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Aminoglycosides - A Complete Overview

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1. Introduction

• Polycationic, polar molecules - poor lipid solubility
• Bactericidal activity (concentration-dependent killing)
• Activity primarily against aerobic gram-negative bacilli and some gram-positive organisms
• Narrow therapeutic window - significant toxicity potential

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2. Classification

By Source:

Naming tip: Drugs from Streptomyces end in -mycin; drugs from Micromonospora end in -micin.

By Generation / Clinical Use:

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3. Mechanism of Action

Step 1 - Entry into the bacterial cell:

1. Passive diffusion across the outer membrane via porin channels
2. Active transport across the inner (cell) membrane driven by the transmembrane electrochemical gradient (oxygen-dependent proton pump mechanism)

• Low pH and anaerobic conditions reduce this gradient and impair transport - this is why aminoglycosides are ineffective against anaerobes
• Cell wall-active drugs (penicillin, vancomycin) enhance aminoglycoside uptake, forming the basis of synergy

Step 2 - Ribosomal binding and protein synthesis inhibition:

1. Interference with initiation complex formation - blocks the start of translation
2. mRNA misreading - causes incorporation of incorrect amino acids into the growing peptide chain, producing nonfunctional or toxic proteins
3. Polysome breakup - polysomes fragment into nonfunctional monosomes

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4. Pharmacokinetics

Dosing Strategy - Once-Daily vs. Traditional:

• Preferred in most clinical situations
• Gentamicin/tobramycin: 5-7 mg/kg once daily (if CrCl >60 mL/min)
• Amikacin/plazomicin: 15 mg/kg once daily
• Check levels between 18-24 hours; goal trough <1 mcg/mL
• Avoid in: renal failure (CrCl <60), pregnancy, neonates, enterococcal/staphylococcal prosthetic valve endocarditis

• Peak target: 5-10 mcg/mL (8-10 mcg/mL for serious infections)
• Trough target: <2 mcg/mL (<1 mcg/mL optimal)
• Required for endocarditis combination therapy

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5. Pharmacodynamics

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6. Mechanisms of Resistance

1. Enzymatic inactivation (most common clinically) - transferase enzymes modify aminoglycosides by:
   • Adenylation (adenylyltransferases - ANTs)
   • Acetylation (acetyltransferases - AACs)
   • Phosphorylation (phosphotransferases - APHs)
   • These act on amino and hydroxyl groups of the drug
2. Impaired entry - mutation/deletion of porin proteins or disruption of the electrochemical gradient (also occurs under anaerobic conditions)
3. Altered 30S ribosomal receptor - mutation or deletion of the target protein

Amikacin advantage: Amikacin has a bulky side chain (HABA - 2-hydroxy-4-aminobutyric acid) that sterically protects most enzymatic modification sites, making it active against many gentamicin-resistant strains.

Plazomicin advantage: Plazomicin is designed to overcome most aminoglycoside-modifying enzyme resistance.

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7. Individual Drugs

A. Gentamicin

• Source: Micromonospora purpurea (note: -micin ending)
• Spectrum: Broad gram-negative (E. coli, Klebsiella, Enterobacter, Pseudomonas, Serratia, Proteus); gram-positive synergy (Staph, Enterococcus)
• Indications: Serious gram-negative infections (septicemia, UTI, pneumonia, endocarditis with penicillin, osteomyelitis)
• Dosing (traditional): Peak 5-10 mcg/mL, trough <2 mcg/mL
• Key points:
  • Most widely used aminoglycoside
  • Activity against Pseudomonas aeruginosa
  • Topical use for eye/ear infections
  • Synergy with ampicillin for Enterococcus endocarditis

B. Tobramycin

• Source: Streptomyces tenebrarius
• Spectrum: Similar to gentamicin; superior activity against Pseudomonas aeruginosa
• Indications:
  • Serious Pseudomonas infections
  • Inhaled tobramycin (TOBI) - chronic Pseudomonas infection in cystic fibrosis
  • Eye drops for bacterial conjunctivitis
• Key points:
  • Drug of choice for CF pulmonary exacerbations
  • Similar nephrotoxicity/ototoxicity to gentamicin
  • Cross-resistance with gentamicin is common

C. Amikacin

• Source: Semi-synthetic, derived from kanamycin
• Spectrum: Broadest of the aminoglycosides; active against many gentamicin/tobramycin-resistant strains
• Indications: MDR gram-negative infections, nontuberculous mycobacteria (NTM), TB (second-line)
• Dosing: 15 mg/kg once daily; peaks 20-30 mcg/mL, troughs <10 mcg/mL
• Key points:
  • Reserved for MDR organisms - do NOT use as first-line to preserve activity
  • Also available as inhaled formulation (Arikayce) for NTM lung disease
  • Resistant to most aminoglycoside-modifying enzymes due to HABA side chain

