Amphotericin B deoxycholate belongs to the polyene class of antifungals. It is also known by the name conventional amphotericin B and has been in use for the treatment of invasive fungal infections for more than 50 years. It was first isolated as a natural product of a soil actinomycete.[1][2]
Newer lipid formulations that are less nephrotoxic as compared with conventional amphotericin B are available.[3] These include:
These lipid formulations permit a higher daily dose, provide better delivery to organs within the reticular endothelial system such as the lungs, liver, and spleen, have similar efficacy when compared to conventional amphotericin B, and are less nephrotoxic.[4]
With the advancement of newer antifungals, such as azoles (e.g., voriconazole) and Echinocandins (e.g., caspofungin), amphotericin B is typically only reserved for selected invasive fungal infections.
Common indications in yeast and invasive mold infections are listed below:
Dose: The recommended daily dose depends upon the type of infection, the organ involved, the host (immunocompetent versus immunocompromised), and ranges from 0.7 to 1 mg/kg per day over 2 to 4 hours as tolerated.
When prescribing amphotericin B, the clinician should take into consideration: the indication, immune status of the patient, and side effect profile. Also, the resistance to amphotericin B remains low for Candida species except for Candida lusitaniae. Aspergillus and opportunistic molds have a more variable susceptibility pattern. Secondary resistance is uncommon and is not usually a clinical problem. Clinicians should consider in vitro susceptibility testing in cases of clinical failure, and when treating pathogens such as Candida lusitaniae, Trichosporon species, Fusarium species, or Psudoallescheria boydii.
Clinicians should recall that amphotericin B exerts a concentration-dependent fungicidal activity against susceptible fungi such as Candida spp., Cryptococcus spp., and Aspergillus spp. It also has a prolonged post-antifungal effect of up to 12 hours.
Amphotericin B acts by binding to ergosterol in the cell membrane of most fungi. After binding with ergosterol, it causes the formation of ion channels leading to loss of protons and monovalent cations, which results in depolarization and concentration-dependent cell killing.[5][6]
Additionally, amphotericin B also produces oxidative damage to the cells with the formation of free radicals and subsequently increased membrane permeability. Additionally, amphotericin B has a stimulatory effect on phagocytic cells, which assists in fungal infection clearance.
The half-life of amphotericin B is from 24 hours to 15 days.
Amphotericin B is amphoteric (can act as both an acid and a base) and virtually water-insoluble. It is not absorbable via oral or intramuscular administration.[7]
Amphotericin B intravenous (IV) infusion administration is over 2 to 6 hours. If the patient experiences any of the following; fever, hypertension, chills, or nausea, premedication 30 to 60 minutes before administration with a combination of acetaminophen/ibuprofen plus diphenhydramine and/or hydrocortisone should merit consideration. The risk of nephrotoxicity increases at doses greater than 1 mg/kg, and there is no evidence supporting doses greater than 1.5 mg/kg per day. Pretreating the patient with 1 liter of normal saline can attenuate nephrotoxicity.
Topical use of amphotericin B for peritoneal or bladder wash has been reported in the literature but not recommended. Topical amphotericin B is irritating to the skin; therefore, the decision to use topical amphotericin B should be made based on expert consultation.
Amphotericin B achieves high concentrations in tissue such as liver, spleen, bone marrow, kidney, and lungs. Although concentrations in cerebrospinal fluid (CSF) are low (5% of serum), it is effective in the treatment of fungal infections of the central nervous system (CNS) when given intrathecally (higher risk of toxicity).
A high interindividual variability characterizes the reported pharmacokinetic data in children. Children seem to clear the drug from plasma more rapidly than adults.
About 80% of the patients will develop either infusion-related or renal toxicity. Amphotericin B also interacts with cholesterol in human cell membranes, which is responsible for its toxicity. The most common side effects of amphotericin B include:
Absolute contraindications include a history of anaphylactic reaction to amphotericin B.
Before potential administration, drug-drug interactions require a thorough review. Concomitant steroid use should be reconsidered to reduce the risk of hypokalemia. Hypokalemia can also potentiate digoxin toxicity and can cause rhabdomyolysis. Simultaneous infusion of amphotericin B and granulocytes has correlations with acute pulmonary reactions, and clinicians should avoid the combination.
The monitoring of amphotericin B concentrations in the serum or CSF is of little value because the relationships between plasma and tissue concentrations and clinical efficacy or toxicity have not had adequate research performed.
Monitoring is a recommendation to evaluate for the presence of side effects. Initially, a daily electrolyte panel, including potassium and magnesium concentrations until the dose increases to its therapeutic level, and after that, weekly electrolyte concentrations are sufficient. Clinicians should obtain potassium concentrations immediately if the patient presents with any signs of hypokalemia, such as muscle weakness, cramps, drowsiness, or ECG changes of hypokalemia.
Amphotericin exhibits infusion-related toxicity, which accounts for its extended administration times. Infuse slowly over 3 hours; rapid infusion can cause cardiotoxicity.
Due to the similarity of mammalian and fungal membranes, which both contain sterols (the therapeutic target for amphotericin B), amphotericin B can exhibit cellular toxicity.
Healthcare workers, including nurse practitioners who prescribe amphotericin B, should be very familiar with its administration and side effects. Close to 80% of the patients will develop either infusion-related or renal toxicity. Consider pretreatment with acetaminophen, diphenhydramine, and/or hydrocortisone before the infusion to attenuate side effects. Meperidine treatment may decrease the duration of rigors. Following infusion, the renal function requires monitoring.
Given its interaction and adverse event profile, it is not surprising that amphotericin B use is not common. However, physicians may need to employ it for recalcitrant infections, and consultation with the pharmacist is necessary to ensure there will be no drug-drug interactions, or that a different agent might achieve the desired therapeutic result. Nursing also needs to understand the side effect profile of this drug, as well as the potential for infusion reactions; in the event of any concerns, the nursing staff should immediately alert the treating physician. This drug may have been around for many years. Still, its use requires a robust, collaborative interprofessional healthcare team effort to be able to achieve desired patient outcomes with minimal adverse effects. [Level V]
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[2] | Jansook P,Fülöp Z,Ritthidej GC, Amphotericin B loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): Physicochemical and solid-solution state characterizations. Drug development and industrial pharmacy. 2019 Jan 11; [PubMed PMID: 30632399] |
[3] | Ullmann AJ,Sanz MA,Tramarin A,Barnes RA,Wu W,Gerlach BA,Krobot KJ,Gerth WC, Prospective study of amphotericin B formulations in immunocompromised patients in 4 European countries. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2006 Aug 15 [PubMed PMID: 16838223] |
[4] | Hamill RJ, Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013 Jun [PubMed PMID: 23729001] |
[5] | Al Balushi A,Khamis F,Klaassen CHW,Gangneux JP,Van Hellemond JJ,Petersen E, Double Infection With {i}Leishmania tropica{/i} and {i}L. major{/i} in an HIV Patient Controlled With High Doses of Amphotericin B. Open forum infectious diseases. 2018 Dec; [PubMed PMID: 30619911] |
[6] | Rybak JM,Fortwendel JR,Rogers PD, Emerging threat of triazole-resistant Aspergillus fumigatus. The Journal of antimicrobial chemotherapy. 2018 Dec 17; [PubMed PMID: 30561652] |
[7] | Lestrade PPA,Meis JF,Melchers WJG,Verweij PE, Triazole resistance in Aspergillus fumigatus: recent insights and challenges for patient management. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2018 Dec 20; [PubMed PMID: 30580035] |