What are the main side effects of amphotericin B. How does amphotericin B work against fungal infections. What are the risk factors for amphotericin B nephrotoxicity. How can the toxicity of amphotericin B be reduced.

Understanding Amphotericin B: Mechanism of Action and Importance

Amphotericin B (AmB) is a crucial antifungal agent used in the treatment of serious systemic fungal infections. Its importance in the medical field cannot be overstated, as it often serves as a last line of defense against life-threatening fungal diseases. But how does this powerful drug actually work?

The mechanism of action of AmB is based on its ability to bind to ergosterol, a key component of fungal cell membranes. This binding creates a transmembrane channel that allows the cytoplasmic contents of the fungal cell to leak out, ultimately leading to cell death. This unique mode of action makes AmB effective against a wide range of fungal pathogens.

Despite its efficacy, the use of AmB is often limited by its significant side effects and toxicity. In some cases, these adverse effects can be so severe that treatment must be discontinued, even in the face of a life-threatening infection. This delicate balance between efficacy and toxicity has led to ongoing research into ways to improve AmB’s safety profile.

Acute Side Effects of Amphotericin B: What to Expect During Infusion

When administering AmB, healthcare providers must be prepared for a range of acute side effects that can occur during or shortly after infusion. These effects are believed to result from the production of proinflammatory cytokines triggered by the drug.

• Nausea and vomiting
• Rigors (severe shivering)
• Fever
• Blood pressure fluctuations (hypertension or hypotension)
• Hypoxia (low oxygen levels)

These infusion-related reactions can be distressing for patients and may require careful management. In some cases, premedication with antipyretics or antihistamines may be used to mitigate these effects. Additionally, slow infusion rates and proper hydration can help reduce the severity of these acute reactions.

Chronic Toxicity: The Renal Impact of Amphotericin B

While the acute side effects of AmB can be challenging, it’s the drug’s chronic toxicity that often poses the greatest concern for healthcare providers and patients alike. The principal long-term adverse effect of AmB is nephrotoxicity, or kidney damage.

AmB is believed to cause renal injury through multiple mechanisms, including:

1. Direct damage to renal tubular cells
2. Vasoconstriction of renal blood vessels
3. Alterations in renal electrolyte handling

The clinical manifestations of AmB nephrotoxicity can be diverse and may include:

• Renal insufficiency (decreased kidney function)
• Hypokalemia (low potassium levels)
• Hypomagnesemia (low magnesium levels)
• Metabolic acidosis
• Polyuria due to nephrogenic diabetes insipidus

These renal effects can have significant implications for patient health and may necessitate close monitoring and management throughout the course of treatment.

Risk Factors for Amphotericin B Nephrotoxicity: Who’s Most Vulnerable?

Not all patients are equally susceptible to the nephrotoxic effects of AmB. Identifying those at highest risk can help guide treatment decisions and monitoring strategies. The following factors have been associated with an increased risk of AmB-induced nephrotoxicity:

• Male gender
• Higher average daily dose of AmB (≥ 35 mg/day)
• Diuretic use
• Body weight ≥ 90 kg
• Concomitant use of other nephrotoxic drugs
• Abnormal baseline renal function

Patients with multiple risk factors may require more intensive monitoring of renal function and electrolyte levels during AmB therapy. In some cases, alternative antifungal agents or modified dosing regimens may be considered to minimize the risk of nephrotoxicity.

Strategies to Mitigate Amphotericin B Toxicity: From Lipid Formulations to Sodium Loading

Given the significant toxicity associated with AmB, considerable research has focused on developing strategies to improve its safety profile without compromising efficacy. Two main approaches have shown promise:

1. Lipid Formulations of Amphotericin B

One of the most significant advancements in improving AmB’s safety has been the development of lipid-based formulations. These preparations encapsulate the AmB molecule within a lipid complex, altering its pharmacokinetics and tissue distribution. How do these lipid formulations compare to conventional AmB deoxycholate?

• Reduced nephrotoxicity
• Decreased infusion-related reactions
• Potential for higher dosing
• Maintained or improved antifungal efficacy

While lipid formulations of AmB have demonstrated a superior safety profile, their higher cost can be a limiting factor in some healthcare settings.

