Anti-fungal Therapy

Janet Wong, M.D.

Spectrum of Anti-fungal Agents

Class Topicals Griseofulvin Azoles Ketoconazole Fluconazole Itraconazole Polyenes Nystatin Amphotericin B XXX XXX XXX Superficial XXX XXX XXX XXX Cutaneous Systemic XXX

The topical antifungal agents are only useful for superficial mycoses. Griseofulvin is also useful for superficial mycoses and nothing else. Azoles are really the only antifungal agents which can go across the board and have utility in superficial, cutaneous and systemic mycoses. Among the polyenes, nystatin is useful only in superficial candidiasis, for example, such as thrush. Amphotericin B is typically reserved for more serious cutaneous disease and systemic therapy.

Topical Antifungal Agents

Topical antifungal agents. Naftifine, which is an allylamine derivative, is quite useful in ringworm, provided it is not on the scalp, in tinea versicolor, and in candidiasis. Clotrimazole is a

Agent Naftifine Clotrimazole Nystatin

Ringworm XXX XXX -

T. versicolor XXX XXX -

Candidiasis XXX XXX

representative of the azole category, and it also is useful for all three types of superficial mycoses. Nystatin, on the other hand, is a polyene and of no utility in ringworm or tinea versicolor and must be reserved for superficial candidiasis such as thrush.

Topical Anti-fungal Agents

All of these topical agents are contraindicated in the more serious

CLASS Naftifine - allylamine derivative Clotrimazole - imidazole Nystatin - polyene METABOLISM Naftifine renal Clotrimazole - hepatic Nystatin - fecal

cutaneous mycoses. Now, here they are yet again. This is naftifine. This is an allylamine derivative. The other allylamine that you may encounter is terbinafine and these of course, as allylamine derivatives, inhibit fungal metabolism very high up in the pathway of fungal cell-wall construction. They inhibit really the first step in the conversion of squalene to lanosterol. The imidazoles and the triazoles inhibit at a secondary step in the building of the fungal cell wall. The imidazoles and the triazoles inhibit 14 alpha demethylase, which mediates the conversion of lanosterol to ergosterol. The polyenes, nystatin (a topical antifungal agent) and amphotericin as (systemic antifungal agent), inhibit the actual synthesis of ergosterol, the major component of the fungal cell membrane.

Topical Anti-fungal Agents

Uses for the topical antifungal agents. These are useful really for

Uses: Superficial dermatophyte infections and candidiasis Creams, gels, solutions are used for inflamed intertriginous areas Powder is used for milder lesions in the identical areas Ointment is often times too occlusive Lesions on the head usually require oral therapy

superficial dermatophyte infections as well as for superficial candidiasis. Such things as Candida diaper rash, mild intertrigo. The creams, the gels and solutions are very helpful in inflamed intertriginous areas such as the toe webs, the groin and the scrotum. Powder formulations are useful for milder lesions in the identical areas. If its wet, dry it, if its dry, wet it - so that if this is a wet diaper area then a powder may be very helpful. The powders, like clotrimazole powders, the imidazole powders, are extremely useful in stoma infections. So if you have for example a cancer patient with a colectomy or a child with short-gut syndrome who has a stoma and then has a bag. Those are typically very, very wet areas. Ointments and creams really dont get the job done. The powders are very useful in those wet areas. Ointments in particular are typically much too occlusive and the dermatophytes and particularly Candida love that sort of moist area. So usually I dont use the ointment formulations of these topical antifungals. The major exception to the use of topical antifungal agents are dermatophyte lesions of the head. Ringworm of the scalp, tinea capitus and kerion will require oral therapy, usually with griseofulvin.

Griseofulvin
Griseofulvin is a product of Penicillium, so it is an antifungal

CLASS: product of Penicillium ACTION: inhibition of fungal nucleic acid synthesis METABOLISM: hepatic USE: superficial fungal infections, such as tinea capitis and unguium, especially with extensive involvement of skin, head, or nails

agent made by a mold and it inhibits nucleic acid synthesis at the elongating tip of the hypha, as we would see in dermatophyte infections. It is hepatically metabolized and it is useful particularly in superficial fungal infections such as tinea capitus and unguium (tinea infections of the fingernails). It is not, however, useful for chronic candidal infection of the fingernails. But if there is extensive involvement of skin, head or nails, griseofulvin, given orally, is the drug of choice. It will be inefficacious in mucocutaneous candidiasis. So griseofulvin is active against the superficial dermatophytes, but not against Candida. It is contraindicated in porphyria and should not be used orally in pregnancy. Its side effects include hepatotoxicity in porphyria, allergic reactions such as pruritic rash, prolongation of warfarin anticoagulants and a very important one that we certainly can see in childhood is neutropenia. So when I am treating a child who has a kerion, and I may well have to treat that child for six to 10 weeks on daily griseofulvin. Im going to monitor that white blood cell count and differential on a weekly basis because the drug can induce a neutropenia.

