Impact of exposure to triazole

A. Angoulvant


The arrival of fluconazole and itraconazole there are nearly 3 decades has revolutionized the treatment of fungal infections, including invasive. Good systemic spread and especially their good tolerance, have made ​​these first triazole molecules of choice for both curative and prophylactic fungal infections. However, the increasing use of new immunosuppressive therapies was associated with an increased prevalence of invasive fungal infections (IFIs), especially due to Candida non albicans , and filamentous fungi (13) little or not covered by the activity spectra of these two molecules. It took almost 15 years before the triazole 2 nd generation, voriconazole and pozaconazole are available. They are distinguished by their broad spectrum of activity covering both yeasts that most filamentous fungi, Mucorales extended to for pozaconazole, and the fungicide capacity of voriconazole on most Aspergillus sp ..

We can not assess the impact of the use of triazole regardless of chronology, first with that of fluconazole and itraconazole for which we have nearly 30 years of follow then that voriconazole and pozaconazole, newer and particulars of which have been more limited. This impact appears at two levels: that of the population, human or fungal, with changes in the epidemiology of IFIs for an antifungal and sensitivities within a genus or species to another and that of the individual with the possible acquisition of resistance in vivo of a given strain.

These two aspects will be discussed in view of the given literature, with yeasts, particularly Candida sp. initially and filamentous fungi including Aspergillus sp ..

The use of fluconazole prophylaxis is associated with a decreased incidence of candidemia in neutropenic patients with hematological malignancy (12). However, this was accompanied by a switch in the distribution of species responsible for candidiasis. The emergence of C. glabrata decreased susceptibility and / or C. kruseiresistant to fluconazole, was observed in hematology units with patients who received a prolonged fluconazole prophylaxis (8) in intensive care units (1), but also in patients exposed to fluconazole before the episode candidemia, whatever their underlying disease (5). Although the absence of an epidemiological change has also been reported (15), the guidelines for treatment of candidemia IDSA take account of previous treatment with fluconazole for the choice of the molecule prior identification of the causative species (11). It was also reported intra specific epidemiological change with an increased prevalence of reduced sensitivity to fluconazole strains within species known as sensitive as C. albicans , C. tropicalis , C. parapsilosis (10). Itraconazole on the data, the pozaconazole, although fewer reported the same type of data with increasing the proportion of C. glabrataamong Candida isolated in patients who received prophylaxis with these molecules, accompanied by a significant increase in CMI between the beginning and the end of treatment (7). Exposure to azoles, in patients with with high fungal load (HIV APECED) is reported as a risk factor for resistance, often cross, in C. albicans, with both the selection of resistant strains that acquired resistance in a given strain (9).

Although Candida sp. remain the leading etiology of the IFIs in the post fluconazole era, filamentous fungi have become a major concern in hematology as responsible for high mortality. Posaconazole and voriconazole showed their superiority in the prophylaxis and cure of these infections and more particularly aspergillosis (6). As for yeast, the prophylactic use of antifungals may influence the epidemiology of IFIs in filamentous. The recent "emergence" of Zygomycetes in some centers was associated with high use of voriconazole, prophylactic or empirical basis. However, it is unclear whether this association reflects a true epidemiological link or is a marker of the evolution of immunosuppression practices (14). An increase in the frequency of Aspergillus non fumigatuswas correlated to prior exposure to amphotericin B or azole (4). Finally a recent increase in the prevalence of strains resistant to azoles within the complex A. fumigatus has been reported (3). Cases for itraconazole or voriconazole therapy resistance development has been reported (2). However found in the environment of multi resistant strains which have the same genetic profiles as described in patients (16). The hypothesis of the acquisition of environmental resistant strains is supported by studies showing the isolation of such strains in patients who did not receive azole. As for C. albicans resistant strains appear to be more frequently isolated in a context of high fungal load (aspergilloma, ABPA, cystic fibrosis).

The combination of these given the emergence of resistance to triazoles including those of 2 nd generation raises concerns. It must be stressed that they have been reported in some centers and / or countries and they do not seem generalizable. Knowledge of the epidemiology is essential for therapeutic decisions and necessarily requires monitoring at the individual and local level including conducting routine sensitivity tests in vitro antifungal.International monitoring programs are also important to estimate the extent of the problem of the emergence of resistance to azoles.


Full conference title: 

Réunion Interdisciplinaire de Chimiothérapie Anti Infectieuse
    • RICAI 31st (2011)