A Nail That Will Not Clear
A 54-year-old man with type 2 diabetes (HbA1c 9.2%) is referred for a 2-year history of a thickened, discoloured right great toenail. He has completed three courses of oral terbinafine (250 mg daily for 12 weeks each) and one course of itraconazole, with only partial improvement. On examination the nail plate is yellow-brown, dystrophic and lifted distally, with subungual hyperkeratosis; the lateral nail fold is slightly swollen but not tender. There is no history of trauma. Potassium hydroxide mount from subungual debris is negative on two occasions, and a fungal culture is negative. He asks whether he should take another course of terbinafine.
1. How would you approach the diagnosis before prescribing further antifungal therapy?
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Do not simply repeat terbinafine. Three adequately dosed courses with partial response plus negative KOH and culture should prompt re-evaluation of the diagnosis.
Differential:
- Onychomycosis with a non-dermatophyte mould or mixed infection - culture may be falsely negative; a mould may not respond to terbinafine.
- Onychomycosis with a resistant dermatophyte - consider squalene epoxidase mutations, more likely after repeated exposure.
- Psoriasis or lichen planus of the nail - pitting, oil spots, longitudinal ridging, nail-fold changes; check skin and scalp.
- Subungual exostosis or tumour (e.g. subungual melanoma, squamous cell carcinoma) - unilateral single-nail dystrophy, especially with a swollen fold, warrants imaging and biopsy if suspected.
- Trauma/onycholysis and secondary colonisation - but no trauma history.
Work-up: repeat sampling with nail plate clipping and subungual curettage (not just surface debris), sent for histology with PAS staining and culture; consider molecular PCR for dermatophytes if available. If histology is negative and the nail remains dystrophic, nail unit biopsy to exclude tumour. Optimise glycaemic control, as poor control predisposes to treatment failure.
2. Histology shows fungal hyphae in the nail plate and culture grows a non-dermatophyte mould. What is your treatment strategy, and what monitoring does he need?
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Interpretation: a non-dermatophyte mould in the nail plate with histologically confirmed hyphae is a true infection rather than colonisation, but these organisms respond variably to standard antifungals.
Strategy:
- Identify the organism (e.g. Aspergillus, Fusarium, Scopulariopsis, Neoscytalidium) - susceptibility differs and some are resistant to terbinafine and azoles.
- Combine systemic and topical therapy: oral itraconazole (pulse or continuous) or terbinafine guided by susceptibility, plus topical ciclopirox or amorolfine and, where feasible, nail avulsion/chemical or surgical debridement to reduce fungal load.
- Treat for longer than dermatophyte regimens - 3–6 months or more, with clinical review every 3 months until the nail grows out.
- Address predisposing factors: glycaemic control, footwear, and consider podiatry.
Monitoring: baseline and periodic LFTs (itraconazole and terbinafine both hepatotoxic); drug interactions - itraconazole is a CYP3A4 inhibitor and interacts with statins, some antidiabetics and warfarin; terbinafine inhibits CYP2D6. Check for heart failure history with itraconazole. Warn about photosensitivity with some mould-active agents. Set realistic expectations: cure rates are lower than for dermatophytes and relapse is common.