Amphotericin B binds to sterols, preferentially to the primary fungal cell membrane sterol, ergosterol. This binding disrupts osmotic integrity of the fungal membrane, resulting in leakage of intracellular potassium, magnesium, sugars, and metabolites and then cellular death ₃,₄ .

Acute reactions to amphotericin B are seen within 90 minutes of the infusion and usually remit by 3-4 hours. Most common is fever with or without chill and rigors, headache, nausea, vomiting, malaise and generalized aches. Hypotension and anaphylaxis are rare. Up to 50% of patients will have immediate infusion-related adverse reactions ₁₁ . Tolerance to the immediate reactions usually develops over time. Therefore if premedications are used in the treatment course, their need should be reevaluated weekly.

Acetaminophen 650-1000 mg per oral /per rectal. 30 minutes prior to amphotericin B. Other non-steroidal anti-inflammatory drugs (NSAIDS) like aspirin, ibuprofen and diphenylhydramine can be used if not contraindicated ₄,₅,₆ . Hydrocortisone: if patients experience severe rigors with previous infusion, start at 25 mg IV 30 minutes prior to amphotericin B (may increase to 50 mg and can be added directly to the transfusion bottle ₅ ).Nausea and vomiting generally are managed by administration of phenothiazines such as prochlorperazine or promethazine. Meperidone is used most commonly for the treatment of amphotericin-B related rigors ₇ .

It occurs up to 80% of patients, manifested by azotemia, eletrolyte wasting (potassium and magnesium), a decrease in urinary concentrating ability, distal renal tubular acidosis ₄,₅,₈ . It is usually reversible after cessation of the drug. Sodium loading may minimize azotemia (administer 500 ml of normal saline both before and after amphotericin B infusion ₈,₉ ).Other nephrotoxic drugs should be avoided if possible. If azotemia occurs with a serum creatinine> 3 mg/dl, the dose of amphotericin B may be reduced or held after a careful assessment of the risks versus benefits to the patient.

Phlebitis can occur with infusion via peripheral veins ₄,₁₀ . If peripherally administered, concentration should not exceed 0.1 µg/ml of D5W. Phlebitis can be prevented by decreasing the rate of infusion or further diluting infusion, adding heparin 1000 units/L to the solution, using central vein and rotating the infusion site ₄ .

Normochromic, normocytic anemia with decrease in hemoglobin of up to 35% from baseline has been reported routinely following extended therapy with amphotericin B ₄,₅,₁₀ . The proposed mechanism is a direct suppression of erythropoietin production and a decrease in the production of erythrocytes that may occur in patients with deteriorating renal function ₁₁,₁₂ . Neutropenia and thrombocytopenia is associated infrequently with amphotericin B therapy ₄,₁₀,₁₃ .

Usual dose is 0.25-1.0mg/kg/day (most commonly 0.4 to 0.7 mg/kg/d ₄,₁₀ ). Maximum daily dose-1.2mg/kg/day in adults and 1.5mg/kg/day in children. Alternate day therapy - double the daily dose to a maximum of 1.5 mg/kg/d. Liposomal amphotericin-B-1-5 mg/kg, ABLC-5mg/kg/day, ABCD-3-5mg/kg/day.Total cumulative dose is of 2-4gms (4-6 gms in case of intracranial extension).

Prior to starting treatment, a test dose of 1 mg of amphotericin B in 50 ml of 5% is usually infused over 20 minutes in order to assess the patient for immediate adverse events ₄,₁₀ . The patient's vital signs are monitored every 15 minutes for an hour. If no serious adverse reactions occur, the remainder of the desired daily dose is administered over 2-6 hours as follows: Doses < 0.5 mg/kg/day -- infuse over 2 hours, Doses > 0.5 mg/kg/day -- give first full dose over 4 hours and if tolerated, may decrease infusion time to 2 hours

The following should be monitored more aggressively during the therapy:

1. Blood urea nitrogen, Serum-creatinine-twice a week, 2. Potassium, magnesium, sodium, and other electrolytes-twice a week, and 3. Complete blood count-once a week.

Amphotericin B still remains as the mainstay of antifungal therapy. Its lipid formulations, on the other hand, are promising due to their ability to reduce the toxicity of amphotericin B. They are currently licensed for use when amphotericin B therapy fails or is unacceptably toxic. The use of lipid formulations in specific clinical settings is under continuing investigation.

