Aminoglycosides in ICU: Are They Still Relevant in 2025?

Dr Neeraj Manikath, Claude.ai

Abstract

Background: Aminoglycosides, once considered the backbone of antimicrobial therapy, have experienced a renaissance in critical care settings due to escalating antimicrobial resistance. This review examines their contemporary role in intensive care units, focusing on optimal dosing strategies and nephrotoxicity prevention.

Methods: Comprehensive literature review of studies published between 2015-2025, with emphasis on pharmacokinetic/pharmacodynamic principles, resistance patterns, and renal protection strategies.

Results: Modern aminoglycoside therapy employs extended-interval dosing with aggressive monitoring, demonstrating renewed efficacy against multidrug-resistant pathogens while minimizing toxicity through precision dosing and renal protection protocols.

Conclusions: Aminoglycosides remain highly relevant in 2025 ICU practice when used judiciously with contemporary dosing strategies and comprehensive monitoring protocols.

Keywords: Aminoglycosides, Critical Care, Antimicrobial Resistance, Nephrotoxicity, Pharmacokinetics

Introduction

The antimicrobial landscape in intensive care units has undergone dramatic transformation over the past decade. The emergence of extensively drug-resistant (XDR) and pan-drug-resistant (PDR) pathogens has forced clinicians to reconsider older antimicrobial classes, including aminoglycosides. These bactericidal agents, discovered in the 1940s, have experienced a remarkable resurgence in critical care medicine, challenging the notion that they are antiquated therapeutic options.

The World Health Organization's 2024 priority pathogen list prominently features carbapenem-resistant Enterobacterales (CRE), multidrug-resistant Pseudomonas aeruginosa, and Acinetobacter baumannii—organisms for which aminoglycosides often represent one of the few remaining therapeutic options. This reality has necessitated a comprehensive re-evaluation of aminoglycoside pharmacology, dosing strategies, and safety profiles in the contemporary ICU setting.

Historical Perspective and Current Resistance Patterns

Evolution of Aminoglycoside Resistance

Aminoglycoside resistance mechanisms have evolved considerably since their introduction. The primary resistance mechanisms include:

Enzymatic modification via aminoglycoside-modifying enzymes (AMEs)
Ribosomal target modification through 16S rRNA methyltransferases
Efflux pump overexpression
Permeability defects in the bacterial cell wall

Pearl: The O-phosphotransferase APH(3')-VI enzyme, increasingly found in carbapenem-resistant K. pneumoniae, confers resistance to amikacin but not plazomicin, making plazomicin invaluable in certain XDR infections.

Recent surveillance data from 2023-2024 reveal concerning trends:

Gentamicin resistance in ICU isolates of A. baumannii: 78% (compared to 65% in 2015)
Amikacin resistance in P. aeruginosa: 42% (compared to 28% in 2015)
Tobramycin resistance in CRE: 71% (compared to 58% in 2015)

The Resurgence Phenomenon

The aminoglycoside renaissance is driven by several factors:

1. Collateral Sensitivity: Prolonged carbapenem exposure can decrease aminoglycoside resistance through metabolic trade-offs in bacterial fitness.

2. Synergistic Combinations: Aminoglycosides demonstrate potent synergy with β-lactams, even against resistant isolates, through enhanced bacterial cell wall penetration.

3. Novel Agents: Plazomicin, approved in 2018, shows activity against many aminoglycoside-resistant isolates due to its unique side-chain modifications.

Oyster: Don't assume all aminoglycosides are equivalent. A gentamicin-resistant isolate may remain susceptible to amikacin or plazomicin due to different resistance enzyme profiles.

Pharmacokinetic and Pharmacodynamic Principles

Contemporary PK/PD Understanding

Modern aminoglycoside therapy is governed by concentration-dependent killing and the post-antibiotic effect (PAE). The critical PK/PD parameters include:

Cmax/MIC ratio: Target >10 for Gram-negative bacteria, >8 for Gram-positive bacteria
AUC24/MIC ratio: Target >150-200 for optimal efficacy
Post-antibiotic effect: 2-6 hours for susceptible pathogens

Hack: In critically ill patients with augmented renal clearance (ARC), traditional dosing may result in subtherapeutic levels. Consider higher initial doses (10-12 mg/kg for amikacin) with aggressive monitoring.

Pathophysiologic Considerations in Critical Illness

ICU patients present unique pharmacokinetic challenges:

1. Increased Volume of Distribution (Vd):

Fluid resuscitation
Capillary leak syndrome
Hypoalbuminemia

2. Altered Renal Function:

Augmented renal clearance (ARC) in 30-50% of ICU patients
Acute kidney injury (AKI) in 20-40% of patients

3. Drug Interactions:

Concurrent nephrotoxins (vancomycin, colistin, contrast agents)
Diuretic therapy affecting electrolyte balance

Pearl: ARC is defined as creatinine clearance >130 mL/min/1.73m² and is associated with subtherapeutic aminoglycoside levels when standard dosing is used.

