Antifungal Membrane Function Inhibitors (Amphotericin B)


Article Author:
Asif Noor


Article Editor:
Charles Preuss


Editors In Chief:
James Beauchamp
Mark Pellegrini
Nicole Hale-Crutch


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
9/2/2019 7:27:05 AM

Indications

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 which are less nephrotoxic as compared with conventional amphotericin B are available.[3] These include:

  • Amphotericin B, which is more commonly administered in a liposomal formulation and exhibits increased tolerability and a reduced toxicity profile
  • An amphotericin B lipid complex in which amphotericin B is tightly packed in a ribbon-like structure
  • Amphotericin B cholesteryl sulfate complex

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:

  1. Invasive candidiasis (FDA approved). It is effective against the majority of the Candida species, including Candida albicans, Candida krusei, Candida tropicalis, and Candida parapsilosis
  2. In neonatal candidiasis, conventional amphotericin B is less toxic than in adults and well-tolerated.
  3. Opportunistic fungal infections in immunocompromised children, including HIV
  4. Life-threatening fungal infections in both normal and immunocompromised hosts
  5. Empiric treatment in a persistently febrile neutropenic host.
  6. Cerebral cryptococcosis along with flucytosine for induction therapy
  7. Mucormycosis and other molds including Fusarium spp. and penicilliosis
  8. Severe cases of sporotrichosis
  9. Coccidioidomycosis and paracoccidioidomycosis, especially in severe disease
  10. Histoplasmosis, for disseminated disease
  11. Blastomycosis, for severe disease
  12. Aspergillosis, for salvage therapy in cases not responding to voriconazole
  13. Visceral and cutaneous leishmaniasis (a protozoan infection)

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.

Mechanism of Action

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.

Administration

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 (greater 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.

Adverse Effects

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:

  1. Loss of potassium
  2. Loss of magnesium
  3. Anaphylaxis
  4. Fevers
  5. Nephrotoxicity: Renal toxicity has been associated with conventional amphotericin B and can lead to renal failure and requirement for dialysis. But the azotemia often stabilizes with therapy and renal damage is reversible after discontinuation of amphotericin B. Avoiding concomitant use of other nephrotoxic agents, and appropriate hydration with normal saline may significantly decrease the likelihood and severity of azotemia associated with amphotericin B.
  6. Other potential uncommon side effect includes demyelinating encephalopathy in patients with bone marrow transplant with total body irradiation or who are receiving cyclosporine.
  7. The long-term administration is associated with normochromic, normocytic anemia due to low erythropoietin levels.

Contraindications

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.

Monitoring

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. Potassium concentrations should be obtained immediately if the patient presents with any signs of hypokalemia such as muscle weakness, cramps, drowsiness, or ECG changes of hypokalemia.

Toxicity

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.

Enhancing Healthcare Team Outcomes

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, but its use requires a robust, collaborative interprofessional healthcare team effort to be able to achieve desired patient outcomes with minimal adverse effects. [Level V]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Antifungal Membrane Function Inhibitors (Amphotericin B) - Questions

Take a quiz of the questions on this article.

Take Quiz
A 25-year-old man presents to the emergency room unconscious after a serious motorcycle accident. While recovering in the hospital for several weeks, the patients develop a nosocomial systemic fungal infection. The clinician is considering treatment with amphotericin B. Which of the following is the least responsive to amphotericin B treatment?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following drugs has antifungal activity?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is true about amphotericin B?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 3-year-old child who had a hematopoietic stem cell transplant 3 months ago and now has a right septic knee joint. The fungal culture grew Fusarium spp. What is the antifungal of choice?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following can be given to a patient prior to administering amphotericin B in order to attenuate infusion-related reactions?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 65-year-old man with a ten-year history of type 2 diabetes mellitus presents with a severe infection caused by Rhizopus orzyae. The patient receives treatment with amphotericin B. Which of the following is the most likely side effect of amphotericin B treatment?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is the most likely mechanism of action of amphotericin B?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient develops hypokalemia, hypomagnesemia, and anemia. Which antifungal agent is most likely associated with these side effects after prolonged use?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 36-year-old woman presents with a systemic fungal infection. The clinician decides to empirically treat with amphotericin B. Which of the following is the mechanism of action of amphotericin B?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following antifungal agent is most likely to cause anemia after prolonged use?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following antifungal drug is fungicidal and appropriate for systemic use?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which antifungal agent is used empirically to treat life-threatening fungal infections?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 7-year-old boy with acute lymphoblastic leukemia develops respiratory distress with fever. His absolute neutrophil count was 250 cells/mm3, and he was started on cefepime. After persistent fevers for four days, bronchoalveolar lavage was done. The fungal culture grew Aspergillus spp., and he was started on amphotericin B. Which of the following is true about amphotericin B?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following drugs typically is reserved for more serious, potentially life-threatening fungal infections?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Antifungal Membrane Function Inhibitors (Amphotericin B) - References

References

Vasileiou E,Apsemidou A,Vyzantiadis TA,Tragiannidis A, Invasive candidiasis and candidemia in pediatric and neonatal patients: A review of current guidelines. Current medical mycology. 2018 Sep;     [PubMed]
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]
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]
Rybak JM,Fortwendel JR,Rogers PD, Emerging threat of triazole-resistant Aspergillus fumigatus. The Journal of antimicrobial chemotherapy. 2018 Dec 17;     [PubMed]
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]
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]
Hamill RJ, Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013 Jun     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Pharmacy-Technician (PTCB). The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Pharmacy-Technician (PTCB), it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Pharmacy-Technician (PTCB), you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Pharmacy-Technician (PTCB). When it is time for the Pharmacy-Technician (PTCB) board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Pharmacy-Technician (PTCB).