Historical Timeline

The discovery of streptomycin

Nomenclature convention

“-mycin” suffix

• Derived from Streptomyces species
• Examples: Streptomycin, Neomycin, Kanamycin, Tobramycin

“-micin” suffix

• Derived from Micromonospora species
• Examples: Gentamicin, Sisomicin, Plazomicin

Currently FDA-approved agents

Streptomycin: Limited availability (TB, plague, tularemia)

Chemical structure overview

Structural classification

Streptidine-containing:

• Streptomycin (unique structure)

2-Deoxystreptamine (4,5-disubstituted):

• Neomycin, Paromomycin

2-Deoxystreptamine (4,6-disubstituted):

• Kanamycin, Amikacin, Tobramycin
• Gentamicin, Sisomicin, Plazomicin

Key chemical properties

• Polycationic at physiological pH
• Highly polar (water soluble)
• Heat stable
• Not absorbed orally (< 1%)
• Not metabolized (excreted unchanged)

These properties directly influence:

• Distribution (limited to extracellular fluid)
• Elimination (renal, GFR-dependent)
• Drug interactions (binding to cell membranes)

Aminoglycosides:MOA

Why aminoglycosides are bactericidal

Unique among ribosomal inhibitors:

Reason: Mistranslated membrane proteins cause irreversible damage

Concentration-dependent killing

Higher peak concentrations = Greater bacterial kill

Post-Antibiotic Effect (PAE)

Definition: Continued suppression of bacterial growth after drug removal

Duration: 3-8 hours for gram-negative bacteria

Clinical implication: Supports extended-interval dosing

PK/PD target parameters

Historical target:

• C_max/MIC ratio ≥ 8-10

Current understanding:

• AUC/MIC is primary efficacy driver
• Target AUC/MIC: 80-120 (organism-dependent)

For extended-interval dosing:

• Target peak: 15-20 mg/L (gentamicin/tobramycin)
• Target peak: 56-64 mg/L (amikacin)
• Target trough: Undetectable (< 1 mg/L)

Synergy with β-lactams

Spectrum of activity: Overview

Agent selection by organism

Plazomicin: Overcoming resistance

Designed to evade:

• Aminoglycoside-modifying enzymes (AMEs)
• Most common resistance mechanism

Active against:

• CRE (carbapenem-resistant Enterobacteriaceae)
• ESBL producers
• Most aminoglycoside-resistant strains

Limitations:

• Inactivated by 16S rRNA methyltransferases
• More expensive than legacy agents

Resistance mechanisms

Clinical indications

Primary indications (usually combination therapy):

• Sepsis/septic shock
• Hospital-acquired/ventilator-associated pneumonia
• Complicated intra-abdominal infections
• Complicated urinary tract infections
• Neutropenic fever
• Infective endocarditis

Additional clinical uses

• Tuberculosis (MDR-TB regimens)
• NTM infections (MAC, M. abscessus)
• Surgical prophylaxis (GI/GU procedures)
• Orthopedic cement (arthroplasty)
• Ophthalmic infections (topical)
• Cystic fibrosis (inhaled tobramycin)
• Selective digestive decontamination

Endocarditis: Synergy dosing

Enterococcal endocarditis:

• Ampicillin + Gentamicin
• Gentamicin 3 mg/kg/day divided q8h
• Duration: 4-6 weeks (gent for 2-4 weeks)
• Check for high-level resistance (MIC > 500)

Staphylococcal endocarditis (native valve):

• Optional gentamicin × 3-5 days
• Controversial benefit vs. toxicity risk

Empiric therapy: Neutropenic fever

Traditional regimen:

• Anti-pseudomonal β-lactam + aminoglycoside

Current guidelines (IDSA 2010):

• Monotherapy often sufficient (cefepime, piperacillin-tazobactam, anti-pseudomonal carbapenem)
• Add aminoglycoside if:
  • Hemodynamic instability
  • Suspected resistant gram-negative
  • High local resistance rates

