# Antimicrobial Therapy in Sepsis — SCCM/ESICM 2021

## Antibiotic Timing

The SSC 2021 guideline introduces a **stratified approach** to antibiotic timing based on diagnostic certainty and shock status.

### Septic Shock or High Likelihood of Sepsis

The SSC **recommends** administering antimicrobials **immediately, ideally within 1 hour** of recognition in adults with possible septic shock or a high likelihood for sepsis (Strong recommendation, Low quality of evidence for septic shock; Very Low for non-shock sepsis with high likelihood).

- Each hour of delay in antimicrobial administration is associated with **1.04 increased odds of in-hospital mortality** (per retrospective data).
- Blood cultures should be obtained before antibiotic administration, but culture collection should **not delay** antibiotic therapy.

### Possible Sepsis Without Shock

The SSC **suggests** a **rapid assessment of infectious versus non-infectious causes** within 3 hours, followed by administration of antimicrobials **within 3 hours** if infection remains suspected (Weak recommendation, Very Low quality of evidence).

- This represents a new stratified approach: patients without shock and with diagnostic uncertainty are given a brief window for rapid clinical assessment.
- Goal: reduce unnecessary antibiotic exposure while still treating true infections promptly.

### Low Infection Likelihood Without Shock

The SSC **suggests** deferring antimicrobials while **continuing to closely monitor** the patient, in adults without shock where infection likelihood is low (Weak recommendation, Very Low quality of evidence).

- Approximately **one-third** of initial sepsis diagnoses are ultimately attributed to non-infectious conditions.
- Continuous re-evaluation and searching for alternative diagnoses is essential (Best Practice Statement).
- Antimicrobials should be discontinued if an alternative non-infectious cause is demonstrated or strongly suspected.

## Antibiotic Timing Decision Algorithm

```
Suspected sepsis identified
  --> Assess shock status and infection likelihood
      --> Septic shock OR high likelihood sepsis?
          --> Administer antimicrobials IMMEDIATELY (within 1 hour)
          --> Obtain blood cultures before antibiotics (do NOT delay therapy for cultures)
      --> Possible sepsis WITHOUT shock?
          --> Rapid assessment for infectious vs non-infectious cause (within 3 hours)
              --> Infection remains suspected?
                  --> Administer antimicrobials within 3 hours
              --> Alternative diagnosis identified?
                  --> Discontinue empiric antimicrobials
                  --> Treat underlying condition
      --> Low infection likelihood WITHOUT shock?
          --> Defer antimicrobials
          --> Close clinical monitoring
          --> Reassess frequently
              --> Clinical worsening or new evidence of infection?
                  --> Administer antimicrobials promptly
```

## Biomarkers for Antibiotic Initiation

The SSC **suggests against** using procalcitonin plus clinical evaluation to **decide when to initiate** antimicrobials, compared to clinical evaluation alone (Weak recommendation, Very Low quality of evidence).

- Meta-analysis of 3 RCTs (n = 1,769) showed no mortality difference with procalcitonin-guided initiation (RR 0.99; 95% CI 0.86-1.15).
- Procalcitonin sensitivity 77%, specificity 79% for bacterial sepsis.
- Procalcitonin may still have a role in guiding antimicrobial **de-escalation** (see below), but should not drive the initial decision to start antibiotics.

## Empiric Antimicrobial Selection

### MRSA Coverage

- The SSC **recommends** using empiric antimicrobials **with MRSA coverage** for adults with sepsis or septic shock at **high risk** for MRSA (Best Practice Statement).
  - Risk factors: prior MRSA colonisation or infection, recent antibiotic exposure, indwelling invasive devices, recent hospitalisation, haemodialysis.
- The SSC **suggests against** using empiric antimicrobials with MRSA coverage for adults with sepsis or septic shock who are at **low risk** for MRSA (Weak recommendation, Low quality of evidence).
  - MRSA accounts for approximately **5%** of culture-positive infections in sepsis.

### Double Gram-Negative Coverage

- The SSC **suggests** using **two antimicrobials with gram-negative coverage** for empiric treatment of adults with sepsis or septic shock at **high risk** for multidrug-resistant (MDR) organisms (Weak recommendation, Very Low quality of evidence).
  - Risk factors: known MDR colonisation, local high-resistance epidemiology, recent broad-spectrum antibiotic exposure, recent prolonged hospitalisation.
- The SSC **suggests against** using double gram-negative coverage for patients at **low risk** for MDR organisms (Weak recommendation, Very Low quality of evidence).

### Empiric Antifungal Therapy

- The SSC **suggests** using empiric antifungal therapy for adults with sepsis or septic shock at **high risk** for fungal infection (Weak recommendation, Low quality of evidence).
  - Risk factors: Candida colonisation at multiple sites, immunosuppression, neutropenia, prolonged ICU stay, GI perforation or anastomotic leak, TPN.
- The SSC **suggests against** empiric antifungal therapy in patients at **low risk** for fungal infection (Weak recommendation, Low quality of evidence).
  - The EMPIRICUS trial showed no mortality benefit of empiric antifungals in the general ICU sepsis population.

