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Intensive care


Treatment for suspected (empirical) invasive Candida infection in non-neutropenic patients


Based on clinical assessment of risk factors, serologic markers for invasive candidiasis, and/or culture data from non-sterile sites (BIII)


BIII YES Echinocandin


anidulafungin (200→ 100mg/day), caspofungin (70→ 50mg/day), or micafungin (100 mg/day)


BIII YES Fluconazole (800→ 400mg/day) Figure 2: Therapy of (suspected) candidaemia/Candida infection (IDSA)1 Treatment for candidaemia in non-neutropenic patients AI Echinocandin


anidulafungin (200→ 100mg/day) caspofungin (70→ 50mg/day) or micafungin (100 mg/day)


cAmB (0.7–1.0mg/day) Figure 3: Therapy of candidaemia/Candida infection (ESCMID)5


Table 1: Pharmacological properties of echinocandins6 Anidulafungin


Caspofungin


Administration Dosage


Cmax (mg/l)


AUC (mg/hour/l) Clearance (hours)





Volume of distribution Protein binding Elimination


Biotransformation IV


200mg/100mg 7.2


110.3


1 l/hour 24


30–50 >99%


Faeces 30%


Spontaneous degradation


amphotericin B deoxycholate is not recommended for any indication due to severe side effects.5


Voriconazole or


fluconazole are recommended as step-down therapy in selected cases (either oral or IV).


A unique role 20 Echinocandins are cyclic lipopeptide www.hospitalpharmacyeurope.com IV


70mg/50mg 9.9


57.8


10–12 ml/min 9–11 8–10 97%


Faeces 35%


Hydrolysis + acetylation in liver


IV


100mg 10.1 115


0.15–0.3 ml/min/kg 10–17 18–19 >99%


Faeces 70%


Enzymatic degradation in liver


molecules that inhibit the synthetic cell wall enzyme complex, β-1,3-D-glucan synthase. Inability of the organism to build β-1,3-D-glucan destabilises the integrity of the fungal cell wall, leading to osmotic instability and cell death. Echinocandins are known to be active against Candida and Aspergillus species but are also active against Pneumocystis


DI CI Fluconazole (800→ 400mg/day) YES? C. parapsilosis BI


Liposomal AmB


(3mg/kg/day) Voriconazole


6→ 3mg/kg twice a day


Moderately-to-severely ill patients and/or C. glabrata/krusei


NO Recent azole exposure BIII NO BIII


jirovecii. Echinocandins are fungicidal against yeast and fungistatic against mould and have a similar spectrum of antifungal activity. They are not active at clinically relevant concentrations against Zygomycetes, Cryptococcus neoformans, or Fusarium species. In addition, echinocandin activity can persist in a drug-free environment following drug exposure (post-antifungal effect). Pharmacological properties are shown in Table 1.


However, the echinocandins have structural and pharmacokinetic differences.6


Differences between the


three echinocandins with regard to the route of metabolism, requirement for a loading dose, dose adjustment in patients with moderate-to-severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered (Figure 2). Drug–drug interactions are rare. None are major p-glycoprotein substrates and none are metabolised significantly by cytochrome P450.6


Micafungin


All echinocandins have good tissue penetration, but none penetrate sufficiently into the central nervous system or the eye, therefore they are not recommended as the drug of choice for treatment of patients with fungal meningitis or endophthalmitis. Unlike fluconazole, the echinocandins have also shown activity against biofilms. Importantly, with all echinocandins, no dose modification is required in patients with renal insufficiency or moderate hepatic impairment. However, the area under the curve may be increased by up to 75% for caspofungin and a dose reduction to 35mg/day may be required. These agents have an excellent safety profile that is similar to that of fluconazole and a low potential for drug interactions.


Data from prospective randomised trials comparing either: (i) micafungin (100mg/day) with L-AmB (3mg/kg/day); (ii) micafungin (at 100mg/day and 150mg/day, respectively) with caspofungin (70mg/day on day 1 followed by 50mg/day from day 2); and (iii) anidulafungin (200mg IV loading dose followed by 100mg IV daily) compared with fluconazole (800mg IV loading dose followed by 400mg IV daily) for invasive candidosis and candidaemia have been published. According to the results from these trials, echinocandins are strongly recommended for targeted initial treatment of candidaemia, whereas liposomal amphotericin B and


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