Introduction

Combined use of terbinafine and itraconazole has gained recent attention for effectively treating various fungal diseases, including refractory cases. This combination shows promise for enhanced antifungal effects due to their distinct mechanisms.

Aim

To investigate the effects of terbinafine + itraconazole combined treatment in fungal skin diseases, compared with terbinafine monotherapy or itraconazole monotherapy.

Patient Profile

• Patients aged 15–50 yrs
• Patients with tinea manuum and pedis, tinea corporis and cruris, onychomycosis, sporotrichosis, and fungal genital inflammation were included
• Clinical symptoms included pruritus, rhagades, keratinization, erythema, scale, papule, or exudation

Methods

• 152 patients were randomly distributed to 3 groups by randomly selecting random numbers and were treated with.
  • Terbinafine monotherapy (n=51)
  • Itraconazole monotherapy (n=51)
  • terbinafine + itraconazole therapy (n= 50)

Treatment

Terbinafine group

Terbinafine hydrochloride was administered orally, 0.25 g per day. For patients with  tinea manuum and pedis for 4 weeks, tinea corporis and cruris for 2 weeks, onychomycosis for 8 weeks, sporotrichosis for 12 weeks, and fungal genital inflammation for 1 week

Itraconazole group

Itraconazole was administered orally, 0.2 g per day. Treatment durations   for tinea manuum and pedis was 4 weeks, tinea corporis & cruris 2 weeks, onychomycosis 8 weeks, sporotrichosis 12 weeks, and fungal genital inflammation 1 week

Terbinafine + Itraconazole group

Doses of the terbinafine + itraconazole group were as the same as the terbinafine group and the itraconazole group, respectively.

Study Outcomes

• For the first 2 weeks, the recovery situation of fungal lesions was recorded daily. After 2 weeks, observation was performed once a week until the patient was cured.
• Clinic symptom scores, mycology examination, the cure rate & cure time was used for assessing efficacy
  • Cure was referred to the elimination of clinical symptoms, combined with negative results of mycology evaluation
  • At second week, rating scores of 0–3 was used to evaluate the severity and recovery situation of clinical symptoms, including pruritus, rhagades, keratinization, erythema, scale, papule, and exudation: 0= none, 1=mild, 2=moderate, and 3=severe.
• At the fourth week, diseased tissues from lesions were collected for in vitro fungus culture and microscopic examination.
• Adverse events, relapse of disease, and patient’s satisfaction level were recorded during follow-up.

Results

• At day 14 post-treatment, the terbinafine + itraconazole grp exhibited a significantly greater reduction in symptom scores compared to the terbinafine & itraconazole monotherapy grps (p < 0.05 for both comparisons).
• By day 28, mycological & microscopic examination revealed fungal infection eradication in 37 patients (74%) in the combination grp, significantly higher than in the monotherapy grps (37% patients in itraconazole grp; 50% patients in terbinafine grp) (p< 0.05 for both comparisons).
• All 50 patients (100%) in the terbinafine + itraconazole group achieved clinical cure.
• In the monotherapy arms, incomplete cure was observed in 3 (6% patients treated with terbinafine and 6 (12%) patients treated with itraconazole, respectively.

Table 1: Therapeutic Efficacy

Items	Terbinafine (n=51)	Itraconazole (51)	Terbinafine + Itraconazole (n=50)
Fungology evaluation
Eradicated	26 (50%)	19 (37%)	37 (74%)
Not eradicated	24 (47%)	32 (63%)	13 (26%)
P value	P1 < 0.05*	P2< 0.05*
Observation of clinical effects
Effective treatment	48 (94%)	45 (88%)	50 (100%)
Ineffective treatment	3 (6%)	6 (12%)	0
P value	P1= 0.24	P2< 0.05*

P₁: terbinafine + itraconazole group versus terbinafine group; P₂: terbinafine + itraconazole group versus itraconazole group. *Statistically significant.

Faster Cure Times with Combination Therapy

The terbinafine + itraconazole group achieved cure in the shortest time across all fungal infection types (tinea manuum and pedis, tinea corporis and cruris, onychomycosis, sporotrichosis, and fungal genital inflammation).

Table 2: The cure time of fungal skin diseases

Items	Tinea manuum and pedis (Days)	Tinea corporis and cruris (Days)	Onychomycosis (Days)	Sporotrichosis (Days)	Fungal genital Inflammation (Days)
Terbinafine	29.53 + 6.47	15.75 +3.33	64.38 + 6.28	90.67 + 6.25	8.57 + 0.98
Itraconazole	35.71 + 8.00	18.42 + 3.37	70.57 + 6.75	95.40 + 8.91	9.83 + 1.47
Terbinafine + Itraconazole	24.57 + 5.96	12.00 + 3.30	53.00 + 4.58	85.14 + 5.01	7.14 + 0.90
P1 value	P1< 0.05*	P1 < 0.05*	P1 < 0.05*	P1 = 0.10	P1 <0.05*
P2 value	P2 < 0.05*	P2 < 0.05*	P2 < 0.05*	P2 <0.05*	P2 < 0.05*

P₁: terbinafine + itraconazole group versus terbinafine group; P₂: terbinafine + itraconazole group versus itraconazole group. *Statistically significant.

Improved Cure Rates at Each Time Point

• Terbinafine + itraconazole combination therapy demonstrated the best improvement, increasing the percentage of cured patients not only in short-term diseases (tinea manuum/pedis, tinea corporis/cruris, fungal genital inflammation) but also in long-term diseases (onychomycosis and sporotrichosis).

Enhanced Overall Therapeutic Effect

• The combination of terbinafine & itraconazole significantly improved the overall clinical therapeutic effects on fungal skin diseases by both increasing the percentage of cured patients & reducing the time to cure.

Safety Analysis

• No adverse events were recorded in the terbinafine and terbinafine + itraconazole group.
• Mild nausea & emesis were observed in 2 cases in the itraconazole grp.

Relapse/ follow up and patient satisfaction

• During a 1-year follow-up, no relapse of fungal skin diseases occurred in the terbinafine + itraconazole group, whereas relapses were reported in 8 (15%) patients in the terbinafine group and 15 (29%) patients in the itraconazole group
• Patient satisfaction with the therapeutic effect was significantly higher in the terbinafine + itraconazole grp (98%) compared to the terbinafine (88%) & itraconazole (67%) monotherapy grps

Conclusion

The study demonstrated that combination therapy  of terbinafine & itraconazole could alleviate the disease severity of symptoms, eliminate the fungus effectively and completely, accelerate, reduce cure time and increase cure rate and patient’s satisfaction level in fungal skin disease compared with terbinafine or itraconazole monotherapy.

Reference

American Journal of Therapeutics. 2021;28:2