Antibiotic Stewardship

Definition and Goals

1. Optimize clinical outcomes - cure infection, minimize toxicity and adverse events
2. Preserve antimicrobials - curb the development of resistance within patient populations by limiting selection pressure that drives resistant strains
3. Reduce harm - decrease adverse effects such as C. difficile infection, drug toxicity, and drug-drug interactions
4. Control costs - reduce hospital antimicrobial expenditure and length of stay

• Harrison's Principles of Internal Medicine 22E, p. 1222; Goldman-Cecil Medicine, p. 261

The CDC Core Elements Framework

For Hospitals (7 Core Elements)

For Outpatient Settings (4 Core Elements, CDC 2016)

1. Commitment to improving antibiotic prescribing
2. Action - implement at least one policy/practice to improve prescribing and assess its effectiveness
3. Tracking and Reporting - monitor prescribing and feed data back to clinicians
4. Education and Expertise - provide clinician education and access to stewardship experts

• Red Book 2021 (AAP), p. 1328; CDC Core Elements

Key Stewardship Strategies

1. Prospective Audit with Feedback

2. Formulary Restriction and Preauthorization

• Formulary restriction: limits indiscriminate use of selected antimicrobials absent demonstrated benefit; controls costs
• Preauthorization: clinicians must obtain approval before using certain agents (broad-spectrum, highly toxic, or expensive drugs). This is one of the most commonly used and most effective strategies.

3. De-escalation

• Selects the narrowest effective agent based on susceptibility data and PK/PD properties
• Is guided by inflammatory biomarkers - procalcitonin (PCT) has been validated in randomized trials and meta-analyses as an effective adjunct for safe de-escalation, reducing antibiotic days without adverse effects on mortality
• Has been shown safe and may improve survival outcomes in sepsis and VAP
• Murray & Nadel's Respiratory Medicine, p. 1133; Fishman's Pulmonary Diseases, p. 3159

4. Duration Optimization

5. IV-to-Oral (IV-to-PO) Conversion

6. Clinical Decision Support (CDS)

7. Education and Communication Training

• Making a clear diagnosis and communicating it to the patient
• Focusing on positive actions patients can take to feel better
• Reviewing the expected course of illness
• Describing red-flag symptoms warranting return to care

Ambulatory Antibiotic Stewardship

• Peer comparison - showing clinicians their prescribing rates vs. peers
• Accountable justification - requiring prescribers to document reasoning for antibiotic use
• Precommitment - asking clinicians to commit in advance to evidence-based prescribing
• Patient education materials explaining when antibiotics are and are not needed
• Telemedicine (phone, video, or electronic messaging) - potential to improve convenience and reduce inappropriate prescribing

• Delayed prescribing (giving a prescription and asking patients not to fill it unless symptoms don't improve) is conceptually flawed, ignores the natural history of self-limited respiratory infections (5-14 days), shifts clinical decision-making to patients, and sends a mixed message about antibiotic appropriateness.
• Procalcitonin and CRP testing remain unproven or non-durable for outpatient antibiotic reduction.
• Harrison's Principles of Internal Medicine 22E, p. 296

Choosing Wisely: AAP/PIDS Recommendations

1. Always obtain blood, urine, or appropriate cultures before initiating empiric antibiotic therapy for suspected invasive bacterial infection (except in exceptional cases)
2. Do not use broad-spectrum agents for perioperative prophylaxis, and do not continue prophylaxis after incision closure for clean/clean-contaminated procedures
3. Do not treat uncomplicated CAP in otherwise healthy, immunized hospitalized patients with therapy broader than ampicillin
4. Avoid treating asymptomatic bacteriuria (except in pregnancy or pre-urologic procedure)
5. Do not use antibiotics for uncomplicated acute otitis media in children ≥2 years with mild disease

• Red Book 2021, p. 1329

Outcomes of Stewardship Programs

• Significant reductions in total antimicrobial use
• Reduced rates of antimicrobial resistance among healthcare-associated pathogens
• Reduced C. difficile infection incidence
• Improved clinical outcomes
• Significant cost savings in hospital antimicrobial expenditure

Recent Developments (2025-2026)

• AI-driven stewardship: A 2025 systematic review (PMID: 39955846) examined artificial intelligence approaches in antibiotic stewardship programs, showing promise for optimizing prescription practices through decision support algorithms.
• CDC 2026 Outpatient Core Elements Update: The CDC is updating outpatient Core Elements in 2026 to focus specifically on the role of health system leadership in supporting and expanding outpatient ASP programs across networks, standardizing implementation for more consistent quality of care. (CDC 2025 Stewardship Report)
• Dental stewardship: A 2025 systematic review (PMID: 39400429) specifically examined dental antibiotic stewardship interventions, reflecting the growing recognition that dentistry is a major contributor to outpatient antibiotic use.

