Real World Analysis of Response Rate and Efficacy of Oral Ketoconazole in Patients with Recalcitrant Tinea Corporis and Cruris

ABSTRACT.

Recalcitrant dermatophytosis has had an alarming rise in India with concomitant decreased effectiveness of conventional antifungal agents. This has prompted the use of second-line agents for treatment. In this retrospective study, we aimed to analyze the response rate, efficacy, relapse rate, and side effects of oral ketoconazole (KZ) in the treatment of recalcitrant tinea corporis and cruris. Institutional records were reviewed for patients presenting with tinea cruris or corporis who had failed treatment with conventional antifungal drugs and treated with oral KZ. Potassium hydroxide (KOH) findings, culture reports, and response to treatment was noted based on the percentage improvement in lesions and reduction in itching compared with baseline. Fourty-three patients (mean age 31.3 years) with tinea corporis/cruris who had taken prior treatment with antifungals were recruited in the study. KOH mount and culture were positive in 76.7% patients. Trichophyton mentagrophytes was the commonest species, isolated in 62.8% of patients. Ketoconazole showed the lowest minimum inhibitory concentration on antifungal susceptibility tests with various antifungals. With a dose of 400 mg daily, 67.4% of patients were cured of disease with mean duration of 9.4 weeks. Patients having less than 40% clearance at 2 weeks had a 68.9% less probability of getting cured of disease. Of the 29 patients cured, 37.9% relapsed because of various predisposing factors. Two patients developed increase in liver enzymes on treatment. Our analysis suggests that KZ can be used as alternative drug in cases with failure to conventional antifungal drugs. Though there are relapses, these can be partially explained by various predisposing factors that support fungal survival and transmission.

INTRODUCTION

The current epidemic of dermatophytosis is posing a challenge for the practicing dermatologists with recalcitrance to standard antifungal therapy, which has multiple causes.¹ Although in the western literature terbinafine is still the drug of choice, India has witnessed a high failure rate with this drug, which has been confirmed to be consequent to squalene epoxidase gene mutation.² While up dosing of the drug is found to be associated with better cure rates, this is not a consistent finding in clinical practice and is not an approved dosimetry.³

Although minimum inhibitory concentration (MIC) reported for itraconazole is low with no resistance reported leading to replacement of terbinafine with itraconazole, the drug has limitations in the form of drug interactions and quality variation leading to inadequate drug levels.⁴ Minimum inhibitory concentrations of griseofulvin are higher precluding its use as an effective agent to treat tinea of glabrous skin.⁵

Ketoconazole (KZ), an imidazole group of azole antifungals, was the first broad spectrum oral antifungal available for treatment of superficial and systemic mycoses. The drug was approved by the Food and Drug Administration (FDA) for the treatment of systemic mycoses in the year 1981.⁶ In multiple small studies, KZ was found to be effective against dermatophytes. Though there have been reports of hepatotoxicity our experience does not mirror this view. The drug is still available in India with a listed use of superficial mycosis.

In this article, we examined the role of KZ as an option for treating tinea of glabrous skin in patients who had failed treatment with oral antifungal drugs.

METHODS

Institutional records were reviewed for patients presenting with tinea cruris or corporis who had failed treatment with at least one antifungal drug given for a minimum duration of 3 weeks (terbinafine, itraconazole, fluconazole, griseofulvin in combination or sequential) and treated with oral KZ during the period January 2019 to December 2020. Approval from the institutional ethics committee was taken for the same. The records included written informed consent from the patients.

Primary objective was to identify the clinical cure rate of ketoconazole 200 mg twice daily in recalcitrant cases of tinea corporis and tinea cruris whereby recalcitrance was defined as patients not responding to 3 weeks of therapy with oral antifungals agents. Clinical cure was defined as complete resolution of symptoms and signs with or without postinflammatory changes at the end of treatment confirmed by potassium hydroxide (KOH) examination. The point of clinical cure was taken as the end of treatment. Partial response was defined as improvement in the lesions without complete clearance. Clinical failure was defined as no improvement in the existing lesions or appearance of new lesions even after 4 weeks of treatment. Secondary objectives were to analyze the time to initial improvement, efficacy, side effects, and relapse rate with this drug. Relapse or recurrence was defined as reoccurrence of infection usually after 4 weeks of completion of approved systemic therapy.