Griseofulvin
Absorption is augmented if one uses the Ultramicrosize. The drug

Not effective in mucocutaneous candidiasis CONTRAINDICATIONS: porphyria, pregnancy SIDE EFFECTS: hepatotoxicity in porphyria, allergic reactions, prolongation of warfarin anticoagulants Neutropenia - Must monitor WBC/DIFF DOSE: Ultramicrosize: 15 mg/kg/day q 24 hrs

comes in two forms; a Microsize and an Ultramicrosize. Use the Ultramicrosize form, and the dose is approximately 15 mg/kg per day given once a day as a single dose. Griseofulvin is an oral agent. Typically for dermatophyte infections of the head or fingernails.

Imidazoles/triazoles
Imidazoles and the triazoles. The imidazoles are drugs like

CLASS:

Imidazoles/triazoles block the conversion of lanosterol to ergosterol and increasing membrane permeability

clotrimazole, miconazole, ketoconazole. The triazoles are fluconazole and itraconazole. Now these antifungals agents inhibit 14-alpha-demethylase, blocking the conversion of lanosterol to ergosterol and thereby increasing membrane permeability. So all the antifungal agents that we are talking about have activity on the fungal cell membrane. Levels of antifungal agents in the blood stream or even in the lesions have not been accurately correlated with clinical outcome. In part thats because many of the patients who acquire fungal infections have other compromises in host defenses. So the antifungal agent itself may or may not be sufficient, depending upon the whole in-host defense, to cure the patient. So clinical course and level of fungal agent have really not been appropriately correlated for this category of antimicrobials. The examples of the imidazoles and the triazoles are ketoconazole, fluconazole, and itraconazole. The metabolism is hepatic metabolism for ketoconazole and itraconazole, and renal metabolism for fluconazole.

EXAMPLES: (1) Ketoconazole (2) Fluconazole (3) Itraconazole METABOLISM: Ketoconazole and itraconazole: Hepatic Fluconazole: Renal

Uses of Azoles
General uses of azoles. They can be used predominately for oral

USES: Oral therapy Severe mucocutaneous candidiasis Deep cutaneous infections Less severe systemic fungal infections, especially in hosts without major immunocompromise

therapy. They are especially useful in severe mucocutaneous candidiasis, the hereditary syndromes where one sees abundant candidal colonization at the mouth, on the skin, on the fingernails, and, in females, in the vagina. This is a T-cell defect, although it is thought to be a T-cell defect; the precise genetic deficit has not been worked out. The other azoles can be useful for deep cutaneous infections such as sporotrichosis and for less severe systemic fungal infections, especially in hosts without major immunocompromise. The hosts degree of immunocompromise becomes a very important factor when one is deciding whether you are going to use an azole and go with oral therapy, or whether one is going to use amphotericin B, the first line agent for severe fungal infections. The azoles, with the exception that ketoconazole, have typically failed pretty badly in the treatment of systemic mycoses, especially in immunocompromised hosts. So if the host any degree of immunocompromise, one is going to be unlikely to be treating that patient with oral ketoconazole. On the other hand, fluconazole and itraconazole have been used with good success in systemic mycoses, but predominantly in patients who do not have severe immune defects, such as prolonged neutropenia or pancytopenia due to bone marrow transplants.

