Aminoglycosides

Chemistry & Members

• Streptomyces: streptomycin, neomycin, kanamycin, tobramycin
• Micromonospora: gentamicin, sisomicin
• Semisynthetic: amikacin (from kanamycin), netilmicin (from sisomicin), plazomicin

Mechanism of Action

1. Bind irreversibly to the 30S ribosomal subunit
2. Cause misreading of mRNA → production of aberrant proteins
3. Cause premature dissociation of the ribosome from mRNA → interruption of protein synthesis

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

Spectrum of Activity

Pharmacodynamics

• Concentration-dependent killing: Higher peak concentrations → faster, greater bacterial kill
• Postantibiotic effect (PAE): Bactericidal activity persists for several hours beyond measurable drug levels
• PD index: AUC/MIC ratio (or peak:MIC ratio) is the target linked to bacterial killing
• These properties justify once-daily dosing (extended-interval dosing)

Pharmacokinetics

Dosing Strategies

Once-Daily (Extended-Interval) Dosing

• Preferred in most clinical settings (normalrenal function, CrCl > 60 mL/min)
• Gentamicin/tobramycin: 5–7 mg/kg/day; amikacin/plazomicin: 15 mg/kg/day
• Target: serum concentration < 1 mcg/mL at 18–24 hours post-dose (Hartford nomogram)
• Toxicity risk is equal or lower compared to conventional dosing due to reduced time above toxic trough threshold
• Exceptions: Not well-defined for endocarditis (enterococcal/staphylococcal on prosthetic valve), pregnancy, neonates, obesity

Conventional (Multiple Daily) Dosing

• Gentamicin/tobramycin: peak 8–10 mcg/mL, trough < 2 mcg/mL (optimal < 1 mcg/mL)
• Peak drawn 30–60 min post-dose; trough drawn just before next dose
• Required when CrCl < 60 mL/min

Adverse Effects

1. Nephrotoxicity

• Most common serious adverse effect
• Accumulation in the proximal tubular cells of the renal cortex
• Manifests as non-oliguric renal failure, rising creatinine
• Risk factors: prolonged therapy (>5 days), high doses, elderly, pre-existing renal insufficiency, concurrent nephrotoxins (NSAIDs, contrast, amphotericin B, vancomycin)
• Trough > 2 mcg/mL predicts toxicity
• Generally reversible with discontinuation

2. Ototoxicity

• Cochleotoxicity (hearing loss) and/or vestibulotoxicity (vertigo, ataxia)
• Streptomycin preferentially causes vestibular damage
• Other aminoglycosides preferentially cause cochlear damage
• Often irreversible due to destruction of hair cells in the organ of Corti
• Risk factors: same as nephrotoxicity + loop diuretics (furosemide)
• AUC/MIC graphs below show the overlap between therapeutic effect and nephrotoxicity probability:

Goldman-Cecil Medicine — Effect and nephrotoxicity probability as a function of AUC for organisms with MIC of 0.25, 0.5, and 1.0 mg/L.

3. Neuromuscular Blockade

• Rare; occurs at very high doses
• Curare-like effect → respiratory paralysis
• Reversed by calcium gluconate (promptly) or neostigmine
• Caution in patients with myasthenia gravis or receiving neuromuscular blockers

Resistance Mechanisms

1. Enzymatic modification (most common):
   • Phosphotransferases (APHs), adenylyltransferases (ANTs), acetyltransferases (AACs) modify amino/hydroxyl groups → drug no longer binds ribosome
   • Encoded on plasmids or transposons
   • Amikacin is less susceptible to these enzymes due to structural modifications; plazomicin is the most resistant to modifying enzymes
2. Decreased uptake / permeability defect: Mutation or deletion of outer membrane porins; seen with Pseudomonas; produces low-level cross-resistance to all aminoglycosides
3. Ribosomal binding site mutation: Requires mutation of multiple rRNA gene copies — uncommon; limits streptomycin (single binding site)
4. Active efflux: Occurs only in gram-negative bacteria; rarely clinically significant

Clinical Uses

Key "Must-Know" Points

• Bactericidal, concentration-dependent killers with postantibiotic effect → support once-daily dosing
• No oral bioavailability — parenteral only (or topical/inhaled for local infections)
• Inactive in anaerobic conditions and against obligate anaerobes
• Synergistic with β-lactams against gram-positives (enterococci, streptococci)
• Monitoring: renal function + drug levels (especially with conventional dosing or prolonged therapy)
• Major toxicities: nephrotoxicity (reversible) and ototoxicity (often irreversible)
• Plazomicin: newest agent, retains activity against many aminoglycoside-modifying enzyme–expressing organisms

