A 3‑year‑old child (≈15 kg) on high‑dose oral amoxicillin‑clavulanate for a respiratory infection now has recurrent fever, leukopenia (total white‑blood‑cell count 3000/µL, absolute neutrophil count ~1350/µL) and a negative C‑reactive protein—should I stop the amoxicillin‑clavulanate and start IV ceftriaxone?

Stop Amoxicillin-Clavulanate and Provide Supportive Care—This Is Most Likely a Viral Illness or Drug-Induced Leukopenia

The combination of recurrent fever beyond 72 hours on appropriate high-dose amoxicillin-clavulanate, leukopenia with an absolute neutrophil count of 1350/µL, and a negative CRP strongly suggests either a viral etiology or antibiotic-induced bone marrow suppression rather than treatment-failure bacterial infection—discontinue the antibiotic and do not start IV ceftriaxone. 1

Why This Is Not Treatment-Failure Bacterial Infection

• Fever persisting > 72 hours after starting an appropriate antibiotic indicates treatment failure, resistant organisms, or—critically—a non-bacterial cause. 1
• Bacterial pneumonia and sinusitis typically resolve fever within 24–48 hours for pneumococcal infections and within 2–4 days for other bacterial pathogens when treated with adequate therapy. 1
• A negative CRP in the setting of recurrent fever argues strongly against an active bacterial infection, which would be expected to elevate inflammatory markers. 1
• The child is already on high-dose amoxicillin-clavulanate (90 mg/kg/day), which provides coverage for penicillin-resistant S. pneumoniae, β-lactamase-producing H. influenzae, and M. catarrhalis—the three key respiratory pathogens in this age group. 1, 2

The Leukopenia Is a Red Flag Against Bacterial Infection

• Leukopenia (WBC 3000/µL) with an ANC of 1350/µL is inconsistent with typical bacterial respiratory infection, which usually causes leukocytosis or at least a normal white count with left shift. 1
• This pattern is more consistent with viral infection (which commonly causes leukopenia) or drug-induced bone marrow suppression from amoxicillin-clavulanate itself. 3, 4
• Children younger than 3 years have the highest risk of penicillin-resistant S. pneumoniae infection, but if there is no clinical improvement after 5 days of appropriate high-dose therapy, hospitalization for diagnostic work-up is indicated—not empiric escalation to IV ceftriaxone. 1

What to Do Instead

• Discontinue the amoxicillin-clavulanate immediately. Antibiotics in viral illness cause more harm than benefit, and the majority of upper respiratory infections in children < 5 years are viral and do not benefit from antibiotics. 1
• Provide supportive care: analgesics for pain, antipyretics for fever, saline nasal irrigation, and adequate hydration. 1
• Reassess the child clinically within 24–48 hours to ensure fever resolution and rising white blood cell count, which would confirm viral etiology or drug-induced leukopenia. 1, 2
• Repeat CBC in 48–72 hours to document recovery of the white count after stopping the antibiotic. 1

When IV Ceftriaxone Would Be Appropriate

• IV ceftriaxone 50 mg/kg is indicated when oral intake is unreliable or when a child shows signs of severe bacterial infection: respiratory rate > 50 breaths/min, oxygen saturation ≤ 92%, grunting, cyanosis, or inadequate feeding. 1
• Hospitalization is indicated if there is no clinical improvement after 5 days of appropriate therapy or if the child deteriorates—but this child has leukopenia and negative CRP, making bacterial infection unlikely. 1
• A single dose of ceftriaxone 50 mg/kg IM/IV may be given with reassessment after 24 hours only if bacterial infection remains a strong clinical concern despite the laboratory findings. 1

Critical Pitfalls to Avoid

• Do not continue the same antibiotic beyond 72 hours without clinical improvement; this constitutes treatment failure requiring intervention—but the intervention is stopping antibiotics when bacterial infection is not confirmed, not escalating to IV therapy. 1
• Do not assume purulent nasal discharge alone indicates bacterial infection; it is common in viral URIs and does not warrant antibiotics. 1
• Do not prescribe antibiotics for isolated tympanic membrane redness without meeting the full acute otitis media diagnostic criteria. 1
• Do not use first-generation cephalosporins or macrolides as monotherapy for respiratory infections because they inadequately cover penicillin-resistant S. pneumoniae. 1