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CORRESPONDENCE
Year : 2019  |  Volume : 64  |  Issue : 4  |  Page : 329-330
Antifungal therapeutic failure – Need for a more comprehensive review


Department of Dermatology and Dermatosurgery, Skinnocence, The Skin Clinic and Research Centre, Gurugram, Haryana, India

Date of Web Publication5-Jul-2019

Correspondence Address:
Sidharth Sonthalia
Department of Dermatology and Dermatosurgery, Skinnocence, The Skin Clinic and Research Centre, Gurugram, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.IJD_472_18

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How to cite this article:
Sonthalia S. Antifungal therapeutic failure – Need for a more comprehensive review. Indian J Dermatol 2019;64:329-30

How to cite this URL:
Sonthalia S. Antifungal therapeutic failure – Need for a more comprehensive review. Indian J Dermatol [serial online] 2019 [cited 2019 Jul 18];64:329-30. Available from: http://www.e-ijd.org/text.asp?2019/64/4/329/262177




Sir,

The epidemic of “antifungal therapeutic failure (AFTF)” in South Asian region warrants comprehensive albeit tactful cerebration. I read the review “Antifungal resistance in Dermatology” by Pai et al.,[1] hoping it to be a comprehensive unambiguous revision of this aspect. Although the overall summarization of important issues by authors is commendable, certain inconsistencies and crucial issues are worth highlighting:

  1. The missing distinction between AFTF and “antifungal resistance (AFR)”: AFR is one of the many contributors to AFTF; the latter being more panoptic referring to the clinical dimension (in vivo) of lack of response of a fungal infection despite an appropriate course (including at least drug dose and duration and ensuring patient compliance) of antifungal drug(s). Pending a formal consensus on the clinical terminology encompassed under AFTF, terms such as recurrence, relapse, recalcitrance, and chronic persistence seem to represent its varied clinical presentations.[2] Authors used a term, “clinical resistance,” which in my opinion is different from AFTF (that should include facets of only clinical non- or suboptimal-response) and includes the dichotomy between the in vivo and in vitro response to a particular drug/therapy. The rationale of this distinction is the prevalent confusion amongst dermatologists, and the need for according weighted emphasis to contributing factors other than AFR, to harness the epidemic of AFTF in toto
  2. It is regrettable that ciclopirox (CPX), one of the most promising solutions to the emerging antifungal resistance, was not even mentioned; despite its approval for superficial mycoses having been given in 1985 and 1996 by the Drug Controller General of India and US-FDA, respectively. Not a single case of clinical or in vivo resistance to CPX has been reported despite more than three decades of its frequent use for tinea and mucocutaneous yeast infections globally.[3] Further, in vitro susceptibility to CPX of multiple strains of yeasts have been reported to be better than various azoles including itraconazole and ketoconazole.[4] The reported penetrance of topical CPX into the hair follicles and sebaceous glands [3] also offsets the problem of treatment failures potentially attributable to the recently elucidated dermatophytic invasion of vellus hair in tinea corporis.[5] Finally, laboratory and clinical studies reporting development of resistance and cross resistance of dermatophytes to ergosterol synthesis inhibitors (ESI) specifically itraconazole, terbinafine, and amorolfine following repeated subcultures in sub-inhibitory drug concentrations (in vitro) and prolonged clinical therapy with azoles (in vivo) respectively, failed to show emergence of resistance to CPX.[3] The two most important factors plausibly contributing to the above phenomenon include: 1) unique ESI-independent antifungal mechanism of CPX that involves inhibition of the trivalent metal ion-dependent enzymes leading to accumulation of intracellular peroxides, and 2) irreversible binding to intracellular structures rescuing CPX from drug efflux mechanisms.[3] The potent anti-inflammatory activity of CPX (equivalent to 2.5% hydrocortisone) is a boon, as cognizance of this fact can prevent prescription of steroid-based combination topicals that are often prescribed by clinicians to provide early relief to the patient; albeit at the cost of increasing the likelihood of therapeutic failure and the abuse of and dependence on such topicals by the patients.[3]
  3. The role of agricultural fungicides contributing to primary azole resistance was mentioned, but the Indian scenario was missed out. Although European countries lead the globe in the usage of agricultural fungicides, trends in India are worrisome with a fungicide-to-total pesticide use ratio of 19% reported in 2007, resulting in incidence of azole-resistant filamentous fungi from soil samples in India increasing dramatically from 0% to 5% in 2002–2004 and to 17%–20% just 5 years later, confirming the emergence and spread of azole-resistant fungi in the environment.[6] Despite unaltered overall consumption of pesticides in Indian agroindustry from 2012 to 2016, an estimated 34.2% increase occurred in use of fungicides [7]
  4. The emergence of multi-triazole-resistant and multi-drug-resistant Aspergillus fumigatus, and other saprophytic molds and yeasts posing a real threat of untreatable invasive and systemic infections in immunocompromised individuals in India was missing, a vital aspect that deserved substantial discussion.


Although there are many other issues worth deliberation, the aforementioned are the most important. I strongly recommend that any future reviews/commentaries addressing this issue must ensure a more comprehensive approach with emphasis on data from the Indian subcontinent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Pai V, Ganavalli A, Kikkeri NN. Antifungal resistance in dermatology. Indian J Dermatol 2018;63:361-8.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Shivanna R, Inamadar AC. Clinical failure of antifungal therapy of dermatophytosis: Recurrence, resistance, and remedy. Indian J Drugs Dermatol 2017;3:1-3.  Back to cited text no. 2
  [Full text]  
3.
Sonthalia S, Agrawal M. Topical ciclopirox - Recalling a forgotten ally in the fight against cutaneous mycoses. EC Microbiol 2018;14:515-34.  Back to cited text no. 3
    
4.
Carrillo-Muñoz AJ, Brió S, Alonso R, del Valle O, Santos P, Quindós G. Ciclopiroxolamine: In vitro antifungal activity against clinical yeast isolates. Int J Antimicrob Agents 2002;20:375-9.  Back to cited text no. 4
    
5.
Gómez-Moyano E, Crespo-Erchiga V. Tinea of vellus hair: an indication for systemic antifungal therapy. Br J Dermatol 2010;163:603-6.  Back to cited text no. 5
    
6.
Chowdhary A, Kathuria S, Xu J, Meis JF. Emergence of azole-resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health. PLoS Pathog 2013;9:e1003633.  Back to cited text no. 6
    
7.
Pesticidewise Consumption of Indigenous Pesticides during 2010-11 to 2015-16 [Internet]. Directorate of Plant Protection, Quarantine & Storage, Department of Agriculture, Cooperation & Farmers Welfare, Ministry of Agriculture & Farmers Welfare, Government of India; 9 November 2016 [cited]. Available from: http://ppqs.gov.in/statistical-database/pesticidewise-consumption-indigenous-pesticides-during-2010-11-2015-16. [Last accessed on 2018 Sep 15].  Back to cited text no. 7
    




 

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