Critically evaluate the role off fluconazole in the management of the critically ill patient CICM Answer JFICM

answer Fluconazole is an azole antifungal agent that has good bioavailability (can be administered enterally). It has a proven role in treatment of candidal (skin / mucosal / systemic) and cryptococcal infections as an alternative to amphoteracin. It has much less activity against other fungal infections (eg aspergillus). Usual duration of therapy is until evidence of active fungal infection has subsided. Specific antifungal sensitivities may be required. usually fluconazole is very well tolerated, but observed adverse reactions include an increase in transaminase enzymes, other gastrointestinal and haematological problems, adrenal suppression and rare cases of QT prolongation and torsades de pointes. As fluconazole is predominantly renally excreted as the unchanged drug, dose adjustment is required with renal impairment. Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP2C, and as such may increase the concentrations of various drugs (e warfarin, theophylline, cyclosporin, oral hypoglycaemics, phenytoin and midazolam). Recent interest has surrounded empiric therapy in patients with septic shock. One small prospective randomised trial suggests improved 30 day mortality and hopsital mortality when 200mg fluconazole was administered daily to patients with septic shock (due to either intraabdominal sepsis or nosocomial pneumonia) until resolution of shock. The majority of the benefits were attributable to the group with intraabdominal sepsis. Fluconazole also has a role in prophylactic therapy (eg HIV) and in prolonged maintenance therapy (eg HIV patients with cryptococcal meningitis or recurrent oropharyngeal candidiasis.

Study Group Answer Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections It is less toxic and less expensive, available both oral and IV. Major role of fluconazole in ICU is treatment of Candida septicaemia in patents who are hemodynamically stable and not immunocompromised. There is some concern that it does not cover Candida non albicans such as C. krusei or C. glabrata but these organisms is involved in only 5 to 10% of ICU infections. It is not for treatment of aspergillus infections. In patients who are immunocompromised as the risk of non albicans is higher fluconazole can be used after an initial course of amphotericin though it is debated.

It is also used as a prophylaxis of candidiasis in immunocompromised people and patients with extensive peritoneal soiling and severe necrotizing pancreatitis, again this is highly debated as it can lead to selective emergence of non ablicans infection but depends upon the local pattern of Candida infection in the ICU. Mode of action: fluconazole inhibits the fungal cytochrome P450 enzyme 14demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of Lanosterol to ergosterol, an essential component of the fungal Cytoplasmic membrane, and subsequent accumulation of 14-methyl sterols. Fluconazole is primarily fungistatic, however may be fungicidal against certain organisms in a dose-dependent manner. Fluconazole therapy has been associated with QT interval prolongation, which may lead to serious cardiac arrhythmias. Thus it is used with caution in patients with risk factors for prolonged QT interval such as electrolyte imbalance or use of other drugs which may prolong the QT interval (particularly cisapride). Fluconazole has also rarely been associated with severe or lethal hepatotoxicity and liver function tests are usually performed regularly during prolonged fluconazole therapy. Additionally, it is used with caution in patients with pre-existing liver disease. Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozymes CYP2C9 and CYP3A4. In theory, therefore, fluconazole decreases the metabolism and increases the concentration of any drug metabolised by these enzymes eg warfarin In critically ill adults with risk factors for invasive candidiasis, empirical fluconazole did not clearly improve a composite outcome more than placebo in some clinical studies but it was found beneficial in Cochrane review. The reviewers conclude "In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should Inhibits fungal ergosterol synthesis