2. Sodium Loading

An intriguing and cost-effective strategy for reducing AmB-induced nephrotoxicity is sodium loading. Human studies have convincingly shown that increasing sodium intake above usual dietary levels can significantly reduce both the incidence and severity of AmB-related kidney damage. This approach is thought to work by:

• Increasing renal blood flow
• Reducing vasoconstriction in the kidneys
• Improving the handling of electrolytes

The simplicity and effectiveness of sodium loading make it an attractive option for many patients receiving AmB therapy, particularly when lipid formulations are not available or feasible.

Special Considerations: Amphotericin B in Hematopoietic Stem Cell Transplantation

Patients undergoing hematopoietic stem cell transplantation (HSCT) represent a unique population with regard to AmB use. These individuals are often at high risk for invasive fungal infections due to prolonged immunosuppression, yet they are also particularly vulnerable to drug toxicities. How does AmB perform in this critical patient group?

Studies have shown that lipid formulations of AmB can be particularly beneficial in HSCT recipients. These preparations have been found to:

• Preserve and stabilize renal function
• Allow for effective antifungal prophylaxis and treatment
• Reduce the need for dose modifications or treatment discontinuation

The use of lipid-based AmB formulations in HSCT patients underscores the importance of tailoring antifungal strategies to specific patient populations and clinical contexts.

Monitoring and Management of Amphotericin B Therapy: A Multidisciplinary Approach

Given the complex side effect profile of AmB, successful therapy requires a comprehensive monitoring and management strategy. What key elements should be included in this approach?

1. Regular assessment of renal function (creatinine, BUN, GFR)
2. Frequent electrolyte monitoring (potassium, magnesium, sodium)
3. Evaluation of acid-base status
4. Monitoring of liver function tests
5. Assessment of infusion-related reactions
6. Close follow-up of antifungal efficacy

A multidisciplinary team approach, involving infectious disease specialists, nephrologists, pharmacists, and nursing staff, can help optimize AmB therapy while minimizing toxicity. This collaborative effort ensures that patients receive the full benefit of this powerful antifungal agent while mitigating its potential harms.

Future Directions: Improving Amphotericin B Safety and Efficacy

As our understanding of AmB’s mechanisms of action and toxicity continues to evolve, researchers are exploring new ways to enhance its therapeutic index. What promising avenues are being investigated?

• Novel drug delivery systems (e.g., nanoparticles, cochleates)
• Combination therapies to allow for lower AmB doses
• Genetic and molecular approaches to identify patients at highest risk for toxicity
• Development of AmB analogues with improved safety profiles

These ongoing research efforts hold the potential to further refine our use of AmB, potentially expanding its application while reducing its associated risks. As we continue to face the challenge of invasive fungal infections, particularly in immunocompromised populations, the importance of improving this critical antifungal agent cannot be overstated.

In conclusion, amphotericin B remains a cornerstone of antifungal therapy, despite its significant toxicity profile. By understanding its mechanisms of action, recognizing its side effects, and implementing strategies to mitigate its toxicity, healthcare providers can optimize the use of this powerful drug. As research continues to advance, we can look forward to new approaches that may further enhance the safety and efficacy of amphotericin B, ensuring its continued role in the fight against life-threatening fungal infections.

Amphotericin B: side effects and toxicity

Review

. 2009 Dec 31;26(4):223-7.

doi: 10.1016/j.riam.2009.06.003.

Rafael Laniado-Laborín 
¹
, Maria Noemí Cabrales-Vargas

Affiliations

Affiliation

• ¹ Facultad de Medicina Tijuana, Universidad Autónoma de Baja California, Mexico. [email protected]

• PMID:

  19836985

• DOI:

  10.1016/j.riam.2009.06.003

Free article

Review

Rafael Laniado-Laborín et al.

Rev Iberoam Micol.

2009.

Free article

. 2009 Dec 31;26(4):223-7.

doi: 10.1016/j.riam.2009.06.003.

Authors

Rafael Laniado-Laborín 
¹
, Maria Noemí Cabrales-Vargas

Affiliation

• ¹ Facultad de Medicina Tijuana, Universidad Autónoma de Baja California, Mexico. [email protected]

• PMID:

  19836985

• DOI:

  10.1016/j.riam.2009.06.003

Abstract

Amphotericin B (AmB) is a crucial agent in the management of serious systemic fungal infections. In spite of its proven track record, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. The mechanism of action of AmB is based on the binding of the AmB molecule to the fungal cell membrane ergosterol, producing an aggregate that creates a transmembrane channel, allowing the cytoplasmic contents to leak out, leading to cell death. Most of the efforts at improving AmB have been focused on the preparation of AmB with a lipid conjugate. AmB administration is limited by infusion-related toxicity, an effect postulated to result from proinflammatory cytokine production. The principal acute toxicity of AmB deoxycholate includes nausea, vomiting, rigors, fever, hypertension or hypotension, and hypoxia. Its principal chronic adverse effect is nephrotoxicity. AmB probably produces renal injury by a variety of mechanisms. Risk factors for AmB nephrotoxicity include male gender, higher average daily dose of AmB (> or = 35 mg/day), diuretic use, body weight > or = 90 kg, concomitant use of nephrotoxic drugs, and abnormal baseline renal function. Clinical manifestations of AmB nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic academia, and polyuria due to nephrogenic diabetes insipidus. Human studies show convincingly that sodium loading in excess of the usual dietary intake notably reduces the incidence and severity of AmB-induced nephrotoxicity.

Similar articles

• Lipid formulations of amphotericin B preserve and stabilize renal function in HSCT recipients.

  Miller CB, Waller EK, Klingemann HG, Dignani MC, Anaissie EJ, Cagnoni PJ, McSweeney P, Fleck PR, Fruchtman SM, McGuirk J, Chao NJ.

  Miller CB, et al.
  Bone Marrow Transplant. 2004 Mar;33(5):543-8. doi: 10.1038/sj.bmt.1704408.
  Bone Marrow Transplant. 2004.

  PMID: 14730342

• Development of liposomal amphotericin B formulation.

  Gulati M, Bajad S, Singh S, Ferdous AJ, Singh M.

  Gulati M, et al.
  J Microencapsul. 1998 Mar-Apr;15(2):137-51. doi: 10.3109/02652049809006844.
  J Microencapsul. 1998.

  PMID: 9532520

  Review.

• Incorporation of amphotericin B (AMB) into liposomes alters AMB-induced acute nephrotoxicity in rabbits.

  Joly V, Dromer F, Barge J, Yeni P, Seta N, Molas G, Carbon C.

  Joly V, et al.
  J Pharmacol Exp Ther. 1989 Oct;251(1):311-6.
  J Pharmacol Exp Ther. 1989.

  PMID: 2795463

• Risk factors of amphotericin B toxicty in the nonneonatal pediatric population.

  Dutta A, Palazzi DL.

  Dutta A, et al.
  Pediatr Infect Dis J. 2012 Sep;31(9):910-4. doi: 10.1097/INF.0b013e31825d649a.
  Pediatr Infect Dis J. 2012.

  PMID: 22581225

• Sodium chloride treatment of amphotericin B nephrotoxicity. Standard of care?

  Anderson CM.

  Anderson CM.
  West J Med. 1995 Apr;162(4):313-7.
  West J Med. 1995.

  PMID: 7747495
  Free PMC article.

  Review.

See all similar articles

Cited by

• Roles of ADP-Ribosylation during Infection Establishment by Trypanosomatidae Parasites.

  Dowling J, Doig CL.

  Dowling J, et al.
  Pathogens. 2023 May 12;12(5):708. doi: 10.3390/pathogens12050708.
  Pathogens. 2023.

  PMID: 37242378
  Free PMC article.

  Review.

• Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity.

  Li-Zhulanov NS, Zaikova NP, Sari S, Gülmez D, Sabuncuoğlu S, Ozadali-Sari K, Arikan-Akdagli S, Nefedov AA, Rybalova TV, Volcho KP, Salakhutdinov NF.

  Li-Zhulanov NS, et al.
  Antibiotics (Basel). 2023 Apr 27;12(5):818. doi: 10.3390/antibiotics12050818.
  Antibiotics (Basel). 2023.

  PMID: 37237723
  Free PMC article.

• Scaffold repositioning of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies.

  de Oliveira Viana J, Silva E Souza E, Sbaraini N, Vainstein MH, Gomes JNS, de Moura RO, Barbosa EG.

  de Oliveira Viana J, et al.
  Sci Rep. 2023 May 5;13(1):7320. doi: 10.1038/s41598-023-33279-9.
  Sci Rep. 2023.

  PMID: 37147323
  Free PMC article.

• Antifungal Development and the Urgency of Minimizing the Impact of Fungal Diseases on Public Health.

  de Oliveira HC, Bezerra BT, Rodrigues ML.

  de Oliveira HC, et al.
  ACS Bio Med Chem Au. 2022 Nov 18;3(2):137-146. doi: 10.1021/acsbiomedchemau.2c00055. eCollection 2023 Apr 19.
  ACS Bio Med Chem Au. 2022.

