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Factors That Affect Veterinary Antibiotic Ranking and Usage

Table of Contents

1. Introduction: Why Antibiotic Ranking Matters

Defining Antibiotic Rank

Veterinary antibiotics and factors affecting their rankingAntibiotic ranking, exemplified by frameworks such as the Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT), is a comparative evaluative system used to classify antibiotics based on clinical, microbiological, and stewardship-related outcomes. These ranking models integrate multiple criteria to provide a balanced assessment of antibiotic desirability and therapeutic appropriateness.

Drawing from these frameworks, antibiotic ranking generally incorporates four key dimensions:

  1. Clinical Effectiveness or Activity:
    The ranking prioritizes treatments containing an active agent against the infecting pathogen. The DOOR MAT framework, for instance, evaluates whether a therapeutic choice is active or inactive against a confirmed organism, directly linking activity with patient outcomes.
  2. Resistance Rates and Spectrum of Activity:
    Ranking methods also consider the relationship between antimicrobial spectrum and resistance potential. Narrow-spectrum antibiotics, such as penicillin V, amoxicillin, and dicloxacillin, are typically ranked higher in desirability because they exert less selective pressure on the microbiota. In contrast, broad-spectrum agents, including third-generation cephalosporins (e.g., ceftriaxone), fluoroquinolones (e.g., ciprofloxacin, levofloxacin), and carbapenems (e.g., meropenem), tend to rank lower due to their greater ecological impact and higher risk of promoting resistance. Frameworks like the Antibiotic Spectrum Index (ASI) quantify these differences by assigning spectrum scores to each agent, enabling objective comparison and stewardship-based decision-making.
  3. Safety Profile and Cost Considerations:
    Although not always included in the primary ranking score, additional factors—such as toxicity, cost, availability, ease of administration, and drug–drug interactions—inform antibiotic appropriateness. For example, antibiotics within the WHO “Access” category are generally considered safer and more affordable options.
  4. Stewardship Importance:
    Ranking frameworks also evaluate antibiotics based on their role in antimicrobial stewardship, emphasizing the use of agents that balance clinical efficacy with the minimization of resistance development.

The Role of Antibiotic Ranking in Clinical and Policy Decisions

Antibiotic ranking systems are essential tools in clinical governance and global health policy, particularly in addressing the growing threat of antimicrobial resistance (AMR).

  1. Guiding Treatment Guidelines and Formulary Decisions:
    Ranking methods provide a structured and quantitative means of assessing antibiotic appropriateness. They assist institutional committees in developing treatment protocols by integrating local surveillance data, such as antibiograms, to match antibiotic selection with resistance profiles. The guiding principle is to ensure that antibiotic therapy—when justified—is both targeted and evidence-based. Narrow-spectrum agents are therefore prioritized over broad-spectrum alternatives whenever clinical efficacy is maintained.
  2. Informing AMR Policy and Stewardship Programs:
    Because 30% to 50% of antibiotic prescriptions are considered inappropriate, ranking frameworks are vital for identifying and reducing misuse. They help stewardship teams evaluate prescribing patterns and adjust therapeutic choices to minimize selective pressure on bacterial populations. Global policy initiatives, such as the WHO’s Access, Watch, Reserve (AWaRe) classification, further support the rational distribution of antibiotic use. Similarly, the WHO Bacterial Priority Pathogens List (BPPL) ranks pathogens based on their resistance threat, thereby guiding research and development (R&D) priorities for new antimicrobials.

The WHO AWaRe Classification: A Model of Stewardship-Based Ranking

The WHO AWaRe Classification, launched in 2017, is a globally recognized model designed to improve antibiotic use and curb resistance by categorizing antibiotics according to their public health importance and resistance risk.

The system divides antibiotics into three stewardship-based categories:

  • Access:
    These antibiotics pose a lower risk of resistance and are recommended as first- or second-line treatments for common infections. They are typically safe, affordable, and suitable for wide availability without restriction.
  • Watch:
    Broad-spectrum agents associated with higher resistance potential fall into this group. Their use should be limited to specific indications or cases where Access antibiotics are ineffective.
  • Reserve:
    These represent last-resort antibiotics reserved for infections caused by multidrug-resistant organisms. Their use should be tightly controlled and guided by expert consultation.

 

The WHO recommends that more than 60% of national antibiotic consumption should derive from the Access group. The WHO recommends that more than 60 percent of national antibiotic consumption should come from the Access group. Organizations such as the Global Antibiotic Research and Development Partnership (GARDP) have proposed refinements to the AWaRe framework, particularly regarding Reserve antibiotics, to keep the system clinically relevant and responsive to evolving global resistance patterns.

2. Clinical Efficacy and Spectrum of Activity

Broad vs. Narrow Spectrum: How Therapeutic Coverage Shapes Rank

Antibiotic ranking frameworks prioritize therapeutic coverage based on the dual goals of effective patient treatment and antimicrobial stewardship. The general preference is for narrow-spectrum agents over broad-spectrum agents, provided that patient outcomes are not compromised.

Key aspects of how spectrum shapes rank include:

  • Minimizing Selective Pressure:
    Effective stewardship requires evaluating not only the efficacy of an antibiotic but also its spectrum of activity to minimize selective pressure, which drives the emergence of future resistance.
  • Defining Desirability:
    Frameworks such as the Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT) classify treatment selection according to two primary principles:
    1. Treatments containing an active agent are more desirable than inactive ones; and
    2. Narrow-spectrum antibiotics are more desirable than broad-spectrum agents when equally effective.
  • Ranking Overtreatment:
    In systems such as DOOR MAT, inappropriate therapy is defined as treatment that is active but unnecessarily broad in spectrum, known as overtreatment. Overtreatment is stratified into ordered categories, such as slight overtreatment, moderate overtreatment, and severe overtreatment. All of these rank lower than ideal treatment, which is the narrowest active therapy.
  • Quantitative Measurement:
    The Antibiotic Spectrum Index (ASI) provides a quantitative measure of antibiotic exposure based on spectrum of activity. Each antibiotic receives a score from 1 to 13, allowing classification into four categories: Narrow (1–2), Intermediate (3–4), Broad (5–7), and Very Broad (≥8).
    Studies using ASI have shown that the mean ASI increases with the level of care, rising from Narrow in outpatients to Broad and Very Broad in hospitalized or ICU patients, illustrating the link between clinical setting and antibiotic breadth.