L-AMB is used as a salvage agent when amphotericin B therapy fails or is unacceptably toxic ₁₄,₁₅ . It is not a first-line drug for any of the fungal infections. It is also licensed as an empirical therapeutic agent in febrile neutropenia not responding to broad spectrum antibiotic treatment more than 96 hours. Its potency in different clinical settings is under continuing investigation. Among the lipid amphotericin B formulations, L-AMB is one of the more commonly used preparations

Advantages over conventional Amphotericin B: 1. Drastically Reduced Toxicity specially Nephrotoxicity. 2. Increased therapeutic effects.3. Reduced morbidity and mortality, well tolerated.4. High therapeutic index, rare drug resistance

Advantages of L- amphotericin B over the other lipid formulations

1. L- amphotericin B has unique lipid composition, a safe formulation with higher therapeutic index than other lipid formulations. 2.In case of other liposomal formulation, before transfusion MLVs (multi-lamellar vesicles) are converted to SUVs (small unilamellar vesicles) but L- amphotericin B does not need reconstitution.3.Infusion time of L- amphotericin B is only one hour.4.L- amphotericin B is most cost effective and affordable.5.Per kg dose of L- amphotericin B is lowest of all the lipid preparations of Amphotericin B.

In general, the azole antifungal agents are thought to work principally by inhibiting the cytochrome P450 14a-demethylase (P45014DM) ₁₀,₁₇,₁₈ . This enzyme is involved in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Inhibition of this enzyme leads to accumulation of lanosterol that in turn leads to perturbation of the fungal cell membrane.

IMIDAZOLE-Ketoconazole has been used successfully for systemic severe invasive mycoses ₁₀,₁₇ . Its use largely has been replaced by triazoles especially itraconazole.

TRIAZOLE- Fluconazole: Both oral, IV preparations are available. It is not used in fungal sinusitis but used in invasive mucocutaneous candidiasis.

Itraconazole: Oral-bioavailability is highly variable and less predictable. Absorption is affected by the presence of food, gastric pH ₁₇,₁₈ . Tab/cap formulation better absorbed with food and co-administration of acidic beverages enhances absortion. Patient with achlorhydria and taking H2 receptor impaired the absorption ₁₉ . Protein binding is greater than 95%. A CSF level is low. Serum half life time is 25-50 hours. Metabolized extensively in liver and excretion occurs primarily in the urine and feces. Dosage adjustment is not required in patient with compromised renal function.

Gastrointestinal upset-Most common. Mild elevation in liver enzymes occurs in 1-7% of patients. Rash and headache are less common. Alopecia-following long course of therapy with high dose fluconazole. Aldosterone like effect with hypertension, hypokalemia and peripheral extremity edema when dose of itraconazole exceeds >600mg/day.All azoles have the potential for embryotoxicity and teratogenicity. Azoles should not be given during pregnancy.

Itraconazole. Preparation: capsule, oral solution, and intravenous formulation. Initial dosage of 600 to 8oo mg daily in two divided dose for 3 days and a subsequent dosage of 200 to 400 mg daily in two divided doses continued for 6 to 12 months ₁₇,₁₈ . Itraconazole blood levels are helpful in documenting absorption because of the varying degree of oral absortion 2 hrs after the dose. Measured therapeutic concentration should be at least equal to or greater than 1µg/ml.

INTRAVENOUS ITRACONAZOLE: The excipient for the intravenous formulation of both itraconazole and voriconazole is cyclodextrin ₂₀ . As cyclodextrin is renally excreted, the intravenous formulation of these drugs should be carefully used in patients who have renal impairment particularly when a ceatinine clearance is < 50 ml/min ₂₁ .

Dosing-200 mg ,IV, BD for 4 Doses followed by oral 200mg,IV, OD for 2Wks

Use: Itraconazole has been shown to have a comparable response rate to amphotericin B for invasive aspergillosis in patients who are not strikingly immunosuppresssd, who can tolerate oral medications, and who are adherent to medication intake. An attractive sequence would be the use of intravenous amphotericin B or one of its lipid formulations until the disease progression is halted, followed by oral itraconazole for an extended period of time ₂₂ .

Voriconazole: It is a second-generation triazole anti-fungal agent is a synthetic derivative of fluconazole. INDICATION: Invasive aspergillosis, febrile neutropenic patients who do not respond to at least for 96 hours treatment with antibiotics. DOSING: 6mg/kg IV every 12hrly for two doses followed by maintenance doses of 4mg/kg IV 12hrly for 30 days.In improving patients, the regimen can changed to oral 200 mg bd for 20 weeks completing a total duration of therapy for 24 weeks ₂₃,₂₄ . SIDE EFFECT: Transient visual disturbances (color changes, blurring) in 30% of pts, Hepatotoxicity in 10% and Rash in 5% of patients ₂₄ .

Investigational triazoles: POSACONAZOLE AND RAVUCONAZOLE, both are active against Aspergillus species in vitro. Ravuconazole is notable for a half life of approximately 1 week.SCH5962-It is an azole which is being studied for its role in invasive fungal sinusitis and is under phase II trial is considered to be more potent than voriconazole.