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

Disclosures

Future Microbiol. 2014;9(3):307-325. 

In This Article

How Can We Administer Antifungals & Reduce the Selection of Antifungal Resistance in the Clinic?

At present, the number of clinically approved antifungal drugs is limited (Table 1), and while antifungal selection pressure can and does occur, if the long-term clinical use of existing agents is necessary for patient treatment, then the immediacy of an ill person will always outweigh the risk of resistance. The potential for human health consequences resulting from widespread prophylaxis or the application of triazoles in agri-/horti-/aqua-culture settings is arguably less defensible; however, economic and crop (food) security issues are important here.[61,77] As recently discussed, prophylactic antifungal use could result in commensal fungi becoming resistant[50] or replacement species that are intrinsically resistant becoming more common as seen in fluconazole prophylaxis given to AIDS patients. The solution may be to give intermittent prophylaxis as this reduces competitiveness of resistance and favors the re-establishment of a normal flora; given the toxicity of many antifungals to liver and renal function intermittent prophylaxis might also help improve quality of life for certain patients. The fact that many immunocompromised people (e.g., cancer patients postchemotherapy and HIV-positive people receiving highly active antiretroviral therapy) can, and do, eventually recover immune function, potentially making shorter term prophylaxis feasible, is also important. With these considerations in mind, future antifungal stewardship initiatives and clinical protocols should promote heightened awareness and vigilance with regard to fungal infection and practical 'point-of-care' interventions, including:

  • Indications for therapy and/or evidence-based prophylaxis guidelines (e.g., avoid prophylaxis where it has not proven efficacious and avoid treating urinary, respiratory or GI colonization);

  • Timing of therapy (generally too late);

  • Using the right agent at the correct dose and for the correct duration;

  • Proper use of therapeutic drug monitoring;

  • Prompt attention to source control (catheter management);

  • Use of follow-up blood culture (e.g., candidemia);

  • Assessment of local epidemiology in terms of species and antifungal resistance;

  • Assessment of outcomes in terms of frequency of infection, response to therapy and costs.

Regardless of the origin of antifungal resistance traits (i.e., acquired versus intrinsic) there remains a need to identify novel therapies and treatment regimens that are effective when drug-refractory and drug-resistant fungal isolates are encountered in the clinic; several approaches offer promise. First, combination therapies (the use of two or more antifungal agents to treat a single fungal disease) constitute one option for the treatment of fungal infections against which antifungal monotherapies are ineffective. From an antifungal stewardship perspective, the benefits of using combination therapies include improved efficacy, lower and therefore less costly drug doses and reduced toxicity.[92] Combination regimens are already recommended and used for the treatment of certain fungal pathogens including Cryptococcus[93,94] and the impetus to determine and validate further combination treatments continues to attract medical and research attention. Pioneering work in this area has included a systems-level approach to rationally predict and exploit drug synergy between possible combination agents[60] in order to repurpose existing biochemical space. A repurposing approach has recently identified several drugs that exhibit fungicidal activity and pharmacological properties relevant to treating cryptococcosis.[59] Finally, studies investigating the genetic and genomic architecture of C. albicans have recently established how multiple mechanisms can underpin the evolution of resistance to antifungal drug combinations.[95] It is anticipated that the methodology developed in this study will provide a foundation for predicting and preventing the evolution of drug resistance to multiple agents in other fungi.

In addition to combination therapies, the development of novel antifungal peptides[96] and modified chemical entities based on existing agents and antifungal drug targets (e.g., Viamet small molecule inhibitors of sterol 14α-demethylase [Viamet Pharmaceutical Holdings LLC, NC, USA] – the classical target of azoles) are also feasible.[97,98] Here, one of the most important facets of future drug design is the need to produce less stable chemical entities and to better understand the biological implications and longer-term selection pressure(s) exerted by drug metabolites and the byproducts of chemical degradation. Aside from new chemical entities that target fungi themselves, the potential to prime the host immune response to augment conventional antifungal therapy is a clear avenue for research and development. With advances in our knowledge of fungal–host interactions the rational design of novel immunotherapeutics is gaining momentum; antifungal immunotherapy now encompasses the possibility of antifungal vaccines[99] and adoptive immunotherapy,[100] both of which could help prevent fungal infections in high-risk patients. Given the motion towards holistic treatment regimens it is interesting to note findings in the recent publication by Lin et al.[101] that indicate how prophylaxis with amphotericin B might increase influenza A virus infection by preventing IFITM3-mediated restriction. The 'off-target' immunomodulatory effects and wider health implications of antifungal (including prophylactic) treatments are important and are now poised to attract much greater scientific attention.

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