Uses of Azoles
Ketoconazole is a useful agent for superficial mycoses and

Superficial Ketoconazole Fluconazole Itraconazole XXX XXX XXX

Cutaneous XXX XXX XXX

Systemic XXX XXX

cutaneous mycoses. It fails badly in halting disseminated fungal infections such as aspergillus, candidiasis, histo, blasto in the immunocompromised host (i.e. neutropenic bone marrow transplant patients or HIV infected patients). The other caveat for ketoconazole of course is that the drug does not penetrate the cerebrospinal fluid. Some other limitations of ketoconazole about which we need to be careful, the first is that it is absolutely contraindicated in patients with hepatic failure. The drug is hepatically excreted and therefore will accumulate to toxic levels in patients with hepatic failures. Secondly, the high pH that one would typically get in the stomach of a patient on H2 blockers or patients who have achlorhydria (no HCL in the stomach) will prevent absorption of ketoconazole. So one has to be very careful how one uses the drug, especially in the presence of H2 blockers. One can get hypertension with long term use. Treatment with isoniazid is a relative contraindication because levels of ketoconazole are affected. We are not going to use this drug for fungal meningitis. That is a contraindication because it doesnt penetrate the CNS. Other contraindications would include the use of ketoconazole in patients who are taking certain antihistamines, terfenadine and astemizole. This could lead to a prolongation of the Q-T interval and cardiac arrhythmias if ketoconazole is used with those antihistamines. Also for those of us who deal with immunocompromised hosts, especially those undergoing bone marrow transplants, we know that ketoconazole can markedly elevate levels of cyclosporine, typically leading to neurotoxicity and additive renal toxicity. So the antihistamines, contraindications to the use of ketoconazole and cyclosporine - you simply have to watch your cyclosporine levels very carefully if you have the patient on any of the azoles.

Ketoconazole Weaknesses
Additional side effects: if you are going to use ketoconazole, be

Ketoconazole has failed to halt disseminated fungal infections (aspergillosis, candidiasis, histoplasmosis, blastomycosis) in the immunocompromised host (eg, neutropenia, HIV infection) The drug does not penetrate the CSF

aware that this drug will elevate the hepatic transaminases typically to about three to four times normal. If the patient actually gets beyond that, and we are talking about hepatic transaminases in the 500s or above, most people would stop ketoconazole. Gynecomastia will occur in 20% of males taking oral

ketoconazole. Many would find this a very objectionable side effect. In addition to the gynecomastia, virtually all males will have some suppression of testosterone levels and this may affect libido. It is also important to recognize that one of the major effects of ketoconazole is treatment-limiting neutropenia. Neutropenia has been a recognized side effect of ketoconazole. So if one is going to use ketoconazole, youve got to watch those white cell counts and differentials because neutropenia can supervene.

Fluconazole Usage
Fluconazole is a triazole like imidazole. It is being used exten-

Prophylaxis for candidiasis in bone marrow transplant patients C krusei is resistant de novo to fluconazole Used for Candida esophagitis, peritonitis, vaginitis, but should not be use as primary therapy for aspergillosis in the immunocompromised host Good CSF penetration in cryptococcal meningitis

sively. We know that fluconazole has been used as prophylaxis for candidiasis in bone marrow transplant patients. Systemic infections due to Candida albicans were suppressed with fluconazole prophylaxis in adult bone marrow transplant patients but unfortunately there was an eight-fold increase in systemic infections due to Candida krusei because this particular Candida species is resistant to fluconazole de novo. All Candida krusei are a priori resistant to fluconazole. So although we can use fluconazole as prophylaxis in a bone marrow transplant patient, we have to be very careful. Many places doing bone marrow transplants will do surveillance cultures and see; if Candida krusei is in that particular patients surveillance cultures of the stool, then I am going to be very worried about using fluconazole. It does have additional utility in more defined infections such as Candida esophagitis, Candida peritonitis, Candida vaginitis even Candida cystitis provided there is no evidence of systemic spread from the kidneys. It should not be used as primary therapy for aspergillosis in the immunocompromised host. Now in contrast to ketoconazole, fluconazole has very good CSF penetration and these studies have been done largely in patients with cryptococcal meningitis where fluconazole has proven extremely useful as maintenance therapy, not as initial therapy, but as maintenance therapy in HIV infected patients with cryptococcal meningitis.

Itraconazole Use
Itraconazole is a triazole, and this one is the aspergillus drug.

