Antimicrobial stewardship program implementation remains suboptimal in the intensive care setting, where frequent prescription of broad-spectrum antimicrobial therapy and its misuse pose significant risk of antimicrobial resistance, adverse effects, and economic burden. |
Biomarkers can be considered promising adjuncts for antimicrobial stewardship but knowledge of their strengths and limitations is key to avoiding misinterpretation and misuse. |
Procalcitonin-guided therapeutic decisions have been linked to decrease in antimicrobial therapy duration; however, no clear mortality benefit has been found. |
Procalcitonin study limitations such as low protocol adherence, high risk of bias, and longer antimicrobial therapy duration in non-procalcitonin groups call for future well-structured trials. |
Modified pharmacokinetics in the critically ill, such as augmented renal clearance and increased volume of distribution, pose as risks for suboptimal antimicrobial therapy and therapeutic failure. |
Digital Features
Introduction
Methods
Antimicrobial Stewardship: What is the Problem?
Antibiotic Stewardship Programs in ICU
Antimicrobial De-escalation
Biomarkers
Role in Predicting Infection, Diagnosis, and Initiation of Antimicrobial Therapy
Potential role | Author/year | Study | Population | Total N (biomarker/control) | Biomarker | Findings | Primary endpoint/objective | Mortalitya N (%) |
---|---|---|---|---|---|---|---|---|
Risk prediction | Póvoa/2006 [41] | Prospective observational cohort | ICU admissions > 72 h | 63 | CRP | 88% risk with CRP variation > 4.1 mg/dL plus CRP > 8.7 mg/dL | CRP progression patterns | – |
Póvoa/2016 [42] (BioVAP) | Prospective observational | ICU, mechanical ventilation > 72 h | 22 | CRP/PCT | Increase of 1 mg/dL/day CRP with 62% greater chance of VAP | Predictive accuracy of CRP, PCT, and MR-proADM for VAP management | – | |
Diagnosis and treatment initiation | Christ-Crain/2004 [43](ProCAP) | RCT | Hospital admissions with suspected LRTIs | 243 (124/119) | PCT | 0.49 RR of ATB exposure (95% CI 0.44–0.55; p < 0.0001) with PCT | Use of antibiotics | – |
Christ-Crain/2006 [44](ProRESP) | RCT | Emergency department admissions with CAP | 302 (151/151) | PCT | ATB withheld from 15% vs 1% (PCT vs control) p < 0.001 | Total ATB use and duration | 18 (12)/20 (13), NS PCT/control | |
Schuetz/2009 [45](ProHosp) | RCT | Emergency department admissions with LRTIs | 1359 (671/688) | PCT | ATB duration 5.7 vs 8.7 days (PCT vs control) | Noninferiority endpoint of adverse outcomes: death, ICU admission, disease complications, recurrence of LRTI | 34 (5.1)/33 (4.8) PCT/control | |
Jensen/2011 [48] | RCT | ICU admissions > 24 h | 1200 (604/596) | PCT | ATB initiation NS 18% vs 17.6% decision not to initiate (PCT vs control) | Death from any cause at day 28 | 190 (31.5)/191 (32), NS PCT/control | |
Layios/2012 [49] | RCT | ICU admissions > 48 h | 509 (258/251) | PCT | Withheld ATB: 46% vs 33%, NS (PCT vs control) | Reduction of antibiotic use | 56 (22)/53 (21), NS PCT/control | |