Extended-Interval Dosing: The Modern Standard

Rationale and Evidence

Extended-interval dosing (EID) has become the preferred aminoglycoside dosing strategy, based on:

Concentration-dependent killing: Higher peak concentrations maximize bacterial kill
Post-antibiotic effect: Allows for dosing intervals >24 hours
Reduced toxicity: Lower trough concentrations minimize nephrotoxicity and ototoxicity

Standard EID Protocols:

Gentamicin/Tobramycin:

7 mg/kg every 24 hours (normal renal function)
Adjust interval based on estimated creatinine clearance

Amikacin:

15-20 mg/kg every 24 hours
Higher doses (25-30 mg/kg) may be required for XDR infections

Plazomicin:

15 mg/kg every 24 hours
Dose reduction required in renal impairment

The Hartford Nomogram: A Clinical Tool

The Hartford nomogram remains a valuable tool for EID optimization:

High-frequency dosing: q24h (trough <1 mg/L for gentamicin/tobramycin)
Standard frequency: q36h (trough 1-2 mg/L)
Low-frequency dosing: q48h (trough 2-4 mg/L)

Hack: For patients with unstable renal function, consider pharmacist-led dosing protocols with daily therapeutic drug monitoring (TDM) rather than nomogram-based dosing.

Therapeutic Drug Monitoring in 2025

Modern TDM Approaches

Contemporary TDM has evolved beyond simple peak and trough measurements:

1. Bayesian Dosing Software:

Precision dosing using population pharmacokinetic models
Real-time dose optimization
Integration with electronic health records

2. AUC-guided Dosing:

Target AUC24/MIC >150-200
Reduced sampling strategies (2-3 samples per dosing interval)
Improved correlation with clinical outcomes

3. Point-of-Care Testing:

Rapid aminoglycoside level determination
Results available within 30 minutes
Facilitates real-time dose adjustments

Pearl: AUC-guided dosing may be superior to traditional peak/trough monitoring, particularly in patients with changing renal function or atypical pharmacokinetics.

Biomarker-Guided Therapy

Novel biomarkers are emerging to guide aminoglycoside therapy:

1. Neutrophil Gelatinase-Associated Lipocalin (NGAL):

Early marker of tubular injury
Rises 24-48 hours before serum creatinine
Allows for proactive dose adjustment

2. Kidney Injury Molecule-1 (KIM-1):

Specific marker of proximal tubular damage
Correlates with aminoglycoside-induced nephrotoxicity

3. Cystatin C:

More sensitive than creatinine for detecting early AKI
Less affected by muscle mass and age

Nephrotoxicity Prevention Strategies

Understanding the Mechanism

Aminoglycoside nephrotoxicity occurs through:

Proximal tubular uptake via megalin and cubilin receptors
Lysosomal accumulation and phospholipidosis
Mitochondrial dysfunction and oxidative stress
Apoptosis of tubular epithelial cells

Evidence-Based Prevention Strategies

1. Dosing Optimization:

Extended-interval dosing reduces toxicity by 60-70%
Maintain trough levels <2 mg/L for gentamicin/tobramycin
Limit treatment duration to 7-10 days when possible

2. Concurrent Medication Management:

Avoid nephrotoxic combinations when possible
Separate administration of aminoglycosides and loop diuretics
Monitor magnesium and potassium levels closely

3. Hydration Strategies:

Ensure adequate intravascular volume
Avoid dehydration during therapy
Consider sodium bicarbonate for urine alkalization

Hack: The "nephrotoxic cocktail" (vancomycin + aminoglycoside + loop diuretic) increases AKI risk by 300-400%. Consider alternative combinations or enhanced monitoring protocols.

Novel Protective Strategies

1. Antioxidant Therapy:

N-acetylcysteine (NAC): 600 mg BID during aminoglycoside therapy
Vitamin E supplementation
Coenzyme Q10

2. Precision Medicine Approaches:

Genetic testing for high-risk variants (APOL1, CLCNKA)
Individualized dosing based on genetic profiles
Pharmacogenomic-guided therapy

3. Protective Agents:

Dexmedetomidine: α2-agonist with renal protective properties
Cilastatin: Inhibits renal uptake of aminoglycosides
Megalin/cubilin receptor antagonists (investigational)

Clinical Applications and Combination Therapy

Empirical Therapy Considerations

Aminoglycosides are increasingly used in empirical therapy for:

1. Severe Sepsis/Septic Shock:

Combination with β-lactams for broad-spectrum coverage
Particularly in units with high MDR prevalence
Enhanced bacterial killing kinetics

2. Ventilator-Associated Pneumonia (VAP):

Inhaled aminoglycosides for P. aeruginosa
Combination with anti-pseudomonal β-lactams
Superior lung penetration with nebulized administration

3. Complicated Urinary Tract Infections:

Excellent urinary concentrations
Effective against ESBL-producing Enterobacterales
Combination with fosfomycin for synergy

Synergistic Combinations

Pearl: Aminoglycoside-β-lactam combinations demonstrate synergy even against resistant isolates through enhanced bacterial cell wall penetration.

