Amphotericin B, the first commercially significant antifungal drug, has been available for more than 30 years. This polyene macrolide antifungal agent continues to play a major role in the treatment of systemic fungal infections, despite the introduction of newer agents such as the azoles. Given the proved efficacy of amphotericin B--and the increasing number of indications for antifungal agents--an extensive review of this drug is warranted. This paper discusses the clinical uses of amphotericin B, including its application in AIDS-related fungal infections, in neutropenic cancer patients who are persistently febrile, and in infections of the central nervous system, lung, peritoneum, genitourinary system, eye, and skin. The paper also reviews the drug's adverse reactions, with a discussion of administration techniques that may reduce these reactions, and its spectrum of activity, pharmacokinetics, and dosage and administration.

Amphotericin B: 30 Years of Clinical Experience

We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.

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A Comparison of Amphotericin B Alone and Combined with Flucytosine in the Treatment of Cryptoccal Meningitis

The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood-cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable.

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

Background Treatment with low-dose amphotericin B (0.4 mg per kilogram of body weight per day) or oral azole therapy in patients with the acquired immunodeficiency syndrome (AIDS) and cryptococcal meningitis has been associated with high mortality and low rates of cerebrospinal fluid sterilization. Methods In a double-blind multicenter trial we randomly assigned patients with a first episode of AIDS-associated cryptococcal meningitis to treatment with higher-dose amphotericin B (0.7 mg per kilogram per day) with or without flucytosine (100 mg per kilogram per day) for two weeks (step one), followed by eight weeks of treatment with itraconazole (400 mg per day) or fluconazole (400 mg per day) (step two). Treatment was considered successful if cerebrospinal fluid cultures were negative at 2 and 10 weeks or if the patient was clinically stable at 2 weeks and asymptomatic at 10 weeks. Results At two weeks, the cerebrospinal fluid cultures were negative in 60 percent of the 202 patients receiving amphotericin ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199707033370103

Treatment of Cryptococcal Meningitis Associated with the Acquired Immunodeficiency Syndrome

Flucytosine (5-FC) is a synthetic antimycotic compound, first synthesized in 1957. It has no intrinsic antifungal capacity, but after it has been taken up by susceptible fungal cells, it is converted into 5-fluorouracil (5-FU), which is further converted to metabolites that inhibit fungal RNA and DNA synthesis. Monotherapy with 5-FC is limited because of the frequent development of resistance. In combination with amphotericin B, 5-FC can be used to treat severe systemic mycoses, such as cryptococcosis, candidosis, chromoblastomycosis and aspergillosis. Recently, 5-FC has been combined with newer azole antifungal agents; it also plays an important role in a new approach to the treatment of cancer. The severe side effects of 5-FC include hepatotoxicity and bone-marrow depression. In most patients, these side effects are concentration dependent, predictable, possibly avoidable with close monitoring to maintain 5-FC concentrations at <100 mg/L, and reversible with drug discontinuation or reduction of dose. 5-FC is well absorbed after oral administration, penetrates into body tissues well and is excreted mainly by the kidneys. In renal failure, major dose adjustments have to be made. The most important drug interaction of 5-FC occurs with concomitant administration of 5-FC and nephrotoxic drugs, especially amphotericin B. Owing to the crucial role of glomerular filtration in 5-FC elimination, drugs that impair this mechanism will decrease the elimination of 5-FC and thus prolong its half-life.

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Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions.

Flucytosine and Amphotericin B: Hemodialysis Effects on the Plasma Concentration and Clearance: Studies in Man

The efficacy of hemodialysis in removing flucytosine (5-fluorocytosine) and amphotericin B from blood was studied in eight adult patients with renal failure who required chronic hemodialys...

