Amphotericin B

Dosage for Amphotericin B is highly individualized based on the patient's weight, the type of infection, and the specific formulation used. Because the formulations are not interchangeable, healthcare providers must be extremely careful to ensure the correct dose is administered for the specific product prescribed.

• Conventional Amphotericin B Deoxycholate: The typical dose ranges from 0.5 mg/kg to 1.5 mg/kg daily. Higher doses are rarely used due to extreme toxicity. A 'test dose' of 1 mg is often given over 20-30 minutes to check for immediate allergic reactions.
• Liposomal Amphotericin B (AmBisome): Doses are generally higher, typically ranging from 3 mg/kg to 5 mg/kg daily. For certain infections like Mucormycosis, doses may reach 7.5 mg/kg or 10 mg/kg.
• Amphotericin B Lipid Complex (Abelcet): The standard dose is usually 5 mg/kg daily, administered as a single infusion.

Amphotericin B is used in pediatric patients, including neonates, for systemic fungal infections. Dosing is weight-based and similar to adult protocols.

• Conventional: 0.25 mg/kg to 1 mg/kg per day.
• Liposomal: 3 mg/kg to 5 mg/kg per day.

Studies have shown that children often tolerate Amphotericin B better than adults, experiencing fewer infusion-related reactions, though renal monitoring remains critical.

Renal Impairment

If a patient's serum creatinine increases significantly (e.g., exceeding 3.0 mg/dL), healthcare providers may temporarily discontinue the drug, reduce the dose, or switch to a lipid formulation. Nephrotoxicity is often dose-dependent and may be reversible if caught early.

Hepatic Impairment

While Amphotericin B is not primarily metabolized by the liver, patients with pre-existing liver disease should be monitored closely for signs of hepatotoxicity during treatment.

Elderly Patients

Geriatric patients are at a higher risk for kidney damage. Healthcare providers typically start at the lower end of the dosing range and monitor renal function more frequently.

Amphotericin B is administered as a slow intravenous infusion. It is never given as a rapid injection (bolus).

• Preparation: Conventional Amphotericin B must be reconstituted with Sterile Water and then diluted ONLY with 5% Dextrose Injection (D5W). Using saline (saltwater) solutions will cause the drug to precipitate (clump up).
• Infusion Time: Infusions typically last between 2 to 6 hours. Rapid infusion (less than an hour) can lead to dangerous heart rhythm problems or cardiac arrest.
• Hydration: To protect the kidneys, healthcare providers often administer a 'salt loading' regimen (500 mL to 1000 mL of normal saline) before and after the infusion.
• Pre-medication: To prevent infusion-related reactions, patients are often given acetaminophen (Tylenol), diphenhydramine (Benadryl), or corticosteroids 30 to 60 minutes before the infusion starts.

Because Amphotericin B is administered in a hospital or clinical setting, missed doses are rare. If a dose is delayed, the medical team will adjust the schedule. Patients should not attempt to 'double up' on doses if they are receiving home infusion therapy; instead, they should contact their infusion nurse or doctor immediately.

An overdose of Amphotericin B can be fatal, primarily due to cardiac or respiratory arrest. Symptoms of overdose include severe electrolyte imbalances, kidney failure, and dangerous heart arrhythmias. If an overdose is suspected, the infusion must be stopped immediately, and emergency supportive care (including monitoring of heart rhythm and electrolytes) must be initiated. There is no specific antidote for Amphotericin B; it is not effectively removed by hemodialysis.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose or attempt to self-administer this medication without professional medical guidance.

Amphotericin B is known for a high incidence of side effects, particularly during the infusion process.

• Infusion-Related Reactions: Often called 'shake and bake,' these include high fever, shaking chills (rigors), nausea, vomiting, and headache. These typically occur 1 to 3 hours after starting the infusion and are most severe with the first few doses.
• Nephrotoxicity: Up to 80% of patients receiving conventional Amphotericin B experience some degree of kidney impairment. This may feel like decreased urination or swelling in the legs.
• Electrolyte Imbalances: Significant loss of potassium (hypokalemia) and magnesium (hypomagnesemia) is very common. Patients may feel muscle weakness, cramps, or fatigue.
• Anemia: A decrease in red blood cells is common due to the drug's effect on the kidneys' ability to produce erythropoietin (a hormone that triggers red blood cell production).

