Antimicrobial Stewardship Pharmacology

## Overview

Antimicrobial stewardship programs (ASPs) are coordinated interventions to improve the appropriate use of antibiotics by optimizing drug selection, dose, route, and duration. Inappropriate antibiotic use drives resistance, Clostridioides difficile infection, adverse drug reactions, and increased healthcare costs. ASPs combine clinical pharmacology, infectious disease expertise, and systems-level interventions.

## Core Stewardship Interventions

**Prospective audit and feedback**: ASP pharmacists/physicians review ongoing antibiotic therapy and make recommendations to prescribers. Most effective stewardship intervention for reducing antibiotic consumption.

**Prior authorization (pre-approval)**: Broad-spectrum or high-risk antibiotics (carbapenems, daptomycin, ceftaroline) require stewardship approval before dispensing. Restricts most concerning agents but may delay treatment if not staffed 24/7.

**Formulary restriction**: Limiting availability of certain antibiotics reduces selection pressure. However, restriction of one class may increase use of another (squeezing the balloon).

## De-escalation

De-escalation is the transition from broad-spectrum empiric therapy to targeted, narrower-spectrum therapy based on culture and susceptibility results. Key principles:
- Obtain cultures BEFORE starting antibiotics (blood cultures, urine, respiratory samples)
- Review cultures at 48-72 hours; de-escalate based on identified pathogen and susceptibility
- Discontinue antibiotics if cultures negative and clinical syndrome does not support infectious etiology

## IV-to-Oral (IVPO) Switching

IV-to-oral switching reduces catheter-associated infections, hospital length of stay, and costs. Agents with high oral bioavailability (fluoroquinolones >80%, metronidazole 100%, trimethoprim-SMX >90%, linezolid 100%, doxycycline >90%) are ideal candidates. IVPO switch criteria: clinical improvement, functioning GI tract, no condition requiring IV (meningitis, endocarditis, bacteremia).

## PK/PD Optimization

Pharmacokinetic/pharmacodynamic optimization maximizes efficacy and minimizes toxicity:
- Extended/continuous infusion of time-dependent antibiotics (piperacillin-tazobactam, meropenem) increases T>MIC
- Vancomycin AUC/MIC monitoring (target 400-600) reduces nephrotoxicity while maintaining efficacy
- Aminoglycoside extended-interval dosing (once daily) optimizes Cmax/MIC and reduces nephrotoxicity
- Therapeutic drug monitoring (TDM) for vancomycin, aminoglycosides, voriconazole

## Biomarkers in Stewardship

**Procalcitonin (PCT)**: Rises rapidly in bacterial infections, declines with effective treatment. PCT-guided discontinuation algorithms reduce antibiotic duration in respiratory infections (CAP, COPD exacerbation, VAP) without increasing mortality. PCT does not reliably differentiate bacterial from fungal or viral infections.

**C-reactive protein (CRP)**: Less specific than PCT; useful in primary care for decision to prescribe antibiotics for respiratory infections.

## Duration Optimization

Evidence-based shorter courses are as effective as traditional longer courses for many infections:
- Uncomplicated UTI: 3-5 days (women), 7 days (men)
- CAP: 5 days if clinical stability achieved
- Uncomplicated skin infections: 5 days
- Intraabdominal infection: 4 days after source control
- Shorter courses reduce resistance selection pressure and adverse effects

## Key Takeaways

- De-escalation from broad-spectrum empiric therapy to targeted therapy based on cultures is a cornerstone of stewardship
- IV-to-oral switching with high-bioavailability agents reduces catheter infections, LOS, and costs
- PK/PD optimization (extended infusions, AUC-guided vancomycin dosing) maximizes efficacy
- Procalcitonin-guided algorithms safely reduce antibiotic duration in respiratory infections