Chapter 35  ·  Module 4  ·  Antibacterial Agents
Aminoglycosides
Mechanism, dosing strategy, toxicity, and resistance at a glance
Abbreviations: MIC = minimum inhibitory concentration  ·  Cmax = peak drug concentration  ·  PAE = post-antibiotic effect  ·  EID = extended-interval dosing  ·  TDM = therapeutic drug monitoring  ·  AME = aminoglycoside-modifying enzyme  ·  HLAR = high-level aminoglycoside resistance  ·  CF = cystic fibrosis
Mechanism of Action
Concentration-Dependent Bactericidal Killing
Step 1
Outer Membrane Binding
Polycationic drug displaces Mg²/Ca² from lipopolysaccharide — membrane disruption begins
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Step 2
Proton Motive Force Transport
Active uptake across inner membrane — requires electron transport chain (anaerobes resistant)
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Step 3
30S Ribosome Binding
Binds decoding site of 16S ribosomal RNA — mRNA misreading, aberrant proteins produced
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Result
Self-Amplifying Lysis
Aberrant proteins insert into inner membrane — more drug entry — rapid, irreversible killing
Key Agents — Spectrum, Toxicity, and Clinical Niche
Agent Spectrum Highlight Principal Toxicity Key Clinical Use
Gentamicin Broad gram-negative; enterococcal synergy Vestibulotoxicity; nephrotoxicity Gram-negative bacteremia; enterococcal endocarditis synergy (if ampicillin-ceftriaxone not used)
Tobramycin Pseudomonas (2–4× more potent than gentamicin) Cochleotoxicity; nephrotoxicity Pseudomonas bacteremia/pneumonia; inhaled suppression in cystic fibrosis
Amikacin Broadest (1-N-acyl group resists most AMEs) Cochleotoxicity; nephrotoxicity Gentamicin/tobramycin-resistant gram-negative; multidrug-resistant organisms
Streptomycin Mycobacterium tuberculosis; Brucella; Yersinia Vestibulotoxicity (severe) Drug-resistant tuberculosis; plague; tularemia; brucellosis
Neomycin Gram-negative decontamination; topical Most cochleotoxic — systemic use absolutely contraindicated Bowel prep; hepatic encephalopathy; topical wound care only
Toxicity Overview
Nephrotoxicity
Proximal Tubular Accumulation
  • Non-oliguric acute kidney injury after 5–10 days
  • Creatinine rise lags tubular injury by 24–48 hours
  • Risk factors: volume depletion, vancomycin co-use, prolonged duration
  • EID reduces risk (drug-free trough allows tubular clearance)
  • Reversible if recognized early
Ototoxicity
Irreversible Hair Cell Destruction
  • Cochlear: high-frequency hearing loss first (above speech range)
  • Vestibular: oscillopsia, imbalance, chronic disequilibrium
  • Gentamicin/streptomycin: vestibular-predominant
  • Amikacin/tobramycin: cochlear-predominant
  • Neomycin: most cochleotoxic — never systemic
  • A1555G mitochondrial variant: severe risk with single dose
Key Rules

Pharmacodynamic driver: Cmax/MIC > 8–10. Anaerobes intrinsically resistant (no proton motive force for uptake). Tobramycin preferred for Pseudomonas. Amikacin preferred when AME resistance suspected.

Vancomycin + aminoglycoside = highest nephrotoxicity risk. Monitor renal function daily. High-level aminoglycoside resistance (gentamicin MIC ≥ 500 mcg/mL) eliminates synergy for endocarditis.