• Hypotension or Hypertension: Fluctuations in blood pressure during the infusion.
• Tachypnea: Rapid breathing or shortness of breath.
• Diarrhea and Abdominal Pain: General gastrointestinal distress.
• Phlebitis: Inflammation of the vein where the IV is inserted, which can be painful and cause redness.

• Thrombocytopenia: A low platelet count, which increases the risk of bleeding or bruising.
• Hepatotoxicity: Rare instances of liver failure or jaundice (yellowing of the skin/eyes).
• Hearing Loss: Tinnitus (ringing in the ears) or transient hearing impairment.
• Vision Changes: Blurred vision or double vision.

> Warning: Stop the infusion (if at home) and call your doctor immediately or seek emergency care if you experience any of the following:

• Anaphylaxis: Signs include hives, swelling of the face or throat, and difficulty breathing. This is a life-threatening allergic reaction.
• Cardiac Arrhythmias: Feeling like your heart is skipping beats, racing, or pounding. This can be caused by rapid infusion or severe potassium loss.
• Acute Renal Failure: A sudden, sharp decrease in urine output, or dark-colored urine, indicating the kidneys have stopped functioning correctly.
• Seizures or Encephalopathy: Sudden neurological changes, confusion, or tremors.
• Severe Skin Reactions: Rare cases of Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) have been reported.

Prolonged use of Amphotericin B can lead to permanent kidney damage (chronic kidney disease). It may also lead to persistent anemia that requires treatment with erythropoietin injections or blood transfusions. Some patients may develop 'renal tubular acidosis,' where the kidneys cannot properly remove acid from the blood, requiring long-term bicarbonate supplementation.

Amphotericin B carries a prominent FDA Black Box Warning regarding its use and potential for error. The warning states that the drug should be used primarily for the treatment of progressive and potentially fatal fungal infections and not for non-invasive fungal diseases (such as oral thrush or vaginal yeast infections) in patients with normal neutrophil counts. Furthermore, the warning emphasizes that the different formulations (conventional vs. lipid) have vastly different dosages; an overdose of conventional Amphotericin B (if mistaken for a lipid dose) can result in fatal cardiac arrest.

Report any unusual symptoms to your healthcare provider. Monitoring of blood work is essential throughout the entire course of therapy.

Amphotericin B is a high-alert medication. It must only be administered under the supervision of a physician experienced in the use of systemic antifungals. Patients must be hospitalized during the initial phase of treatment to monitor for acute reactions. Because the drug can remain in the body for several weeks, side effects or interactions can occur even after the treatment has ended.

Warning: Formulation Confusion and Toxicity

Amphotericin B deoxycholate (conventional) should be used only for the treatment of patients with progressive and potentially fatal fungal infections. It should not be used to treat non-invasive fungal diseases.

Critical Note: Different formulations of Amphotericin B (e.g., AmBisome, Abelcet, and conventional deoxycholate) have different dosages and are not interchangeable. Healthcare providers must verify the product name and dosage before administration. A dose of 5 mg/kg is standard for lipid products but could be fatal if given as the conventional deoxycholate formulation.

• Nephrotoxicity: Kidney damage is the most significant limiting factor of Amphotericin B therapy. Patients with pre-existing renal disease are at extreme risk. Daily monitoring of serum creatinine and BUN (blood urea nitrogen) is mandatory.
• Infusion Reactions: Acute reactions (fever, chills, hypotension) are common. While they usually subside with repeated doses or pre-medication, they can be severe enough to require discontinuation.
• Electrolyte Depletion: The drug causes the kidneys to leak potassium and magnesium. Severe hypokalemia can lead to fatal heart rhythms. Supplements are almost always required during treatment.
• Pulmonary Toxicity: In patients also receiving leucocyte (white blood cell) transfusions, Amphotericin B has been linked to acute lung injury. It is generally recommended to separate the timing of these two treatments as much as possible.

Patients receiving Amphotericin B require intensive laboratory monitoring, typically daily or every other day:

1. 1Renal Function: Serum creatinine, BUN, and creatinine clearance.
2. 2Electrolytes: Specifically potassium, magnesium, and phosphorus.
3. 3Liver Function: ALT, AST, and bilirubin levels to check for hepatotoxicity.
4. 4Complete Blood Count (CBC): To monitor for anemia (low red blood cells) or thrombocytopenia (low platelets).

Because Amphotericin B can cause dizziness, headaches, and blurred vision, patients should not drive or operate heavy machinery while receiving the infusion or if they feel unwell after a treatment session.

