Mitigation of Human-Pathogenic Fungi That Exhibit Resistance to Medical Agents: Can Clinical Antifungal Stewardship Help?

Claire M Hull; Nicola J Purdy; Suzy C Moody


Future Microbiol. 2014;9(3):307-325. 

In This Article

We Must Not Approach the Problem of Antifungal Resistance From a Numbers Angle

It has been concluded that whilst the expansion of drug-resistant bacteria is expedited through the horizontal transfer of mobile genetic elements, the uptake of exogenous DNA, including that which might encode resistance mechanism(s), is rare in fungi. A rapid increase in resistance, particularly towards medically relevant agents, is therefore considered unlikely.[14–16] Indeed, on a numbers basis, drug-resistant fungi currently have a lower institutional incidence relative to infections caused by multiresistant bacteria and available surveillance data indicate that, in general, rates of antifungal resistance have remained stable over the last two decades.[3,4,17] Nonetheless, the morbidity and mortality rates associated with certain human-pathogenic fungi (e.g., multiazole-resistant Aspergillus fumigatus causing pulmonary aspergillosis and drug refractory Candida glabrata causing bloodstream candidemia) are unacceptably high.[20,21] In fact, contemporary epidemiological considerations[3–5] indicate that the present scale of antifungal resistance in human-pathogenic fungi – however vast or modest – must not be disregarded, not least because the most susceptible demographic groups (e.g., the immunocompromised, very young and frail elderly) are increasing in number and will continue to do so. The prophylactic use of antifungals deserves particular consideration (see section 'How can we administer antifungals and reduce the selection of antifungal resistance in the clinic?') given changes and continuing improvements in the treatment regimens, prognosis and rates of survivorship associated with several serious health conditions (e.g., cancer and HIV infection). Importantly, whilst Candida albicans is recognized historically as the main causative agent of human Candida infections, over the last decade mycoses due to non-albicans species (e.g., C. glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei) have been reported with increasing frequency.[3,4,20] Of these non-albicans species, C. krusei is intrinsically resistant to fluconazole and C. glabrata is poorly sensitive and also able to acquire resistance to several other antifungals including polyene and echinocandin agents (see section 'Weighing up the threat of fungi exhibiting resistance to medical antifungal agents'). It has been suggested that the emergence of drug-refractory non-albicans species may, in part, be due to widespread prophylaxis with azoles;[20] continued surveillance and research to inform evidence-based guidelines for therapy and/or prophylaxis are needed. Infections caused by azole-resistant A. fumigatus are also an emergent public health concern[5,17,19] and have been given exclusive consideration (see section 'Human-pathogenic molds present in the environment'). Aside from epidemiological considerations, there remains much to discover about the relationship between the human host and fungal pathogens,[7] and the trajectory of antifungal resistance (including any association with comorbidities, health-linked and demographic data) in future is unknown. Finally, only a limited selection of antifungal agents (Table 1) are currently approved for use, underscoring the need for a cautious evaluation of the present scale of clinical antifungal resistance. The most effective and costly of these agents are often unavailable in developing nations[22] where the incidence and epidemiology of some of the most devastating and frequently drug-refractory human-pathogenic infections (e.g., mucormycosis) remains uncharted.[23–25] This knowledge deficit is compounded by an absence of species-specific diagnostic tools (including genetic screens for resistance traits) and the sheer diversity of fungal agents of disease (Table 2 & Table 3).