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An Introduction to Anti-fungal Pharmacology

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1 An Introduction to Anti-fungal Pharmacology
The following slides were generously supplied by Professor Russell E. Lewis, Pharm.D., BCPS University of Houston College of Pharmacy, University of Texas M.D. Anderson Cancer Center. With lecture notes written by Hannah Woodcock and Jenny Bartholomew, University of Manchester, UK.

2 Types of fungal infections - Mycoses
Superficial mycoses Affect the skin, hair and nails Subcutaneous mycoses (tropical) Affect the muscle and connective tissue immediately below the skin Systemic (invasive) mycoses Involve the internal organs Primary vs. opportunistic Allergic mycoses Affect lungs or sinuses Patients may have chronic asthma, cystic fibrosis or sinusitis Fungal infections are termed ‘mycoses’ and in general can be divided into: Superficial mycoses: These types of infections do not penetrate the body and have few symptoms. Most people are concerned about the cosmetic effects of the infection. Examples include athlete’s foot, cradle cap, ringworm (not a worm at all) and thrush Subcutaneous mycoses: The fungi that cause subcutaneous mycoses normally live in soil and on decaying vegetation. They cause infection by entering the skin through an injury. Feet are most often affected. Characterized by hard lumps (abscesses) beneath the skin at the original point of injury. These abscesses can be present for a long time and, if left untreated, can become disfiguring. If these types of infections spread to the internal organs through blood or lymphatics they can be life-threatening. However, this is a rare occurrence and usually occurs if the host is immunocompromised. Superficial mycoses occur primarily in tropical areas. Systemic mycoses: most often acquired via inhalation of airborne spores and is initiated in the lungs. The initial pulmonary infection is often subclinical or mild and resolves on its own. However, some patients may develop progressive disease involving spread to other parts of the body. Many of the fungi that cause mycoses live in association with humans as commensals or are present in the environment; but until recently, serious superficial infections were relatively uncommon and systemic infections were very uncommon indeed-at least in cool and temperate climatic zones. In these zones, a fungal infection usually meant athlete’s foot or vaginal thrush, which caused discomfort but were not life threatening. But in the last 30 years there has been a steady increase in the incidence of serious secondary systemic fungal infections. One factor has been the widespread use of broad-spectrum antibiotics, which eliminate or decrease the non pathogenic bacterial populations that normally compete with fungi. Another has been the increase in the number of individuals with reduced immune responses due to AIDS or the action of immunosuppressant drugs or cancer chemotherapy agents; this has led to an increased prevalence of opportunistic infections i.e. infections with fungi which are either innocuous or readily overcome in immunocompetent individuals. In the UK, the commonest systemic fungal disease is systemic candidiasis. Others include cryptococcal meningitis, pulmonary aspergillosis (invasive pulmonary aspergillosis is now a leading cause of death in recipients of bone marrow transplants). However in other parts of world, blastomycosis, histoplasmosis, coccidioidomycosis and paracoccidioidomycosis are the commonest; these are often primary infections i.e. they are not secondary to reduced immunological function or altered commensal microorganisms. Allergic mycoses – allergic bronchopulpmonary aspergillosis (ABPA). This is a condition produced by an allergy to the spores of the Aspergillus moulds. It is quite common in asthmatics; up to 20% of asthmatics might get this at some time during their lives. ABPA is also common in cystic fibrosis patients, as they reach adolescence and adulthood. The symptoms are similar to those of asthma: intermittent episodes of feeling unwell, coughing and wheezing. Some patients cough up brown-coloured plugs of mucus. The diagnosis can be made by X-ray or by sputum, skin and blood tests. In the long term ABPA can lead to permanent lung damage (fibrosis) if untreated. There is some overlap between these groups

3 What are the targets for antifungal therapy?
Cell membrane Fungi use principally ergosterol instead of cholesterol DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. There are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity. Cell Wall Unlike mammalian cells, fungi have a cell wall Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

4 Cell Membrane Active Antifungals
• Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical) • Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals) Above are antifungals which target the cell membrane. First of all we will look at the azole family. These drugs are far less toxic than amphotericin B.

5 Azole Antifungals for Systemic Infections
Ketoconazole (Nizoril) Itraconazole (Sporanox) Fluconazole (Diflucan) Voriconazole (Vfend) Imidazole Triazoles “2nd generation triazole” The azoles are a very large group of synthetic agents, which includes drugs used in bacterial and parasitic as well as fungal infections. The majority are used as a topical treatment. The drugs listed here are the few which are suitable for systemic administration. The azoles are widely used because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Members of the azole group have either an imidazole or triazole ring with N carbon substitution. Imidazole ring: five-membered ring structure containing two nitrogen atoms. Triazole ring: five-membered ring structure containing three nitrogen atoms. While ketoconazole was more widely used before the development of newer, less toxic, and more effective triazole compounds, fluconazole and itraconazole, its use has now been limited. Unfortunately, azoles are generally fungistatic (especially in Candida) and resistance to fluconazole is emerging in several fungal pathogens. Fluconazole Ketoconazole

6 Azoles - Mechanism In fungi, the cytochrome P450-enzyme lanosterol 14-a demethylase is responsible for the conversion of lanosterol to ergosterol Azoles bind to lanosterol 14a-demethylase inhibiting the production of ergosterol Some cross-reactivity is seen with mammalian cytochrome p450 enzymes Drug Interactions Impairment of steroidneogenesis (ketoconazole, itraconazole) The azoles inhibit the fungal P450 enzymes responsible for the synthesis of ergosterol, the main sterol in the fungal cell membrane. The azoles act through an unhindered nitrogen, which binds to the iron atom of the heme, preventing the activation of oxygen which is necessary for the demethylation of lanosterol. In addition to the unhindered nitrogen, a second nitrogen in the azoles is thought to interact directly with the apoprotein of lanosterol demethylase. It is thought that the position of this second nitrogen in relation to the apoprotein may determine the specificity of different azole drugs for the enzyme. The resulting depletion of ergosterol alters the fluidity of the membrane and this interferes with the action of membrane-associated enzymes. The overall effect is an inhibition of replication (ie. the azoles are fungistatic drugs). A further repercussion is the inhibition of transformation of candidal yeast cells into hyphae-the invasive and pathogenic form of the parasite. Since no drug acts with complete specificity, it is not surprising that the azoles also have some effect on the closely related mammalian p450 enzymes. These are a large family of haem proteins. Hepatic p450 enzymes are involved in the detoxification of drugs whereas extrahepatic enzymes play an important part in several synthetic pathways including steroid biosynthesis in the adrenal gland.

