Comparison of efficacy combination oral terbinafine pulse-dosed and topical 8% ciclopirox olamine with terbinafine monotherapy for

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Journal of General - Procedural Dermatology & Venereology Journal of General - Procedural Dermatology & Venereology Indonesia

Indonesia

Volume 2

Number 1 August Edition Article 4

8-31-2017

Comparison of efficacy combination oral terbinafine pulse-dosed Comparison of efficacy combination oral terbinafine pulse-dosed and topical 8% ciclopirox olamine with terbinafine monotherapy and topical 8% ciclopirox olamine with terbinafine monotherapy for onychomycosis: An evidence-based case report

for onychomycosis: An evidence-based case report

Marsha Bianti

Department of Dermatology and Venereology Faculty of Medicine Universitas Indonesia, dr.Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia

Teffy Nuary

Sandra Widaty

Follow this and additional works at: https://scholarhub.ui.ac.id/jdvi

Part of the Dermatology Commons, Integumentary System Commons, and the Skin and Connective Tissue Diseases Commons

Recommended Citation Recommended Citation

Bianti, Marsha; Nuary, Teffy; and Widaty, Sandra (2017) "Comparison of efficacy combination oral terbinafine pulse-dosed and topical 8% ciclopirox olamine with terbinafine monotherapy for onychomycosis: An evidence-based case report," Journal of General - Procedural Dermatology &

Venereology Indonesia: Vol. 2: No. 1, Article 4.

DOI: 10.19100/jdvi.v2i1.38

Available at: https://scholarhub.ui.ac.id/jdvi/vol2/iss1/4

This Article is brought to you for free and open access by UI Scholars Hub. It has been accepted for inclusion in Journal of General - Procedural Dermatology & Venereology Indonesia by an authorized editor of UI Scholars Hub.

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J Gen Proced Dermatol Venereol Indones. 2017;2(1):24-30. 24 Case report

Comparison of efficacy combination oral terbinafine pulse-dosed and topical 8% ciclopirox olamine with terbinafine monotherapy for

onychomycosis: An evidence-based case report

Marsha Bianti, Teffy Nuary, Sandra Widaty

Email : [email protected]

Abstract

Background: Onychomycosis is a fungal infection of the nails, which manifested as nail discoloration, thickening, and detachment from the nail bed. It is not life-threatening, however inappropriate treatment of onychomycosis might lead to complications and affect the patient’s quality of life; making the management of the disease a challenge for clinicians.

Objective: Investigate the efficacy of pulse-dosed oral terbinafine combined with topical 8% ciclopirox olamine to treat onychomycosis.

Methods: Literature search was performed in Pubmed and Cochrane databases using the keywords 'combination' AND 'oral terbinafine' AND 'ciclopirox' AND ‘onychomycosis treatment’ along with their synonyms and related terms.

Results and Discussion: After critical appraisal, studies by Avner et al. and Jaiswal et al. found to be valid, important, and applicable to the patient. The first study found that oral terbinafine combined with topical 8%

ciclopirox olamine is more effective and safe compared to terbinafine as a monotherapy (p<0.05). The second study found similar results, but without statistical significance (p>0.05).

Conclusions: Oral terbinafine combined with topical 8% ciclopirox olamine is more effective than monotherapy, despite statistical irrelevance in one of the studies appraised. Further studies are needed to support the implementation of combination therapy.

Key words: ciclopirox, efficacy, combination, onychomycosis, terbinafine

Introduction

Onychomycosis is a fungal infection of the nails which causes nail discoloration, thickening, and detachment from the nail bed,¹ which is the most commonly encountered nail disease in daily clinical practice (over 50%).² Onychomycosis is experienced by 10% of the population, mostly by the elderly. The prevalence of this problem in individuals over 60-70 years old is 20%, and 50%

in people over 70 years old.¹ Peripheral vascular system, immunological problems, and diabetes mellitus are thought to play a role. Risk of developing onychomycosis in patients with

diabetes mellitus is 1.9 to 2.8 times higher than the general population.³

Toenails are more prone than other fingernail to fungal infections due to their slower growth, less blood flow, and more exposure to humid and closed environments. Risk factors for onychomycosis are history of nail injury, family history, hyperhidrosis, history of other fungal infections within the same time period, psoriasis, history of smoking, usage of closed-toe footwear, and usage of public restrooms.^3,4

