Amikacin
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Amikacin
Drug Class & Overview
Amikacin is a semisynthetic aminoglycoside antibiotic, derived from kanamycin. It is bactericidal and is one of the most clinically useful members of its class, primarily because of its broad resistance to the bacterial enzymes that inactivate other aminoglycosides.
- Katzung's Basic and Clinical Pharmacology, 16th Ed.
- Goodman & Gilman's Pharmacological Basis of Therapeutics
Mechanism of Action
Aminoglycosides, including amikacin, kill bacteria by irreversibly binding to the 30S ribosomal subunit. This has two main effects:
- Fixation of the 30S-50S ribosomal complex at the start codon (AUG) of mRNA, blocking initiation of protein synthesis and forming abnormal "streptomycin monosomes."
- Misreading of mRNA, producing aberrant (non-functional or toxic) proteins, which causes membrane damage and accelerates bacterial killing.
This activity is concentration-dependent (killing proportional to peak concentration). Penetration into the bacterial cell is an aerobic, energy-dependent process - this is why:
-
Strict anaerobes are intrinsically resistant (lack the transport system)
-
Streptococci/enterococci require co-administration with a cell wall-active agent (penicillin, ampicillin, vancomycin) to facilitate aminoglycoside uptake
-
Goodman & Gilman's, Fig. 59-2
-
Medical Microbiology 9e
Spectrum of Activity
| Organism Group | Coverage |
|---|---|
| Gram-negative rods (Enterobacteriaceae) | Excellent - Proteus, Pseudomonas, Enterobacter, Serratia |
| Pseudomonas aeruginosa | Good |
| Acinetobacter spp. | Covered |
| Multidrug-resistant M. tuberculosis | Active (streptomycin-resistant strains) |
| Nontuberculous mycobacteria (NTM/MAC) | Active |
| Anaerobes | None (intrinsic resistance) |
| Streptococci (alone) | Resistant |
Key advantage: Many gram-negative bacteria inhibited at 1-20 mcg/mL. Most multidrug-resistant (MDR) M. tuberculosis strains remain amikacin-susceptible because M. tuberculosis is inhibited at concentrations of 1 mcg/mL or less.
- Katzung's, 16th Ed.
Why Amikacin Has the Broadest Spectrum Among Aminoglycosides
Amikacin is resistant to most aminoglycoside-modifying enzymes (phosphorylases, adenylases, acetylases) that inactivate gentamicin and tobramycin. Structurally, it is a suitable substrate for only a few of these enzymes, making it active against strains resistant to all other aminoglycosides. This is the primary reason it is reserved as a "last-resort" aminoglycoside in clinical practice.
Exception: Kanamycin-resistant strains often show cross-resistance to amikacin (shared enzymatic target). Gentamicin-resistant Enterococcus also confers cross-resistance to amikacin via a bifunctional modifying enzyme.
- Goodman & Gilman's
Pharmacokinetics
| Parameter | Details |
|---|---|
| Route | IV / IM (poor oral absorption, like all aminoglycosides) |
| Distribution | Poor CNS penetration (intrathecal/intraventricular required for CNS infections) |
| Protein binding | Minimal |
| Elimination | Renal - glomerular filtration (dose must be reduced in renal failure) |
| Half-life | ~2 hours (prolonged in renal impairment) |
- Jawetz Melnick & Adelberg's Medical Microbiology 28th Ed.