7 Effect of azoles on C. albicans
Before exposure After exposure This electron micrograph shows the fungistatic effect of the azoles. There is reduced budding from the parent cells.

8 Azoles - Pharmacodynamics
Concentration-independent fungistatic agents Dosage escalation may be necessary when faced with more resistant fungal species (e.g. Candida glabrata) Goal of dosing is to maintain AUC:MIC >50 i.e. maintain concentrations 1-2 x MIC for the entire dosing interval Studies have been done with Candida albicans, but not other fungi, and so the pharmacodynamic relationships with fungi such as Aspergillus spp. or Histoplasma capsulatum are not known.

9 Ketoconazole Spectrum: yeasts and moulds - poor absorption limits its role for severe infections, generally used in mucosal infections only Pharmacokinetics Variable oral absorption, dependent on pH (often given with cola or fruit juice) T1/ hours Protein binding > 99% Hepatic, bile and kidney elimination Ketoconazole was the first azole that could be given orally to treat thrush and systemic fungal infections. It is effective against several different types of fungi. It is however, somewhat toxic and relapse is common after apparently successful treatment. Imidazole antifungal agent. Marketed as Nizoral. Has oral tablet, cream and dandruff shampoo formulations. The only member of the imidazole class that is currently used for treatment of systemic infections. Highly lipophilic compound. Leads to high concentrations in fatty tissues and purulent exudates. Distribution is poor into the CSF even in the presence of inflammation. Affinity for fungal cell membranes is less compared to that of fluconazole and itraconazole. Therefore, it is more likely to affect mammalian cell membranes and induce toxicity. Spectrum: activity against a wide range of yeasts and moulds e.g. Candida and Cryptococcus but its activity is limited compared to that of fluconazole and itraconazole. It is also active against dimorphic moulds but fluconazole and itraconazole are at least as effective and are safer. Thus, ketoconazole remains as an alternative second-line drug for treatment of infections due to dimorphic fungi. Due to its limited penetration of CSF, it is clinically ineffective against meningeal fungal infections. It has no activity against Aspergillus spp. Pharmacokinetics: It is erractically absorbed from the gastrointestinal tract (absorption is optimal at acid pH). Ketoconazole is a dibasic compound (pKa(1) = 6.51; pKa(2) = 2.94) and almost insoluble in water except at a pH lower than 3. Therefore any conditions that lower the acidity or increase the pH of stomach will decrease the absorption and hence reduce the bioavailability of ketoconazole. This is demonstrated in studies involving the co-administration of ketoconazole with H2-receptor blockers. Ketoconazole is highly protein bound (significance: slowly cleared from the body, and less free drug available for activity) Metabolised by the liver and the metabolites are excreted in the bile. The hepatic clearance of ketoconazole is saturable such that AUC increases disproportionally with increasing dose. Less than 1% of an oral dose is excreted unchanged in the urine.

10 Ketoconazole - Adverse effects
N&V, worse with higher doses (800 mg/day) Hepatoxicity (2-8%), increase in transaminases, hepatitis Dose related inhibition of CYP P450 responsible for testosterone synthesis Gynecomastia, oligosperma, decreased libido Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesis The major drawbacks in ketoconazole therapy are from the occasionally seen adverse affects. It may induce anorexia, nausea and vomiting. High doses of ketoconazole may decrease testosterone and cortisol levels, resulting in painful gynecomastia (enlargement of breasts) and oligospermia (low sperm count) in men and menstrual irregularities in women. Transient transaminase elevations develop in 5-10% of patients on oral ketoconazole. Treatment should be discontinued if these persists, if the abnormalities increase, or if symptoms associated with hepatic dysfunction appear. The serious hepatotoxic side-effects of ketoconazole are idiosyncratic and rare, occuring in 1 in 10,000 patients treated for longer than 2 weeks. In most cases, hepatic damage is reversible when the drug is discontinued. Liver function tests should be performed before starting, 14 days after starting, then at monthly intervals. Other side effects: headache, photophobia, dizziness, drowsiness.

11 Ketoconazole - Drug Interactions
Potent inhibitor of cytochrome P450 3A4 Rifampin and phenytoin decrease ketoconazole levels Ketoconazole increases cyclosporin, warfarin, astemizole, corticosteroid, and theophylline levels Many of these drug interactions are severe Drugs that increase gastric pH will decrease blood levels of ketoconazole Antacids, omeprazole, H2 blockers One potential limitation of the azole antifungal drugs is the frequency of their interactions with coadministered drugs, which results in adverse clinical consequences One type of azole-drug interaction may lead to decreased plasma concentration of the azole, related to either decreased absorption or increased metabolism of the azole. E.g. rifampin decreases ketoconazole concentrations by enhancing its metabolism. Drugs that increase gastric pH will decrease drug absorption and therefore blood levels of ketoconazole and vice-versa. A second type of azole-drug interaction may lead to an unexpected toxicity of the coadministered drug, relating to the ability of the azoles to increase plasma concentrations of other drugs by altering hepatic metabolism via the cytochrome P-450 system. E.g. ketoconazole increases warfarin levels and therefore potentiates its anticoagulant effect. It also prolongs the half-life of cyclosporin in organ transplant recipients causing nephrotoxicity. Ketoconazole should not be taken with H1 receptor antagonists, such as astemizole or terfenadine, because of the potential for cardiac ventricular dysrhythmias. For a comprehensive list of antifungal drug interactions, visit

12 The time taken for peak serum concentrations to be reached is 2-4 hrs
The time taken for peak serum concentrations to be reached is 2-4 hrs. This is determined by several factors including: disintegration/dissolution rate (favoured by acidic pH?) Gastric emptying rate Intestinal transit time Intestinal metabolism (CYP 3A4 in intestinal wall) Rate of absorption from the intestine First Pass effect (metabolism in liver) Clearance rate. Food delays absorption, but does not decrease peak serum concentrations significantly.