The most common organisms causing onychomycosis are dermatophytes from

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J Gen Proced Dermatol Venereol Indones. 2017;2(1):24-30. 25 Trichophyton, Microsporum, and Epidermophyton

genera.^2,5 T. rubrum is the most common species.

Other than dermatophytes, nondermatophytes and yeast can also cause nail fungal infections.

Onychomycosis is classified into several classes according to the morphology, clinical manifestation, and modes of invasion (table 1).

This clinical classification is important in determining the diagnosis, appropriate treatment, and prognosis of the disease.

Onychomycosis is not a life-threatening condition and is often regarded lightly, while the disease can affect quality of life and cause complications, such as cellulitis and foot ulcer in patients with diabetes mellitus.⁵ Treating this infection can pose as a challenge for clinicians. There are several treatment options: debridement, nail avulsion (both surgical and non surgical), topical antifungals (5%

and 8%), systemic antifungals (terbinafine, itraconazole, fluconazole), laser, and a combination of different modalities. Combining treatment modalities is considered to be more effective, which is why we aim to compare the efficacy of pulse-dosed oral terbinafine combined with topical 8% ciclopirox olamine to pulse-dosed oral terbinafine as a monotherapy.

Case Illustration

A 43 year-old woman presented with yellow and whitish discoloration and thickening of the right big toe with minimal discomfort since six months before coming to the clinic. She experienced no pain or itch and could not recall any significant history of toe physical injury. She had previously applied over-the-counter topical antifungals and observed no improvement, but no change was observed. She was a housekeeper. Her daily routine works included washing clothes, cooking, and cleaning her house. She often worked in wet environments around the house. She was experiencing this problem for the first time. She was diagnosed with diabetes mellitus four years ago and was undertreatment of 500 mg metformin three times daily.

Physical examination revealed the patient was alert, mildly ill, 156 cm tall and weighed 68 kgs.

Blood pressure was 120/80 mmHg, heart rate was 86 beats per minute, respiratory rate was 12 per minute, with 36.4°C temperature. Dermatological examination revealed whitish yellow to brown distal nail discoloration on the right big toe, with thick and dystrophic appearance. Pain and itch was absent.

There was no erythema on the skin surrounding the nail and there was no palpable induration. There were no other abnormalities on physical examination. The patient’s immediate bloodsugar level was 177 mg/dL. Fungal examination could from laboratory examination. Lesion scraping was not be performed due to limited resources in the clinic. The patient had a working diagnosis of onychomycosis.

Clinical Question

A clinical question was raised based on the case reported above:

In patients with onychomycosis, is combined therapy of pulse-dosed oral terbinafine and 8%

ciclopirox olamine more effective while compared to pulse-dosed oral terbinafine as a monotherapy?

The PICO (P: patient, population or problem, I:

intervention, C: comparison, O: Outcome) model was used to find the best answer to this clinical question. Description of PICO is described below:

P : patient with onychomycosis I : a combination of pulse-dosed oral terbinafine and 8% ciclopirox olamine C : pulse-dosed oral terbinafine monotherapy O : shows greater efficacy

Type of clinical question: therapy

Methods

Literature search was performed in PubMed and Cochrane databases on February 23 2016 using the keywords 'combination' AND 'oral terbinafine AND 'ciclopirox' AND ‘onychomycosis treatment’

along with their synonyms and related terms.

(Table 2) Selection

We found a total of 15 articles from the literature search. The first step of selection is done by screening titles or abstracts, eliminating double publications. The remaining articles were reviewed using our inclusion criteria, which included suitability to the clinical question and availability of full text versions of the articles. There were two selected articles that suited the clinical question of this evidence based case report (EBCR). (Figure 1) Critical appraisal

The two relevant articles, which are by Avner S, et al⁶ and Jaiswal, et al⁷ were reviewed by authors according to criterias on validity, importance, and applicability.