Children below 18 years and patients on topical antifungals were excluded from the study. Also, patients for whom follow-up records were not available were not included in the analysis. Patients were diagnosed based on clinical examination. Direct microscopic examination using 10% KOH was done using skin scrapings from active border of the lesions. The specimens were cultured in Sabouraud’s dextrose agar with dermatophyte test medium and incubated at 37°C and 25°C for up to 6 weeks. Culture media were checked for growth every 3 days, and fungal growth was identified by slide culture techniques, as per the standard diagnostic procedures. As per the data available in the records, KOH findings and culture reports were noted. Terbinafine, fluconazole, itraconazole, ketoconazole, and luliconazole were the antifungals tested using broth microdilution assay for antifungal susceptibility testing of dermatophytes and MIC 90 values were recorded.

Response to treatment was graded as 1 ≤ 25%, 2 = 25–49%, 3 = 50–74%, 4 = 75–99%, 5 = 100% based on the percentage improvement in lesions compared with baseline. Pruritus was graded as a percentage improvement considering 100% as baseline. Hemogram, liver function tests (LFTs), kidney function tests (KFTs), prothrombin time (PT), and partial thromboplastin time with international normalized ratio (INR) were done as baseline investigations before starting treatment as per department protocol. Electrocardiogram (ECG) was done in patients above 60 years. Liver function test was repeated once monthly till completion of treatment.

RESULTS

A total of 104 patients were identified who were treated with oral KZ in the dose of 200 mg twice daily. Out of these, 43 patients fulfilled the pre specified criteria as mentioned earlier and were included for further analysis. Figure 1 depicts overview of the study.

Figure 1.

Overview of study design.

Patient characteristics.

The age of the patients’ ranged from 17 to 84 years with a mean age of 31.3 years. Of the 43 patients, 33 were male and 10 were female. The duration of disease ranged from 4 weeks to 10 years with a mean of 69 weeks that is 18.2 months. Eleven of the 43 patients (25.6%) gave history of associated hyperhidrosis, two had diabetes mellitus, one patient each had hypertension and hypothyroidism. Family history of dermatophytic infection was present in 20 patients (46.5%) with 25.6% patients reporting conjugal transmission. None of the patients owned any pets at home. The demographic characteristics of study group are depicted in Table 1.

Table 1.

Disease characteristics of study group

Characteristic	Total, N = 43 (%)	Treatment success group, N = 29(%)	Treatment failure group, N = 14 (%)	P value
Gender
Male	33	21 (72.4)	12 (85.7)	0.574 (FE test)
Female	10	8 (27.6)	2 (14.3)
Mean Age (years)	31.3	29.1	35.8	0.136
Duration of disease (months)	18.2	18.9	13.7	0.557
Associated conditions	15 (34.9)	11 (37.9)	4 (28.6)	0.803 (FE test)
Family history of dermatophytosis	20 (46.5)	13 (44.8)	7 (50.0)	0.750
Conjugal transmission	11(25.6)	7 (24.1)	4 (28.6)	0.999 (FE test)
KOH positivity	33 (76.7)	22 (75.9)	11 (78.6)	0.999 (FE test)
Culture positivity	33 (76.7)	23 (79.3)	10 (71.4)	0.833 (FE test)
Species
T. mentagrophytes	27	20	7	0.490 (FE test)
T. rubrum	2	1	1	0.999 (FE test)
T. tonsurans	1	1	0
Aspergillus	2	1	1
Alternaria	1	0	1
No Growth	10	6	4
Duration of treatment (weeks)	9.42	9.55	9.14	0.525

FE = Fisher exact test.

Treatment history.

All patients had taken prior treatment in the form of oral or topical antifungals. As KZ is not the firstline of treatment for dermatophytosis, all our patients had taken oral antifungals for variable duration of 2 weeks to 8 weeks. The most commonly used drugs were itraconazole (18 patients) and terbinafine (15 patients). Thirty-eight patients (88.4%) had used topical antifungals in the past. In our study group, 22 patients (51.7%) gave history of use of topical steroids either alone or in combination with antifungals. Various topical steroid preparations used were clobetasol, betamethasone, and beclomethasone. Systemic steroids were used by 11 patients (25.6%) out of which five used injectable steroids namely triamcinolone.

Clinical and mycological characteristics.

Sixteen patients (37.2%) had only tinea cruris, whereas 27 (62.8%) had tinea cruris et corporis. None of the patients had any scalp involvement while one patient had associated nail involvement. Associated cutaneous disease was present in three patients (6.9%) with one patient each with steroid induced striae, extensive acneiform eruptions, and localized vitiligo. In 33 patients, KOH was positive (76.7%), whereas culture yielded growth in similar number. Trichophyton mentagrophytes was the commonest dermatophytic species isolated (62.8%). Other species isolated were T. tonsurans (one patient), T. rubrum (two patients), Alternaria (one patient), Aspergillus flavus (one patient), and Aspergillus fumigatus (1 patient). Results are outlined in Table 1.