Mechanism of Action: Bactericidal vs. Bacteriostatic Distinction

The mechanism of action determines an antibiotic’s pharmacological effect on its target pathogen and is a major factor influencing its ranking and clinical appropriateness.

  1. General Mechanism:
    Antibiotics are selectively cytotoxic to microbial cells. They typically act either by disrupting the peptidoglycan cell wall or by interfering with essential metabolic processes within the bacterial cell.
  2. Lysis/Killing Action:
    For example, β-lactam antibiotics weaken the peptidoglycan mesh, causing bacteria with high internal osmotic pressure (such as Gram-positive species) to lyse and die, a clear example of bactericidal activity.
  3. Pharmacodynamic (PD) Patterns:
    The interaction between drug and pathogen (pharmacodynamics) defines the optimal dosing strategy and therapeutic efficacy:
    • Concentration-dependent killing with long post-antibiotic effect (PAE):
      Efficacy correlates with Cmax/MIC or AUC/MIC. Higher concentrations produce better killing (e.g., aminoglycosides).
    • Time-dependent killing with minimal PAE:
      Efficacy depends on maintaining drug levels above the MIC for a sufficient proportion of time (T>MIC), typically >50% of a 24-hour period (e.g., β-lactams). In critically ill patients, continuous or prolonged β-lactam infusions are often used to optimize T>MIC.
    • Time-dependent killing with prolonged PAE:
      Efficacy is linked to AUC/MIC (e.g., macrolides such as azithromycin, and lincosamides like clindamycin).
  4. Host Clearance:
    While antibiotics suppress bacterial growth or kill pathogens, the host immune system ultimately clears the infection. Thus, patient immune status is a key contextual factor in ranking antibiotic efficacy.

Target-Specific Effectiveness: Ranking Based on Pathogen Susceptibility

Antibiotic ranking fundamentally depends on whether a selected treatment is active (effective) or inactive (ineffective) against the infecting pathogen.

  • Susceptibility and Activity:
    Ranking systems like DOOR MAT rely on resistance/activity profiles, cross-classifying the antibiotic’s spectrum with the known or inferred susceptibility of the organism.
  • Resistance Profiles:
    Resistance profiles determine susceptibility (S) or resistance (R) across multiple drug classes.
  • Spectrum by Organism Type:
    Mechanism of action often dictates spectrum: antibiotics targeting the peptidoglycan layer are generally more effective against Gram-positive bacteria, whereas Gram-negative bacteria, protected by an outer membrane, require agents that disrupt internal metabolic or membrane processes.
  • WHO Priority Pathogens (AMR Threat):
    The World Health Organization ranks pathogens by criticality in its Bacterial Priority Pathogens List (BPPL), highlighting those requiring urgent R&D efforts:
    • Critical Priority Pathogens — resistant to last-line antibiotics:
      • Carbapenem-resistant Acinetobacter baumannii (CRAB)
      • Carbapenem-resistant Enterobacterales (Klebsiella spp., E. coli)
      • Third-generation cephalosporin-resistant Enterobacterales
    • High Priority Pathogens — major clinical and hospital challenges:
      • Carbapenem-resistant Pseudomonas aeruginosa (CRPA), which moved from Critical to High Priority in the 2024 WHO list
      • Methicillin-resistant Staphylococcus aureus (MRSA)
      • Vancomycin-resistant Enterococcus faecium (VRE)
      • Staphylococcus aureus strains resistant to vancomycin

Standardized Breakpoints for Determining Clinical Efficacy

Clinical efficacy depends on ensuring that the antibiotic concentration achieved in the patient matches or exceeds that required to inhibit the target pathogen.

  • Minimum Inhibitory Concentration (MIC):
    The MIC is the lowest concentration of a drug that prevents visible bacterial growth under standardized conditions. It serves as the core measurement of susceptibility in clinical microbiology.
  • Clinical Determination:
    Effective therapy requires maintaining drug concentrations at the infection site above the MIC for an appropriate duration. These values are determined through antimicrobial susceptibility testing (AST).
  • Application in DOOR MAT:
    Within the DOOR MAT framework, the resistance profile of the infecting pathogen is determined or inferred from AST results. Treatments are categorized as active or inactive based on these data. Susceptibility can be established directly, inferred from class representatives, or estimated using proxies across related antimicrobial agents.
  • Breakpoint Setting Organizations:
    Standardized MIC breakpoints are defined by expert committees such as the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). These benchmarks ensure consistency across clinical laboratories and underpin global comparability of antibiotic efficacy data.

3. Prevalence of Resistance: Regional or Hospital-Based Antibiograms

Affecting Rank

The prevalence of antibiotic resistance is a critical factor influencing antibiotic ranking, as these data are dynamic and context-dependent, varying over time, across regions, and among healthcare settings.

  1. Local Data in Ranking Systems:
    Ranking frameworks such as the Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT) rely heavily on resistance data to evaluate treatment desirability. An institution’s antibiogram, which aggregates local resistance trends, serves as a key input for ranking. By tallying combinations of resistance profiles and treatment selections, institutions can develop treatment protocols that reflect local epidemiology.
  2. Quantifying the Impact of Prevalence:
    DOOR MAT can compare treatment appropriateness across cohorts with different resistance prevalence. Simulations showed that the same empirical regimen, piperacillin–tazobactam for Klebsiella pneumoniae bacteremia, yielded a lower desirability score in regions with higher carbapenem resistance, scoring 57 at 10 percent resistance versus 62 at 3 percent. This illustrates that rising local resistance directly reduces the desirability of a treatment regimen.
  3. Limitations in Local Context:
    Some quantitative ranking tools, such as the Antibiotic Spectrum Index (ASI), do not incorporate local resistance patterns. For example, in settings where penicillin resistance is high, a broader agent such as ceftriaxone (ASI 5) may be clinically appropriate compared to a narrower agent like amoxicillin (ASI 2), even though ASI would rank the latter as more desirable. This underscores the importance of interpreting predefined spectrum scores in conjunction with local susceptibility data.