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J Gen Proced Dermatol Venereol Indones. 2017;2(1):24-30. 26 Table 1. Clinical classification of onychomycosis⁵

Onychomycosis class

Clinical features Causative fungus

Mode of infection Comments

Distal and lateral subungual

Begins distally at the hyponychium and spreads to the nail plate and bed;

hyperkeratotic debris accumulates and results in

onycholysis; nail thicken, chip, become dystrophic, and turn yellow-white or brown-black;

infection can progress proximally, causing linear channels or “spikes”

that can make treatment difficult;

commonly associated with paronychia

Epidermophyton floccosum Trichophyton mentagrophytes Trichopyton rubrum Fusarium sp.

Scopulariopsis bervicaulis Scytalidium sp.

Candida albicans

Fungal invasion through break in the skin at the lateral or distal undersurface of the nail

Most common form

Endonyx subungual

Nail develops a milky white appearance, indentations, and lamellar splitting; no hyperkeratosis or onycholysis

Tricophyton soudanense Tricophyton violaceum

Fungus invades the full thickness of the nail from directly under the skin without infecting the nail bed

Rare;

considered a subtype of distal and lateral subungual onychomycosis Proximal

subungual

Debris accumulates under the proximal portion of the nail, causing onycholysis and a white color that spreads distally

T. rubrum Aspergillus sp.

Fusarium sp.

C.albicans

Fungus invades the proximal nail fold and cuticle; may also develop secondary to paronychia

Suggests an immunosuppres ive condition (e.g HIV infection) Superficial Nail appears to have

powder-like patches of transverse striae on the surface

T.

mentagrophytes T. rubrum Acremonium sp.

Fusarium sp.

Scytalidium sp.

May appear on the superficial nail plate or emerge from under the nail fold;

may be deep penetration of the superficial infection

Previously known as superficial white onychomycosis, but some organisms produce black debris

Total dystrophic Complete destruction of the nail from long- standing infection;

thickening of the nails, and nail structure is lost

- - Can result from

any of the other classes, although it is most often from severe distal and lateral subungual onychomycosis

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J Gen Proced Dermatol Venereol Indones. 2017;2(1):24-30. 27 Table 2. Results of literature search on February 26 2016

Results

We found two randomized controlled trials from our literature search. In the first study, 68 subjects aged 23-56 years old with onychomycosis were divided into two random groups. All the subjects had onychomycosis on the toenails and six of them also had onychomycosis on the fingernails. The most common causative fungus was T.rubrum.

The first group received oral terbinafine 250 mg four times daily for 16 weeks and the second group received combination therapy with oral terbinafine 250 mg q.d. for 16 weeks and ciclopirox nail lacquer applied once daily for nine months. After nine months of treatment, only 58.8% of subjects in the first group experienced clinical improvement, compared to 82.4% of subjects in the second group. Mycological improvement was found in 64.7% of subjects in the first group and in 88.2% of subjects in the second group.

The second study studied 96 subjects aged 11-70 years old with onychomycosis. Eighty-six subjects were female, and ten were male. Results from potassium hydroxide examination and fungi culture revealed the dermatophyte T.rubrum as the main etiology of the subjects’ onychomycosis. This study also found that onychomycosis mostly happened on finger nails.

Subjects were divided into three groups: the first group consisting of 48 patients in the first group received oral terbinafine 250 mg twice daily for one week every month (pulse dose); 24 patients in the second group received oral terbinafine 250 mg twice daily combined with topical 8% ciclopirox olamine nightly; 24 patients in the third group received oral terbinafine 250 mg four times daily combined with 5% once a week at night. After 36 weeks, 71.73%, 82.6%, and 73.91% from each group, respectively, experienced clinical improvement.

