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The role of tinea pedis and onychomycosis prevention in diabetic education: A literature review

Posted on September 30, 2019 | Comments Off on The role of tinea pedis and onychomycosis prevention in diabetic education: A literature review

by Ebony Love DPM1, Tracey Vlahovic DPM1*, Lauren Christie DPM1

The Foot and Ankle Online Journal 12 (3): 2

The prevalence of individuals with diabetes has steadily been increasing, creating both a health and economic crisis world-wide.  Previous studies have suggested that foot fungal infections, including onychomycosis and tinea pedis, increase the risk of developing a diabetic foot ulcer. Through a thorough PubMed search, this article aims to review relevant literature relating to superficial fungal infections and patients with diabetes.  

Keywords: Tinea pedis, diabetes, onychomycosis, patient education

ISSN 1941-6806
doi: 10.3827/faoj.2018.1203.0002

1 – Temple University School of Podiatric Medicine, Philadelphia, PA
* – Corresponding author: traceyvlahovicdpm@yahoo.com

The prevalence of individuals with diabetes has steadily been increasing, creating both a health and economic crisis world-wide [1,2]. Diabetic foot infections, one of the major complications associated with diabetes, have significantly contributed to both an increase in mortality and financial burden in the diabetic population. The incidence of diabetic foot ulceration has been reported in up to 19% of the diabetic population, which has been associated with lower limb amputation and mortality [3,4]. In the efforts to prevent these complications from occurring, patients with diabetic foot infections tend to have more frequent outpatient visits, increase frequency of visits to the emergency room, increased frequency and duration of hospital stays, and an increased need for home health care; further increasing the economic crisis of this disease [2].

Previous studies have suggested that foot fungal infections, including onychomycosis and tinea pedis, increase the risk of developing a diabetic foot ulcer [5,6,7]. Diabetics are 2.77 times more likely to develop onychomycosis compared to non-diabetics, negatively impacting their physical and physiological health [8,9]. If left untreated, onychomycosis and tinea pedis can lead to cutaneous injury and ulceration due to dystrophic, brittle nails penetrating the skin and/or interdigital or moccasin skin fissuring, especially in patients with neuropathy or peripheral vascular disease (PVD) [10].

Patient education is critical in diabetic foot care to help manage and prevent diabetic foot infections, other comorbidities, and mortality. The objective of this review is to assess the current literature on foot fungal infections in patients with diabetes as it relates to diabetic foot care education.

Methods 

A PubMed review of literature with keywords of tinea pedis and onychomycosis in patients with type II diabetes was reviewed.

Results 

The frequency of foot fungal infections is significantly higher in diabetics compared to non-diabetics. In a 2016 study, Oz et al., found that while elderly males are at an increased risk of developing onychomycosis regardless of whether they have diabetes, 14% of those in the diabetic group versus 5.9% of those in the control group had tinea pedis and/or onychomycosis [11]. According to Papini et al., in 2013, 69.3% of diabetics with a foot complication present with a foot fungal infection. Dermatophytes were the most common fungal species present, but non-dermatophytes, such as Candida albicans were also noted. Additionally, they found that diabetics with a previous toe amputation were significantly more likely to present with both tinea pedis and onychomycosis concomitantly. They concluded that specific treatment of the fungus involved is necessary for mycological cure to prevent diabetic foot complications, such as ulceration, loss of limb, and loss of life [12].

Another study by Gulcan et al., in 2014, found 25.3% of diabetic subjects mycologically had mycotic nails, out of the 161/321 diabetic patients who clinically presented with mycotic nails. Additionally, there was a significant association between onychomycosis and family history of the disease, BMI, longer duration of being diabetic, neuropathy, and retinopathy. They suggested that diabetic patients who have any of the risk factors found to be associated with onychomycosis in this study, should be properly educated diabetic and fungal infection education, to prevent the development of secondary lesions [13].

In addition to being more prevalent in the diabetic population, fungal foot infections occur in diabetics at a significantly earlier age compared to non-diabetics. In 2008, Legge et al., obtained scrapings from interdigital maceration of 40 diabetics and 40 non-diabetics. Of the 40% of samples collected that tested positive for fungal infection, patients in the diabetic group were on average 6.3 years younger than the non-diabetic group. They concluded that patients with diabetes may be more susceptible to developing tinea pedis at a younger age [14].

In 2017, Takehara et al., analyzed 30 patients with diabetes, 16 of which had tinea pedis, and found the number of times scrubbing between toes while washing with soap was significantly lower in subjects with tinea pedis compared to those who did not have tinea pedis. The number of times subjects scrubbed between toes with soap was also significantly lower in those who had difficulty reaching their feet. The authors suggested that each web space should be scrubbed 4-5 times for tinea pedis prevention and that proper education and intervention should be given to patients who have difficulty reaching their feet on more convenient foot washing positions [15].

It has well been known that foot fungal reinfection can occur from contaminated socks and sneakers. Broughton in 1955 found that individuals who wore cotton or wool socks were particularly susceptible to reinfection in hot, moist conditions, even after six wash cycles [16]. To reduce the risk of relapse, they suggested modifications and materials used to make socks and footwear and improved hygiene could potentially help.

Modifications to cotton socks have been found to have antifungal properties for diabetic patients. In 2012, Tarbuk et al., found modified cotton socks worn by diabetic subjects with active carbon, natural mineral, or zeolite had antimicrobial properties against Candida albicans after 15 washing cycles, unlike the pure cotton control. Modified cotton socks with zeolite additionally had antimicrobial properties to S. aureus. The authors concluded that the active carbon and mineral particles found in the modified cotton socks did not directly prevent microbial infection, but through creating a drier environment for the foot by absorbing more moisture, were able to prevent microbial growth in patients with diabetes [17].

Another treatment that has been shown to be beneficial in reducing fungal load is ultraviolet treatment of shoes of those infected with dermatophytes. Ghannoum et al., in 2012, found that ultraviolet treatment of shoes infected with dermatophytes was significantly effective in reducing fungal load in shoes. There was a 76.28% mean reduction of colony-forming units/ml of Trichophyton rubrum after 3 cycles of UV C radiation treatment. They suggested that by sanitizing shoes, it can stop the cycle of reinfection while being treated for fungal infection by other means and it can help prevent relapse [18].

