What is the next step in managing a patient with a persistent ulcerated lesion on the penis, who initially improved with cephalexin (Cephalosporin antibiotic) 200mg twice daily (BD) for 7 days, but still has the lesion?

Management of Persistent Penile Ulcer After Initial Antibiotic Treatment

This patient requires an urgent biopsy of the penile lesion to establish a definitive diagnosis, as persistent ulceration despite antibiotic therapy raises concern for non-infectious etiologies including malignancy, autoimmune conditions, or atypical infections. 1, 2

Immediate Diagnostic Workup

The persistence of the ulcer after cephalosporin treatment indicates this is not a simple bacterial infection. The following tests must be performed:

Essential Laboratory Testing

• Serologic testing for syphilis (darkfield microscopy or direct fluorescent antibody for Treponema pallidum) - syphilis is one of the most common causes of genital ulcers in the United States and can present with painless ulcers after initial painful presentation 3, 2
• HSV culture or PCR - herpes simplex virus is the other leading cause of genital ulcers and may have atypical presentations 3, 2
• HIV testing and counseling - HIV increases risk of atypical presentations and complications 3, 4
• Tuberculosis testing if the patient is from an endemic area or has risk factors, as penile TB can present as non-healing ulcers 5

Tissue Diagnosis is Critical

• Punch, excisional, or incisional biopsy must be performed when there is doubt about the nature of the lesion 3, 1
• Biopsy is essential to rule out penile squamous cell carcinoma, which commonly presents as ulcerative lesions and is the most common penile malignancy 3, 1
• Histopathology can also identify granulomatous inflammation, autoimmune conditions like Behçet syndrome, lichen sclerosus, or atypical infections 3, 6

Why the Antibiotic Failed

Cefpodoxime (a third-generation cephalosporin) would be expected to cover common bacterial causes of penile ulceration. The fact that pain resolved but the ulcer persists suggests:

• The initial pain may have been from secondary bacterial superinfection, which responded to antibiotics, but the underlying cause remains untreated 2
• Non-infectious etiologies are now the primary concern, including penile intraepithelial neoplasia (PeIN), invasive squamous cell carcinoma, lichen sclerosus, Behçet syndrome, or traumatic ulceration 3, 1
• Atypical infections such as syphilis (which can have painless ulcers), tuberculosis, or fungal infections require different antimicrobial approaches 3, 2, 5

Clinical Examination Details to Document

Before biopsy, carefully document:

• Ulcer characteristics: exact diameter, depth, border regularity, base appearance (clean vs. necrotic), presence of induration 3, 1
• Location: glans (34.5% of penile cancers), prepuce (13.2%), or shaft (5.3%) 3, 1
• Associated findings: discharge, bleeding, foul odor (suggests delayed diagnosis of malignancy), phimosis (increases cancer risk 25-60%) 3, 1
• Inguinal lymph nodes: palpable nodes may indicate metastatic disease or reactive lymphadenopathy 3, 1

Imaging Considerations

• MRI of the penis should be considered if there is uncertainty about depth of invasion or if organ-sparing treatment is being contemplated 3, 1
• Ultrasound can be used if MRI is unavailable 3, 1
• Physical examination alone is reliable for estimating tumor size and clinical T stage in most cases 1

Treatment Cannot Proceed Without Diagnosis

Do not initiate empiric treatment beyond the initial antibiotic course without tissue diagnosis. 3, 1, 2 The differential diagnosis is too broad and includes:

Infectious Causes Requiring Specific Therapy

• Syphilis: requires penicillin G benzathine 2.4 million units IM single dose 3, 2
• Herpes simplex: requires acyclovir 400mg PO TID for 7-10 days (first episode) 3, 2
• Tuberculosis: requires 6-9 months of multi-drug anti-tubercular therapy 5

Non-Infectious Causes Requiring Different Approaches

• Penile cancer/PeIN: may require topical therapy, laser, wide local excision, or partial penectomy depending on stage 3, 1
• Lichen sclerosus: requires potent topical corticosteroids as first-line treatment 3
• Behçet syndrome: requires topical steroids initially, with colchicine for prevention of recurrence 3
• Traumatic ulceration: requires only topical wound care and avoidance of trauma 2, 7

Critical Red Flags

Watch for these concerning features that suggest malignancy:

• Age over 50 years (median age for penile cancer is 68 years) 1
• Presence of phimosis (25-60% increased cancer risk) 3, 1
• History of HPV, tobacco use, or lichen sclerosus (all increase cancer risk) 3, 1
• Ulcer with irregular borders, induration, or fungating appearance 3, 1
• Palpable inguinal lymphadenopathy (strongest prognostic factor if malignancy) 1

Common Pitfall to Avoid

The most critical error would be continuing empiric antibiotic therapy or trying multiple antimicrobial agents without establishing a tissue diagnosis. 3, 1, 6 This delays diagnosis of potentially curable malignancy and allows disease progression. One case report documented a patient initially treated as infection who ultimately required glansectomy for necrotizing granulomatous inflammation that could have been managed earlier with corticosteroids if properly diagnosed 6.