Sepsis and Septic Shock — Part 3: Antimicrobial Therapy & Source Control
Timing of antibiotics, empiric broad-spectrum regimens by suspected source, de-escalation, duration of therapy, procalcitonin-guided discontinuation, antifungal considerations, and source control procedures.
1. Timing of Antimicrobial Administration
1.1 Guideline Recommendations
The timing of antimicrobial administration is one of the most critical determinants of survival in sepsis and septic shock.1 2
Recommendation: For adults with possible septic shock or a high likelihood of sepsis, the panel recommends administering antimicrobials immediately, ideally within 1 hour of recognition.
Strength: Strong recommendation (septic shock); Best practice statement (high likelihood sepsis)1
Recommendation: For adults with possible sepsis without shock, the panel suggests a time-limited course of rapid investigation and, if concern for infection persists, administration of antimicrobials within 3 hours of the time when sepsis was first recognized.
Strength: Weak recommendation, very low quality of evidence1
1.2 Evidence for Early Antibiotic Administration
| Study | Key Finding |
|---|---|
| Kumar et al. (2006) | Each hour of delay in effective antibiotic administration after onset of septic shock hypotension was associated with a 7.6% decrease in survival (adjusted OR)2 |
| Seymour et al. (2017) | In a retrospective analysis of 49,331 ED patients with sepsis, faster antibiotic administration was associated with lower in-hospital mortality, with each additional hour of time-to-antibiotics associated with higher odds of death3 |
| Alam et al. (2018) | Meta-analysis of 11 studies (n = 16,178): every hour delay in antibiotic administration was associated with an OR of 1.04 (95% CI 1.02–1.07) for mortality4 |
| Liu et al. (2017) | Retrospective cohort (n = 35,000): In sepsis without shock, each additional hour of antibiotic delay was associated with a 0.3–1.0% absolute increase in in-hospital mortality5 |
1.3 The Diagnostic Uncertainty Challenge
The infectious disease professional societies have emphasized that the mandate for immediate antibiotics must be balanced against the risks of antibiotic overuse in patients with diagnostic uncertainty:6
- In patients with definite septic shock, antibiotics should be administered immediately — the benefit of early treatment clearly outweighs any risk of unnecessary antibiotics
- In patients with possible sepsis without shock, a brief period (up to 3 hours) of focused investigation is reasonable to clarify the diagnosis before committing to broad-spectrum therapy
- The key is urgent evaluation, not automatic antibiotic reflexes — perform a focused history, examination, and targeted diagnostics rapidly, then make a treatment decision
1.4 Blood Cultures Before Antibiotics
Recommendation: For adults with suspected sepsis or septic shock, the panel recommends obtaining blood cultures before administering antimicrobials, provided that this does not substantially delay antibiotic administration.
Strength: Best practice statement1
Practical guidance:
- Obtain at least 2 sets of blood cultures (aerobic and anaerobic bottles) from 2 separate venipuncture sites or 1 venipuncture site + 1 existing vascular access device
- Each “set” consists of 1 aerobic + 1 anaerobic bottle with 20–30 mL of blood per set (10–15 mL per bottle) — inadequate volume is the most common cause of false-negative blood cultures
- Do not delay antibiotics by more than 45 minutes to obtain blood cultures
- If the patient has an existing central venous catheter, draw one set through the catheter and one set peripherally (to help identify catheter-related bloodstream infections)
- Culture additional sites based on clinical suspicion: urine, sputum, wound, cerebrospinal fluid, joint fluid, peritoneal fluid
2. Empiric Antimicrobial Selection by Suspected Source
2.1 General Principles
Recommendation: For adults with sepsis or septic shock, the panel recommends initiating empiric broad-spectrum therapy with one or more antimicrobials to cover all likely pathogens.
