Role of liposomal amphotericin B in intensive care unit: an expert opinion paper

Introduction

Invasive fungal infections (IFI) are life-threatening in ICU patients, with rising incidence and persistently high mortality. The increase is linked to complex care needs, immunocompromised states, comorbidities, broad-spectrum antibiotic use, and invasive procedures that disrupt protective barriers. While candidiasis remains most common, non-albicans species and invasive aspergillosis are increasing, along with infections from rare molds like Mucorales and Fusarium. Management is difficult due to limited rapid diagnostics, antifungal testing, and treatment data.

Antifungal resistance to fluconazole, triazoles, and echinocandins is a growing concern, with outbreaks of resistant Candida species and emerging multidrug-resistant C. auris. Azole-resistant A. fumigatus is also spreading globally. Though new antifungals are in development, evidence in critically ill patients is limited.

Liposomal amphotericin B (L-AmB) offers broad-spectrum activity with reduced nephrotoxicity compared to conventional formulations. It is recommended for resistant or refractory candidiasis, aspergillosis, and as a first-line treatment for mucormycosis and other filamentous fungi. Given current limitations of first-line agents, an expert panel was convened to provide guidance on L-AmB use in managing IFIs in ICU patients.

Method

A panel of 16 experts in infectious diseases, microbiology, pharmacology, and intensive care developed consensus statements on managing ICU patients at risk of invasive fungal infections and the role of liposomal amphotericin B (L-AmB). The process, defined in October 2023, involved drafting and refining statements based on literature reviews, followed by evaluation from 51 ICU clinicians using a 9-point scale. Statements scoring below 8.0 were revised before final inclusion.

Results

General statements about the role of liposomal amphotericin B

1. Treatment for invasive fungal infections (IFIs) in ICU patients must be individualized, as multiple patient-specific factors—such as infection type, risk profile, and organ function—affect antifungal selection.
2. Liposomal amphotericin B (L-AmB) is a strong antifungal option due to its broad activity, low resistance risk, minimal drug interactions, good tissue penetration, no TDM requirement, and acceptable safety profile.

Microbiology

Background
The use of microbiological biomarkers for diagnosing invasive fungal infections (IFI) in ICUs remains debated. While molecular and antigen-based tests have improved diagnostic speed and sensitivity, classical culture remains essential for confirmation and species identification, though it is time-consuming and affected by antifungal exposure or sample quality. Antifungal susceptibility testing (AST) and emerging molecular resistance assays are valuable for guiding therapy but are not yet widely available. ICU patients are at higher risk of resistant infections due to prolonged hospitalization, prior antifungal use, and environmental factors. Reports of resistant strains like C. auris, C. parapsilosis, and azole-resistant A. fumigatus highlight the growing need for timely, accurate diagnostics.

IFI epidemiology is evolving due to improved diagnostics, more at-risk patients, antifungal exposure, and climate change. Timely, accurate diagnosis and access to mycology expertise are crucial for managing infections and resistance.

Statements

1. GM testing from BALF shows higher diagnostic accuracy for IPA than serum GM, while both BALF and serum BDG tests have limited specificity.
2. Quantitative GM testing, especially from BALF, is useful for diagnosing IA in ICUs but must be interpreted alongside clinical and radiological findings.
3. PCR testing from BALF helps diagnose aspergillosis, especially in high-risk patients, but accuracy depends on population and method. Standardized PCR protocols improve reliability.
4. Beta-glucan testing aids in diagnosing invasive candidiasis and should be part of decision-making to rule out systemic Candida infection due to its high negative predictive value.
5. Classical culture remains essential for confirming IA, identifying pathogens, and guiding appropriate antifungal therapy.
6. Blood cultures are the gold standard for diagnosing candidemia, identifying species, testing drug sensitivity, and tracking treatment response.
7. Advanced PCR tests, including pan-fungal and plasma DNA panels, enable early, accurate detection of diverse fungal pathogens, improving patient outcomes.

