What is the differential diagnosis of a rash on both palms and feet in a patient with a history of fever, cough, sore throat, and recent receipt of Augmentin (amoxicillin/clavulanate) 5 days ago?

Differential Diagnosis of Palmar and Plantar Rash Following Augmentin Therapy

Most Likely Diagnosis

This presentation is most consistent with a drug hypersensitivity reaction to Augmentin (amoxicillin-clavulanate), particularly given the temporal relationship of rash onset 5 days after antibiotic initiation. 1

The FDA label for amoxicillin-clavulanate explicitly warns that serious hypersensitivity reactions, including skin rashes, occur in patients receiving beta-lactam antibacterials, and are more likely in individuals with a history of penicillin hypersensitivity. 1 The timing of 5 days post-initiation falls within the typical window for drug eruptions (2-3 weeks, but can occur earlier). 2

Critical Differential Diagnoses to Consider

1. Drug Hypersensitivity Reaction (Most Likely)

• Drug eruptions can present as fine reticular maculopapular rashes or broad, flat erythematous macules and patches, and can include involvement of palms and soles. 2, 3
• The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes, though this is relevant only if the patient is on allopurinol. 1
• A case report documented amoxicillin-induced fever, rash, and altered sensorium, demonstrating that amoxicillin can cause significant systemic reactions beyond simple cutaneous manifestations. 4

2. Viral Exanthem with Secondary Bacterial Infection

• The prodrome of fever, cough, and sore throat suggests a viral upper respiratory infection that may have been the original indication for Augmentin. 5
• Epstein-Barr virus (EBV) causes maculopapular rash, especially if the patient received ampicillin or amoxicillin—this is a critical consideration given the history of sore throat and Augmentin use. 2, 6
• The FDA label specifically warns that a high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash, and amoxicillin-clavulanate should not be administered to patients with mononucleosis. 1
• However, enteroviral infections typically spare palms, soles, face, and scalp, making this less likely given the palmar and plantar involvement. 2, 6

3. Rocky Mountain Spotted Fever (RMSF) - Life-Threatening

• RMSF presents with rash on palms and soles, though this typically occurs late in disease (day 5-6) and in only half of cases. 7, 6
• The rash begins as small, blanching, pink macules on ankles, wrists, or forearms appearing 2-4 days after fever onset, then progresses to maculopapular with central petechiae. 6
• Critical red flag: RMSF carries a 5-10% mortality rate, and delays in treatment significantly increase death risk. 3, 6
• However, up to 20% of RMSF cases never develop a rash, and up to 40% of patients do not report tick exposure. 3, 6
• The CDC recommends initiating doxycycline 100 mg twice daily immediately without waiting for laboratory confirmation if fever + rash + headache + tick exposure (or endemic area exposure) are present. 3, 6

4. Secondary Syphilis

• Secondary syphilis can present with maculopapular rash involving palms and soles. 3
• Patients should undergo RPR/VDRL testing and sexual history evaluation. 3

5. Other Infectious Causes

• Disseminated gonococcal infection is characterized by maculopapular or petechial rash with associated arthritis. 7, 3
• Infective endocarditis can present with petechial rash on extremities, particularly with fever and new heart murmur. 7, 3
• Streptobacillus moniliformis (rat-bite fever), Neisseria meningitidis, and certain enteroviruses can cause palmar and plantar rash. 7
• Human Monocytic Ehrlichiosis (HME) rash occurs in only 30% of adults and rarely involves palms and soles. 3, 6

Immediate Diagnostic Workup Required

Laboratory testing must be obtained immediately to differentiate life-threatening infectious causes from drug reaction:

• Complete blood count with differential: Look for leukopenia, thrombocytopenia (suggests RMSF, HME, or ITP), or bandemia (suggests bacterial infection). 7, 3
• Comprehensive metabolic panel: Look for hyponatremia and elevated hepatic transaminases (suggests RMSF or HME). 7, 3
• Peripheral blood smear: If thrombocytopenia is present, differentiate ITP from TTP or other causes. 2
• Acute serology for R. rickettsii, E. chaffeensis, and A. phagocytophilum: Do not wait for results before initiating treatment if RMSF is suspected. 7, 3
• Blood cultures: If sepsis is suspected. 3
• Monospot or EBV serology: Given the sore throat history and Augmentin use. 2, 6
• RPR/VDRL: If sexually active or other risk factors present. 3

Critical Clinical Decision Points

When to Initiate Empiric Doxycycline (Life-Saving Decision)

Initiate doxycycline 100 mg twice daily immediately if ANY of the following are present:

• Fever + rash + headache + tick exposure or endemic area exposure 3, 6
• Thrombocytopenia and/or hyponatremia in the setting of fever and rash 3, 6
• Normal WBC with increased bands, thrombocytopenia, and hyponatremia 7

The CDC emphasizes that clinical improvement is expected within 24-48 hours of initiating doxycycline, and severe complications (meningoencephalitis, ARDS, multiorgan failure) can occur if treatment is delayed. 6

When to Discontinue Augmentin (Most Likely Scenario)

Discontinue Augmentin immediately if drug reaction is suspected:

• The offending agent should be stopped immediately, with symptomatic treatment using antihistamines for pruritus. 2
• The FDA label mandates that if an allergic reaction occurs, amoxicillin-clavulanate should be discontinued and appropriate therapy instituted. 1

Common Pitfalls to Avoid

• Do not exclude RMSF based on absence of tick bite history: 40% of patients do not report tick exposure. 3
• Do not wait for serologic confirmation before starting doxycycline if RMSF is suspected: Mortality increases significantly with treatment delays. 3, 6
• Do not overlook drug history: Up to 40% of patients may not recall or report new medications. 2
• Do not miss EBV-associated rash: The combination of sore throat, Augmentin use, and rash is classic for EBV with amoxicillin exposure. 2, 6, 1
• In darker-skinned patients, petechial rashes may be difficult to recognize, increasing risk of delayed diagnosis. 2

Expected Clinical Course and Red Flags

If Drug Reaction (Most Likely)

• Rash should improve within 48-72 hours after discontinuing Augmentin. 2
• Symptomatic treatment with antihistamines for pruritus is appropriate. 2

Red Flags Requiring Immediate Re-evaluation

• Development or persistence of fever 2, 3
• Progression of petechiae to purpura or ecchymoses 2
• Development of systemic symptoms (headache, altered mental status, respiratory distress) 2
• Thrombocytopenia on CBC 2, 3
• Hyponatremia or elevated hepatic transaminases 3, 6

Algorithmic Approach

1. Immediately assess for life-threatening causes: Check for fever, headache, thrombocytopenia, hyponatremia, or tick exposure history
2. If ANY red flags present: Initiate doxycycline 100 mg twice daily immediately 3, 6
3. If no red flags: Discontinue Augmentin, initiate antihistamines, and obtain monospot/EBV serology 2, 1
4. Obtain complete laboratory workup as outlined above 7, 3
5. Re-evaluate in 24-48 hours: If no improvement or worsening, reconsider infectious etiologies 2, 6