Prophylactic application of topical antifungals in diabetic patients has also been suggested, given the potential complications that onychomycosis can cause in diabetics and the high reinfection relapse [19]. A study by Sigurgeirsson et al., in 2010, found that patients previously cured from onychomycosis who were prophylactically treated with amorolfine twice a week statistically benefited from prophylaxis up to 12 months after cure. Although relapse rates at 12 months of those treated prophylactically was 8.3% compared to 31.8% of those who were not prophylactically, there were insignificant differences in relapse rates between study groups at 36 months post-cure. While it is unknown if increasing the frequency of dosing would create a better protection against onychomycosis, it is still unclear whether prophylactic application of antifungal medications help prevent onychomycosis in diabetic patients [20].

Conclusion

Onychomycosis and tinea pedis have been attributed to increasing the risk of diabetic foot ulceration and infections, especially in the elderly male population, individuals having diabetes for a longer duration, and diabetics with neuropathy and/or PVD. Based on this review, preventative measures for foot fungal infections including foot washing hygiene, wearing modified socks, shoe wear sanitation, potentially using prophylactic topical antifungal medication on nails, and stressing the importance of attending routine diabetic foot risk assessment appointments in accordance to the Lavery-Armstrong guidelines should be considered during diabetic foot care education [21].

References

  1. Wild S, Roglic G, Green A, Sicree R, and King H. Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 27: 1047-1053, 2004.
  2. Rice JB, Desai U, Cummings AKG, Birnbaum HG, Skornicki M, and Parsons NB. Burden of Diabetic Foot Ulcers for Medicare and Private Insurers. Diabetes Care. 37: 651-658, 2014.
  3. Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, and Veves A. Screening Techniques to Identify People at High Risk for Diabetic Foot Ulceration. Diabetes Care. 23: 606-611, 2000.
  4. Johannesson A, Larsson GU, Ramstrand N, Turkiewicz A, Wiréhn AB, and Atroshi I. Incidence of Lower-Limb Amputation in the Diabetic and Nondiabetic General Population. Diabetes Care. 32: 275-280, 2009.
  5. Boyko EJ, Ahroni JH, Cohen V, Nelson KM, and Heagerty PJ. Prediction of Diabetic Foot Ulcer Occurrence Using Commonly Available Clinical Information: The Seattle Diabetic Foot Study. Diabetes Care. 29: 1202-1207, 2006
  6. Zhong A, Li G, Wang D, Sun Y, Zou X, and Li B. The risks and external effects of diabetic foot ulcer on diabetic patients: A hospital-based survey in Wuhan area, China. Wound Repair and Regeneration. 25: 858-863, 2017.
  7. Gupta AK, Gupta MA, Summerbell RC, Cooper EA, Konnikov N, Albreski D, et al. The epidemiology of onychomycosis: possible role of smoking and peripheral arterial disease. J Eur Acad Dermatol Venereol. 14: 466–469, 2000.
  8. Gupta AK, Konnikov N, MacDonald P, Rich P, Rodger NW, Edmonds MW, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br J Dermatol. 139:665-671, 1998.
  9. Drake LA, Scher RK, Smith EB, Faich GA, Smith SL, Hong JJ, et al. Effect of onychomycosis on quality of life. Journal of the American Academy of Dermatology. 38: 702-704. 1998
  10. Rich P, and Hare A. Onychomycosis in a special patient population: focus on the diabetic. Int J of Dermatol. 38: 17-19, 1999.
  11. Oz Y, Qoraan I, Oz A, and Balta I. Prevalence and epidemiology of tinea pedis and toenail onychomycosis and antifungal susceptibility of the causative agents in patients with type 2 diabetes in Turkey. International Journal of Dermatology. 56: 68-74, 2017. 
  12. Papini M, Cicoletti M, Fabrizi V, and Landucci P. Skin and nail mycoses in patients with diabetic foot. G Ital Dermatol Venereol. 148: 603-608, 2013
  13. Gulcan A, Gulcan E, Oksuz S, Sahin I, Kaya D. Prevalence of Toenail Onychomycosis in Patients with Type 2 Diabetes Mellitus and Evaluation of Risk Factors. JAPMA. 101: 49-54, 2011.
  14. Legge BS, Grady JF, and Lacey AM. The Incidence of Tinea Pedis in Diabetic versus Nondiabetic Patients with Interdigital Macerations. JAPMA. 98: 353-356, 2008.
  15. Takehara K, Amemiya A, Mugita Y, Tsunemi Y, Seko Y, Ohashi Y, et al. The Association between Tinea Pedis and Feet-Washing Behavior in Patients with Diabetes: A Cross-sectional Study. Adv Skin Wound Care. 11: 510-516, 2017.
  16. Broughton RH. Reinfection from socks and shoes in tinea pedis. Br J Dermatol. 67: 249-254, 1995.
  17. Tarbuk A, Grancarić AM, and Magaš S. Modified Cotton Socks- Possibility to Protect from Diabetic Foot Infection. Coll Antropol. 39: 177-183, 2015. 
  18. Ghannoum MA, Isham N, and Long L. Optimization of an infected shoe model for the evaluation of an ultraviolet shoe sanitizer device. JAPMA. 102: 309-313, 2012.
  19. Vlahovic TC. Onychomycosis: Evaluation, Treatment Options, Managing Recurrence, and Patient Outcomes. Clin Podiatr Med Surg. 33: 305-318, 2016.
  20. Sigurgeirsson B, Olafsson JH, Steinsson JT, Kerrouche N, and Sidou F. Efficacy of amorolfine nail lacquer for the prophylaxis of onychomycosis over 3 years. JEADV. 24: 910-915, 2010.
  21. Boulton AJ, Armstrong DG, Albert SF, Frykberg RG, Hellman R, Kirkman MS, et al. Comprehensive Foot Examination and Risk Assessment. Endocrine Practice. 14: 576-583, 2008.