Pharmacology

Background
Liposomal amphotericin B (L-AmB) exhibits concentration-dependent fungicidal activity, with efficacy linked to the Cmax/MIC ratio. Pharmacokinetic studies in critically ill patients show interindividual variability, though factors like renal function or CRRT do not significantly affect drug levels. ECMO may alter drug distribution, and obese patients may face higher nephrotoxicity risks at doses above 5 mg/kg/day, suggesting a maximum of 5 mg/kg/day or 500 mg for those over 100 kg. Meta-analyses indicate that higher doses (>5 mg/kg/day) do not improve outcomes and may increase mortality and renal toxicity, except in select cases like mucormycosis or leishmaniasis. Compared to amphotericin B deoxycholate, L-AmB is safer with a lower risk of nephrotoxicity due to reduced renal accumulation. Studies in ICU patients, including those on renal replacement therapy, confirm L-AmB’s favorable safety profile, supporting its role as an effective antifungal option in critically ill patients.

The optimal L-AmB dose for critically ill patients is 3–5 mg/kg/day (max 500 mg for >100 kg). Higher doses offer no added benefit and increase nephrotoxicity risk, except a single 10 mg/kg dose may be used for visceral leishmaniasis or cryptococcal meningitis.

Statements

1. The optimal L-AmB dose for critically ill patients is 3–5 mg/kg/day (max 500 mg for >100 kg). Higher doses offer no added benefit and increase nephrotoxicity risk, except a single 10 mg/kg dose may be used for visceral leishmaniasis or cryptococcal meningitis.
2. L-AmB (3–5 mg/kg/day) has a significantly lower risk of nephrotoxicity compared to amphotericin B deoxycholate.
3. No dose adjustment of L-AmB is needed in renal dysfunction or patients on dialysis, as elimination is non-renal and adverse event rates are similar to non-RRT groups.

Specific clinical settings

Molds and SARS-CoV-2 and/or influenza virus coinfections

Severe influenza and COVID-19 increase the risk of invasive pulmonary aspergillosis (IPA), termed influenza-associated (IAPA) and COVID-19-associated (CAPA) pulmonary aspergillosis. Virus-induced lung injury and immune dysfunction promote Aspergillus invasion, forming a distinct condition known as virus-associated pulmonary aspergillosis (VAPA). Guidelines recommend screening for IPA in patients with severe viral pneumonia or respiratory failure using galactomannan testing on BALF at ICU admission and weekly thereafter. However, antifungal prophylaxis is not routinely advised, as IAPA and CAPA incidence varies by region.

Statements

1. In severe viral pneumonia cases without additional IPA risk factors, anti-mold therapy should wait for microbiological confirmation. However, in patients with added risks like corticosteroid use, COPD, or immunosuppression, empiric antifungal treatment may be warranted.
2. Routine anti-mold prophylaxis for critically ill patients with viral pneumonia is not supported by current evidence.

Patients on therapy with corticosteroids or immunomodulatory drugs

Background
Long-term high-dose corticosteroid use is a well-known risk factor for pulmonary aspergillosis and is included in diagnostic criteria like EORTC-MSG and AspICU. In severe influenza and COVID-19, corticosteroids such as dexamethasone reduce mortality but increase the risk of IPA and CAPA by impairing macrophage defense and promoting fungal growth. Similarly, COVID-19 treatments like IL-6 inhibitors (e.g., tocilizumab) are also linked to a higher CAPA risk.

Statement
Chronic therapy with corticosteroids or immunomodulatory drugs should lead to a high index of suspicion of IPA in critically ill patients with pulmonary infiltrates, driving an early diagnostic approach.

Chronic obstructive pulmonary disease

Background
COPD patients are at increased risk of invasive pulmonary aspergillosis (IPA), but distinguishing true infection from colonization can be challenging in critically ill cases. Given IPA’s poor prognosis, diagnostic algorithms combining clinical and microbiological data can aid early treatment. A pre-emptive strategy using biomarkers (GM, PCR, BDG) and imaging shows promise, while a recent risk model highlights low serum albumin, severe COPD, prior steroid use, and prolonged antibiotic therapy as key predictors.