Stewardship Team Composition

• Infectious disease physician (program leader)
• Clinical pharmacist with ID training (co-leader)
• Clinical microbiologist
• Hospital epidemiologist / infection preventionist
• Information systems / informatics specialist

Opioid-Free Anaesthesia (OFA)

Based on Miller's Anesthesia, 10th Edition (2-Volume Set)

1. Concept and Rationale

• The opioid crisis and risks of prescription opioid misuse and dependence
• Postoperative nausea and vomiting (PONV) - a major cause of unplanned hospital admission after ambulatory surgery
• Opioid-induced hyperalgesia (OIH) - paradoxical increased pain sensitivity with opioid use
• Respiratory depression - particularly dangerous in obese patients, OSA, elderly
• Postoperative delirium and neurocognitive dysfunction
• Immunosuppression - opioids may suppress natural killer cell activity and affect cancer recurrence

• Obese patients and those with obstructive sleep apnea (OSA)
• Patients at high risk for PONV
• Patients with chronic pain or opioid use disorder
• Patients undergoing ambulatory/day-case surgery
• Bariatric surgery

"OFA seems not to be the solution but, by using a multimodal pharmacologic and technical approach, the anesthesiologist can still make important contributions to ameliorate the prescription opioid crisis."

• Miller's Anesthesia 10e, p. 6868

2. The Multimodal Analgesic Foundation

"Multimodal analgesia relies on the additive or synergistic combination of drugs acting at various points on the pain pathway. Typical combinations include local anesthetic wound infiltration or regional techniques and routine NSAIDs."

• Miller's Anesthesia 10e, p. 10023

3. Pharmacological Pillars of OFA

A. Ketamine (NMDA Receptor Antagonist)

• Antagonises the NMDA (N-methyl-D-aspartate) receptor - the excitatory glutamatergic receptor central to central sensitisation and hyperalgesia
• Inhibits nociceptive central hypersensitisation
• Reduces the release of pronociceptive transmitters from the dorsal horn
• Also occupies mu-opioid receptors in brain and spinal cord - contributing to some of its analgesic effect
• Has antidepressant properties

• Plasma level ≥0.1 mcg/mL elevates pain thresholds (subanesthetic analgesic dose)
• Short duration due to rapid redistribution from brain to tissues
• Prevents opioid-induced hyperalgesia (OIH) - the NMDA receptor mediates both hyperalgesia and antinociceptive tolerance induced by opioids; preventive ketamine blocks this
• S(+) enantiomer (esketamine) offers 10% faster hepatic biotransformation and quicker recovery

• Low-dose boluses (0.1-0.5 mg/kg IV) intraoperatively
• Infusion continued postoperatively: common postoperative infusion doses are 0.1-0.2 mg/kg/hr
• Analgesic, opioid-sparing, and antidepressant effects
• Does NOT cause or prevent postoperative delirium (large multicenter trial)
• Particular value in thoracotomy - used as part of multimodal therapy combining regional analgesia and anti-inflammatories

B. Dexmedetomidine (Selective α2-Agonist)

• Highly selective α2A/α2C-adrenoceptor agonist (α2:α1 selectivity ratio 1620:1 vs. clonidine's 220:1)
• Analgesic mechanism: Stimulates α2C- and α2A-receptors in the dorsal horn, directly suppressing pain transmission by:
  • Reducing release of substance P and glutamate
  • Hyperpolarising inhibitory interneurons
• Sedation mechanism: Activates locus coeruleus → releases inhibition of VLPO → VLPO releases GABA onto TMN → inhibits histamine release → induces NREM-like sleep
• Provides sedation without significant respiratory depression (key advantage)

• Systemic infusion provides significant opioid-sparing effect intraoperatively and postoperatively
• In the ICU/postoperative setting: reduces narcotic requirements by ~50% compared with placebo
• When used as part of an anaesthetic regimen: reduces MAC of inhaled anaesthetics
• Useful in OSA patients - minimal effects on pharyngeal tone unlike opioids and benzodiazepines
• Also used as adjuvant to regional blocks: prolongs sensory block duration (e.g., 1 mcg/kg added to bupivacaine) by prolonged hyperpolarisation of unmyelinated C-fibres

C. NSAIDs and COX-2 Inhibitors

• Non-selective NSAIDs (naproxen, ibuprofen, diclofenac, ketorolac): inhibit both COX-1 and COX-2
• Selective COX-2 inhibitors (celecoxib): spare platelet COX-1, lower GI bleeding risk
• Can be given orally, rectally, intramuscularly, or intravenously
• IV diclofenac and ketorolac: well-evidenced for acute postoperative pain

D. Paracetamol (Acetaminophen)

• Often underestimated - has equivalent and sustained analgesic effects compared with other perioperative analgesics
• Routes: oral, rectal, or IV
• Opioid-sparing effect is inconsistent in the literature - some RCTs and meta-analyses show reduction in opioid consumption; others do not
• Given its high safety profile, its use as a routine analgesic adjuvant is considered reasonable
• Best given preoperatively or at the start of surgery for preemptive effect

