Aminoglycoside Antibiotics Used in Pediatric Age
Overview of Aminoglycosides
Aminoglycosides are a class of antibiotics characterized by their ability to inhibit bacterial protein synthesis. They are derived from various Streptomyces species and Micromonospora purpurea.
Key Features:
- Bactericidal activity against many gram-negative aerobic bacteria
- Concentration-dependent killing
- Post-antibiotic effect
- Synergistic activity with beta-lactams against certain gram-positive organisms
Common Aminoglycosides Used in Pediatrics:
- Gentamicin
- Tobramycin
- Amikacin
- Neomycin (topical use)
Streptomycin, kanamycin, and paromomycin are less commonly used in pediatric practice.
Mechanism of Action
Aminoglycosides exert their antibacterial effect through the following mechanisms:
- Ribosomal Binding: They bind irreversibly to the 30S subunit of bacterial ribosomes.
- Protein Synthesis Inhibition: This binding leads to:
- Misreading of mRNA
- Premature termination of protein synthesis
- Production of abnormal or nonfunctional proteins
- Membrane Disruption: Aminoglycosides can also disrupt bacterial cell membranes, enhancing their own uptake and contributing to their bactericidal effect.
Spectrum of Activity:
- Primarily active against aerobic gram-negative bacteria (e.g., Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa)
- Some activity against certain gram-positive organisms (e.g., Staphylococcus aureus)
- Synergistic activity with beta-lactams against some gram-positive bacteria (e.g., enterococci)
- Not effective against anaerobes or intracellular pathogens
Pharmacokinetics
Understanding the pharmacokinetics of aminoglycosides is crucial for their safe and effective use in pediatrics:
- Absorption:
- Poor oral absorption; typically administered parenterally
- Can be absorbed from topical applications on large wound surfaces
- Distribution:
- Primarily distribute in extracellular fluid
- Poor penetration into cerebrospinal fluid (CSF) and bronchial secretions
- Accumulate in renal cortex and inner ear
- Metabolism:
- Not significantly metabolized
- Elimination:
- Primarily excreted unchanged in urine via glomerular filtration
- Half-life in patients with normal renal function: 2-3 hours
- Half-life prolonged in renal impairment, neonates, and burn patients
The volume of distribution can be significantly altered in certain pediatric populations (e.g., neonates, critically ill children), necessitating careful dosing considerations.
Clinical Use in Pediatrics
Aminoglycosides are used in various pediatric infections, often in combination with other antibiotics:
- Sepsis and Septic Shock:
- Empiric therapy in combination with beta-lactams
- Particularly for suspected gram-negative infections
- Neonatal Sepsis:
- Often used as part of initial empiric therapy
- Hospital-Acquired Infections:
- Including ventilator-associated pneumonia
- Complicated Urinary Tract Infections:
- Particularly those caused by Pseudomonas or resistant gram-negative organisms
- Infective Endocarditis:
- In combination with beta-lactams for synergistic effect
- Cystic Fibrosis Exacerbations:
- Particularly for Pseudomonas aeruginosa infections
- Tuberculosis:
- Amikacin or streptomycin may be used in multidrug-resistant tuberculosis
The use of aminoglycosides in pediatrics requires careful consideration of potential toxicities and local resistance patterns.
Dosing Considerations
Dosing of aminoglycosides in pediatrics requires careful consideration of several factors:
- Age and Weight:
- Neonates and young infants require lower mg/kg doses due to immature renal function
- Dosing is typically based on mg/kg body weight
- Renal Function:
- Dose adjustment required in renal impairment
- Regular monitoring of renal function is essential
- Site and Severity of Infection:
- Higher doses may be needed for severe infections or less susceptible organisms
- Dosing Interval:
- Traditional multiple daily dosing vs. extended-interval (once-daily) dosing
- Extended-interval dosing is increasingly used in pediatrics due to potentially reduced toxicity and similar efficacy
General Dosing Guidelines (may vary based on specific indications and institutional protocols):
- Gentamicin/Tobramycin:
- Multiple daily dosing: 2.5 mg/kg/dose every 8 hours
- Extended-interval dosing: 5-7.5 mg/kg/dose every 24 hours
- Amikacin:
- Multiple daily dosing: 5-7.5 mg/kg/dose every 8 hours
- Extended-interval dosing: 15-20 mg/kg/dose every 24 hours
Therapeutic drug monitoring is essential for optimizing efficacy and minimizing toxicity.