  PMID: 37101810
  Free PMC article.

  Review.

• Neurodegeneration, Mitochondria, and Antibiotics.

  Suárez-Rivero JM, López-Pérez J, Muela-Zarzuela I, Pastor-Maldonado C, Cilleros-Holgado P, Gómez-Fernández D, Álvarez-Córdoba M, Munuera-Cabeza M, Talaverón-Rey M, Povea-Cabello S, Suárez-Carrillo A, Piñero-Pérez R, Reche-López D, Romero-Domínguez JM, Sánchez-Alcázar JA.

  Suárez-Rivero JM, et al.
  Metabolites. 2023 Mar 12;13(3):416. doi: 10.3390/metabo13030416.
  Metabolites. 2023.

  PMID: 36984858
  Free PMC article.

  Review.

See all “Cited by” articles

Publication types

MeSH terms

Substances

Amphotericin B – StatPearls – NCBI Bookshelf

Continuing Education Activity

Amphotericin B deoxycholate belongs to the polyene class of antifungals. It is also known by the conventional name amphotericin B and has been used for the treatment of invasive fungal infections for more than 50 years. Newer lipid formulations that are less nephrotoxic as compared with conventional amphotericin B are available. This activity reviews the indications, contraindications, activity, adverse events, toxicity, and other key elements of antifungal uses of amphotericin B in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients who present with mycotic infections.

Objectives:

• Identify the approved indications of amphotericin B.

• Review the mechanism of action of amphotericin B.

• Describe the adverse of amphotericin B.

• Summarize interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with amphotericin B therapy to treat mycotic infections to optimal patient outcomes and mitigate toxicity and adverse events.

Access free multiple choice questions on this topic.

Indications

Amphotericin B deoxycholate belongs to the polyene class of antifungals. It is also known by the conventional name 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 sp.[1][2]

Newer lipid formulations that 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 spp. 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 the 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.

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 correlates with conventional amphotericin B use 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 concentrations.

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 concentration, 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.

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 professionals, including physicians, physician assistants, and 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 cautiously used. 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. Nurses also need 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]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

Vasileiou E, Apsemidou A, Vyzantiadis TA, Tragiannidis A. Invasive candidiasis and candidemia in pediatric and neonatal patients: A review of current guidelines. Curr Med Mycol. 2018 Sep;4(3):28-33. [PMC free article: PMC6315202] [PubMed: 30619967]

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 Dev Ind Pharm. 2019 Apr;45(4):560-567. [PubMed: 30632399]

3.

Ullmann AJ, Sanz MA, Tramarin A, Barnes RA, Wu W, Gerlach BA, Krobot KJ, Gerth WC., Longitudinal Evaluation of Antifungal Drugs (LEAD I) Investigators. Prospective study of amphotericin B formulations in immunocompromised patients in 4 European countries. Clin Infect Dis. 2006 Aug 15;43(4):e29-38. [PubMed: 16838223]

4.

Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013 Jun;73(9):919-34. [PubMed: 23729001]

5.

Al Balushi A, Khamis F, Klaassen CHW, Gangneux JP, Van Hellemond JJ, Petersen E. Double Infection With Leishmania tropica and L. major in an HIV Patient Controlled With High Doses of Amphotericin B. Open Forum Infect Dis. 2018 Dec;5(12):ofy323. [PMC free article: PMC6306567] [PubMed: 30619911]

6.

Rybak JM, Fortwendel JR, Rogers PD. Emerging threat of triazole-resistant Aspergillus fumigatus. J Antimicrob Chemother. 2019 Apr 01;74(4):835-842. [PMC free article: PMC6657284] [PubMed: 30561652]

7.

Lestrade PPA, Meis JF, Melchers WJG, Verweij PE. Triazole resistance in Aspergillus fumigatus: recent insights and challenges for patient management. Clin Microbiol Infect. 2019 Jul;25(7):799-806. [PubMed: 30580035]

Disclosure: Asif Noor declares no relevant financial relationships with ineligible companies.

Disclosure: Charles Preuss declares no relevant financial relationships with ineligible companies.