Greatest utility is for aspergillosis in patients who are unable to tolerate amphotericin B or who are progressing while on amphotericin B Prophylaxis for chronic granulomatous disease Detectable drug has not been found in the CSF, but responses have been seen in chronic coccidioidal meningitis and cryptococcal meningitis in HIV infection. Sustained response typically requires continuous therapy

Although it does have affects against other systemic fungi, its greatest utility is in aspergillosis for patients who are unable to tolerate amphotericin B or whose disease is progressing on polyene (amphotericin B) therapy. With any antifungal agent in aspergillosis, especially pulmonary aspergillosis, in the immunocompromised host is 50-80% fatal if the neutrophils dont return. In many cases if those neutrophils arent going to come back, you cant put your money on an antifungal agent; whether its itraconazole or amphotericin B or even liposomal amphotericin B in order to cure that patient. So curing aspergillus requires normal neutrophils. Itraconazole has been useful, however, for prophylaxis for chronic granulomatous disease. These patients can get systemic fungi. Typically aspergillus in unusual locations, such as the vertebrae; and itraconazole does indeed seem to help avoid these fungal infections. With itraconazole, in contrast to fluconazole, has never been found in the CSF but responses have been seen in chronic coccidioidal meningitis and in cryptococcal meningitis in HIV infections. But a sustained response typically requires continuous therapy. So as we will see when we start reviewing first line antifungal agents, most people would treat coccidioidal meningitis or cryptococcal meningitis initially with amphotericin B and then when they are moving to a maintenance phase are going to have long-term disease such as HIV infected patients, switch to oral itraconazole.

Limitations of Ketoconazole
Side effects of the azoles. The advantage of fluconazole and

Contraindications Hepatic failure H2 blockers or achlorhydria prevent absorption of ketoconazole Hypertension with long-term use Treatment with isoniazid Not indicated for fungal meningitis Side Effects of Ketoconazole Elevated hepatic transaminases Gynecomastia Suppression of testosterone levels Treatment-limiting neutropenia

itraconazole is that their side effects are substantially fewer. In particular GI upset, which can be a major side effect with ketoconazole, is much reduced with oral fluconazole or itraconazole. Ketoconazole can have a decreased cortisol response to ACTH impetus and decreased libido and gynecomastia in 20% of males. None of these related side effects occur with fluconazole or itraconazole. Neutropenia, a ketoconazole side effect, does not occur with fluconazole or itraconazole. With those two agents, although the GI upset is reduced, we will see transient increases in transaminases. With ketoconazole we will typically see increases in transaminases that may continue to rise. So we have to be careful about ketoconazole and elevation of the LFTs. All three of these drugs will increase cyclosporine levels. So if you are using these azoles in a bone marrow transplant patient on cyclosporine, those levels are going to go up; perhaps with toxic side effects.

Side Effects of Imidazoles

The point is that ketoconazole is very difficult to absorb when we

Ketoconazole: GI upset, impotence and decreased libido, decreased cortisol response to ACTH, gynecomastia in 20%, neutropenia Fluconazole: less GI upset, transient increase in transaminases Itraconazole: less GI upset, transient increase in transaminases

are in an achlorhydric situation or when the pH of the stomach is not acid. In terms of tissue penetration we get very good penetration of ketoconazole into the sputum, into the skin, but very poor into the CNS. Metabolism is hepatic. Dilantin, INH and rifampin will all affect ketoconazole levels. The half life of ketoconazole is the shortest among the azoles. Its 6-8 hours and the dose is 5-10 mg/kg given q.12-24 h.

Fluconazole does not have the same difficulties of absorption as does ketoconazole. And in contrast to ketoconazole, fluconazole gives excellent levels weve said into the CNS and into a number of other sites. So this is the drug that penetrates. This is the azole that gets into the CSF. Its metabolism is divided between hepatic and renal. Renal is the predominant site of excretion and fluconazole will inhibit the metabolism of anticoagulants, cyclosporine and digoxin. The half-life is about 18-24 hours, and the dose is thought to be more efficacious if given as an initial loading dose of 10 mg/kg and then 4-6 mg/kg q.12-24 hours. Most people will give a single daily dose of fluconazole after the loading dose has been attained.

Itraconazole. It gives us very good levels in the sputum and the nails, but again poor CNS levels. Here is its metabolism which is largely hepatic and its important to point out here that because of the pH-dependent effects of itraconazole absorption, we like to give itraconazole separately from DDI when we are treating HIV infected patients. In addition, like fluconazole, itraconazole will inhibit the metabolism of anticonvulsants, anticoagulants, digoxin and cyclosporine. It has the longest half-life; at least 24 hours and its dose is 5-10 mg/kg typically given as a single daily dose.