Dosing
Adults
- General infections: 15 mg/kg/day IV/IM divided Q8-12h (max 1.5 g/day initially)
- MDR Tuberculosis: 15 mg/kg once daily, then intermittent dosing 2-3x/week (always in combination)
- Peak serum level (Q12h dosing): 20-40 mcg/mL; Trough: 4-8 mcg/mL
Pediatric (Harriet Lane)
| Postconceptional Age | Postnatal Age | Dose | Interval |
|---|---|---|---|
| ≤29 wk | 0-7 days | 18 mg/kg | Q48h |
| ≤29 wk | 8-28 days | 15 mg/kg | Q36h |
| ≤29 wk | >28 days | 15 mg/kg | Q24h |
| 30-34 wk | 0-7 days | 18 mg/kg | Q36h |
| 30-34 wk | >7 days | 15 mg/kg | Q24h |
| ≥35 wk | All | 15 mg/kg | Q24h |
- Infant/Child: 15-22.5 mg/kg/24h Q8h IV/IM
- Cystic fibrosis: 30 mg/kg/24h Q8h IV (or high-dose extended interval 30-35 mg/kg Q24h)
Therapeutic Drug Monitoring (TDM) Goals
| Dosing Method | Peak | Trough |
|---|---|---|
| Conventional dosing | 20-30 mg/L (25-30 for CNS, pulmonary, Pseudomonas) | 5-10 mg/L |
| High-dose extended interval (CF) | 80-120 mg/L | <10 mg/L |
| Extended interval for NTM (Q24h) | 20-40 mg/L | <10 mg/L |
- Harriet Lane Handbook, 23rd Ed.
Clinical Uses
- Serious gram-negative infections - including multi-drug resistant strains where gentamicin/tobramycin have failed
- MDR/XDR Tuberculosis - injectable agent for streptomycin-resistant or MDR-TB (always in combination regimen)
- Nontuberculous mycobacteria (NTM/MAC) - part of multi-drug regimen
- Cystic fibrosis - management of chronic Pseudomonas infection
- Febrile neutropenia - empirical coverage
- Intraocular infections - intravitreal amikacin 400 mcg/0.1 mL for endophthalmitis
- Amikacin Liposome Inhalation Suspension (ALIS / Arikayce) - approved in adults for MAC lung disease as part of a multi-drug regimen
- Katzung's; Harriet Lane; Harrison's Principles of Internal Medicine 22E (2025)
Adverse Effects
1. Nephrotoxicity
- Dose-dependent proximal tubular injury
- Risk increased with prolonged therapy, high trough levels, concurrent nephrotoxins (NSAIDs, amphotericin B, cisplatin, cyclosporine), and volume depletion
- Monitor serum creatinine and drug levels
2. Ototoxicity
- Primarily cochlear (auditory) toxicity - high-frequency hearing loss, which may progress to irreversible deafness
- Vestibular toxicity also possible
- Loop diuretics (furosemide) significantly potentiate ototoxicity - avoid concurrent use or use with extreme caution
- Monitor audiometry in prolonged therapy
3. Neuromuscular Blockade
- Rare but can cause respiratory paralysis, especially with concurrent neuromuscular blocking agents or in myasthenia gravis
- Reversible with calcium gluconate or neostigmine
4. Rash
-
Uncommon
-
Katzung's; Harriet Lane; Cummings Otolaryngology
Resistance Mechanisms
- Enzymatic inactivation (most common acquired mechanism) - aminoglycoside-modifying enzymes encoded on resistance plasmids (phosphorylases, adenylases, acetylases). Amikacin's structure is a substrate for only a few of these.
- Impermeability - reduced uptake across cell membrane (slowly increasing in clinical isolates)
- Low ribosomal affinity - mutation of the 30S ribosomal binding site
- Goodman & Gilman's
Special Considerations
- Renal dosage adjustment: Mandatory - dose or interval must be extended based on creatinine clearance
- Obesity: Use adjusted body weight (ABW) for initial dosing: ABW = IBW + 0.4 × (TBW - IBW)
- Cystic fibrosis/burns/febrile neutropenia: Rapidly eliminated - may need higher or more frequent doses
- Neonates on indomethacin (for PDA): Longer dosing intervals needed due to reduced renal clearance
- Pregnancy: Teratogenic potential (aminoglycosides can cause fetal renal/auditory toxicity) - use only when necessary
- Sulfite sensitivity: Injectable formulations may contain sodium bisulfite
Summary Points
- Broadest-spectrum aminoglycoside, reserved for resistant gram-negative infections
- Concentration-dependent killing - peak/MIC ratio drives efficacy
- Requires TDM (therapeutic drug monitoring) in all patients
- Avoid with furosemide (ototoxicity), monitor renal function throughout
- Key second-line injectable for MDR tuberculosis; ALIS (Arikayce) approved for MAC lung disease
Amikacin
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Amikacin
Drug Class
Amikacin is a semisynthetic aminoglycoside antibiotic, derived from kanamycin. It is the broadest-spectrum member of its class and is reserved primarily for infections caused by organisms resistant to gentamicin and tobramycin.