Cross-Resistance: Impact of Shared Resistance Mechanisms (ESBLs, Carbapenemases, mcr-1)

Shared resistance mechanisms significantly influence antibiotic ranking by rendering entire drug classes—or multiple agents within the same class—ineffective, thereby necessitating broader, less desirable therapeutic choices.

  • Gram-Negative Threat and Resistance Spread:
    Gram-negative bacteria pose a distinct global threat due to their inherent capacity to acquire and share resistance determinants. Through horizontal gene transfer, these bacteria can exchange resistance genes across species, perpetuating resistance within both clinical and community environments.
  • Ranking Resistance Profiles:
    When constructing resistance profiles for ranking systems, resistance to a given antibiotic often implies resistance to other agents within the same class that have narrower spectra. This hierarchical categorization reflects clinical realities in which multidrug-resistant organisms (MDROs) limit available therapeutic options.
  • Specific Resistance Mechanisms in Ranking:
    The WHO Bacterial Priority Pathogens List (BPPL) categorizes pathogens by their resistance mechanisms to guide research and development (R&D) efforts:
    • Critical Priority Pathogens:
      • Carbapenem-resistant Acinetobacter baumannii (CRAB)
      • Carbapenem-resistant Enterobacterales
    • Third-Generation Cephalosporin-Resistant Enterobacterales:
      Listed separately in the 2024 BPPL, these pathogens exemplify the global burden of Extended-Spectrum β-Lactamase (ESBL) production, which erodes the efficacy of broad β-lactams and drives the use of last-resort agents.
  • Challenges for Ranking Systems:
    Frameworks such as DOOR MAT may struggle to capture complex or emerging resistance mechanisms, including inhibitor-resistant β-lactamases, which complicate the interpretation of susceptibility even within the same antibiotic class.

Surveillance Programs: WHO GLASS, CDC AR Threats Report, EARS-Net Data as Ranking Inputs

Antibiotic ranking and policymaking are grounded in epidemiological surveillance data that identify the most urgent resistance threats and inform evidence-based prioritization.

  1. WHO Bacterial Priority Pathogens List (BPPL):
    The WHO periodically updates the BPPL to categorize antibiotic-resistant bacterial families into critical, high, and medium priority groups for R&D and policy focus. The changes between the 2017 and 2024 lists illustrate the evolving nature of antimicrobial resistance (AMR) and the necessity of dynamic, data-driven ranking systems.
  2. CDC Antimicrobial Resistance Threats Report:
    The U.S. Centers for Disease Control and Prevention (CDC) publishes the Antibiotic Resistance Threats in the United States report, which quantifies AMR’s domestic and global impact. The report highlights the urgent need for novel therapeutics and reinforces the connection between surveillance data and antibiotic prioritization.
  3. Global Burden of AMR:
    The Global Burden of Antimicrobial Resistance (GRAM) study, a major research initiative, concluded that AMR has reached an “alarming tipping point.” The study estimates that AMR-related deaths may increase by more than 70% by 2050, primarily driven by the spread of multidrug-resistant Gram-negative infections. Such epidemiological data provide critical inputs for global ranking frameworks and stewardship planning.
  4. AWaRe Classification Refinement:
    The GRDP has proposed refinements to the WHO AWaRe framework, advocating the use of “Difficult-to-Treat Resistance (DTR)” instead of “Multidrug-Resistant (MDR)” as a defining criterion for Reserve antibiotics. This change better reflects clinical practice by emphasizing resistance to all safe and effective first-line therapies and improving the alignment between clinical decision-making and stewardship classification.

Rising Resistance Trends and the Demotion of Certain Antibiotics (e.g., Fluoroquinolones in E. coli UTIs)

Rising resistance trends lower the desirability—or rank—of an antibiotic by increasing the probability of undertreatment (ineffective therapy) or by accelerating the development of further resistance through selective pressure.

  • Demotion through Resistance:
    As pathogen resistance to a particular antibiotic increases, the desirability of that antibiotic diminishes, particularly for empirical therapy.
  • Official Ranking Changes:
    The WHO periodically revises its BPPL in response to emerging data. For instance, carbapenem-resistant Pseudomonas aeruginosa (CRPA) shifted from the Critical to the High Priority category in the 2024 BPPL, reflecting observed decreases in global resistance. This reclassification demonstrates how evolving resistance data influence official threat rankings.
  • Fluoroquinolone Resistance:
    Increasing fluoroquinolone resistance has led to the elevation of fluoroquinolone-resistant Salmonella Typhi and fluoroquinolone-resistant Shigella spp. to the High Priority category in the WHO list. These designations emphasize the urgent need for R&D investment into alternative therapeutic options.

4. Pharmacokinetic and Pharmacodynamic (PK/PD) Parameters

Antibiotic efficacy is governed by the interplay between how the host processes the drug (pharmacokinetics) and how the drug interacts with the pathogen (pharmacodynamics). Understanding these parameters is essential, as dosing must always be contextualized: a drug must achieve and maintain an effective concentration at the infection site for a sufficient duration to produce the desired therapeutic effect.

Absorption, Distribution, Metabolism, and Excretion (ADME): Drugs with Optimal PK Profiles Often Rank Higher for Efficacy

Pharmacokinetics (PK) describes how the body absorbs, distributes, metabolizes, and eliminates a drug. Optimal PK profiles are critical for efficacy, if a drug fails to reach therapeutic levels, treatment becomes ineffective (undertreatment), which ranks lowest in desirability within frameworks such as DOOR MAT.