Amphotericin B
Amphotericin B is a polyene. Again produced by Streptomyces

CLASS: Polyene produced by Streptomyces nodosus; binds ergosterol in the fungal cell wall METABOLISM: Predominantly renal, but also biliary FORMULATIONS: 1. IV complexed with desoxycholate for solubility 2. liposomal-drug intercalated into the phospholipid bilayer, rather than into the aqueous phase Indications for Amphotericin B: First-line therapy for disseminated fungal infections in normal and immunocompromised hosts

nodosus, and it binds ergosterol. Renal excretion is the predominant mechanism of excretion but you will also get some amphotericin B into the biliary tract and about 40% of excretion of amphotericin B is not known how it is excreted. So this drug, although it has tremendous utility, there are still a lot of questions that havent been answered about amphotericin. We now have two formulations. The standard intravenous formulation in which the drug is complexed with the deoxycholate for solubility. Then the new liposomal formulations in which the drug has been intercalated into the phospholipid bilayer rather than into the aqueous phase. This is thought not only to increase uptake by fatty tissues but also to decrease side effects, particularly the nephrotoxicity. Amphotericin B is first-line therapy for disseminated fungal infections in normal and immunocompromised hosts. And it is the gold-standard for antifungal therapy.

Amphotericin B Warnings
Aspergillosis in the immunocompromised host is going to be a

Ineffective against Aspergillosis in the immunocompromised host (50-8O% mortality without neutrophils) Primary Resistance Pseudallescheria boydii Trichosporon beigelii Fusaria Non-albicans (2-3%)

serious and often fatal infection if the neutrophils dont return. So that even though one will use amphotericin B at what is considered the standard dose for aspergillosis, which is 1.5 mg/kg per day, you are still going to lose 50-80% of the time if those neutrophils dont return. There are, unfortunately, some additional fungi which have primary a priori resistance to amphotericin B;

Pseudallescheria boydii, Trichosporon beigelii, and Fusarium species. So when we see one of these fungi in an immunocompromised host we dont have much to go on. Nonalbicans Candida species, 2-3% of these will also be resistant to amphotericin B. Resistance among Candida albicans is extremely low. So thats why its important to speciate the Candida that one may grow from an immunocompromised host because we want to make sure that if its Candida krusei we are not going to try to treat with fluconazole. If its a non-albicans species we do have a bit of a worry about amphotericin B resistance as well.

Side effects of amphotericin B. Fever and chills, nausea and vomiting, hypotension, nephrotoxicity, cardiac arrhythmia, hepatotoxicity, anemia, thrombocytopenia, phlebitis, renal losses of potassium and magnesium, anaphylactoid reactions and convulsions. In children we may see some fever and chills; we may see some nausea and vomiting, a little bit of anemia and of course renal losses and nephrotoxicity, but by and large many of these other side effects such as hypotension, arrhythmias, hepatotoxicity, convulsions, are very rare in childhood. Children tolerate amphotericin B much better than do adults; and neonates, even premature neonates, tolerate amphotericin much better than do children. Many of these side effects can be abated or at least markedly decreased by pre-infusion with Benadryl and hydrocortisone to decrease fever and chills, nausea and vomiting or phlebitis. In patients in whom nausea and vomiting or severe headache is a particularly bad side effect, then the Meperidine (Demerol) can be given intravenously and that also will be very helpful in reducing the side effects. In patients who have more severe side effects such as decreased blood pressure etc., amphotericin B infusions, although typically given as one daily dose, can be divided into three daily doses with equal efficacy, and that can help to ameliorate some of the side effects such as hypotension.

Side Effects of Amphotericin B

The most common side effect of amphotericin B: we are talking

Fever and chills Nausea and vomiting Hypotension Nephrotoxicity Cardiac arrhythmia Hepatotoxicity

Anemia Thrombocytopenia Phlebitis Hypokalemia, hypomagnesemia Anaphylactoid reaction Convulsions

now about the deoxycholate formulation, is nephrotoxicity. Virtually every patient who gets amphotericin B will have an elevation of their BUN and creatinine. And this indeed can progress to cylindruria, casts, potassium and magnesium wasting from tubular disease. However, the nephrotoxicity of amphotericin is typically reversible and this is very important to remember because aggressive treatment of fungal infections in the immunocompromised host typically requires that one give amphotericin B to the point of rising BUN and creatinine.

Nephrotoxicity
Many of the nephrotoxic effects can be prevented by sodium

Occurs in 80% Manifests as rising BUN and creatinine Progresses to cylindruria, casts, potassium wasting Nephrotoxicity can be prevented by sodium loading Typically reversible

loading. A quick infusion of about 100 cc (in a large size child) prior to the amphotericin dose has been shown to be very helpful in preventing the nephrotoxic effects of amphotericin B.