Aside from clinical improvements, mycological improvements regarding dermatophytes, nondermatophytes, and yeast in all three subject groups were evaluated. In the first group, 88.9%

improvement on dermatophytes, 50% on nondermatophytes, and 66.7% on yeast were observed. In the second group, 88.9% of dermatophytes, 0% of nondermatophytes, and 100% of yeasts were improved. In the third group, mycological improvements were found in 85.7%

dermatophytes, 0% nondermatophytes, and 50%

yeast.

Discussions

Two articles were appraised from the performed literature search according to the clinical question.

Both of the studies were randomized controlled trials, without double-blinding; which may lead to possible bias in the studies’ results. Table 3 shows whether the results of this single preventive or therapeutic trial valid or not. Table 4 shows whether the results of these randomized trial important or not. Table 5 shows whether both trials applicable about therapy in caring for the patient.

Subjects in both of the studies consisted of patients with onychomycosis aged between 23-56 years old (the first study) and 11-70 years old (the second study). The variety of age in the subject population shows onychomycosis can affect people of various age, thus the subjects of both studies are deemed similar to our reported patient.

The studies’ findings differed regarding predilection of the disease. The first study found toe nails to be a predilection site, while the second study found finger nails as the main predilection site. Our reported patient suffered from toe nail onychomycosis in accordance with the findings.

Toe nails are more susceptible to onychomycosis while compared to fingernails due to their slower growth, less circulation, and more exposure to humid and closed environments. Our patient was a housewife with frequent contact to water in her Database

searched Searching methods Amount of articles found

Pubmed 'combination' AND 'oral terbinafine' AND 11 'ciclopirox' AND 'onychomycosis treatment'

Cochrane 'combination' AND 'oral terbinafine' AND 4 'ciclopirox' AND 'onychomycosis treatment’

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J Gen Proced Dermatol Venereol Indones. 2017;2(1):24-30. 28 daily routine works and a history of diabetes

mellitus; both risk factors for onychomycosis.

The diagnosis of onychomycosis is determined by clinical symptoms in the form of nail discoloration, thickening, and detachment from the nail bed.¹ The supporting examination that is regarded as a gold standard examinations to confirm diagnosis of onychomycosis are nail scraping and fungi culture.

The most common etiology is fungi culture. The most common etiology of onychomycosis is Trichophyton rubrum (a dermatophyte), but due to limited resources, diagnosis in the reported patient was made based on clinical symptoms only,

leading us to only evaluate clinical improvements and disregard mycological improvements.

To our knowledge, treatment for onychomycosis still pose as a challenge for clinicians. Treatments for onychomycosis include debridement, nail avulsion (both surgical and non-surgical), topical antifungal agents (amorolfine and ciclopirox), systemic antifungal agents (terbinafine, itraconazole, fluconazole), laser, and a combination of the listed modalities. Combination therapy was regarded to be more effective for treating onychomycosis.

Figure 1.Flowchart of Literature Search Avner et al (2005) and

Jaiswal et al (2007)

*Search was performed on 23 February 2016, 10.57 AM Review full text articles

Critical appraisal of two articles 2

Inclusion criteria:

- In accordance with the clinical question - Full text

available Screening of titles and abstracts

11

11 4

Filter for double publications

Pubmed Cochrane

Oral terbinafine

Combination Onychomycosis

Treatment A

N D

A N D

A N Ciclopirox D

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J Gen Proced Dermatol Venereol Indones. 2017;2(1):24-30. 29 Table 3. Critical appraisal on validity

Avner et al Jaiswal et al

Was the assignment of patients to treatments randomised? Yes Yes

Was the randomisation list concealed? No No

Was follow-up of patients sufficiently long and complete? Yes Yes Were all patients analysed in the groups to which they were Yes Yes randomised?

Were patients and clinicians kept “blind” to treatment? No No

Were the groups treated equally, apart from the experimental Yes Yes treatment?