  • PK Barriers and Critical Illness:
    Physiological barriers, including the blood–brain barrier and poor gastrointestinal (GI) absorption, significantly affect drug efficacy. Pharmacokinetics can also be profoundly altered in critically ill patients, requiring tailored dosing strategies.
  • Distribution (D) and Clearance (E/M):
    In critical illness, physiological changes alter drug behavior across ADME parameters:
    • Hypervolemia (fluid overload): Increases the volume of distribution (Vd), leading to lower serum concentrations and potential underdosing.
    • Hypoalbuminemia: Raises the free (active) drug fraction, enhancing clearance but also increasing the risk of toxicity.
    • Renal dysfunction: Represents the most common reason for antibiotic dose adjustment due to impaired excretion.
    • Hepatic impairment: Reduces or unpredictably alters metabolism, complicating drug clearance.
  • Inflammation and Metabolism:
    Systemic inflammation, indicated by elevated C-reactive protein (CRP), can significantly modify PK. Inflammatory mediators may downregulate cytochrome P450 (CYP450) enzymes (notably CYP2C19, CYP3A4, and CYP2C9), reducing hepatic drug clearance, especially for hepatically metabolized antibiotics.
  • Route of Administration (A):
    In severe infections such as sepsis, rapid systemic availability is essential. Intravenous (IV) administration provides predictable plasma concentrations for high bacterial loads. Conversely, in stable patients, agents with high oral bioavailability may achieve therapeutic levels effectively—hence the stewardship principle that “oral is the new IV” when clinically appropriate.

PK/PD Indices: Time-Dependent vs. Concentration-Dependent Killing (T>MIC, Cmax/MIC, AUC/MIC)

Pharmacodynamics (PD) describes how the antibiotic exerts its effect on the pathogen, often measured relative to the Minimum Inhibitory Concentration (MIC)—the lowest concentration that inhibits visible bacterial growth. The relationship between PK and PD defines three principal efficacy patterns:

  1. Concentration-Dependent Killing with Long Post-Antibiotic Effect (PAE):
    • Efficacy Measure: Cmax/MIC (peak concentration to MIC ratio) or AUC/MIC (area under the concentration–time curve to MIC ratio).
    • Principle: Higher peak concentrations result in faster and more effective bacterial killing.
    • Examples: Aminoglycosides and daptomycin.
  2. Time-Dependent Killing with Minimal PAE:
    • Efficacy Measure: T>MIC (time above MIC).
    • Principle: Maintaining drug levels above the MIC is key, as higher concentrations beyond a threshold do not improve outcomes. Typically, maintaining T>MIC for >50% of a 24-hour dosing interval is sufficient.
    • Examples: β-lactams, which are often administered via continuous or extended infusions in intensive care settings to optimize T>MIC.
  3. Time-Dependent Killing with Prolonged PAE:
    • Efficacy Measure: AUC/MIC.
    • Principle: Sustained drug exposure prolongs bacterial suppression after concentrations fall below the MIC.
    • Examples: Azithromycin, tetracyclines, and clindamycin.

Tissue Penetration: Importance for Site-Specific Infections (CNS, Respiratory, Urinary, etc.)

A central principle of antibiotic selection is ensuring adequate drug penetration at the infection site. Therapeutic success requires that the antibiotic not only achieves sufficient plasma levels but also reaches the target tissue or compartment where infection resides.

  • Determinants of Penetration:
    Penetration depends on lipid solubility, passive diffusion, active transport, and protein binding. Drugs with high lipid solubility and low protein binding typically penetrate tissues more effectively.
  • Central Nervous System (CNS) Infections:
    In diseases such as meningitis, the ability to cross the blood–brain barrier is essential. Lipid solubility and molecular size largely determine CNS penetration, and inflammation can temporarily increase barrier permeability.
  • Intracellular Infections:
    Infections caused by intracellular pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila) require antibiotics that can penetrate host cells. Macrolides, tetracyclines, and fluoroquinolones exhibit this property, explaining their efficacy against atypical respiratory pathogens.
  • Urinary Tract Infections (UTIs):
    Antibiotics effective for UTIs must achieve high concentrations in the urinary tract. The current development pipeline includes agents targeting urinary pathogens with optimized PK/PD properties and excretion profiles—for instance, sulopenem–etzadroxil/probenecid, now in Phase 3 trials for uncomplicated urinary tract infections.

5. Safety, Toxicity, and Cost Consideration in Antibiotic Ranking

Antibiotic ranking frameworks must integrate safety and toxicity parameters, as these clinical considerations fundamentally determine whether an antibiotic is appropriate for an individual patient, regardless of its in vitro potency or antimicrobial spectrum.

Therapeutic Index: Drugs with Narrow Safety Margins Rank Lower Despite Potency

While formal quantitative frameworks such as the Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT) primarily emphasize activity and spectrum over toxicity, they nonetheless recognize that safety and tolerability are essential dimensions of clinical appropriateness.

  1. Integration into Ranking:
    The core DOOR MAT scores are designed to measure the desirability of treatment based on activity and spectrum, not direct patient outcomes. However, the framework acknowledges that toxicity introduces complexity into clinical implementation and must be factored into treatment decisions when it meaningfully affects overall appropriateness.
  2. Narrow Therapeutic Index Drugs:
    Antibiotics associated with higher toxicity profiles are typically reserved for multi-drug-resistant infections, even when highly potent. Such agents occupy the highest stewardship priority category. For example, colistin and polymyxin B—included in the WHO’s Reserve group—are last-line options indicated only for infections unresponsive to safer alternatives.
  3. Prescriber Decision-Making:
    Despite known risks, empirical evidence suggests that adverse effect profiles exert limited influence on prescriber behavior, particularly in inpatient settings. Physicians frequently exhibit a bias toward action, driven by fear of missing an infection and a perceived need to “be on the safe side.” This defensive prescribing behavior is reinforced by concern over negative patient outcomes, medicolegal consequences, and potential reputational risks.

Patient Populations: Adjusted Rankings for Pediatrics, Geriatrics, and Renal or Hepatic Impairment

Antibiotic selection—and consequently, its relative rank or appropriateness—must be adapted to account for physiological variation among patients, particularly in populations with altered pharmacokinetics or increased vulnerability.

