Gentamicin - Drug Monograph

Introduction

Gentamicin is an aminoglycoside antibiotic derived from Micromonospora purpurea. First introduced in the 1960s, it remains a cornerstone in the treatment of serious gram-negative bacterial infections despite the development of newer antimicrobial agents. As a concentration-dependent bactericidal antibiotic, gentamicin requires careful therapeutic drug monitoring due to its narrow therapeutic index and potential for nephrotoxicity and ototoxicity.

Mechanism of Action

Gentamicin exerts its bactericidal effect by binding to the 30S ribosomal subunit of susceptible bacteria, thereby inhibiting protein synthesis. This action results in:

• Misreading of mRNA codons, leading to incorporation of incorrect amino acids into polypeptide chains
• Disruption of the initial complex formation during protein synthesis
• Breakup of polysomes into nonfunctional monosomes

The antibiotic demonstrates concentration-dependent killing, meaning higher peak concentrations result in more rapid and complete bacterial eradication. Gentamicin also exhibits a significant post-antibiotic effect, particularly against gram-negative organisms, allowing continued bacterial suppression even after drug concentrations fall below the minimum inhibitory concentration.

Indications

Gentamicin is FDA-approved for:

• Treatment of serious infections caused by susceptible strains of Pseudomonas aeruginosa, Escherichia coli, Proteus species, Klebsiella-Enterobacter-Serratia species, Citrobacter species, and Staphylococcus species
• Empirical therapy in suspected gram-negative infections before susceptibility results are available
• Synergistic combination with beta-lactam antibiotics for treatment of enterococcal endocarditis
• Treatment of plague (Yersinia pestis) and tularemia (Francisella tularensis)

Common clinical applications include:

• Sepsis and bacteremia
• Hospital-acquired pneumonia
• Complicated urinary tract infections
• Intra-abdominal infections
• Skin and soft tissue infections
• Bone and joint infections
• Meningitis (intrathecal administration)

Dosage and Administration

• Adults: 3-5 mg/kg/day IV or IM, typically administered as a single daily dose
• Extended-interval dosing: 5-7 mg/kg IV every 24 hours (preferred method for most patients with normal renal function)
• Traditional dosing: 1-1.7 mg/kg IV every 8 hours

• CrCl 60-90 mL/min: Administer every 12-24 hours
• CrCl 30-59 mL/min: Administer every 24-48 hours
• CrCl 10-29 mL/min: Administer every 48-72 hours
• Hemodialysis: Administer dose after dialysis session

• Neonates: 2.5 mg/kg IV every 12-24 hours (dosing varies by gestational and postnatal age)
• Elderly: Reduced dosing due to age-related decline in renal function
• Obese patients: Dosing based on adjusted body weight: IBW + 0.4 (TBW - IBW)
• Cystic fibrosis patients: Higher doses (up to 10 mg/kg/day) may be required

• IV infusion over 30-60 minutes
• IM injection into large muscle mass
• Never administer IV push due to risk of neuromuscular blockade

Pharmacokinetics

• Poor oral bioavailability (<1%) due to high polarity
• Well absorbed after intramuscular administration (peak concentrations within 30-90 minutes)

• Volume of distribution: 0.2-0.3 L/kg in healthy adults
• Low protein binding (<30%)
• Poor penetration into cerebrospinal fluid (CSF concentrations ~10-20% of serum levels)
• Achieves therapeutic concentrations in renal cortex, perilymph, and endolymph

• Minimal metabolism; primarily excreted unchanged

• Half-life: 2-3 hours in adults with normal renal function
• Prolonged half-life in renal impairment (up to 70+ hours in ESRD)
• Primarily excreted renally by glomerular filtration
• Removed by hemodialysis (50-60% removal per session)

Contraindications

• History of hypersensitivity to gentamicin or other aminoglycosides
• Cross-sensitivity with other aminoglycosides may occur

Warnings and Precautions

• Risk factors: prolonged therapy, high doses, preexisting renal impairment, advanced age, dehydration, concurrent nephrotoxic agents
• Usually reversible if detected early but may progress to permanent damage

• Vestibular and auditory toxicity may be irreversible
• Higher risk with prolonged therapy, high peak concentrations, concurrent ototoxic drugs
• Monitor for tinnitus, hearing loss, vertigo, dizziness

• May potentiate neuromuscular blockade in patients receiving anesthetic agents or in those with neuromuscular disorders
• Particular caution in patients with myasthenia gravis or Parkinson's disease

• Use during pregnancy only if potential benefit justifies potential risk (Category D)
• Caution in nursing mothers (excreted in breast milk)
• Risk of superinfection and Clostridium difficile-associated diarrhea

Drug Interactions

• Vancomycin
• Amphotericin B
• Cisplatin
• Cyclosporine
• IV contrast media
• Loop diuretics

• Loop diuretics (furosemide, ethacrynic acid)
• Vancomycin
• Platinum-based chemotherapeutic agents

• Anesthetic agents
• Skeletal muscle relaxants
• Botulinum toxin

• Penicillins: Physical incompatibility when co-administered IV; may chemically inactivate gentamicin
• Indomethacin: May reduce gentamicin clearance in neonates

Adverse Effects

• nausea
• vomiting
• rash
• fever
• lethargy

• Nephrotoxicity (5-25%)
• Ototoxicity (2-25%)
• Neurotoxicity (rare)
• Neuromuscular blockade (rare)
• Hypersensitivity reactions
• Blood dyscrasias (rare)
• Hepatotoxicity (rare)

Monitoring Parameters

• Peak concentration: Draw 30 minutes after completion of 30-minute infusion

- Target: 4-10 μg/mL for traditional dosing; 15-20 μg/mL for extended-interval dosing

• Trough concentration: Draw immediately before next dose

- Target: <1-2 μg/mL for traditional dosing; <1 μg/mL for extended-interval dosing

• Serum creatinine at baseline and every 2-3 days during therapy
• Calculate creatinine clearance for dosing adjustments

• Baseline audiogram if possible
• Monitor for subjective symptoms (tinnitus, hearing changes, vertigo)
• Formal audiometric testing if prolonged therapy (>2 weeks)

• Complete blood count
• Liver function tests
• Signs of superinfection
• Neuromuscular function in susceptible patients

Patient Education

• Complete the full course of therapy as prescribed
• Report any hearing changes, ringing in ears, dizziness, or balance problems immediately
• Maintain adequate hydration unless contraindicated
• Inform all healthcare providers about gentamicin use
• Report decreased urine output or changes in urination pattern
• Be aware of potential for diarrhea and report severe or bloody diarrhea
• Do not take any new medications without consulting healthcare provider
• Keep all follow-up appointments for blood tests and monitoring

References

1. Gilbert DN, Chambers HF, Eliopoulos GM, et al. The Sanford Guide to Antimicrobial Therapy. 52nd ed.; 2022. 2. Lexicomp Online. Gentamicin: Drug Information. Wolters Kluwer Clinical Drug Information, Inc.; 2023. 3. Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39(3):650-655. 4. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82-98. 5. FDA Prescribing Information: Gentamicin Injection. Revised December 2022. 6. Begg EJ, Barclay ML, Duffull SB. A suggested approach to once-daily aminoglycoside dosing. Br J Clin Pharmacol. 1995;39(6):605-609. 7. Bartal C, Danon A, Schlaeffer F, et al. Pharmacokinetic dosing of aminoglycosides: a controlled trial. Am J Med. 2003;114(3):194-198.