Strength: Strong recommendation, moderate quality of evidence1
Key principles for empiric selection:
- Cover all likely pathogens based on the suspected source of infection, local antibiogram data, and patient-specific risk factors (recent antibiotics, healthcare exposure, immunocompromised status, colonization history)
- Consider MRSA coverage when risk factors are present (prior MRSA infection/colonization, recent hospitalization, hemodialysis, IV drug use, indwelling devices, high institutional MRSA prevalence)
- Consider double gram-negative coverage (two agents with activity against gram-negative organisms from different antibiotic classes) in patients with septic shock, high risk for multidrug-resistant organisms, or when local resistance rates for first-line agents exceed 10–15%1
- Adjust for local antibiogram — empiric regimens should be guided by institution-specific susceptibility patterns
2.2 Empiric Regimens by Suspected Source
Pulmonary Source (Community-Acquired Pneumonia with Sepsis)
| Severity | Recommended Regimen | Alternative |
|---|---|---|
| Standard risk | Ceftriaxone 2 g IV q24h + Azithromycin 500 mg IV q24h | Levofloxacin 750 mg IV q24h (if beta-lactam allergy) |
| High severity / ICU | Ceftriaxone 2 g IV q24h + Azithromycin 500 mg IV q24h | Ceftriaxone + Levofloxacin 750 mg IV q24h |
| Pseudomonas risk factors | Piperacillin-tazobactam 4.5 g IV q6h (or cefepime 2 g IV q8h, or meropenem 1 g IV q8h) + Levofloxacin 750 mg IV q24h (or azithromycin) | Cefepime 2 g IV q8h + Ciprofloxacin 400 mg IV q8h |
| MRSA risk factors | Add Vancomycin 25–30 mg/kg IV loading dose, then 15–20 mg/kg IV q8–12h (target trough 15–20 μg/mL or AUC/MIC 400–600) OR Linezolid 600 mg IV q12h | — |
| Aspiration / anaerobic concern | Add Metronidazole 500 mg IV q8h (or use ampicillin-sulbactam, piperacillin-tazobactam, or a carbapenem which already cover anaerobes) | — |
Hospital-Acquired / Ventilator-Associated Pneumonia with Sepsis
| Risk Category | Recommended Regimen |
|---|---|
| Low MDR risk, early onset (< 5 days) | Ceftriaxone 2 g IV q24h or Cefepime 2 g IV q8h |
| High MDR risk or late onset (≥ 5 days) | Anti-pseudomonal beta-lactam: Piperacillin-tazobactam 4.5 g IV q6h (extended infusion preferred) OR Cefepime 2 g IV q8h OR Meropenem 1–2 g IV q8h (extended infusion) PLUS Anti-pseudomonal second agent: Ciprofloxacin 400 mg IV q8h or Tobramycin/Amikacin PLUS Anti-MRSA agent: Vancomycin or Linezolid 600 mg IV q12h |
Intra-Abdominal Source
| Setting | Recommended Regimen | Alternative |
|---|---|---|
| Community-acquired, mild-moderate | Ceftriaxone 2 g IV q24h + Metronidazole 500 mg IV q8h | Ertapenem 1 g IV q24h |
| Community-acquired, severe / septic shock | Piperacillin-tazobactam 4.5 g IV q6h OR Meropenem 1 g IV q8h | Cefepime 2 g IV q8h + Metronidazole 500 mg IV q8h |
| Healthcare-associated / post-operative | Meropenem 1 g IV q8h OR Piperacillin-tazobactam 4.5 g IV q6h + Vancomycin (if MRSA risk) | Imipenem-cilastatin 500 mg IV q6h |
| Concern for Enterococcus (biliary, post-operative) | Add Ampicillin 2 g IV q4h or Vancomycin | — |
| Concern for Candida (tertiary peritonitis, TPN, recent abdominal surgery) | Add Micafungin 100 mg IV q24h or Fluconazole 400–800 mg IV q24h | Anidulafungin 200 mg IV load then 100 mg IV q24h |
Urinary Tract Source (Complicated UTI / Urosepsis)
| Setting | Recommended Regimen | Alternative |
|---|---|---|
| Community-acquired, no MDR risk | Ceftriaxone 2 g IV q24h | Ciprofloxacin 400 mg IV q12h (if local E. coli FQ resistance < 10%) |
| MDR risk / healthcare-associated | Piperacillin-tazobactam 4.5 g IV q6h OR Cefepime 2 g IV q8h | Meropenem 1 g IV q8h (if ESBL risk) |
| Enterococcal risk (recent instrumentation, indwelling catheter) | Add Ampicillin 2 g IV q4h or Vancomycin | — |
Skin and Soft Tissue Source
| Type | Recommended Regimen | Alternative |
|---|---|---|
| Cellulitis / erysipelas (streptococcal likely) | Cefazolin 2 g IV q8h | Vancomycin (if MRSA suspected) |
| Purulent / abscess / MRSA risk | Vancomycin 25–30 mg/kg IV load, then 15–20 mg/kg q8–12h | Linezolid 600 mg IV q12h or Daptomycin 6–8 mg/kg IV q24h |