  1. Physiological Adjustments (PK/PD):
    The efficacy of an antibiotic depends on achieving therapeutic concentrations at the infection site for an adequate duration. Altered pharmacokinetic parameters in special populations include:
    • Renal dysfunction, the most common cause of dosing modification due to impaired clearance.
    • Hepatic impairment, which complicates metabolic predictability and drug elimination.
    • Hypervolemia, which increases the volume of distribution (Vd), potentially lowering serum concentrations.
    • Hypoalbuminemia, which raises the proportion of free (active) drug, enhancing both clearance and toxicity risk.
  2. Age-Related Vulnerability:
    The WHO Bacterial Priority Pathogens List (BPPL) identifies critical priority pathogens—such as carbapenem-resistant Gram-negative organisms—prevalent in vulnerable populations, including hospitalized and long-term care patients.
    Medium-priority pathogens, such as Group A and B Streptococci and Streptococcus pneumoniae, require special attention in pediatric and elderly populations due to their distinct immune and metabolic profiles.
  3. Prescribing Context:
    Patient-specific factors—such as age, sex, comorbidities, and immune status—are consistently identified as determinants of antibiotic prescribing behavior in clinical settings. These considerations often outweigh ranking-based desirability when patient safety is at risk.

Drug Interactions and Allergic Potential: β-Lactam Allergy and the Clinical Substitution Hierarchy

Drug–drug interactions and allergic reactions are critical determinants of antibiotic suitability and must be considered when determining the relative rank of a therapy for a specific patient.

  1. Impact of Drug Interactions:
    Drug–drug interactions represent a significant modifier of treatment appropriateness and can be integrated into frameworks such as DOOR MAT. Systemic inflammation, reflected by elevated C-reactive protein (CRP), can further alter pharmacokinetics by downregulating cytochrome P450 enzymes (CYP2C19, CYP3A4, and CYP2C9), leading to drug accumulation and hepatotoxicity for agents undergoing hepatic metabolism.
  2. Allergic Potential:
    Patient allergies are explicitly recognized as a major influence on antibiotic prescribing decisions. Hypersensitivity reactions to β-lactams, in particular, are common and can significantly constrain first-line therapeutic choices.
  3. β-Lactam Use and Desirability:
    β-lactam antibiotics (e.g., amoxicillin, ampicillin) are typically preferred as first-line treatments for uncomplicated bacterial infections such as pneumonia. Their desirability is supported by narrow activity, safety, and time-dependent pharmacodynamics (T>MIC). However, β-lactam allergy necessitates substitution with the narrowest feasible active alternative.
  4. Substitution and Spectrum Trade-offs:
    Clinical substitution for allergic patients must balance safety and antimicrobial spectrum. Replacing a narrow β-lactam with a broader alternative (e.g., a fluoroquinolone or macrolide) may lower the treatment’s desirability score when measured purely by spectrum but simultaneously increase its appropriateness from a safety perspective. This trade-off illustrates the inherent tension between stewardship objectives and individualized patient care.

6. Stewardship Priority and Regulatory Classification

Antibiotic ranking is strongly shaped by stewardship priorities and regulatory frameworks designed to preserve the efficacy of essential medicines and mitigate the escalating global threat of antimicrobial resistance (AMR).

WHO AWaRe Framework

The World Health Organization’s (WHO) AWaRe Classification, launched in 2017, is a globally recognized system that categorizes antibiotics into three groups based on their risk of resistance development and medical importance. This framework provides a practical foundation for stewardship programs worldwide, promoting rational antibiotic use while safeguarding effectiveness for future generations.

The three groups represent a hierarchy of stewardship priority:

Access: First-Line Agents with Low Resistance Potential

Access group antibiotics exhibit a low risk of resistance and are generally recommended as first or second line treatments for common infections. They are typically inexpensive, safe, and widely available, making them suitable for broad clinical use whenever appropriate.

  • Examples: Amikacin, amoxicillin, amoxicillin–clavulanic acid, ampicillin, cefalexin, clindamycin, doxycycline, metronidazole, and nitrofurantoin.
  • Goal: The WHO recommends that ≥60% of a country’s antibiotic consumption should come from the Access group to minimize resistance pressure.

 

Watch: Broader Agents with Higher Resistance Potential

Watch group antibiotics are broad spectrum agents with a higher potential to drive resistance. Their use should be reserved for situations in which Access group options are unsuitable or ineffective.

  • Examples: Azithromycin, ciprofloxacin, clarithromycin, several cephalosporins (e.g., cefixime), and vancomycin. Oral fosfomycin is also categorized in this group.
  • Characteristics: These agents are often more expensive and should be used under stricter monitoring, typically highlighted in yellow in stewardship frameworks.

 

Reserve: Last-Resort Antibiotics

Reserve antibiotics are last line agents reserved for treating infections caused by multidrug resistant organisms when no other effective options remain.

  • Examples: Ceftazidime–avibactam, colistin, polymyxin B, and linezolid. While carbapenems (e.g., imipenem, meropenem) are categorized as broad-spectrum in DOOR MAT, they are often treated as critical last-resort options in clinical practice.
  • GARDP Refinement: The GARDP has proposed redefining Reserve antibiotics by replacing “multidrug resistant (MDR)” with “difficult to treat resistance (DTR)”. This shift better reflects cases where pathogens resist all first line, safe, and effective therapies, aligning the classification more closely with real world clinical decision making.

National Guidelines: Stewardship Committees and Formulary-Based Restrictions

Antimicrobial Stewardship Programs (ASPs) and hospital committees operationalize ranking frameworks through guideline development, formulary restrictions, and behavioral interventions to promote judicious antibiotic use.

  1. Guiding Decisions:
    Ranking systems provide structured, quantitative tools for assessing antibiotic appropriateness and guide institutional leadership in establishing protocols for empirical and targeted therapy.
  2. Formulary Restrictions:
    Stewardship interventions based on frameworks such as AWaRe enforce narrow-spectrum preference when clinically feasible. Access to broad-spectrum or Reserve agents is typically restricted to ensure their preservation for critical indications.
  3. Behavioral Interventions:
    Stewardship committees employ both policy mechanisms and behavioral strategies to influence prescribing behavior:
    • Decision Support Tools: Embedding antibiograms, guidelines, and evidence-based protocols within prescribing interfaces.
    • Antibiotic Timeouts: Automated reminder prompts or pop-up windows in electronic prescribing systems to encourage clinicians to reassess ongoing antibiotic therapy for continued appropriateness.
    • Prior Authorization: Requiring pre-approval from infectious disease specialists or stewardship teams before certain antibiotics (e.g., Reserve agents) can be dispensed—providing social oversight and reinforcing accountability.
    • Integrated Pathways: Incorporating stewardship recommendations directly into clinical decision pathways and electronic health records (EHRs) for seamless adherence.

