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antifungals in that at therapeutically achievable concentrations, they may exhibit anti-cytokine and anti-chemokine activity, as demonstrated in an experimental model of Candida glabrata infection.6

This activity, by decreasing

the amount of the inflammatory response, might be especially relevant when echinocandins are used for the treatment of candidaemia or other forms of invasive candidiasis in patients with severe sepsis and/or with septic shock. In fact, as cytokine burden has been frequently correlated with mortality rate during severe sepsis or septic shock,7


may be speculated that early use of an echinocandin for the treatment of candidaemia might be helpful in decreasing mortality rate among critically ill patients.

Resistance to echinocandins is not inducible by fluconazole Studies have shown that the activity of echinocandins against Candida species is unaffected by the development of resistance to fluconazole.8

This is

extremely relevant from the clinical standpoint because it means that echinocandins may maintain unchanged efficacy in some peculiar circumstances, as, for example, in the treatment of candidaemia in those patients who previously received antifungal prophylaxis with fluconazole, or for salvage therapy of candidaemia in those patients who were unresponsive to fluconazole.

PK properties: pros and cons Pros

The echinocandins are hydrophilic compounds, the pharmacokinetic behaviours of which are expected to be only marginally affected by the severity of illness in the critically ill patient (Table 2). In fact, these drugs are only minimally excreted by the kidney as unchanged moieties and this means that no dosage adaptation is required in the presence of the significant changes of renal function, which may usually occur among critically ill patients, neither when continuous renal replacement therapies are applied.9

been hypothesised that because all echinocandins are very highly bound to plasma protein (>96%),

hypoalbuminaemia, a relatively frequent occurrence among critically ill patients, might cause underexposure when these drugs are used at standard dosages.

Table 1: Comparative pharmacodynamic characteristics of echinocandins and fluconazole against Candida species


Antifungal activity Type of activity

Anti-biofilm activity Anti-cytokine activity

Echinocandins Rapid, fungicidal

Concentration-dependent Yes Yes

Fluconazole Slow, fungistatic Time-dependent No No

Table 2: Pharmacokinetic characteristics of the echinocandins Characteristic Loading dose (mg)

Maintenance dose (mg/daily) Protein binding (%)

Fraction excreted unchanged in urine (%)

Anidulafungin 200 100

>99.0 <1.0

Dose adjustment in renal failure Not necessary Hepatic metabolism

None. Slow spontaneous

degradation to inactive product

Caspofungin 70 50

96.0–97.0 <1.5

Not necessary

Yes. Slow peptide hydrolysis,

N-acetylation and spontaneous degradation to inactive product

Dose adjustment in hepatic failure

Not necessary for all of the three classes of Child-Pugh

Child-Pugh 5–6: not necessary

Child-Pugh 7–9: reduce

maintenance dose to 35mg/daily

Child-Pugh >9: do not use because no data

Although no definitive evidence exists to date on this topic, it should be mentioned that recently it was shown that there was no correlation between anidulafungin exposure and disease severity or plasma protein

Conversely, it has

concentrations in a group of critically ill patients treated with anidulafungin.10 Additionally, although anidulafungin exposure was lower in these patients than in the general patient population, the authors considered that this drug exposure could be sufficient in most cases, while it might represent a problem only in those patients with less- susceptible Candida albicans or glabrata strains.10 Finally, as far as hepatic insufficiency is concerned, it should be borne in mind that anidulafungin is the only echinocandin whose elimination is unaffected by the degree of severity of hepatic damage, so that, in contrast to caspofungin and micafungin, it is licensed to be used in patients with any Child-Pugh score (Table 2).

As far as the potential of drug–drug pharmacokinetic interaction is concerned, it is worth mentioning that

Micafungin None 100

99.8 <1.0

Not necessary

Yes. Catechol-O- methyltransferase pathway

Child-Pugh 7–9: No specific

recommendation but AUC significantly decreased

compared with healthy subjects

the echinocandins are only minimally involved, since they are not substrates, inducers or inhibitors neither of the P450 cytochrome system nor of the P-glycoprotein.1

This obviously may

greatly simplify the management of therapy among the critically ill patients who usually received several drug co-treatments.


Although from the pharmacokinetic point of view the echinocandins have several advantages compared with other classes of antifungals, as, for example, the azoles, it should not be overlooked that a major limit of these compounds is the fact that they are unable to diffuse through the anatomical barriers (Table 2).1

This may be clinically relevant considering that one of the major complications of candidaemia is endophthalmitis. This means that when Candida endophthalmitis is suspected and/or documented, echinocandin monotherapy could be sub-optimal and alternative or additional antifungals with high penetration rates through the blood–ocular barrier, such as


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