Antifungal Susceptibility Testing for Dermatophytosis. When and How? (A Brief Review) 1
Hari Pankaj Vanam, and 2P.Narsimha Rao
1
Assistant Professor, Mycology Division, Department of Microbiology, Bhaskar Medical College and General Hospital,RR.District,Hyderabad,Telangana,India-500075. 2
Professor, Department of Dermatology-DVL, Bhaskar Medical College and General Hospital, RR.District, Hyderabad, Telangana, India-500075. Corresponding Author: Hari Pankaj Vanam, Assistant Professor, Mycology Division, Department of Microbiology, Bhaskar Medical College and General Hospital, Bhaskar Nagar, Yenkapally, Moinbad, R.R. District,Hyderabad, Teleganga – 500 075. Tel:+ 91 773 106 3436 | Facsimile:084 132 354 47 | Email:
[email protected]
orcid.org/0000-0002-4897-335X The Magnitude of Menace of Dermatophytosis in Indian scenario: We are in a predicament to define the sudden upsurge in dermatophytosis in India- is it an endemic or hyper endemic? With the very reason that we lack concrete data and systematic approach. Over years, the dermatologist in India inculcated experienced-based approach rather than evidenced-based treatment to address dermatophytosis. Opening the Pandora box - we are posed with a multitude of issues starting with the menace of T.mentagrophytes , protean manifestations of tinea, erratic and unethical use of topical steroids and formulations like FDCs (fixed drug combinations),introduction of some products which doesn’t even have efficacy data, environmental factors like rise in temperatures, host factors, multiple infected persons in family, dermatophytosis in patient with comorbidities, concomitant infections, spread of fomites which have become the part-and-parcel of prolonging the course of tinea thus opening the doors for a new era “the changing face of dermatophytosis”. It’s a proven fact that Antifungal susceptibility testing (AFST) is a useful tool to provide information to clinicians to help guide therapy, we have had learned significant experiences. Given the technical setbacks and laborious nature of these procedures, they are more confined to reference laboratories for research-based studies. Putting this as a perspective it’s time to introspect: Aren’t we still following a fluke to tackle this herculean task?
Dermatophytes Drug Resistance! Aetiological agents attributed in causing Dermtophytosis fall in the group of a keratinophilic moulds of three genera Trichophyton, Epidermophyton and Microsporum. It’s easy to coil the term “rise in antifungal resistance” but do we have any evidence to support this term. Over decades we have learned that treatment failure can be an attribute of antifungal resistance which is considered independently for each antifungal class and for each fungal genus. As we evolve with systematic studies, we are in a state to define these quintessential terms: Microbiological Resistance and Clinical Resistance, wherein the former confers no susceptibility of an antifungal drug either intrinsically or by an acquisition mechanism in the form of higher MICs (Minimum Inhibitory Concentrations) in antifungal susceptibility testing (AFST), whereas the latter can be of multifactorial. Furthermore, reports confirming putative genes implicated in resistance mechanisms in T.rubrum and T.mentagrophytes will strengthen the correlations.
AFST: A Mere Clinical utility or Clinical significance? Where do we stand now! Under the auspices of CLSI (Clinical and Laboratory Standards Institute), The EUCAST (European Union Committee on Antimicrobial Susceptibility Testing), and BSAC (British Society of Antimicrobial Chemotherapy) standardized the microdilution method with reference documents CLSI M38-A2 & EUCAST Edef 9.2, respectively. The validation and the clinical significance using this method demands determination of MIC breakpoints for dermatophytes and in-vitro and in-vivo correlation studies. By far the most data accrued to support the clinical relevance of AFST results come from Candida against fluconazole. Taking the gravity of situation both national and global forums are taking up dermatophytes AFST to accumulate as much data as possible to predict the ECV’s (Epidemiological cut-off values) at all the geographical levels. With several agents now available for treating infections due to dermatophytes, susceptibility testing will serve as a valuable tool for clinicians as they choose the most appropriate treatment option. Studies are still needed to establish interpretive breakpoints for antifungal agents used in the treatment of cutaneous mycoses. While some infections do respond to topical therapy, others, particularly involving the scalp and nails, require prolonged systemic therapy. Therefore, determining the susceptibility patterns of dermatophytes will allow clinicians to choose the most appropriate antifungal therapy.