Amphotericin B
To come in

magazine
MED-info
directory
medicines and institutions
consultations
ask a doctor
mobile
apps

VIDEO

The database is current for 2015

Institutions
Medications
Diseases

org/DrugClass”>
antibiotics


Amphotericin B
from 22 P Amphotericin B liof d/inf 50000ED fl N1x1 Synthesis of AKO ROS
from 22 P Amphotericin B liof d/inf 50mg vial N1x1 Synthesis AKO ROS
AMPHOTERICIN B

Pharmacological action

Broad-spectrum antifungal antibiotic from the polyene group. It is produced by the actinomycete Streptomyces nodosus. It has a fungicidal or fungistatic effect, depending on the concentration in biological fluids and the sensitivity of the pathogen.
The mechanism of action of the drug is based on its ability to bind to sterols (ergosterols) located in the cell membrane of a fungus sensitive to amphotericin B. As a result, the permeability of the membrane is disturbed, and intracellular components enter the extracellular space.
Active against fungi of the genus Candida, Histoplasma capsulatum, Cryptococcus neoformans, Aspergillus, Coccidioides immitans, Blastomyces dermatitidis, Sporothtrix schenckii, Fonsecaea, and Leishmania.

Pharmacokinetics

Distribution

Distributed in most organs and tissues, not detected in cerebrospinal fluid. Plasma protein binding is 90%.

Removal

Excreted by the kidneys, very slowly. 2-5% of the administered dose is excreted in the active form. May be detected in urine up to 7 weeks after withdrawal.

Indications for use of the drug AMPHOTERICIN B

Parenteral and inhalation

– candidiasis of the gastrointestinal tract, intestinal candidiasis;

– candidiasis of internal organs;

– chronic granulomatous and disseminated forms of candidiasis;

– coccidioidomycosis;

– cryptococcosis;

– histoplasmosis;

– North American blastomycosis;

– chromomycosis;

– mold mycoses;

– aspergillosis;

– sporotrichosis.

Outdoor

– candidiasis of the skin and mucous membranes.

Dosing regimen

IV administration
Before each infusion, the exact weight of the patient is determined and the dose of the drug is calculated.
The dose of Amphotericin B is set for each patient individually at the rate of 250 IU/kg of body weight. Pre-inject 100 IU/kg (to determine individual tolerance). In the future, in the absence of side effects and if necessary, the dose can be gradually increased to 1000 IU / kg.
The drug is administered every other day or 1-2 times a week (because of the risk of cumulation).
The duration of the course of treatment depends on the severity and localization of the process, the duration of the disease and is at least 4-8 weeks in order to avoid relapses. The total dose of Amphotericin B per course of treatment averages 1.5-2 million units (18-20 infusions).
The daily dose of Amphotericin B for children and adolescents depends on age.

The first course of treatment consists of 20 intravenous drip infusions, which are carried out 2 times a week.
After a month break, it is desirable to repeat the course of treatment.
With good tolerance and the absence of side effects, the severity of which is significantly reduced with intermittent course treatment, both courses of treatment (30-40 infusions) are carried out for 5-6 months. In case of intolerance to the drug, the daily and course doses of Amphotericin B should be reduced, and the intervals between infusions and breaks between the first and second courses should be increased.
Repeated courses of treatment begin with the smallest doses of the drug, gradually increasing them during treatment.
Inhalation administration
Inhalations are prescribed 1-2 days. lasting up to 15-20 minutes at doses of 50,000 IU (10 ml) per inhalation, which corresponds to a daily dose of 1000-2000 IU / kg of the patient’s body weight.
When using inhalers that work only on inspiration, a single dose is reduced to 25,000 IU (5 ml). The duration of the course of treatment is 10-14 days and depends on the severity and duration of the disease. If necessary, a second course is prescribed after a 7-10-day break.
Rules for the preparation and administration of the drug
IV drip the drug is administered over 3-6 hours at a rate of 20-30 drops/min. The solution is prepared immediately before use. All preparation and administration procedures should be carried out without exposing the solution to bright light . As a solvent for Amphotericin B, a 5% glucose solution for injection should be used. In the event of the appearance of a precipitate in the solution / in the introduction is unacceptable.
For intravenous administration, the concentration of the drug is 100-125 IU in 1 ml of the solvent. 5-10 ml of water for injection is added to the vial with the preparation. The mixture is then shaken until the powder is completely dissolved. The solution from the vial is drawn with a needle into a sterile syringe and poured into a vial with 400 ml of 5% glucose solution.
No more than 50,000 IU of the drug must be dissolved in the indicated amount of solvent.
Dose calculation
If the patient’s body weight is 75 kg, then based on the calculation of 250 U / kg of body weight, 250 U x 75 kg are needed, which is 18,750 U of Amphotericin B. Since 410 ml of a 5% glucose solution should contain 50,000 IU of Amphotericin B, then the required dose of Amphotericin B – 18,750 IU – will be contained in 150 ml of solution:
18,750 IU x 410 ml
————- = 150 ml
50,000 AU
Amphotericin B solution for inhalations is prepared immediately before use by dissolving the contents of the vial (50,000 IU) in 10 ml of water for injection.
For inhalation, AI, PAI-1 type inhalers are recommended, but other types may be used.
External application
The ointment is applied to the affected areas of the skin in a thin layer for 2-4 days. The course of treatment for candidiasis of skin folds – 1-3 weeks, for diaper rash in children – 1-2 weeks, for lesions of the interdigital spaces and paronychia – 2-4 weeks.