Protocols for Administration

There are at least a couple of protocols for administration. First a

Rapid Initiation 1. Give 1 mg test dose 2. Wait 4 hours 3. Initiate 0.3-0.5 mg/kg/day 4. Wait 24 hours 5. Increase to 0.5-1.0 mg/kg/day

test dose of 1 mg, Many of us have now moved to rapid initiation protocols. Where we give a 1 mg test dose, typically again over approximately four hours. It doesnt need to go in over six. We are giving that test dose to look for severe side effects; such as hypotension or convulsions. Then we are going to wait four hours and then we are going to start a therapeutic dose. The therapeutic dose of amphotericin at the initial level of therapeusis is about 0.3 mg/kg. There are no reasons to stay at 0.3 mg/kg if one is treating systemic fungal infections, but most MICs of most Candida species for example are down about 0.1. So if you are here at about 0.3 mg/kg you are above the MIC of most Candida albicans species. After this first dose at the therapeutic level you then wait 24 hours and then immediately jump to the therapeutic dose. Most people would say that for systemic fungal disease, especially in the immunocompromised host, although the dosage range for adults is roughly 0.5 - 0.7 mg/kg, in young children we have no difficulty going to 1.0 mg/kg. For systemic candidal infections thats where you want to be. About 1 mg/kg for neonate, in toddler and in children. Adults typically use 0.7 or 0.75 mg/kg.

Amphotericin B in Renal Compromise

Decrease dosage: 0.5-1.0 mg/kg/day (1.5 for aspergillosis) Sodium loading When creatinine doubles or exceeds 3.5 gm/dL, reduce dose to 50% of daily dose for 2-5 days Return to standard dose
Amphotericin B in patients with renal compromise. In children 1.0 mg/kg per day. If you are treating aspergillosis, 1.5 mg/kg per day. Sodium loading can help to decrease the incidence of nephrotoxicity in patients whose kidneys are normal, but when the creatinine doubles (if we are talking about a very young child, for example a neonate with a creatinine of 0.4) or when the creatinine in an older child (with a typical creatinine of 0.9) or an adolescent exceeds 3.5 gm/dl, cut back to about 50% of the daily dose for 2 5 days, the creatinine will drift down. Not to a totally normal level but to a midway value and then you can return to your standard dose.

Another issue that we confront frequently is treatment failure with amphotericin B. Often there are real reasons for treatment failure, which are not the fault of the drug. The biggest one is failure to remove the line in systemic candidal infection in patients with Hickman or other intravascular catheters. These plastic sources are a wonderful adhesive site for Candida. Candida surface adhesions find plastic very appetizing. If we dont take out the line we are not going to be able to clear the candidal infection.

Common Reasons for Amphotericin B Treatment Failure

Failure to remove an infected line Failure to recognize an intravascular focus Fungus ball in atrium Infected cardiac graft or patch Lesion requires surgical approach Dosage too low (#0.5 mg/kg/day) Inadequate length of therapy (ie, <7 days for line infection) Resistant organism
The second issue is continued fungemia while on adequate doses of amphotericin B ascribable to failure to recognize an intravascular focus. So the neonate who had a line in place, who has an intravascular fungus ball, or a clot. Sometimes occurring in the atrium or sometimes occurring in the IVC. There may be an infected cardiac graft or patch. So if I have removed the line and Im adequately treating that patient with amphotericin B and fungemia is continuing, Im going to have them echo this patient looking for intravascular foci that require either removal or a surgical approach. The other problems include too low a dose. Less than 0.5 mg/kg per day is much too low. In children we really dont like to drop below 0.75 mg/kg per day. Ideally we would like to be at about 1.00 mg/kg per day for most systemic fungal infections, and 1.5 for aspergillus. Too short a course. For example, less that 7 days for a line infection because of a rising creatinine. And lastly, we have to think of a resistance organism. So when I have continued fungemia in a patient on adequate doses of amphotericin B, I run the list because almost assuredly something in here has been omitted.

