21.2 Antimicrobial Therapy, Stewardship and ICU-Acquired Infections
Key Takeaways
Beta-lactams show time-dependent killing (efficacy depends on the time free drug concentration stays above the MIC), whereas aminoglycosides show concentration-dependent killing with a post-antibiotic effect, so they are given once daily.
Critically ill patients may need higher loading doses of hydrophilic antibiotics because of an increased volume of distribution, and augmented renal clearance can cause subtherapeutic beta-lactam levels.
Antimicrobial stewardship means taking cultures before antibiotics when possible, choosing appropriate empirical cover, reviewing at 48-72 hours, de-escalating to the narrowest effective agent and using the shortest effective duration.
Ventilator-associated pneumonia occurs after at least 48 hours of mechanical ventilation; prevention includes head-up positioning, daily sedation interruption, subglottic secretion drainage and minimising ventilation duration.
Catheter-related bloodstream infection is reduced by insertion bundles (hand hygiene, full barrier precautions, chlorhexidine-alcohol skin preparation, avoiding the femoral site where possible) and prompt removal of unnecessary catheters.
21.2 Antimicrobial Therapy, Stewardship and ICU-Acquired Infections
Antibiotic Classes and Mechanisms
| Class | Examples | Mechanism | Key points |
|---|---|---|---|
| Penicillins | Amoxicillin, piperacillin-tazobactam, flucloxacillin | Inhibit cell wall synthesis (bind penicillin-binding proteins) | Time-dependent; beta-lactamase inhibitors extend spectrum |
| Cephalosporins | Cefazolin, ceftriaxone, ceftazidime | As penicillins | Cross-reactivity with penicillin allergy is low (about 1-2%), mainly with similar side chains |
| Carbapenems | Meropenem | As penicillins; stable to most beta-lactamases | Reserve for resistant Gram-negatives (ESBL producers); lower seizure threshold (imipenem) |
| Glycopeptides | Vancomycin, teicoplanin | Inhibit cell wall synthesis (Gram-positive only) | Vancomycin: infuse slowly (flushing reaction); monitor levels; nephrotoxic |
| Aminoglycosides | Gentamicin, amikacin | Inhibit 30S ribosome | Concentration-dependent; nephrotoxic and ototoxic; potentiate neuromuscular block |
| Macrolides | Clarithromycin, azithromycin | Inhibit 50S ribosome | QT prolongation; CYP3A4 inhibition (clarithromycin) |
| Fluoroquinolones | Ciprofloxacin, levofloxacin | Inhibit DNA gyrase | QT prolongation, tendon rupture, seizures, aortic aneurysm risk |
| Lincosamides | Clindamycin | 50S ribosome | Toxin suppression in necrotising infection; C. difficile risk |
| Oxazolidinones | Linezolid | 50S ribosome | MRSA and VRE; serotonin syndrome with SSRIs; thrombocytopenia |
| Nitroimidazoles | Metronidazole | DNA damage in anaerobes | Disulfiram-like reaction; potentiates warfarin |
| Polymyxins | Colistin | Disrupt cell membrane | Last-line for carbapenem-resistant Gram-negatives; nephrotoxic |
Pharmacokinetics and Pharmacodynamics in Critical Illness
Killing Patterns
| Pattern | Target | Examples | Dosing strategy |
|---|---|---|---|
| Time-dependent | Time free drug concentration exceeds the minimum inhibitory concentration () | Beta-lactams | Frequent doses or extended/continuous infusions |
| Concentration-dependent | Peak concentration to MIC ratio () | Aminoglycosides | Large once-daily doses (also reduces toxicity) |
| Exposure-dependent | Area under the curve to MIC ratio (AUC/MIC) | Vancomycin, fluoroquinolones | Dose to AUC targets; therapeutic drug monitoring |
Altered Handling in the Critically Ill
- Increased volume of distribution (capillary leak, fluid resuscitation) lowers concentrations of hydrophilic drugs (beta-lactams, aminoglycosides, vancomycin), so loading doses should not be reduced even in renal impairment.
- Augmented renal clearance (creatinine clearance above about 130 mL/min, common in young trauma, sepsis and head injury patients) causes subtherapeutic beta-lactam levels.
- Renal replacement therapy and ECMO alter clearance and sequestration; therapeutic drug monitoring helps.
- Hypoalbuminaemia increases the free fraction and clearance of highly protein-bound drugs such as ceftriaxone and teicoplanin.
Antimicrobial Stewardship
The aims are to improve outcomes, reduce toxicity and limit resistance.
- Take cultures before antibiotics when this does not cause a significant delay (blood cultures, relevant sites).
- Give appropriate empirical therapy promptly in sepsis and septic shock, based on local resistance patterns, the likely source, and risk factors for resistant organisms.
