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voriconazole or liposomal amphotericin B, should be considered.


The theoretical ideal partner for combination therapy Although, to date, no clinical study has shown superiority of combination therapy in comparison with monotherapy in the treatment of most fungal infections, it is worth noting that the echinodandins may represent the theoretical ideal partner if it is decided to


Consistently, a very effective strategy to balance echinocandin use could be an early step-down strategy to oral azoles (fluconazole or voriconazole) in those patients who improve and achieve clinical stability. In an open-label, non-comparative study that evaluated an intravenous to oral step-down strategy in patients with candidaemia and/or invasive candidiasis treated with intravenous anidulafungin for five days with subsequent step-down to oral azole


”A very effective strategy to balance echinocandin use could be an early step-down strategy to oral azoles in those patients who improve and achieve clinical stability”


treat single cases with a combination of different antifungals. In fact, it was shown that the echinocandins, thanks to the unique mechanism of action located within the fungal cell wall, often act synergistically either with azoles or with amphotericin B.11


This may result


especially helpful in some difficult-to- treat infections, such as aspergillosis. Interestingly, a recent systematic review of animal and human studies concerning combination therapy of echinocandin and triazole in treating invasive aspergillosis showed a trend towards improved overall survival.12


However,


randomised clinical trials are necessary to clarify the effectiveness of the combination therapy. A prospective, randomised, double-blind clinical trial of combination antifungal therapy (voriconazole and anidulafungin vs voriconazole monotherapy) for invasive aspergillosis showed that although the difference in all-cause mortality in the primary analysis was not statistically significant, the combination was beneficial in patients with a diagnosis of probable IA based on a positive galactomannan result.13


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Step-down strategy to preserve echinocandin efficacy Given the potent efficacy of the echinocandins and their current role as primary therapy in the treatment of Candida infections according to several international guidelines, it is expected that their use could increase significantly in the next few years. However, it should not be overlooked that the increase of use could determine an increase in echinodandin resistance rates.14


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therapy (fluconazole or voriconazole) if in the presence of prespecified criteria, this strategy was an effective and well-tolerated approach.15


Safety profile


The echinocandins are very safe compared with other classes of antifungals, even if a warning of possible hepatic dysfunction exists.1


In this


regard it is worth noting the findings of a recent study that assessed the safety of anidulafungin in adult solid organ transplantation (SOT) recipients who received treatment or prophylaxis with anidulafungin for at least 48 hours. Of 86 SOT recipients (56 liver transplant recipients, 20 lung transplant recipients, eight kidney transplant recipients and two heart transplant recipients), no patient discontinued anidulafungin because of severe adverse effects. Only one patient developed mild liver toxicity, but the liver function normalised without drug withdrawal, thus suggesting that anidulafungin is a well-tolerated drug in SOT recipients.16 l


References 1. Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs 2011;71:11–41.


2. Deshpande A, Gaur S, Bal AM. Candidaemia in the non-neutropenic patient: a critique of the guidelines. Int J Antimicrob Agents 2013;42: 294–300.


3. Kett DH et al. Anidulafungin compared with fluconazole in severely ill patients with candidemia and other forms of invasive candidiasis: support for the 2009 IDSA treatment guidelines for candidiasis. Crit Care 2011;15:R253. 4. Maiolo EM et al. Activities of fluconazole,


caspofungin, anidulafungin, and amphotericin B on planktonic and biofilm Candida species determined by microcalorimetry. Antimicrob Agents Chemother 2014;58:2709–17.


5. Bink A et al. The nonsteroidal antiinflammatory drug diclofenac potentiates the in vivo activity of caspofungin against Candida albicans biofilms. J Infect Dis 2012;206:1790–7.


6. Baltch AL et al. Effects of anidulafungin and voriconazole, singly and in combination, on cytokine/chemokine production by human monocyte-derived macrophages infected with Candida glabrata or activated by lipopolysaccharide. Chemotherapy 2012;58: 146–51.


7. Wang H, Ma S. The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. Am J Emerg Med 2008;26:711–5.


8. Rautemaa R et al. Activity of amphotericin B, anidulafungin, caspofungin, micafungin, posaconazole, and voriconazole against Candida albicans with decreased susceptibility to fluconazole from APECED patients on long-term azole treatment of chronic mucocutaneous candidiasis. Diagn Microbiol Infect Dis 2008;62:182–5.


9. De Rosa FG et al. Pharmacokinetics of anidulafungin in two critically ill patients with septic shock undergoing CVVH. J Chemother 2013;25:376–8.


10. van Wanrooy MJ et al. Low but sufficient anidulafungin exposure in critically ill patients. Antimicrob Agents Chemother 2014;58:304–8.


11. Ostrosky-Zeichner L. Combination antifungal therapy: a critical review of the evidence. Clin Microbiol Infect 2008;14 Suppl 4:65–70.


12. Zhang M et al. Efficacy of combination therapy of triazole and echinocandin in treatment of invasive aspergillosis: a systematic review of animal and human studies. J Thorac Dis 2014;6:99–108.


13. Marr K et al. A randomised, double-blind study of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis. ECCMID 2012;Abstr LB2812.


14. Alexander BD et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 2013;56:1724–32.


15. Vazquez J et al. Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial. BMC Infect Dis 2014;14:97.


16. Aguado JM et al. Safety of anidulafungin in solid organ transplant recipients. Liver Transpl 2012;18:680–5.


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