What is the recommended antibiotic treatment for fever of unknown origin?

Antibiotic Treatment for Fever of Unknown Origin

For neutropenic fever of unknown origin, the recommended first-line antibiotic treatment is monotherapy with an antipseudomonal β-lactam such as piperacillin-tazobactam, while low-risk patients may receive oral ciprofloxacin plus amoxicillin-clavulanate. 1

Classification of Patients with Fever of Unknown Origin

• Fever of unknown origin (FUO) is defined as fever higher than 38.3°C persisting for at least 3 weeks without diagnosis despite adequate evaluation 2, 3
• For neutropenic FUO specifically, fever is defined as a single temperature of 38.3°C or a temperature of 38.0°C sustained over 1 hour in patients with an absolute neutrophil count <0.5 × 10^9 cells/L 1
• Patients should be stratified into risk categories to guide antibiotic selection 1:
  • High-risk: Profound neutropenia (ANC <100 cells/mm³) expected to last >7 days
  • Low-risk: Less severe neutropenia expected to resolve within 7 days

Antibiotic Recommendations by Risk Category

High-Risk Patients

• First-choice therapy: Monotherapy with an antipseudomonal β-lactam 1

  • Piperacillin-tazobactam is the preferred agent 1
  • Alternatives include cefepime, ceftazidime, or a carbapenem (meropenem or imipenem-cilastatin) 1

• For hemodynamically unstable patients: Add a second agent 1

  • Amikacin (preferred aminoglycoside) 1
  • Vancomycin (if MRSA suspected or evidence of catheter-related infection) 1

• For persistent fever after 4-7 days of antibiotics: Consider adding empiric antifungal therapy 1, 4

  • Echinocandins, voriconazole, or liposomal amphotericin B are appropriate options 1, 4

Low-Risk Patients

• First-choice therapy: Oral combination of ciprofloxacin plus amoxicillin-clavulanate 1

• Alternative regimens (less well studied but commonly used) 1:

  • Levofloxacin monotherapy
  • Ciprofloxacin plus clindamycin

• Important note: Patients receiving fluoroquinolone prophylaxis should not receive fluoroquinolones for empiric therapy 1

Duration of Antibiotic Therapy

• For unexplained persistent fever 1:

  • Traditional approach: Continue antibiotics until neutrophil recovery (ANC >500 cells/mm³) 1
  • Newer approach (ECIL-4 guidelines): Consider discontinuation after 72 hours or later in clinically stable patients who have been afebrile for at least 48 hours, regardless of neutrophil count 1

• For microbiologically documented infections: Continue antibiotics for at least the duration of neutropenia and longer if clinically necessary 1

Special Considerations

• Empiric antibiotics should be avoided in non-neutropenic FUO except in critically ill patients 3, 5
• For patients with recurrent fever or clinical deterioration after initial improvement, reassess and broaden antibiotic coverage 1
• Hospital readmission is required for persistent fever or signs of worsening infection in outpatients 1
• Vancomycin can be discontinued after 2 days if there is no evidence of gram-positive infection 1

Monitoring and Follow-up

• All neutropenic patients must be monitored closely for response, adverse effects, emergence of secondary infections, and development of drug-resistant organisms 1
• Clinical reassessment should be performed daily 1
• If fever persists but the patient is clinically stable, empirical antibiotic changes are rarely required 1

Pitfalls to Avoid

• Avoid using fluoroquinolones empirically in patients already receiving fluoroquinolone prophylaxis 1
• Do not use ciprofloxacin as monotherapy due to poor coverage of gram-positive organisms 1
• Avoid empiric antibiotics in non-neutropenic FUO patients unless they are critically ill 3, 5
• Do not continue vancomycin empirically if there is no evidence of gram-positive infection after 48 hours 1