University of Pennsylvania Medical Center Guidelines for Antibiotic Use

Amphotericin B Deoxycholate Dosing and Administration Guidelines

Restrictions:

Use is restricted to Rhoads 6 and 7 if the dose is < 1 mg/kg/day. All other use of amphotericin B deoxycholate requires Infectious Diseases Approval (215-306-0336).

Dosing:

Optimal dosing of amphotericin B deoxycholate for most fungal infections is not known. The following are suggested guidelines:

Indication
Dose*
Oral or esophageal candidiasis
0.1-0.3 mg/kg/day
Empiric therapy in patients with febrile neutropenia
0.5-1 mg/kg/day
Documented systemic candidiasis
0.5-1 mg/kg/day
Presumed or documented aspergillosis
1-1.5 mg/kg/day
* Note that the maximum dose of amphotericin B is 1.5 mg/kg/day

Administration:

Rationale for the following recommendations is included at the end of this document.

The following are suggested guidelines for infusion and monitoring of amphotericin B:

Infusion Guidelines:

  • The preferred rate of infusion of amphotericin B deoxycholate is < 0.08 mg/kg/hour.
  • If the prolonged infusion rate cannot be used routinely because of access issues, then it is recommended that the INITIAL infusion be over 6 hours, with a subsequent shorter infusion period as given below.

    If the patient tolerates the initial 6-hour infusion, subsequent infusions may be performed over 4 hours if necessary.
  • Since the administration of normal saline has been shown in studies to reduce the risk of nephrotoxicity, 250-500 mL of normal saline should be administered prior to and following the dose of amphotericin B deoxycholate. Note: amphotericin B deoxycholate is incompatible with saline solutions; therefore, separate sites of administration are necessary.

Monitoring Guidelines:

  • Baseline vital signs are to be taken prior to the infusion. For the first two doses of the initial treatment course, vital signs should be recorded every 15 minutes for the first 30 minutes, then blood pressure and temperature every hour during the infusion.
  • For subsequent infusions, vital signs should be recorded every 15 minutes for the first 30 minutes, then blood pressure and temperature recorded every 2 hours during the infusion.
  • The patient should be instructed to report any untoward side effects immediately. In the event of serious symptoms, such as hypotension, cardiac arrhythmias, multiple episodes of vomiting, rash, shortness of breath, orofacial swelling, seizures, severe rigors, and temperature greater than 38.5° C (101.3° F), the infusion should be stopped and the physician notified. In the case of non-life-threatening adverse events (i.e. fever, chills, rigors, nausea), the infusion may be restarted at a slower infusion rate when the symptoms subside.

Note: If symptoms consistent with anaphylaxis/anaphylactoid reaction such as severe hypotension or shortness of breath are observed, the infusion should not be restarted and Infectious Diseases should be called for advice.

Management of Infusion-related Adverse Events:

Acute infusion-related adverse reactions to amphotericin B deoxycholate are typically seen within 90 minutes of the infusion and usually remit within 3-4 hours. The most common reactions observed are fever with or without rigors. Tolerance to the infusion-related reactions usually develops over time; therefore, if premedications are used early in the treatment course, their need should be re-evaluated weekly. Consider withholding premedications after several days if the infusion-related adverse events have resolved.

Premedication with acetaminophen and/or hydrocortisone may be given if the patient develops fevers and rigors during the initial infusion. Meperidine may also be administered as needed for the treatment of rigors that occur during the infusion.

Medications and Doses:

Medication
Dosage
Acetaminophen oral, rectal
650-1000 mg 30 minutes prior to amphotericin B (nonsteroidal anti-inflammatory drugs, NSAIDS, may be used if not contraindicated)
Hydrocortisone IV
25 mg initial dose prior to infusion of amphotericin B deoxycholate may be administered (if not contraindicated) to patients who have experienced severe rigors to prior infusions of amphotericin B. The dose of hydrocortisone may be increased to 50 mg if needed. Reassess need every 3-7 days.
Meperidine IV
25 mg every 15 minutes as needed for rigors up to a maximum of 100 mg in 1 hour. Use with caution in patients with renal insufficiency.

Management of Nephrotoxicity:

Renal insufficiency (with associated electrolyte disturbances) is frequent and often stabilizes at a creatinine of 2-3 mg/dL. Other nephrotoxic drugs such as aminoglycosides, NSAIDS, and cisplatin can add to azotemia and should be avoided if possible. Salt repletion, by administering 250-500 mL of normal saline immediately prior to and following amphotericin B deoxycholate, may minimize azotemia. If azotemia occurs with a serum creatinine > 2.5 mg/dL, contact Infectious Diseases for advice. Serum creatinine and BUN should be measure initially and periodically thereafter.

Other Adverse Effects:

  • Phlebitis can occur with infusion via peripheral veins. If peripherally administered, the concentration should not exceed 0.1 mg/mL D5W. If phlebitis develops, decreasing the rate of infusion may help.
  • Anemia - check CBC initially and periodically thereafter
  • Distal renal tubular acidosis, hypokalemia, hypomagnesemia, hypocalcemia - monitor K, Mg, Ca, bicarbonate intially and periodically thereafter
  • Pulmonary infiltrates in patients receiving concomitant WBC transfusion - separate from amphotericin B by at least 6 hours

References:

1. Eriksson et al. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomized, controlled trial. British Medical Journal 2001;322:579-82.

2. Peleg AY and Woods ML. Continuous and 4 hour infusion of amphotericin B: a comparative study involving high-risk hematology patients. Journal of Antimicrobial Chemotherapy 2004;54:803-808.

3. Imhof A, Walter RB, and Schaffner A. Continuous infusion of escalated doses of amphotericin B deoxycholate: an open-label observational study. Clinical Infectious Diseases 2003;36:943-51.

Rationale for Administration Guidelines:

Previous recommendations were that a test dose be administered prior to the first dose of amphotericin B deoxycholate. However, test dosing is not always predictive of a severe reaction to amphotericin B deoxycholate. Some patients will go on to develop a reaction to subsequent infusions despite tolerating the test dose. In addition, test dose administration sometimes results in delays in the administration of the full dose and/or missed doses.

Several studies have demonstrated a reduction in infusion-related adverse events and nephrotoxicity with prolonged infusion rates of amphotericin B deoxycholate1,2. One study demonstrated that patients who received a continuous infusion of amphotericin B deoxycholate over 24 hours had fewer infusion-related adverse events and nephrotoxicity compared to patients who received a standard four-hour infusion1. A second study comparing four-hour infusion rates to a continuous infusion showed that less nephrotoxicity was observed when amphotericin B deoxycholate was infused at a rate of < 0.08 mg/kg/hour2.

Given these data, and issues surrounding test dosing, the Antibiotic Subcommittee of the Pharmacy and Therapeutics Committee recommends that test dosing of amphotericin B deoxycholate NOT be performed. Instead, it is recommended to infuse the drug over a period as long as possible (preferably at a rate of < 0.08 mg/kg/hour) with appropriate patient monitoring.

written by Ann Marie Marr 7/10/2006

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