13 Ketoconazole - Dose Serious infections 800 mg/day PO
Other: mg/day PO Oral ketoconazole is used at a dose of 200 to 400 mg/day in treatment of oral and chronic mucocutaneous candidiasis. The dose can be increased to mg/day in patients not responding to regular doses. However, high doses carry the risk of high incidence of toxicity. Ketoconazole is sometimes used as a cyclosporine saver, as cyclosporine is very expensive and ketoconazole reduces its use to about a third. Cost $2.50 per 200 mg tablet

14 Fluconazole Well tolerated IV/PO formulations
Advantages Disadvantages Well tolerated IV/PO formulations Favorable pharmacokinetics Fungistatic Resistance is increasing Narrow spectrum (Drug interactions) Fluconazole is a triazole antifungal drug. It is marketed as Diflucan. It can be given orally or intravenously.

15 Fluconazole - spectrum
Good activity against C. albicans and Cryptococcus neoformans Non-albicans Candida species more likely to exhibit primary resistance Fluconazole is principally active against Candida spp. and Cryptococcus spp. However, the spectrum of activity is very wide and includes: 1)Dermatophytes e.g Trichophyton species 2)Dimorphic fungi 3)Some yeasts e.g. C. albicans, C. parapsilosis, C. tropicalis and Cryptococcus neoformans. A limitation of the azoles is the emergence of resistance in fungi , especially Candida species to fluconazole. Non-albicans isolates are often more resistant to fluconazole compared to C. albicans isolates. Candida krusei is intrinsically resistant to fluconazole. Also, isolates of Candida glabrata often generate considerably high fluconazole MICs, with as many as 15% of isolates being completely resistant. Acquired resistance to fluconazole among C. albicans strains has been reported particularly in HIV-infected patients. Most, but not all, C. albicans strains resistant to fluconazole are cross-resistant to other azoles. There are a few reports of fluconazole-resistant strains of C. neoformans recovered from AIDS patients with relapsed meningitis. Fluconazole has no meaningful activity against Aspergillus spp. or most other mould fungi. Always resistant Sometimes resistant C. krusei > C. glabrata > C. parapsilosis C. tropicalis C. kefyr

16 Fluconazole - resistance
Primary resistance (seen in severely ill or immunocompromised patients) Selection of resistant species or subpopulations Replacement with more resistant strain Secondary resistance (seen in patients with AIDS who experienced recurrent orophayrngeal candidiasis and received long-term fluconazole therapy) Genetic mutation Upregulation of efflux pumps As azole antifungal agents have become important in the treatment of mucosal candidiasis in AIDS patients, reports of resistance have increased. In fact, azole resistance has now been found in patients not infected with HIV and, in some situations, in patients not previously exposed to antifungal agents. Patients infected with HIV frequently develop oral candidiasis. Candida colonizes the mouths of 64 to 84% of these patients and causes symptomatic disease in up to 46%. Reports of azole resistance developing in this setting are numerous. In a case-control study, advanced immunosuppression and previous exposure to oral azoles were found to be risk factors for the development of resistance. Both primary resistance and secondary resistance have been documented in HIV-infected patients. Several factors can lead to the presence of a resistant strain in a patient: intrinsic resistance of endogenous strains, replacement with a more resistant species (C. krusei, C. glabrata), replacement with a more resistant strain of C. albicans, genetic alterations that render an endogenous strain resistant, transient gene expression that renders an endogenous strain temporarily resistant, alteration in cell type (yeast/hypha, switch phenotype), size and variability of the population, and population “bottlenecks.” Resistance can be primary i.e. present when the drug is first given, or secondary i.e. developing during the treatment with the drug.

17 Mechanisms of antifungal resistance
Target enzyme modification Ergosterol biosynthetic pathway Efflux pumps Drug import Molecular mechanisms of azole resistance. In a susceptible cell, azole drugs enter the cell through an unknown mechanism, perhaps by passive diffusion. The azoles then inhibit lanosterol 14-a demethylase (ERG11) (pink circle), blocking the formation of ergosterol. Two types of efflux pumps are expressed at low levels. The CDR proteins are ABC transporters (ABCT) with both a membrane pore (green tubes) and two ABC domains (green circles). The MDR protein is an Major Facilitator transport protein (MF) with a membrane pore (red tubes). ABC transporters use ATP as their energy source, whereas MF transporters use the proton motive force. In a “model” resistant cell, the azoles also enter the cell through an unknown mechanism. In a resistant cell, the azoles are blocked from interacting normally with the target enzyme because the enzyme can be modified. Lanosterol 14-a demethylase is encoded by the gene ERG11. Several genetic alterations have been identified that are associated with the ERG11 gene of C. albicans, including point mutations in the coding region, overexpression of the gene, gene amplification (which leads to overexpression) and gene conversion or mitotic recombination. Several different specific point mutations (dark slices in pink circles) have been identified by comparing azole-resistant clinical isolate with a sensitive isolate from a single strain of C. albicans. The first point mutation to be identified within ERG11 of a clinical isolate of C. albicans which altered the fluconazole sensitivity of the enzyme was discovered in 1997 by White et al. This mutation results in the replacement of arginine with lysine at amino acid 467 of the ERG11 gene (abbreviated R467K). Overexpression of ERG11 has been described in several different clinical isolates. In each case, the level of overexpression is not substantial (less than a factor of 5). It is difficult to assess the contribution of ERG11 overexpression to a resistant phenotype, since these limited cases of overexpression have always accompanied other alterations associated with resistance, including the R467K mutation, and overexpression of genes regulating efflux pumps. In addition to alterations in the lanosterol demethylase, a common mechanism of resistance is an alteration in other enzymes in the same biosynthetic pathway (dark slices in blue spheres). The sterol components of the plasma membrane are modified (darker orange of membrane). Finally, the azoles are removed from the cell by overexpression of the CDR genes (ABCT) and MDR (MF). The CDR pumps are effective against many azole drugs, while MDR appears to be specific for fluconazole. Overexpression of the transporters may be a result of gene amplification or increased gene transcription. The more efficient removal of the azoles means that the drugs never reach their therapeutic concentrations within the cell. For more detail read: White T.C., Marr K.A., Bowden R.A. Clinical Microbiology Reviews ; Available on internet at White TC, Marr KA, Bowden RA. Clin Microbiol Review 1998;11:

18 Fluconazole - What is not covered
Candida krusei +/- Candida glabrata Aspergillus species and other moulds

19 Fluconazole - Pharmacokinetics
Available as both IV and PO Bioavailibility > 90% Linear pharmacokinetics t 1/2 = ~24 hours Cmax (400 mg IV) = 20 µg/ml (steady state) Protein binding < 12% Vd 0.85 L/kg (widely distributed) >90% excreted unchanged through the kidney Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage.

20 Fluconazole - adverse effects/monitoring
N&V, rash: More likely with high doses and in AIDS patients Asymptomatic increase in LFTs (7%) Drug interactions: May increase phenytoin, cyclosporin, rifabutin, warfarin, and zidovudine concentrations Rifampin reduced fluconazole levels to half (even though FLU is not a major substrate) Fluconazole is generally quite well tolerated. Unwanted effects, which are generally mild, include nausea, headache and abdominal pain. However, exfoliative skin lesions (including Stevens-Johnson syndrome) have been reported-primarily in AIDS patients who are being treated with multiple drugs. In common with all azole antifungal agents, fluconazole may cause hepatotoxicity. In the doses usually used, fluconazole does not produce the same level of inhibition of hepatic drug metabolism and of steroidogenesis which occurs with ketoconazole. However, drug interactions are present.

21 Fluconazole - Dosing Mucosal candidiasis Systemic fungal infections
mg/day (150 mg tablet vulvovaginal candidiasis) Systemic fungal infections mg q24h > 800 mg q24h in unstable patient, S-DD isolate, or if non-albicans spp. (except C. krusei) Maintenance for cryptococcal meningitis 400 mg q24h

22 Key Biopharmaceutical Characteristics of the Triazole Antifungals
Fluconazole Itraconazole Voriconazole Spectrum vs. Candida and Aspergillus C. albicans, C. tropicalis +/ C. glabrata No Aspergillus Similar Candida coverage as fluconazole, + Aspergillus Broad, includes most Candida spp., Aspergillus, Fusarium sp. Not Zygomycoses Oral formulation (% bioavailibility) Tablet (>90%) Capsule (6-25%) Solution (20-60%) Intravenous formulation Available, no solubilizer Available, cyclodextrin Clearance Renal (80%) Hepatic 3A4 Hepatic 2C19, 3A4 Serum half life (hr) 24 24-30 6-24 CSF penetration Excellent Poor CYP 3A4 inhibition Weak Strong Moderate-Strong Adverse effects N&V, hepatic N&V, diarrhea (solution), hepatic, CHF N&V, visual disturbances, hepatic, rash Unlike fluconazole, other triazole antifungals, itraconazole and voriconazole can be used to treat aspergillosis. Itraconazole: Can be given orally or intravenously. Oral availability is variable (improved if given with food or acidic beverage) Extensive hepatic metabolism (into large number of metabolites-most of which are inactive) and excreted in the bile. It isn’t excreted as an unchanged drug in the urine. Relatively long half-life- approx 30hrs. No penetration of CSF (therefore not used as treatment for meningeal fungal infections) Unwanted effects include gastrointestinal disturbances, headache and dizziness. Rare unwanted effects are hepatitis, hypokalemia, impotence, transient abnormalities of liver enzymes and allergic skin reactions (including Stevens-Johnson syndrome). Inhibition of steroidogenesis has not been reported. Drug interactions due to inhibition of p450 enzymes do occur (similar to those described for ketoconazole previously). Voriconazole: Oral/IV Almost complete oral absorption. Extensive hepatic metabolism. Approx 80% of a single dose appears in the urine, but less than 5% is excreted in its unchanged form. Widely distributed into body tissues and fluids, including the brain and CSF. Unwanted effects include mild to moderate visual disturbances (more detail later, rashes and transient abnormalities of liver enzymes. R.E. Lewis Exp Opin Pharmacother 3:

23 Itraconazole Solution - Side Effects
Taste disturbances Nausea and vomiting Osmotic diarrhea (especially at doses > 400 mg/day) Long-term compliance often difficult

24 Voriconazole - Side Effects
Visual disturbances (~ 30%) Decreased vision, photophobia, altered color perception and ocular discomfort IV > oral No evidence of structural damage to retina Reversible alterations in function of retinal rods and cones Testing 2 weeks after the end of treatment demonstrates a return to normal function Long term effects?..caution against night-time driving Effects may be intensified by hallucinations (2-5%)

25 Amphotericin B Polyene antibiotic
Fermentation product of Streptomyces nodusus Binds sterols in fungal cell membrane Creates transmembrane channel and electrolyte leakage. Active against most fungi except Aspergillus terreus, Scedosporium spp. Around 100 polyene antibiotics have been described, but few have been developed for clinical use. Amphotericin B was first isolated by Gold et al from Streptococcus nodosus in It is an amphoteric compound composed of a hydrophilic polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the other. Amphotericin B is poorly soluble in water. It binds to sterols of susceptible fungal cells. Amphotericin B has a selective action, binding avidly to membranes of fungi and less avidly to mammalian cells. The relative specificity for fungi may be due to the drug’s greater avidity for ergosterol than for cholesterol. On binding to the fungal cell membranes, Amphotericin B interferes with permeability and transport functions. The drug is thought to form a pore in the membrane, the hydrophilic core of the molecule creating a transmembrane ion channel. One of the repercussions of this is a loss of intracellular potassium, magnesium, sugars and metabolites and then cellular death. Until the introduction of voriconazole, amphotericin B was the most broad spectrum intravenous antifungal available, although not always very potent.

