A 42 year old woman was admitted to the intensive care unit with necrotising pancreatitis. She required sedation and mechanical, vasopressors to maintain adequate mean arterial pressure and extensive crystalloid resuscitation. Enteral nutrition was initially maintained via nasogastric feeding. She was treated with empirical broad-spectrum antibiotics (meropenem) and was prescribed antifungal prophylaxis (fluconazole) at the request of the hepatobiliary surgical team.

 

The patient experienced a prolonged systemic inflammatory response syndrome. She ultimately underwent a pancreatic necrosectomy and required recurrent radiologically-guided percutaneous drainage of intra-abdominal collections. For a large proportion of her ICU admission, enteral nutrition failed and the patient required total parenteral nutrition. Candida albicans was isolated from central venous catheter exits sites, drain exit sites, drain fluid, urine and sputum on several occasions, but there was never any evidence of invasive fungal disease.

The patient was eventually discharged from ICU and survived to discharge from hospital. She was left dependent on pancreatic enzyme replacement and subcutaneous insulin therapy.

Describe the incidence, clinical features and management of fungal infections in non-neutropaenic, non-transplant critical care patients.

Christopher Westall

Invasive fungal disease (IFD) is common, responsible for 5-10% of all ICU-acquired infections.¹ At the time of admission to ICU, 5-15% of patients are colonised with Candida spp. and 50% will ultimately become colonised.^2,3 Neutropaenic and transplant patients are at high risk for acquiring IFD and the benefit of anti-fungal prophylaxis in these patients is beyond doubt, however the majority of IFD occurs in non-neutropaenic, non-transplant critically ill patients, and in this group the value of prophylactic or pre-emptive antifungal therapy is debatable.

Contemporary data found that IFD occurred in 0.6% of 60,778 non-neutropaenic, non-transplant patients admitted to UK intensive care units. The median time of diagnosis was on day 4 of ICU admission. Candida spp. were responsible for 94% of cases (C. albicans 61%, non-albicans 29%), Aspergillus spp. accounted for only 2%. Fungal blood-stream infection accounted for 55% of cases, peritoneal and pleural fluid 25% and 10% respectively. The ICU-mortality associated with IFD was 29.9%, rising to 39.6% for hospital-mortality, and proven IFD was associated with longer ICU and hospital length of stay, higher rates of organ support and greater illness-severity scores. Despite this the rate of anti-fungal prophylaxis was low (<5%).² This agrees with data from a recent pan-European survey where C. albicans accounted for 54% of IFD and mortality from all IFD was 38.8%. The rate of prophylaxis use in mainland Europe appears higher, but notably 16.5% of patients receiving prophylaxis subsequently developed IFD.³

International consensus guidelines categorize IFD as proven, probable and possible. Proven disease requires the presence of fungus in material from a sterile site (confirmed by culture, microscopy, histopathologic or cytopathologic methods) or blood culture in the context of a compatible clinical picture. As a reflection of the high rates of colonisation seen in critically ill patients, a “sterile site” excludes samples taken from drains placed >24 hours ago, bronchoalveolar lavage, urine and cranial sinuses. Probable disease requires the presence of a host risk factor (such as steroid use equivalent to ≥0.3/mg/kg/day of prednisolone ≥3 weeks) in the presence of clinical signs of infection and mycological criteria (fungal “elements” on microscopy of sterile site samples or indirect evidence for fungal elements such as galactomannan or β-D-glucan positivity). A diagnosis of possible IFD simply requires the presence of a risk factor and clinical signs of infection.⁴ Conceptually treatment may then be defined as prophylactic, pre-emptive (for possible IFD), empirical (for probable IFD) and targeted (proven IFD).¹ International guidelines advise that pre-emptive and empirical treatment use the same regime. Fluconazole or an echinocandin (caspofungin) are recommended as initial therapy for most adult patients, with an echinocandin recommended for more unwell patients or those with recent azole exposure. Amphotericin is the recommended alternative only if either of these is unavailable. The standard treatment course is 2 weeks, unless there is evidence of metastatic spread.⁵

It has been estimated that 70% of antifungal treatment in critical care is pre-emptive or empirical, however there is no evidence that this improves mortality or prevents the development of proven IFD. Two recent studies, from North America and mainland Europe, concluded that pre-emptive and empirical antifungal treatment for non-neutropaenic, non-transplant critically ill patients had no significant impact on rates of proven IFD or mortality.^6,7 The North American trial examined a prospective cohort of 1491 patients in which 100 patients (6.7%) were empirically treated; 22% of these subsequently developed proven IFD with a 30-day mortality of 24.3%.⁶ The European trial was a randomized double-blind placebo-control trial of pre-emptive echinocandin therapy in 241 patients admitted to ICU following emergency surgery for intra-abdominal sepsis; there was no significant difference in the rate of proven IFD between the treatment arms.⁷