Antifungal susceptibility.

Five antifungal drugs (terbinafine, fluconazole, itraconazole, ketoconazole, and luliconazole) were tested and the mean MIC₉₀ values obtained for T. mentagrophytes, the commonest species isolated were terbinafine (1.984 µg/mL), fluconazole (6.235 µg/mL), itraconazole (1.461 µg/mL), ketoconazole (0.783 µg/mL), and luliconazole (2.950 µg/mL).

Minimum inhibitory concentration data indicates that the order of potency of antifungal drugs against T. mentagrophytes was ketoconazole > itraconazole > terbinafine > luliconazole > fluconazole.

Response to treatment with ketoconazole.

Patients received oral KZ in the dose of 200 mg twice daily. The duration of treatment ranged from 4 to 12 weeks. Using the Intention to treat analysis, duration of treatment had a mean of 9.5 and SD 1.8 in the cured group and a mean of 12 weeks and SD of 0 in the uncured group. Twenty-nine patients (67.4%) were cured of disease that is showed complete clearance of lesions with KOH negativity on completion of treatment. Seven patients showed improvement without complete clearance, whereas seven patients did not show any improvement with treatment. These 14 patients constituted the failure group for further analysis of response (Figure 1). There was no significant difference between the age (P = 0.303), disease duration (P = 0.871), and other characteristics in the two groups (Table 1). There was significant improvement in the area cleared with treatment in the treatment success group compared with the treatment failure at 2 weeks (P = 0.011), 4 weeks (0.004), 6 weeks (0.004), 8 weeks (0.001), 10 weeks (< 0.001), and 12 weeks (< 0.001) as outlined in Table 2. Also, overall there was a significant increase in the grade of improvement and reduction in itching from 2 weeks to 12 weeks as depicted in Table 3. Further analysis showed that the area of clearance at 2 weeks of treatment could predict the chances of cure. Patients having less than 40% clearance at 2 weeks of treatment had a 68.9% less probability of getting cured of disease (Figure 2). The number of patients cured of disease at various weeks of treatment are shown in Figure 3. It was observed that with a treatment duration of 10 weeks maximum number of patients achieved cure.

Table 2.

Treatment outcome with regard to area of clearing at 2, 4, 6, 8, 10, and 12 weeks of treatment

Time duration	Treatment outcome at 12 weeks (on follow up/numbers with full clearing)	Area of clearing mean ± SD	P value
2 weeks	Success (29/2)	64.48 ± 24.51	0.011 (s)
	Failure (14/0)	42.5 ± 27.23
4 weeks	Success (27/3)	75.92 ± 21.79	0.004 (s)
	Failure (14/0)	54.28 ± 21.90
6 weeks	Success (24/4)	80.42 ± 23.78	0.004 (s)
	Failure (14/0)	56.07 ± 23.92
8 weeks	Success (20/7)	88.75 ± 24.39	0.001 (s)
	Failure (14/0)	57.87 ± 24.72
10 weeks	Success (13/10)	96.75 ± 22.88	< 0.001 (s)
	Failure (14/0)	62.86 ± 23.45
12 weeks	Success (3/3)	100 ± 0.00	< 0.001 (s)
	Failure (14/0)	63.21 ± 23.66

Table 3.

Comparison of disease grading and improvement in itching by repeated measure ANOVA

	2 weeks Mean ± SD	4 weeks	6 weeks	8 weeks	10 weeks	12 weeks	P value using Friedman’s test
Grade of improvement	2.98 ± 1.084	3.52 ± 1.056	3.90 ± 0.995	4.41 ± 0.636	4.48 ± 0.849	4.67 ± 0.516	0.001
Itch improvement	63.9 ± 28.096	71.79 ± 27.891	85.95 ± 21.658	89.81 ± 13.151	87.14 ± 17.869	94.17 ± 9.174	0.001

ANOVA = analysis of variance. Nonparametric Friedman test was used and showed a significant result (P value 0.001).

Figure 2.

Cox hazard graph for 40% cut-off for clearance of lesions. This figure appears in color at www.ajtmh.org.

Figure 3.