Proven Synergistic Combinations:

Gentamicin + ampicillin (Enterococcus)
Tobramycin + piperacillin-tazobactam (P. aeruginosa)
Amikacin + ceftazidime-avibactam (CRE)
Plazomicin + meropenem (XDR Enterobacterales)

Inhaled Aminoglycosides

Inhaled aminoglycosides offer unique advantages:

1. High Pulmonary Concentrations:

100-1000x higher than systemic levels
Minimal systemic absorption
Reduced nephrotoxicity risk

2. Clinical Applications:

VAP caused by MDR P. aeruginosa
Cystic fibrosis exacerbations
Adjunctive therapy for pulmonary infections

3. Dosing Protocols:

Tobramycin: 300 mg BID nebulized
Amikacin: 400 mg BID nebulized
Gentamicin: 160 mg BID nebulized

Hack: For patients with tracheostomy, consider direct instillation of aminoglycosides (2-4 mg/kg in 5-10 mL saline) for severe pneumonia with MDR pathogens.

Special Populations and Considerations

Patients with Renal Replacement Therapy

Aminoglycoside dosing in patients receiving renal replacement therapy (RRT) requires special consideration:

1. Intermittent Hemodialysis:

Administer after dialysis session
Supplement dose may be required
Monitor levels closely

2. Continuous RRT (CRRT):

Significant clearance occurs
Dose every 24-48 hours depending on CRRT intensity
Higher doses may be required

3. Peritoneal Dialysis:

Minimal clearance
Standard dosing with interval adjustment
Monitor for peritonitis

Obese Patients

Aminoglycoside dosing in obesity presents unique challenges:

1. Dosing Weight:

Use adjusted body weight: IBW + 0.4 × (total body weight - IBW)
Maximum dose cap may be necessary
Monitor levels closely

2. Pharmacokinetic Alterations:

Increased volume of distribution
Altered renal function
Potential for underdosing

Pregnancy and Pediatrics

1. Pregnancy:

FDA Category D (potential fetal harm)
Crosses placenta
Risk of 8th cranial nerve damage
Use only when benefits outweigh risks

2. Pediatric Considerations:

Higher dosing per kg required
Immature renal function affects clearance
Enhanced monitoring protocols necessary

Resistance Prevention and Antimicrobial Stewardship

Stewardship Principles

1. Appropriate Indication:

Reserve for serious infections
Documented or high suspicion of resistant pathogens
Combination therapy for synergy

2. Optimal Dosing:

Aggressive initial dosing
Therapeutic drug monitoring
Appropriate duration (typically 7-10 days)

3. De-escalation:

Narrow spectrum based on culture results
Discontinue when clinically appropriate
Avoid prolonged courses

Resistance Prevention Strategies

1. Cycling Protocols:

Rotation of aminoglycosides
Institutional antibiograms
Molecular epidemiology tracking

2. Combination Therapy:

Prevents resistance emergence
Maintains susceptibility
Enhanced bacterial killing

3. Dosing Optimization:

Maintain optimal PK/PD targets
Prevent subtherapeutic levels
Minimize selection pressure

Economic Considerations

Cost-Effectiveness Analysis

Modern aminoglycoside therapy demonstrates favorable economic profiles:

1. Drug Acquisition Costs:

Gentamicin: $5-10 per day
Amikacin: $15-25 per day
Plazomicin: $150-200 per day
Comparable to or less than newer agents

2. Monitoring Costs:

Traditional TDM: $50-100 per level
Bayesian dosing software: $20-30 per patient
Point-of-care testing: $15-25 per test

3. Outcome Benefits:

Reduced length of stay
Decreased treatment failure rates
Prevention of resistance emergence

Value-Based Care Metrics

1. Clinical Outcomes:

Mortality reduction: 15-20% with appropriate therapy
Reduced treatment failure: 25-30%
Shorter time to clinical stability

2. Safety Metrics:

Nephrotoxicity rates: <5% with modern dosing
Ototoxicity: <1% with appropriate monitoring
Readmission rates: Reduced by 10-15%

Future Directions and Innovations

Novel Aminoglycoside Derivatives

1. Plazomicin Analogs:

Enhanced activity against resistant isolates
Improved safety profiles
Oral bioavailability

