Differential Diagnosis of Palmoplantar Rash in Augmentin Use
The palmoplantar rash from Augmentin is most likely a drug eruption (hypersensitivity reaction), but the differential diagnosis must include infectious causes (hand-foot-mouth disease, secondary syphilis, Rocky Mountain spotted fever), inflammatory conditions (palmoplantar pustulosis, dyshidrotic eczema, psoriasis), and other drug-induced patterns (fixed drug eruption, erythema multiforme). 1
Primary Consideration: Drug-Induced Eruption
The FDA label for amoxicillin-clavulanate explicitly lists skin rashes and urticaria as occurring in 3% of patients, with serious hypersensitivity reactions including erythema multiforme and Stevens-Johnson syndrome reported in post-marketing surveillance 1. The timing (typically within days to 2 weeks of starting therapy) and distribution pattern are critical diagnostic clues 2.
Specific Drug Eruption Patterns to Consider:
Maculopapular/exanthematous eruption: The most common drug reaction pattern, presenting as symmetric erythematous macules and papules that may involve palms and soles 2
Fixed drug eruption: Presents as well-demarcated erythematous plaques that recur in the same location with re-exposure; palmoplantar involvement is possible 2
Erythema multiforme: Target lesions with acral distribution including palms and soles; can be triggered by beta-lactam antibiotics 1, 2
Urticarial reaction: Pruritic wheals that may involve any body surface including palmoplantar areas 1, 2
Critical Differential Diagnoses Beyond Drug Eruption
Infectious Etiologies:
Hand-foot-mouth disease (HFMD): Caused by enteroviruses (CV-A6, CV-A16, enterovirus 71); presents with vesicles on palms, soles, and oral mucosa—the vesicular morphology distinguishes it from drug eruptions 3
Secondary syphilis: Can present with palmoplantar macules or papules; requires serologic testing (RPR/VDRL with confirmatory treponemal testing) 3
Rocky Mountain spotted fever: Blanching pink macules evolving to petechiae involving palms and soles, accompanied by fever and tick exposure history 3
Inflammatory Dermatoses:
Palmoplantar pustulosis (PPP): Chronic inflammatory condition with sterile pustules on palms and soles; distinguished by pustular rather than maculopapular morphology and chronic recurrent course 4
Dyshidrotic eczema: Intensely pruritic vesicles on lateral fingers, palms, and soles; vesicles are deeper-seated than HFMD 4
Psoriasis (palmoplantar variant): Well-demarcated erythematous plaques with silvery scale; chronic course distinguishes from acute drug eruption 5, 4
Hyperkeratotic hand eczema: Thickened, fissured skin on palms; chronic presentation unlike acute drug reaction 5
Other Drug-Induced Patterns (if patient on multiple medications):
Chemotherapy-induced palmar-plantar erythrodysesthesia (PPES): Caused by agents like capecitabine, 5-fluorouracil, doxorubicin; progresses from dysesthesia and tingling to burning pain, swelling, erythema, and potentially blisters 5, 6, 7
Hand-foot skin reaction (HFSR): Associated with BRAF/MEK inhibitors and tyrosine kinase inhibitors; presents with painful hyperkeratosis at pressure-bearing areas 5
Lichenoid drug eruption: Lichen planus-like lesions with possible palmoplantar hyperkeratosis; reported with various medications including imatinib 8
Systemic Conditions:
Kawasaki disease (primarily pediatric): Erythema and edema of palms/soles with subsequent periungual desquamation at 2-3 weeks, but lacks vesicles; accompanied by fever, conjunctivitis, and other systemic features 3
Drug hypersensitivity syndrome (DRESS): Severe reaction with facial edema, diffuse rash (may include palmoplantar involvement), fever, lymphadenopathy, eosinophilia, and organ involvement; typically occurs 2-8 weeks after drug initiation 9
Diagnostic Approach
Immediately assess for severe cutaneous adverse reactions (SCARs): Look for mucosal involvement, facial edema, confluent erythema, skin pain, blistering, or systemic symptoms (fever, lymphadenopathy, organ dysfunction) that would indicate Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS 1, 9. If present, discontinue Augmentin immediately and consider hospitalization 1.
Key Historical Elements:
- Timing: Drug eruptions typically appear 7-14 days after first exposure or within 1-3 days on re-exposure 2
- Morphology: Vesicles suggest HFMD or dyshidrotic eczema; pustules suggest PPP; target lesions suggest erythema multiforme; maculopapular pattern suggests exanthematous drug eruption 3, 2, 4
- Associated symptoms: Burning/tingling suggests PPES (if on chemotherapy); pruritus is common in drug eruptions; pain suggests HFSR or severe drug reaction 5
- Concurrent medications: Review for chemotherapy agents, TKIs, or other drugs associated with palmoplantar reactions 5, 7
- Infectious exposures: Sick contacts (HFMD), tick exposure (RMSF), sexual history (syphilis) 3
Physical Examination Priorities:
- Distribution: Symmetric involvement favors drug eruption; unilateral or asymmetric suggests other causes 2
- Mucosal involvement: Oral lesions with palmoplantar rash suggest HFMD, erythema multiforme, or SJS/TEN 3, 1, 2
- Periorbital sparing: Typical of EGFR inhibitor reactions, not expected with Augmentin 5
- Systemic signs: Fever, lymphadenopathy, or hepatosplenomegaly suggest DRESS, Kawasaki disease, or infectious etiology 3, 9
Common Pitfalls
Mononucleosis misdiagnosis: Patients with infectious mononucleosis who receive amoxicillin develop an erythematous rash in a high percentage of cases; this is not a true allergy but rather a drug-virus interaction 1. Consider monospot or EBV serology if clinical suspicion exists.
Delayed recognition of DRESS: Unlike typical drug eruptions, DRESS can present 2-8 weeks after drug initiation with systemic involvement; check CBC with differential, liver enzymes, and renal function if systemic symptoms present 9
Confusing PPES with drug allergy: If patient is on chemotherapy (particularly capecitabine, 5-FU, or doxorubicin), the palmoplantar eruption may be PPES rather than Augmentin-related; PPES has characteristic progression from dysesthesia to painful erythema 5, 6, 7