Economic and Policy Factors: Cost, Availability, and Stewardship Incentives Influencing Rank

Non-clinical factors—such as cost, drug availability, and policy environment—also play a decisive role in shaping antibiotic ranking and use across healthcare systems.

  1. Cost and Availability (Access):
    • Economic Gradient: Access group antibiotics are generally low-cost and widely accessible, while Watch and Reserve agents are often significantly more expensive.
    • Access Disparities: In low- and middle-income countries (LMICs), limited use of Reserve agents often reflects restricted availability rather than optimal stewardship.
    • Supply Chain Barriers: Interruptions in supply chains and poor distribution infrastructure are persistent challenges influencing clinical prescribing decisions.
    • Patient Cost Sensitivity: Physicians frequently consider the patient’s financial capacity and insurance coverage when selecting an antibiotic, particularly in out-of-pocket healthcare systems.
  2. Policy, Financial, and Stewardship Incentives:
    • Policy Gaps: Public policy has historically underemphasized the role of economic incentives in shaping antibiotic stewardship.
    • Incentive Strategies:
      • Financial Incentives: Linking funding or performance bonuses to adherence with stewardship protocols.
      • Material Incentives: Allocating additional departmental resources to clinical units demonstrating high compliance with institutional prescribing standards.
      • Performance Remuneration: Rewarding clinicians who achieve measurable improvement (e.g., ≥10%) in the appropriateness of antibiotic prescribing.
    • R&D Policy Context: The WHO Bacterial Priority Pathogens List (BPPL) encourages governments to establish funding mechanisms and private-sector incentives that accelerate antibiotic innovation, addressing the chronic shortage of new therapeutic agents.
  3. Clinical Environment and Resource Constraints:
    The “environmental context and resources” within healthcare settings profoundly affect prescribing behavior. High workloads, time pressure, and limited diagnostic resources frequently lead to defaulting toward broader-spectrum antibiotics. Moreover, ease of prescribing, such as pre-selected electronic defaults, reduces cognitive effort but risks undermining stewardship goals.

7. Veterinary and One Health Considerations

Antimicrobial ranking in animal medicine is guided by international frameworks established by the World Organisation for Animal Health (WOAH, formerly OIE), the Food and Agriculture Organization (FAO), and the World Health Organization (WHO). Together, these institutions advance the One Health framework, recognizing that antimicrobial resistance (AMR) is a shared threat linking human, animal, and environmental health within a single global ecosystem.

Frameworks Guiding Antimicrobial Stewardship in Veterinary Medicine

The WOAH and FAO outline stewardship principles through regulatory and policy instruments rather than numerical scoring systems.

  1. WOAH List of Antimicrobial Agents of Veterinary Importance
     WOAH categorizes veterinary antimicrobials based on their therapeutic indispensability for animal health and their potential to contribute to resistance affecting human medicine.
     * Critically Important Antimicrobials (CIAs): indispensable for managing severe animal diseases with few or no alternative therapies.
     * Highly Important Antimicrobials (HIAs): broadly used across species but with some therapeutic substitutes.
     * Important Antimicrobials (IAs): agents with multiple alternatives and lower potential human-health impact.
     This list is periodically revised to reflect evolving resistance trends, scientific advances, and global usage data.

  2. FAO–WOAH–WHO Tripartite Collaboration
     The FAO and WOAH collaborate with WHO through the Tripartite Joint Secretariat on AMR, promoting harmonized antimicrobial policies across human, veterinary, and agricultural domains. Their priorities include prudent antimicrobial use, surveillance of drug consumption in food-producing animals, and the development of sustainable husbandry practices that minimize antimicrobial dependence.
     These organizations advocate eliminating non-therapeutic antibiotic use (such as for growth promotion) and establishing national stewardship programs paralleling those in human healthcare.

Cross-Sector Classification of Critically Important Antimicrobials

The WHO List of Critically Important Antimicrobials for Human Medicine and the WOAH List of Antimicrobial Agents of Veterinary Importance jointly form a global antibiotic hierarchy balancing animal-health needs with human-health protection.

Antimicrobial classes such as fluoroquinolones, third and fourth generation cephalosporins, macrolides, and polymyxins are critical in both human and animal health, which is why their veterinary use is tightly restricted. Resistance determinants like mcr-1, which confers colistin resistance, and blaCTX-M, associated with extended spectrum β lactamase production, illustrate how resistance genes can move between animal reservoirs and human pathogens. In response, WOAH advises member states to incorporate antimicrobial importance rankings into veterinary licensing, prescription guidelines, and national legislation to ensure that antibiotic use supports both animal welfare and public health.

Maintaining a Cross-Sector Hierarchy to Prevent Zoonotic Resistance Spread

The One Health framework emphasizes a unified hierarchy of antimicrobial use across species. Safeguarding the efficacy of human-critical antibiotics requires coordinated restrictions and strategic innovation in animal medicine.

Key strategies include:

  • Restricting Shared-Class Antibiotics: Limiting the veterinary use of fluoroquinolones, macrolides, and polymyxins to justified therapeutic cases only.
  • Developing Veterinary Alternatives: Expanding vaccines, probiotics, and bacteriophage therapies to reduce prophylactic use.
  • Surveillance Integration: Linking human and animal AMR monitoring systems (e.g., WHO GLASS and WOAH Annual Reports) to detect emerging resistance determinants across sectors.
  • Environmental Safeguards: Controlling antibiotic residues and resistant bacteria released via livestock effluents to reduce environmental reservoirs of AMR.