| Necrotizing fasciitis / gas gangrene | Meropenem 1 g IV q8h (or piperacillin-tazobactam 4.5 g IV q6h) + Vancomycin + Clindamycin 900 mg IV q8h (for toxin suppression) | Cefepime + Metronidazole + Vancomycin + Clindamycin |
| Fournier’s gangrene | Same as necrotizing fasciitis + urgent surgical debridement | — |
Central Nervous System Source (Meningitis)
| Patient Population | Recommended Regimen |
|---|---|
| Adults 18–50 years, community-acquired | Ceftriaxone 2 g IV q12h + Vancomycin 15–20 mg/kg IV q8–12h + Dexamethasone 0.15 mg/kg IV q6h × 4 days (initiate before or with first antibiotic dose) |
| Adults > 50 years or immunocompromised | Ceftriaxone 2 g IV q12h + Vancomycin + Ampicillin 2 g IV q4h (for Listeria coverage) + Dexamethasone |
| Post-neurosurgical / VP shunt | Meropenem 2 g IV q8h + Vancomycin |
Catheter-Related Bloodstream Infection (CRBSI)
| Pathogen Concern | Recommended Regimen |
|---|---|
| Empiric (pending cultures) | Vancomycin + Cefepime 2 g IV q8h (or Piperacillin-tazobactam 4.5 g IV q6h) |
| Gram-positive on Gram stain | Vancomycin (consider Daptomycin 8–10 mg/kg IV q24h if vancomycin-resistant enterococcus risk) |
| Gram-negative on Gram stain | Cefepime 2 g IV q8h or Meropenem 1 g IV q8h |
| Candidemia | Micafungin 100 mg IV q24h or Anidulafungin 200 mg load then 100 mg IV q24h; remove the catheter |
Unknown Source / Empiric Septic Shock Coverage
| Risk Level | Recommended Regimen |
|---|---|
| No MDR risk factors | Piperacillin-tazobactam 4.5 g IV q6h (extended infusion) + Vancomycin |
| MDR risk factors present | Meropenem 1 g IV q8h (extended infusion) + Vancomycin |
| Critical illness / septic shock requiring double gram-negative coverage | Meropenem 1 g IV q8h + Amikacin 15–20 mg/kg IV q24h + Vancomycin |
2.3 Extended and Prolonged Infusion Strategies
Recommendation: For adults with sepsis or septic shock, the panel suggests using prolonged infusion of beta-lactams for maintenance (after an initial bolus dose), rather than conventional bolus dosing.
Strength: Weak recommendation, moderate quality of evidence1
| Agent | Conventional Dosing | Extended Infusion | Continuous Infusion |
|---|---|---|---|
| Piperacillin-tazobactam | 4.5 g IV over 30 min q6h | 4.5 g IV over 3–4 hours q6–8h | 18 g/day continuous after loading dose |
| Meropenem | 1–2 g IV over 30 min q8h | 1–2 g IV over 3 hours q8h | Not typically used (stability concerns) |
| Cefepime | 2 g IV over 30 min q8h | 2 g IV over 3–4 hours q8h | 6 g/day continuous after loading dose |
Evidence: A meta-analysis of 29 studies (n = 2,206) demonstrated that prolonged infusion of beta-lactams was associated with significantly lower mortality compared with intermittent bolus dosing (RR 0.70, 95% CI 0.56–0.87).7
3. De-Escalation of Antimicrobial Therapy
3.1 Principles
Recommendation: For adults with sepsis or septic shock, the panel recommends daily assessment for de-escalation of antimicrobials over using fixed durations of therapy without daily reassessment.
Strength: Best practice statement1
De-escalation should be considered once:
- Culture and sensitivity results are available (typically 48–72 hours)
- The clinical trajectory is improving (defervescence, decreasing vasopressor requirements, improving lactate)
- The source of infection has been identified or is being effectively controlled
3.2 De-Escalation Strategies
| Scenario | Action |
|---|---|
| Blood cultures negative at 48–72 hours, patient improving | Consider narrowing spectrum; discontinue empiric MRSA coverage if no MRSA identified; consider discontinuing double gram-negative coverage |
| Blood cultures positive with susceptibilities | Narrow to the most targeted effective agent |
| MRSA cultures negative, low clinical suspicion | Discontinue vancomycin/linezolid |
| No Pseudomonas identified | Narrow from anti-pseudomonal to narrower-spectrum agent if appropriate |
| Source controlled, patient improving | Consider transition from IV to oral therapy when: afebrile ≥ 48 hrs, tolerating oral intake, no ongoing bacteremia, adequate oral bioavailability |
4. Duration of Antimicrobial Therapy
4.1 Guideline Recommendations
Recommendation: For adults with an initial diagnosis of sepsis or septic shock, the panel suggests using shorter over longer courses of antimicrobial therapy.