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Clinical clearing of moderate and severe onychomycosis with the Nd:YAG 1064nm laser and post treatment prevention with tolnaftate

Posted on March 31, 2017 | Comments Off on Clinical clearing of moderate and severe onychomycosis with the Nd:YAG 1064nm laser and post treatment prevention with tolnaftate

by Myron A. Bodman DPM1*, Marie Mantini Blazer DPM1, Bryan D. Caldwell DPM1, Rachel E. Johnson DPM1

The Foot and Ankle Online Journal 10 (1): 3

Background: Many patients prefer local treatment to systemic therapy for onychomycosis but efficacy rates, especially in moderate and severe cases have been poor.  The aim of this study was to assess laser therapy clearing in all degrees of severity.  
Methods: Thirty-two patients with mycologically proven onychomycosis received three laser treatments with a long pulse ND:YAG 1064nm laser. The proximal clear zones (PCZ), onychomycosis severity index (OSI) and responses to standardized nail quality of life (Nail Q of L) questions were recorded.  The patients were followed for one year at 9 week intervals while using a tolnaftate in oil topical antifungal after the laser treatments were completed.
Results: The PCZ improved an average of 3.46mms (p<.05), OSI improved an average of 54.6% (p<.05) while the 15.8% improvement in the Nail Q of L responses was found to be not statistically significant.
Conclusions: Severe total dystrophic type of onychomycosis improves significantly with laser therapy. Clinically measuring the onychomycosis severity index and proximal clear zone can help to guide management of an infection that can only improve one mm per month over 9-12 months.  Satisfaction surveys should not be performed frequently but may yield significant results if limited to baseline and after one complete nail growth cycle.  This study found improvement in both PCZ and OSI with the 1064 YAG laser and it encourages further research combining the laser and either pulsed oral or continuous topical antifungal therapies.  

Keywords onychomycosis, ND:YAG 1064nm laser, onychomycosis severity index, nail quality of life.

ISSN 1941-6806
doi: 10.3827/faoj.2017.1001.0003

1 – Cleveland Foot and Ankle Clinic of the Kent State University, College of Podiatric Medicine
* – Corresponding author: mbodman1@kent.edu

OOnychomycosis is a progressive fungal infection of the nail unit that leads to destruction and deformity [1,2]. Approximately 2%-26% of patients amongst various populations worldwide are affected [3]. Patients with concurrent diabetes mellitus and onychomycosis have an increased risk of subungual ulceration and gangrene that can lead to amputation [4]. Onychomycosis can result in significant psychosocial and emotional concerns that may have a significant impact on quality of life [5,6]. It accounts for about half of all nail disorders, and it is the most common nail disease in adults [7]. Although many different modalities are utilized for treatment, laser therapy offers a non-systemic option that many patients prefer. Laser therapy is a FDA approved indication for the temporary clearing of nail for patients with onychomycosis [8]. The long pulsed Nd: YAG laser at the wavelength of 1064nm has shown improvements for patients with onychomycosis between 14% – 56% [9,10]. This 1064nm wavelength is best absorbed by darker fungal pigments resulting in fungal cell apoptosis [11,12]. We offer additional evidence of the successful partial clearing of toenail onychomycosis when treated with a 1064 nm diode Nd: YAG laser. The aim of this study was to assess the clinical clearing of moderate and severe onychomycosis of the great toes with the long pulsed Nd: YAG 1064nm laser and reduction of recurrence with tolnaftate topical solution.

Materials and Methods

The subjects for this study were recruited from the patient populations of the Cleveland Foot and Ankle Clinics.  This study was approved by the Kent State University College of Podiatric Medicine Institutional Review Board.  All subjects signed informed consent forms prior to participating. Thirty-five adult subjects with dermatophyte positive mycology determined by PAS stained nail plate biopsies, were enrolled over a 14-month period.  Fungal cultures are done in FDA drug approval protocols but podiatric physicians often use PAS pathology which is more sensitive, timely and less costly than fungal cultures. Any subjects with less than 25% of nail involvement or negative mycology were excluded. Subjects were not excluded with severe onychomycosis. Due to the difficulty in measuring lesser toenail progress accurately, data collection was limited to only hallux toenails, however all ten toenails were treated. Subjects were excluded who had received oral antifungal therapy within the last 6 months or topical antifungal therapy within last 3 months. Patients with peripheral arterial disease, severe neuropathy, immunocompromised status, current cancer, or pregnancy were excluded (Table 1).

 

Characteristic % (N)
Male 58% (18)
Female 42% (13)
Caucasians 71% (22)
African Americans 29% (9)
Age Range 31-84 years

Table 1 Study cohort.

Figure 1 Digital thermogram of an actual laser procedure as a pulse was delivered to a right third toe temporarily raising the temperature of the nail unit to 41.4C.  Not a study patient.

We used a Nd: YAG 1064 long pulse laser with a spot size of 5mm (Figure 1) [8]. Data was collected at baseline, 6, 12, 18, 36, and 52 weeks. The maximal extent of the infection was measured by determining the proximal clear zone (PCZ) by measuring the distance between the proximal extent of the infection and the central cuticle. Digital photos were taken and onychomycosis severity index (OSI) score was calculated. A nail quality of life (Nail Q of L) survey was administered at each visit. Lubeck’s 15 question nail q of l survey was administered and scored on a 0-100 scale where 0 equals never; 25 equals rarely, 50 equals sometimes, 75 equals often, and 100 equals always, at each visit (Figure 2) [5]. The validated OSI of Carney et al was determined at each observation (Table 2) [13].  

OSI points [13] Baseline % (N) Final  % (N)
Cured (0 pts) 0% (0) 1.7% (1)
Mild (1-5 pts) 0% (0) 21.0% (12)
Moderate (6-15 pts) 14% (8) 17.5% (10)
Severe (16-35pts) 86% (49) 59.6% (34)
All hallux nails 100% (57) 100% (57)

Table 2 Distribution of Study Severities over Time.

