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ORIGINAL ARTICLE  
Year : 2019  |  Volume : 44  |  Issue : 5  |  Page : 74-76
 

Emergence of fluconazole-resistant candida infections in diabetic foot ulcers: Implications for public health


1 Department of Podiatry and Endocrinology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
2 Department of Microbiology, Amrita Institute of Medical Sciences, Kochi, Kerala, India

Date of Submission20-Mar-2019
Date of Acceptance26-Aug-2019
Date of Web Publication15-Oct-2019

Correspondence Address:
Dr. Chankramath S Arun
Department of Podiatry and Endocrinology, Amrita Institute of Medical Sciences, Edapally, Kochi - 682 041, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijcm.IJCM_111_19

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   Abstract 


Background: It is well documented in the literature that fungal infections are common in diabetic foot ulcers (DFUs). This has led to an overuse of antifungal agents, namely fluconazole, with a consequent risk of emergence of resistance to this drug. Previous studies have shown a 3.9% prevalence of fluconazole resistance in DFU, but limited data exist regarding the change in resistance pattern over the last decade. Objectives: Our aim was to study the prevalence of resistance to fluconazole in patients with DFU and culture-proven fungal infections. Materials and Methods: We retrospectively studied 1438 patients with type 2 diabetes and nonhealing foot ulcers who had fungal cultures performed during the course of their treatment. The data were collected for all patients who presented to our foot clinic over a period of 18 months. Results: The prevalence of positive fungal culture was 17.38% (250/1438). 151/200 positive cultures belonged to Candida species. Resistance to fluconazole was observed in 9.3% (17/200). The most common organism with resistance to fluconazole was Candida auris (10/17). Conclusions: High prevalence of fluconazole resistance is a potential cause of concern, and the rational use of this drug is important in the community. The above results could have an impact on public health, as fluconazole is one of the safest and effective oral antifungal agents available. The spread of resistance could have implications for its use in other situations including systemic fungal infections.


Keywords: Candida albicans, Candida infection, Candida parapsilosis, diabetic foot ulcer, fluconazole resistance


How to cite this article:
Arun CS, Raju P, Lakshmanan V, Kumar A, Bal A, Kumar H. Emergence of fluconazole-resistant candida infections in diabetic foot ulcers: Implications for public health. Indian J Community Med 2019;44, Suppl S1:74-6

How to cite this URL:
Arun CS, Raju P, Lakshmanan V, Kumar A, Bal A, Kumar H. Emergence of fluconazole-resistant candida infections in diabetic foot ulcers: Implications for public health. Indian J Community Med [serial online] 2019 [cited 2019 Nov 21];44, Suppl S1:74-6. Available from: http://www.ijcm.org.in/text.asp?2019/44/5/74/267803





   Introduction Top


Diabetic foot ulcers (DFUs) are common in the community with prevalence rates ranging from 5% to 10%. The overall lifetime risk of developing DFU in patients with diabetes is estimated to be around 25%.[1],[2] Poor and delayed healing with recurrent infections is a characteristic of DFU. Consequently, the risk of amputations in this group of patients is more than ten times in comparison to nondiabetic individuals.[2],[3] While the predominant microorganism-causing infections in DFU are bacteria, few studies have reported the presence of filamentous fungi and low pathogenic yeast.[3],[4],[5],[6],[7]Candida spp. is the most commonly isolated yeast from these ulcers with a prevalence of 5%–21%.[8],[9]

Fluconazole is recommended as the primary therapeutic option for the treatment of Candida albicans.[4] However, both inherent and acquired resistances to fluconazole are increasingly being reported and are a serious concern.[5],[10]Candida glabrata and Candida krusei are reported to be more resistant to antifungal agents, particularly to fluconazole.[11] Protracted therapy and increased use for recurrent candidiasis are risk factors for the development of resistance to fluconazole.[12],[13] The aim of our study was to document the current prevalence of fluconazole-resistant Candida infections in our patients with DFUs and identify any predisposing factors.


   Materials and Methods Top


This was a retrospective study done on type 2 diabetes patients with DFU who attended the outpatient foot clinic at the endocrinology department of a tertiary care 1200-bedded teaching hospital in South India from January 2014 to October 2015.