Table 1. Comparative Overview of Human and Veterinary Antibiotic Ranking Frameworks

Framework / Organization

Primary Purpose

Classification Categories

Basis of Ranking

Examples of Antimicrobials

Stewardship Implications

WHO AWaRe Classification (Human Medicine)

To guide rational antibiotic use and monitor global antibiotic consumption by resistance risk and clinical importance.

Access – First/second-line, low resistance risk

Watch – Broad-spectrum, high resistance potential

Reserve – Last-resort agents

Spectrum, resistance potential, and stewardship priority

Access: Amoxicillin, Doxycycline

Ciprofloxacin, Ceftriaxone

Reserve: Colistin, Linezolid

Encourages ≥60% of national antibiotic use from Access group; restricts Watch and Reserve to slow resistance development.

WOAH (OIE) List of Antimicrobial Agents of Veterinary Importance

To guide veterinary antimicrobial use based on animal health needs and human-health impact.

Critically Important (CIA)

Therapeutic necessity, zoonotic risk, and resistance potential

CIA: Fluoroquinolones, 3rd/4th-gen cephalosporins, ColistinHIA: Penicillins, MacrolidesIA: Sulfonamides, Tetracyclines

Restricts CIA use to treatment-only purposes; discourages prophylactic and growth-promotion use.

FAO Antimicrobial Stewardship Framework

To promote responsible antimicrobial use in agriculture and aquaculture.

No fixed ranking; applies risk-based framework across food systems.

AMR risk through food production, ecological and occupational exposure

Broad classes used in livestock and aquaculture

Encourages elimination of non-therapeutic antibiotic use and adoption of alternatives (vaccines, probiotics, improved biosecurity).

WHO–FAO–WOAH Tripartite One Health Collaboration

To align global AMR surveillance and policy across human, animal, and environmental sectors.

Integrates AWaRe and WOAH CIA classifications for cross-sector prioritization.

Cross-sector resistance risk, zoonotic transmission potential

Shared critical classes: Fluoroquinolones, Polymyxins, Cephalosporins, Macrolides

Promotes integrated surveillance (GLASS + WOAH data) and harmonized global policy frameworks.

Preserving antibiotic efficacy demands a coordinated human–animal–environmental hierarchy. Maintaining this balance—ensuring critical classes are not overused across sectors—is essential for preventing zoonotic transmission of resistance.

Stewardship in veterinary medicine is not an adjunct to human healthcare; it is a central determinant of global therapeutic resilience.

Future Perspectives: Data-Driven and Molecular Ranking

Antibiotic ranking frameworks are entering a new phase driven by digital innovation, molecular epidemiology, and real-time surveillance. Emerging systems aim to integrate clinical data, resistance mechanisms, and stewardship principles into dynamic, data-driven models capable of providing personalized and context-sensitive antibiotic evaluations.

Machine Learning and Molecular Surveillance: Dynamic Updating of Antibiotic Ranks

Although current frameworks do not explicitly employ machine learning or molecular surveillance as core algorithms, the direction of antimicrobial ranking is unmistakably shifting toward data-driven adaptability. These evolving systems will rely on rapid diagnostics, genomic surveillance, and predictive modeling to refine antibiotic selection in real time.

  • Rapid Diagnostics and Decision Support:
     Structured ranking models such as the Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT) can incorporate genotypic diagnostic data to enhance clinical decision-making. In a simulation comparing empirical therapy (piperacillin-tazobactam) with genetically informed treatment selection, the latter achieved a significantly higher desirability score (85 vs. 62), underscoring the role of rapid genetic testing in optimizing antibiotic ranking.
  • Dynamic Updating Based on Resistance Prevalence:
     DOOR MAT’s framework inherently accommodates changes in local resistance patterns. Simulations demonstrate that as carbapenem resistance prevalence increases (e.g., from 3% to 10%), the mean desirability score of empirical regimens declines, reflecting a dynamic demotion of antibiotic rank in response to real-world epidemiological data.

 

These findings suggest that future antibiotic ranking tools will function as adaptive learning systems, continuously recalibrating desirability scores in response to shifting pathogen profiles and treatment outcomes.

Integration of Resistome Data, Genome Sequencing, and Local Antibiograms

Next-generation frameworks will integrate molecular and clinical datasets to move beyond static categorizations and toward personalized antibiotic ranking.

  • Local Antibiograms and Resistance Profiles:
     Modern frameworks already utilize local antibiograms—aggregated institutional resistance data—to inform therapeutic choices. DOOR MAT applies pathogen-specific resistance profiles derived from antimicrobial susceptibility testing (AST) to classify therapy as active or inactive.
     Incorporating such localized data ensures that antibiotic desirability reflects the true clinical context rather than a generalized efficacy profile.

  • Molecular Resistance Mechanisms:
     Genomic surveillance enables the identification of specific resistance determinants, such as blaCTX-M (ESBL), blaNDM (carbapenemase), or mcr-1 (colistin resistance). The WHO underscores that Gram-negative pathogens pose the greatest threat due to their capacity for horizontal gene transfer, facilitating rapid dissemination of these genes across bacterial species.
     Integrating resistome data (the complete set of resistance genes within a microbiome) into ranking systems would allow for nuanced prediction of therapeutic efficacy and resistance evolution.

  • Precision in Spectrum Selection:
     The ultimate goal of these systems is to select the narrowest active agent—a principle aligned with antimicrobial stewardship. By incorporating pathogen genotyping and rapid phenotypic AST, future ranking models will reduce reliance on broad-spectrum empirical therapy.

Toward “Next-Generation” Ranking Systems: Integrating Clinical, Economic, and Ecological Dimensions

Existing models such as the Antibiotic Spectrum Index (ASI) and DOOR MAT primarily quantify treatment appropriateness by activity and spectrum. However, future systems are expected to integrate additional layers—clinical outcomes, cost-effectiveness, and ecological sustainability—to support comprehensive decision-making.

