Introduction
(Article introduction authored by ICU Editorial Team)
Invasive fungal infections, particularly those caused by moulds, pose significant morbidity and mortality risks. Limited antifungal classes suffer from toxicities and increasing resistance.
This study reviews the use of high-dose lipid formulation of amphotericin B (≥7.5 mg/kg/day) through a case series and literature review.
The case series included nine patients treated between June 2012 and August 2021, primarily for mould infections, with doses averaging 8.9 mg/kg/day over 11 days. The literature review included 11 studies (260 patients), showing response rates from 8% to 100%.
High-dose liposomal amphotericin B was well tolerated, with serum creatinine changes being the most common adverse event. Despite mixed response rates (8-62%), it may be a viable option for managing invasive fungal infections when other treatments fail.
The increasing incidence of mould infections is linked to broad-spectrum antifungal prophylaxis and intensive immunosuppressive therapies.
While antifungal options are limited and resistance is growing, high-dose lipid formulations of amphotericin B offer a potential strategy with improved tolerability and efficacy.
Methodology
For the case series, patients admitted to the University of Mississippi Medical Center between June 2012 and August 2021 who received high-dose lipid complex or liposomal amphotericin, defined as daily receipt of ≥ 7.5 mg/kg/day, were included.
Amphotericin dosing at this institution is at the discretion of the provider, and there is no formal protocol or guidelines for use.
Most patients included in this retrospective case series were escalated to higher-than-standard doses based on severity of infection or lack of therapeutic response.
This case series was approved by the Institutional Review Boards at the University of Mississippi Medical Center and University of Mississippi School of Pharmacy.
All patient information was deidentified, and patient consent was not required. Favourable response was defined as having no inpatient mortality, no infection-related readmission within 90 days and no repeated cultures positive for the same organism within 6 months.
A systematic search of PubMed was performed with the search terms “amphotericin B” and “high dose” (Figure 1). All English-language studies completed in humans were reviewed.
Studies referencing treatment with high-dose amphotericin, defined as daily receipt of an amphotericin B lipid formulation (lipid complex or liposomal) at doses ≥7.5 mg/kg were included.
Studies referencing one-time loading doses, prophylaxis, in vitro or animal studies, or those with leishmaniasis were excluded. References of relevant articles were reviewed and added as appropriate.
Results
Case series
Nine patients met the inclusion criteria for the case series (Table 1). Patients received an average of 8.9 ± 1.3 mg/kg of liposomal amphotericin B for a duration of 11.0 ± 10.8 days (range 1–34) predominantly for mould infections, including Mucorales, Fusarium species and aspergillosis. The average patient age was 49.4 ± 16.8 years, body weight was 88.0 ± 31.3 kg, and most patients (56%) were cared for in the intensive care unit. The average length of hospital stay was 46.3 ± 46.8 days. Most patients (89%) had previously received amphotericin B at an average dose of 4.66 ± 2.22 mg/kg in the course of the same infection as well as other concurrent antifungals (100%). Three patients (33%) were cured of their infection and 6 (67%) died during (n=4) or after (n=2) their stay. The main adverse effects were increased serum creatinine (n=3), changes in heart rhythm (n=3) and decreases in potassium levels (n=1).
Review of the literature
A total of 959 articles were identified through the PubMed search and review of references. After limiting articles to humans and English language, 637 articles were screened to determine eligibility for inclusion based on pre-determined criteria. A total of 11 manuscripts met inclusion criteria and were included in this review. Of these, seven were case reports or case series, one was a retrospective evaluation, and three were prospective studies (1 pilot, one open label, one randomized controlled trial). A total of 260 patients, ranging from 8 to 69 years of age, were represented in the published literature. Most patients had an underlying haematological malignancy, and many had previously received lower doses of amphotericin B or alternative antifungal therapies. Favourable response with high-dose therapy across all published literature ranged from 8% to 100%. In multi-patient reports, rates of nephrotoxicity, hepatotoxicity and hypokalaemia were higher in the high-dose groups.
Discussion
High doses of liposomal amphotericin B for difficult-to-treat invasive mould or dimorphic fungal infections were fairly well tolerated, with increased serum creatinine being the primary adverse effect. Clinicians should monitor kidney function and electrolytes daily. Response and mortality rates in our case series were similar to previous reports, with multi-patient studies showing low favourable response rates (8-68%).
Some studies suggest alternative or concomitant therapies might be beneficial. Five reports included surgical resection, showing high success in individual cases, though likely influenced by publication bias. One multi-patient study reported 21% mortality with 71% undergoing surgery. Combination therapies with azoles, echinocandins, or topical treatments showed varied success. Two studies compared high-dose lipid formulation amphotericin with other treatments, finding posaconazole more effective and noting increased nephrotoxicity at higher amphotericin doses. These older studies indicate the need for updated research reflecting current practices.
Conclusion
Given the small patient numbers, lack of direct comparators, underwhelming results, and higher adverse effects, it’s unsurprising that high-dose liposomal amphotericin B has seen slow clinical uptake.
However, its use is increasing at our institution, likely due to comorbidities or concomitant therapies making other options less desirable. Thus, high-dose liposomal amphotericin B, alone or combined with other antifungals, may be a viable strategy for treating invasive fungal infections with limited options.