How are antibiotics classified?

Antibiotic Classification

Antibiotics are classified using multiple complementary systems: the WHO AWaRe framework (Access, Watch, Reserve) for stewardship purposes, first-choice versus second-choice designations for clinical selection, and traditional categorization by mechanism of action (cell wall inhibitors, protein synthesis inhibitors, nucleic acid inhibitors, membrane-active agents). 1

WHO AWaRe Framework (Primary Classification for Stewardship)

The WHO uses a traffic-light approach to categorize 257 antibiotics globally into three groups based on resistance potential and appropriate use 1:

Access Group (Green Light)

• Narrow-spectrum agents with favorable risk-benefit ratios and low resistance levels 1
• Should be widely available, affordable, and of assured quality in all healthcare facilities 1
• Recommended as empiric first- or second-choice treatment for common clinical infections 1
• Lower resistance potential compared to other groups 1

Watch Group (Orange Light)

• Broader-spectrum agents with higher resistance potential and greater toxicity concerns 1
• Includes highest priority critically important antimicrobials such as fluoroquinolones and carbapenems 1
• Should be key targets of antimicrobial stewardship and monitoring programs 1
• Often first- or second-choice for specific indications but require careful monitoring 1
• Generally associated with more adverse events and higher cost 1

Reserve Group (Red Light)

• Last-resort options for multidrug-resistant organisms (MDROs) 1
• Only eight antibiotics identified in this category 1
• Should be used exclusively for confirmed or suspected infections when other alternatives have failed 1
• Show consistent activity against organisms resistant to first- and second-choice options 1
• Major targets for antimicrobial stewardship programs with mandatory monitoring 1

Clinical Selection Framework

First-Choice Antibiotics

• Usually narrow-spectrum agents with benefits outweighing risks 1
• Relatively low levels of reported resistance 1
• Preferred initial empiric therapy for specific indications 1

Second-Choice Antibiotics

• Generally broader-spectrum agents with higher resistance rates or less favorable risk-benefit ratios 1
• Used when first-choice options are inadequate or contraindicated 1

Important caveat: The first/second-choice level and AWaRe categories are independent systems—a Watch antibiotic may be first-choice for certain infections 1

Mechanism of Action Classification

Antibiotics are traditionally organized by their cellular targets 2, 3:

Cell Wall Inhibitors

• β-lactams (penicillins, cephalosporins, carbapenems, monobactams) interfere with bacterial cell wall biosynthesis 4, 5
• Differ in stability to β-lactamases and antimicrobial spectrum 4

Protein Synthesis Inhibitors

• Target bacterial ribosomal machinery 3, 5
• Include aminoglycosides and macrolides 3

Nucleic Acid Inhibitors

• Fluoroquinolones inhibit DNA gyrase and topoisomerase IV, preventing DNA replication, transcription, repair, and recombination 6
• Different mechanism from β-lactams, aminoglycosides, and macrolides, allowing activity against bacteria resistant to those classes 6, 7, 6

Membrane-Active Antibiotics

• Disrupt bacterial cell membrane integrity 3

Susceptibility Classification

Bacteria are categorized based on laboratory testing 1:

Susceptible (S)

• Pathogen likely inhibited if antimicrobial reaches usual achievable blood concentrations 1
• Defined by minimum inhibitory concentration (MIC) breakpoints 1

Intermediate (I)

• Variable response to therapy; may respond if drug is concentrated at infection site or dosage increased 1
• Provides technical buffer zone preventing minor variations from causing interpretation errors 1

Resistant (R)

• Microbiological resistance: Organisms possess resistance mechanisms demonstrated phenotypically or genotypically 1
• Clinical resistance: Infection highly unlikely to respond even to maximum antibiotic doses 1
• May be qualified as low-level, moderate, or high-level resistance 1

Spectrum Classification

Antibiotics are characterized by their range of activity 1:

• Gram-positive, Gram-negative, aerobic, facultatively anaerobic, or obligate anaerobes 1
• Acquired resistance alters spectrum patterns over time and location 1

Cross-Resistance Patterns

• Complete or partial insusceptibility to antibiotic groups 1
• Strictly applies to same chemical class (e.g., β-lactams, aminoglycosides, macrolides) 1
• Resistance mechanisms like impermeability or efflux may affect multiple classes (associated resistance) 1

Clinical pitfall: Fluoroquinolone resistance develops slowly through multiple mutations (10⁻⁹ to 10⁻¹⁰ frequency), with cross-resistance between fluoroquinolones but not with other antibiotic classes 6