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Medicines in neonates
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Flucytosine is de-aminated into the fungal cell and acts as an inactive pyrimi-dine substitute interfering with DNA synthesis. High concentrations are thought to be hepatotoxic. The mechanism of action is the inhibition of the synthesis of ergosterol, through the inhibition of the cytochrome P-450 system.
Adverse Reactions to Antibiotics in the Critical Care Unit
Published in Cheston B. Cunha, Burke A. Cunha, Infectious Diseases and Antimicrobial Stewardship in Critical Care Medicine, 2020
Diane M. Parente, Cheston B. Cunha, Michael Lorenzo
Vancomycin-induced neutropenia usually occurs after over 2 weeks of intravenous treatment [7,63]. Flucytosine is known for causing hematological toxicities (e.g., leukopenia, thrombocytopenia, and myelosuppression), particularly with concentrations greater than 100 mg/L [64]. Bone-marrow depression from flucytosine commonly develops within the first 2‒4 weeks of therapy. Appropriate dose reductions based on renal function are necessary to minimize the risk of bone-marrow toxicity. Therapeutic drug monitoring of flucytosine is essential when high doses or prolonged therapy is utilized. Flucytosine peaks should be obtained after three to five doses at 2 hours post-dose. A goal peak of 50–80 mg/L is considered adequate. Peaks greater than 100 mg/L require dose reduction to minimize bone-marrow suppression.
Gastrointestinal and liver infections
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Caution should be exercised in renal impairment, the elderly and those with blood disorders. Routine monitoring of liver, kidney and bone marrow function are required. Flucytosine is teratogenic in animals and thus should be avoided in pregnancy and breastfeeding.
Efficacy and acceptability of different anti-fungal interventions in oropharyngeal or esophageal candidiasis in HIV co-infected adults: a pilot network meta-analysis
Published in Expert Review of Anti-infective Therapy, 2021
Bing-Syuan Zeng, Bing-Yan Zeng, Chao-Ming Hung, Tien-Yu Chen, Yi-Cheng Wu, Yu-Kang Tu, Pao-Yen Lin, Kuan-Pin Su, Brendon Stubbs, Cheuk-Kwan Sun, Yu-Shian Cheng, Dian-Jeng Li, Chih-Sung Liang, Chih-Wei Hsu, Yen-Wen Chen, Ping-Tao Tseng, Chang-Hua Chen
We believe that combination of itraconazole-flucytosine is a potential alternate candidate and its function essentially requires further probing. This combination therapy provided a similar cure rate (OR = 0.69, 95%CIs = 0.22 to 2.18, p = 0.522) and relapse rate (OR = 0.64, 95%CIs = 0.10 to 4.16, p = 0.642) in the esophageal candidiasis management compared to fluconazole. Itraconazole and fluconazole share similar azole-associated activities in terms of their anti-fungal effects. Flucytosine possibly exerts its anti-fungal effect by increasing the levels of noncompetitive inhibitor thymidilate synthetase and inhibiting fungal DNA synthesis [59,60]. Therefore, their combination provides a synergistic effect and enhances the therapeutic efficacy by 30% [59]. However, this observation was mainly based on one RCT [59] that was not designed for specific baseline HIV severity. In a previous study, the baseline HIV severity was shown to alter the prognosis of esophageal candidiasis [2]. Therefore, the current circumstances demand large-scale and well-designed RCTs based on different baseline HIV severity in future. This would aid in investigating the role of itraconazole-flucytosine combination in order to support the findings of our NMA.
How urgent is the need for new antifungals?
Published in Expert Opinion on Pharmacotherapy, 2021
Adam G. Stewart, David L. Paterson
Currently, there are three main classes of registered systemic antifungals – azoles, echinocandins, and polyenes [10]. Flucytosine is a fluoropyrimidine antifungal that sits outside of these three main classes which is usually used in combination with another antifungal agent due to the development of rapid resistance seen with monotherapy [11]. Azoles exert their effect by preventing the conversion of lanosterol to ergosterol by inhibiting CYP450-dependent lanosterol 14α-demethylase, which disrupts fungal cell membranes [12]. Echinocandins are semisynthetic lipopeptides which inhibit (1→3)-β-d-glucan synthase, an important enzyme in fungal cell wall synthesis [13]. Polyenes are lipophilic molecules that bind sterols and insert into the fungal cytoplasmic membrane orienting as head-to-tail oligomers causing an increase in membrane permeability and potassium ion leak [14]. Among these three groups of antifungal agents, limitations exist with regards to their use which include spectrum of activity, resistance, toxicity, suboptimal pharmacokinetics, drug–drug interactions, and poor bioavailability.
Antifungal agents and the kidney: pharmacokinetics, clinical nephrotoxicity, and interactions
Published in Expert Opinion on Drug Safety, 2021
Athanasios Tragiannidis, Anastasia Gkampeta, Maria Vousvouki, Eleni Vasileiou, Andreas H. Groll
Elimination from the body is predominantly via glomerular filtration with no relevant tubular reabsorption or secretion, resulting in the need for dose modification in renal dysfunction. The half-life of flucytosine can be extended by up to 85 h in patients with severe renal insufficiency, as renal insufficiency alters the drug’s pharmacokinetics by decreasing clearance [89]. The mechanisms of toxicity of flucytosine are still not fully understood. Nausea, vomiting, diarrhea and hepatic toxicity, including elevation of serum transaminases and alkaline phosphatase, occur in approximately 0–25% of the patients. The most significant adverse event, particularly after oral administration, is myelosuppression, which may be due to the conversion of the compound into fluorouracil by the intestinal microbiota.