Strength: Weak recommendation, very low quality of evidence1
4.2 Recommended Durations by Source
| Infection Source | Recommended Duration | Notes |
|---|---|---|
| Pneumonia (community-acquired) | 5–7 days | Minimum 5 days; patient should be afebrile ≥ 48 hrs and clinically stable before stopping |
| Pneumonia (ventilator-associated) | 7 days | Can extend to 14 days for non-fermenting gram-negatives (Pseudomonas, Acinetobacter) with slow clinical response |
| Urinary tract infection (complicated/urosepsis) | 7–14 days | 7 days if rapid clinical response; 14 days if slow response or urinary obstruction |
| Intra-abdominal infection (adequate source control) | 4–7 days | STOP-IT trial: 4 days after adequate source control was non-inferior to longer courses8 |
| Intra-abdominal infection (inadequate source control) | Continue until source control achieved | — |
| Skin and soft tissue (cellulitis) | 5–7 days | Longer if slow clinical response |
| Skin and soft tissue (necrotizing) | Until surgical debridement complete + clinical stability | Often 2–4 weeks |
| Bloodstream infection (uncomplicated) | 7–14 days | Depends on organism; S. aureus bacteremia typically requires minimum 14 days (see below) |
| S. aureus bacteremia | Minimum 14 days (uncomplicated); 4–6 weeks (complicated) | Complicated = endocarditis, metastatic infection, prosthetic material, persisting bacteremia > 72 hrs |
| Catheter-related bloodstream infection | 7–14 days after catheter removal (for most pathogens) | Candidemia: minimum 14 days after first negative blood culture |
| Meningitis (bacterial) | 7–21 days depending on organism | N. meningitidis: 7 days; S. pneumoniae: 10–14 days; Listeria: 21 days; GNR: 21 days |
5. Procalcitonin-Guided Antibiotic Discontinuation
5.1 Recommendations
Recommendation: For adults with an initial diagnosis of sepsis or septic shock and adequate source control, the panel suggests using procalcitonin AND clinical evaluation to decide when to discontinue antimicrobials, over clinical evaluation alone.
Strength: Weak recommendation, low quality of evidence1
5.2 Procalcitonin-Guided Algorithm
| PCT Trend | Clinical Context | Recommendation |
|---|---|---|
| PCT decreased by ≥ 80% from peak value | Patient clinically improving | Strongly consider discontinuing antibiotics |
| PCT decreased to < 0.5 ng/mL | Patient clinically improving | Strongly consider discontinuing antibiotics |
| PCT decreased by 50–79% from peak | Patient improving | Consider discontinuation based on clinical context |
| PCT plateaued or not declining | Patient improving clinically | Continue antibiotics; reassess in 24–48 hours; evaluate for source control adequacy |
| PCT rising | Patient not improving or worsening | Continue antibiotics; reassess source control; consider broadening spectrum; evaluate for secondary infection |
5.3 Key Evidence
- PRORATA trial (2010): PCT-guided antibiotic therapy reduced antibiotic exposure by 2.7 days without increasing mortality (21.2% vs. 20.4%, p = 0.71) or relapse rates.9
- SAPS trial (2016): PCT-guided discontinuation in sepsis reduced antibiotic duration by 2 days (median 5 vs. 7 days) without difference in 28-day mortality.10
- Meta-analysis (Lam et al., 2018): Across 16 RCTs (n = 5,158), PCT-guided antibiotic discontinuation reduced antibiotic duration by a mean of 1.5 days and was associated with lower 28-day mortality (21.1% vs. 23.7%, RR 0.89, 95% CI 0.80–0.99).11
5.4 Limitations of Procalcitonin
- False elevations: Major surgery, severe burns, cardiogenic shock, acute graft-versus-host disease, certain malignancies, end-stage renal disease (impaired clearance)
- False low values: Early infection (first 2–4 hours), localized infections (uncomplicated UTI, abscess without systemic response), intracellular pathogens (Mycoplasma, Chlamydia, viruses)
- Clinical judgment remains paramount: PCT should not override clinical assessment — it is an adjunctive tool, not a sole determinant
6. Antifungal Considerations in Sepsis
6.1 When to Suspect Invasive Fungal Infection
Risk factors for invasive candidiasis in critically ill patients:
- Prolonged ICU stay (> 7 days)
- Total parenteral nutrition (TPN)
- Broad-spectrum antibiotic exposure
- Recent abdominal surgery, especially with anastomotic leak
- Hemodialysis or renal replacement therapy
- Multifocal Candida colonization (≥ 2 non-contiguous body sites)
- Central venous catheters
- Immunosuppression (neutropenia, solid organ transplant, corticosteroids)
6.2 Empiric Antifungal Therapy
Recommendation: For adults with sepsis or septic shock at high risk for fungal infection, the panel suggests empiric antifungal therapy in patients who are not improving on appropriate antibacterial therapy.
