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

Mapping the Epidemiology of Resistance: Considerations & Challenges

Perhaps one of the most important characteristics of A. fumigatus is its potential to disperse via the production of airborne conidia (Figure 1). However, other well-known environmentally ubiquitous molds (including plant-commensal and plant-pathogenic species) that cause opportunistic diseases in humans ( Table 2 & Table 3 ) produce airborne spores that could provide a vehicle for the dispersal of resistance traits. In addition to airborne spores, the persistence of drug-refractory spores from Aspergillus spp. and countless other molds in soil, plant debris and water (fresh and saline) ( Table 3 ), many of which can exploit alternative infection routes (e.g., traumatic inoculation, ingestion and mucosal surface invasion) is largely uncharted. From an epidemiological perspective this knowledge deficit is significant because outbreaks of mucormycosis and invasive fungal disease caused by filamentous fungi and molds are known to account for high morbidity and mortality following natural disasters.[83,84] Moreover, because the environmental niches and natural reservoirs of numerous fungal pathogens remain unknown (e.g., Paracoccidioides brasiliensis) or ill-defined (e.g., Blastomyces dermatitidis[85]) and because even some better-known pathogens (e.g., A. fumigatus) can be hard to culture,[86] difficult to differentiate morphologically or cannot be identified using contemporary diagnostic tools, it is currently impossible to predict the environmental epidemiology of these. The implications of climatic variation (e.g., on airborne spore counts;[87]) that could ultimately affect the geographic distribution of plant- and human-pathogenic fungi are also important and further complicate the task of designing and implementing clinical antifungal stewardship guidelines over space and time.

Animal Vectors & Human Host Factors

If the impact of abiotic factors on the distribution of human-pathogenic fungi that are resistant to antifungal agents is difficult to gauge, then the role of animal vectors is even more complicated. Candida spp. that exhibit in vitro resistance to medical azoles have been isolated from several wild animals,[88–90] yet the explanation as to why and how these resistant isolates persist is unclear. In fact, aside from a handful of classical examples (e.g., Cryptococcus and Histoplasma spp. in bird or bat guano), the extent to which certain human-pathogenic fungi exist as commensals or pathogens in animals at large (including migratory and domestic species) is poorly defined. Regional trends in the animal and plant host spectrum of human-pathogenic fungi are important from a disease distribution perspective, especially because many communities worldwide live and work in close proximity to local flora and fauna.

The epidemiology of intrinsic resistance traits within both human-commensal and human-pathogenic species is also a major research frontier. Recent findings from the SENTRY Antimicrobial Surveillance Program[4] exemplify how species distribution and antifungal resistance patterns vary with patient age and underscore how little we know with regard to the epidemiology of fungal infections, including those that exhibit resistance. The risk of secondary fungal infections in immunocompromised patients has long been recognized, and antifungal prophylaxis is already recommended for high risk individuals.[20] Conversely, the importance of fungi in the health of the immunocompetent human host is less well-acknowledged. The influence of patient-specific factors, including general health and immunity, drug regimens, lifestyle, ethnicity and demographic information with respect to the human-commensal fungal microbiotia is uncharted[85] and the impact of human host factors on fungal infections[7] and associations between health conditions (e.g., asthma) and infection with fungal pathogens[6] are emergent research areas.

Monitoring & Surveillance of Fungal Diseases at the Population Level

Health informatics is one approach that promises to enhance research capacity in the area of infection surveillance and disease control.[91] First, it will enabe the rapid retrieval of baseline metrics regarding the overall prevalence of infectious disease and secondly, it will allow more detailed (anonymized data-linked) enquiries into the relationship between certain infections and demographic factors and/or wider health issues. The power of data-linkage will increase over time as more specific diagnostic tools and standardized surveillance protocols for infection are implemented across healthcare settings. Indeed, because the scale and epidemiology of fungal infections is poorly mapped, suitable preventative measures, treatment guidelines and diagnostic information for at-risk patient groups and healthcare professionals may be lacking. Fungal infections, including intrinsically drug-resistant species, may have more significant relationships with other human health problems than are currently acknowledged. In the future, health informatics could allow us to identify associations that inform antifungal stewardship and the development of treatment regimens that are more appropriate for certain patient groups and ultimately, individual patients.