Statement
Patients with COPD are at higher risk of developing IPA. Therefore, a prompt diagnostic approach must be pursued in any case of infection-related respiratory worsening.

Diabetes

Background
Diabetes mellitus is a major risk factor for mucormycosis, especially rhino-orbital-cerebral forms, with cases rising globally alongside increasing diabetes prevalence. COVID-19 further heightens this risk. Early clinical suspicion, imaging, and prompt antifungal therapy are crucial since diagnosis can be delayed. High-dose liposomal amphotericin B (L-AmB) is the first-line treatment, though doses above 5 mg/kg/day show no added survival benefit. Isavuconazole or posaconazole may be used as second-line options, while combination therapy remains inconclusive. Surgical debridement and strict glycemic control are essential for effective management.

Statements

1. In the last 50 years, diabetes has evolved as one of the major risk factors for mucormycosis, while more recently, underlying malignancy, severe immunodepression conditions, and SARS-CoV-2 infection emerged as important risk factors.
2. L-AmB demonstrated efficacy in the treatment of mucormycosis with various organ involvement patterns. The daily dose should be 5 mg/kg per day.

End-stage liver disease

Background
Increasing cases of invasive pulmonary aspergillosis (IPA) are being reported in critically ill patients with acute liver failure or cirrhosis, mainly due to immune dysfunction and low platelet counts that reduce defense against Aspergillus. The incidence is notably high in severe alcoholic hepatitis (~15%) with nearly 100% mortality and up to 14% in end-stage liver disease, particularly in Child–Pugh C and high MELD score patients requiring ventilation or dialysis. In ICU cohorts, around 28% of cirrhotic patients with Aspergillus culture had proven or probable IPA, with a mortality rate of about 71%. Diagnosis relies on compatible clinical signs and a positive GM antigen (ODI ≥1) on BALF. Current ESCMID-ECMM-ERS guidelines recommend liposomal amphotericin B (L-AmB) for treatment, given the hepatotoxicity risk associated with azoles in liver failure.

Statements

1. In critically ill patients, acute on chronic liver failure and decompensated cirrhosis are recognized main risk factors for IA
   Therapeutic approach to mold infections in patients with severe viral pneumonia, chronic corticosteroids or immunomodulatory therapy, COPD, diabetes, and end-stage liver disease
2. L-AmB may be preferred over azoles in treatment failure cases, regions with high azole resistance, patients with liver disease or drug interactions, and where voriconazole TDM isn’t feasible.
3. L-AmB shows limited pharmacokinetic variability in critically ill patients, so therapeutic drug monitoring (TDM) is not required.

Solid organ transplantation

Background
In solid organ transplant (SOT) recipients, invasive fungal infections (IFI) vary by transplant type and region, being most common after small bowel, lung, and liver transplants. Candida and Aspergillus species are the main pathogens—Candida dominates in abdominal transplants, while Aspergillus is frequent after lung transplants. Non-albicans Candida species and azole-resistant Aspergillus are rising concerns. IFIs usually occur within six months post-transplant, linked to reoperation, renal therapy, or CMV infection. Targeted antifungal prophylaxis is preferred over universal use, with L-AmB showing the lowest breakthrough infection rates in high-risk liver transplant patients. Triazoles have significant drug–drug interactions, making L-AmB pulsed dosing (10 mg/kg weekly) a safer prophylactic choice. For treatment, L-AmB remains preferred when azoles are unsuitable, while isavuconazole offers efficacy with fewer immunosuppressant interactions.

Statements

1. In SOT recipients, antifungal prophylaxis should be risk-based. Considering drug interactions, safety, and breakthrough infection risk, L-AmB is a suitable option.
2. Azole antifungals may cause significant interactions with immunosuppressants in SOT patients; L-AmB serves as a valuable empirical alternative.
3. For invasive candidiasis in SOT recipients, L-AmB is a reasonable alternative to echinocandins.
4. Targeted or pre-emptive antifungal strategies are key to antifungal stewardship and should be applied across all transplant settings, including lung transplants.