26 Lipid Amphotericin B Formulations
Abelcet ® ABLC Amphotec ® ABCD Ambisome ® L-AMB Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size (µm): Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size (µm): Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol Particle size (µm) : 0.08 DMPC-Dimyristoyl phospitidylcholine DMPG- Dimyristoyl phospitidylcglycerol HSPC-Hydrogenated soy phosphatidylcholine DSPG-Distearoyl phosphitidylcholine

27 Amphotericin B Classic amphotericin B deoxycholate (Fungizone™) formulation: serious toxic side effects. Less toxic preparations: 1) Liposomal amphotericin B 2) Amphotericin B colloidal dispersion 3) Amphotericin B lipid complex The original preparation of amphotericin B for intravenous use is a deoxycholate dispersion in dextrose. This traditional micellar suspension formulation is often associated with serious toxic side effects, in particular renal damage, and this has stimulated efforts to develop new, less toxic preparations. It was discovered that the toxic side effects were partially ameliorated when a lipid carrier was used. Three lipid-associated formulations have been licensed for use: Liposomal : drug is encapsulated in phospholipid-containing liposomes Colloidal dispersion: drug is packaged into small lipid disks containing cholesterol sulphate Lipid complex: drug is complexed with phospholipids to produce ribbon-like structures. These formulations appear to be less toxic than the micellar suspension because of their altered pharmacological distribution. They permit higher doses to be administered, however, they are considerably more expensive (10-50 fold higher in cost per dose). Efficacy is maintained. For more detailed information on the different Amphotericin B formulations visit

28 Amphotericin B - Pharmacokinetics
Absorption from the GI tract is negligible Oral solution sometimes used to decontaminate gut; few side effects Only reliable method of administration is IV Selective distribution into deep tissue sites, with slow release of drug Given orally, amphotericin B is very poorly absorbed, and it is therefore only given by this route for fungal infections of the gastrointestinal tract. For systemic infections, it is delivered intravenously. However, there are a number of commonly observed infusion-related side effects of amphotericin B deoxycholate, including fever, chills, and myalgia. Infusion-related reactions are uncommon in patients receiving liposomal amphotericin B. 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, the remainder is thought to bind to tissue cell membranes, the highest concentrations being found in the reticulo-endothelial system (lungs, spleen, liver). 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 bone is poor.  Tissue contraction 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 liposomal amphotericin B.  Pharmacokinetics of the different lipid-based formulations are quite diverse. High Low kidney > liver > spleen > lung > heart > skeletal muscle > brain > bone > CSF > eye

29 Amphotericin B - Metabolic elimination
Metabolic fate is unknown, drug accumulates in tissues and then is slowly released Drug levels can be measured in the kidney, liver, and spleen up to 1 year after receiving drug Dosages of amphotericin B are generally not altered due to decreased elimination of the drug in kidney dysfunction Hemodialysis does not alter serum drug concentrations except in hyperlipidemic patients About 2-5% of a given dose of amphotericin B appears in the urine within 24h, but the fate of the rest in unknown. No metabolites have been identified. Blood concentrations are unchanged in hepatic or renal failure. Likewise, hemodialysis does not influence serum concentrations unless the patient is hyperlipidemic, in which case there is some drug loss due to adherence to the dialysis membrane.

30 Amphotericin B - Elimination
Inverse correlation between patient age and elimination of AmB, á Age, â elimination, á side effects Paediatric patients often tolerate amphotericin B better than adults

31 Amphotericin B - Nephrotoxicity
Most significant delayed toxicity Renovascular and tubular mechanisms Vascular-decrease in renal blood flow leading to drop in GFR, azotemia Tubular-distal tubular ischemia, wasting of potassium, sodium, and magnesium Enhanced in patients who are volume depleted or who are on concomitant nephrotoxic agents The commonest and most serious side effect of amphotericin B is renal toxicity. Some degree of reduction of renal function occurs in more than 80% of patients receiving the drug, and though this generally recovers after treatment has stopped, some impairment of glomerular filtration may remain. Decreased renal function arises due to 2 reasons: Increased renal vascular resistance Increased tubular permeability Azotemia: accumulation of urea in the bloodstream.

32 Amphotericin B - Manoeuvers employed to blunt nephrotoxicity…
Sodium loading-> blunt the vasoconstriction and tubular-glomerular feedback Administration of 500 ml ml of NaCl before and after amphotericin B infusion There are limited reports indicating that correction of sodium depletion may reverse amphotericin-induced nephrotoxicity. However, assessment of sodium status and correction of deficiency should precede amphotericin administration. The mechanism of renal toxicity is not entirely clear. Unfortunately, amphotericin B does have a weak affinity for the cholesterol molecules found in mammalian cell membranes. This results in the formation of intramembranous pores that alter the cell membrane permeability. In the kidney, this may cause direct renal tubular damage. Since the drug alters cell membrane permeability and probably as a consequence alters tubular and vascular smooth muscle cell function, Amphotericin B is thought to affect tubuloglomerular feedback. Tubuloglomerular feedback (TGF) provokes constriction of the afferent arteriole, which, in turn, causes azotemia. It is believed that TGF is augmented by renal electrolyte loss during a hyponatremic state. The resulting decreased renal blood flow appears to play a major role in amphotericin B-induced reduction of GFR and recurrent ischemia may be the basis of permanent structural nephrotoxic effects. In order to avoid this hyponatremic state, sodium "loading" prior to administering IV amphotericin B is in practice.

33 Amphotericin B - Drug Interactions
Enhanced nephrotoxicity Nephrotoxic drugs Cyclosporine, aminoglycosides, foscarnet, pentamidine Antineoplastic agents Cisplatin, nitrogen mustards Drugs which potentiate sodium loss or nephrotoxicity should be avoided.