Extended-interval vs. Traditional dosing

Extended-interval is preferred for most indications

Extended-Interval Dosing Regimens

Use actual body weight unless obese

Traditional dosing (Synergy)

Target peaks: 3-4 mg/L

Target troughs: < 1 mg/L

Used for:

• Enterococcal endocarditis
• Staphylococcal endocarditis (if used)
• Gram-positive synergy

Dosing in obesity

Definition of obesity for dosing:

• Actual weight > 120% of ideal body weight, OR
• BMI ≥ 30 kg/m²

Calculate adjusted body weight (ABW):

\[ABW = IBW + 0.4 \times (Actual - IBW)\]

Ideal body weight (IBW):

• Males: 50 kg + 2.3 kg per inch over 5 feet
• Females: 45.5 kg + 2.3 kg per inch over 5 feet

Obesity dosing example

Patient: 180 kg male, 5’10” (70 inches)

Step 1: Calculate IBW \[IBW = 50 + 2.3(70-60) = 73 kg\]

Step 2: Calculate ABW \[ABW = 73 + 0.4(180-73) = 73 + 42.8 = 115.8 kg\]

Step 3: Calculate dose \[Gentamicin = 7 mg/kg \times 116 kg = 812 mg\]

Round to 800 mg IV q24h

Dosing in renal impairment

Key principle: Aminoglycoside clearance ≈ GFR

Alternative: Reduce dose, maintain interval

Extended-interval- monitoring

Hartford nomogram

Hemodialysis dosing

Conventional hemodialysis:

• Dose q48-72h (non-dialysis days)
• Give after dialysis
• OR give 50% supplemental dose post-dialysis

High-flux hemodialysis:

• Greater drug removal
• May need larger supplemental doses
• TDM essential

Measure levels to guide dosing

CRRT dosing

Continuous renal replacement therapy:

• Drug clearance ≈ effluent rate
• Typical: CrCl equivalent of 10-50 mL/min
• Use standard doses with extended intervals (q24-48h)
• TDM mandatory

Nephrotoxicity: mechanism

Nephrotoxicity: Risk factors

Patient factors:

• Pre-existing renal disease
• Advanced age
• Volume depletion
• Hypotension

Drug factors:

• Duration > 5-7 days
• Elevated trough concentrations
• Total cumulative dose
• Concurrent nephrotoxins

Concurrent nephrotoxins:

• Amphotericin B, vancomycin, NSAIDs
• IV contrast, cisplatin, cyclosporine

Ototoxicity: Two forms

Cochlear toxicity (hearing loss):

• High-frequency hearing loss first
• May progress to speech frequencies
• Often irreversible
• Associated with: amikacin, kanamycin, neomycin

Vestibular toxicity:

• Vertigo, nystagmus, ataxia
• May improve with time/compensation
• Associated with: gentamicin, streptomycin, tobramycin

Ototoxicity: mechanism

Genetic risk: MT-RNR1 mutation

m.1555A>G mitochondrial mutation:

• Prevalence: ~1 in 500 individuals
• Makes mitochondrial ribosome resemble bacterial ribosome
• Single dose can cause permanent deafness

Implications:

• Point-of-care testing available
• Being implemented for neonatal screening
• Family history of aminoglycoside-induced deafness

Neuromuscular blockade

Mechanism:

• Inhibition of presynaptic acetylcholine release
• Blockade of postsynaptic receptor

Risk factors:

• Myasthenia gravis
• Concurrent neuromuscular blockers
• Hypocalcemia, hypomagnesemia
• Rapid IV infusion

Management:

• Calcium gluconate
• Neostigmine (limited efficacy)

Drug interactions

When is TDM Needed?