- Review at 48-72 hours with culture results: stop, de-escalate to a narrower agent, switch to oral, or continue.
- Shortest effective duration: for many infections 5-7 days is enough once source control has been achieved (for example intra-abdominal infection after source control, uncomplicated pneumonia).
- Procalcitonin can support decisions to stop antibiotics, but it should not delay starting them in suspected sepsis.
- Source control (drainage, debridement, removal of infected devices) is as important as antibiotic choice.
Multidrug-Resistant Organisms
| Organism | Resistance mechanism | Treatment options |
|---|---|---|
| MRSA | Altered penicillin-binding protein (PBP2a, mecA gene) | Vancomycin, teicoplanin, linezolid, daptomycin (not for pneumonia) |
| VRE | Altered cell wall target | Linezolid, daptomycin |
| ESBL-producing Enterobacterales | Extended-spectrum beta-lactamases | Carbapenems |
| Carbapenemase producers (CPE), e.g. KPC, NDM, OXA-48 | Carbapenem-hydrolysing enzymes | Newer combinations (for example ceftazidime-avibactam for KPC and OXA-48), colistin, specialist advice |
| Pseudomonas aeruginosa | Efflux pumps, porin loss, beta-lactamases | Anti-pseudomonal beta-lactam (piperacillin-tazobactam, ceftazidime, meropenem), guided by susceptibility |
Infection prevention (hand hygiene, contact precautions, screening and cohorting) is essential to limit spread.
ICU-Acquired Infections
Ventilator-Associated Pneumonia (VAP)
Definition: pneumonia developing after at least 48 hours of invasive mechanical ventilation. Diagnosis combines new or progressive infiltrates, fever or leucocytosis, purulent secretions and worsening oxygenation, ideally with quantitative cultures from lower respiratory samples.
Prevention bundle:
- Head of the bed elevated 30-45°.
- Daily sedation interruption and spontaneous breathing trials to shorten ventilation.
- Subglottic secretion drainage tubes and appropriate cuff pressure (about 20-30 cmH2O).
- Oral care (routine chlorhexidine mouthwash is now debated because of possible harm).
- Avoid unplanned extubation and re-intubation; use non-invasive ventilation where appropriate.
Treatment: empirical cover based on local resistance and risk factors (early-onset VAP within about 4 days is more often caused by community organisms; late-onset by resistant hospital organisms), de-escalated with cultures; a 7-day course is usually sufficient.
Catheter-Related Bloodstream Infection (CRBSI)
- Diagnosed by matching organisms in peripheral and catheter blood cultures, with earlier positivity of the catheter culture (differential time to positivity of 2 hours or more) or catheter tip culture.
- Prevention (insertion bundle): hand hygiene, full sterile barrier precautions, 2% chlorhexidine in 70% alcohol skin preparation, ultrasound guidance, avoiding the femoral site in adults where possible, and daily review.
- Treatment: remove the catheter in most cases (always for Staphylococcus aureus and Candida), and give appropriate antibiotics (at least 14 days for S. aureus bacteraemia, with echocardiography to exclude endocarditis).
Clostridioides difficile Infection
Risk factors: broad-spectrum antibiotics (clindamycin, cephalosporins, fluoroquinolones), proton pump inhibitors, age and hospital stay. Treat with oral vancomycin or fidaxomicin, stop unnecessary antibiotics, use contact precautions, and wash hands with soap and water (alcohol gel does not kill spores). Severe disease can cause toxic megacolon.
Fungal Infection
Invasive candidiasis risk factors include broad-spectrum antibiotics, central venous catheters, parenteral nutrition, abdominal surgery and renal replacement therapy. Echinocandins (for example caspofungin) are first-line for invasive candidiasis in critically ill patients.
Why is gentamicin given as a single large daily dose rather than in divided doses?
Concentration-dependent killing with a post-antibiotic effect; once-daily dosing also limits toxicity
Its killing is time-dependent, so maintaining levels above the MIC throughout the day is essential
It is eliminated mainly by the liver, so divided doses accumulate
It has no post-antibiotic effect, so bacteria regrow quickly between doses
A young trauma patient in ICU has a measured creatinine clearance of 180 mL/min and is receiving standard-dose piperacillin-tazobactam for pneumonia but is not improving. What is the most likely pharmacological problem?
Accumulation of piperacillin causing toxicity
Increased protein binding in hypoalbuminaemia reducing the free drug fraction to zero
Augmented renal clearance causing subtherapeutic beta-lactam levels
Concentration-dependent killing requiring once-daily dosing
Which measure is part of a central venous catheter insertion bundle to prevent catheter-related bloodstream infection?
Routine replacement of all central lines every 3 days over a guidewire to prevent colonisation
Prophylactic systemic antibiotics at insertion
Preferential use of the femoral site in adults
Full sterile barrier precautions with chlorhexidine-alcohol skin preparation
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