Fungal infections in the ICU

Contents

Overview

Invasive fungal infections are an important cause of morbidity and mortality in critically ill patients. Candida species cause the majority of ICU fungal infections, predominantly as candidaemia and invasive candidiasis. Aspergillus causes invasive pulmonary aspergillosis (IPA), increasingly recognised in non-classically immunocompromised patients. Early identification, appropriate antifungal selection, and source control (particularly catheter removal in candidaemia) are critical.

Invasive Candidiasis

Epidemiology and Risk Factors

Candida is the fourth most common bloodstream pathogen in hospital settings and the most common fungal pathogen in the ICU. Mortality from candidaemia is 30–45%.

Risk factors for invasive candidiasis in ICU patients:

  • Prolonged ICU stay (>5 days)
  • Broad-spectrum antibiotics (disrupting gut colonisation resistance)
  • Central venous catheter
  • Total parenteral nutrition
  • Abdominal surgery (particularly for gastrointestinal perforation)
  • Renal replacement therapy
  • High-dose corticosteroids or immunosuppression
  • Diabetes mellitus
  • Prior Candida colonisation (multiple sites)

Species Distribution

Candida albicans remains the most common species (~50%). Non-albicans Candida species are increasingly prevalent:

  • C. glabrata (now Nakaseomyces glabrata): reduced azole susceptibility; common in patients with prior azole exposure
  • C. krusei: intrinsically resistant to fluconazole
  • C. parapsilosis: associated with catheter-related infections and neonates
  • C. tropicalis: more virulent, associated with haematological malignancy
  • C. auris: emerging multidrug-resistant pathogen; major infection control concern (see below)

Clinical Presentations

Candidaemia: Candida isolated from blood culture. Presents as fever unresponsive to antibacterials in a patient with risk factors. May cause septic shock.

Deep organ candidiasis: Hepatosplenic candidiasis (typically in neutropenic patients recovering from chemotherapy), endophthalmitis (20–30% of candidaemia if untreated), myocarditis, osteomyelitis.

Invasive abdominal candidiasis: Peritonitis, intra-abdominal abscess — particularly following bowel surgery, perforation, or anastomotic leak. Blood cultures may be negative.

Diagnosis

Blood cultures: Positive in candidaemia. Sensitivity is low (~50–70%) — multiple sets improve yield. Cultures must be incubated for 5 days on dedicated fungal media. Time to positivity typically 2–3 days.

Beta-D-glucan (BDG): Cell wall component of most fungi (not Cryptococcus or zygomycetes). A serum level >80 pg/mL has a sensitivity of ~80% and specificity of ~60% for invasive candidiasis. Useful as an adjunctive test and for early detection, but not species-specific. Can be positive in patients on IV immunoglobulin, albumin, or certain beta-lactam antibiotics (false positives).

Candida PCR: From blood — high sensitivity, not universally available.

Ophthalmological examination: All patients with candidaemia should have dilated fundoscopy to exclude endophthalmitis (occurs in approximately 15% of candidaemia episodes).

Management

Remove the central venous catheter: In all cases of candidaemia, the CVC must be removed and cultures taken from the tip. Catheter removal improves outcomes.

Antifungal treatment:

  • Echinocandin (anidulafungin, micafungin, caspofungin): first-line for most ICU patients, particularly those who are severely ill, have prior azole exposure, or where C. glabrata or C. krusei is suspected.
  • Fluconazole: acceptable in non-severely ill patients with no prior azole exposure, where C. albicans is likely. Not active against C. krusei (intrinsically resistant) and has variable activity against C. glabrata.

Treatment duration: minimum 14 days from the first negative blood culture and clinical improvement.

Step-down to fluconazole after clinical stabilisation if the isolate is susceptible.

Candida auris

C. auris is a multidrug-resistant emerging pathogen with particular propensity for healthcare-associated outbreaks. Characteristics:

  • Frequently resistant to fluconazole, sometimes to amphotericin B; most isolates remain susceptible to echinocandins
  • Persistent environmental contamination requiring enhanced environmental cleaning
  • Cannot be reliably identified by standard diagnostic equipment (requires MALDI-TOF or molecular testing)
  • UKHSA mandates notification and specific infection control measures

Invasive Pulmonary Aspergillosis

Epidemiology

IPA is classically a disease of the profoundly immunocompromised (haematological malignancy, solid organ transplant, prolonged high-dose corticosteroids). However, IPA increasingly occurs in non-classical hosts: patients with severe influenza, COVID-19 (COVID-associated pulmonary aspergillosis, CAPA), chronic lung disease (COPD), liver failure, and those receiving moderate doses of corticosteroids. Recognition of IPA in non-immunocompromised ICU patients is improving.