The value of prophylactic treatment for IFD in non-neutropaenic, non-transplant critically ill patients is intensely debated. There are a handful of small studies examining prophylaxis in high-risk surgical patients that demonstrate a reduction in the incidence of IFD, but no significant impact on overall mortality.⁸ The evidence relating to prophylaxis in non-surgical patients is scarce. Ostrosky-Zeichner and colleagues published the results of MSG-01 in 2014, a randomised double-blind placebo-control trial of antifungal prophylaxis using an echinocandin in 222 ICU patients. This showed no statistically significant difference in the rate of proven or probable IFD between the intervention and control arms in a population deemed high-risk using an established clinical risk scoring tool.⁹

Ultimately the debate regarding antifungal prophylaxis is limited by a lack of robust scientific data. Research in this area is dogged by the same criticisms applied to much research in critical care; study populations that are too heterogeneous, treatment effects that are overestimated and trials that are underpowered or unfeasible in terms of cost, recruitment and duration. Many attempts have been made to design clinical prediction rules to identify patients at high-risk of IFD, none thus far have been successfully validated and arguably the most well-known of these (the “Candida score”) formed the basis for patient selection in the negative-outcome MSG01 trial discussed earlier.^2,9-12

Characteristics identified as indicative of a high-risk for IFD are remarkably consistent between studies and are typically formulated as mechanical ventilation >72 hours and the presence of a central venous catheter and systemic antibiotic use (particularly ciprofloxacin) in addition to one of; gastrointestinal surgery (particularly for perforated viscus), acute pancreatitis, systemic steroid or immunosuppressant use, renal-replacement therapy or parenteral nutrition. The “burden” of fungal colonisation is not consistently identified as a risk factor. Probably the most articulate summary of current thinking can be taken from the ICNARC FIRE (Fungal Infection Risk Evaluation) study “the current most cost-effective treatment strategy among non-neutropaenic, critically ill adult patients admitted to NHS adult general critical care units is a strategy of risk assessment and antifungal prophylaxis at the end of calendar day 3, but this finding is highly uncertain and future studies should consider the potential impact of increased resistance”.²

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Lessons learnt

IFD is common in ICU and is associated with high mortality and morbidity. Current rules to identify patients at high risk of IFD would result in prescription of antifungal prophylaxis to approximately 20% of non-neutropaenic, non-transplant critically ill patients without robust evidence for reduction of proven IFD or reduction in overall mortality. There is some evidence that prophylaxis may result in lower rates of proven IFD in pure populations of high-risk surgical patients.

My current practice would be to administer antifungal prophylaxis to all critically ill neutropaenic and transplant patients, patients with fulminant hepatic failure (expert recommendation and local practice) and patients with acute severe pancreatitis (particularly those on parenteral nutrition). A low index of suspicion of IFD should be maintained in other patient groups.

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References

1. Eggimann P, Bille J, Marchetti. Diagnosis of invasive candidiasis in the ICU. Annals of Intensive Care, 2011; 1:37

2. Harrison D, Muskett H, Harvey S, et al. Development and validation of a risk model for identification of non-neutropenic, critically ill adult patients at high risk of invasive Candida infection: the Fungal Infection Risk Evaluation (FIRE) Study. Health Technol Assess, 2013; 17

3. Klingspor L, Tortorano AM, Peman J, et al. Invasive Candida infections in surgical patients in intensive care units: a prospective, multicentre survey initiated by the European Confederation of Medical Mycology (ECMM) (2006-2008). Clin Microbiol Infect, 2015; 21:87.e1-87.e10

4. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis, 2008; 46:1813-21

5. Pappas PG, Kauffmann CA, Andes D, et al. Clinical Practice Guidelines for the management of Candidiasis: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis, 2009; 48:503-35

6. Bailly S, Bouadma L, Azoulay E, et al. Failure of Empirical Systemic Antifungal Therapy in Mechanically Ventilated Critically Ill Patients. Am J Respir Crit Care Med, 2015; 191:1139-46

7. Knitsch W, Vincent JL, Utzolino S, et al. A randomized, placebo-controlled trial of pre-emptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-abdominal infections. Clin Infect Dis, 2015; 61:1671-8

8. Schorr AF, Chung K, Jackson WL, et al. Fluconazole prophylaxis in critically ill surgical patients: a meta-analysis. Crit Care Med, 2005; 33:1928-35

9. Ostrosky-Zeichner L, Shoham S, Vazquez J, et al. MSG-01: A randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis, 2014; 58:1219-26

10. Paphitou NI, Ostrosky-Zeichner L, Rex JH. Rules for identifying patients at increased risk for candida infections in the surgical intensive care unit: approach to developing practical criteria for systematic use in antifungal prophylaxis trials. Medical Mycology, 2005; 43:235-43

11. Leon C, Ruiz-Santana S, Saavedra P, et al. A bedside scoring system (“Candida score”) for early antifungal treatment in non-neutropenic critically ill patients with Candida colonization. Crit Care Med, 2006; 34:730-7

12. Ostrosky-Zeichner L, Sable C, Sobel J, et al. Multicentre retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis, 2007; 26:271-6