With the increased use of artificial implants the management of related infections has become an important challenge. Normally an infected implant would be removed. In many cases this might be contraindicated and drug treatment remains as the only alternative. As microbiological eradication is often impossible, especially in fungal infections at artificial implants (FIAI) long-term suppressive therapy might be required. The objective of this study was to determine the therapeutic value of fluconazole (F) in the management of FIAI. Clinical data of 56 patients (pts) with proven or suspected fungal infections and artificial implants (FIAI) subsequently treated with F were analyzed retrospectively. FIAI caused by species with intrinsic resistance to F have been excluded from the study. The following implants were involved: prosthetic valve endocarditis (PVE) 25 pts (44.6%), intraocular lenses (IL) 9 pts (16.1%), ventriculoperitoneal shunts (VPS) 6 pts (10.7%), knee prostheses (KP) 5 pts (8.9%), biliary stents (BS) 4 pts (7.1 %), venous access devices (VAS) 3 pts (5.4%), urinary stents (US) 2 pts (3.6%), breast implant and pacemaker 1 patient (1.8%) each. Underlying diseases were valve insufficiency (in PVE), cataract surgery (in IL), prematurity in newborns (in VPS), arthrosis (in KP), biliary obstruction (in BS), cystic fibrosis (in VAS), and obstructive renal calculi (in US). Candida species (C. spp.) were the most frequently detected causative agents with C. parapsilosis as the leading cause (n = 19; 33.9%). Furthermore C. albicans (n = 15; 26.8%), C. spp. and fungi not further specified (n = 8; 14.3%), C. tropicalis (n = 3; 5.4%), C. glabrata (n = 3; 5.4%), and C. lusitaniae (n = 1; 1.8%) were identified. Acremonium kiliense has been detected in 4 pts (7.1%), Cryptococcus neoformans in 2 pts (3.6 %). Histoplasma capsulatum was identified in 1 patient (1.8%). The maximum duration of treatment with F was lifelong with a maximum recorded duration of 4,5 years. The maximum dosage used was 750 mg/d or 50 mg/kg BW in premature infants. No major adverse events were observed. In conclusion, especially the excellent safety profile as well as the documented therapeutic experience justify the use of F as long-term suppressive therapy in FIAI. Higher dosages and even life-long treatment may be needed.

Summary. Fluconazole dosages greater than 800 mg day‐1 have been reported in about 900 patients treated for candidemia, oropharyngeal candidiasis and cryptococcal meningitis in HIV‐infected patients, and for initial therapy of endemic mycoses*. In patients with life‐threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, results of a limited number of dose‐finding trials with non‐neutropenic and HIV‐infected patients show dose‐dependent responses. These study results indicate that higher daily doses of fluconazole than are currently approved for these indications are well tolerated and tend to provide better clinical efficacy in selected patient populations. An excellent safety profile of dosages up to 2000 mg day‐1 and linear predictable pharmacokinetics up to 1600 mg day‐1 appear to justify further clinical investigations to better determine the optimum dosage and duration of treatment. Zusammenfassung. Der klinische Einsatz von Fluconazol in Dosierungen 800 mg/die ist bei etwa 900 Patienten für die Indikationen Candidämie, oropharyngeale Candidose und Cryptococcus‐Meningitis bei HIV‐infizierten Patienten sowie bei der Akuttherapie endemischer Mykosen bereits gut dokumentiert**. Insbesondere bei Patienten mit lebensbedrohlichen, durch Candida spp., Cryptococcus neoformans sowie durch Coccidioides immitis verursachten Infektionen zeigen die Ergebnisse einer begrenzten Anzahl von Dosisfindungsstudien mit immunkompetenten und HIV‐infizierten Patienten dosisabhängige Ansprechraten. Dies stellt ein wesentliches Argument für die Applikation auch hoher Fluconazoldosen dar, wobei die Evaluierung dieses Sachverhaltes noch nicht abgeschlossen ist. Die gute Verträglichkeit auch bei Dosierungen bis zu 2000 mg/die sowie die vorhersagbare, lineare Pharmakokinetik bis zu 1600 mg/die liefern konkrete Anhaltspunkte für die große therapeutische Sicherheit von Fluconazol und rechtfertigen weitere prospektive, randomisierte klinische Prüfungen mit möglichst homogenen Patientenkollektiven zur Definition der optimalen Dosierung und Behandlungsdauer.

