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Echinocandins: pharmacokinetics and pharmacodynamics

Particular pharmacokinetic/pharmacodynamic properties of the echinocandins confer advantages over fluconazole in the treatment of candidaemia in the non-neutropenic patient

Federico Pea MD Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy; and Department of Experimental and Clinical Medical Sciences, University of Udine, Italy

The echinocandins are a class of antifungal agents that includes three different compounds, namely anidulafungin, caspofungin and micafungin. Although these semi- synthetic lipopeptides differ from each other chemically, being obtained by modifying different natural products of fungi, they all have similar potent broad-spectrum in vitro activity against Candida and Aspergillus species.1


act by inhibiting the activity of 1,3-b-D- glucan synthase, an enzyme located within the fungal cell wall, and this lead to rapid concentration-dependent fungicidal activity especially against Candida species.1

Candidiasis in Adults, the Joint Recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy (GSMS-PES), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guideline for the Diagnosis and Management of Candida Diseases, and the Brazilian (BZL) Guidelines for the Management of Candidiasis) recommend the echinocandins as primary therapy in the treatment of candidaemia in the non- neutropenic patient, especially in presence of critical illness.2

compared with fluconazole in a secondary analysis of data concerning patients with critical illness (APACHE II score of ≥15; evidence of severe sepsis and/or patient in intensive care), which were extrapolated from a previously published prospective, randomised, double-blind, clinical trial.3

Anti-biofilm activity The reason for

this is related to particular pharmacokinetic/pharmacodynamic (PK/PD) properties of these antifungals that may confer them several advantages versus fluconazole in this setting, especially when candidaemia is associated with severe sepsis or with septic shock (Table 1).

Conversely, fluconazole,

an azole antifungal, acts by inhibiting the 14 a-demethylase, an enzyme located in the fungal membrane and exhibit slow time-dependent fungistatic activity against Candida species.

Pharmacokinetic/ 22

pharmacodynamics properties Currently, international guidelines (the Infectious Diseases Society of America (IDSA) Guidelines for the Management of Candidiasis 2009, the Canadian Clinical Practice (CCP) Guidelines for Invasive

Rapid fungicidal activity The echinocandins exhibit rapid concentration-dependent fungicidal activity against Candida species, in contrast to fluconazole, which is characterised by a slower time-dependent fungistatic activity. From a clinical point of view, this may explain why the echinocandins may exhibit a significantly faster clinical response in the treatment of severely ill patients with candidaemia or with other forms of invasive candidiasis. For example, this was recently shown for anidulafungin

The echinocandins are characterised by a potent anti-biofilm activity, differently from that occurring with azoles. This has been documented in several experimental models showing that the echinocandins at therapeutically achievable concentrations are greatly effective, not only when Candida is in the planktonic status, but also when it is embedded in the exopolysaccharidic matrix of the biofilm.4 Conversely, fluconazole has no anti- biofilm activity neither at supra- therapeutic concentrations.4


pharmacodynamic property of the echinocandins may be helpful in the management of candidaemia, especially in those patients with indwelling intravascular devices, because this may prevent or reduce the adherence of Candida to plastic material. Interestingly, it has been recently shown that this anti-biofilm activity of the echinocandins may be also potentiated by a non- steroidal anti-inflammatory drug such as diclofenac.5

Anti-cytokine activity The echinocandins are unique among

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