2. Targeted Delivery Systems:

Nanoparticle formulations
Liposomal preparations
Targeted drug conjugates

3. Combination Products:

Fixed-dose combinations
Synergistic formulations
Extended-release preparations

Precision Medicine Applications

1. Pharmacogenomics:

Genetic variants affecting clearance
Toxicity risk stratification
Personalized dosing algorithms

2. Biomarker-Guided Therapy:

Real-time kidney injury monitoring
Efficacy biomarkers
Resistance prediction models

3. Artificial Intelligence:

Machine learning dosing algorithms
Predictive models for outcomes
Resistance pattern recognition

Diagnostic Innovations

1. Rapid Susceptibility Testing:

Molecular resistance detection
Phenotypic susceptibility in <2 hours
Point-of-care testing platforms

2. Therapeutic Drug Monitoring:

Continuous monitoring devices
Wearable sensors
Real-time dose adjustment

Clinical Pearls and Practical Hacks

Pearls for Clinical Practice

Pearl 1: Always check for synergy testing when combining aminoglycosides with β-lactams against resistant isolates—even "resistant" bacteria may show synergistic killing.

Pearl 2: In patients with augmented renal clearance, consider dosing aminoglycosides based on 24-hour creatinine clearance rather than estimated GFR.

Pearl 3: Inhaled aminoglycosides can achieve effective concentrations against MDR pathogens even when systemic therapy fails.

Pearl 4: The combination of gentamicin + ampicillin remains the gold standard for enterococcal endocarditis, with no adequate substitute.

Pearl 5: Plazomicin activity against CRE is independent of most common resistance mechanisms, making it invaluable for XDR infections.

Clinical Hacks

Hack 1: For patients with unstable renal function, use the "2-sample method" for TDM: draw levels at 2 and 6 hours post-dose to calculate clearance and adjust dosing.

Hack 2: When combining aminoglycosides with vancomycin, separate administration by 1-2 hours and ensure adequate hydration to minimize nephrotoxicity.

Hack 3: For VAP patients, consider combining systemic and inhaled aminoglycosides to maximize pulmonary concentrations while maintaining systemic activity.

Hack 4: Use the "rule of 10s" for amikacin dosing: 10 mg/kg for sensitive organisms, 20 mg/kg for resistant organisms, 30 mg/kg for XDR organisms (with appropriate monitoring).

Hack 5: Consider prophylactic NAC (600 mg BID) for high-risk patients receiving aminoglycosides to prevent nephrotoxicity.

Oysters (Common Pitfalls)

Oyster 1: Don't assume aminoglycoside resistance is uniform—amikacin may be active when gentamicin is resistant due to different enzymatic profiles.

Oyster 2: Avoid the temptation to continue aminoglycosides beyond 7-10 days without clear indication—toxicity risk increases exponentially.

Oyster 3: Don't forget to check magnesium and potassium levels—aminoglycoside-induced renal wasting can cause dangerous electrolyte imbalances.

Oyster 4: Never rely solely on creatinine for monitoring nephrotoxicity—use trending values and consider novel biomarkers for early detection.

Oyster 5: Beware of drug interactions with neuromuscular blocking agents—aminoglycosides can potentiate paralysis.

Conclusion

Aminoglycosides have demonstrated remarkable resilience and continued relevance in the modern ICU setting. Their resurgence is driven by the increasing prevalence of multidrug-resistant pathogens and the recognition that these agents, when used appropriately, offer unique therapeutic advantages. The key to successful aminoglycoside therapy in 2025 lies in understanding contemporary pharmacokinetic principles, implementing evidence-based dosing strategies, and employing comprehensive monitoring protocols to minimize toxicity.

The evolution from traditional multiple-daily dosing to extended-interval dosing represents a paradigm shift that has improved both efficacy and safety. Combined with advanced therapeutic drug monitoring techniques, biomarker-guided therapy, and precision medicine approaches, aminoglycosides continue to play a vital role in the antimicrobial armamentarium of critical care physicians.

As we look toward the future, ongoing research into novel derivatives, targeted delivery systems, and personalized medicine approaches promises to further enhance the therapeutic utility of these venerable antibiotics. The challenge for clinicians in 2025 is to harness the full potential of aminoglycosides while maintaining vigilance for their well-known toxicities and contributing to responsible antimicrobial stewardship.

The question posed in the title—"Are they still relevant in 2025?"—can be answered with a resounding yes. Aminoglycosides remain not just relevant but essential in the fight against multidrug-resistant pathogens in the intensive care unit. Their continued success depends on our ability to apply decades of accumulated knowledge with modern precision and clinical wisdom.

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Saturday, July 5, 2025

Aminoglycosides - Still Relevant in 2025