The number of patients cured at 4, 6, 8, 10, and 12 weeks of treatment. This figure appears in color at www.ajtmh.org.

Adverse effects.

Two patients developed increase in liver enzymes on treatment. In one of these patients the rise was double of baseline (12 weeks). The other patient had an increase that was four to five times (serum glutamic oxaloacetic transaminase (SGOT): 182 U/L, serum glutamic pyruvic transaminase (SGPT): 272 U/L, alkaline phosphatase (ALP): 528 U/L) the baseline values and occurred at 6 weeks of therapy. The enzymes returned to normal level after withdrawal of drug. One female patient developed menorrhagia and diarrhea on treatment that subsided with continued treatment

Relapse.

Of the 29 patients who were cured 18 patients did not develop relapse in the 6 months of follow-up. Eleven patients (37.9%) relapsed with a mean duration of 31.3 days

Out of the 11 patients that showed relapse, seven had one or more predisposing factors in the form of excessive physical exercise and outdoor activity (2), tight clothing (4) hyperhidrosis (4), uncontrolled diabetes (2), tinea unguim (1), tinea pedis (1), and untreated family members (1).

DISCUSSION

Our retrospective analysis noted that 67.4% of patients achieved clearance of lesions in a mean duration of 9.4 weeks. We also noted that most of patients had a chronic disease (mean duration 18 months) with 62.8% of the patients having a disease duration greater than 6 months.

There are many factors implicated in chronicity of tinea including inadequate dose and duration of treatment with antifungals, variation in quality of oral antifungals, and various host factors.^7,8

One of the important factors is the use of steroids by the patients in the form of various over-the-counter creams inappropriately prescribed by various practitioners who are unaware of the consequences of such a practice. About 51.1% of our patients gave the history of application of topical steroids (Figure 4). It has been seen that topical steroids suppress the localized T-cell-mediated (Th1) immune response that contains the infection.⁹ A shift to Th2 response makes the disease chronic and difficult to treat. Although the patient experiences relief in pruritus, the infection continues to spread centrifugally. One-fourth of the patients had used systemic steroids earlier. However, the immunosuppressive effect of systemic steroids is less profound than topical as the latter causes local suppression of T-cell-mediated immune response to the dermatophyte. This leads to ineffective elimination of the dermatophyte and also atypical morphology of the lesions.

Figure 4.

(A) A patient with extensive tinea cruris et corporis who was applying topical steroids. (B) Complete clearing of lesions at 8 weeks of treatment. This figure appears in color at www.ajtmh.org.

Five of our patients had history of use of intramuscular triamcinolone injections.

All patients in the study group had taken treatment earlier in the form of oral and topical antifungals. Eighty-six percent had taken oral treatment most commonly itraconazole and terbinafine but failed to achieve satisfactory response owing to inadequate duration of treatment and other factors. Terbinafine, a highly effective drug for dermatophytosis in the past, is showing decreased effectiveness in standard doses.¹⁰ Recent studies have found a cure rate of as low as 30% with dose of 7.5 mg/kg used for 8 weeks.¹¹ The poor response to terbinafine can be attributed to decreased sensitivity to Trichophyton owing to mutation in the squalene epoxidase gene that has been detected in various studies. Khurana et al. identified SQLE mutations in isolates with TRB MICs ranging from 4 to > 32 µg/mL.¹⁰ The authors also found that higher dose or duration of therapy can surmount the resistance to some degree. Similar findings have been noted in other studies.

Similar to our study, many studies have found low MIC with itraconazole thus largely negating resistance as a cause of failure of treatment to itraconazole.^12–14 One of the reasons for lack of response could be marked variation in the morphometric pellet characteristics of itraconazole formulations available in India that leads to significant quality variations and inconsistent serum levels.⁴ Many of our patients had been taking generic brands of ITR previously explaining the lack of effect.

Notably the MIC data reveals that KZ had the lowest MIC, which accounts for its response in cases that had failed other oral antifungal drugs. We noted that in a dose of 400 mg/day majority had a complete response and patients showed a rapid response with a mean clearance of 63.6% by 2 weeks of therapy (Figure 5). This initial rapid response at 2 weeks even in recalcitrant dermatophytosis can be explained by the pharmacokinetics of oral KZ. The major route by which KZ rapidly reaches the stratum corneum is via the sweat glands.¹⁵ Pharmacokinetic studies have shown that at a dose of 400 mg daily for 2 weeks, KZ appeared in eccrine glands as early as 1 hour after the first dose. Also, the sweat concentrations were maintained at a mean of 0.072 mg/L after 7 and 14 days of treatment which is consistent with our clinical findings.¹⁶ Further, statistical analysis showed that probability of failure in the subjects having < 40% area of clearing at 2 weeks of treatment was 68.9%. Hence, 40% response at 2 weeks can be taken as a cut-off to predict response to treatment and to avoid unnecessary exposure to the drug in patients who do not respond adequately at 2 weeks. It was also observed in the current study that the maximum number of patients achieved cure at 10 weeks, which may be considered as the appropriate duration of treatment with KZ.