Side effect

For parenteral use
From the digestive system: nausea, vomiting, epigastric pain, loss of appetite, increased activity of liver enzymes.
From the side of the hematopoietic system: anemia, leukopenia, thrombocytopenia.
From the side of the central nervous system and peripheral nervous system: headache, polyneuropathy, blurred vision, diplopia.
From the side of the cardiovascular system: arterial hypotension, arterial hypertension, arrhythmia, ECG changes.
From the urinary system: impaired renal function, incl. increased serum creatinine concentration, proteinuria, azotemia, hypokalemia, acidosis.
Allergic reactions: skin rash, itching, Quincke’s edema, bronchospasm (with inhalation use), allergic contact dermatitis (with external use).
From the side of water and electrolyte balance: hypokalemia.
Local reactions: in / in the introduction – thrombophlebitis; when inhaled – sore throat, cough, runny nose.
Other: fever, chills.
For external use
When applying the ointment – burning sensation, tingling, skin hyperemia; rarely – dry skin

Contraindications to the use of AMPHOTERICIN B

– severe liver dysfunction;

– severe impairment of kidney function;

– diseases of the hematopoietic system;

– diabetes mellitus;

– hypersensitivity to the components of the drug.

Use of AMPHOTERICIN B during pregnancy and lactation

Amphotericin B crosses the placenta. Adequate and strictly controlled studies of the safety and efficacy of the drug in pregnant women have not been conducted. The use of the drug is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

It is not known if Amphotericin B is excreted in breast milk. Therefore, if necessary, use during lactation should decide on the termination of breastfeeding.

Use in hepatic dysfunction

Contraindicated in severe hepatic impairment.

Use in disorders of kidney function

Contraindicated in severe renal impairment.

Use in children under 12 years of age

The daily dose of Amphotericin B for children and adolescents depends on age.

The first course of treatment consists of 20 intravenous drip infusions given twice a week

Special instructions

If anemia develops, treatment with Amphotericin B should be discontinued.

In the process of treatment, systematic monitoring of liver function, kidney function, peripheral blood picture and potassium levels in blood plasma is necessary.

With the development of a pyrogenic effect with intravenous administration of the drug, antipyretic drugs, antihistamines, B vitamins, ascorbic acid, NSAIDs, iron preparations, potassium salts are prescribed.

The inhalation route of administration is used in cases of predominant localization of mycotic processes in the lungs and upper respiratory tract or the impossibility of intravenous administration of Amphotericin B in other localizations of mycoses. For better tolerability of Amphotericin B, it is recommended to add 10-15 drops of medical glycerin to the solution for inhalation.

The ointment should not be used under occlusive dressings.

In the absence of effect from the use of ointment Amphotericin B After 1-2 weeks, it is necessary to clarify the diagnosis and further treatment tactics.

Overdose

No cases of overdose of Amphotericin B have been reported to date.

Drug interactions

With the simultaneous use of Amphotericin B with potentially nephrotoxic antibiotics, cyclosporine, diuretics, the risk of developing a nephrotoxic effect increases.

When used simultaneously with drugs that depress bone marrow function, the risk of developing anemia and other hematological disorders increases.

Amphotericin B may cause an increase in the effects of cardiac glycosides (especially against the background of potassium deficiency in the body) and non-depolarizing muscle relaxants.

When used simultaneously with flucytosine Amphotericin B reduces the clearance of the latter, as a result, the toxic effects caused by flucytosine may increase.

Treatment of the skin with products containing benzyl alcohol before applying the ointment Amphotericin B may cause precipitation of the drug.

Conditions and terms of storage

List B. The drug should be stored in a dry, dark place at a temperature of 2° to 8°C. The shelf life of the lyophilized powder is 4 years. The shelf life of the ointment is 2 years.
Unused solution for infusion should not be stored. The solution for inhalation remaining in the vial can be used within 24 hours if stored in a refrigerator.
Pharmacy conditions
The drug is dispensed by prescription.