Were the groups similar at the start of the trial? Yes Yes

Table 4. Critical appraisal on importance

RRR ARR NNT

CER EER CER-EER CER-EER 1/ARR

CER

Avner 14/34= 6/34= 0,4117-0,1764 0,4117-0,1764 1/0,2353

et al. 0,4117 0,1764 0,4117

= 0,2353 (23%)

= 4,2498 ~ 4

= 0,5715 (57%)

Jaiswal 13/46= 4/23=0,1739 0,2826-0,1739 0,2826-0,1739 1/0,1087

et al. 0,2826 0,2826 = 0,1087 (11%) =9,1996 ~ 9

= 0,3846 (38%) RRR : Relative risk reduction

ARR : Absolute Risk Reduction CER : Control Event Rate EER : Experimental Event Rate NNT : Number Needed to Treat

The second study divided the subjects to three treatment groups, but we did not review the third group (who received a combination of oral terbinafine and topical 5% amorolfine hydrochloride) further because of amorolfine hydrochloride was unavailable in Indonesia, therefore irrelevant to our case. The results of this study showed combined therapy of oral terbinafine and topical 8% ciclopirox olamine was superior to monotherapy with oral terbinafine, but the result was not statistically significant, which might be due to a difference in oral terbinafine dose given to the patients. The second study used twice the recommended dose of terbinafine.

The first study showed the use of pulse-dosed oral terbinafine combined with topical ciclopirox was safer and more effective than oral terbinafine monotherapy (p<0.05) and suggested that the combination therapy was more superior than terbinafine alone as a new, broad-spectrum antifungal agent had a good nail-penetrating abilities and could last up to a few months after treatment cessation. Ciclopirox olamine is also associated with fewer side effects.⁷

The fact that there were only two articles that fit our criteria for critical appraisal indicated the lack of studies on combination therapy for onychomycosis, therefore became a limitation of our critical appraisal process.

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J Gen Proced Dermatol Venereol Indones. 2017;2(1):24-30. 30 Table 5. Critical appraisal on applicability.

Avner et al Jaiswal et al Do these results apply to your patient?

Is your patient so different from those in the study that its results cannot apply?

No No

Is the treatment feasible in your setting?

Yes Yes

What are your patient’s potential benefits and harms from the therapy?

Benefits:

- Improvement on onychomycosis - Shorter duration of therapy - Less side effect

Harms:

- Systemic antifungal side effects might still appear, but the risk is minimized by combining it with topical antifungal.

Are your patient’s values and preferences satisfied by the regimen and its consequences?

Do your patient and you have a clear assessment of their values and preferences?

Yes Yes

Are they met by this regimen and its consequences?

Yes Yes

Level of Evidence: 1b based on The Oxford Centre of Evidence-based Level of Evidence

Conclusion

From the critical appraisals performed, we concluded that combination therapy of pulse-dosed oral terbinafine with topical 8% ciclopirox olamine was more effective compared to monotherapy, despite the lack of statistical significance in one of the appraised studies. To support the implementation of combination therapy as standard practice, further studies were needed.

References

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2. Welsh O, Vera-Cabrera L, Welsh E.

Onychomycosis. Clin Dermatol. 2010;28:151-9.

3. Mayser P, Freund V, Budihardja D. Toenail onychomycosis in diabetic patients: issues and

management. Am J Clin Dermatol.

2009;10(4):211-20.

4. 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. 2000;14(6):466-9.

5. Westerberg DP, Voyack MJ. Onychomycosis:

current trends in diagnosis and treatment. Am Fam Physician. 2013;88(11):762-770.

6. Avner S, Nir N, Henri T. Combination of oral terbinafine and topical ciclopirox compared to oral terbinafine for the treatment of onychomycosis. J Dermatol Treat. 2005;16(5- 6):327-30.

7. Jaiswal A, Sharma RP, Garg AP. An open randomized comparative study to test the efficacy and safety of oral terbinafine pulse as a monotherapy and in combination with topical ciclopirox olamine 8% or topical amorolfine hydrochloride 5% in the treatment of onychomycosis. Indian J Dermatol Venereol Leprol. 2007;73(6):393-6.