What is the recommended empirical treatment for a patient with fever of unknown origin?

Empirical Treatment for Fever

For non-neutropenic, non-critically ill patients with fever of unknown origin, avoid empirical antibiotics entirely and pursue diagnostic workup instead, as up to 75% of cases resolve spontaneously without treatment. 1, 2

Risk Stratification Determines Treatment Approach

The decision to initiate empirical antimicrobial therapy hinges entirely on patient risk category:

High-Risk Patients Requiring Immediate Empirical Antibiotics

Neutropenic patients (absolute neutrophil count <500 cells/mm³):

• Initiate broad-spectrum antipseudomonal β-lactam monotherapy within 60 minutes of presentation 3
• Preferred agents: Cefepime 2g IV every 8 hours 3, 4, piperacillin-tazobactam 4.5g IV every 6-8 hours 1, 3, meropenem 1g IV every 8 hours 1, 3, or imipenem-cilastatin 500mg IV every 6 hours 1
• Continue until absolute neutrophil count >500 cells/mm³ for at least 48 hours AND patient afebrile for ≥48 hours 3

Critically ill ICU patients with septic shock:

• Initiate empirical antifungal therapy with an echinocandin (caspofungin 70mg loading dose then 50mg daily, micafungin 100mg daily, or anidulafungin 200mg loading dose then 100mg daily) OR liposomal amphotericin B 3-5 mg/kg daily if risk factors for invasive candidiasis present 5
• Add vancomycin 15-20mg/kg IV every 8-12 hours ONLY if: clinically apparent catheter-related infection, skin/soft tissue infection, hemodynamic instability, known MRSA colonization, or high local MRSA prevalence 1, 3

Low-Risk Patients: Withhold Empirical Antibiotics

For immunocompetent, hemodynamically stable patients:

• Do NOT initiate empirical antibiotics 1, 2, 6
• Obtain at least two sets of blood cultures (ideally 60mL total) from different anatomical sites before any antibiotics 5, 1
• Perform chest radiography 5, 1
• Order complete blood count, comprehensive metabolic panel, urinalysis with culture, ESR, and CRP 1

Special Populations and Modifications

Persistent Fever in Neutropenic Patients (4-7 days)

Add empirical antifungal therapy if:

• High-risk features present (prolonged neutropenia expected, recent bone marrow transplant, hematologic malignancy) 5, 3, 7
• Preferred agents: Caspofungin or liposomal amphotericin B (L-AmB) 5
• In children: caspofungin was better tolerated than L-AmB in prospective trials, though both are equally effective 5
• Continue until resolution of neutropenia (ANC 100-500/μL) in absence of documented invasive fungal disease 5

High-Risk Neutropenic Patients at Presentation

Patients at highest risk for severe infection should NOT receive monotherapy: 4

• Recent bone marrow transplantation 4
• Hypotension at presentation 4
• Underlying hematologic malignancy 4
• Severe or prolonged neutropenia 4
• Add aminoglycoside or fluoroquinolone to β-lactam for these patients 3

Low-Risk Neutropenic Patients (MASCC score ≥21)

Oral step-down after 48 hours if:

• Afebrile for 48 hours 3
• Clinically stable with no new symptoms 3
• Blood cultures remain negative 3
• Able to tolerate oral intake 3
• Regimen: Ciprofloxacin plus amoxicillin-clavulanate 3

Critical Pitfalls to Avoid

Do NOT:

• Change antibiotics based on persistent fever alone if patient clinically stable 1, 3
• Remove central venous catheters systematically without microbiological evidence of catheter-related infection 1
• Use high-dose steroids without specific indication (increases hospital-acquired infection risk, hyperglycemia, GI bleeding, delirium) 1
• Delay antibiotics in neutropenic patients while awaiting cultures—mortality in untreated neutropenic sepsis is unacceptably high 1
• Use fluoroquinolone-based empirical therapy in patients receiving fluoroquinolone prophylaxis due to resistance 3

Diagnostic Workup During Empirical Therapy

For persistent fever without identified source:

• Perform CT imaging if recent thoracic, abdominal, or pelvic surgery 5
• Consider 18F-fluorodeoxyglucose PET/CT if other diagnostic tests fail and transport risk acceptable 5, 7
• In neutropenic patients with pulmonary infiltrates: perform bronchoalveolar lavage at segmental bronchus supplying radiographic abnormality 7
• Test for viral pathogens (including SARS-CoV-2) if respiratory symptoms present 5

Duration and Discontinuation

Stop empirical antifungal therapy if:

• After 4-5 days, patient clinically improved with no subsequent evidence of invasive candidiasis 5
• Negative non-culture-based diagnostic assay with high negative predictive value 5

Continue antibacterial therapy:

• In neutropenic patients: until ANC >500 cells/mm³ AND afebrile ≥48 hours 3
• For documented infections: treat for at least duration of neutropenia or longer based on infection site 3