1. Goodman & Gilman's The Pharmacological Basis of Therapeutics
2. Katzung's Basic and Clinical Pharmacology, 16th Edition
3. Lippincott Illustrated Reviews Pharmacology

• Source the aminoglycosides topic from Goodman & Gilman or Lippincott — both are highly detailed and cover the same content as Tripathi (mechanism, spectrum, PK, toxicity, clinical uses)
• Lippincott in particular uses a presentation style similar to Tripathi — concise, exam-oriented, with clear tables

Aminoglycosides

Lippincott Illustrated Reviews: Pharmacology

A. Mechanism of Action

1. Interfere with assembly of the functional ribosomal apparatus
2. Cause the 30S subunit to misread the genetic code → aberrant, nonfunctional proteins

Figure 30.2 — Mechanisms of action of protein synthesis inhibitors (Lippincott Illustrated Reviews: Pharmacology)

• Concentration-dependent bactericidal activity — efficacy depends on peak (Cmax) / MIC ratio
• Target Cmax: 8–10 × MIC
• Exhibit a postantibiotic effect (PAE) — continued bacterial suppression even after drug falls below MIC; the larger the dose, the longer the PAE
• These two properties are the rationale for high-dose extended-interval (once-daily) dosing, which also reduces nephrotoxicity and increases convenience

B. Antibacterial Spectrum

Synergy: Aminoglycosides are combined with β-lactams for serious gram-positive infections (particularly enterococcal endocarditis). The β-lactam disrupts the cell wall, allowing aminoglycoside entry → bactericidal synergy.

Anaerobes, Streptococcus, Enterococcus are intrinsically resistant when aminoglycosides are used alone (no oxygen-dependent transport possible).

C. Resistance

1. Efflux pumps — active export of drug out of the cell
2. Decreased uptake — altered outer membrane permeability
3. Enzymatic modification and inactivation (most common clinically) — plasmid-encoded enzymes (phosphotransferases, acetyltransferases, adenylyltransferases) inactivate the drug

Each modifying enzyme has its own aminoglycoside specificity, so cross-resistance cannot be assumed. Amikacin and plazomicin are less vulnerable to these enzymes than other members of the class.

D. Pharmacokinetics

Figure 30.8 — Administration and fate of aminoglycosides (Lippincott)

1. Absorption

• Highly polar, polycationic structure → not absorbed orally
• Must be given parenterally (IV, IM) to achieve adequate serum concentrations
• Neomycin exception: Never given parenterally (severe nephrotoxicity); administered topically (skin infections) or orally (GI decontamination before colorectal surgery)
• Intrathecal (IT) route used for CNS infections

2. Distribution

• Hydrophilic → poor tissue penetration; subtherapeutic concentrations in most body fluids
• Does not penetrate the CNS — concentrations inadequate even with inflamed meninges → intrathecal or intraventricular routes required for CNS infections
• Cross the placental barrier → accumulate in fetal plasma and amniotic fluid (teratogenic risk)

3. Elimination

• 90% excreted unchanged in the urine (renal filtration)

• Accumulates in renal dysfunction → dose adjustment mandatory
• Neomycin (oral): excreted unchanged in feces

E. Adverse Effects

1. Ototoxicity

• Vestibular (vertigo, loss of balance) and auditory (hearing loss/deafness) damage
• Directly related to high peak plasma concentrations and duration of treatment
• Drug accumulates in endolymph and perilymph of the inner ear
• Deafness may be irreversible and can affect the developing fetus
• Streptomycin preferentially causes vestibular toxicity (vertigo)
• Potentiated by concurrent cisplatin or loop diuretics (furosemide)

2. Nephrotoxicity

• Retention by proximal tubular cells disrupts calcium-mediated transport processes
• Ranges from mild, reversible renal impairment to severe acute tubular necrosis (potentially irreversible)
• Risk increases with prolonged therapy, high doses, elderly patients, pre-existing renal disease

3. Neuromuscular Blockade

• Associated with rapid concentration increase (high doses given over a short period) or concurrent use of neuromuscular blocking agents
• Patients with myasthenia gravis are particularly at risk
• Reversed promptly by calcium gluconate

4. Allergic Reactions

• Contact dermatitis is a common reaction to topically applied neomycin

Summary Table