Strength: Weak recommendation, low quality of evidence1
| Clinical Scenario | Recommended Agent | Dosing | Notes |
|---|---|---|---|
| Empiric (suspected invasive candidiasis) | Micafungin | 100 mg IV q24h | Echinocandin preferred for empiric therapy |
| Empiric (suspected invasive candidiasis) | Anidulafungin | 200 mg IV load, then 100 mg IV q24h | Alternative echinocandin |
| Empiric (suspected invasive candidiasis) | Caspofungin | 70 mg IV load, then 50 mg IV q24h | Alternative echinocandin |
| Confirmed candidemia (Candida albicans, susceptible) | Fluconazole | 800 mg IV load, then 400 mg IV q24h | Step-down from echinocandin after species confirmation and clinical stability |
| Confirmed candidemia (Candida glabrata, krusei, or unknown species) | Echinocandin | As above | Do not use fluconazole empirically due to resistance concerns |
| Suspected invasive aspergillosis | Voriconazole | 6 mg/kg IV q12h × 2 doses (load), then 4 mg/kg IV q12h | First-line for invasive aspergillosis; monitor drug levels (target trough 1–5.5 μg/mL) |
6.3 Beta-D-Glucan and Galactomannan
| Test | Sensitivity | Specificity | Best Use |
|---|---|---|---|
| 1,3-Beta-D-Glucan (BDG) | 70–85% for invasive candidiasis | 80–90% | Screening for invasive candidiasis; elevated in most fungal infections except Mucor/Rhizopus and Cryptococcus |
| Galactomannan (serum) | 65–80% for invasive aspergillosis | 85–95% | Diagnosis of invasive aspergillosis; better performance in neutropenic patients |
| Galactomannan (BAL) | 85–95% for pulmonary aspergillosis | 90–95% | Higher sensitivity than serum in non-neutropenic ICU patients |
7. Source Control
7.1 Principles
Recommendation: For adults with sepsis or septic shock, the panel recommends that a specific anatomic source of infection be identified or excluded as rapidly as possible and that any required source control intervention be implemented as soon as medically and logistically practical.
Strength: Best practice statement1
Recommendation: The panel recommends prompt removal of intravascular access devices that are a possible source of sepsis or septic shock after other vascular access has been established.