All patients with a positive fungal tissue culture during this period were included in the study. 1438 fungal cultures were done during this period, of which 17.38% (250/1438) were positive for Candida species. Nonrepetitive Candida isolates from DFU tissue were identified using VITEK 2 system (bioMérieux, Marcy I'Etoile, France). Antifungal susceptibility for fluconazole, amphotericin B, caspofungin, micafungin, flucytosine, and voriconazole were done using the Vitek 2 semiautomated system (AST-YSO1 cards, bioMérieux). Susceptibility of Candida spp. was interpreted using the CLSI M27-S4 guidelines.[14] Complete clinical and laboratory data were available in 200 patients. The data collected included age, sex, HbA1c, serum creatinine, details of type of procedure, type of organism, and sensitivity pattern. Statistical analysis was done using SPSS 21.


   Results Top


Among the fungal culture isolates, 75.5% (151/200) belonged to Candida species and 6% (12/200) belonged to Trichosporon species. The most common fungal infection was Candida parapsilosis at 30% (60/200), followed by C. albicans (14.5%; 29/200) and Candida auris (5.5%; 11/200). Fluconazole resistance was observed in 17/182 (9.3%) isolates. Of 17 isolates with resistance, 10 were C. auris. 78.5% (157/200) of patients studied were male. The mean age of the study population was 62 ± 10 years and HbA1c 9.1% ± 2.0% [Table 1].
Table 1: Baseline characteristics of patients with positive fungal cultures (n=200)

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Of 17 patients with fluconazole resistance, 7 had undergone toe amputation, 9 had debridement, and 1 patient had foot reconstructive surgery. None of these patients had recurrence of nonhealing ulcers or required higher amputations. HbA1c in the fluconazole resistant group was 9.1% ± 1.5%, which was similar to those with sensitive fungal infection. Amphotericin resistance was 7% (12/183), flucytosine 7.9% (11/143), and voriconazole 4% (7/177) [Table 2].
Table 2: Antifungal resistance pattern in diabetic foot wound cultures

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   Discussion Top


In our study, the prevalence of fluconazole resistance in fungal isolates from DFU was 9.3%. This is significant when compared to a previous study in 2008 from our center, which estimated resistance to fluconazole to be much lower (3.9%). A similar study by Tan et al.[15] showed a fluconazole resistance of 3.2% in all Candida infections in the bloodstream. The reason for this rise in resistance is unclear, although it could be the result of increasing use of fluconazole in our subset of patients.

The prevalence of positive fungal culture in our study was 17.4%. The previous study from our center had found a higher prevalence of 27.2%.[9] The reduction in positive fungal culture could be attributed to genuine reduction in infection secondary to increasing use of fluconazole.

A wide spectrum of fungal isolates was obtained in our study (28 in total) in keeping with previous reports. Candida parapsilosis was the most common infection, followed by C. albicans and Candida tropicalis, which is similar to the finding from our center in 2008.[9] There are previous reports which showed that C. parapsilosis has dramatically increased in significance and prevalence over the past two decades and is now one of the leading causes of invasive candidiasis.[16] A study from Singapore on blood-borne infection had shown similar fungal pattern with low resistance to fluconazole of 3.2%. C. albicans (37%), C. tropicalis (27%), and C. glabrata (16%) were more common in that study with C. parapsilosis less common.[16] Only 1/60 patients with C. parapsilosis infection had fluconazole resistance in our study, which is reassuring. Resistance to other antifungal agents was comparable to previous studies with amphotericin resistance 7%, flucytosine 7.9%, and voriconazole 4%. It is unclear at present whether this is due to limited use of these agents in the community compared to fluconazole.

Patients with fungal infections usually have poor glucose control.[5] Our study showed that those with fungal infection have uniformly poor control although this may not have any implication on antifungal resistance.

Follow-up of our patients with positive fungal culture and resistance to fluconazole showed that all underwent minor amputations or debridement with no evidence of recurrence. Hence, fluconazole resistance was not associated with any clinical deterioration or higher amputation level.

The strengths of our study are the large number of isolates studied and the reporting of the cultures from the same standardized laboratory. The limitations are the retrospective nature of study and the lack of information about previous fluconazole intake in these patients. A prospective study including data on previous fluconazole use and a longer follow-up of these patients will help understand the magnitude of the problem better.

