| Therapy | ||
|---|---|---|
| Disease | Primary | Alternative |
| Aspergillosis: invasive | Voriconazole 6 mg/kg IV q12h for 2 doses then 4 mg/kg or 200–300 mg PO q12h | Liposomal formulations of AmB (see Table 207.3 for dosage) Caspofungin 70 mg IV × 1 dose, then 50 mg IV/d AmB, 1.0–1.5 mg/kg/d IV Posaconazole 300 mg BID on day 1 then 300 mg QD (tablet and IV); 800 mg/d in 2–4 doses (oral suspension) Itraconazole 400 mg/d PO (oral solution preferred) |
| Blastomycosis | Itraconazole, 200–400 mg/d PO for 6 mo; or AmB or L-AmB | Fluconazole, 400–800 mg/d for at least 6 mo |
| Candidiasis | ||
| Candidemia | Caspofungin, 70 mg IV × 1 dose then 50 mg IV/d, or micafungin, 100 mg IV/d, or anidulafungin, 200 mg IV × 1 dose then 100 mg IV/d, followed by fluconazole 400–800 mg/d IV/PO (for susceptible organisms) or voriconazole when clinically stable to complete 14-d course after last positive blood culture If neutropenic, longer courses – until neutropenia resolves – may be necessary | Fluconazole 400–800 mg/d IV/PO for less seriously ill In patients who fail to respond or deteriorate, lipid formulations may be necessary Avoid fluconazole in patients with recent azole exposure, or if Candida krusei likely |
| Hepatosplenic candidiasis | L-AmB 3–5 mg/kg/d or Fluconazole, 800 mg/d IV | AmB lipid complex (ABLC), 5 mg/kg/d |
| Coccidiomycosis | ||
| Nonmeningeal (AIDS and non-AIDS) | Fluconazole, 400–800 mg/d PO for 12–18 mo | Itraconazole, 200 mg BID PO × 12–18 mo, or AmB, 0.6–1.0 kg/d IV; total dose, ≥2.5 g In HIV, suppressive treatment with fluconazole, 200–400 mg/d PO, or itraconazole, 200–400 mg/d PO Posaconazole, voriconazole investigational |
| Meningeal (AIDS and non-AIDS) | Fluconazole, 400–800 mg/d PO indefinitely | L-AmB/AmB IV as for nonmeningeal Posaconazole, voriconazole investigational |
| Cryptococcosis | ||
| Nonmeningeal | AmB, 0.7 mg/kg/d IV ± 5-FC 25 mg/kg PO q6h until response, then fluconazole, 400 mg/d PO for 8–10 wk, or Lipid AmB 3–5 mg/kg/d IV ± 5-FC as above | Fluconazole 400–800 mg/d IV Posaconazole, voriconazole investigational |
| Meningeal | AmB, 0.7 mg/kg/d IV ± 5-FC, 25 mg/kg PO q6h for 2 wk, then fluconazole, 400 mg/d PO for 8–10 wk, or fluconazole, 400 mg/d PO for 8–10 wk (for less severely ill patients) | Oral fluconazole less favorable success rates; Posaconazole, voriconazole investigational |
| Histoplasmosis | ||
| Non-AIDS | Itraconazole, 400 mg/d PO for 9 mo; if life threatening, AmB, 0.7–1.0 mg/kg/d or lipid AmB 3–5 mg/kg/d IV × 14 d, followed by itraconazole, 400 mg/d × 8–10 wk if clinical response | |
| Disseminated/AIDS | AmB, 0.7–1.0 mg/kg/d IV or lipid AmB 3–5 mg/kg/d × 14 d, followed by itraconazole, 400 mg/d × 8–10 wk, then begin suppressive treatment with itraconazole 200 mg/d PO | Itraconazole, 300 mg BID PO × 3 d, then 200 mg BID PO × 12 wk, or 400 mg/d × 12 wk, then 200 mg/d PO (less seriously ill) |
| Mucormycosis | Surgery plus lipid AmB 5–7.5 mg/kg/d IV | Posaconazole, AmB 0.8–1.5 mg/kg/d IV |
| Sporotrichosis | ||
| Lymphocutaneous | Itraconazole, 200 mg/d PO × 6 mo | Potassium iodide solution (SSKI), 10–15 gtt TID × 6–12 wk |
| Extracutaneous | AmB or L-AmB (may require adjunctive intra-articular therapy or surgery) | Itraconazole, 200–300 mg PO BID × 6 mo, then 200 mg PO BID long term |
Note: Dosages and duration of therapy given are approximations based on clinical response and underlying condition in the host. Individual responses and therapeutic requirements may vary.
Abbreviations: AmB = amphotericin B; 5-FC = flucytosine; AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus.
