Antifungal agents

CHAPTER 92


Antifungal agents


The antifungal agents fall into two major groups: drugs for systemic mycoses (ie, systemic fungal infections) and drugs for superficial mycoses. A few drugs are used for both. Systemic infections occur much less frequently than superficial infections, but are much more dangerous. Accordingly, therapy of systemic mycoses is our main focus.




Drugs for systemic mycoses


Systemic mycoses can be subdivided into two categories: opportunistic infections and nonopportunistic infections. The opportunistic mycoses—candidiasis, aspergillosis, cryptococcosis, and mucormycosis—are seen primarily in debilitated or immunocompromised hosts. In contrast, nonopportunistic infections can occur in any host. These latter mycoses, which are relatively uncommon, include sporotrichosis, blastomycosis, histoplasmosis, and coccidioidomycosis. Treating systemic mycoses can be difficult: These infections often resist treatment and hence may require prolonged therapy with drugs that frequently prove toxic. Drugs of choice for systemic mycoses are summarized in Table 92–1.



The systemic antifungal drugs fall into four classes: polyene antibiotics, azoles, echinocandins, and pyrimidine analogs. Class members and mechanisms of action are summarized in Table 92–2.




Amphotericin B, a polyene antibiotic


Amphotericin B [Abelcet, Amphotec, AmBisome, Fungizoneimage] belongs to a drug class known as polyene antibiotics, so named because their structures contain a series of conjugated double bonds. Nystatin, another antifungal drug, is in the same family.


Amphotericin B—an important but dangerous drug—is active against a broad spectrum of pathogenic fungi and is a drug of choice for most systemic mycoses (see Table 92–1). Unfortunately, amphotericin B is highly toxic: To varying degrees, infusion reactions and renal damage occur in all patients. Because of its potential for harm, amphotericin B should be employed only against infections that are progressive and potentially fatal.


Amphotericin B is available in four formulations: a conventional formulation (amphotericin B deoxycholate) and three lipid-based formulations. The lipid-based formulations are as effective as the conventional formulation and cause less toxicity—but are much more expensive. For treatment of systemic mycoses, all formulations are administered by IV infusion. Infusions are given daily or every other day for several months.



Mechanism of action

Amphotericin B binds to components of the fungal cell membrane, thereby increasing permeability. The resultant leakage of intracellular cations (especially potassium) reduces viability. Depending on the concentration of amphotericin B and the susceptibility of the fungus, the drug may be fungistatic or fungicidal.


The component of the fungal membrane to which amphotericin B binds is ergosterol, a member of the sterol family of compounds. Hence, for a cell to be susceptible, its cytoplasmic membrane must contain sterols. Since bacterial membranes lack sterols, bacteria are not affected.


Much of the toxicity of amphotericin is attributable to the presence of sterols (principally cholesterol) in mammalian cell membranes. When amphotericin binds with cholesterol in mammalian membranes, the effect is similar to that seen in fungi. However, there is some degree of selectivity: Amphotericin binds more strongly to ergosterol than it does to cholesterol, and hence fungi are hurt more than we are.




Therapeutic uses

Amphotericin B is a drug of choice for most systemic mycoses (see Table 92–1). Before this drug became available, systemic fungal infections usually proved fatal. Treatment is prolonged; 6 to 8 weeks is common. In some cases, treatment may last for 3 or 4 months. In addition to its antifungal applications, amphotericin B is a drug of choice for leishmaniasis (see Chapter 99).



Pharmacokinetics


Absorption and distribution.

Amphotericin is poorly absorbed from the GI tract, and hence oral therapy cannot be used for systemic infection. Rather, amphotericin must be administered IV. When the drug leaves the vascular system, it undergoes extensive binding to sterol-containing membranes of tissues. Levels about half those in plasma are achieved in aqueous humor and in peritoneal, pleural, and joint fluids. Amphotericin B does not readily penetrate to the cerebrospinal fluid (CSF).






Adverse effects

Amphotericin can cause a variety of serious adverse effects. Patients should be under close supervision, preferably in a hospital.



Infusion reactions.

Intravenous amphotericin frequently produces fever, chills, rigors, nausea, and headache. These reactions are caused by release of proinflammatory cytokines (tumor necrosis factor, interleukin-1, interleukin-6) from monocytes and macrophages. Symptoms begin 1 to 3 hours after starting the infusion and persist about an hour. Mild reactions can be reduced by pretreatment with diphenhydramine plus acetaminophen. Aspirin can also help, but it may increase kidney damage (see below). Intravenous meperidine or dantrolene can be given if rigors occur. If other measures fail, hydrocortisone (a glucocorticoid) can be used to decrease fever and chills. However, since glucocorticoids can reduce the patient’s ability to fight infection, routine use of hydrocortisone should be avoided. Infusion reactions are less intense with lipid-based amphotericin formulations than with the conventional formulation.


