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  Table of Contents  
LETTER TO THE EDITOR
Year : 2019  |  Volume : 10  |  Issue : 6  |  Page : 737-738  

Clinical implications of antifungal drug susceptibility testing of dermatophytes


1 Department of Dermatology, Dr. Ram ManoharLohia Hospital and PGIMER, University of Delhi, New Delhi, India
2 Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India

Date of Web Publication1-Nov-2019

Correspondence Address:
Ananta Khurana
Department of Dermatology, Dr. Ram ManoharLohia Hospital and PGIMER, New Delhi - 110 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/idoj.IDOJ_253_19

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How to cite this article:
Khurana A, Sardana K, Chowdhary A, Sethia K. Clinical implications of antifungal drug susceptibility testing of dermatophytes. Indian Dermatol Online J 2019;10:737-8

How to cite this URL:
Khurana A, Sardana K, Chowdhary A, Sethia K. Clinical implications of antifungal drug susceptibility testing of dermatophytes. Indian Dermatol Online J [serial online] 2019 [cited 2019 Nov 13];10:737-8. Available from: http://www.idoj.in/text.asp?2019/10/6/737/270205



Dear Editor,

We read with interest the editorial by Dogra et al. titled “Antifungal Drug Susceptibility Testing of Dermatophytes: Laboratory Findings to Clinical Implications” and congratulate the authors for an explicit review on the methodology of antifungal susceptibility testing (AFST) in dermatophytes and problems thereof.[1] We reiterate that in routine microbiology laboratories; the complexity of susceptibility testing procedure in dermatophytes hampers the determination of actual burden of antifungal resistance. Further, as the authors point out, the lack of epidemiological cutoffs (ECV) and clinical break points (CBP) hinders clinical application of AFST data on dermatophytes. We agree with the authors that as with many other pathogenic molds, in dermatophytes too the availability of clinical outcome for determining the CBPs is by and large lacking. Nonetheless, some significant papers on outcome data on dermatophytoses including individual reports, case series and clinical trials are available that will benefit the readers interested in dermatohytoses research, specifically pertaining to AFST and its clinical implications, and are summarized below.

The earliest attempt at correlating minimum inhibitory concentrations (MIC) within vivo response was possibly by Artis et al. (1981).[2] The study came after a few individual reports of lack of response to Griseofulvin (GRI) in infections by Trichophyton tonsurans[3] and Epidermophyton flocossum[4] with reported MICs of 10-20 μg/ml and 1.6-1.8 μg/ml (increased to 6.8-7.0 μg/ml later) respectively. Artis et al. described 43 patients with tinea corporis/pedis/manuum who had failed GRI therapy.[2] The failure was defined as absence of substantial improvement despite atleast 4 months of GRI 250 mg twice a day therapy. Specimens from all 43 patients grew Trichophyton rubrum on culture. The mean MIC of failures in the tinea corporis group was 6.3 μg/ml versus 1.6 μg/ml in the control group (responders). In the tinea pedis/manuum group the corresponding values were 3 μg/ml and 1 μg/ml. The authors suggested that an MIC of ≥3 μg/ml may be taken as indicative of relative GRI resistance. Notably, the reported MIC 90 of GRI in some recent Indian studies are 64,[5] 4[6] and 8 μg/ml.[7]

For terbinafine (TRB), there are a few reports of therapeutic failure correlated within vitro MICs. The earliest report was described in a patient of onychomycosis who failed treatment with TRB 250 mg/day for 24 weeks.[8] This was the first, and for a long time the only, report ofin vivo TRB failure, confirmed with high MICs and presence of mutations of the target enzyme, squalene epoxidase (SQLE).[9] The MIC of TRB was reported as 4 μg/ml at the start of treatment. Interestingly, the subsequent MICs remain unchanged when measured by the broth micro-dilution method, but an increasing trend was observed when AFST was performed using the macro-dilution method.[9]