Amphotericin B
Amphotericin B is a polyene antifungal synthesized by Streptomyces nodosus. Its chemical structure confers it with amphoteric properties that are essential for the drug’s ability to form channels through the cytoplasmatic membrane. The pores formed from preferential binding of amphotericin B to ergosterol, the primary fungal cell sterol, result in an increase in membrane permeability, leading to a loss of essential elements such as potassium and other molecules that impairs fungal viability. Amphotericin B binds with less affinity to cholesterol, the primary cell sterol of mammalian cells, which are therefore less affected by amphotericin B than is the fungal target.
Amphotericin B is commercially available as a complex with sodium deoxycholate: commercial vials contain amphotericin B, 50 mg, sodium deoxycholate, 41 mg, and a sodium phosphate buffer, 25.2 mg. The clinical pharmacology of amphotericin B is characterized by extensive binding to plasma proteins (>95%) and wide distribution to the peripheral compartment with preferential accumulation in liver and spleen, with lesser amounts in kidney and lung. Intravenous administration of therapeutic doses results in peak plasma levels of 1.0 to 1.5 μg/mL falling to 0.5 to 1.0 μg/mL 24 hours later. At therapeutic doses, less than 5% of the drug is excreted in the urine. The elimination of amphotericin B is not altered in patients with renal or liver dysfunction and does not require dose adjustment in patients who are anephric or undergoing hemodialysis. Cerebrospinal fluid (CSF) levels are low, although higher concentrations occur in brain tissue. Amphotericin B also diffuses poorly into other body fluids such as saliva, amniotic fluid, aqueous humor, and vitreous humor. However, drug concentrations in inflamed pleura, peritoneum, aqueous humor, and joint spaces are roughly two-thirds of the trough plasma concentration.
For clinical administration, amphotericin B is diluted in 5% dextrose (at a concentration of ≤0.1 mg of amphotericin B per milliliter of diluent) and infused intravenously over 2 to 4 hours at dosages of 0.5 to 1.5 mg/kg/day. The most common side effects of amphotericin B treatment are acute infusion-related reaction and nephrotoxicity. The acute infusion-related reaction consists of a syndrome of chills/rigors, fever, and tachypnea that typically occurs 30 to 45 minutes after beginning the first infusion and may last for 2 to 4 hours. Premedication with acetaminophen (650 mg given orally or rectally), hydrocortisone (25 to 50 mg given intravenously or mixed with the amphotericin B infusion solution), and diphenhydramine (50 mg given orally or rectally) can diminish the frequency and severity of these reactions. Chills and rigors may be terminated by the administration of meperidine (50 mg given intravenously). The acute symptoms associated with amphotericin B infusion can be serious. The occurrence of severe infusion reactions is considered an indication for use of lipid-associated amphotericin B preparations, which are usually significantly better tolerated (see below).
The other major side effect of amphotericin B is the development of nephrotoxicity, which occurs through a decrease in the glomerular filtration rate as a result of a direct vasoconstrictive effect on afferent renal arterioles, reducing glomerular and renal tubular blood flow, and by direct effects on the distal tubules resulting in the loss of cations. The nephrotoxicity may be exacerbated by other nephrotoxic agents. There is evidence that renal vasoconstriction is partially reversible by salt loading with 500 to 1000 mL of normal saline before each infusion. Other renal effects include potassium and bicarbonate wasting and decreased erythropoietin production. Permanent loss of renal function can occur if the drug is continued in the setting of worsening renal function. Other chronic toxicities include nausea and vomiting, anorexia, normocytic normochronic anemia (with the hematocrit rarely falling below 20% to 25%), and, rarely, thrombocytopenia, leukopenia, and peripheral vein phlebitis.
Amphotericin B is active against most fungal pathogens that cause systemic or deep-seated infections. Despite its significant dose-limiting toxicities, amphotericin B remains an option for many mycoses because of its broad spectrum of activity and fungicidal activity, although the availability of better tolerated and effective alternative agents (including lipid formulations of amphotericin B, the extended-spectrum azoles, or the echinocandins) have limited indications for the use of amphotericin B deoxycholate. Recommendations for appropriate dosages of amphotericin B and for duration of therapy remain poorly defined for most infections. In the past, total doses of 1 to 2 g for serious infections (which is approximately 15 to 30 mg/kg over a 6-week period) were usually recommended. However, the dosage and duration of amphotericin B depend largely on response of infection to therapy and resolution of underlying host immunodeficiency (e.g., resolution of neutropenia). Increasingly, a therapeutic approach that includes aggressive “induction” courses of amphotericin B followed by “consolidation” therapy with an azole, which can be administered orally, is used. This strategy has been evaluated most thoroughly in cryptococcal meningitis, but clinical reports have documented success of sequential amphotericin B to azole therapy in candidemia (using oral fluconazole), invasive aspergillosis (with an oral anti-Aspergillus azole such as voriconazole, posaconazole, or itraconazole), and endemic fungi (coccidioidomycosis and histoplasmosis with fluconazole and itraconazole, respectively). Generally, a 2-week (or until signs of infection have resolved or significantly improved) course of amphotericin B can be followed by azole therapy although none of the azoles are licensed for use in that manner.
