Fungal Infections

Amphotericin B

Amphotericin B is a macrocyclic type compound similar in structure to nystatin. It was discovered by E R Squibb and Sons which is now part of Bristol-Myers Squibb.  It was selected over other amphotericins and nystatin as being less toxic for intravenous administration.  Its mechanism of action has not been fully elucidated but it involves binding to the cell membrane, leakage of potassium from the cell and possibly initiation of a lipid peroxidation cascade which irreversibly damages the cell membrane of fungi.  It has a substantially greater affinity for ergosterol (present in fungal cell membranes) than cholesterol explaining its greater effects against fungal cells than human cells and also its lack of activity against Pneumocystis jirovecii (which contains cholesterol in its cell membrane rather than ergosterol).  The first studies with amphotericin B were in the late 1950's and it was made available for general use in the early 60's.

 Dose & Delivery        

Amphotericin B can be given intravenously, orally or topically.  It is not absorbed at all after oral or topical administration and so this mode of delivery is simply for prophylaxis or the treatment of mucosal infection.

The original preparation of amphotericin B for intravenous use is a deoxycholate dispersion in dextrose (Fungizone).  It is not compatible with sodium chloride or other ionic solutions.  Various lipid-incorporated preparations have developed and four are licensed and marketed.  The first to reach market was AmBisome (Gilead) which is a small unilamellar liposome (liposomal amphotericin B).  Subsequent to this amphotericin B lipid complex (Abelcet, ABLC; Sigma Tau, Cephalon etc.) was developed and it comprises ribbons of lipid amphotericin B. The third marketed variety uses an alternative approach of combining cholestyrl sulphate complexes with amphotericin B to produce small discs of lipid amphotericin B together (Amphocil, Amphotec, ABCD; Alkpoharma, Indochina Healthcare, etc.). The fourth was developed in India and is known as Fungisome (Lifecare). Amphotericin B has been administered in Intralipid intravenously, but the efficacy of this mode of delivery is in doubt.

The maximum dose of intravenous amphotericin B is governed by toxicity.  It is rarely possible to administer more than 1.5mg/kg body weight daily of the original amphotericin B deoxycholate preparation and most patients do not tolerate more than 0.8mg - 1mg/kg body weight daily.  Larger doses of the lipid incorporated drugs have been used typically 3-5mg/kg body weight of AmBisome, 5mg/kg body weight of Abelcet and 4mg/kg body weight of Amphocil. The optimal dose of Fungisome is not known, but the approved dose of 1mg/kg may be too low for some indications such as invasive aspergillosis. Dosing of amphotericin B has been rather empirical and it has been difficult to show clear dose response relationships either with the daily dose administered or the total dose.  Test doses (to detect anaphylaxis) are not necessary any longer as the preparations of amphotericin B are purer. Detailed guidance on administration is given here [1]

Oral amphotericin B has been given in doses varying from 10-500mg 4 times a day with a 10mg dose administered as a pastille for the treatment of oral thrush.  Large doses such as 200mg have been used in the prophylaxis of fungal infections during neutropenia and also for the treatment of azole resistant oropharyngeal candidiasis. [2]

Topical amphotericin B has also be administered with flucytosine in a pessary for azole-resistant Candida glabrata vaginitis. [3]

Examples of topical use of amphotericin B include bladder instillation, surgical wound irrigation, intraperitoneal catheter usage, intravitreal (eye) and use in the lumbar, ventricular, cisternal or subarachnoid spaces.  Doses vary widely for these indications and need to be checked.

Fungi sensitive to amphotericin B:      

Amphotericin B is probably the most broad spectrum intravenous antifungal available.  It has activity against Aspergillus spp., Blastomyces dermatitidis,Candida (all species except some isolates of Candida krusei and Candida lusitaniae), Coccidioides spp, Cryptococcus spp., Histoplasma spp, Paracoccidioides brasiliensis and most of the agents of zygomycosis (Mucorales), Fusarium spp. and other rarer fungi. It is not adequately active against Scedosporium spp., Aspergillus terreus, Trichosporon spp., most of the species causing mycetoma and systemic infections due to Sporothrix schenckii. Acquired resistance to amphotericin B has been described in occasional isolates, usually after long term therapy in the context of endocarditis, but is rare.

Typical regimens    

Oral therapy

  • Oral thrush 10mg 4x daily
  • Azole resistant oral thrush 10 - 200mg 4x daily
  • Prophylaxis of Candida infections in neutropenia 200 - 500mg 4x daily

Intravenous therapy

The general approach to treating patients with serious infections is to use the maximum tolerated dose initially.  The drug should never be administered in less than 60 minutes as it may cause arrhythmias and 2 - 4 hours is preferable for amphotericin B deoxycholate and Amphocil. 

