What are the reconstitution steps for liposomal amphotericin B in a critically ill patient with compromised immune system and impaired renal function?

Reconstitution of Liposomal Amphotericin B

Reconstitute liposomal amphotericin B by adding 12 mL of Sterile Water for Injection to each 50 mg vial to achieve a concentration of 4 mg/mL, then dilute the required dose in 5% Dextrose Injection to a final concentration of 1-2 mg/mL for intravenous infusion over 2 hours. 1

Critical Reconstitution Steps

Initial Reconstitution

• Add 12 mL of Sterile Water for Injection (without bacteriostatic agents) to each 50 mg vial to create a 4 mg/mL concentrate 1
• Shake the vial immediately until the solution is clear and the liposomal cake is completely dispersed 1
• Use a sterile needle with minimum 20-gauge diameter for reconstitution 1

Dilution for Infusion

• Further dilute the reconstituted solution in 5% Dextrose Injection (D5W) to achieve a final concentration of 1-2 mg/mL 1
• The pH of the dextrose solution must be above 4.2 before use 1
• If pH is below 4.2, add 1-2 mL of phosphate buffer (dibasic sodium phosphate 1.59 g + monobasic sodium phosphate 0.96 g per 100 mL water) before diluting the amphotericin 1

Administration Parameters

• Infuse over 2 hours minimum (some sources recommend up to 6 hours depending on dose and patient tolerance) 1
• Use an in-line membrane filter with mean pore diameter of at least 1.0 micron to ensure passage of the liposomal dispersion 1

Dosing for Critically Ill Patients with Renal Impairment

For critically ill patients with compromised immune systems and impaired renal function, liposomal amphotericin B at 3-4 mg/kg/day is the preferred formulation over conventional amphotericin B deoxycholate. 2, 3

Standard Dosing Regimens

• Invasive fungal infections (Candida, Aspergillus, Cryptococcus): 3-4 mg/kg/day 2, 3
• Alternative lipid formulations may use 5 mg/kg/day if cost or tolerability concerns exist 2
• Do not exceed 5 mg/kg/day routinely - higher doses (10 mg/kg/day) show no efficacy benefit but significantly worse tolerability 3

Renal Impairment Considerations

• Liposomal amphotericin B does not require dose adjustment for renal impairment or renal replacement therapy 2, 4, 3
• Neither dialysis nor hemofiltration significantly reduces serum amphotericin B concentrations 2, 4, 3
• Pre-existing renal impairment is NOT a contraindication to liposomal amphotericin B (unlike conventional formulation) 3

Nephrotoxicity Prevention Strategies

Administer 0.9% normal saline hydration intravenously 30 minutes before each liposomal amphotericin B infusion to reduce nephrotoxicity risk. 4, 5, 3

Mandatory Monitoring

• Monitor serum creatinine and electrolytes at minimum once or twice weekly 4, 5, 3
• Approximately 19-50% of patients will experience some degree of renal injury, but this is manageable in most cases 2, 4, 3
• Renal injury typically manifests within the first 9 days of treatment 6
• Only 12% of patients require readmission for nephrotoxicity-related adverse events 2, 4

Risk Mitigation

• Volume expansion with salt loading immediately prior to dosing is essential 4
• Avoid concomitant nephrotoxic medications whenever possible 4, 5
• Use the lowest effective dose and shortest duration of therapy 4, 5, 3
• High doses above 5 mg/kg/day are the primary risk factor for nephrotoxicity 2, 4, 3

Critical Pitfalls to Avoid

Reconstitution Errors

• Never use saline solutions for reconstitution or dilution - this will cause precipitation of the drug 1
• Never use diluents containing bacteriostatic agents (e.g., benzyl alcohol) - these cause precipitation 1
• Do not use the solution if any precipitation or foreign matter is visible 1
• Strict aseptic technique is mandatory as no preservatives are present 1

Clinical Management Errors

• Do not substitute conventional amphotericin B deoxycholate in patients with pre-existing renal disease - liposomal formulation is mandatory in this population 5, 3
• Do not discontinue liposomal amphotericin B prematurely due to mild renal impairment in severe infections - the mortality benefit outweighs nephrotoxicity risk 2, 7
• In many cases, renal impairment improves despite continued liposomal amphotericin B treatment 2

Drug Interactions

• Monitor calcineurin inhibitors (cyclosporine, tacrolimus) closely as concentrations may be affected 3
• Liposomal amphotericin B has minimal drug-drug interactions compared to azoles, which is advantageous in critically ill patients 2

Pharmacokinetic Considerations in Critical Illness

Liposomal amphotericin B pharmacokinetics in critically ill patients are not significantly different from healthy volunteers, despite considerable inter-patient variability. 2

• Cmax values at 3 mg/kg/day: 20.0 mg/L (range 14.1-27.9) 2
• Cmax values at 5 mg/kg/day: 43.7 mg/L (range 41.3-64.4) 2
• The lipophilic characteristics of amphotericin B result in tissue exposure that may be less affected by pathophysiological changes than hydrophilic drugs 2
• Active amphotericin B remains within the liposome, which explains the reduced toxicity profile 2