Drug Resistance in Candidal Infections

Drug resistance in candidal infections. Theres primary resistance

Primary resistance to amphotericin B (MIC>2.0 ug/mL) Rare: 2-3% Non-albicans species are resistant

to amphotericin B. Thats defined as an MIC greater than 2 /ml. It is rare. It occurs only 2-3 % of Candida, and these are typically non-albicans species. Unfortunately theres both primary and secondary resistance if we are using fluconazole for Candida infections. Primary resistance to fluconazole occurs with those species, non-albicans species, especially Candida krusei, but also with Candida glabrata and Candida tropicalis. Secondary resistance to fluconazole, which is the emergence of a resistant species while the patient is under treatment with fluconazole, is now increasing for Candida albicans and it will occur in HIV-positive patients who are on therapy with the azoles, and it has been reported rarely to occur in patients without previous exposure. So these patients when cultured, for example for thrush, will show a Candida albicans. Its originally sensitive to fluconazole. They will not get any azoles, but over time they will develop secondary resistance to fluconazole and subsequent cultures will show a resistant albicans species. So the problem of Candida resistance to fluconazole is probably just beginning. This drug may not be effective for more than another two to three years.

Primary resistance to fluconazole (MIC>1.2 Fs/mL) C krusei, C glabrata, tropicalis Secondary resistance to fluconazole Increasing for C albicans Can occur in HIV positive patients without previous exposure

Fluconazole vs. Amphotericin B

So, fluconazole is the drug of choice for fungal prophylaxis in the

Fluconazole is the drug of choice for fungal prophylaxis in the neutropenic host Fluconazole is of equal efficacy for treatment of disseminated candidiasis in adults without neutropenia

bone marrow transplant patient who is neutropenic. Fluconazole is of equal efficacy with amphotericin B for treatment of disseminated candidiasis in adults without neutropenia.

First-line Drugs for Fungal Infections

First line drugs for fungal infections. For systemic candidiasis the

Indication Candidiasis (systemic) Histoplasmosis Mild/moderate Severe ICH CNS AIDS: acute AIDS: maintenance Cryptococcosis Meningeal other sites AIDS: acute AIDS: maintenance Coccidiomycosis meningeal other sites AIDS: initial AIDS: maintenance Blastomycosis mild, moderate severe: CNS, GU, ICH Aspergillosis

Drug of Choice Amphotericin B 5FC

Alternate --

drug of choice is still amphotericin B. Weve not talked about the addition of 5 FC. For histoplasmosis of mild to moderate disease mild, say pneumonitis with symptoms of more that three or four weeks - one can use oral itraconazole. But if the host is immunocompromised with CNS disease, amphotericin B is the drug of choice. In acute histoplasmosis and HIV infections,

Itraconazole Amphotericin B Amphotericin B Itraconazole

Amphotericin B --Fluconazole

amphotericin B. Maintenance therapy with itraconazole. In Cryptococcus, in meningeal disease amphotericin B is the drug of choice, but one can use maintenance therapy with fluconazole. Other sites of Cryptococcus and acute disease in HIV-infected patients will require amphotericin B.

Coccidioidomycosis meningeal disease is very serious and it

Amphotericin B 5FC Amphotericin B Amphotericin B Fluconazole

Fluconazole Fluconazole -Amphotericin B

requires amphotericin B, both intravenously and intrathecally. The same is true for other sites of Coccidioidomycosis. Theres really no other drug than amphotericin for Coccidioidomycosis. For blastomycosis, this is the one area where ketoconazole may have some utility, but frankly even if I have mild to moderate disease with blastomycosis I greatly prefer amphotericin B to gain control. For severe CNS disease, genitourinary disease, or the

Amphotericin B (IV, IT) Amphotericin B Amphotericin B (IV, IT) Amphotericin B

-----

immunocompromised host with blastomycosis, there is nothing but amphotericin B.

For aspergillus we are talking amphotericin B, itraconazole as an alternative. The two may be given together in severe cases. Mucormycosis, the choice is amphotericin B. For sporotrichosis, lymphocutaneous disease can actually be treated orally with

Ketoconazole Amphotericin B Amphotericin B (+5FC or rifabutin

Amphotericin B -Itraconazole

itraconazole. Deep seated sporotrichosis will require amphotericin B. Then we have several of these agents, such as Pseudallescheria boydii: resistant to amphotericin B. Miconazole has been efficacious in some cases, but they have also been helped by the return of neutrophils. Malassezia furfur by and large doesnt need treatment when we see it in the neonatal nursery as a consequence

Mucormycosis Sporotrichosis lymphocutaneous deep-seated

Amphotericin B

--

of intralipid infusion. But if one does need to treat it, miconazole is the drug of choice. For Fusarium we actually have no treatment.

Itraconazole Amphotericin B

Potassium iodide Itraconazole

References
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