1. My nail condition hurts.
2. I worry that my nail condition may be serious.
3. I am ashamed of my nail condition.
4. I worry that my condition may get worse.
5. The skin around my nails is irritated.
6. I am embarrassed about my nail condition.
7. I am frustrated with my nail condition.
8. The skin around my nails and or nail is sensitive.
9. I am annoyed by my nail condition.
10. I have felt frustrated by the lack of improvement of my nails with previous treatment.
11. My nails are difficult to cut.
12. I rely on other people to help cut my nail(s).
13. My nails make me feel less attractive.
14. My nails make me feel self-conscious.
15. I am worried I may give my nail fungus to other people.

Figure 2 Nail Quality of Life Survey Questions.

At each visit, nails were debrided as needed utilizing a nail nipper and rotary burr as in standard clinical practice. The nails were cleansed with alcohol and allowed to dry. Each subject received 3 laser treatments at six week intervals.  The Nd: YAG 1064 long pulse laser total fluence was set at 16 Joules/cm2, 0.3 milliseconds duration and two pulses per second.  Each hallux nail unit received 400 pulses at each laser treatment.  Rest periods were allowed between lasing cycles to accommodate an individual subject’s heat tolerance. At week 18, after completing the 3 laser treatments, patients were dispensed a topical solution of tolnaftate in oil for daily application to prevent reinfection [14].  Treatment failure was defined as an actual reduction in the proximal clear zone rather than slow improvement. Post treatment mycology was not performed since mycological cure was not the goal of this study.

The PCZ, OSI and Nail Q of L data were statistically analyzed using either a One Way Repeated Measures ANOVA or a Friedman Repeated Measures ANOVA on Ranks, depending on whether the data was normally distributed or not.  Significance was defined as p<0.05.  When significance was detected, pairwise multiple comparison procedures were performed using the Holm-Sidak method for normally distributed data or the Tukey test for data that was not normally distributed.  Again, significance was defined as p<0.05.

Results

Thirty-five patients were enrolled in the study over a period of 14 months (Figure 3) (Table 3). Thirty-one patients with 59 infected great toenails completed all three laser treatments. Four patients failed to complete the treatment phase. One patient was excluded because his baseline mycology failed to confirm onychomycosis. One enrolled patient elected oral therapy during the study and was excluded from the results enrolled.  Two patients were lost to follow up after not completing all three laser treatments.

 

Figure 3 Progress of typical study patient’s hallux nail. A: before laser treatment, B: 9 month follow-up, C: 12 month follow-up.

Both the PCZ (P<.001) and OSI (P<0.05) of the moderately and severely infected great toe nails (57) improved significantly and steadily over duration of the study (P<.001) (Figures 4 and 5).  

Figure 4 The average PCZ improved 3.46mms in all patients (p<.05).

Figure 5 OSI score reduced an average of 15.1 points over one year (P<0.05).

Interestingly, the 49 severely infected great toenails, improved their PCZ and OSI scores over the course of the study as well (P<0.001).  Although the Nail Q of L survey responses generally improved, the degree of improvement was not statistically significant (P=0.245) (Figure 6).

Figure 6 Average Nail Q of L scores over one year. Although the Nail Q of L survey responses improved over one year, the improvement was not statistically significant (P=0.245).

Discussion  

The FDA has approved Nd: YAG 1064nm lasers for the temporary increase of clear nail [8]. Several recent articles have studied the Nd: YAG 1064nm laser for mild to moderate onychomycosis while this study looked at the more difficult to treated severe toenail onychomycosis (59.6% N=34).  Recently, Renner, et al., studied the 1064 YAG laser and measured the OSI [9].  In our study, we evaluated the OSI, as well as the Nail Q of L, over one year.  Renner, et al., also allowed patients with recent oral or topical therapy to be enrolled while we excluded them. We did not perform fungal cultures because they are less sensitive, costlier and take longer.  Many practitioners use clinical judgement, supplemented by PAS pathological studies, which are faster, more sensitive and less costly to diagnose onychomycosis [1,7,9].  In this clinical study, to help reduce the anticipated reinfection and recurrence rates that patients can incur, patients were given a preventative topical tolnaftate 1% solution after completing all the laser treatments.  There is no evidence that tolnaftate solution alone improves cure rates and tolnaftate solution does not have an FDA indication for onychomycosis but is commonly used to decrease surface contamination [15].  This study found improvement in both PCZ and OSI with the 1064 YAG laser and it encourages further research with comparative studies combining laser therapy and pulsed oral or continuous topical antifungal therapies [16].

Acknowledgements

The authors would like to acknowledge the contributions of Jill Kawalec, PhD, Director of Research, and Joan Lannoch, the Senior Graphic Designer, at Kent State University College of Podiatric Medicine.   

