Flucytosine (5-Fluorocytosine/5-FC) – Antifungals

00:01 Flucytosine is a water-soluble pyrimidine analog related to the chemotherapeutic agent 5-fluorouracil (5-FU).

00:10 It disrupts both DNA and RNA synthesis.

00:13 It has a narrow spectrum of action but is usually combined with amphotericin B to treat severe cryptococcal pneumonia and meningoencephalitis The mechanism of action involves flucytosine being taken up by fungal cells via the enzyme cytosine permease, as noted in step 1.

00:34 In step 2, it is converted to 5-fluorouracil (5-FU) by cytosine deaminase, which is not present in mammalian cells, which is an example of selective toxicity.

00:46 In Step 3, 5-FU is further metabolized into 5-fluorodeoxyuridine monophosphate (5-FdUMP), which inhibits thymidylate synthase, an enzyme crucial for the synthesis of thymidine monophosphate (dTMP), a necessary precursor for DNA synthesis.

01:04 This inhibition disrupts DNA synthesis, preventing cell replication.

01:09 5-FU is also converted into 5-fluorouridine monophosphate (5-FUMP), as seen in step 4.

01:17 In step 5, 5-FUMP is phosphorylated to form 5- fluorouridine triphosphate (5-FUTP).

01:24 5-FUTP is incorporated into RNA in place of uridine, leading to the production of faulty RNA, which disrupts protein synthesis and interferes with essential cellular processes.

01:36 So both DNA and RNA synthesis are interrupted; this is unlike other antifungal agents, which target the cell membrane, like amphotericin B and azoles or the cell wall, like the echinocandins. Synergy with both amphotericin B and azole drugs has been demonstrated.

01:54 Flucytosine is most commonly used in combination with amphotericin B for the treatment of severe cryptococcal pneumonia and meningoencephalitis.

02:03 This combination is highly effective in managing these serious fungal infections, particularly in immunocompromised patients, such as those with HIV/AIDS.

02:13 While less frequently used, 5-FC can also be part of a combination regimen for certain invasive candidal infections.

02:20 It’s especially considered when the infections are particularly severe or resistant to other treatments.

02:26 Flucytosine is used in selected cases of chromoblastomycosis, a chronic fungal infection caused by dematiaceous molds.

02:33 In these cases, the drug may be combined with other antifungals to enhance efficacy.

02:38 Monotherapy with flucytosine is generally avoided due to the high incidence of resistance.

02:43 However, it may be used in specific situations, such as treating fluconazole-resistant candidal urinary tract infections. This is one of the few scenarios where 5-FC might be used alone, but even then, it’s often reserved for less severe infections where alternative treatments are not viable.

03:02 Understanding the pharmacokinetics of 5-FC is essential particularly when treating patients with compromised renal function.

03:09 Flucytosine is primarily eliminated by glomerular filtration, with a half-life of 3 to 4 hours in patients with normal renal function.

03:17 Importantly, 5-FC is removed by hemodialysis, which has implications for dosing in patients undergoing dialysis.

03:25 In patients with renal impairment, 5-FC levels can rise rapidly, leading to potential toxicity. This is particularly a concern in AIDS patients and those with renal insufficiency.

03:37 In these populations, close monitoring of drug levels is essential, and dose reductions are often necessary to avoid adverse effects.

03:45 The standard dosage of 5-FC in patients with normal renal function is 100 mg per kilogram per day, divided into multiple doses.

03:54 It's crucial to adjust this dosage in patients with impaired renal function to prevent toxicity.

03:59 In North America, 5-FC is available only in oral formulations, which may limit its use in certain clinical scenarios where intravenous administration would be preferred.

04:10 Flucytosine’s adverse effects primarily arise from its metabolism into the toxic compound 5-fluorouracil (5-FU), which can occur possibly through the action of intestinal flora. This metabolic pathway is concerning because 5-FU is a well-known antineoplastic agent, and its toxicity can be significant, particularly in vulnerable populations.

04:35 The most common adverse effect of flucytosine is bone marrow toxicity, eading to cytopenias such as anemia, leukopenia, and thrombocytopenia.

04:46 This toxicity is particularly problematic in AIDS patients and those with renal insufficiency, as they are more susceptible to the accumulation of toxic metabolites.

04:55 Although less common, flucytosine can also cause hepatic necrosis, which is typically reflected in elevated liver enzymes.

05:03 This requires careful monitoring of liver function during treatment.

05:07 Another potential, though less frequent, adverse effect is toxic enterocolitis, which can lead to significant gastrointestinal distress.

05:16 Given the narrow therapeutic window of flucytosine, regular monitoring of drug levels and patient health is essential to avoid toxicity while ensuring the drug remains effective.

05:27 It is important to measure peak serum concentrations of flucytosine periodically. This helps in adjusting the dose to maintain therapeutic levels while minimizing the risk of toxicity.

05:38 Due to the risk of bone marrow suppression, a complete blood count should be monitored every other day.

05:43 This frequent monitoring helps in early detection of cytopenias, allowing for timely intervention if toxicity develops.

05:51 Resistance to flucytosine is a significant clinical challenge and can arise through mutations in several key enzymes within the fungal cell, including cytosine permease: which is responsible for transporting flucytosine into the fungal cell.

06:06 Mutations that impair its function can prevent the drug from entering the cell, rendering it ineffective.

06:12 Once inside the cell, flucytosine is converted to 5-FU by cytosine deaminase.

06:18 Mutations in this enzyme can block this conversion, stopping the drug from becoming active and thus leading to resistance.

06:25 Uracil phosphoribosyl transferase converts 5-FU into 5-fluorouridine monophosphate, a crucial step in the drug’s mechanism of action.