catheter and care Hand washing 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

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