References

  1. Scher RK, Coppa LM, Advances in the diagnosis and treatment of onychomycosis, Hosp Med. 1998; 34:11-20.
  2. Matricciani L, Talbot K, Jones A. Safety and efficacy of tinea pedis and onychomycosis treatment in people with diabetes: a systematic review, J Foot Ankle Res. 2011; 4:26:E1-E12.
  3. Taheri A, Davis SA, Huang KE, Feldman SR, Onychomycosis Treatment in the United States, Cutis. 2015;95:E15-E21.
  4. Crissey JT, Common dermatophyte infections, A simple diagnostic test and current management, Postgrad Med 1998; 103(2):191-1,197-200, 205.
  5. Lubeck DP, Measuring health-related quality of life in onychomycosis, J Am Acad Dermatol. May 1998; 38(5 Pt 3): S64-8. 
  6. Drake LA, Scher RK, Smith EB, et al, Effect of onychomycosis on quality of life,  J Am Acad Dermatol. 1198;38(5 part 1):702-704.
  7. Scher RK, Tavakkol, Sigurgeirsson AB, et al, Onychomycosis: diagnosis and definition of cure, J Am Acad Dermatol. 2007; 56(6):939-944.
  8. Genesis Plus laser®, Cutera Inc., 3240 Bayshore Boulevard, Brisbane, CA 94005. Food and Drug Administration Web site. https://www.accessdata.fda.gov/cdrh_docs/pdf10/K103626.pdf.  Accessed July 1, 2015.
  9. Renner R, Gruber K, Sticherling M. 1064-nm Diode Laser Therapy of Onychomycosis: Results of a Prospective Open Treatment of 82 Toenails, Dermatology. 2015;230(2):128-134.
  10. Zhang RN, Wang DK, Zhuo FL, et al, Long-pulse Nd: YAG 1064-nm laser treatment for onychomycosis, Chin Med J (Engl). 2012;125: 3288–3291.
  11. Wanitphakdeedecha R, Thanomkitti K, Bunyaratavej S, Manuskiatti W. Efficacy and safety of 1064-nm Nd:YAG laser in treatment of onychomycosis, J Dermatolog Treat. 2015 Apr 17:1-5.
  12. Armour EP, McEachern D, Wang Z, et al. Sensitivity of human cells to mild hyperthermia, Cancer Res. 1993;53: 2740–2744.
  13. Dubois MF, Hovanessian AG, Bensuade S. Heat shock-induced denaturation of proteins. Characterization of the insolubilization of the interferon-induced p68 kinase, J Biol Chem. 1991;266:9707–9711.
  14. Carney C, Tosti A, Daniel R, , et al. A New Classification System for Grading the Severity of Onychomycosis: Onychomycosis Severity Index, Arch Dermatol. Nov 2011:147 (11): 1277-1282.
  15. Formula3 (tolnaftate in oils) The Tetra Corporation, Eaton Rapids, MI 48827. http://thetetracorp.com/products/formula3-antifungal/. Accessed July 1, 2015.
  16. Zaias N, Tosti A, Rebel G, , et al. Autosomal dominant pattern of distal subungual onychomycosis caused by Trichophyton rubrum, J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):302-304.

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Therapeutic approach for toenail onychomycosis: Literature review and cost-effectiveness analysis

Posted on June 30, 2014 | Comments Off on Therapeutic approach for toenail onychomycosis: Literature review and cost-effectiveness analysis

by Antonio Córdoba-Fernández DP PhD1, Priscila Távara-Vidalón DP2, María José Mandredi-Márquez DP3pdflrg

The Foot and Ankle Online Journal 7 (2): 3

Toenail onychomycosis is a very prevailing pathology (50% of the onycopathologies) with rather high rates of failure and relapse.  Most of the cases originate from dermatophytes. The type of onychomycosis, the causative agent, and the factors dependant on the hosts are determining for the correct therapeutic approach of this pathology with rather high failure and relapse rates. Here, we analyse different treatment options focusing on the ideal pharmacologic approach according to current research of cost-effectiveness, pharmacoeconomics and safety.

Key words: onychomycosis, therapeutic, antifungal, pharmacoeconomics

ISSN 1941-6806
doi: 10.3827/faoj.2014.0702.0003

Address correspondence to: Antonio Córdoba-Fernández, Departamento de Podología, Universidad de Sevilla, Edificio Docente de Fisioterapia y Podología, Calle Avicena s/n 41009- Sevilla, Spain.

1 Titular Professor. Departamento de Podología, Sevilla, Universidad de Sevilla, Edificio Docente de Fisioterapia y Podología, Calle Avicena s/n 41009- Sevilla, Spain. (034) 954486539 acordoba@us.es
2 Clinic Assistant . Departamento de Podología, Sevilla, Universidad de Sevilla, Edificio Docente de Fisioterapia y Podología, Calle Avicena s/n 41009- Sevilla, Spain. priscilatavara16@hotmail.com.
3 Clinic Assistant. Departamento de Podología, Sevilla, Universidad de Sevilla, Edificio Docente de Fisioterapia y Podología, Calle Avicena s/n 41009- Sevilla, Spain. mariajo_manfredi@hotmail.com

Superficial dermatophytosis and onychomycosis (OM) are the two most common dermatologic diseases in the United States [1]. The incidence of onychomycosis increases with age, and some studies suggest that up to 48% of the population may be affected by age 65 years [2]. Toenail infection is several times more common than fingernail infection and is generally more difficult to treat because of the slow rate of toenail growth. A recent 12-center North American study found a prevalence of confirmed onychomycosis of 13.8% [1]. The OM incidence may have increased dramatically in recent years as a result of such factors as the aging of the population, higher incidence of diabetes mellitus, greater use of immunosuppressive and antibiotic agents, increased exposure to infecting organisms, and the acquired immunodeficiency syndrome epidemic [3].

Oral medications are associated with high recurrence rates and treatment failure, and are not suitable for many cases due to potential adverse effects. Topical medications are recommended only for mild to moderate cases. The cost of therapies may also be prohibitive in some cases. In the light of these issues, more research is warranted for the investigation and development of more effective and economical options for the treatment and prophylaxis of toenail onychomycosis. In patient populations such as diabetic individuals, where onychomycosis can provoke lower extremity complications, professional podiatric care of toenails and feet should be encouraged [4]. OM has several clinical presentations; distal and lateral subungual onychomycosis (DLSO), proximal subungual (PSO), white superficial (WSO), total nail dystrophy (TDO), and candida onychomycosis (CO).

Etiopathogenesis and risk factors

Dermatophytes are the most frequently implicated causative agents in OM. Dermatophyte invasion of the nail plate is termed tinea unguium. Trichophyton rubrum is responsible for approximately 90% of cases of toenail OM followed by Trichophyton mentagrophytes [1]. Although dermatophytes were
the main causative agents, non-dermatophyte molds and yeasts are also not uncommon etiological agents of OM [5]. Yeasts represent a last common cause of nail fungal infection in the world, and candida albicans and candida parapsilosis are the two most common species in immunosuppressed and diabetic patients [6]. The microorganisms described here do not appear in healthy nails. The presence of those is associated with different predisposing or risk factors such as family history of OM and previous injury to the nails, as well as advanced age and compromised peripheral circulation or previous nail dystrophy. Patients with a compromised immune function, vascular or neurological systematic diseases, diabetes or psoriasis may have an increased risk for OM and are susceptible to infection with less common dermatophytes and nondermatophyte organisms [1].