Hematologic malignancies

Background
Patients with prolonged neutropenia after chemotherapy for AML or undergoing allogeneic HSCT are at high risk of IFIs. Similar risks exist in those receiving immunotherapy or CAR T-cell therapy. Although antifungal prophylaxis—especially with posaconazole—has reduced IFI incidence, breakthrough infections (bIFIs) still occur due to sub-therapeutic drug levels, azole-resistant Aspergillus, or infections by intrinsically resistant molds like Mucorales and Fusarium. In such cases, L-AmB is preferred for its broad antifungal coverage.

Triazoles remain standard for prevention and treatment, but require therapeutic drug monitoring (TDM) because of variable pharmacokinetics and interactions. Voriconazole and isavuconazole levels should be monitored, especially in ICU patients, to ensure efficacy and safety. Where TDM is unavailable, L-AmB is a reliable alternative.

In high-risk hematology patients, pre-emptive therapy with L-AmB may be initiated based on clinical suspicion or diagnostic indicators (imaging, cultures, GM, PCR), with treatment discontinued if IFI is not confirmed.

Statements

1. Antifungal prophylaxis is advised only for selected high-risk hematology patients — fluconazole for Candida coverage and posaconazole for molds (e.g., AML induction, allogeneic HSCT, or GVHD cases).
2. Hematologic patients on mold-active azole prophylaxis who develop breakthrough IFI should be treated with L-AmB and undergo full diagnostic evaluation.
3. ICU-admitted hematology patients with IFI who lack access to azole TDM or face high drug-interaction risk should receive L-AmB treatment.
4. For high-risk hematology patients (prolonged neutropenia or post-HSCT) with suspected IFI, empirical L-AmB therapy may be started during diagnostic evaluation and stopped if IFI is not confirmed.

Abdominal surgery

Background
Intra-abdominal candidiasis (IAC) is the most common form of deep-seated candidiasis and often occurs without bloodstream infection, making diagnosis difficult. Due to its poor prognosis, empirical antifungal therapy is frequently used in critically ill patients, though microbiological confirmation is rare. While echinocandins are guideline-recommended as first-line therapy, their limited penetration in the abdominal cavity and low drug exposure may reduce efficacy. In contrast, liposomal amphotericin B (L-AmB) shows strong fungicidal and anti-biofilm activity, good tissue penetration, and stable pharmacokinetics even in critically ill patients or those on CRRT. Hence, L-AmB is increasingly considered a first-line option for IAC, especially in cases involving sepsis, prior echinocandin or azole exposure, or resistant Candida species like C. glabrata or C. auris. Effective source control remains essential for successful treatment.

Statements

1. Diagnosing IAC is difficult; it relies on microscopy or culture from surgical or aspirated samples, while blood cultures often lack sensitivity. Non-culture tests like BDG may help rule out fungal causes.
2. Empirical antifungal therapy should consider host and infection factors. L-AmB is preferred for IAC with sepsis, N. glabratus or C. parapsilosis risk, or prior echinocandin use.
3. Echinocandins may be used in non-critical cases, but limited abdominal penetration can lead to suboptimal exposure and possible resistance, especially with non-albicans species.
4. Combination therapy of L-AmB and echinocandin can be used as rescue treatment for C. auris infections.
5. In critically ill patients, empirical antifungal therapy for suspected IC (including abdominal cases) can be safely stopped early using a biomarker-guided approach.

Conclusion

Treating IFIs in critical care remains difficult due to increasing at-risk patients and rising drug resistance. L-AmB, with its broad-spectrum activity and better safety, offers a strong therapeutic option in many ICU scenarios. A panel of 16 Italian experts developed 35 statements based on current evidence to guide its appropriate use. While based on expert opinion and limited ICU data, this document highlights practical clinical applications where L-AmB can serve as front-line therapy. Despite economic and availability constraints, it provides useful guidance for clinicians and encourages further high-quality studies to strengthen evidence on L-AmB use in critical care.

Source: Bussini, L., Bartoletti, M., Bassetti, M. et al. Role of liposomal amphotericin B in intensive care unit: an expert opinion paper. J Anesth Analg Crit Care 5, 23 (2025). https://doi.org/10.1186/s44158-025-00236-z