Strength: Best practice statement1
7.2 Source Control Interventions by Site
| Source | Intervention | Timing |
|---|---|---|
| Intra-abdominal abscess | Percutaneous drainage (image-guided) or surgical drainage | Within 6–12 hours of identification |
| Perforated viscus | Surgical repair / resection | Emergency — as soon as possible |
| Biliary obstruction (cholangitis) | ERCP with biliary drainage or percutaneous transhepatic drainage | Within 12–24 hours; emergent if septic shock |
| Acute cholecystitis (gangrenous or emphysematous) | Cholecystectomy or percutaneous cholecystostomy | Within 24 hours; sooner if septic shock |
| Necrotizing soft tissue infection | Surgical debridement | Emergency — within 6–12 hours; delay increases mortality by approximately 25% per 24-hour delay |
| Infected joint prosthesis | Irrigation and debridement ± prosthesis exchange | Within 24–48 hours |
| Empyema | Chest tube drainage or video-assisted thoracoscopic surgery (VATS) | Within 12–24 hours |
| Infected central venous catheter | Catheter removal | Immediate — within 2–4 hours of suspicion |
| Infected urinary catheter with obstruction | Catheter replacement + relieve obstruction | Immediate |
| Epidural abscess | Surgical drainage (neurosurgical emergency) | Emergency — within 6–12 hours |
| Infected pancreatic necrosis | Step-up approach: percutaneous drainage → minimally invasive debridement → open necrosectomy | Delay intervention until ≥ 4 weeks if possible (walled-off necrosis); earlier if clinical deterioration |
7.3 Timing of Source Control
- Source control should be achieved as soon as possible after the diagnosis is confirmed, ideally within 6–12 hours
- The only exception is infected pancreatic necrosis, where delayed intervention (≥ 4 weeks) to allow demarcation of the necrosis is preferred unless clinical deterioration mandates earlier intervention12
- Antimicrobials alone are generally insufficient without source control — infected collections, necrotic tissue, and foreign bodies serve as ongoing reservoirs of infection
- The choice between percutaneous and surgical drainage should be individualized based on the site, size, complexity, and patient factors
7.4 Special Considerations
- Damage control surgery: In patients with septic shock and hemodynamic instability, an abbreviated surgical approach may be preferred — source control with temporary abdominal closure, resuscitation in the ICU, and planned return to the operating room when hemodynamically stable
- Timing vs. resuscitation: Source control should not be excessively delayed for hemodynamic optimization, as the source of infection is often the primary driver of hemodynamic instability. However, a brief period of resuscitation (1–2 hours) to achieve some hemodynamic improvement before surgery is reasonable in most cases.
References
Evans L, Rhodes A, Alhazzani W, et al. “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021.” Crit Care Med. 2021;49(11):e1063-e1143. DOI: 10.1097/CCM.0000000000005337 ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Kumar A, Roberts D, Wood KE, et al. “Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.” Crit Care Med. 2006;34(6):1589-1596. DOI: 10.1097/01.CCM.0000217961.75225.E9 ↩︎ ↩︎
Seymour CW, Gesten F, Prescott HC, et al. “Time to treatment and mortality during mandated emergency care for sepsis.” N Engl J Med. 2017;376(23):2235-2244. DOI: 10.1056/NEJMoa1703058 ↩︎
Alam N, Oskam E, Stassen PM, et al. “Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial.” Lancet Respir Med. 2018;6(1):40-50. DOI: 10.1016/S2213-2600(17)30469-1 ↩︎
Liu VX, Fielding-Singh V, Greene JD, et al. “The timing of early antibiotics and hospital mortality in sepsis.” Am J Respir Crit Care Med. 2017;196(7):856-863. DOI: 10.1164/rccm.201609-1848OC ↩︎
Rhee C, Chiotos K, Gershengorn HB, et al. “Infectious Diseases Society of America Position Paper: Recommended Revisions to the National Severe Sepsis and Septic Shock Early Management Bundle (SEP-1).” Clin Infect Dis. 2021;72(4):541-552. DOI: 10.1093/cid/ciaa059 ↩︎
Roberts JA, Abdul-Aziz MH, Davis JS, et al. “Continuous versus intermittent β-lactam infusion in severe sepsis: a meta-analysis of individual patient data from randomized trials.” Am J Respir Crit Care Med. 2016;194(6):681-691. DOI: 10.1164/rccm.201601-0024OC ↩︎
Sawyer RG, Claridge JA, Nathens AB, et al. “Trial of short-course antimicrobial therapy for intraabdominal infection.” N Engl J Med. 2015;372(21):1996-2005. DOI: 10.1056/NEJMoa1411162 ↩︎
Bouadma L, Luyt CE, Tubach F, et al. “Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial.” Lancet. 2010;375(9713):463-474. DOI: 10.1016/S0140-6736(09)61879-1 ↩︎
de Jong E, van Oers JA, Beishuizen A, et al. “Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial.” Lancet Infect Dis. 2016;16(7):819-827. DOI: 10.1016/S1473-3099(16)00053-0 ↩︎
Lam SW, Bauer SR, Fowler R, Duggal A. “Systematic review and meta-analysis of procalcitonin-guidance versus usual care for antimicrobial therapy in critically ill patients: focus on subgroups based on antibiotic initiation, cessation, or mixed strategies.” Crit Care Med. 2018;46(5):684-690. DOI: 10.1097/CCM.0000000000002953 ↩︎
van Santvoort HC, Besselink MG, Bakker OJ, et al. “A step-up approach or open necrosectomy for necrotizing pancreatitis.” N Engl J Med. 2010;362(16):1491-1502. DOI: 10.1056/NEJMoa0908821 ↩︎