Alcohol should be avoided during Amphotericin B therapy. Alcohol can worsen dehydration and increase the strain on both the liver and kidneys, potentially exacerbating the drug's toxic effects.

Amphotericin B does not typically cause a 'withdrawal syndrome,' but stopping the drug prematurely can lead to a relapse of the fungal infection, which may then become resistant to treatment. The duration of therapy is determined by the clinical response and the total cumulative dose administered.

> Important: Discuss all your medical conditions, especially kidney or heart disease, with your healthcare provider before starting Amphotericin B.

Certain drugs should never be used alongside Amphotericin B due to the high risk of catastrophic toxicity:

• Cisplatin: This chemotherapy agent is highly nephrotoxic. Combining it with Amphotericin B almost guarantees severe, potentially permanent kidney failure.
• Aminoglycosides (e.g., Gentamicin, Amikacin): These antibiotics also damage the kidneys. Simultaneous use significantly increases the risk of acute tubular necrosis.

• Flucytosine: While often used together for synergy (especially in Cryptococcal meningitis), Amphotericin B can increase the toxicity of Flucytosine by slowing its renal clearance. This can lead to severe bone marrow suppression.
• Cyclosporine and Tacrolimus: These immunosuppressants are nephrotoxic. Using them with Amphotericin B requires very frequent monitoring of kidney function and drug levels.
• Corticosteroids (e.g., Prednisone): These can worsen the potassium-wasting effect of Amphotericin B, leading to severe hypokalemia and heart problems.
• Digitalis Glycosides (e.g., Digoxin): Amphotericin B-induced hypokalemia (low potassium) significantly increases the risk of digitalis toxicity, which can cause fatal heart arrhythmias.

• Skeletal Muscle Relaxants: Low potassium levels caused by Amphotericin B can enhance the effects of muscle relaxants (like curare-type drugs), potentially leading to respiratory distress.
• Antineoplastic Agents: Drugs like methotrexate or nitrogen mustard may increase the risk of kidney damage or blood disorders when used with Amphotericin B.

Since Amphotericin B is administered intravenously, traditional food-drug absorption interactions are not a concern. However, nutritional status is vital. Patients may need a diet high in potassium and magnesium to counteract the losses caused by the medication. Dehydration must be avoided at all costs, as it increases the concentration of the drug in the kidneys.

• Licorice Root: Real licorice contains glycyrrhizic acid, which can cause potassium loss. Combining this with Amphotericin B can lead to dangerously low potassium levels.
• Nephrotoxic Herbs: Herbs like pennyroyal or certain traditional Chinese medicines known to affect the kidneys should be strictly avoided.

Amphotericin B can interfere with certain laboratory results:

• Serum Creatinine: Levels will likely rise, reflecting drug-induced renal strain.
• Liver Function Tests: May show transient elevations in transaminases.
• Blood Glucose: In some cases, the drug may affect glucose metabolism, though this is less common.

For each interaction, the primary management strategy is either dose adjustment, switching to a lipid formulation, or intensive monitoring of electrolytes and renal markers.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers like NSAIDs (Ibuprofen, Naproxen), which can further stress the kidneys.

Amphotericin B is contraindicated in patients who have a known hypersensitivity (severe allergy) to Amphotericin B or any of the components in the specific formulation being used.

• Mechanism: An allergic reaction occurs when the immune system overreacts to the drug molecule or the lipid/deoxycholate carrier. This can lead to anaphylaxis, characterized by airway swelling and cardiovascular collapse.
• Formulation Specifics: A patient may be allergic to the phospholipids in a lipid formulation but not to the conventional drug itself, or vice versa.

Relative contraindications require a careful risk-benefit analysis by the medical team:

• Pre-existing Renal Disease: Because the drug is inherently nephrotoxic, patients with a baseline GFR (Glomerular Filtration Rate) below 30 mL/min are at high risk. However, if the fungal infection is life-threatening and no other drug is effective, it may still be used with extreme caution.
• Severe Electrolyte Imbalance: Patients with uncorrected, severe hypokalemia or hypomagnesemia should have these corrected before starting the infusion to prevent cardiac arrest.
• Concurrent Nephrotoxic Therapy: If a patient is already taking other drugs that damage the kidneys, the use of Amphotericin B is highly risky.