Adverse Effects
Aminoglycosides can cause significant adverse effects, particularly with prolonged use or high doses:
- Nephrotoxicity:
- Acute tubular necrosis
- Usually reversible if detected early
- Risk factors: pre-existing renal impairment, prolonged therapy, concurrent nephrotoxic drugs
- Ototoxicity:
- Vestibular and cochlear damage
- Can be irreversible
- May present as hearing loss, tinnitus, or balance disorders
- Neuromuscular Blockade:
- Rare but potentially serious
- Increased risk with concurrent use of neuromuscular blocking agents
- Allergic Reactions:
- Uncommon but can occur
- Skin rashes, fever, eosinophilia
Regular monitoring of renal function, audiometry, and drug levels is crucial to minimize the risk of adverse effects.
Therapeutic Drug Monitoring
Therapeutic drug monitoring (TDM) is essential for optimizing aminoglycoside therapy in pediatrics:
- Peak Concentrations:
- Measured 30-60 minutes after completion of infusion
- Assesses adequacy of dosing
- Target ranges vary by indication and specific aminoglycoside
- Trough Concentrations:
- Measured just before the next dose
- Assesses risk of toxicity
- Generally aim for <2 mg/L for gentamicin and tobramycin, <10 mg/L for amikacin
- Frequency of Monitoring:
- Initially after 2-3 doses
- More frequent monitoring in unstable patients or those with renal impairment
- Extended-Interval Dosing:
- May use single serum level drawn 6-14 hours post-dose
- Interpreted using nomograms or pharmacokinetic software
TDM allows for individualization of therapy, maximizing efficacy while minimizing toxicity.
Antibiotic Resistance
Resistance to aminoglycosides is an increasing concern in pediatric practice:
- Mechanisms of Resistance:
- Enzymatic modification of the antibiotic
- Decreased drug uptake or increased efflux
- Modification of the ribosomal target site
- Prevalence:
- Varies by pathogen and geographic region
- Particularly concerning in Pseudomonas aeruginosa and certain Enterobacteriaceae
- Cross-resistance:
- Resistance to one aminoglycoside may not confer resistance to all
- Amikacin often retains activity against gentamicin-resistant organisms
- Prevention Strategies:
- Judicious use of aminoglycosides
- Appropriate dosing and duration of therapy
- Use in combination with other antibiotics when appropriate
- Regular surveillance of local resistance patterns
Monitoring local resistance patterns is crucial for guiding empiric therapy with aminoglycosides in pediatric infections.
Gentamicin
Gentamicin is one of the most widely used aminoglycosides in pediatric practice.
Key Characteristics:
- Broad spectrum of activity against many gram-negative organisms
- Synergistic activity with beta-lactams against certain gram-positive bacteria
- Relatively low cost
Pediatric Uses:
- Neonatal sepsis (empiric therapy)
- Gram-negative septicemia
- Complicated urinary tract infections
- Infective endocarditis (in combination with beta-lactams)
Dosing in Children:
- Traditional multiple daily dosing:
- Neonates: 2.5 mg/kg/dose every 12-24 hours (depending on gestational and postnatal age)
- Infants and children: 2.5 mg/kg/dose every 8 hours
- Extended-interval dosing:
- 5-7.5 mg/kg/dose every 24 hours (adjust based on serum levels and renal function)
Therapeutic Drug Monitoring:
- Peak levels: 5-10 μg/mL for conventional dosing
- Trough levels: <2 μg/mL before next dose
Advantages:
- Well-established efficacy and safety profile
- Cost-effective
- Good activity against many gram-negative pathogens
- Synergistic with beta-lactams against some gram-positive organisms
Disadvantages:
- Potential for nephrotoxicity and ototoxicity
- Narrow therapeutic index requiring careful monitoring
- Increasing resistance among some pathogens
Special Considerations in Pediatrics:
- Neonatal Use: Gentamicin is commonly used in neonatal sepsis. However, neonates have reduced renal clearance and a larger volume of distribution, necessitating careful dosing and monitoring.
