How to administer liposomal amphotericin B to a critically ill patient with a compromised immune system and potential impaired renal function for a suspected or confirmed fungal infection?

Administration of Liposomal Amphotericin B in Critically Ill Patients

Administer liposomal amphotericin B at 3-5 mg/kg/day as a slow intravenous infusion over 2-6 hours, with mandatory pre-hydration using 0.9% saline 30 minutes before infusion to reduce nephrotoxicity risk. 1, 2, 3

Dosing Recommendations

Standard Dosing for Invasive Fungal Infections

• Liposomal amphotericin B: 3-5 mg/kg/day intravenously 1, 2, 4
• This is significantly higher than conventional amphotericin B deoxycholate (0.6-1.0 mg/kg/day) due to altered pharmacokinetics of the lipid formulation 2, 5
• The higher dosing is necessary to achieve equivalent tissue concentrations 2

Dosing Based on Clinical Scenario

• For suspected invasive candidiasis in ICU patients with intolerance to echinocandins or azoles: 3-5 mg/kg/day 1
• For invasive aspergillosis or other mold infections: 3-5 mg/kg/day 1, 2
• For cryptococcal meningitis or disseminated histoplasmosis: 3-5 mg/kg/day 4, 6

Critical Dosing Caveat

• Do NOT exceed 5 mg/kg/day in routine practice 2
• The AmBiLoad trial demonstrated that 10 mg/kg/day provided no efficacy benefit over 3 mg/kg/day but significantly increased nephrotoxicity 2, 6
• High doses above 5 mg/kg/day are identified as a major risk factor for renal toxicity 1

Preparation and Administration Protocol

Reconstitution (for conventional amphotericin B deoxycholate - NOT typically needed for liposomal formulation)

• Liposomal amphotericin B comes pre-formulated and requires different preparation than conventional amphotericin B 3
• Follow manufacturer-specific instructions for the liposomal formulation being used 3

Infusion Parameters

• Infusion duration: 2-6 hours depending on dose 3
• Target concentration: 0.1 mg/mL (1 mg/10 mL) for conventional formulation 3
• NEVER administer as rapid intravenous infusion - this has been associated with hypotension, hypokalemia, arrhythmias, and shock 3

Pre-Infusion Preparation

• Mandatory hydration with 0.9% saline IV 30 minutes before infusion 2, 5, 3
• This significantly ameliorates nephrotoxicity risk 2, 5
• Consider premedication with acetaminophen or diphenhydramine to reduce infusion-related reactions (fever, chills, nausea) 4, 3

Monitoring Requirements

Renal Function Monitoring

• Monitor serum creatinine and electrolytes at minimum once or twice weekly 2, 5, 3
• Particular attention to potassium and magnesium levels - amphotericin B causes renal tubular wasting 4, 3
• Approximately 19-50% of patients will experience some degree of renal injury even with liposomal formulation, but this is manageable in most cases 1, 2

Additional Monitoring

• Liver function tests regularly 4, 3
• Blood counts and hemoglobin concentrations 3
• Temperature, pulse, respiration, and blood pressure every 30 minutes for 2-4 hours after first dose 3

Special Considerations for Critically Ill Patients

Renal Impairment

• Liposomal amphotericin B is the ONLY acceptable formulation in patients with pre-existing renal dysfunction 1, 2
• Pre-existing renal impairment is NOT an absolute contraindication to liposomal amphotericin B, unlike conventional formulation 2
• Neither dialysis nor hemofiltration significantly reduces amphotericin B serum concentrations, so dose adjustment for renal replacement therapy is NOT required 1, 2

Drug Interactions in ICU Patients

• Avoid concomitant nephrotoxic medications when possible (aminoglycosides, cyclosporine, pentamidine) 3
• If unavoidable, intensive renal function monitoring is mandatory 3
• Monitor calcineurin inhibitor levels closely (cyclosporine, tacrolimus) due to potential interactions 2
• Avoid concurrent leukocyte transfusions - separate infusions as far as possible due to risk of acute pulmonary reactions 3

Electrolyte Management

• Amphotericin B-induced hypokalemia may potentiate digitalis toxicity - monitor cardiac function closely in patients on digoxin 3
• Corticosteroids and ACTH may potentiate hypokalemia - avoid concomitant use unless necessary to control amphotericin B side effects 3
• Promptly correct any potassium or magnesium deficits 3

Duration of Therapy

For Candidemia

• Continue for 2 weeks after the last positive blood culture AND resolution of signs and symptoms 1, 4
• May switch to fluconazole (IV or oral) after clinical stabilization in appropriate patients 1

For Other Invasive Fungal Infections

• Duration depends on clinical response, radiographic improvement, and resolution of immunosuppression 1, 2
• Continue therapy until reversible underlying predispositions have abated 1
• For aspergillosis, continue until neutropenia resolves and clinical/radiographic abnormalities are improving 1

Interruption of Therapy

• If therapy is interrupted for >7 days, resume at lowest dosage (0.25 mg/kg for conventional; restart at 3 mg/kg/day for liposomal) and increase gradually 3

Critical Pitfalls to Avoid

Formulation Confusion

• NEVER confuse conventional amphotericin B deoxycholate with liposomal amphotericin B - they have completely different dosing regimens 2, 5, 3
• Conventional: 0.6-1.0 mg/kg/day 5
• Liposomal: 3-5 mg/kg/day 5
• Verify product name and dosage before EVERY administration 3

Contraindications to Conventional Formulation

• NEVER use conventional amphotericin B deoxycholate in patients with pre-existing renal disease when liposomal formulation is available 1, 2, 4
• The Kidney Disease: Improving Global Outcomes guidelines provide Grade 1A recommendation to use azoles/echinocandins rather than conventional amphotericin B when equal efficacy can be assumed 5

Infusion Rate Errors

• Rapid infusion is associated with potentially fatal cardiac or cardiopulmonary arrest 3
• Always infuse over 2-6 hours 3

Inadequate Hydration

• Failure to pre-hydrate significantly increases nephrotoxicity risk 2, 5
• This is a simple, evidence-based intervention that should NEVER be omitted 2, 5

Empiric Therapy Considerations

• In critically ill ICU patients with suspected invasive candidiasis, echinocandins are preferred first-line over liposomal amphotericin B 1
• Liposomal amphotericin B is reserved for intolerance to other agents or specific resistant organisms 1
• For suspected mold infections (aspergillosis, mucormycosis), liposomal amphotericin B remains a first-line option 1, 2

Tolerability Profile

Advantages Over Conventional Formulation

• Significantly fewer infusion-related adverse events compared to conventional amphotericin B deoxycholate 1, 6
• Dramatically reduced nephrotoxicity compared to conventional formulation 1, 2, 6
• Both formulations have equivalent antifungal efficacy when dosed appropriately 1, 2

Comparison to Other Antifungals

• Echinocandins (caspofungin, micafungin) are better tolerated than liposomal amphotericin B with fewer infusion-related events and less nephrotoxicity 6
• However, liposomal amphotericin B has broader spectrum including molds and has minimal drug-drug interactions, which is advantageous in critically ill patients 1

Adverse Event Management

• Adverse events occurred in approximately 28% of ICU patients but were severe in only 2% 7
• Only 12% of patients required readmission for adverse events when used as outpatient therapy 1
• Treatment discontinuation due to adverse events is rare (approximately 1 patient per study) 1