I. Epidemiology and Incidence of Antibiotic Resistance in Critical Care

Summary: Antibiotic resistance in the ICU is driven by global trends, unit-specific practices, and surveillance limitations. Understanding local and regional patterns informs empirical choices and stewardship priorities.

1.1 Global Trends and Regional Variability

• High-income ICUs report 20–30% carbapenem-resistant Enterobacterales; low- and middle-income units often exceed 50%.
• ESBL producers dominate in Asia/Latin America; VRE is rising in Europe and North America.
• Drivers: antibiotic overuse, infection control resources, formulary access.

1.2 ICU-Specific Resistance Patterns and Drivers

• Risk factors: prolonged ventilation, central lines, immunosuppression, broad-spectrum exposure.
• Up to 50% of ICU antibiotics are inappropriate in spectrum or duration.
• Common MDR pathogens: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae.

1.3 Surveillance Methods and Data Interpretation

• Phenotypic cultures vs. rapid molecular assays (PCR, MALDI-TOF) to detect resistance genes.
• Unit-specific antibiograms guide empiric therapy but may lag emerging trends.
• Statistical tools (funnel plots, CUSUM) track resistance clusters over time.

II. Pathophysiologic Basis for Altered Antimicrobial PK/PD in Critical Illness

Summary: Sepsis and organ dysfunction alter absorption, distribution, metabolism, and excretion, affecting drug exposure and efficacy. PK/PD principles guide dosing adjustments.

2.1 Pharmacokinetic Alterations

2.1.1 Augmented Renal Clearance (ARC)

• Hyperdynamic GFR (>130 mL/min/1.73 m²) leads to subtherapeutic β-lactam and aminoglycoside levels.
• Action: measure 8–24 h CrCl and increase dose or frequency accordingly.

2.1.2 Hypoalbuminemia and Distribution Changes

• Low albumin increases free fraction of protein-bound drugs (e.g., ceftriaxone).
• Interpret TDM on unbound concentrations when possible.

2.1.3 Metabolic and Excretory Variations

• Hepatic hypoperfusion reduces phase I/II metabolism (e.g., linezolid half-life ↑).
• CRRT removes hydrophilic agents unpredictably; adjust per effluent rate.

2.2 Pharmacodynamic Considerations

III. Impact of Chronic Diseases on PK/PD and Stewardship

Summary: Pre-existing renal and hepatic dysfunction alter drug clearance and toxicity risk. Polypharmacy elevates interaction potential, requiring integrated stewardship.

3.1 Renal Dysfunction

• Creatinine Clearance Estimation: Cockcroft-Gault may overestimate GFR in low-muscle ICU patients. Preferred: measured urinary CrCl or Bayesian dosing software for vancomycin, fluoroquinolones.
• Renal Replacement Therapy (RRT): CRRT removes small hydrophilic drugs. For vancomycin, a typical approach is loading with 25–30 mg/kg, then maintenance of 15–20 mg/kg q24–48h, adjusted by effluent flow and TDM.

3.2 Hepatic Impairment

• Metabolism Alterations: Reduced CYP450 activity prolongs agents like erythromycin. Consider a 25–50% dose reduction for linezolid or fluconazole in Child-Pugh Class C.
• Monitoring: Track LFTs and drug-specific toxicities (e.g., linezolid-induced thrombocytopenia).

IV. Social Determinants of Health Influencing Antimicrobial Use

Summary: Medication access, health literacy, and socioeconomic status shape adherence and prescribing. Multidisciplinary strategies can mitigate disparities.

4.1 Medication Access and Formulary Constraints

• Shortages and insurance restrict spectrum; stewardship must balance cost vs. adequacy.
• Advocate for patient assistance and institutional formulary updates.

4.2 Health Literacy and Patient Education

• Use teach-back methods and simplified schedules to improve oral regimen adherence.
• Involve bedside pharmacists in discharge rounds for counseling.

4.3 Socioeconomic Factors and Adherence Challenges

• Out-of-pocket costs drive early discontinuation of oral therapy.
• Collaborate with social work to secure generics and compliance support.

V. Integrating Stewardship into Critical Care Practice

Summary: Effective ICU stewardship combines protocols, PK/PD–driven dosing, rapid diagnostics, and real-time feedback in a multidisciplinary model.

5.1 Core Elements of an ICU Antimicrobial Stewardship Program

• Prospective audit with feedback and formulary restriction/preauthorization.
• Rapid diagnostics and TDM integration to guide de-escalation.

5.2 Incorporating PK/PD Principles into Protocols

• Implement extended-infusion β-lactam pathways and aminoglycoside peak-based dosing.
• Use population PK/Bayesian models for individualized regimens.

5.3 Multidisciplinary Collaboration and Technology Enablers

• Engage ID physicians, pharmacists, microbiology, nursing, and IT.
• Leverage clinical decision support for alerts on ARC, organ dysfunction, and TDM results.