Pathophysiology

Aspergillus fumigatus conidia (spores) are inhaled and usually cleared by alveolar macrophages and neutrophils. In immunocompromised hosts, this clearance fails and germinating hyphae invade pulmonary tissue, causing angioinvasion, thrombosis, and haemorrhagic infarction.

Clinical Features

Fever unresponsive to antibacterials, dyspnoea, cough (haemoptysis in severe cases), pleuritic chest pain. Radiological features: nodules with halo sign (ground-glass halo around a central dense nodule — representing haemorrhagic infarction), wedge-shaped infarcts, cavitation (air-crescent sign as neutrophil recovery occurs). CT is more sensitive than CXR.

Diagnosis

The EORTC/MSGERC classification defines proven, probable, and possible IPA based on host factors, clinical/radiological features, and mycological evidence.

Galactomannan: A polysaccharide component of the Aspergillus cell wall. Detectable in serum and BAL by ELISA. Serum galactomannan sensitivity is lower in non-neutropenic patients; BAL galactomannan has higher sensitivity in this group.

BAL culture: Positive in ~50% of IPA cases. Culture from non-sterile site must be interpreted in clinical context.

Aspergillus PCR: From BAL or serum. High sensitivity; specificity issues in patients with colonisation.

CT chest: Nodular or consolidative infiltrates; halo sign is specific in the right clinical context.

Bronchoscopy + BAL: Required for galactomannan, culture, PCR, and cytology.

Management

Voriconazole: First-line treatment. IV loading doses followed by oral step-down. Requires TDM (target trough 1–5.5 mg/L). CYP2C19 polymorphism causes variable metabolism — check trough early.

Isavuconazole: Alternative to voriconazole; fewer drug interactions, no hepatic toxicity concerns. Increasingly preferred.

Liposomal amphotericin B: Second-line; used if azole-resistant Aspergillus or intolerance to azoles.

Combination therapy: Not recommended routinely; may be considered in refractory cases.

Duration: minimum 6–12 weeks; continue until clinical and radiological resolution and immune reconstitution.

Antifungal Agents

Class Examples Mechanism Spectrum Key Issues
Azoles Fluconazole, voriconazole, isavuconazole, posaconazole Inhibit ergosterol synthesis (CYP51/14α-demethylase) Candida (variable), Aspergillus (not fluconazole) Drug interactions (CYP enzymes), hepatotoxicity, QT prolongation (azoles), TDM needed for voriconazole
Echinocandins Caspofungin, micafungin, anidulafungin Inhibit (1,3)-β-D-glucan synthase (cell wall) Candida (broad), limited Aspergillus, no Cryptococcus, no Zygomycetes IV only, few interactions, preferred in severe candidaemia
Polyenes Amphotericin B (liposomal) Binds ergosterol, disrupts membrane Broad including Mucor, Cryptococcus Nephrotoxicity (conventional > liposomal), infusion reactions
Flucytosine Flucytosine Inhibits DNA synthesis Candida, Cryptococcus Used in combination only (rapid resistance if monotherapy); monitor bone marrow

Prophylaxis vs Empirical vs Targeted Therapy

Prophylaxis: Antifungal given to prevent infection in high-risk patients. Used in haematological malignancy (posaconazole in AML/MDS during induction chemotherapy), stem cell transplantation (fluconazole, posaconazole), and selected solid organ transplant recipients. Not routinely recommended in unselected ICU patients.

Empirical (pre-emptive) therapy: Antifungal started on clinical suspicion without confirmatory evidence. Appropriate in critically ill patients with risk factors, deteriorating despite antibacterials, and no alternative explanation. BDG and Candida score (clinical prediction tool) can support this decision.

Targeted therapy: Treatment commenced on confirmed microbiological diagnosis (positive blood culture, proven IPA). Always required for confirmed infection.

The Candida score assigns points for TPN (0.908 points), surgery (0.997 points), colonisation at ≥2 sites (1.112 points), and severe sepsis (2.038 points). Score >2.5 predicts Candida infection in ICU patients with a sensitivity of ~77% and supports consideration of empirical antifungal therapy.

Other Fungal Infections

Cryptococcal meningitis: Affects immunocompromised patients (HIV, organ transplant). Presents with subacute meningitis, raised ICP. Diagnosed by cryptococcal antigen (CrAg) in CSF and serum, India ink stain, CSF culture. Treated with liposomal amphotericin B + flucytosine for induction, then fluconazole for consolidation and maintenance. CSF pressure management is critical.