Meanwhile, the increase in antifungal resistance in the community is worrying as this could lead to spread of resistance to hematogenous or invasive fungal infection, which could be potentially lethal. Moreover, lack of other alternative antifungal agents in treatment of severe fungal infections makes it important to prevent spread of resistance.


   Conclusions Top


A rise in fluconazole-resistant Candida infections in DFU raises concern regarding inappropriate use of these agents, especially in diabetes patients. Fluconazole is one of the most commonly used and safest antifungal agents in the primary care with very little side effects. The increase in resistance highlights the importance of drawing up a clear public health policy regarding the use of fluconazole in the community.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Armstrong DG, Wrobel J, Robbins JM. Guest editorial: Are diabetes-related wounds and amputations worse than cancer? Int Wound J 2007;4:286-7.  Back to cited text no. 1
    
2.
Rastogi A, Bhansali A. Diabetic foot infection- An Indian scenario. J Foot Ankle Surg 2016;3:71-9.  Back to cited text no. 2
    
3.
Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005;293:217-28.  Back to cited text no. 3
    
4.
Berkow EL, Lockhart SR. Fluconazole resistance in Candida species: A current perspective. Infect Drug Resist 2017;10:237-45.  Back to cited text no. 4
    
5.
Chellan G, Shivaprakash S, Karimassery Ramaiyar S, Varma AK, Varma N, Thekkeparambil Sukumaran M, et al. Spectrum and prevalence of fungi infecting deep tissues of lower-limb wounds in patients with type 2 diabetes. J Clin Microbiol 2010;48:2097-102.  Back to cited text no. 5
    
6.
Fata S, Saeed Modaghegh M, Faizi R, Najafzadeh M, Afzalaghaee M, Ghasemi M, et al. Mycotic infections in diabetic foot ulcers in Imam Reza hospital, Mashhad, 2006–2008. Jundishapur J Microbiol 2011;4:1-16.  Back to cited text no. 6
    
7.
Missoni EM, Kalenic S, Vukelic M, De Syo D, Belicza M, Babic V. Candida infections of diabetic foot ulcers. Diabetol Croat 2005;34:29-35.  Back to cited text no. 7
    
8.
Chincholikar DA, Pal RB. Study of fungal and bacterial infections of the diabetic foot. Indian J Pathol Microbiol 2002;45:15-22.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Bansal E, Garg A, Bhatia S, Attri AK, Chander J. Spectrum of microbial flora in diabetic foot ulcers. Indian J Pathol Microbiol 2008;51:204-8.  Back to cited text no. 9
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10.
Nithyalakshmi J, Nirupa S, Sumathi G. Diabetic foot ulcers and Candida co-infection: A single centered study. Int J Curr Microbiol App Sci 2014;3:413-6.  Back to cited text no. 10
    
11.
Sardi JC, Scorzoni L, Bernardi T, Fusco-Almeida AM, Mendes Giannini MJ. Candida species: Current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. J Med Microbiol 2013;62:10-24.  Back to cited text no. 11
    
12.
Chander J. Candidiasis – A Textbook of Medical Mycology. 3rd ed. New Delhi: Mehta Publishers; 2009. p. 266-90.  Back to cited text no. 12
    
13.
Gadepalli R, Dhawan B, Sreenivas V, Kapil A, Ammini AC, Chaudhry R. A clinico-microbiological study of diabetic foot ulcers in an Indian tertiary care hospital. Diabetes Care 2006;29:1727-32.  Back to cited text no. 13
    
14.
Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Fourth Informational Supplement, M27-S4. Wayne, PA, USA: Clinical and Laboratory Standards Institute; 2012.  Back to cited text no. 14
    
15.
Tan TY, Tan AL, Tee NW, Ng LS. A retrospective analysis of antifungal susceptibilities of Candida bloodstream isolates from Singapore hospitals. Ann Acad Med Singapore 2008;37:835-40.  Back to cited text no. 15
    
16.
Trofa D, Gácser A, Nosanchuk JD. Candida parapsilosis, an emerging fungal pathogen. Clin Microbiol Rev 2008;21:606-25.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2]



 

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