Over past 2 years, a few more cases and a clinical trial have been added to the existing literature onin vivo correlation of TRB MICs. Digby et al. from Denmark reported a patient with Darier's disease and extensive dermatophytoses, who failed to respond to two 30-day courses of TRB 250 mg/day.[10] The MIC of TRB was reported as >4 μg/ml.[10] Subsequently, another report from Denmark described a child with icthyosis who failed to respond to TRB.[11] The MIC of TRB was 4 μg/ml.[11] All of these three reports were with T. rubrum infections.[8],[9],[10],[11] The most recent is a prospective study from India where 30 patients of tinea corporis/cruris were treated with increasing durations and up-dosing (250 mg BD) of TRB as per a fixed protocol and the clinical outcomes compared within vitro MICs and SQLE mutation data.[6] A significant finding of the study was that patients infected with a strain with TRB MIC of ≤1 μg/ml were 2.5 times more likely to respond to TRB than those infected with strains with higher MICs. Most of the non-responders had MIC of ≥32 μg/ml. The group which responded to OD dose with standard/prolonged treatment durations had a GM MIC of 1.515 μg/ml, while the group in which TRB was up-dosed to effect a response had a GM MIC of 5.039 μg/ml.[6] The study and the previous reports highlight that a MIC beyond 4-5 μg/ml may preclude therapeutic success with TRB. However, the interpretation has limitation of small patient numbers and warrants further research.

Unfortunately, to the best of our knowledge, noin vivo correlation of MIC data is as yet available for systemic azoles used in dermatophytoses. This is however highly needed in the present scenario, with itraconazole being increasingly used for the infection. To conclude, there are various factors which hinder the routine use of AFST for dermatophytes.[1] However, in the wake of the recalcitrance being seen in the country, there is an imminent need to conduct high-quality research encompassing AFST and itsin vivo correlation to facilitate best utilization of the available antifungal drugs against dermatophytoses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Dogra S, Shaw D, Rudramurthy SM. Antifungal drug susceptibility testing of dermatophytes: Laboratory findings to clinical implications. Indian Dermatol Online J 2019;10:225-33.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Artis WM, Odle BM, Jones HE. Griseofulvin-resistant dermatophytosis correlates with in vitro resistance. Arch Dermatol 1981;117:16-9.  Back to cited text no. 2
    
3.
Michaelides P, RosenthaL SA, Sulzberger MB, Witten VH. Trichophyton tonsurans infection resistant to griseofulvin. A case demonstrating clinical and in vitro resistance. Arch Dermatol 1961;83:988-90.  Back to cited text no. 3
    
4.
Fisher BK, Smith JG Jr, Crounse RG, Roth FJ Jr, Blank H. Verrucous epidermophytosis. Its response and resistance to griseofulvin. Arch Dermatol 1961;84:375-80.  Back to cited text no. 4
    
5.
Rudramurthy SM, Shankarnarayan SA, Dogra S, Shaw D, Mushtaq K, Paul RA, et al. Mutation in the squaleneepoxidase gene of Trichophyton interdigitale and Trichophyton rubrum associated with allylamine resistance. Antimicrob Agents Chemother 2018;62:pii: e02522-17.  Back to cited text no. 5
    
6.
Khurana A, Masih A, Chowdhary A, Sardana K, Borker S, Gupta A,et al. Correlation of in vitro susceptibility based on MICs and squalene epoxidase mutations with clinical response to terbinafine in patients with tinea corporis/cruris. Antimicrob Agents Chemother 2018;62:pii: e01038-18.  Back to cited text no. 6
    
7.
Singh A, Masih A, Khurana A, Singh PK, Gupta M, Hagen F,et al. High terbinafine resistance in Trichophyton interdigitale isolates in Delhi, India harbouring mutations in the squalene epoxidase gene. Mycoses 2018;61:477-84.  Back to cited text no. 7
    
8.
MukherjeePK, Leidich SD, Isham N, Leitner I, Ryder NS, Ghannoum MA. Clinical Trichophyton rubrum strain exhibiting primary resistance toterbinafine. Antimicrob Agents Chemother 2003;47:82-6.  Back to cited text no. 8
    
9.
Osborne CS, Leitner I, Favre B, Ryder NS. Amino acid substitution in Trichophyton rubrum squalene epoxidase associated with resistance to terbinafine. Antimicrob Agents Chemother 2005;49:2840-4.  Back to cited text no. 9
    
10.
Digby SS, Hald M, Arendrup MC, Hjort SV, Kofoed K. Darier disease complicated by terbinafine-resistant Trichophyton rubrum: A case report. Acta Derm Venereol 2017;97:139-40.  Back to cited text no. 10
    
11.
Schøsler L, Andersen LK, Arendrup MC, Sommerlund M. Recurrent terbinafine resistant Trichophyton rubrum infection in a child with congenital ichthyosis. Pediatr Dermatol 2018;35:259-60.  Back to cited text no. 11
    




 

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