What are the mechanisms of action for each class of antibiotics?

Mechanisms of Action for Antibiotic Classes

β-Lactam Antibiotics (Penicillins, Cephalosporins, Carbapenems)

β-lactam antibiotics inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), specifically blocking the transpeptidase and DD-carboxypeptidase enzymes that cross-link peptidoglycan chains in the final stages of murein biosynthesis. 1

• The β-lactam ring structure has steric similarity to the D-alanyl-D-alanine dipeptide substrate, causing the enzyme to act on the antibiotic instead of the natural substrate 2
• This results in incomplete cell wall formation, producing fragile bacteria that cannot maintain structural integrity 2
• β-lactams are bactericidal agents that kill in a time-dependent fashion, with efficacy dependent on the time that serum concentration remains above the organism's minimal inhibitory concentration (MIC) 1
• Most β-lactams achieve less than 50% of their serum concentration in lung tissue, which affects dosing strategies 1
• β-lactams generally have minimal or short post-antibiotic effect (PAE) against gram-negative bacilli, except for carbapenems (imipenem, meropenem) which demonstrate PAE against organisms like P. aeruginosa 1
• Optimal dosing requires frequent administration or continuous infusion to maintain levels above the MIC for as long as possible 1

Fluoroquinolones (Ciprofloxacin, Levofloxacin)

Fluoroquinolones are bactericidal agents that inhibit bacterial DNA replication by blocking topoisomerase II (DNA gyrase) and topoisomerase IV, enzymes essential for DNA replication, transcription, repair, and recombination. 3

• These agents kill bacteria in a concentration-dependent fashion, killing more rapidly at higher concentrations 1
• Fluoroquinolones exhibit a prolonged post-antibiotic effect (PAE) against gram-negative bacilli, allowing for less frequent dosing 1
• They achieve lung concentrations equal to or exceeding serum concentrations in bronchial secretions, providing excellent tissue penetration 1
• The mechanism of action differs completely from penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines, meaning organisms resistant to these classes may remain susceptible to quinolones 3
• Optimal dosing involves maximizing initial serum concentrations, with once-daily dosing taking advantage of both concentration-dependent killing and the post-antibiotic effect 1

Aminoglycosides (Gentamicin, Tobramycin, Amikacin)

Aminoglycosides bind irreversibly to the 30S ribosomal subunit, causing misreading of mRNA and producing defective proteins, ultimately leading to bacterial cell death. 1

• Specifically, the 3'-OH function reacts with lysine from the S12 protein component of the 30S subunit 2
• This causes alteration in mRNA reading, false translation, cessation of protein biosynthesis, decrease in polyribosomes, and formation of inert 70S ribosomes 2
• Aminoglycosides are bactericidal in a concentration-dependent fashion, killing more rapidly at high concentrations 1
• They demonstrate a prolonged post-antibiotic effect (PAE) against gram-negative bacilli 1
• Once-daily dosing maximizes efficacy by combining concentration-dependent killing with the post-antibiotic effect, though clinical trials show conflicting results regarding toxicity reduction 1

Macrolides and Azalides (Erythromycin, Clarithromycin, Azithromycin)

Macrolides inhibit bacterial protein synthesis by binding to the 23S rRNA of the 50S ribosomal subunit, blocking the transpeptidation/translocation step and preventing assembly of the 50S ribosomal subunit. 1, 4, 5

• Azithromycin specifically binds to the 23S rRNA at positions corresponding to A2058 and A2059 in the E. coli numbering system 5
• These agents are generally bacteriostatic, though they can be bactericidal against autolytic species like pneumococci 1
• Macrolides concentrate in phagocytes and fibroblasts, with intracellular to extracellular concentration ratios exceeding 30:1 after one hour 5
• Azithromycin penetrates gram-negative bacterial cells more effectively than erythromycin due to better permeability across the outer cell envelope 1
• Activity is pH-dependent, with better antibacterial activity in neutral to basic environments; at low pH, macrolides become positively charged and cannot readily cross biological membranes 1

Glycopeptides (Vancomycin)

Vancomycin is bactericidal in a time-dependent fashion, with killing dependent on the time that serum concentration remains above the organism's MIC. 1

• The degree of bacterial killing depends on maintaining adequate drug levels above the MIC rather than achieving high peak concentrations 1
• This time-dependent mechanism requires dosing strategies that maintain therapeutic levels throughout the dosing interval 1

Oxazolidinones (Linezolid)

Linezolid inhibits bacterial protein synthesis through a unique mechanism, and is bacteriostatic in vitro against enterococci. 6

• Linezolid achieves lung concentrations equal to or exceeding serum concentrations in bronchial secretions 1
• The American Heart Association notes the bacteriostatic nature as a potential limitation in serious infections like endocarditis 6
• In immunocompromised patients or deep-seated infections, combination therapy or alternative agents may be considered due to its bacteriostatic activity 6

Ketolides (Telithromycin)

Ketolides have a mechanism similar to macrolides but with higher affinity for the 23S rRNA target binding sites on the 50S ribosomal subunit, providing greater activity against macrolide-resistant strains. 1

• Ketolides exhibit concentration-dependent antimicrobial killing 1
• Structural modifications prevent ribosomal methylase-mediated resistance common with macrolides, and may retain activity against strains with erm determinants 1
• AUC/MIC ratios of approximately 200 correlate with bacteriostatic activity, while ratios ≥1000 are needed for bactericidal activity 1

Tetracyclines (Doxycycline)

Tetracyclines inhibit bacterial protein synthesis by reversibly binding to the 30S ribosomal subunit, preventing binding of transfer RNA (t-RNA). 1

• This mechanism blocks RNA-dependent protein synthesis 1
• Tetracyclines are generally bacteriostatic agents 1

Rifamycins (Rifampin)

Rifampin binds to the β subunit of bacterial RNA polymerase, blocking RNA transcription by suppressing the initiation of chain formation, resulting in bactericidal activity. 1, 2

• Hydroxyl and ketone functions at specific positions link to the β subunit of RNA polymerase, causing conformational changes in the RNA polymerase-DNA complex 2
• This inhibits the catalytic action of the enzyme, stopping RNA messenger and protein synthesis 2
• Rifampin is active against intracellular and extracellular microorganisms, including gram-positive and gram-negative bacteria 1
• Resistance develops rapidly with monotherapy, so it should not be used alone or for prolonged duration 1

Lincosamides (Clindamycin)

Clindamycin binds to the 50S ribosomal subunit of susceptible bacteria, suppressing protein synthesis through a concentration-dependent mechanism. 1

• Despite structural differences from macrolides, clindamycin acts at overlapping ribosomal binding sites 1
• It demonstrates concentration-dependent antimicrobial activity 1