Echinocandin combinations against Aspergillus:
Do they really work?
For three good reasons, antifungal combinations are a major topic of current interest in treatment of invasive aspergillosis and some other opportunistic mycoses.
First, as with the other invasive mycoses, the incidence of invasive aspergillosis tends to increase parallel to the increase in the number of immunosuppressed patients and the changing face of the epidemiology of the systemic fungal infections. Second, invasive aspergillosis is still difficult-to-treat and associated with mortality rates > 50%. Third, the existence of novel antifungal drugs, particularly of those that act via a different mechanism of action compared to the old ones, now provides the opportunity to search for more effective therapies in combination.
Although the interaction of antifungal drugs in combination merits extensive investigation, the issue is hampered due to the lack of standard in vitro methods. Moreover and more importantly, the correlation of in vitro interaction data with clinical outcome remains yet unknown. Thus, the available data remain preliminary and await further investigation.
One of potential combinations to be investigated in treatment of invasive aspergillosis is the combination of an echinocandin with amphotericin B deoxycholate or one of its lipid formulations. Of the echinocandins under development, the most data are available for caspofungin. Caspofungin is active particularly against the cells at growing hyphal tips of the fungus [
288]. The initial in vitro data showed that the combination of amphotericin B and caspofungin was synergistic or additive for more than half of the
Aspergillus isolates tested and no antagonism was observed for any of the
Aspergillus isolates included in the study [
111]. Other approaches have combined echinocandins with the newer triazoles [
558]. Caspofungin with voriconazole had favorable in vitro efficacy [
1597] and showed improved clearance of
Aspergillus from tissues [
1094].
Following these promising results, a retrospective evaluation of the efficacy of caspofungin and liposomal amphotericin B combination in patients with documented or possible invasive aspergillosis was reported. These data suggested that the combination was more effective when used for primary rather than salvage therapy in documented aspergillosis (clinical response rates of 41% vs. 6%, respectively) [
1119].
Recently, the efficacy of caspofungin and liposomal amphotericin B combination in acute leukemic patients with pneumonia due to
Aspergillus or other fungi refractory to amphotericin B therapy was also reported. Of 20 leukemic patients who received the combination therapy, 75% showed improvement of clinical and radiological signs, although, as the authors note, few of the patients had documented aspergillosis and that further trials were warranted [
38]. To date, clinical reports of the echinocandins with voriconazole or other azoles have been anecdotal.
In summary, the data available on the efficacy of combination of echinocandins with amphotericin B preparations or the newer azoles in aspergillosis appear promising but remain limited. Randomized, comparative, large-scale clinical trials are awaited to clarify the possible advantage of these therapeutic modalities over monotherapy.