D. Streptomycin

• Source: Streptomyces griseus (first aminoglycoside discovered, 1943)
• Spectrum: M. tuberculosis, Francisella tularensis (tularemia), Yersinia pestis (plague), Brucella, Enterococcus (with penicillin)
• Indications:
  • Tuberculosis (second-line, in resistant cases or initial intensive phase)
  • Plague, tularemia, brucellosis
  • Enterococcal and streptococcal endocarditis (with penicillin)
  • Streptomycin is still first-line for plague and tularemia
• Key points:
  • High rate of resistance in M. tuberculosis now
  • Given IM only (no IV formulation widely available)
  • Most vestibulotoxic of all aminoglycosides (preferentially damages vestibular apparatus)

E. Neomycin

• Source: Streptomyces fradiae
• Spectrum: Gram-negative enteric organisms, some gram-positives
• Indications:
  • Topical only (too toxic for systemic use)
  • Pre-operative bowel preparation (oral - not absorbed, sterilizes gut)
  • Hepatic encephalopathy (oral - reduces ammonia-producing gut bacteria)
  • Triple antibiotic ointments (with polymyxin B and bacitracin)
• Key points:
  • Most nephrotoxic and ototoxic aminoglycoside - contraindicated systemically
  • Contact dermatitis/sensitization is common with topical use
  • Small amounts absorbed orally can cause toxicity if renal failure present

F. Kanamycin

• Source: Streptomyces kanamyceticus
• Spectrum: Gram-negative bacilli; second-line TB activity
• Indications:
  • Pre-op bowel sterilization (oral)
  • Second-line drug for MDR-TB (now largely replaced by amikacin)
  • Limited clinical use
• Key points:
  • Cross-resistance with neomycin
  • Largely superseded by amikacin in clinical practice

G. Paromomycin

• Source: Streptomyces rimosus
• Unique: Antiparasitic aminoglycoside
• Indications:
  • Intestinal amoebiasis (Entamoeba histolytica)
  • Giardiasis, Cryptosporidiosis
  • Leishmaniasis (parenteral)
  • Hepatic encephalopathy (similar to neomycin)
• Key points:
  • Not absorbed orally - acts locally in gut
  • Only aminoglycoside with significant antiparasitic use

H. Plazomicin (Zemdri)

• Source: Semi-synthetic, derived from sisomicin
• Spectrum: Designed for carbapenem-resistant Enterobacteriaceae (CRE), including KPC-producing strains
• Indications: Complicated UTI and pyelonephritis caused by CRE
• Dosing: 15 mg/kg IV once daily (extended-interval strategy only)
• Key points:
  • Newest aminoglycoside approved by FDA
  • Designed to overcome most aminoglycoside-modifying enzymes
  • Does NOT overcome 16S rRNA methyltransferase resistance
  • Reserved for drug-resistant gram-negative infections

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8. Adverse Effects

A. Nephrotoxicity

• Mechanism: Aminoglycosides concentrate in renal cortex proximal tubule cells. They bind to phospholipids, cause membrane damage, lysosomal disruption, and proximal tubular cell necrosis.
• Manifestation: Non-oliguric acute kidney injury; rise in serum creatinine; decreased creatinine clearance
• Onset: After 5-7 days of therapy typically
• Risk factors: Pre-existing renal disease, prolonged therapy, high trough levels, advanced age, volume depletion, concurrent nephrotoxins (NSAIDs, amphotericin B, cisplatin, vancomycin), liver disease
• Monitoring: BUN/creatinine regularly; keep troughs <2 mcg/mL (gentamicin/tobramycin) or <10 mcg/mL (amikacin)
• Key point: Usually reversible on discontinuation. ODD (once-daily dosing) is less nephrotoxic.
• Most nephrotoxic: Neomycin > gentamicin = tobramycin > amikacin > streptomycin

B. Ototoxicity

• Damage is often irreversible - cochlear hair cells cannot regenerate
• Risk factors: High doses, prolonged therapy, renal failure, pre-existing hearing loss, concurrent ototoxins (loop diuretics - furosemide, ethacrynic acid, cisplatin), genetic susceptibility (mitochondrial 12S rRNA mutations)
• High-frequency hearing loss may go undetected until advanced
• Audiometric monitoring recommended for prolonged courses

C. Neuromuscular Blockade

• Mechanism: Aminoglycosides inhibit presynaptic acetylcholine release and block postsynaptic nicotinic receptors
• Risk: When given rapidly IV or during surgery; enhanced by neuromuscular blocking agents (curare, succinylcholine)
• Manifestation: Acute flaccid paralysis, respiratory arrest
• Treatment: IV calcium gluconate reverses blockade
• Caution: Avoid or use extreme care in myasthenia gravis patients

D. Other Effects

• Hypersensitivity: Rare; contact dermatitis with topical neomycin is common
• Hypomagnesemia: Prolonged therapy causes renal magnesium wasting
• Fetal toxicity: Cross placenta - can cause irreversible VIII nerve damage in fetus (vestibular and cochlear); Category D in pregnancy
• Superinfection: Oral neomycin/kanamycin can cause candidal overgrowth

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Summary Table

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