  1. Clinical Outcomes Integration:
     The DOOR MAT framework measures desirability of treatment but currently lacks direct linkage to patient outcomes. Its developers note that future iterations should evaluate desirability across multiple perspectives—patient, provider, health system, and society—to ensure alignment between stewardship objectives and clinical efficacy.
  2. Economic and Cost Factors:
     Economic considerations are increasingly recognized as integral to ranking systems. The cost of antibiotics, patient affordability, and institutional reimbursement incentives all influence prescribing behavior. Incorporating these variables into ranking algorithms will enable context-sensitive optimization, particularly in low- and middle-income countries where cost barriers affect drug accessibility.
  3. Ecological and Stewardship Impact:
     Antibiotic ranking must continue to reflect the ecological footprint of antimicrobial use. The Antibiotic Spectrum Index (ASI) offers a quantifiable measure of antibiotic exposure, ranking agents from narrow (1–2) to very broad (≥8). Its ability to translate spectrum into measurable stewardship outcomes positions it as a key indicator for clinical trials and stewardship interventions.
     Parallel to this, the GARDP has proposed the Difficult-to-Treat Resistance (DTR) Index, emphasizing access to effective therapies in regions facing constrained antibiotic availability.
  4. Behavioral and Contextual Integration:
     Finally, next-generation frameworks must consider behavioral drivers of prescribing. Environmental factors—such as time constraints, workload, and access to clinical decision support—exert significant influence on antibiotic choice. Embedding ranking algorithms within clinical decision systems and electronic health records (EHRs) can provide real-time prompts (“antibiotic timeouts”) that encourage reassessment and reinforce rational prescribing.

 

Antibiotic ranking is evolving from static categorization to dynamic, data-driven ecosystems that synthesize molecular biology, epidemiology, and clinical outcomes.
Future frameworks will integrate genomic resistance data, economic modeling, and behavioral insights to continuously refine treatment desirability and ensure precision stewardship.

The convergence of machine learning, molecular diagnostics, and real-time surveillance will define the next generation of antibiotic ranking—where therapy selection is adaptive, personalized, and globally harmonized.

9. Conclusion

Antibiotic Ranking: A Multifactorial, Evidence-Based Framework

Antibiotic ranking represents a multifactorial, quantitative, and evidence-driven framework designed to evaluate the desirability and appropriateness of antibiotic selection. This structured approach balances four key dimensions — efficacy, spectrum, resistance, and safety — to ensure that treatment decisions align with both patient outcomes and long-term public health priorities.

  1. Clinical Efficacy (Activity):
     The foremost criterion in antibiotic ranking is clinical effectiveness. A desirable treatment must contain an active agent against the infecting pathogen. The interplay between pharmacokinetics (PK) and pharmacodynamics (PD) defines drug performance, influencing how long and at what concentration the antibiotic acts at the infection site. In ranking frameworks such as the Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT), an inactive regimen is classified as undertreatment and occupies the lowest desirability tier.
  2. Spectrum and Stewardship (Ecological Impact):
     Ranking integrates stewardship principles, prioritizing narrow-spectrum antibiotics to minimize ecological pressure and slow the emergence of resistance. Tools like the Antibiotic Spectrum Index (ASI) quantify antibiotic exposure by spectrum breadth, offering a data-based metric to monitor stewardship performance and optimize prescribing practices.
  3. Resistance and Epidemiological Context:
     Antibiotic ranking is inherently data-driven, drawing upon local and regional resistance prevalence. Institutional antibiograms provide the empirical foundation for ranking decisions. As resistance rates rise, the desirability of a given empirical treatment decreases proportionally. For example, the DOOR MAT framework demonstrates how higher carbapenem resistance prevalence lowers the average appropriateness score for standard empirical regimens.
  4. Safety and Appropriateness:
     While systems such as DOOR MAT focus on activity and spectrum, safety remains integral to clinical appropriateness. Toxicity, pharmacological interactions, cost, and accessibility shape the real-world feasibility of antibiotic choices. Importantly, prescribing behavior is also influenced by psychological and contextual factors — clinicians frequently cite fear of under-treating infections as a driver of overprescription, underscoring the behavioral dimension of stewardship.

Preserving Efficacy and Informing Global AMR Policy

Antibiotic ranking is not solely a clinical exercise — it is a strategic instrument for preserving antimicrobial efficacy and shaping global policy on antimicrobial resistance (AMR).

  • Preserving Efficacy through Stewardship Frameworks:
     The WHO AWaRe Classification (Access, Watch, Reserve) remains the cornerstone of global antibiotic stewardship. It directs countries to ensure that at least 60% of national antibiotic consumption comes from Access group agents — those with lower resistance potential — while Watch and Reserve antibiotics are safeguarded for limited or last-line use. Ranking frameworks thus provide the empirical foundation for interventions that reduce both overtreatment and undertreatment, ensuring that antibiotic efficacy is preserved for future generations.
  • Guiding Research, Development, and Policy:
     The WHO Bacterial Priority Pathogens List (BPPL) 2024 exemplifies the use of ranking principles to inform research and development priorities. By categorizing pathogens as critical, high, or medium priority, the BPPL guides investment and innovation toward areas of highest clinical urgency — such as carbapenem-resistant Gram-negative bacteria. These hierarchies empower governments and pharmaceutical stakeholders to allocate resources efficiently and address the global shortfall in new antibiotic classes.
  • Driving Effective Stewardship Interventions:
     Behavioral and environmental determinants — such as time pressure, access to diagnostic tools, and institutional culture — strongly influence antibiotic prescribing. Incorporating ranking data into decision-support systems, electronic prescribing prompts, and educational initiatives enables clinicians to reflect, reassess, and choose the most appropriate therapy in real time. These “antibiotic timeouts” convert ranking frameworks into actionable, behaviorally-informed tools that enhance stewardship at the point of care.

A Shared Responsibility for Global Stewardship

The future of antibiotic ranking lies in precision stewardship, integrating molecular diagnostics, predictive analytics, and behavioral insights to guide therapy at both the bedside and the policy level.
Its success depends not only on data but also on cross-sector cooperation — between human medicine, veterinary practice, and environmental management — under the One Health paradigm.

At Bioguard Corporation, we are committed to advancing global diagnostic standards that empower clinicians, laboratories, and policymakers in the fight against antimicrobial resistance.
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