Self/2017 [47] | Prospective observational cohort | Hospitalized adults with CAP | 1735 | PCT | Discrimination between bacterial (n = 236) and viral pathogens (n = 409): area under the ROC curve of 0.73 (95% CI 0.69–0.77) | Predictive accuracy of admission PCT for underlying pathogen | – | |
Coelho/2018 [51] | Prospective observational | ICU patients with VAT or VAP | 404 | CRP/PCT | CRP 18 mg/dL vs 14 mg/dL, p = 0.001 PCT 2.1 ng/dL vs 0.64 ng/dL, p < 0.001 (VAP vs VAT) | CRP and PCT on day of diagnosis | – | |
Treatment response & treatment duration | Bouadma/2010 [56](PRORATA) | RCT | Non-surgical ICU patients with suspected bacterial infection | 621 (307/314) | PCT | 14.3 ± 9.1 vs 11.6 ± 8.2 ATB-free days p < 0.0001 (PCT vs control) | Mortality at day 28 and day 60; antibiotic-free days by day 28 | 65 (21)/64 (20), NS PCT/control |
Póvoa/2011 [59] | Prospective observational | ICU admissions with CAS | 891 | CRP | Odds of death for slow or no responseb: 1.6 (95% CI 0.9, 2.9), p = 0.119); 3.0 (95% CI 1.8, 5.1), p < 0.001 | CRP course during first 5 days of ICU admission; day 28 mortality | 23%, 30%, 41% in fast, slow, and no response b, p = 0.001 (N for analyses = 566) | |
Oliveira/2013 [60] | RCT | ICU patients with sepsis | 94 (45 CRP/49 PCT) | CRP/PCT | ATB duration, 6 vs 7 days, NS CRP vs PCT | ATB duration | 47 (21)/43 (21), NS CRP/PCT | |
De Jong/2016 [58] | RCT | ICU admissions with presumed infection | 1575 (761/785) | PCT | ATB duration 5 vs 7 days, p < 0.0001 (PCT vs control) | ATB daily dose and duration | 149 (20)/196 (25), p = 0.0122 PCT/control | |
Borges/2020 [23] | RCT | ICU admissions with infection | 130 (64/66) | CRP | ATB suspension of 35.9% vs 10.6% until day 5 (OR 4.7, 95% CI 1.9–12, p = 0.001) ATB duration 8 vs 10 days, NS Total ATB exposure 8 vs 8.5 days, NS | ATB duration | 28 (18)/23 (15), NS CRP/control |
Assessment of Treatment Response and Impact on Duration of Antimicrobial Therapy
Barriers to PCT Implementation
Biomarkers in Progress
Pharmacokinetics and Pharmacodynamics of the ICU Patient in Antimicrobial Stewardship
Pharmacokinetics
Pharmacodynamics
Antibiotic Dosing and Monitoring in ICU
Antimicrobial class | Monitoring | Sampling | Target | Toxicity threshold |
---|---|---|---|---|
Aminoglycosides | AUC-based Cmax/MIC Cmin | Two samplesa One sampleb One samplec | AUC 80–120 mg h/L Cmax/MIC ≥ 8–10 | Nephrotoxicity/ototoxicity |
Gentamicin/tobramicin | Cmin < 0.5 mg/L | Cmin > 1 mg/L | ||
Amikacin | Cmin < 2.5 mg/L | Cmin > 5 mg/L | ||
Beta-lactams | Cmin Css | One samplec One sampled | 100% fT > MIC Css > MIC | Nephrotoxicity/neurotoxicity |
Penicillins | 50–100% fT > MIC | Cmin > 361 mg/L (piperacillin nephro-/neurotoxicity) | ||
Cephalosporins | 45–100% fT > MIC | Cmin > 20 mg/L (cefepime neurotoxicity) | ||
Carbapenems | 50–100% fT > MIC | Cmin > 44.5 mg/L (meropenem nephro-/neurotoxicity) | ||
Glycopeptides | ||||
Vancomycin | AUC/MIC Cmin Css | Two samplese One samplec One sampled | AUC (0–24)/MIC ≥ 400 Cmin ≥ 15–20 mg/Lg Css 20–25 mg/L | Nephrotoxicity Cmin > 20 mg/L |
Teicoplanin | Cmin | One samplec | Cmin ≥ 15–30 mg/L | No definite data |
Others | ||||
Linezolidf | Cmin | One samplec | Cmin 2–7 mg/L | Cmin > 7 (hematological) |