ICU · pharmacology

ICU Antibiotic Pharmacology — Comprehensive (PK/PD in Critical Illness)

Also known as Antibiotic dosing in ICU · PK/PD critical illness · Augmented renal clearance · Beta-lactam continuous infusion · DALI study · BLING trial · Vancomycin AUC monitoring · Therapeutic drug monitoring antibiotics · Beta-lactam fT>MIC · Aminoglycoside once-daily dosing

ICU antibiotic pharmacology — the evidence-based framework for optimising antimicrobial dosing in critically ill patients where altered pharmacokinetics (PK) make standard doses unreliable. Core problem: critical illness DISRUPTS PK in predictable directions — (1) INCREASED VOLUME OF DISTRIBUTION (Vd) from capillary leak and aggressive fluid resuscitation → LOWER plasma concentrations of hydrophilic drugs (beta-lactams, aminoglycosides, glycopeptides) → need HIGHER loading doses; (2) AUGMENTED RENAL CLEARANCE (ARC — measured urinary CrCl >130 mL/min/1.73 m², present in 20-65% of ICU patients) in younger trauma/polytrauma patients → enhanced renal elimination → subtherapeutic levels → need HIGHER and/or MORE FREQUENT doses (especially beta-lactams and vancomycin); (3) renal replacement therapy (RRT/CRRT, KDIGO effluent 20-35 mL/kg/h) clears renally-eliminated drugs → dose for the effluent rate, not for 'renal failure'; (4) HYPOALBUMINAEMIA (up to 40-50% of ICU patients) → increased free (active) drug fraction but also increased Vd and clearance for highly protein-bound drugs (ceftriaxone, teicoplanin, daptomycin). Pharmacodynamic (PD) targets determine HOW to dose: BETA-LACTAMS = time above MIC (fT>MIC — keep free levels above the MIC throughout the interval, via CONTINUOUS or EXTENDED [prolonged 3-4h] infusion); AMINOGLYCOSIDES = Cmax/MIC ratio (concentration-dependent killing + post-antibiotic effect → high ONCE-DAILY dose, 7 mg/kg with single-level nomogram monitoring); FLUOROQUINOLONES = AUC/MIC ratio; VANCOMYCIN = AUC/MIC 400-600 (2020 consensus shifted from trough-based to AUC-guided monitoring, which carries less nephrotoxicity). Key DALI study finding: on STANDARD licensed beta-lactam dosing, 16% of patients treated for infection missed even the 50% fT>MIC target and were 32% less likely to have a positive outcome → underdosing is the rule, not the exception → paradigm shift to PERSONALISED dosing + therapeutic drug monitoring (TDM). Key antibiotic classes: beta-lactams (PIP-TAZO, cefepime, meropenem [ESBL], ceftriaxone [CAP — NO Pseudomonas cover]), glycopeptides (vancomycin [MRSA, enterococcus — TDM], teicoplanin), aminoglycosides (gentamicin [once daily — TDM — nephrotoxicity + ototoxicity]), fluoroquinolones (ciprofloxacin [Pseudomonas], moxifloxacin [CAP — no Pseudomonas]), macrolides (azithromycin [CAP — atypicals]), oxazolidinones (linezolid [VRE, MRSA — thrombocytopenia, serotonin syndrome with SSRIs]), antifungals (caspofungin [Candida], voriconazole [Aspergillus — TDM, CYP2C19 variability], liposomal amphotericin B [broad — nephrotoxic]).