Pharmacological action

Antifungal, polyene antibiotic. It has a fungicidal or fungistatic effect, depending on the concentration in biological fluids and the sensitivity of the pathogen. The mechanism of action of amphotericin B is based on its ability to bind to sterols (ergosterols) located in the cell membrane of the fungus. As a result, the permeability of the membrane is disturbed, and intracellular components enter the extracellular space.

Active against many pathogenic fungi, incl. Candida spp., Histoplasma capsulatum, Cryptococcus neoformans, Aspergillus spp.

Amphotericin B is also active against Leishmania.

Pharmacokinetics

Distributed in most organs and tissues of the body, not detected in the cerebrospinal fluid. Plasma protein binding is 90%. Excreted by the kidneys, very slowly. 2-5% of the administered dose is excreted in the active form. May be detected in urine up to 7 weeks after withdrawal.

Readings

Systemic and/or deep mycoses: disseminated candidiasis, disseminated cryptococcosis and cryptococcal meningitis, invasive and disseminated aspergillosis, coccidioidomycosis, North American blastomycosis, histoplasmosis, hyalologhomycosis, mucormycosis, chronic mycetoma.

Leishmaniasis: visceral, American cutaneous-visceral.

Fever of unknown etiology (resistant to 96 hours of antibiotic therapy in patients with neutropenia and high risk of fungal infections).

Prevention of invasive fungal infections in neutropenic patients with malignant neoplasms, as well as during transplantation of parenchymal organs and bone marrow.

Dosing regimen

When administered intravenously, the initial dose (to determine tolerance) is 1 mg, then the dose can be increased by 5-10 mg to the maximum daily dose. The frequency of administration – every other day or 2 times a week. Children in / in – at an initial dose of 250 mcg / kg, then the dose is gradually increased by 125-250 mcg / kg to a maximum.

When applied topically, amphotericin B is applied to the affected areas of the skin for 2-4 days.

For inhalation, the dose is set depending on the route of administration.

Maximum daily doses: by intravenous infusion for adults – 50 mg, for children – 1 mg / kg.

Side effect

From the digestive system: possible – nausea, vomiting, abdominal pain, increased alkaline phosphatase; rarely – constipation, diarrhea, digestive disorders, increased activity of liver enzymes, bilirubinemia, abnormal liver function, cholestatic hepatitis, damage to liver cells, hepatomegaly, jaundice, pancreatitis.

From the side of the central nervous system and peripheral nervous system: headaches are possible; rarely – asthenia, anxiety, coma, convulsions, depression, dizziness, neurosis, paresthesia, sensory disturbances, tremor.

On the part of the hematopoietic system: rarely – anemia, granulocytopenia, leukopenia, splenomegaly, thrombocytopenia.

From the side of water and electrolyte balance: possible hypokalemia, acidosis.

From the side of metabolism: possible hypokalemia; rarely – an increase in urea nitrogen, an increase in CPK, hyperglycemia, hyperkalemia, hypernatremia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, an increase in LDH, swelling of the legs.

From the side of the cardiovascular system: rarely – heart failure, extrasystole, arterial hypotension, thrombophlebitis, bradycardia, feeling hot, arterial hypertension.

From the respiratory system: rarely – bronchospasm, cough, dysphonia, dyspnea, hypoxia, respiratory failure.

Allergic reactions: rarely – skin rash, itching, anaphylactoid reactions.

Dermatological reactions: possible skin rash; rarely – folliculitis, erythematous rash, blistering rash, maculo-papular rash, increased sweating, urticaria.

Other: possible – fever, chills, cyanosis, edema and leg cramps.

Contraindications

Severe disorders of the liver and kidneys, glomerulonephritis, amyloidosis, diseases of the hematopoietic system, diabetes mellitus, hypersensitivity to amphotericin B.

Use in pregnancy and lactation

There are no adequate and well-controlled studies in pregnant women. Amphotericin B crosses the placental barrier.

It is not known whether amphotericin B is excreted in breast milk. If necessary, use during lactation should decide on the termination of breastfeeding.

Use in hepatic dysfunction

Contraindication: severe liver dysfunction.

Use in disorders of kidney function

Contraindication: severe renal dysfunction, glomerulonephritis.

Special instructions

In the process of treatment, systematic monitoring of the function of the kidneys, liver, blood composition and the content of potassium ions in the blood is necessary.