A Million dollar question is “whether this highly artificial measure can correlate with clinical outcome?” Recently, the CLSI and EUCAST standardized the AFST for moulds and at this juncture, it would be naïve to speak whether an artificial measure can predict the clinical outcome? Lessons learned from Rex and Pfaller through his antibiotic susceptibility testing concludes with the “90–60 rule,” which implies that infections due to susceptible organisms responded favourably to appropriate therapy about 90% of the time, while infections due to resistant ones, when treated with the agent to which they were resistant, responded about 60% of the time hence strengthening the host-organism interactions as an important component. Thus the in-vitro resistance of an organism to an antifungal agent should help predict clinical failure and also suggest the dermatologist up-dose the drug for a good clinical outcome. The story of the Clinical relevance of mould AFST is intriguing and still needs to be addressed systematically Ex: An increase in MIC values for azole drugs found for isolates after therapy might raise the possibility of increased antifungal resistance, or an increase in MIC may warrant up-dosing or change in the regimen itself. In order to establish a relationship between MIC and clinical outcome, one requires not only sufficient numbers of resistant isolates but also a sufficient number of patients infected with resistant isolates and treated with the drug to which the isolate is resistant. Hence understanding this complexity of demonstrating an association between an increased MIC in AFST will not be a fortnight issue and it needs a persistent and systematic investigation taken up both at intra & inter-laboratory collaborations and the results of such multi-centric studies will influence the potential clinical outcome, hence open new avenues in clinical management.
When an AFST in dermatophytosis is warranted: 1.
Tinea capitis and Tinea unguium, and cutaneous lesions with folliculitis which are poor responders of topical treatments and hence require systemic treatment.
2.
Chronic dermatophytosis and cases where multiple members in a family are infected.
3.
Suspected clinical resistance.
4.
Any new antifungal agent or a combination showing promising in-vivo Ex: Statins and antidermatophyte drugs, extracts from alternative practices of medicine.
5.
Conditions mimicking tinea but caused by NDM-Non dermatophytic moulds.
6.
Treating dermatophytosis in patients with multiple comorbidities.
How is it possible to perform AFST at every level? 1.
A need for association- “marriage of a mycologist experience with the dermatologist clinical acumen”.
2.
National wide epidemiological and surveillance studies for AFST to predict endpoints and ECV’s
3.
A moral responsibility of pharma companies to provide the pure drug powder.
4.
Reference laboratories need to establish network laboratories for surveillance studies.
5.
Accessibility of Quality control strains for AFST testing to comply and reproduce the reference methods.
6.
Agenda took up by appropriate academies, State and Federal departments like a national program.
7.
AMR-Antimicrobial Resistance Monitoring wing of ICMR-Indian Council for Medical Research should recognize the rising concerns of recalcitrant dermatophytosis and include the same.
Conclusion: Studies in AFST of dermatophytes are on a right trajectory and results are very promising. The governing bodies have significantly contributed in amending and upbringing the simplified procedures for the otherwise cumbersome technique. The need of the hour is a systematic approach: Multi-centric studies planned and executed both at intra and inter-laboratories under the aegis of the state and national departments. The same shall open the avenues to pool-up the AFST data and predict ECVs and clinical endpoints thus making a way towards an evidence-based approach to treat dermatophytosis.
Acknowledgement: We sincerely wish to thank the IADVL-iTART team –Dr.Majunath Shenoy and Dr.R.Madhu for giving us the opportunity to emphasize upon the need for AFST studies in dermatophytosis.
References:
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Rex JH, Pfaller MA, Walsh TJ et al. Antifungal susceptibility testing: practical aspects and current challenges. Clin Microbiol Rev 2001;14: 643–58. National Committee for clinical laboratory standards. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi. Approved standard M38-A2. NCCLS, Wayne, USA; 2008. J.L. Rodriguez-Tudela, et al., EUCAST Definitive Document EDef 7.1: method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts: In Clinical Microbiology and Infection, Volume 14, Issue 4, 2008, Pages 398-405, ISSN 1198-743X, https://doi.org/10.1111/j.14690691.2007.01935.x. Ghannoum MA, Isham NC, Chand DV. Susceptibility testing of dermatophytes. Curr Fungal Infect Rep 2009; 3: 142–6. Alcazar-Fuoli L, Mellado E. Current status of antifungal resistance and its impact on clinical practice. Br J Haematol. 2014;166:471-84. Dabas, Y.; Xess, I.; Singh, G.; Pandey, M.; Meena, S. Molecular Identification and Antifungal Susceptibility Patterns of Clinical Dermatophytes Following CLSI and EUCAST Guidelines. J. Fungi 2017, 3, 17.