Mucormycosis (Zygomycosis): Angioinvasive infection with Mucor, Rhizopus, Lichtheimia. Associated with uncontrolled diabetes, corticosteroids, haematological malignancy. Rhinocerebral (sinus → orbit → brain), pulmonary, and cutaneous forms. Rapidly fatal without treatment: liposomal amphotericin B plus extensive surgical debridement. Voriconazole and echinocandins are NOT active.

Pneumocystis jirovecii pneumonia (PJP): Diffuse bilateral interstitial infiltrates, progressive hypoxaemia, characteristic "ground glass" CT appearance. Affects immunocompromised patients. Treated with high-dose co-trimoxazole; corticosteroids if PaO2 <9.3 kPa. Not responsive to standard antifungals (echinocandins or azoles); co-trimoxazole is essential.

Viva Questions

A 55-year-old man has been in the ICU for 12 days with abdominal sepsis following a sigmoid perforation. He remains febrile despite broad-spectrum antibacterials. Blood cultures grow Candida albicans. How do you manage this?

Candidaemia requires immediate action. The first step is to remove all central venous catheters and resite to a new location — catheter removal is associated with significantly better outcomes and is mandatory in candidaemia. Antifungal treatment should be started immediately: in a severely ill ICU patient, an echinocandin (anidulafungin, micafungin, or caspofungin) is first-line regardless of species. Once the susceptibility of C. albicans is confirmed (it is typically fully susceptible to fluconazole), step-down to oral or IV fluconazole can occur when the patient is clinically improving and has no concerns about absorption. Treatment must continue for a minimum of 14 days from the first negative blood culture. All patients with candidaemia should undergo dilated ophthalmological examination to exclude endophthalmitis, as this occurs in approximately 15% of cases and requires prolonged antifungal therapy. An echocardiogram should be considered to exclude Candida endocarditis, particularly if bacteraemia is persistent. Repeat blood cultures should be taken every 48–72 hours to confirm clearance. Source control — in this case identifying any residual intra-abdominal collection — must be pursued alongside antifungal therapy.

What is the difference between prophylactic, empirical, and targeted antifungal therapy?

These three strategies differ in the degree of microbiological confirmation required before treatment is started. Prophylaxis is given to high-risk patients with no clinical evidence of infection to prevent fungal disease from developing — for example, posaconazole during induction chemotherapy for AML or MDS, where the risk of Aspergillus infection is very high. Empirical therapy is started on clinical grounds — a patient with risk factors (prolonged ICU stay, broad-spectrum antibiotics, CVC, TPN) who is deteriorating without an identified bacterial cause. It does not require microbiological confirmation, but is guided by clinical prediction tools such as the Candida score and adjunctive biomarkers such as beta-D-glucan. It is a pragmatic strategy for patients where diagnostic delay would be harmful. Targeted therapy is treatment given for a confirmed microbiological diagnosis — a positive blood culture growing Candida, confirmed IPA on BAL. It is the most specific approach and allows narrowing of the antifungal based on the identified pathogen and its susceptibility profile. In the ICU, empirical and targeted approaches are the most relevant. Prophylaxis is generally reserved for haematological patients and transplant recipients.

What are the risk factors for invasive pulmonary aspergillosis in non-neutropenic ICU patients and how is it diagnosed?

IPA in non-neutropenic patients is increasingly recognised and was historically under-diagnosed because classical risk factors for Aspergillus — neutropenia, haematological malignancy, allogeneic stem cell transplant — were absent. Recognised risk factors in non-classically immunocompromised ICU patients include severe influenza (influenza-associated pulmonary aspergillosis, IAPA), COVID-19 (CAPA), chronic obstructive pulmonary disease (COPD — particularly with corticosteroid use), liver failure, and moderate-dose systemic corticosteroids. The proposed mechanism in these patients is impaired alveolar macrophage function rather than neutropenia. Diagnosis requires an integrated approach. CT chest showing characteristic findings (nodules, halo sign, wedge-shaped infarcts, cavitation) raises suspicion. Bronchoscopy with BAL allows galactomannan measurement (sensitivity is higher in BAL than serum in non-neutropenic patients), Aspergillus PCR, and culture. Serum galactomannan has lower sensitivity in this group due to the absence of the translocation from marrow that occurs in neutropenia. The AspICU clinical algorithm and ESCMID/ECMM/ERS guidelines provide frameworks for diagnosis in ICU patients. Treatment with voriconazole or isavuconazole should be started promptly on a probable diagnosis without waiting for proven microbiological confirmation.