Deoxycholate doses 

  • Cryptococcal meningitis: >0.7mg/kg daily (with flucytosine).
  • Candidaemia: 0.6 - 1mg/kg per day.
  • Invasive aspergillosis: 1 - 1.25mg/kg per day.
  • Histoplasmosis, blastomycosis and coccidioidomycosis (acute): 1mg/kg daily.
  • Histoplasmosis and coccidioidomycosis (chronic): 0.5 - 1mg/kg/day.
  • Penicillium marneffei infection: 0.8 - 1mg/kg/day.
  • Mucorales infection: 1 - 1.5mg/kg/day.
  • Doses of lipid amphotericin B preparation are usually 3-5x higher than deoxycholate amphotericin B  

Metabolism and excretion      

Amphotericin B is hardly absorbed from the gut.  After intravenous administration the drug appears to go through three phases of redistribution from the blood into a “fast” tissue compartment and a “slow” tissue compartment.  Over 90% of the drug has gone from the bloodstream 12 hours after administration.  Considerable variations in serum concentrations and tissue concentrations are apparent between different individuals, whether using the lipid-based preparations or the deoxycholate preparation. Penetration into the urine, cerebrospinal fluid, eye and vegetations on heart valves and bone is poor.  Tissue concentration of the lipid-based amphotericins is increased in the reticulo-endothelial system (liver and spleen), brain and slightly reduced in the lung and kidney.  The preparation with the highest brain concentrations is AmBisome.  Amphotericin B is barely metabolised and excreted extremely slowly several weeks after administration.

Drug/Drug interactions          

There are few direct drug/drug interactions with amphotericin B although synergistic nephrotoxicity with certain drugs such as IV contrast media, cyclosporin and aminoglycosides (gentamicin, etc.) can be problematic.  Low blood potassium (which is common) can produce problems with cardiac drugs such as digoxin. View drug interactions database.

Side effects    

Deoxycholate amphotericin B
Many side effects are associated with the intravenous administration of deoxycholate amphotericin B.  Approximately two thirds of patients suffer acute infusion-related toxicity which may include chills, fever, anaphylactoid like reactions and rarely acute confusional states.  Management of these side effects is usually possible with acetoaminophen or paracetamol, ibuprofen or aspirin and, if severe, small doses of opiates.  Hydrocortisone has been extensively used for this indication, but it tends to cause more immunosuppression and it is preferable to avoid it if possible.  If hydrocortisone is used a dose of 25mg is adequate.  Renal dysfunction is common with amphotericin B usage and is primarily dose related, although occasional patients go into acute renal failure, after 1-3 doses.  The administration of saline intravenously (500ml to 1 litre) prior to amphotericin B infusion reduces renal toxicity but rarely abolishes it.  A low blood potassium and magnesium is common after days or weeks of amphotericin B therapy.  This can be partially prevented by the use of the diuretic amiloride (5mg daily).  Chronic anaemia is common after several weeks of amphotericin B in addition to a general feeling of ill health and loss of appetite.  It usually takes 2-4 weeks for these symptoms to recover following a course of amphotericin B.  Amphotericin B tends to damage veins (phlebitis) and is usually therefore best administered through a central (large vein) intravenous line.

Lipid-associated amphotericin B
Lipid based amphotericin B preparations cause less toxicity, particularly less renal toxicity.  Many units routinely use these preparations in patients who already have kidney dysfunction or are taking cyclosporin.  Lipid based preparations also cause less potassium loss. There are differences between the three preparations in their likelihood of acute infusion related toxicities.  Amphocil appears to have more infusion related toxicities than conventional amphotericin B, although these are usually manageable with the measures described above.  Abelcet has fewer infusion related toxicities than conventional amphotericin B and AmBisome fewer still.  Acute anaphylactoid reactions occurring with one preparation may not recur with another for reasons than are not entirely clear.  Anaemia and feelings of chronic ill-health are as common as with amphotericin B deoxycholate, after 2 - 3 weeks of therapy.

Other information      

Lipid associated amphotericin B is considerably more expensive than amphotericin B deoxycholate. Amphotericin B is the systemic antifungal of choice in pregnancy.

Structure of amphotericin B

References

[1] Khoo SH, Bond J, Denning DW. Administering amphotericin B—a practical approach. J Antimicrob Chemother. 1994 Feb; 33(2): 203-13

[2] Hood S, Evans J, Wilkins E, Denning D. The treatment of oropharyngeal candidasis in HIV-infected patients with oral amphotericin B suspension. AIDS Patient Care STDS. 1998 Aug; 12(8): 625-7.

[3] White DJ, Johnson EM, Warnock DW. Management of persistant vulvo vaginal candidosis due to azole-resistant Candida glabrata. Genitourin Med. 1993 Apr; 69(2): 112-4.

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