### Antiviral Therapy

- The SSC **makes no recommendation** on the use of antiviral agents in the general sepsis population.
- Viruses are documented as the causative agent in **< 4%** of infections in large point-prevalence studies.
- For specific viral infections (e.g., influenza, COVID-19), dedicated pathogen-specific guidelines should be followed.

## Antibiotic Delivery Optimisation

### Prolonged Infusion of Beta-Lactams

The SSC **suggests** using **prolonged infusion of beta-lactams** for maintenance (after an initial bolus), rather than conventional intermittent bolus dosing (Weak recommendation, Moderate quality of evidence).

- Meta-analysis demonstrated mortality reduction with prolonged infusion: **RR 0.70 (95% CI 0.57-0.87)**.
- **Extended infusion:** infusion over at least half the dosing interval (e.g., piperacillin-tazobactam over 3-4 hours for a q8h dosing interval).
- **Continuous infusion:** infusion over the entire dosing interval (24 hours).
- After an initial loading dose as a bolus, subsequent doses are delivered via prolonged infusion to maintain time-dependent bactericidal activity above the minimum inhibitory concentration (fT>MIC).

### Pharmacokinetic/Pharmacodynamic (PK/PD) Optimisation

The SSC **recommends** optimising dosing strategies based on accepted PK/PD principles and specific drug properties (Best Practice Statement).

| Drug Class | PK/PD Target | Key Considerations |
|---|---|---|
| **Aminoglycosides** | AUC 70-100; Cmax/MIC 8-10 | Extended-interval dosing; renal dose adjustment |
| **Beta-lactams** | fT>MIC; Cmin > MIC | Prolonged/continuous infusion preferred |
| **Vancomycin** | AUC(0-24)/MIC > 400 | Therapeutic drug monitoring recommended |
| **Fluoroquinolones** | AUC(0-24)/MIC 80-125 | Concentration-dependent with time-dependent component |
| **Daptomycin** | AUC(0-24)/MIC > 200 | Concentration-dependent |

- Consider altered pharmacokinetics in sepsis: augmented renal clearance, acute kidney injury, hypoalbuminaemia, renal replacement therapy, and ECMO.
- Therapeutic drug monitoring (TDM) should be utilised when available.

## Source Control

### Rapid Identification

The SSC **recommends** rapidly identifying or excluding a specific anatomical diagnosis of infection that requires emergent source control, and implementing source control intervention **as soon as medically and logistically practical** (Best Practice Statement).

- Target timing: **6-12 hours** from diagnosis (smaller studies suggest earlier intervention is advantageous).
- Source control methods include:
  - **Abscess drainage** (percutaneous or surgical)
  - **Debridement of infected necrotic tissue**
  - **Removal of potentially infected devices**
  - **Definitive relief of obstruction** (e.g., biliary, urinary)

### Intravascular Device Removal

The SSC **recommends** prompt removal of intravascular access devices that are a potential source of sepsis, **after establishing alternative vascular access** (Best Practice Statement).

- Exception: some tunnelled catheter infections may be treated with systemic antibiotics and antibiotic lock therapy if device removal is impractical.

## De-escalation of Antimicrobials

### Daily Assessment

The SSC **suggests** performing a **daily assessment for de-escalation** of antimicrobials (Weak recommendation, Very Low quality of evidence).

- Meta-analysis of 13 studies (1,968 patients) demonstrated improved mortality with de-escalation (RR 0.72; 95% CI 0.57-0.91).
- De-escalation is associated with shorter hospital stays (mean difference -5.56 days).
- De-escalation should be guided by culture results, clinical response, and antimicrobial susceptibilities.

### Procalcitonin for De-escalation

- While procalcitonin is not recommended for guiding antibiotic initiation, declining procalcitonin levels may support decisions to narrow or discontinue antimicrobials in conjunction with clinical assessment.

## Antibiotic Duration

The SSC **suggests** shorter courses of antimicrobial therapy when adequate source control has been achieved, clinical improvement is evident, and cultures/susceptibilities guide targeted therapy (Weak recommendation, Very Low quality of evidence).

- Typical duration: **7-10 days** for most infections in sepsis, but this should be individualised based on:
  - Source of infection
  - Adequacy of source control
  - Causative pathogen
  - Clinical and biochemical response

## Limitations

- Very low quality evidence supports most antimicrobial choice recommendations (18 of 30+ recommendations in this domain).
- The 1-hour and 3-hour timing targets are derived primarily from retrospective and observational studies rather than prospective RCTs.
- Antimicrobial resistance patterns vary by geography and institution; empiric regimens must be adapted to local antibiograms.
- The prolonged beta-lactam infusion evidence is based largely on non-sepsis-specific studies, though dedicated meta-analyses support benefit.
- Procalcitonin-guided antibiotic initiation was studied in only 3 RCTs; further evidence is needed.