E. IV Lidocaine Infusion (Systemic Local Anaesthetic)

• Reduces postoperative pain, opioid consumption, and accelerates return of bowel function (particularly in abdominal surgery)
• Typical dose: 1.5 mg/kg bolus → 1.5-2 mg/kg/hr infusion intraoperatively
• Can be continued into the postoperative period

F. Dexamethasone

• Used in higher doses than antiemetic doses as part of multimodal analgesia
• Onset of action: 1-2 hours → administer BEFORE surgical trauma
• Meta-analyses show: less postoperative pain, fewer opioids required, shorter PACU stays
• Most effective at intermediate doses (6.4-10 mg IV); given preoperatively
• A large RCT confirmed 8 mg intraoperative dexamethasone does NOT increase surgical site infection rates

G. Gabapentinoids (Gabapentin, Pregabalin)

• Initially anticonvulsants, gained popularity for acute perioperative pain
• However, routine use is NOT justified per current evidence:
  • No clinically significant difference in acute or chronic postoperative pain at multiple time points
  • Lower PONV risk (benefit)
  • BUT: increased length of stay, increased dizziness and visual disturbance
  • Risk of neurological and respiratory adverse reactions, especially in ambulatory patients where they delay discharge

4. Regional and Neuraxial Techniques

• Neuraxial analgesia (epidural, spinal): local anaesthetic-based regimen; intrathecal local anaesthetics provide potent, long-lasting analgesia at subanesthetic doses
• Peripheral nerve blocks: brachial plexus, femoral, sciatic, TAP blocks, paravertebral blocks
• Local infiltration analgesia (LIA): wound infiltration with local anaesthetic
• Topical local anaesthetics: lidocaine patches and glyceryl trinitrate patches have been found effective for some ambulatory procedures

5. OFA vs. Opioid-Sparing Anaesthesia (OSA)

6. Limitations and Cautions of OFA

• Haemodynamic instability: Studies on OFA showed increased demand for vasopressors, hypotensive and bradycardic phases
• Postoperative sedation and falls reported
• Safety concerns: A large proof-of-concept study had to be terminated prematurely due to high incidences of hypoxia and bradycardia
• OFA is not universally applicable - patients with severe uncontrolled pain, those on chronic opioids, and those with opioid use disorder still require individualised management
• Chronic pain patients on long-term opioids must have their preoperative analgesics continued to prevent withdrawal
• The "delayed prescription" strategy (give a prescription but ask the patient not to fill it) is conceptually flawed and should be avoided

7. Special Populations Where OFA is Particularly Valuable

Obese Patients and OSA

• Avoiding respiratory depressants (opioids, benzodiazepines) is paramount
• Full OFA/opioid-sparing with NSAIDs, ketamine, dexmedetomidine, clonidine, epidural LA, peripheral nerve blocks minimises postoperative respiratory arrest risk
• Benzodiazepines actually have a greater effect on pharyngeal tone than opioids and should be avoided in OSA patients

Bariatric Surgery

• High PONV risk
• Respiratory vulnerability due to morbid obesity
• 2025 RCT (PMID: 40269993) confirmed OFA feasibility and benefits in bariatric surgery

Elderly/Cognitive Impairment

• Opioids (especially meperidine and normeperidine), benzodiazepines, and gabapentinoids are associated with delirium
• Ketamine, acetaminophen, NSAIDs, and COX-2 inhibitors may reduce postoperative cognitive dysfunction through opioid-sparing effects
• Processed EEG (bispectral index) guides titration of inhalational agents to age-adjusted MAC

8. Practical OFA Protocol (Miller's Synthesis)

9. Recent Evidence (2023-2025)

• A 2023 systematic review and meta-analysis (PMID: 37515877, J Clin Anesth) on OFA: reduced PONV, but with trade-offs including haemodynamic effects - consistent with Miller's cautionary statements
• A 2025 network meta-analysis (PMID: 38578868, Anesth Analg) in bariatric surgery: OFA superior to conventional analgesia for PONV prevention; opioid-sparing and OFA had comparable analgesic outcomes
• A 2025 RCT in bariatric surgery (PMID: 40269993): OFA was safe and effective, with better PONV profile

Key Take-Home Messages from Miller's

1. OFA is not "the solution" - it is part of a broader multimodal strategy, not a universal replacement for opioids
2. The evidence base is still evolving - some well-designed trials have been terminated early due to haemodynamic complications
3. Dexmedetomidine is the cornerstone α2-agonist - provides sedation without respiratory compromise, reduces MAC, and cuts opioid requirements by ~50%
4. Ketamine is essential - its NMDA antagonism directly blocks central sensitisation and prevents OIH
5. Regional techniques are non-negotiable - OFA without reliable regional anaesthesia is not safe for most surgical procedures
6. Patient selection matters - OFA is particularly valuable in OSA, bariatric, ambulatory, and high-PONV-risk patients