- Once-Daily Dosing: Extended-interval dosing is increasingly used in pediatrics due to potential benefits of reduced toxicity and equal or improved efficacy.
- Concurrent Nephrotoxic Drugs: Care should be taken when using gentamicin with other nephrotoxic drugs (e.g., vancomycin, furosemide).
- Duration of Therapy: Generally limited to 7-10 days to minimize risk of toxicity, unless longer therapy is clinically indicated (e.g., endocarditis).
Tobramycin
Tobramycin is an aminoglycoside with a spectrum of activity similar to gentamicin, but with enhanced activity against Pseudomonas aeruginosa.
Key Characteristics:
- Particularly active against Pseudomonas aeruginosa
- Available in inhaled formulations for use in cystic fibrosis
- Slightly less nephrotoxic than gentamicin
Pediatric Uses:
- Pseudomonas aeruginosa infections, particularly in cystic fibrosis
- Gram-negative septicemia
- Complicated urinary tract infections
- Hospital-acquired pneumonia
Dosing in Children:
- Intravenous administration:
- Traditional dosing: 2.5 mg/kg/dose every 8 hours
- Extended-interval dosing: 5-7 mg/kg/dose every 24 hours
- Inhaled administration (for cystic fibrosis):
- 300 mg twice daily for 28 days, followed by 28 days off
Therapeutic Drug Monitoring:
- Similar to gentamicin
- Peak levels: 5-10 μg/mL for conventional dosing
- Trough levels: <2 μg/mL before next dose
Advantages:
- Superior activity against Pseudomonas aeruginosa compared to gentamicin
- Available in inhaled formulations for targeted therapy in cystic fibrosis
- Slightly lower risk of nephrotoxicity compared to gentamicin
Disadvantages:
- Still carries risk of nephrotoxicity and ototoxicity
- Requires therapeutic drug monitoring
- More expensive than gentamicin
Special Considerations in Pediatrics:
- Cystic Fibrosis: Inhaled tobramycin is a key component of management for Pseudomonas infections in cystic fibrosis patients.
- Bronchiectasis: May be used in non-CF bronchiectasis for Pseudomonas eradication or chronic suppression.
- Combination Therapy: Often used in combination with anti-pseudomonal beta-lactams for synergistic effect.
- Monitoring: Regular audiometry and renal function tests are important, especially with prolonged or repeated courses.
Amikacin
Amikacin is a semi-synthetic aminoglycoside with a broader spectrum of activity and greater resistance to aminoglycoside-modifying enzymes.
Key Characteristics:
- Active against many gentamicin-resistant organisms
- Broader spectrum of activity compared to gentamicin and tobramycin
- Less susceptible to enzymatic inactivation
Pediatric Uses:
- Serious infections caused by multidrug-resistant gram-negative organisms
- Empiric therapy in suspected nosocomial infections
- Neonatal sepsis in areas with high rates of gentamicin resistance
- Multidrug-resistant tuberculosis
Dosing in Children:
- Traditional dosing: 15-22.5 mg/kg/day divided every 8-12 hours
- Extended-interval dosing: 15-20 mg/kg/dose every 24 hours
Therapeutic Drug Monitoring:
- Peak levels: 20-30 μg/mL for conventional dosing
- Trough levels: <10 μg/mL before next dose
Advantages:
- Active against many gentamicin and tobramycin-resistant organisms
- Lower frequency of resistance
- Effective against some mycobacterial species
Disadvantages:
- Higher cost compared to gentamicin and tobramycin
- Still carries risk of nephrotoxicity and ototoxicity
- Requires therapeutic drug monitoring
Special Considerations in Pediatrics:
- Multidrug-Resistant Infections: Amikacin is often reserved for infections caused by organisms resistant to other aminoglycosides.
- Neonatal Use: May be preferred in units with high rates of gentamicin resistance.
- Tuberculosis: Used as part of multidrug regimens for drug-resistant tuberculosis.
- Once-Daily Dosing: Extended-interval dosing is increasingly used, particularly in older children and adolescents.
- Monitoring: Close monitoring of renal function and auditory function is crucial, especially with prolonged use.