34 Amphotericin B - Clinical Uses
The drug of choice for: Cryptococcal meningitis Mucormycosis (zygomycosis) Invasive fungal infection, not responding to other therapy Amphotericin B still remains the standard antifungal therapy, despite its significant toxicity. 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. Amphotericin B has an broad antifungal spectrum which includes most fungi that cause human disease, with the exception of Aspergillus terreus, Scedosporium spp., some isolates of Candida lusitaniae, some species of Paecilomyces causing infection and some of the agents of mycetoma such as Maduralla spp.

35 Amphotericin B - Dosing and Administration
“Test dose” 1.0 mg in ml 5% dextrose infused over 10 minutes used to evaluate possibility of anaphylactic reaction No longer recommended, current product has fewer impurities Current recommendation- Start with ~30% of target dose, infuse for 15 minutes, stop infusion, and monitor patient for adverse effects before resuming infusion Rapidly escalate to full dosages within hours Delay in giving full dose = worse clinical outcome Too detailed? No, a useful practical point for many Administration of amphotericin B on alternate days is widely practised although it has never been proven to reduce nephrotoxicity. Recent data suggests continuous infusion useful in reducing toxicity, but not much efficacy data.

36 Cell Wall Active Antifungals
Cell membrane • Polyene antibiotics • Azole antifungals DNA/RNA synthesis • Pyrimidine analogues - Flucytosine Flucytosine is an anti-metabolite type of antifungal drug. It is a synthetic fluorinated pyrimidine which is available for intravenous infusion or oral administration. It is marketed as Ancotil. Cell wall • Echinocandins -Caspofungin acetate (Cancidas)

37 Flucytosine Fluorinated pyrimidine related to flurouracil.
Mechanism of Action: 5FC itself has no intrinsic antifungal activity; its anti-mycotic activity results from the rapid conversion of 5-FC into 5-FU within susceptible fungal cells. 5FC enters fungal cells aided by cytosine permease enzyme. This system is energy dependent and coupled to a proton gradient. Once inside, it is converted to 5-fluorouracil (5FU) by the enzyme cytosine deaminase. The drug is selectively toxic to fungi because mammalian cells lack cytosine deaminase. Fungi lacking cytosine deaminase are not sensitive to 5-FC. 5-FU on the other hand, cannot be used as an antifungal drug, since it is highly toxic to mammalian cells and also because it is poorly taken up into fungal cells. After uptake of 5-FC into the fungal cell and conversion into 5-FU, two mechanisms can be distinguished by which 5-FU exerts its antifungal activity. The first mechanism: 5FU is converted by UMP pyrophosphorylase into 5-fluorouridylic acid (FUMP), which is phosphorylated further to FUTP. This is incorporated into RNA, resulting in disruption of protein synthesis. The second mechanism: 5FU is also converted to 5-fluorodeoxyuridine monophosphate (fdUMP), a potent inhibitor of thymidylate synthase, which is a key enzyme in the biosynthesis of DNA, since this enzyme is a crucial source of thymidine . Thus, 5FC acts by interfering with pyrimidine metabolism, as well as RNA, DNA, and protein synthesis in the fungal cell. To summarise, it is converted intracellularly to: 5-fluorouracil (5-FU) 5-fluorodeoxyuridine monophosphate (FdUMP)-- DNA synthesis inhibitor (via inhibtion of thymidylate synthase) fluorouridine triphosphate (FUTP) -- RNA synthesis inhibitor 5-FC shows both fungistatic and fungicidal (higher concentrations) activity against yeasts. Only fungistatic activity was observed against Aspergillus fumigatus implying multiple modes of action.

38 Flucytosine Restricted spectrum of activity. Acquired Resistance.
> result of monotherapy > rapid onset Due to: 1) Decreased uptake (permease activity) 2) Altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity) Flucytosine is active against a limited range of systemic fungal infections, being effective mainly in those caused by yeast. It has activity against Candida spp., C. neoformans and some fungi causing chromoblastomycosis. While flucytosine is in clinical use for these few specific indications, its use alone in treatment frequently results in emergence of resistance. This rapid de-novo resistance occurring during therapy has effectively limited its use in the treatment of candida infections (approx 10% of Candida albicans isolates are resistant before treatment starts), and is a major drawback for this compound. In principle, resistance to 5FC may result from decreased uptake (loss of permease activity) or loss of enzymatic activity responsible for conversion to FUMP. Although resistance due to decreased 5FC uptake has been found in S. cerevisiae and C. glabrata, this mechanism does not seem to be important in C. albicans or Cryptococcus neoformans. The most common cause of resistance appears to be loss of cytosine deaminase or UMP pyrophosphorylase activity.

39 Flucytosine - pharmacokinetics
Oral absorption complete Plasma half-life 3-6 hrs Volume of distribution 0.7-1l/kg (low) Plasma protein binding ~12% 5-FC is absorbed very rapidly and almost completely. In patients with normal renal function, peak concentrations are attained in serum and other body fluids within 1-2 hrs. It penetrates well into most body compartments, including CSF because it is small and highly water soluble and is not bound by serum proteins to a great extent. The apparent volume of distribution of 5-FC approaches that of total body water and is not altered by renal failure. 5-FC is subject to minimal metabolism by the liver. Therefore, 90% of a given dose is excreted unchanged in the urine. Renal elimination is via glomerular filtration; no tubular reabsorption or secretion takes place. The half-life of 5-FC is 3-6 hrs in patients with normal renal function, but can be extended up to 85hrs in patients with severe renal insufficiency. This necessitates modification of the dosage regime.