Always recommended:

• Therapy > 3-5 days
• Renal impairment (any degree)
• Critical illness
• Obesity
• Burns
• Pregnancy
• Elderly patients

Optional (short course, normal renal function):

• Duration ≤ 3 days
• Stable patients

Peak and trough Targets

Extended-interval dosing:

Traditional dosing (synergy):

Sample timing approaches

Peak level:

• Draw 30-60 minutes after end of infusion
• Ensures distribution phase complete

Trough level:

• Draw within 30 minutes before next dose

Two-level kinetics:

• Both samples in post-distribution phase
• Separated by at least 1.5 half-lives
• Allows calculation of individual PK parameters

Interpreting TDM results

Elevated peak:

• May indicate distribution issue
• Verify weight used for dosing
• Consider reducing dose

Elevated trough:

• Extend dosing interval
• Consider reducing dose
• Evaluate renal function
• Higher toxicity risk

Both elevated:

• Likely renal impairment
• Recalculate using current renal function

TDM methods comparison

Bayesian methods: Incorporate population PK + patient covariates

Practical TDM approach

Day 1: Give loading dose based on weight/renal function

Day 2-3: Draw levels

• If using nomogram: single level at 6-14 hours
• If using PK: peak (30 min post) + trough

Adjust based on results:

• Low peak → Increase dose
• High trough → Extend interval
• Calculate patient-specific parameters

Repeat: Every 3-5 days or with renal function change

Case 1: Gram-Negative Sepsis

Patient: 72-year-old male, 80 kg, SCr 1.2 mg/dL

Diagnosis: E. coli bacteremia, septic shock

Current therapy: Piperacillin-tazobactam

Question: Should you add an aminoglycoside?

Case 2: Enterococcal endocarditis

Patient: 55-year-old female, 65 kg, native valve endocarditis

Culture: Enterococcus faecalis, susceptible to ampicillin

Question: What gentamicin regimen?

Case 3: Obesity

Patient: 145 kg female, 5’4”, BMI 49

Diagnosis: Pseudomonas pneumonia

Question: How do you dose tobramycin?

Case 4: Renal impairment

Patient: 70 kg male, CrCl 35 mL/min

Need: Gentamicin for gram-negative coverage

Question: Initial regimen?

Case 5: Cystic fibrosis

Patient: 28-year-old with CF, P. aeruginosa exacerbation

Current weight: 55 kg

Question: Tobramycin dosing considerations?

Inhaled aminoglycosides

Indications:

• Cystic fibrosis (chronic P. aeruginosa)
• VAP (adjunctive therapy)
• NTM pulmonary disease

Formulations:

Key takeaways: Mechanism

• Concentration-dependent bactericidal activity
• Bind to 30S ribosomal subunit
• Cause mistranslation → defective proteins
• Post-antibiotic effect of 3-8 hours
• Synergistic with cell wall-active agents
• AUC/MIC is primary PK/PD driver

Key takeaways: Clinical use

• Primarily for gram-negative infections
• Usually combination therapy
• Extended-interval dosing preferred
• Short courses (3-5 days) when possible
• Reserve for serious infections/MDR organisms
• Plazomicin for CRE

Key takeaways: Dosing

• 5-7 mg/kg q24h (gentamicin/tobramycin)
• 15-20 mg/kg q24h (amikacin)
• Use adjusted body weight in obesity
• Extend interval in renal impairment
• Loading dose independent of renal function
• TDM for courses > 3 days

Key takeaways: Safety

• Nephrotoxicity usually reversible
• Ototoxicity may be permanent
• Target undetectable troughs
• Monitor renal function
• Avoid concurrent nephrotoxins
• Consider genetic screening (MT-RNR1)

Summary: The “Aminoglycoside Checklist”

✓ Is an aminoglycoside appropriate?

✓ Which agent? (Based on organism/susceptibility)

✓ Correct weight for dosing? (ABW if obese)

✓ Renal function assessed?

✓ Drug interactions reviewed?

✓ TDM plan in place?

✓ Expected duration defined? (Keep short!)

✓ Monitoring for toxicity?