Amphotericin infusion produces a high incidence of phlebitis. This can be minimized by changing peripheral venous sites often, administering amphotericin through a large central vein, and pretreatment with heparin.



Nephrotoxicity.

Amphotericin is toxic to cells of the kidney. Renal impairment occurs in practically all patients. The extent of kidney damage is related to the total dose administered over the full course of treatment. In most cases, renal function normalizes after amphotericin use stops. However, if the total dose exceeds 4 gm, residual impairment is likely. Kidney damage can be minimized by infusing 1 L of saline on the days amphotericin is given. Other nephrotoxic drugs (eg, aminoglycosides, cyclosporine, nonsteroidal anti-inflammatory drugs [NSAIDs]) should be avoided. To evaluate renal injury, tests of kidney function should be performed every 3 to 4 days, and intake and output should be monitored. If plasma creatinine content rises above 3.5 mg/dL, amphotericin dosage should be reduced. As noted, the degree of renal damage is less with lipid-based amphotericin than with the conventional formulation.





Drug interactions



Flucytosine.

Amphotericin potentiates the antifungal actions of flucytosine, apparently by enhancing flucytosine entry into fungi. Thanks to this interaction, combining flucytosine with low-dose amphotericin can produce antifungal effects equivalent to those of high-dose amphotericin alone. By allowing a reduction in amphotericin dosage, the combination can reduce the risk of amphotericin-induced toxicity.







Preparations, dosage, and administration





Intravenous dosage and administration. 



Fungal infections.


Dosage is individualized and based on disease severity and the patient’s ability to tolerate treatment. Optimal dosage has not been established. A small test dose (1 mg) is often infused to assess patient reaction. After this, therapy is initiated with a dosage of 0.25 mg/kg/day. Maintenance dosages range from 1.5 to 6 mg/kg/day, depending on the severity of the infection and the form of amphotericin used. Dosage should be reduced in patients with renal impairment. The infusion solution should be checked periodically for a precipitate and, if one is seen, the infusion should be stopped immediately. Because the treatment period is prolonged, the administration site should be rotated—so as to reduce the risk of phlebitis and help ensure continued availability of a suitable vein.





Azoles


Like amphotericin B, the azoles are broad-spectrum antifungal drugs. As a result, azoles represent an alternative to amphotericin B for most systemic fungal infections (see Table 92–1). In contrast to amphotericin, which is highly toxic and must be given IV, the azoles have lower toxicity and can be given by mouth. However, azoles do have one disadvantage: they inhibit hepatic cytochrome P450 drug-metabolizing enzymes, and can thereby increase the levels of many other drugs. Of the 14 azoles in current use, only 5—itraconazole, ketoconazole, fluconazole, voriconazole, and posaconazole—are indicated for systemic mycoses. Azoles used for superficial mycoses are discussed separately below.



Itraconazole

Itraconazole [Sporanox] is an alternative to amphotericin B for several systemic mycoses (see Table 92–1), and will serve as our prototype for the azole family. The drug is safer than amphotericin B and has the added advantage of oral dosing. Principal adverse effects are cardiosuppression and liver injury. Like other azoles, itraconazole can inhibit drug-metabolizing enzymes, and can thereby raise levels of other drugs.




Therapeutic use.

Itraconazole is active against a broad spectrum of fungal pathogens. At this time, it is a drug of choice for blastomycosis, histoplasmosis, paracoccidioidomycosis, and sporotrichosis, and an alternative to amphotericin B for aspergillosis, candidiasis, and coccidioidomycosis. Itraconazole may also be used for superficial mycoses.






Adverse effects.

Itraconazole is well tolerated in usual doses. Gastrointestinal reactions (nausea, vomiting, diarrhea) are most common, occurring in about 10% of patients. Other common reactions include rash (8.6%), headache (3.8%), abdominal pain (3.3%), and edema (3.5%). In addition to these relatively benign effects, itraconazole may cause two potentially serious effects: cardiac suppression and liver injury.





Drug interactions. 


Inhibition of hepatic drug-metabolizing enzymes.