Differential diagnosis

The clinical diagnosis of OM is not simple. Given the prevalence of the pathology, it is quite frequently misdiagnosed, especially when it affects nails in an isolated way. There is controversy regarding the necessity to use complimentary tests. A study about the cost-effectiveness carried out to analyse different tests for the OM diagnosis concluded that the execution of a microbiological culture or a direct test entails a long process or requires specialized equipment, as well as professional staff. The research also determined that obtaining a positive culture before the treatment with oral antifungal drugs is more cost-effective than just the treatment of all the patients with suspected OM without previous culture [7]. In any case, the diagnosis must be based fundamentally in the physical examination and in an adequate anamnesis to determine the existence of base diseases (diabetes or other immunosuppression) or other factors of behavioural or occupational hygienic risk. Physical examination must also checking for injury, the reason of the consultation, the exploration of the skin and attached skin, looking for satellite injuries at a distance or the presence of tinea pedis or other dermatopathologies such as psoriasis.

Onychomycotic nails may present with subungual hyperkeratosis, onycholysis, nail plate discoloration, and loss of consistency of the nail plate. Not all abnormal appearing nails are due to onychomycosis; in fact, only one half of all such nails may have mycologic evidence of disease. The differential diagnosis includes anatomic abnormalities of nail, for example, pincer nail, trauma, lichen planus, Darrier-White disease (keratosis follicularis), eczema, and psoriasis (Table 1). Paronychia may be due to Candida species or bacterial infection with the proximal nail fold being infected initially in most instances.

OM1

Table 1 Differential diagnosis.

Non-pharmacologic therapeutic alternatives

There are different therapeutic approaches to the pathology that we will explain by focusing particularly in the pharmacologic treatment alternatives, which according to the existing evidence are much more effective.

Mechanical nail debridement is achieved by nail clipping, filing, and abrasion with a dermabrader device, nail nippers, curettes, rasps, scalpels, and/or electronic rotary burrs. It must be executed on every clinical form of onychomycosis. In high-risk patients that cannot be treated with antifungal drugs (poly-medicated elderly patients, pregnant or breastfeeding women), the use of mechanical and/or chemical treatments (nail avulsion with urea at 40%) combined with antifungal medication can be useful with the consequent evident improvement of the pathology.

OM2

Table 2 Association between the nail thickness and the mycological healing (Extracted from: The Journal of Foot & Ankle Surgery [20]).

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Table 3 Results of the treatment with antifungal lacquers. (Adapted from: Journal of Dermatologic Treatment [13]).

The surgical removal of the nail must be assessed with caution due to post-operative complications, poor aesthetical and functional result, and risk of anomalous growth of the nail with the consequent risk of recurrence [8]. Physical therapy includes photodynamic therapy (PDT) and laser therapy. Photodynamic therapy uses visible spectrum light to activate a topically applied photosensitizing agent, which generates reactive oxygen species that initiate apoptosis. Photodynamic therapy was originally optimized for actinic keratosis, but photosensitizers can also be absorbed by fungi. Existing clinical trials has shown that photodynamic therapy is safe, effective, and well tolerated; it promotes a favorable outcome with good patient adherence and may be considered as a practical and feasible treatment option for toenail OM [9]. Laser therapy for OM is the most popular therapeutic option today. The capacity to concentrate energy with determinate wavelength in such a small area, make it the ideal treatment option given that it generates a structural and functional deterioration of the fungal cells provoking the end of the infectious activity [10].

OM4

Table 4 Treatment of Onychomycosis with pulsate and continuous terbinafine. (Extracted from: Journal of the European Academy of Dermatology and Venereology [22]).

However, currently there is a lack of data concerning the long-term efficacy of laser therapy of OM and certified treatment protocols are needed [11].

Pharmacologic therapy

In the treatment of OM, the criteria of strength and effectiveness of the antifungal medication used is very important. However, other aspects such the patient’s age, the clinical form, the extension and time of evolution of the infection, as well as the possible contraindications of the treatment are also important. The treatment depends, in certain measure, on the degree of acceptance of the assigned pattern and the way of administration. From the point of view of the infection, the problems derived from the structure of the nail are decisive, as well as the affected area, since both factors by themselves have influence in the effectiveness of the treatment. On the other side, the antifungal must remain in the nail plate in concentrations that are at least antifungal to guarantee the end of the fungal invasive activity.

Topical monotherapy is indicated for SWO, and it is also a consideration when there is DSLO that affects less than 50% of the surface area without matrix involvement. Taking into account that the nail matrix is not affected by 74.6% of the OM cases, the number of patients that can use topical therapy is high. Topical treatment is indicated when few (ie, three or four) nails are infected and are also recommended for children with thin, fast-growing nails. It must always be considered first due to the small number of secondary effects [8].

Among the different solutions, lacquer is the most used, since its application is more comfortable and it has a better fulfilment of the treatment. They are also more efficient because the active ingredient remains in contact with the nail longer facilitating its action. Ciclopirox is a hydroxypyridone with antifungal and antibacterial activity through its multiple mechanisms of action. The once-daily application of ciclopirox 8% nail lacquer for 48 weeks is recommended for OM toenails. The advantage of its use is that it has fungicidal activity with anti-inflammatory and anti-allergic properties. As a result of the complexity of its mechanism of action, the potential for the development of resistance to ciclopirox is low. The main inconvenience is that it has a different dosage depending of the period of treatment and the hydro-solubility of its recipients, creating confusion to the patient [12]. Amorolfine is an antifungal agent of the morpholine class that is applied in lacquer at 5%. The advantages of its use are its fungistatic (inhibition of cell growth) and fungicidal (cell death) activities against dermatophytes, non-dermatophytes, molds, and yeasts. Tolerable application side effects such as burning, itching, redness, irritation, and pain are associated with amorolfine use. The drawback is the long duration of the treatment with the risk of neglecting the therapy [13]. Tioconazole is a substituted imidazole and it is used in concentrations of 28%. It has antimicrobial and antifungal properties, and has a broad spectrum of activity in vitro against dermatophytes and yeasts, however the cure rate of the treatment with tioconazole nail solution is only 22% [13].