There is no significant evidence of cross-sensitivity between Amphotericin B and other classes of antifungals like azoles (Fluconazole) or echinocandins (Caspofungin). However, patients sensitive to one polyene (like Nystatin) should be monitored closely, although Nystatin is generally only used topically.

> Important: Your healthcare provider will evaluate your complete medical history, including any previous reactions to medications, before prescribing Amphotericin B.

Amphotericin B is generally classified as Pregnancy Category B (under the old FDA system). This means that animal reproduction studies have failed to demonstrate a risk to the fetus, but there are no adequate and well-controlled studies in pregnant women.

• Clinical Use: It is often considered the drug of choice for treating severe systemic fungal infections in pregnant women because it has a long history of use and does not appear to be teratogenic (causing birth defects).
• Risks: The primary risk is to the mother's kidneys, which can indirectly affect the fetus. It does cross the placenta, and detectable levels have been found in fetal cord blood.

It is not known whether Amphotericin B is excreted in human breast milk. Because many drugs are excreted in milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Amphotericin B is used in children of all ages, including infants. As noted in the usage section, children often tolerate the drug better than adults. However, the risk of long-term renal effects must be considered. Pediatric patients require the same intensive monitoring of electrolytes and kidney function as adults. Weight-based dosing must be calculated with extreme precision.

Elderly patients (over 65) are at a significantly higher risk for Amphotericin B-induced nephrotoxicity. This is because renal function naturally declines with age. Furthermore, elderly patients are more likely to be taking other medications (polypharmacy) that may interact with Amphotericin B. Healthcare providers usually monitor geriatric patients daily and utilize lipid formulations whenever possible to spare kidney function.

In patients with pre-existing renal impairment, the use of conventional Amphotericin B deoxycholate is generally avoided in favor of Liposomal Amphotericin B. Even with lipid formulations, the dose may need to be adjusted or the frequency of administration changed. The drug is not significantly cleared by hemodialysis or peritoneal dialysis; therefore, supplemental doses are not required after a dialysis session.

While the liver is not the primary site of clearance, Amphotericin B can occasionally cause hepatotoxicity. In patients with severe liver disease (Child-Pugh Class C), the drug should be used with caution, and liver enzymes should be monitored at least twice weekly.

> Important: Special populations require individualized medical assessment and often require more frequent laboratory monitoring to ensure safety.

Amphotericin B is a polyene antifungal that targets the fungal cell membrane. Its molecular structure consists of a large lactone ring with both a hydrophobic (water-fearing) polyene chain and a hydrophilic (water-loving) polyhydroxyl chain. This 'amphipathic' nature allows it to insert itself into the lipid bilayer of the fungal cell membrane.

The drug binds specifically to ergosterol. Once bound, multiple Amphotericin B molecules aggregate to form a cylindrical pore. These pores act as unregulated ion channels. Because the concentration of potassium is much higher inside the cell than outside, potassium ions rapidly exit the cell through these pores. This loss of ionic gradient destroys the cell's ability to maintain its membrane potential and produce energy, leading to cell death.

Amphotericin B exhibits concentration-dependent killing. This means that higher concentrations of the drug at the site of infection lead to faster and more thorough eradication of the fungus. It also exhibits a 'Post-Antifungal Effect' (PAFE), where fungal growth continues to be suppressed even after the drug levels drop below the minimum inhibitory concentration (MIC).

| Parameter | Value (Conventional) | Value (Liposomal) |

|---|---|---|

| Bioavailability | 0% (Oral) / 100% (IV) | 100% (IV) |

| Protein Binding | >90% | >90% |

| Half-life (Terminal) | ~15 Days | ~6-7 Days |

| Tmax | End of Infusion | End of Infusion |

| Metabolism | Non-CYP mediated | Minimal |

| Excretion | Renal (2-5%) / Biliary | Primarily Biliary |

• Molecular Formula: C47H73NO17
• Molecular Weight: 924.08 g/mol
• Solubility: Insoluble in water at neutral pH; soluble in dimethyl sulfoxide (DMSO).
• Structure: A macrocyclic lactone containing a conjugated heptaene system and a mycosamine aminosugar.

Amphotericin B is the flagship member of the Polyene Antifungal class. Other drugs in this class include Nystatin (used topically/orally for local infections) and Natamycin (used for ophthalmic infections). It is distinct from the Azole class (e.g., Fluconazole) and the Echinocandin class (e.g., Micafungin) in both its mechanism and its spectrum of activity.