Local instillation is rarely indicated due to the advances in alternative agents. Historically, itrathecal amphotericin B was a mainstay of therapy for coccidioidal meningitis, but the use of intrathecal amphotericin B is associated with substantial toxicity; consequently, that approach is now usually reserved for patients in whom systemic therapy fails, including high dosages of an azole. In other cases, local instillation of amphotericin B into the bladder via a Foley catheter has been used for urinary tract candidiasis, but systemic azole therapy, usually with fluconazole, is well tolerated and effective for that indication.
Lipid preparations of amphotericin B have been developed in an attempt to reduce the nephrotoxicity of the conventional form of amphotericin B deoxycholate. The administration of such liposomal forms modifies the pharmacokinetic and toxicologic properties of amphotericin B and as such these preparations have largely replaced amphotericin B deoxycholate for recommended use in serious fungal infections. Characteristics of the commercially available lipid amphotericin B preparations, liposomal amphotericin B (L-AMB, AmBisome), amphotericin B lipid complex (ABLC, Abelcet), and amphotericin B colloidal dispersion (ABCD, Amphotec), are shown in Table 207.2, although the use of ABCD is limited due to the increased toxicity associated with that formulation. Serum levels of L-AMB are higher than those achieved with standard amphotericin B, but serum levels of ABLC and ABCD are similar to those of amphotericin B deoxycholate. The advantage of the administration of amphotericin B in lipid complexes or in liposomes is the reduced rate of nephrotoxicity, allowing the delivery of larger amounts of the drug. Although few direct comparisons of the preparations have been performed, the fewest infusion reactions appear to occur with L-AMB with slightly more reactions, including chills and fevers, associated with ABLC. The highest incidence of infusion-related toxicities, including hypoxia, has been reported with ABCD. Infusions of L-AMB have been associated with anxiety, nervousness, restlessness, and chest pain, which have been described as a feeling of impending doom.
| Amphotericin B lipid formulations | Structure | Indications | Dosages |
|---|---|---|---|
| Amphotericin B lipid complex (ABLC) (Abelcet) | Ribbonlike structures of a bilayered membrane formed by combining a 7:3 mixture of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol with amphotericin B (drug/lipid ratio of 1:1) | Invasive fungal infections in patients refractory or intolerant to amphotericin B deoxycholate | 5 mg/kg/d as single infusion |
| Amphotericin B cholesteryl sulfate complex colloidal dispersion (ABCD), (Amphotec) | Disklike structures of cholesterol sulfate complexed with amphotericin B in equimolar concentration | Treatment of patients who either failed or are intolerant to amphotericin B deoxycholate; increased toxicity noted | 3–4 mg/kg/d (up to 6 mg/kg/d) |
| Liposomal amphotericin B (Ambisome) | Small unilamellar liposomes about 55–75 nm in diameter made up of a bilayer membrane of hydrogenated soy phosphatidylcholine and distearoyl phosphatidylglycerol stabilized by cholesterol and combined with amphotericin B in a 2:0.8:1:0.4 ratio | Treatment of patients with Aspergillus species, Candida species, and/or Cryptococcus species infection refractory to amphotericin B deoxycholate, or in patients in whom renal impairment or toxicity precludes the use of amphotericin B deoxycholate; empirical treatment for presumed fungal infection | 3–5 mg/kg/d as single infusion |
The lipid amphotericin B formulations have shown efficacy in many indications, including their use as salvage therapy for patients who fail amphotericin B deoxycholate or who are intolerant to it. In addition, L-AMB was shown to have fewer adverse events and to reduce breakthrough invasive fungal infections when used as empiric therapy for persistent fever in febrile neutropenic patients, although no change in overall outcome was noted. However, despite the improved therapeutic index of these amphotericin B formulations as compared with amphotericin B deoxycholate, they have not been shown superior in efficacy. The use of these preparations in patients with severe fungal infection who have baseline renal insufficiency or who are at very high risk for nephrotoxicity (e.g., allogenic bone marrow transplant recipients receiving nephrotoxic medications) is recommended. In addition, in patients who have infections that respond poorly to amphotericin B, including infections caused by members of the order Mucorales, Fusarium species, and other invasive molds such as Aspergillus
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