Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis

Stamm, Alan M.; Diasio, Robert B.; Dismukes, William E.; Shadomy, Smith; Cloud, Gretchen A.; Bowles, Cynthia A.; Karam, George H.; Espinel-Ingroff, Ana

doi:10.1016/0002-9343(87)90691-7

Cited by 240 publications

(144 citation statements)

References 13 publications

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“…Orally administered 5-FC is almost completely adsorbed, reaches peak concentrations in serum within 1-2 h, and easily reaches most body sites (21). 5-FC is also well-tolerated and has very low toxicity as long as serum concentrations are maintained below 50 μg/mL (388 μM) (21,23). This serum level is almost 40-fold higher than the 5-FC concentration (10 μM) able to exert the maximal inhibitory effect in vitro on P. aeruginosa virulence gene expression (Figs.…”

Section: Discussionmentioning

confidence: 97%

Repurposing the antimycotic drug flucytosine for suppression ofPseudomonas aeruginosapathogenicity

Imperi

Massai

Facchini

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

140

144

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Section: Discussionmentioning

confidence: 97%

Repurposing the antimycotic drug flucytosine for suppression ofPseudomonas aeruginosapathogenicity

Imperi

Massai

Facchini

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

140

144

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“…Antifungal drug treatments are toxic and frequently ineffective in eradicating central nervous system infection even after weeks of use. The toxicities of amphotericin B and flucytosine are particularly noteworthy since side effects are of sufficient magnitude and severity to limit the use of these drugs in nearly 50% of those who require 4 weeks of treatment (4,30). This has led to the common practice of using amphotericin B with or without flucytosine for a relatively brief period (2 weeks), followed by azole therapy (31).…”

Section: Discussionmentioning

confidence: 99%

Amphotericin B and Fluconazole, a Potent Combination Therapy for Cryptococcal Meningitis

Larsen

Bauer

Thomas

et al. 2004

Antimicrob Agents Chemother

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We evaluated the antifungal activities of amphotericin B, fluconazole, and flucytosine, alone and in combination, in a murine model of cryptococcal meningitis. The objectives were to determine the greatest antifungal effects achievable with these drugs alone or in combination. Meningitis was established in male BALB/c mice weighing 23 to 25 g by intracerebral injection of Cryptococcus neoformans. Treatment was started on day 2. Amphotericin B was tested at 0.3 to 1.3 mg/kg of body weight/day by slow intravenous injection. Fluconazole at 10 to 40 mg/kg/day and flucytosine at 20 to 105 mg/kg/day were administered in the sole source of drinking water. The mice were killed at 16 days, and the numbers of fungal colonies in the brain were quantified. The association between the response and the dose combination was evaluated by local nonparametric response surface methods; 99% confidence intervals were used to evaluate the antifungal effects. Ninety-five percent of the mice treated with amphotericin B at 0.5 mg/kg survived to the end of the experiment, regardless of the fluconazole or flucytosine dose used. The greatest activity was seen with amphotericin B plus fluconazole with or without flucytosine. However, the addition of flucytosine did not increase the antifungal activity. Given the widespread availability of amphotericin B and fluconazole and the relative safety profile of fluconazole compared to that of flucytosine, the full potential of this two-drug combination deserves further evaluation.

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“…Patients with significant proteinuria (>3 g/l) seem to have a reduced risk of renal tubular toxic effects caused by amphotericin B [94], which might be related to a reduced concentration of free amphotericin B in tubular fluid. [185], with permission RTA is a rare side effect in amphotericin B therapy [95]. Polyuria and nephrogenic diabetes insipidus are more frequent findings in patients during amphotericin B therapy [96].…”

Section: Amphotericin Bmentioning

confidence: 99%

Drug-induced acid-base disorders

et al. 2014

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The incidence of acid-base disorders (ABDs) is high, especially in hospitalized patients. ABDs are often indicators for severe systemic disorders. In everyday clinical practice, analysis of ABDs must be performed in a standardized manner. Highly sensitive diagnostic tools to distinguish the various ABDs include the anion gap and the serum osmolar gap. Drug-induced ABDs can be classified into five different categories in terms of their pathophysiology: (1) metabolic acidosis caused by acid overload, which may occur through accumulation of acids by endogenous (e.g., lactic acidosis by biguanides, propofol-related syndrome) or exogenous (e.g., glycol-dependant drugs, such as diazepam or salicylates) mechanisms or by decreased renal acid excretion (e.g., distal renal tubular acidosis by amphotericin B, nonsteroidal antiinflammatory drugs, vitamin D); (2) base loss: proximal renal tubular acidosis by drugs (e.g., ifosfamide, aminoglycosides, carbonic anhydrase inhibitors, antiretrovirals, oxaliplatin or cisplatin) in the context of Fanconi syndrome; (3) alkalosis resulting from acid and/or chloride loss by renal (e.g., diuretics, penicillins, aminoglycosides) or extrarenal (e.g., laxative drugs) mechanisms; (4) exogenous bicarbonate loads: milk-alkali syndrome, overshoot alkalosis after bicarbonate therapy or citrate administration; and (5) respiratory acidosis or alkalosis resulting from drug-induced depression of the respiratory center or neuromuscular impairment (e.g

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Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis

Cited by 240 publications

References 13 publications

Repurposing the antimycotic drug flucytosine for suppression ofPseudomonas aeruginosapathogenicity

Repurposing the antimycotic drug flucytosine for suppression ofPseudomonas aeruginosapathogenicity

Amphotericin B and Fluconazole, a Potent Combination Therapy for Cryptococcal Meningitis

Drug-induced acid-base disorders

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