The global burden of antibiotic resistance is not abstract. A 2022 Lancet analysis estimated that 1.27 million deaths were directly attributable to antimicrobial resistant infections in 2019, and a further 4.95 million deaths occurred in people with AMR infections (associatively). These figures make AMR the third leading cause of death globally, ahead of HIV/AIDS and malaria. The trajectory of resistance is worsening in most pathogen groups and most geographic regions, driven primarily by antibiotic overuse and misuse in human medicine, agriculture, and aquaculture.
Stewardship is the practical discipline of changing this trajectory at the level of individual prescribing decisions, hospital formulary policies, and national prescribing guidelines.
The WHO AWaRe Classification: A Framework for Stewardship
The WHO AWaRe (Access, Watch, Reserve) classification, updated in 2023, groups antibiotics into three categories based on their importance to human medicine and their relative resistance risk.
Access antibiotics are first- or second-line treatments for common infections, generally with a lower resistance profile, widely available, and inexpensive. They include amoxicillin, amoxicillin-clavulanate, doxycycline, trimethoprim, cefalexin, metronidazole, and many others. The WHO target is for Access antibiotics to constitute at least 60 per cent of total antibiotic consumption in a country or healthcare setting.
Watch antibiotics have higher resistance potential and should be prioritised for stewardship attention. They include cephalosporins (3rd generation), fluoroquinolones, carbapenems, vancomycin, and linezolid. Prescribing of Watch antibiotics should be reviewed against clinical indication.
Reserve antibiotics are the antibiotics of last resort, used only when all other options have failed or are not possible. They include colistin, ceftazidime-avibactam, cefiderocol, and others active against extensively drug-resistant organisms. Reserve antibiotic prescriptions require specialist authorisation in most healthcare systems with functioning stewardship programmes.
Core Stewardship Interventions
Prospective audit and feedback: an AMS pharmacist or physician reviews antibiotic prescriptions on the ward (usually 48 to 72 hours after initiation), assesses appropriateness of indication, dose, route, and duration, and provides real-time feedback to the prescribing clinician. This is one of the most effective AMS interventions with consistent evidence of reducing broad-spectrum antibiotic use without worsening clinical outcomes.
Formulary restriction and pre-authorisation: certain broad-spectrum or Reserve antibiotics require authorisation from an infectious disease consultant, microbiologist, or AMS pharmacist before they can be dispensed. This creates a natural check on inappropriate initiation of these agents.
De-escalation: reviewing empiric broad-spectrum antibiotic therapy once culture and susceptibility results are available and switching to the narrowest-spectrum agent effective against the identified pathogen. De-escalation reduces selection pressure without compromising clinical outcomes.
IV-to-oral (IVOST) switch: transitioning patients from intravenous to oral antibiotics when clinical criteria are met (afebrile, able to take oral medications, functioning gastrointestinal tract, no indication for specifically IV therapy). Many antibiotics have excellent oral bioavailability (co-amoxiclav, fluroquinolones, linezolid, metronidazole, doxycycline) and achieve adequate serum concentrations orally. Unnecessary prolonged IV therapy increases line infection risk, hospitalisation duration, and healthcare cost.
Duration optimisation: many infections are overtreated in terms of antibiotic duration. Clinical trial evidence supports shorter courses for uncomplicated urinary tract infection (3 to 5 days), community-acquired pneumonia (5 days), intra-abdominal infection (4 to 5 days after adequate source control), and cellulitis (5 to 7 days). AMS programmes promote evidence-based duration limits and use of procalcitonin to guide antibiotic discontinuation in respiratory infections.
Procalcitonin as a Stewardship Biomarker
Procalcitonin (PCT) is a precursor protein of calcitonin that is released by virtually all body cells in response to bacterial infection-mediated inflammatory signals (particularly bacterial LPS and bacterial toxins). It rises rapidly (within 2 to 4 hours) and falls rapidly (half-life approximately 24 to 30 hours) when the bacterial stimulus is resolved. Unlike CRP, which peaks 24 to 48 hours after onset of infection, PCT rises and falls faster, making it a better dynamic marker for monitoring response.
In respiratory tract infections, multiple randomised controlled trials have shown that PCT-guided antibiotic decisions reduce antibiotic exposure (shorter courses, more frequent non-initiation of antibiotics for viral infections) without increasing mortality or other adverse outcomes. A PCT below 0.1 mcg/L strongly suggests viral aetiology and supports not initiating or stopping antibiotics. A PCT above 0.5 mcg/L suggests bacterial infection and supports antibiotic initiation.
In ICU patients with sepsis, PCT-guided discontinuation protocols (stopping antibiotics when PCT falls by 80 per cent of peak value or below 0.5 mcg/L) have reduced antibiotic exposure without increasing mortality in multiple trials.