Diabetes mellitus is associated with a higher incidence of certain infections, including fungal infections like rhinocerebral zygomycosis (RCZ) and cutaneous candidosis. As the pathophysiology of increased susceptibility to infection of diabetic patients is very complex, a general therapeutic approach is not existing yet. Appropriate diabetes control remains as the best preventive measure. Nevertheless, effective drug therapy is very often required. Fluconazole has proven efficacy in prophylaxis, treatment and suppressive therapy of both systemic and superficial fungal infections, especially in candidosis and cryptococcosis. Therefore it is used routinely against fungal infections in diabetes (FID). Clinical efficacy of fluconazole against cutaeneous candidosis, oropharyngeal candidosis (OPC) and vulvovaginal candidosis (VVC) has been confirmed in more than 100 studies, involving more than 10.000 patients (pts). The overall success rate is 90%, with a mean dosage of 100-200 mg/d. In severe cases, e.g. in OPC in late-stage AIDS pts or in recurrent VVC, higher dosages of up to 800mg/d may be required. In the treatment of RCZ, therapeutic experience with fluconazole is limited . Four diabetic pts have been treated with dosages of 200-300 mg/d and all of them recovered. Nevertheless, treatment of RCZ should include surgical debridement combined with aggressive antifungal therapy. In conclusion, proven efficacy and the excellent safety profile justify the routine use of fluconazole in the treatment of FID.

Continuous arterio-venous haemofiltration (CAVH), continuous veno-venous haemofiltration (CVVH), continuous arterio-venous haemodialysis (CAVHD) and continuous veno-venous haemodialysis (CVVHD) are increasingly used in patients with acute renal failure (ARF). The elimination rate of fluconazole varies considerably depending on the procedure used. (In Germany, fluconazole is approved for the treatment of life-threatening fungal infections caused by Candida spp. and Cryptococcus neoformans at a dosage of up to 800 mg day-1.) The elimination rate of fluconazole by CVVHD depends on the combined dialysate/ultrafiltrate flow rate, but is much higher than achieved with CVVH and intermittent dialysis, with a fluconazole clearance in patients with CVVHD 2 l h-1 exceeding the values of healthy persons. To achieve therapeutic plasma levels during continuous renal replacement therapy, the same loading dose as in patients without renal failure should be administered, followed by a maintenance dose that is adjusted for anuric patients by multiplying by a factor that takes into account the extracorporeal elimination of the absorbed dose (CAVH, CVVH x 2.2, ultrafiltrate flow 0.5 l h-1; CAVHD, CVVHD x 3.8, combined dialysate/ultrafiltrate flow 1.5 l h-1). Despite the broad therapeutic margin of fluconazole, drug monitoring is recommended to achieve therapeutic drug levels in life-threatening indications because there have been only a few investigations of this, all involving relatively low dosages (up to 200 mg day-1).

For this review, 78 studies regarding the use of fluconazole in a total of 726 children below 1 year of age were evaluated. The range of fluconazole dosage was 2-50 mg kg-1 day-1, with 162 days being the maximum duration of treatment. According to current experience, fluconazole seems to be well tolerated and efficacious against systemic candidosis and candidaemia in children below 1 year of age, including neonates and very low-birthweight infants (VLBWIs). The recommended daily dosage is 6 mg kg-1. (In Germany, fluconazole is approved for children between 1 and 16 years in cases in which there is no therapeutic alternative for treatment of systemic infections caused by Candida spp. and Cryptococcus neoformans in a dosage of 3-6 mg kg-1 day-1 and for superficial Candida infections in a dosage of 1-2 mg kg-1 day-1.) In patients with impaired renal function, the daily dose should be reduced in accordance with the guidelines given for adults. In neonates during the first 2 weeks of life, this dosage should be administered only every 72 h. In weeks 2-4 of life, the same dose should be given every 48 h, following which daily dosing is appropriate. This posology is derived from the age-related pharmacokinetics of fluconazole, with a higher volume of distribution and a prolonged plasma elimination half-life, especially during the first month of life. Drug monitoring during treatment should be performed to ensure therapeutic plasma concentrations of fluconazole within a range between 4 and 20 micrograms ml-1. The benefit of fluconazole should be investigated in prospective studies for treatment of systemic candidosis with administration of higher dosages as well as for early empiric therapy in VLBWIs.