Gentamicin

Classification & Source

• Katzung's Basic and Clinical Pharmacology, 16th Ed.

Mechanism of Action

1. Attaches to a specific receptor protein (P12 equivalent) on the 30S subunit
2. Blocks the "initiation complex" for peptide chain formation (mRNA + formyl-methionine + tRNA)
3. Causes misreading of mRNA at the recognition region, inserting wrong amino acids into the growing peptide chain - producing nonfunctional proteins
4. Causes breakup of polysomes into monosomes incapable of protein synthesis

• Jawetz, Melnick & Adelberg's Medical Microbiology, 28th Ed.

Spectrum of Activity

• Gram-negative bacteria: Pseudomonas aeruginosa, Enterobacterales (including Proteus, Serratia marcescens, Klebsiella, Enterobacter, Acinetobacter)
• Many gram-positive bacteria: staphylococci (at 2-10 mcg/mL)
• Bactericidal at 0.5-5 mcg/mL for many gram-positives and gram-negatives

• Anaerobes (including Bacteroides species) - requires oxygen-dependent active transport to enter cells
• Streptococci and enterococci as monotherapy (poor cell penetration)
• CNS infections by standard route (requires intrathecal delivery for CSF penetration)

• Katzung's Basic and Clinical Pharmacology, 16th Ed.; Jawetz Medical Microbiology, 28th Ed.

Resistance Mechanisms

• Katzung's Basic and Clinical Pharmacology, 16th Ed.; Jawetz Medical Microbiology, 28th Ed.

Pharmacokinetics

• Absorption: Not absorbed orally (highly polar, charged molecule). Must be given IM or IV for systemic infections
• Distribution: Does not penetrate CNS, vitreous humor, or lung secretions well; poor penetration of infected lung tissue
• Elimination: Almost entirely by glomerular filtration. Half-life is approximately 2-3 hours in normal renal function. Prolonged significantly in renal impairment
• Accumulation: Concentrates in renal cortex and inner ear (perilymph) - basis for organ toxicities
• Altered PK: Eliminated more quickly in patients with cystic fibrosis, neutropenia, and burns (larger volume of distribution)

Clinical Uses

1. Systemic (IV/IM) - serious gram-negative infections

• P. aeruginosa, Enterobacter, Serratia marcescens, Proteus, Acinetobacter, Klebsiella
• Always used in combination (aminoglycosides alone insufficient outside the urinary tract)
• Do NOT use as monotherapy for pneumonia - poor lung tissue penetration + local conditions of low pH and O2

2. Endocarditis (combination therapy)

• Gram-positive endocarditis (streptococcal, staphylococcal, enterococcal) - as adjunct to cell wall-active agents
• Gentamicin + nafcillin/penicillin or vancomycin for serious endocarditis
• Penicillin must NOT be mixed with gentamicin in the same IV line (in vitro inactivation)

3. Topical/Ocular

• Gentamicin 0.1-0.3% creams, ointments, solutions for infected burns, wounds, skin lesions
• Ophthalmic: 0.3% drops/ointment for eye infections
• Note: Topical use selects for resistant bacteria; effectiveness is unclear; topical gentamicin is partly inactivated by purulent exudates

4. Intrathecal/Intraventricular (limited/historical)

• 1-10 mg/day for refractory gram-negative meningitis
• Largely replaced by 3rd-generation cephalosporins; may still be used in drug-resistant or treatment-refractory cases, or severe beta-lactam allergy
• Intraventricular gentamicin was shown to be toxic in neonates

5. Intratympanic (for Meniere's Disease)

• Used as a chemical vestibulotomy in medically refractory Meniere's disease
• A 2025 systematic review (PMID 40421807) confirms its role for vertigo control in Meniere's disease

Dosing

Standard IV/IM dosing:

Neonatal dosing (by postconceptional age):

• Harriet Lane Handbook, 23rd Ed. (Johns Hopkins)

Extended-Interval (Once-Daily) Dosing - Rationale

• Exploits concentration-dependent killing - higher peak = greater bactericidal effect
• Post-antibiotic effect (PAE) - bacteria growth remains suppressed even after drug falls below MIC
• Target peak:MIC ratio of 8-10:1
• Single large dose provides a ~13-hour drug-free period below toxicity threshold, vs. the every-8h regimen which provides only three ~1-hour periods below threshold per day
• Reduces nephrotoxicity and ototoxicity via threshold effect

• Goodman & Gilman's Pharmacological Basis of Therapeutics

Therapeutic Drug Monitoring (TDM)

• Obese patients: use adjusted body weight (ABW) = IBW + 0.4(TBW - IBW) for initial dosing
• Dose reduction required in renal impairment

Adverse Effects

1. Nephrotoxicity

• Occurs in 5-25% of patients receiving gentamicin for >3-5 days
• Usually reversible upon drug discontinuation
• Mechanism: accumulation in proximal tubular cells of renal cortex
• Risk factors: prolonged use, high trough levels, pre-existing renal disease, concurrent nephrotoxins

2. Ototoxicity

• Occurs in 1-5% of patients receiving gentamicin for >5 days
• Predominantly vestibular dysfunction (vertigo, loss of balance) - this contrasts with some other aminoglycosides which primarily affect hearing
• Hearing loss can also occur
• Largely irreversible - genetically determined in part (point mutations in mitochondrial DNA increase susceptibility)
• Potentiated by concurrent loop diuretics (furosemide)
• Administered during pregnancy can cause deafness in the newborn

3. Neuromuscular blockade

• Caution with anesthetics, neuromuscular blocking agents, and neuromuscular disorders

4. Hypersensitivity

• Uncommon

5. Interference with lab tests

• Gentamicin is present as an antibacterial additive in some diagnostic reagents (glucose, urate, bilirubin, CK, ALT, AST assays) and can cause spuriously high gentamicin results on carryover
• Katzung; Goodman & Gilman; Harriet Lane Handbook; Tietz Laboratory Medicine

Drug Interactions

Pregnancy & Safety

• Pregnancy category D (IV use) - can cause deafness in neonates
• Category C for ophthalmic use
• Avoid systemic use in pregnancy unless benefit clearly outweighs risk

Available Formulations

• Injection: 10 mg/mL (2 mL, preservative-free); 40 mg/mL (2, 20 mL)
• Premixed IV bags in NS: 60 mg, 80 mg, 100 mg, 120 mg
• Ophthalmic ointment: 0.3% (Gentak)
• Ophthalmic drops: 0.3%
• Topical ointment: 0.1%
• Topical cream: 0.1%
• Trade names: Gentak, generics (previously Garamycin)

Key Mnemonics / Summary Points

• Gram-negative coverage (Pseudomonas, Enterobacterales) + synergy with beta-lactams for gram-positives
• Concentration-dependent killing (not time-dependent) - once-daily dosing preferred
• Nephrotoxicity (reversible) + Vestibular ototoxicity (irreversible) are hallmark toxicities
• Never mix with penicillins in solution
• Requires TDM (peaks and troughs)
• No oral bioavailability; eliminated renally - adjust dose in renal impairment
• Completely inactive against anaerobes