The Consequences of Antibiotic Overuse
Clostridioides difficile infection (CDI) is the most direct consequence of antibiotic overuse in the healthcare setting. Disruption of the gut microbiome by broad-spectrum antibiotics eliminates organisms that compete with C. difficile for nutrients and space, and eliminates bile acid-metabolising bacteria that produce secondary bile acids inhibitory to C. difficile germination. The antibiotic classes most strongly associated with CDI risk are clindamycin, fluoroquinolones, and broad-spectrum cephalosporins.
Selection of resistant organisms: every antibiotic course selects for resistance in the receiving organism and in bystander organisms in the patient's microbiome. A course of cephalosporins does not only treat the target infection; it selects for cephalosporin-resistant organisms throughout the patient's gut flora and potentially in the room and ward environment. The resistance selected does not disappear when the antibiotic course ends.
Adverse drug effects: antibiotics cause allergic reactions (from mild rash to life-threatening anaphylaxis), drug interactions (warfarin interaction with metronidazole and fluconazole, renal toxicity with aminoglycosides and vancomycin), QTc prolongation (fluoroquinolones, azithromycin), tendinopathy (fluoroquinolones), and mitochondrial toxicity (linezolid). Unnecessary antibiotics expose patients to these risks without benefit.
Frequently Asked Questions
What is antimicrobial stewardship?
Antimicrobial stewardship (AMS) is a coordinated programme of interventions to optimise antibiotic use: ensuring the right antibiotic, the right dose, the right route, and the right duration for each patient, while minimising adverse effects and the development of resistance.
What is the WHO AWaRe classification?
AWaRe (Access, Watch, Reserve) classifies antibiotics by their resistance risk and clinical importance. Access antibiotics are first-line agents with lower resistance potential. Watch antibiotics require stewardship attention. Reserve antibiotics are last-resort agents for resistant infections, requiring specialist authorisation. The WHO target is for Access antibiotics to constitute at least 60 per cent of national antibiotic consumption.
What is de-escalation?
De-escalation is the practice of switching from empiric broad-spectrum antibiotic therapy to a narrower-spectrum agent once culture and susceptibility results confirm the causative organism and its susceptibilities. It reduces selection pressure for resistance without compromising clinical outcomes.
What is procalcitonin?
Procalcitonin (PCT) is a biomarker that rises rapidly in response to bacterial infection and falls when the infection resolves. In respiratory infections, PCT-guided protocols reduce antibiotic prescribing compared to clinical judgment alone, without worsening outcomes. A PCT below 0.1 mcg/L strongly supports a viral aetiology.
What is IV-to-oral switch?
IV-to-oral (IVOST) switch is the transition from intravenous to oral antibiotic therapy when the patient meets clinical criteria (tolerating oral intake, clinically stable, no indication for IV route). Many antibiotics have high oral bioavailability and achieve adequate serum levels when given orally. Unnecessary IV therapy prolongs hospitalisation and increases central line infection risk.
Why do fluoroquinolones increase C. difficile risk?
Fluoroquinolones are among the antibiotic classes most strongly associated with Clostridioides difficile infection. Their broad spectrum of activity disrupts the gut microbiome extensively. Additionally, specific fluoroquinolone-resistant C. difficile ribotypes (especially ribotype 027) emerged and spread widely in the 2000s, partly driven by fluoroquinolone use. Restriction of fluoroquinolone prescribing in some countries has been associated with reductions in CDI rates.
What is an antibiotic timeout?
An antibiotic timeout is a structured review of an antibiotic prescription at 48 to 72 hours after initiation, when initial culture results are typically available. The review assesses: is there still an indication for antibiotics? Does the culture result confirm or change the diagnosis? Is the choice of antibiotic optimal? Can the spectrum be narrowed? Can the route be changed to oral? Should the duration be specified or shortened?
What is the ESKAPE group of pathogens?
ESKAPE is an acronym for the six pathogens that escape most commonly used antibiotics through multiple resistance mechanisms: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. These organisms are responsible for the majority of life-threatening drug-resistant healthcare-associated infections globally.
What is prospective audit and feedback?
Prospective audit and feedback (PAF) is an AMS intervention where an AMS team (pharmacist, physician, or both) reviews antibiotic prescriptions on the ward 48 to 72 hours after initiation and provides real-time feedback to the prescribing clinician about appropriateness. It is one of the most evidence-based AMS interventions and consistently reduces broad-spectrum antibiotic use without worsening clinical outcomes.
What does stewardship evidence say about antibiotic duration?
Multiple clinical trials support shorter antibiotic courses for most common infections: uncomplicated UTI in women (3 to 5 days vs historical 7 days), community-acquired pneumonia (5 days vs historical 10 to 14 days in non-severe cases), intra-abdominal infection (4 to 5 days after source control vs historical 7 to 14 days), and cellulitis (5 to 7 days if responding). Procalcitonin-guided discontinuation further reduces duration in respiratory and ICU infections.