Figure 5.

(A) A female with tinea cruris of 1-year duration who had taken treatment with itraconazole and terbinafine earlier. (B) Response to treatment at 2 weeks. There is clearing of lesions with hyperpigmentation. (C) A patient with chronic lesions of tinea with lichenification. (D) Complete clearing at 8 weeks of treatment. This figure appears in color at www.ajtmh.org.

Potassium hydroxide mount and culture were positive in 76.7% of our patients. Similar findings have been reported in earlier studies. Trichophyton mentagrophytes was the commonest species isolated. There has been a shift in the epidemiology of dermatophytosis in India in the last decade with T. mentagrophytes emerging as the predominant causative species. Recent studies have identified T. mentagrophytes in the range of 35% (15) to as high as 97.2%.¹⁷ This epidemiological transformation has important implications on the chronicity of infection and response to standard treatments. The cause for this shift has not been defined and is still under research.

Other factors implicated in persistent infection include hyperhidrosis which was seen in 25.6% of patients. This is an important factor in our country where weather is hot and humid and prolonged outdoor activity can lead to excessive sweating creating moist environment for growth of fungus. Moreover, the trend of wearing tight fitting occlusive garments traps the heat and moisture and creates a favorable environment for growth of fungus. This leads to recurrence of infection even after treatment and clearance of infection.

Only two (4.65%) of our patients developed abnormalities in liver functions tests. While in one patient the rise was less that 2-fold the other patient, who was an elderly male without preexisting liver disease, had a significant elevation requiring withdrawal of drug. The levels returned to normal on discontinuation. Hepatotoxicity was recognized as a significant side effect with use of KZ after few years of its use. In the year 1981–1982, 75 cases of hepatotoxicity because of KZ were reported. Out of these, 64 cases including three deaths were classified as probably or possibly related to the drug. Analysis of these three patients showed that sudden hepatic failure occurred in these patients as treatment termination was delayed in spite of increase in liver enzymes. This led to the withdrawal of the drug by the FDA in 2013. Based on a meta-analysis, the incidence of hepatotoxicity because of oral KZ ranges from 3.6% to 4.2% and is unrelated to dose and duration of therapy.¹⁸ It was more common in women and in the elderly. However, studies have found that the incidence or prevalence of liver dysfunction with ketoconazole is low.¹⁹ In majority of cases, the dysfunction is asymptomatic and detectable only as abnormalities in LFTs. Moreover, the changes are reversible and subside with or without discontinuation of the drug. Nevertheless, serious liver toxicity has been described in various case reports and careful monitoring is required on treatment. The warning and regulatory action by FDA has imposed a medicolegal risk on physicians prescribing ketoconazole owing to which the drug is recommended in few countries “only in the event of severe or life-threatening systemic infections when alternatives are unavailable.”²⁰ However, these alternative antifungals are themselves associated with a risk of liver injury and cannot be ascribed “safer” than ketoconazole. Studies have shown that all antifungal agents can cause hepatic dysfunction, which can range from mild asymptomatic liver injury to fatal life-threatening liver failure.²¹

Based on the data available, it is imperative to use KZ only in cases of failure with first line antifungals and we would like to ascribe it as a third line agent in dermatophytosis. Also, elderly patients should not be prescribed KZ and treatment should be discontinued if any elevation in liver enzymes is seen.

LIMITATIONS

Our study is limited by its retrospective nature. Also, the number of patients is small with a high dropout rate. Moreover, culture was not done at the end of treatment. In a real-world setting it is not practical to perform cultures for all patients at the end of treatment and signifies a financial constraint on the laboratories.

CONCLUSION

Our analysis suggests that in case of therapeutic failure to conventional oral antifungals, KZ can be used as alternative drug whose efficacy is consistent with its low MIC. Though there are relapses, these can be explained by various predisposing factors like hyperhidrosis, use of tight clothing, excessive physical activity, diabetes etc which predict fungal survival and transmission.