Oral systemic antifungal treatments are generally more effective than topical treatments; however, they are also associated with higher risks of adverse events and drug–drug interactions. Oral therapy is recommended when at least 50% of the nail plate surface is affected (with or without involvement of the nail matrix), or multiple nails are involved, as well as for patients whose conditions have not responded after 6 months of topical therapy [11]. Nowadays, oral terbinafine and itraconazole are standard OM treatments. Itraconazole is a triazole that has antifungal activity against dermatophytes, yeasts, and other fungal infections. Terbinafine is an allylamine that penetrates the nail through the nail matrix and the nail bed and is actually the most potent antifungal agent in vitro against dermatophytes [14]. It is strongly lipophilic and is distributed well in the skin, fat, and nails. The main advantage is that it has been shown to be more effective than the antifungal azoles for dermatophyte OM. The main disadvantage is that it is not as effective as itraconazole for the treatment of candida OM [15]. Regarding the safety of terbinafine and itracozanole by oral intake, the adverse effects associated with the use of those antifungal agents are usually mild, transitory and reversible after discontinuing the treatment. In the analysed research two types of risks are mentioned. The first one mentions the risk of interrupting the treatment due to liver injury or toxicity that generally is quite low and even lower with the use of terbinafine associated with a better safety profile. The second one is the risk of presenting adverse reactions, which varies around 5-10%, the most frequent being linked to the gastrointestinal and nervous systems, liver, and skin [16].

Combination therapy is one way of improving the speed of recovery and the overall cure rate of OM. Although monotherapy has proven effective in the short term, a substantial proportion of patients do not experience a complete and lasting cure. Treatment strategies include topical and systemic antifungal therapies, and surgical and chemical nail avulsion. The use of combination strategies and the exploitation of antifungal drug synergy is a well-established principle in mycology. The combination of two or more drugs can result in increased efficacy and rapidity of effects, a broader spectrum of activity and better patient tolerability. These benefits can often be the result of drug synergy, that is, the combination is more effective than the additive effects of each drug alone. The current strategy for combination therapy involves combining oral and topical antifungal agents. The different modes of drug administration allow for complementary drug penetration into areas of infected tissue where each drug alone does not accumulate in effective concentrations; oral drugs rapidly suffuse and accumulate in the nail bed, while topical therapies effectively penetrate the nail plate and may be effective in preventing reinfection of the nail itself [17-19].

Analysis of the cost-effectiveness of the pharmacologic treatments

The inadmissible rate of therapeutic failure of OM with the pharmacologic treatment is due in many cases to a clinic misdiagnosis and in others to the patients failing to follow the treatment, particularly in the case of topic therapy. We have considered an opportunity to make an analysis of the cost-effectiveness and safety from the existing evidence, which serves as reference when indicating a treatment in patients with OM with the aim to increase the success of the pharmacological treatment.

Therefore, we have carried out the revision of several studies that compare two or more therapeutic alternatives for the clinical and mycological resolution of the OM. The first study with a level of evidence Ib (at least a random clinical trial) establishes that in all the clinical forms of OM, a nail debridement through milling must be done, with the aim to reduce the thickness of the nail, remove the infected surface, and allow the penetration of the medicine through the nail plate. The results of this study prove the inverse proportionality of mycological healing with the lower thickness of the nail (Table 2). On the other hand, the study concludes that in the cases where mechanical debridement was accompanied by the local application of antifungal lacquer (Ciclopirox 8%) the mycological healing rate was higher (76.74% in 10.5 months of treatment) [20].

Regarding the topical treatments with ciclopirox, amorolfine and tioconazole, a second study with a level of evidence IIa (at least a well-designed non-random and controlled prospective research), made a comparison between the different antifungal lacquers commercialized in Europe (France, UK, Germany, Italy and Spain) incorporating also the alternative to not treat, with the aim to determine which one of them is more cost-effective for the treatment of OM. The results proved that the use of ciclopirox 8% once a day during 6 months is the treatment with better cost-effectiveness [13] (Table 3).

Regarding the oral treatments, a third study with level of evidence IIa compared both alternatives of dosage presented by amorolfine 5%, given that the technical specifications allow one or two applications per week. The results indicated that the application once a week is more cost-effective, because it favors the fulfilment of the therapeutic treatment [21]. A fourth study (meta-analysis-evidence Ia) checked the complete mycological healing of OM compared to the use of terbinafine with itraconazole used in both continuous and pulsatile therapy. Such study established that the most effective treatment was the terbinafine continuous treatment with a dose of 250mg/day PO for three months, given that it presented a more prolonged effect in time provoking a higher rate of mycological healing with 13% more success (table 4). On the other side, the pulsatile therapy with terbinafine 250mg/12 hours one week a month during 3 months, presented an excellent cost-effectiveness relation, but it was associated with lower rates of complete healing. This same study also executed an analysis of mycological healing through the use of different pharmacologic alternatives by PO for the treatment of OM, concluding that terbinafine taken continuously, is much more effective (76% healing) compared to itraconazole taken continuously (59%) and pulsatile intake of terbinafine (63%), fluconozole (48%) and griseofulvin (60%) [22]. A fifth multi-center study (evidence level Ib) checked the action of mono-therapy of terbinafine PO 250mg once a day during 3 months in comparison to the combined therapy of amorolfine in nail lacquer 5% once a week during 12 months and terbinafine PO 250mg/day. The obtained results showed that the synergic action of the combined treatment presented a higher rate of success (59.2% in the combined therapy and 45% in the mono-therapy) and the treated patients had more probability to be clinically cured after 18 months (66.7% in combined therapy against a 53.5% in mono-therapy). The decrease of the percentage in affectation of the nail was of 85.1% (78.5% in mono-therapy) after 18 months of treatment. The cost-effectiveness analysis indicates that the total costs were higher for the combined treatment, and due to the efficiency significantly higher for the combined therapy during the same period of time, the costs per patient can be considered inferior in the treatment of amorolfine-terbinafine in all the studied countries [23].