Flucytosine and Amphotericin B: Hemodialysis Effects on the Plasma Concentration and Clearance

Isolates of Cryptococcus neoformans from six patients were obtained before and after unsuccessful therapy with 5-fluorocytosine (5-FC). Post-therapy isolates exhibited massive and stable 5-FC resistance. The frequency of drug-resistant mutants in susceptible isolates of C. neoformans was <0.001% (70.4 +/- 17.9 per 10(7) cryptococci), whereas mutant frequencies in resistant isolates approached 100%. Non-drug-induced, spontaneously appearing 5-FC resistant mutants were documented in four susceptible isolates of C. neoformans by use of the statistical method of fluctuation analysis. Mutation rates on these same four isolates ranged from 1.2 x 10(-7) to 4.8 x 10(-7). Total intracellular uptake and incorporation of cytosine-5-(3)H (CyH(3)) and 5-fluorocytosine-2-(14)C (5-FC(14)) into a trichloroacetic acid-insoluble fraction were markedly reduced in six isolates with in vivo-acquired resistance when compared with susceptible pretreatment strains from the same patients. Five of these six isolates also had acquired massive resistance to 5-fluorouracil (5-FU), suggesting that a mutation in the uridine-5'-monophosphate pyrophosphorylase was responsible for drug resistance. The sixth isolate, which remained susceptible to 5-FU, appeared to have a defect in a cytosine-specific permease accounting for 5-FC resistance. A single isolate with in vitro-acquired 5-FC and 5-FU resistance had no reduction in uptake or incorporation of CyH(3) or 5-FC(14). The mechanism of resistance in this isolate is discussed.

5-Fluorocytosine Resistance in Cryptococcus neoformans

A cylinder plate bioassay for 5-fluorocytosine (5-FC) is described which permits determination of 5-FC concentrations in biological fluids in the presence of amphotericin B Using this assay, we determined serum concentrations in 12 patients after a single dose of drug and in 8 patients receiving daily 5-FC at 6-hr intervals (4 to 120 days) Drug was detectable in serum as early as 05 hr and concentrations were measurable as long as 24 hr after a dose, regardless of renal function Peak concentrations occurred 6 hr after the initial drug dose, but were seen between 1 and 2 hr after a dose in all patients receiving a minimum of 4 days of therapy Mild to moderate renal impairment produced marked increases in peak 5-FC concentrations in the serum of a group of eight patients on three different dosage schedules Five patients were studied before and after amphotericin B-induced renal insufficiency Peak concentrations increased from 14 to 142% concomitant with the change in renal function Parallel studies in rabbits confirmed the results in our patients 5-FC half-life in the serum of 10 rabbits increased from 335 ± 027 to 2463 ± 070 hr after experimentally induced acute renal failure Concentrations of 5-FC in the cerebrospinal fluid of five patients ranged from 17 to 62 μg/ml and were 744 ± 56% of simultaneously determined serum concentrations The effect of renal function on 5-FC concentrations in cerebrospinal fluid was similar to that seen with serum

Pharmacological Studies with 5-Fluorocytosine

Summary5-Fluorocytosine and amphotericin B were demonstrated to be at least additive in the therapy of murine cryptococcosis. The mechanism for this effect is not known. However, AmB seemed to inhibit the in vivo development of 5-FC resistance among C. neoformans in our model. These results raise the possibility that combined-drug therapy might reduce AmB toxicity and/or the appearance of 5-FC resistant cryptococci without compromising therapeutic efficacy in cryptococcal disease.We are greatly indebted to Dr. David W. Alling for constant and invaluable advice on the mathematical problems of experimental design and data analysis.

Edward R. Block

Papers

Flucytosine and Amphotericin B: Hemodialysis Effects on the Plasma Concentration and Clearance: Studies in Man

Flucytosine and Amphotericin B: Hemodialysis Effects on the Plasma Concentration and Clearance

5-Fluorocytosine Resistance in Cryptococcus neoformans

Pharmacological Studies with 5-Fluorocytosine

The combined effect of 5-fluorocytosine and amphotericin B in the therapy of murine cryptococcosis.