A 55-year-old man presents to the emergency department with a 2-week history of an expanding ulcer on his left lower leg. He has a history of chronic neutropenia and transfusion-dependent anemia secondary to myelodysplastic syndrome requiring chronic therapy with deferoxamine for hepatic iron overload. He first noticed a red bump on his leg while fishing at his cabin in the woods and thought it was a bug bite. It rapidly enlarged, first as a red swollen area, and then began to ulcerate. He was given dicloxacillin orally, but with no improvement. In the emergency department he is febrile to 39°C (102.2°F), and looks unwell. On his left leg he has a 6 by 12 cm black ulcer with surrounding swelling and erythema that is quite tender. His complete blood count demonstrates an absolute neutrophil count of 300 and a total white blood cell count of 1000. An immediate operative debridement yields pathologic specimens demonstrating broad club-like nonseptate hyphae and extensive tissue necrosis. What initial medical therapy would be most appropriate?
Human fungal infections have increased dramatically in incidence and severity in recent years, owing mainly to advances in surgery, cancer treatment, treatment of patients with solid organ and bone marrow transplantation, the HIVepidemic, and increasing use of broad-spectrum antimicrobial therapy in critically ill patients. These changes have resulted in increased numbers of patients at risk for fungal infections.
For many years, amphotericin B was the only efficacious antifungal drug available for systemic use. While highly effective in many serious infections, it is also quite toxic. In the last several decades, pharmacotherapy of fungal disease has been revolutionized by the introduction of the relatively nontoxic azole drugs (both oral and parenteral formulations) and the echinocandins (only available for parenteral administration). The new agents in these classes offer more targeted, less toxic therapy than older agents such as amphotericin B for patients with serious systemic fungal infections. Combination therapy is being reconsidered, and new formulations of old agents are becoming available. Unfortunately, the appearance of azole-resistant organisms, as well as the rise in the number of patients at risk for mycotic infections, has created new challenges.
The antifungal drugs presently available fall into the following categories: systemic drugs (oral or parenteral) for systemic infections, oral systemic drugs for mucocutaneous infections, and topical drugs for mucocutaneous infections.
Amphotericin A and B are antifungal antibiotics produced by Streptomyces nodosus. Amphotericin A is not in clinical use.
Chemistry & Pharmacokinetics
Amphotericin B is an amphoteric polyene macrolide (polyene = containing many double bonds; macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin B and sodium desoxycholate for intravenous injection. Several formulations have been developed in which amphotericin B is packaged in a lipid-associated delivery system (Table ...