OM5

Table 5 Treatment proposal.

Treatment proposal

Based on existing evidence and in function of the characteristics of each patient and the clinical presentation of OM, we propose in Table 5 and as a summary, the different options of treatment related with the level of scientific evidence of each one of them. It is important to remember that there is a high level of evidence (Ib with recommendation degree A) that proves that the debridement of the nail plate combined with periodic visits to the podiatrist every 2-3 months increases the rate of therapeutic success of OM on toenails.

References

  1. Scher RK, Rich P, Pariser D et-al. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013;32 (2 Suppl 1): S2-4. – Pubmed
  2. Scherer WP, Mccreary JP, Hayes WW. The diagnosis of onychomycosis in a geriatric population: a study of 450 cases in South Florida. J Am Podiatr Med Assoc. 2001;91 (9): 456-64. – Pubmed
  3. Nenoff P, Krüger C, Ginter-hanselmayer G et-al. Mycology – an update. Part 1: Dermatomycoses: causative agents, epidemiology and pathogenesis. J Dtsch Dermatol Ges. 2014;12 (3): 188-209. – Pubmed
  4. Thomas J, Jacobson GA, Narkowicz CK et-al. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther. 2010;35 (5): 497-519.  – Pubmed
  5. Lone R, Bashir D, Ahmad S et-al. A study on clinico-mycological profile, aetiological agents and diagnosis of onychomycosis at a government medical college hospital in kashmir. J Clin Diagn Res. 2013;7 (9): 1983-5. – Pubmed
  6. Ahmed R, Kharal SA, Durrani MA et-al. Frequency of Candida in onychomycosis. J Pak Med Assoc. 2013;63 (3): 350-3. – Pubmed
  7. Lilly KK, Koshnick RL, Grill JP et-al. Cost-effectiveness of diagnostic tests for toenail onychomycosis: a repeated-measure, single-blinded, cross-sectional evaluation of 7 diagnostic tests. J Am Acad Dermatol. 2006;55 (4): 620-6. – Pubmed
  8. Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol. 2013:31 (5): 544-54.  – Pubmed
  9. Figueiredo souza LW, Souza SV, Botelho AC. Randomized controlled trial comparing photodynamic therapy based on methylene blue dye and fluconazole for toenail onychomycosis. Dermatol Ther. 2014:27 (1): 43-7.  – Pubmed
  10. Gupta AK, Simpson F. Newly approved laser systems for onychomycosis. J Am Podiatr Med Assoc. 2012:102 (5): 428-30. – Pubmed
  11. Nenoff P, Grunewald S, Paasch U. Laser therapy of onychomycosis. J Dtsch Dermatol Ges. 2014;12 (1): 33-8. – Pubmed
  12. Monti D, Herranz U, Dal bo L et-al. Nail penetration and predicted mycological efficacy of an innovative hydrosoluble ciclopirox nail lacquer vs. a standard amorolfine lacquer in healthy subjects. J Eur Acad Dermatol Venereol. 2013;27 (2): e153-8.  – Pubmed
  13. Marty JP, Lambert J, Jäckel A et-al. Treatment costs of three nail lacquers used in onychomycosis. J Dermatolog Treat. 2005;16 (5-6): 299-307.  – Pubmed
  14. Gupta AK, Paquet M, Simpson F et-al. Terbinafine in the treatment of dermatophyte toenail onychomycosis: a meta-analysis of efficacy for continuous and intermittent regimens. J Eur Acad Dermatol Venereol. 2013;27 (3): 267-72.  – Pubmed
  15. De backer M, De vroey C, Lesaffre E et-al. Twelve weeks of continuous oral therapy for toenail onychomycosis caused by dermatophytes: a double-blind comparative trial of terbinafine 250 mg/day versus itraconazole 200 mg/day. J Am Acad Dermatol. 1998;38 (5 Pt 3): S57-63.  – Pubmed
  16. Chang CH, Young-xu Y, Kurth T et-al. The safety of oral antifungal treatments for superficial dermatophytosis and onychomycosis: a meta-analysis. Am J Med. 2007;120 (9): 791-8. – Pubmed
  17. Rigopoulos D, Katoulis AC, Ioannides D et-al. A randomized trial of amorolfine 5% solution nail lacquer in association with itraconazole pulse therapy compared with itraconazole alone in the treatment of Candida fingernail onychomycosis. Br J Dermatol. 2003;149 (1): 151-6.  – Pubmed
  18. Lecha M. Amorolfine and itraconazole combination for severe toenail onychomycosis; results of an open randomized trial in Spain. Br J Dermatol. 2001;145 Suppl 60 : 21-6.  – Pubmed
  19. Olafsson JH, Sigurgeirsson B, Baran R. Combination therapy for onychomycosis. Br J Dermatol. 2003;149 Suppl 65 : 15-8.  – Pubmed
  20. Malay DS, Yi S, Borowsky P et-al. Efficacy of debridement alone versus debridement combined with topical antifungal nail lacquer for the treatment of pedal onychomycosis: a randomized, controlled trial. J Foot Ankle Surg. 2009:48 (3): 294-308.  – Pubmed
  21. Pibernat MR, Garcia CI, Carretero LF, et al. Better cost-effectiveness of amorolfine nail lacquer 5% once weekly application vs twice weekly application in the treatment of mild and moderate onychomycosis. Piel. 2006 21(8): 378-85.
  22. Gupta AK, Paquet M, Simpson F et-al. Terbinafine in the treatment of dermatophyte toenail onychomycosis: a meta-analysis of efficacy for continuous and intermittent regimens. J Eur Acad Dermatol Venereol. 2013;27 (3): 267-72.  – Pubmed
  23. Baran R, Sigurgeirsson B, De berker D et-al. A multicentre, randomized, controlled study of the efficacy, safety and cost-effectiveness of a combination therapy with amorolfine nail lacquer and oral terbinafine compared with oral terbinafine alone for the treatment of onychomycosis with matrix involvement. Br J Dermatol. 2007;157 (1): 149-57.  – Pubmed

 

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