Patient monitoring and side effects

Response to antifungal therapy may be slow in patients with a prolonged history of infection or severe manifestations. However, gradual improvements in symptoms and reduction in fever are indicators of response to antifungal therapy. For histoplasmosis and coccidioidomycosis, decreasing antigen titers are also indicative of response to antifungal therapy.1,4

Antifungals used for the treatment of endemic mycoses can be associated with clinically-significant drug interactions and toxicities, especially with the prolonged treatment courses that are often required in the management of endemic mycoses. Itraconazole is available as a capsule formulation and as a liquid. The liquid formulation of itraconazole has several advantages over the capsule: it has a better oral bioavailability and does not require the low gastric pH that is required for dissolution and absorption of the capsule. However, the oral solution is somewhat dilute, has an unpalatable aftertaste (an issue when taking months of therapy), and has a much higher rate of GI side effects. Therefore, the capsule formulation is often preferred provided patients are not on acid-suppression therapy (i.e., proton pump inhibitors, histamine antagonists, or antacids).

Drug interactions are an important concern in patients taking long-term azole therapy. Itraconazole is a substrate and inhibitor of the cytochrome P450 (CYP)3A4 enzyme and the drug transporter, P-glycoprotein. Coadministration of itraconazole with inducers of this enzyme system (e.g., rifampin, phenytoin, and phenobarbital) can dramatically increase the clearance of itraconazole (and to a lesser extent fluconazole), resulting in ineffective plasma and tissue concentrations of the drug.8-11 In general, coadministration of itraconazole with these inducers should be avoided. In some cases, plasma trough levels can be drawn once the patient reaches steady state (greater than 7 days of therapy) to ensure adequate drug absorption. Concentrations less than 0.25 mcg/mL (0.25 mg/L) should be considered evidence of insufficient itraconazole absorption11 as trough concentrations should ideally approach 1 mcg/mL (1 mg/L) by the time the patient is in steady state.12

As a potent inhibitor of CYP450 enzymes including CYP3A4, itraconazole can dramatically decrease the clearance of many important medications metabolized through this enzyme, leading to potentially dangerous drug interactions. Patients receiving anticoagulation therapy with warfarin, immunosuppressive therapy with cyc-losporine or tacrolimus, those taking midazolam, HMG-CoA reductase inhibitors (statins), rifabutin, chemotherapy agents (e.g., vinca alkaloids, busulfan, and cyclophosphamide), and digoxin will require dosage adjustment and careful monitoring

while receiving itraconazole therapy. Although fluconazole is not as potent an inhibitor of CYP3A4 as itraconazole, drug interactions can still be severe, especially at

higher fluconazole dosages (i.e., 800 mg/day).

All azole antifungals carry the potential for rash, photosensitivity, and hepatotox-icity. In general, hepatotoxicity is mild and reversible, presenting as asymptomatic increases in liver transaminases or less commonly, an increase in total bilirubin. Fulminant hepatic failure has been reported with itraconazole. Therefore, serial monitoring of liver function is recommended in all patients on long-term azole therapy. Long-term therapy with itraconazole has also been associated with reversible adrenal suppression and cardiomyopathy associated with the drug's negative inotropic effects. These adverse effects can be prevented or managed with close monitoring and follow-up of patients on long-term therapy.

Amphotericin B is the mainstay of treatment of patients with severe endemic fungal infections. The conventional deoxycholate formulation of the drug can be associated with substantial infusion-related adverse effects (e.g., chills, fever, nausea, rigors, and in rare cases hypotension, flushing, respiratory difficulty, and arrhythmias). Premedication with low doses of hydrocortisone, acetaminophen, nonsteroidal anti-inflammatory agents, and meperidine is common to reduce acute infusion-related reactions. Venous irritation associated with the drug can also lead to thrombophlebitis; hence, central venous catheters are the preferred route of administration in patients receiving more than a week of therapy.

The most severe adverse effect associated with amphotericin B therapy is nephro-toxicity, which occurs through the renal vascular effects of the drug (constriction of the afferent arterioles in the kidney tubule), and direct toxicity to the kidney tubular membrane. Generally, nephrotoxicity with amphotericin B is reversible provided the drug is stopped. However, treatment interruptions can be problematic in patients with severe infections. Precipitous decreases in glomerular filtration occasionally are seen with the initiation of amphotericin B therapy, especially in patients with marked dehydration. Infusion of normal saline before and after amphotericin B, a practice known as "sodium loading" can blunt precipitous decreases in renal perfusion pressure and slow that rate of decline in the glomerular filtration rate. Tubular toxicity can be delayed by avoiding the use of other drugs with known tubular toxicity such as aminoglycosides, cyclosporine, cisplatin, or foscarnet. Generally, tubular toxicity manifests in patients with severe wasting of potassium and magnesium in the urine. Therefore, patient electrolytes must be carefully monitored and potassium and magnesium supplementation is often required. Hypokalemia and hypomagnesemia frequently precede decreases in glomerular filtration (increased serum creatinine) especially in patients who are adequately hydrated.14 Continued tubular damage, however, eventually results in decreases in renal blood flow and glomerular filtration through tubuloglomerular feedback mechanisms that further constrict the afferent arteriole.

During the 1990s, amphotericin B was reformulated into three different lipid-based formulations (Abelcet, Ambisome, and Amphotec) that have reduced rates of nephro-toxicity compared to the conventional deoxycholate formulation (Fungizone). Two of the formulations (Abelcet and Ambisome) have also shown reductions in the rates of infusion-related reactions. Although these lipid formulations are generally considered to be as effective as conventional amphotericin B deoxycholate, they are not dosed equivalently to the standard formulation. Unlike conventional amphotericin B, which is administered at dosages ranging from 0.6 to 1.5 mg/kg/day, lipid formulation doses are threefold to fivefold higher on a milligram-per-milligram basis, ranging from 3 to 5 mg/kg/day. Only one prospective study has directly compared the efficacy of a lipid amphotericin formulation to the conventional formulation.15 In a small study of AIDS patients with moderate to severe histoplasmosis, liposomal amphotericin B (Ambisome) was more effective than amphotericin B, with response rates of 84% and 64%, respectively. Ambisome may also be the preferred agent in patients with CNS infections over other lipid formulations, due to its improved CNS penetration.16

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