In order to avoid the risk of side effects, intravenous administration should be carried out slowly (within 2-6 hours).

If possible, amphotericin B should not be given to patients receiving anticancer drugs. Diuretics should be avoided in patients receiving amphotericin B. If this is not possible, close monitoring of electrolyte balance is necessary.

Drug interactions

With simultaneous use with antimicrobial agents and immunosuppressants that have a nephrotoxic effect, cyclosporine, pentamidine (for parenteral use), an increased risk of nephrotoxic action may be increased.

Against the background of hypokalemia caused by amphotericin B, it is possible to increase the action of neuromuscular blockers, increase the toxicity of cardiac glycosides; Corticosteroids can exacerbate potassium deficiency, while their immunosuppressive effect may be especially pronounced in patients with severe fungal infection.

With the simultaneous use of amphotericin B with flucytosine, a synergistic effect is observed. However, the clearance of flucytosine decreases and its toxic effects increase.

With simultaneous use, the renal excretion of zalcitabine decreases.

In patients with myocardial damage caused by antimonial compounds, the use of amphotericin B increases the risk of developing arrhythmias and cardiac arrest.

Active substance AMPHOTERICIN B (AMPHOTERICINUM B)

Manufacturer:

CAS No: 1397-89-3 C ₄₇ H ₇₃ NO ₁₇

USPDDN: (1R-(1R*,3S*,5R*,6R*,9R*,11R*,15S*,16R*,17R*,18S*,19E,21E,23E,25E,27E,29E, 31E,33R*,35S*,36R*,37S*))-33-((3-amino-3,6-dideoxy- β -D-mannopyranosyl)oxy)-1,3,5,6,9 ,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo(33.3.1)nonatriaconta-19,21,23,25,27,29,31-heptaene-36 -carboxylic acid.

M _m = 926.12 Yes. Hygroscopic powder of yellow or yellow-orange color, practically insoluble in water and alcohol. Sensitive to light and high temperature, inactivated in acidic and alkaline environments. log P (octanol-water) = -2.8.

Presentation: lyophilisate for infusion solution, suspension for infusion solution.

• Pharmacological properties
• Indications AMPHOTERICIN B
• Application of AMPHOTERICIN B
• Contraindications
• Side effects
• Special instructions
• Diagnosis
• Recommended alternatives
• Trade names

Medicinal products containing the active substance AMPHOTERICIN B

Ampholip

suspension for solution for infusion 5 mg/ml vial 10 ml, No. 1

Bharat Serums & Vaccines 90 047

Pharmacy prices

polyene antifungal antibiotic , which has a wide spectrum of activity against yeasts and yeast-like fungi, including Candida albicans . At concentrations that develop in biological fluids, amphotericin B has a more fungistatic than fungicidal effect. Its possible mechanism of action is due to the formation of compounds with sterol rings in the composition of fungal cell membranes. Crystalline amphotericin is insoluble in water, therefore, to obtain dosage forms for parenteral use, the solubility of the antibiotic is increased by adding sodium deoxycholate, as a result of which this mixture forms a colloidal solution upon dissolution.

T _½ amphotericin B when administered intravenously is about 24 hours. It has a high (> 90%) affinity for blood plasma proteins and is poorly dialyzed. Amphotericin B is slowly excreted by the kidneys, 2-5% of the administered dose is excreted in a biologically active form. After stopping treatment, it is detected in the urine for at least 7 weeks.

amphotericin B for intravenous administration is indicated mainly for severe systemic life-threatening fungal infections. Effective for cryptococcosis, North American blastomycosis, disseminated forms of candidiasis, coccidioidomycosis and histoplasmosis, mucormycosis (phycomycosis) caused by strains of the genus Mucor, Rhizopus, Absidia, Entomophthora , and Basidiobolus sporotrichosis ( Sporotrichium schenckii ) , aspergillosis ( Aspergillus fumigatus 902 05 ). It can also be used for American mucocutaneous leishmaniasis, but is not the drug of choice for primary therapy.

is administered by IV slow infusion over 6 hours. The initial daily dose should be 0.25 mg/kg body weight, then gradually increased to 1 mg/kg depending on the clinical situation. In patients in serious condition, the daily dose can be increased to a maximum of 1.5 mg/kg. Given the big T _½ in higher doses can be administered every other day. The duration of treatment can be several months of treatment. A shorter treatment period may lead to insufficient treatment efficacy or disease recurrence.