40 Flucytosine - side effects
Infrequent – include D&V, alterations in liver function tests and blood disorders. Blood concs need monitoring when used in conjunction with Amphotericin B. Gastrointestinal disturbances, bone marrow toxicity [anaemia, neutropenia (decrease in no. of white cells), thrombocytopenia (decrease in no. of platelets)] and alopecia (loss of hair) have occurred, but these are usually mild and are reversed when therapy ceases. Bone marrow toxicity is blood concentration dependant. Hepatitis has been reported but is rare. Since flucytosine is commonly combined with amphotericin B, the renal impairment caused by amphotericin B may increase the flucytosine levels in the body and thus potentiate its toxicity. Therefore the levels of flucytosine need to be monitored. The toxicity of flucytosine is presumably due to 5-fluorouracil which is produced from flucytosine by bacteria in gut lumen. Narrow therapeutic window (toxicity of higher levels; rapid development of resistance at lower, sub-therapeutic levels)

41 Flucytosine – Clinical uses
Monotherapy : now limited } In combination with amphotericin B or fluconazole. Candidiasis Cryptococcosis ?Aspergillosis 5-FC monotherapy is effective in treating infections caused by C. neoformans, Candida spp., and C. glabrata and in chromoblastomycosis. However, the use of 5-FC as a single agent is limited, because of the prevalence of intrinsically resistant strains and the frequent development of resistance during treatment. Monotherapy with 5-FC is now only used in some cases of chromoblastomycosis and in uncomplicated lower urinary tract candidiasis and vaginal candidiasis. In all other cases, 5-FC is used together with other agents, usually amphotericin B, for the treatment of systemic mycoses. Used in combination, these antifungals are more effective. The underlying reason for this synergistic action is not clear. However, it is possible that when using amphotericin B, flucytosine penetration through amphotericin B-damaged fungal cell membranes is increased.

42 Cell Wall Active Antifungals
Cell membrane • Polyene antibiotics • Azole antifungals DNA/RNA synthesis • Pyrimidine analogues - Flucytosine Cell wall • Echinocandins -Caspofungin acetate (Cancidas) Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

43 The Fungal Cell Wall chitin ergosterol mannoproteins b1,3 b1,6 glucans
synthase Cell membrane The most overt distinction between fungal and mammalian cells is the cell wall of fungi. The uniqueness of this structure makes it a premier target of antifungal drugs. Although the cell wall was initially considered an almost inert cellular structure that protected the cell against osmotic offense, more recent studies have demonstrated that it is a dynamic organelle. The major components of the cell wall are glucan and chitin, which are associated with structural rigidity, and mannoproteins. Biosynthesis of β (1-3) glucans is under the control of a membrane protein complex, the glucan synthase. There are at least two subunits of this enzyme, one a catalytic subunit in the plasma membrane, the other a GTP-binding subunit that activates the catalytic subunit. In the periplasmic space, neosynthesized β 1-3 glucans are modified and associated to the other cell wall polysaccharides (chitin, galactomannan and β 1-3, 1-4 glucan) to produce the rigid three-dimensional network characteristic of the cell wall. Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

44 Echinocandins - Pharmacology
Cyclic lipopeptide antibiotics that interfere with fungal cell wall synthesis by inhibition of ß-(1,3) D-glucan synthase Loss of cell wall glucan results in osmotic fragility Spectrum: Candida species including non-albicans isolates resistant to fluconazole Aspergillus spp. but not activity against other moulds (Fusarium, Zygomycosis) No coverage of Cryptococcus neoformans OH H HO NH O 2 N 3 C CH The echinocandins are a recently-developed class of antifungal agents that interfere with fungal cell wall synthesis through the inhibition of glucan synthesis. The lack of glucan synthesis enzymes in mammalian tissue makes this an attractive target for antifungal activity. The mode of action of the echinocandins means they possess an unusual extended spectrum of activity. They are not active at all against Cryptococcus neoformans, since this pathogen has little or no β(1,3)-D-glucan synthase enzyme. On the other hand, they are very active against Pneumocystis carinii. (unlike other antifungal agents) because the wall of the ‘cyst’ form of this fungus contains β(1,3)-D-glucan synthase. They have a fungicidal action. There are currently three such agents at present, 1) Caspofungin 2) Micafungin 3) Anidulafungin Cilofungin, the first member of the group, reached clinical trials but was abandoned because of side effects associated with the carrier used for the parenteral formulation. A major breakthrough in antifungal therapy occurred in January 2001 with FDA fast track approval for the marketing of caspofungin (Cancidas ®), The unique action of this particular class of drug is very useful for 2 reasons: The echinocandins are active against Candida spp. isolates that are resistant to the azoles and amphotericin B. 2) Since their activity is specific to fungal cell walls, it bodes well for minimal toxicity.

45 Echinocandins - spectrum
Highly active Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei Candida kefyr Pneumocystis carinii Low MIC ,with fungicidal activity and good in-vivo activity. Very active Candida parapsilosis Candida gulliermondii Aspergillus fumigatus Aspergillus flavus Aspergillus terreus Candida lusitaniae Low MIC, but without fungicidal activity in most instances. Some activity Coccidioides immitis Blastomyces dermatididis Scedosporium species Paecilomyces variotii Histoplasma capsulatum Detectable activity, which might have therapeutic potential for man (in some cases in combination with other drugs). Echinocandins are highly active against a number of Candida species, with Candida parapsilosis and Candida gulliermondii having a higher MIC. In vitro killing of these species is very rapid. No activity was seen vs Zygomycetes, Cryptococcus neoformans, Fusarium spp and Trichosporon sp.

46 Echinocandins act at the apical tips of Aspergillus hyphae
Caspofungin is the drug of choice for invasive aspergillosis which is unresponsive to other antifungal drugs. High-magnification photomicrographs of caspofungin treated, DiBAC-stained A. fumigatus from a study by Bowman et al 2002. Previous to this study, it was known that caspofungin caused cell death in yeasts and dimorphic fungi such as Candida albicans, but its effects on Aspergillus fumigatus remained unclear. Bowden et al used the fluorescent dyes CFDA and DiBAC, which stain live and dead cells, respectively, to further characterise the anti-fungal activity of caspofungin. They observed a differential effect of the drug as a function of cell position. 88% of apical cells and 61% of sub-apical branching cells failed to stain with the viable dye CFDA, but only 24% of subapical cells were unstained. Complementary results were seen with DiBAC staining. The dye staining patterns illustrate that the cells at the active centres for new cell wall synthesis within the growing A. fumigatus hyphae are more susceptible to lysis after caspofungin treatment, compared to subapical cells with mature cell walls. This antifungal activity occurring at actively growing tips and branching points of Aspergillus hyphae, leads to formation of flattening and swelling tips. DiBAC Bowman et al. Antimicrob Agent Chemother 2002;46:

47 Echinocandins-Spectrum vs. Moulds
Staining with antisera to glucan synthase subunit (Fks1p) Active against Aspergillus species Glucan synthase localized in apical tips Activity against other yeast and moulds is less well described or variable Mycelial forms of endemic mycoses? Echinocandins are only active against fungal species which express the genes for the glucan synthase complex. Beauvais et al investigated this enzymatic complex in Aspergillus fumigatus. The genes encoding the putative catalytic subunit FKs1p and four Rho proteins of A. fumigatus were cloned and sequenced. When aniline blue, a fluorochrome specific for β(1–3) glucans, was added to growing germ tubes, the apex of the germ tube was the point most intensively labeled by the aniline blue, indicating that the newly synthesized β(1–3) glucan was produced at the apex of the germ tube (Fig. C). The apex also was positively labeled with the anti-FKs1p antiserum. This result showed that Af Fks1p was localized at the apical growing region of the mycelium (Fig. A). Aniline blue staining of β (1-3) glucans –stains only at apex Beauvais et al. J. Bacteriol 2001;183:

48 Caspofungin - Pharmacokinetics
Absorption < 2% Distribution (Vd) 9.67 L Protein binding 97% albumin Major metabolic pathway Peptide hydrolysis, slow N-acetylation t 1/2 ß 9-11 hours CNS penetration Dosage adjustment Probably poor Moderate-severe hepatic dysfunction Drug-Drug interactions Significant interactions CSA? FK-506, mycophenolate? Inducers of 3A4? Caspofungin is a semisynthetic derivative of pneumocandin Bo, a lipopeptide fermentation product derived from the fungus Glarea lozoyenesis and no oral echinocandin derivatives are presently available. The echinocandins currently in development have poor oral bioavailability, and therefore require parenteral administration. Although several intravenous preparations are in various stages of development, caspofungin is the only currently approved agent (it is formulated as the acetate for IV infusion). The drug is widely distributed, the highest concentrations being found in the liver. It is thought to be metabolised by the liver and less than 5% of a dose is excreted unchanged in the urine. No dosage adjustment is recommended in patients with renal impairment; however it is recommended for patients with moderate hepatic impairment. Co-administration with cyclosporin has resulted in transaminase elevations of 2/3 times the upper limit of normal, which resolves when both drugs are discontinued. In addition, caspofungin serum concentrations were increased, due to reduced clearance of the drug but there was no effect on cyclosporin pharmacokinetics. This is probably not clinically meaningful. No other significant interactions have been reported. However, caspofungin may reduce tacrolimus (Fk-506) concentrations and therefore immunosuppression efficacy. Hence this combination should be monitored.

49 Caspofungin acetate IV only Indication: Dosage and administration
Invasive candidiasis Invasive aspergillosis refractory to other therapies Dosage and administration 70 mg day 1, followed by 50 mg daily Increase to 70 mg per day in non-responders Decrease to 35 mg per day in moderate-severe hepatic dysfunction (Child-Pugh 7-9) 70mg loading dose + 50mg daily :maintains the mean blood level above 1mg/l throughout treatment. It should be administered by slow infusion over approximately one hour. The duration of therapy depends on the severity of the infection, immune status of the host, and clinical response. Caspofungin is indicated as salvage therapy in cases with invasive aspergillosis who have been refractory or intolerant to amphotericin B, lipid amphotericin B formulations, and/or itraconazole. This is its primary use. Caspofungin has been shown active in invasive candidiasis: In a randomized comparative study, caspofungin (70 mg loading dose then 50 mg/d in adults) was equivalent to but better tolerated than amphotericin B deoxycholate ( mg/kg/d) for invasive candidiasis. Antiviral Drug Products Advisory Committee, January 10,

50 Caspofungin - Adverse effects
Most common AEs are infusion related: Intravenous site irritation (15-20%) Mild to moderate infusion-related AE including fever, headache, flushing, erythema, rash (5-20%) Symptoms consistent with histamine release (2%) Most AEs were mild and did not require treatment discontinuation Most common laboratory AE Asymptomatic elevation of serum transaminases (10-15%) Clinical experience to date suggests that these drugs are extremely well-tolerated Caspofungin administration is associated with possible histamine-mediated symptoms including reports of rash, facial swelling, pruritus, and warmth sensations. These side effects are minimal. Antiviral Drug Products Advisory Committee, January 10,

51 AWP Cost/day for 70kg Patient
Drug Dosage AWP Cost/day for 70kg Patient Polyenes Amphotericin B deoxycholate Lipo-AMB (AmBisome) ABLC (Abelcet) Amphocil 1 mg/kg/day IV 3 mg/kg/day IV 5 mg/kg/day IV £7 £554 £246 £380 Triazoles Fluconazole Itraconazole Voriconazole 400/800 mg IV 400 mg IV 4 mg/kg IV £56/£112 £72 £80 Echinocandins Caspofungin 50 mg IV x 1 day, £334 All drugs have two costs. In addition to their acquisition cost, cost of monitoring and treatment of side effects must also be considered. These secondary costs are especially important with antifungal agents. Invasive fungal infections are often difficult to diagnose, resistant to treatment, and associated with high rates of morbidity and mortality. It is not surprising, then, that invasive fungal infections are also one of the most expensive complications that can be encountered in hospitalized patients. Interest in the pharmacoeconomics of antifungal therapy has grown, however, with the introduction of several lipid formulations of amphotericin B (LFAB). The LFAB were a major advance over conventional amphotericin B deoxycholate (AmbBd), as these formulations appeared to have equivalent efficacy to AmBd, but with reduced nephrotoxicity. If it were not for the 10 to 50-fold higher acquisition cost of LFAB, their first-line use would be widely adopted. Thus, the arrival of these agents onto the market (and more recently the echinocandins) has forced institutions to more closely examine secondary costs associated with antifungal therapy e.g. the management of nephrotoxicity with amphotericin B. An important goal in determining the cost effectiveness of antifungal therapy is finding a balance between primary (acquisition) and secondary costs. (Medical Letter 2002;44:63-65; Lancet 2003;362: )

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