In an adult (or older child) with fever of unknown origin, how should procalcitonin (PCT) levels be used to guide initiation and discontinuation of antibiotics?

Procalcitonin Role in Fever Cases

Procalcitonin should be used primarily to guide antibiotic discontinuation—not initiation—in febrile patients, with measurement reserved for those with low-to-intermediate probability of bacterial infection, while empiric antibiotics must be started immediately in suspected sepsis regardless of PCT level. 1

When to Measure Procalcitonin

Appropriate Clinical Scenarios

• Measure PCT in critically ill patients with new fever and no clear infection focus when bacterial infection probability is low-to-intermediate, as an adjunct to clinical evaluation 1
• Do NOT measure PCT when bacterial infection probability is high—it cannot reliably rule out infection in this setting and should not delay treatment 1
• Avoid using PCT based on fever alone without additional clinical context 2

Timing Considerations

• Obtain baseline PCT before antibiotics (if no substantial delay >45 minutes), but never delay empiric therapy to wait for results 2
• Early sampling (<6 hours after admission) yields false-negative results; optimal initial sampling occurs on day 1 after admission 2
• PCT rises within 2-3 hours of bacterial infection, peaking at 6-8 hours, making it useful for early detection once adequate time has elapsed 1, 2

Antibiotic Initiation Decisions

Critical Rule: Never Withhold Antibiotics Based on PCT Alone

• In suspected sepsis or septic shock, initiate empiric broad-spectrum antibiotics within 1 hour regardless of PCT level 2, 3
• PCT sensitivity ranges only 38-91% for bacterial infection—insufficient to safely exclude bacterial disease 2, 3
• The American Thoracic Society and Infectious Diseases Society of America explicitly recommend against using PCT to decide whether to start antibiotics in community-acquired pneumonia 3

Interpretation for Low-Risk Patients

• PCT <0.25 ng/mL in non-critically ill patients with low pretest probability supports withholding or early discontinuation of antibiotics within 24 hours if clinical picture is compatible 2, 3
• PCT 0.25-0.5 ng/mL indicates possible bacterial infection but requires clinical correlation 4
• PCT >0.5 ng/mL suggests higher probability of bacterial infection and supports antibiotic initiation in appropriate clinical context 4

Antibiotic Discontinuation Decisions (Primary Role)

Evidence-Based Stopping Criteria

Stop antibiotics when BOTH conditions are met: 1, 2

1. PCT has decreased by ≥80% from peak value OR PCT <0.5 ng/mL
2. Patient is clinically stable

Monitoring Protocol

• Measure PCT every 24-48 hours after antibiotic initiation in hospitalized patients 3
• Serial measurements are more valuable than single values for guiding treatment duration 2, 3
• Continue daily PCT monitoring in ICU patients (especially those on mechanical ventilation) until clinical resolution 2

Duration Guidance by Clinical Setting

• Non-ICU patients: PCT <0.25 ng/mL supports early discontinuation 3
• ICU patients: PCT <0.5 ng/mL or ≥80% decrease from peak supports discontinuation 1, 3
• General duration of 5 days is sufficient upon improvement of signs, symptoms, and inflammatory markers 2, 3

Escalation and Worsening Infection

Red Flags Requiring Action

• A ≥50% increase in PCT from previous value at any time point strongly suggests worsening infection or secondary bacterial infection and warrants escalation of therapy 2
• This criterion is more predictive than absolute values in critically ill patients 2, 3

Clinical Interpretation by PCT Level

Reference Ranges and Infection Severity

• Normal: <0.05 ng/mL (healthy individuals) 1
• 0.1-0.25 ng/mL: Low probability of bacterial infection but cannot completely rule it out 4
• 0.6-2.0 ng/mL: Systemic inflammatory response syndrome (SIRS) 2, 4
• 2-10 ng/mL: Severe sepsis 2, 4
• >10 ng/mL: Septic shock 2, 4

Common Pitfalls and Caveats

False Elevations (Non-Infectious Causes)

• Approximately 21% of COVID-19 patients without bacterial co-infection show elevated PCT due to hyperinflammatory states 2, 4
• Shock states (cardiogenic, hemorrhagic) elevate PCT independent of infection 4
• Drug hypersensitivity reactions, malignant hyperthermia, and neuroleptic malignant syndrome can cause elevation 4
• PCT may not elevate with atypical pathogens (Legionella, Mycoplasma) even in presence of infection 4

False Negatives

• Renal dysfunction and renal replacement therapy markedly influence PCT levels 2
• Severely immunocompromised patients were excluded from most PCT trials, limiting generalizability 1

Critical Limitations

• PCT cannot reliably discriminate bacterial from viral etiologies in community-acquired pneumonia—clinical signs and symptoms remain primary determinants 3
• Never make decisions solely based on PCT changes; always integrate with clinical assessment, imaging, and culture results 1, 2

Practical Clinical Algorithm

1. Assess pretest probability of bacterial infection using clinical criteria (fever ≥38°C, focal findings, hemodynamic instability) 1, 2

2. If high probability: Start empiric antibiotics within 1 hour, obtain cultures, measure baseline PCT for later discontinuation guidance 2

3. If low-to-intermediate probability: Measure PCT alongside clinical evaluation 1

   • PCT <0.25 ng/mL: Consider withholding antibiotics if clinically stable 2
   • PCT ≥0.25 ng/mL: Initiate antibiotics based on clinical judgment 4

4. Reassess at 48-72 hours: Review cultures, clinical response, repeat PCT 2

5. Discontinue antibiotics when: PCT <0.5 ng/mL or ≥80% decrease from peak AND patient clinically stable 1, 2

6. Escalate therapy if: PCT increases ≥50% from prior value, suggesting worsening or secondary infection 2

Implementation Requirements

• 24/7 PCT testing availability or minimum twice-daily batching to maximize benefit 2
• Active antimicrobial stewardship program support with pharmacist or infectious disease physician review 2
• The Surviving Sepsis Campaign provides only a weak recommendation (grade 2C, low-quality evidence) for PCT use, reflecting the need for careful clinical integration 1, 2