Itraconazole inhibits CYP3A4 (the 3A4 isozyme of cytochrome P450) and can thereby increase levels of many other drugs (Table 92–3). The most important are cisapride, pimozide, dofetilide, and quinidine. Why? Because, when present at high levels, these drugs can cause potentially fatal ventricular dysrhythmias. Accordingly, concurrent use with itraconazole is contraindicated. Other drugs of concern include cyclosporine, digoxin, warfarin, and sulfonylurea-type oral hypoglycemics. In patients taking cyclosporine or digoxin, levels of these drugs should be monitored; in patients taking warfarin, prothrombin time should be monitored; and in patients taking sulfonylureas, levels of blood glucose should be monitored.




Drugs that raise gastric pH.


Drugs that decrease gastric acidity—antacids, histamine2 (H2) antagonists, and proton pump inhibitors—can greatly reduce absorption of oral itraconazole. Accordingly, these agents should be administered at least 1 hour before itraconazole or 2 hours after. (Since proton pump inhibitors have a prolonged duration of action, patients using these drugs may have insufficient stomach acid for itraconazole absorption, regardless of when the proton pump inhibitor is given.)








Fluconazole









Voriconazole



Actions and uses.


Voriconazole [Vfend], a member of the azole family, is an important drug for treating life-threatening fungal infections. Like other azoles, voriconazole inhibits cytochrome P450–dependent enzymes, and thereby suppresses synthesis of ergosterol, a critical component of the fungal cytoplasmic membrane. As a result, voriconazole is active against a broad spectrum of fungal pathogens, including Aspergillus species, Candida species, Scedosporium species, Fusarium species, Histoplasma capsulatum, Blastomyces dermatitidis, and Cryptococcus neoformans. At this time, voriconazole has four approved indications: (1) candidemia, (2) invasive aspergillosis, (3) esophageal candidiasis, and (4) serious infections caused by Scedosporium apiospermum or Fusarium species in patients unresponsive to or intolerant of other drugs.


According to guidelines from the Infectious Disease Society of America, voriconazole has replaced amphotericin B as the drug of choice for invasive aspergillosis. Voriconazole is just as effective as amphotericin B and poses a much lower risk of kidney damage. However, voriconazole does have its own set of adverse effects, including hepatotoxicity, visual disturbances, hypersensitivity reactions, hallucinations, and fetal injury. In addition, like other azoles, voriconazole can interact with many drugs.




Adverse effects.


The most common adverse effects are visual disturbances, fever, rash, nausea, vomiting, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorders. During clinical trials, the effects that most often led to discontinuing treatment were liver damage, visual disturbances, and rash.







Drug interactions.


Voriconazole can interact with many other drugs. Several mechanisms are involved. Voriconazole is both a substrate for and inhibitor of hepatic cytochrome P450 enzymes. As a result, drugs that inhibit P450 can raise voriconazole levels, and drugs that induce P450 can lower voriconazole levels. On the other hand, because voriconazole itself can inhibit P450, voriconazole can raise levels of other drugs. Therefore




Preparations, dosage, and administration.


Voriconazole [Vfend] is available in 200-mg, single-use vials for IV infusion, and in two oral formulations: tablets (50 and 200 mg) and a powder for oral suspension (40 mg/mL after reconstitution). Treatment is initiated with IV voriconazole and later can be switched to oral voriconazole as appropriate.


Intravenous therapy consists of two loading doses (6 mg/kg each given 12 hours apart) followed by maintenance doses of 4 mg/kg every 12 hours. All IV doses should be infused slowly, over 1 to 2 hours (maximum rate 3 mg/kg/hr). If the response is inadequate, maintenance doses can be increased by 50%. Patients with mild to moderate hepatic cirrhosis should receive the standard two loading doses, but maintenance doses should be halved. (There are no data on dosing in patients with severe cirrhosis.) Patients with significant renal impairment (creatinine clearance less than 50 mL/min), should use oral voriconazole, not IV voriconazole. Why? Because, in the absence of adequate kidney function, the solubilizing agent (not voriconazole itself) in the IV formulation can accumulate to dangerous levels.


After receiving IV loading doses, patients who can tolerate oral therapy may be switched to voriconazole tablets. The usual dosage is 200 mg every 12 hours for patients over 40 kg and 100 mg every 12 hours for patients under 40 kg. If the response is inadequate, doses can be increased by 50%. Oral dosing should be done 1 hour before meals or 1 hour after.



Ketoconazole




Therapeutic use.


Ketoconazole is an alternative to amphotericin B for systemic mycoses. The drug is much less toxic than amphotericin and only somewhat less effective. Specific indications are listed in Table 92–1. Responses to ketoconazole are slow. Accordingly, the drug is less useful for severe, acute infections than for long-term suppression of chronic infections. Ketoconazole is also a valuable drug for superficial mycoses.

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Jul 24, 2016 | Posted by in NURSING | Comments Off on Antifungal agents

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