- Katzung's Basic and Clinical Pharmacology, 16th Ed.
Mechanism of Action
Aminoglycosides kill bacteria by irreversibly binding to the 30S ribosomal subunit, producing two effects:
- Initiation block - the 30S-50S complex is fixed at the start codon (AUG) of mRNA; abnormal "monosomes" accumulate and block further translation
- mRNA misreading - aberrant, non-functional proteins are produced; these insert into the cell membrane, increasing permeability and accelerating aminoglycoside uptake - a self-amplifying cycle that leads to bacterial death
This is a concentration-dependent bactericidal effect (killing proportional to peak:MIC ratio).
Penetration across the cytoplasmic membrane is aerobic and energy-dependent, explaining:
-
Intrinsic resistance of strict anaerobes (no oxidative transport system)
-
Poor activity against streptococci/enterococci unless combined with a cell wall-active agent (penicillin, ampicillin, or vancomycin) that facilitates uptake
-
Goodman & Gilman's Pharmacological Basis of Therapeutics; Medical Microbiology 9e
Spectrum of Activity
| Organism | Activity |
|---|---|
| Gram-negative rods (Proteus, Enterobacter, Serratia, E. coli) | Excellent |
| Pseudomonas aeruginosa | Good |
| Acinetobacter spp. | Covered |
| MDR / XDR Mycobacterium tuberculosis | Active (M. tb inhibited at ≤1 mcg/mL) |
| Nontuberculous mycobacteria (MAC, MAb) | Active |
| Anaerobes | None (intrinsic resistance) |
| Streptococci / Enterococci (alone) | Resistant |
Amikacin is the most active aminoglycoside overall - many gram-negative bacteria are inhibited at 1-20 mcg/mL in vitro. Katzung's, 16th Ed.
Why Amikacin Has the Widest Coverage
The key structural feature: amikacin is a substrate for only a few of the aminoglycoside-modifying enzymes (phosphorylases, adenylases, acetylases) encoded on resistance plasmids - the same enzymes that inactivate gentamicin and tobramycin. This makes amikacin active against many multiply-resistant gram-negative bacilli.
Important cross-resistance points:
-
No cross-resistance between streptomycin and amikacin (different enzyme targets)
-
Kanamycin resistance often predicts amikacin resistance (shared enzyme substrate)
-
High-level gentamicin resistance in Enterococcus confers cross-resistance to amikacin (bifunctional enzyme modifies both)
-
Goodman & Gilman's
Pharmacokinetics
| Parameter | Detail |
|---|---|
| Route of administration | IV / IM only (negligible oral absorption) |
| Distribution | Extracellular fluid; poor CNS penetration (intrathecal/intraventricular needed for meningitis) |
| Protein binding | Minimal |
| Elimination | Renal - glomerular filtration |
| Half-life | ~2 hr (markedly prolonged in renal failure) |
| Special populations | Rapidly eliminated in cystic fibrosis, burns, febrile neutropenia - higher/more frequent doses needed |
CNS penetration is poor beyond early infancy. Neonates on indomethacin (for PDA) require longer dosing intervals due to reduced renal clearance. - Harriet Lane Handbook, 23rd Ed.
Dosing
Adults
- Standard infections: 15 mg/kg/day IV/IM ÷ Q8-12h; max initial dose 1.5 g/24 hr
- MDR tuberculosis: 15 mg/kg once daily initially, then 2-3×/week; always in combination
- Peak (Q12h regimen): 20-40 mcg/mL | Trough: 4-8 mcg/mL
For MDR-TB, peak serum concentrations of 30-45 mcg/mL are achieved 30-60 minutes after a 15 mg/kg IV/IM dose. - Katzung's, 16th Ed.
Neonates (Harriet Lane)
| Postconceptional Age | Postnatal Age | Dose | Interval |
|---|---|---|---|
| ≤29 wk | 0-7 days | 18 mg/kg | Q48h |
| ≤29 wk | 8-28 days | 15 mg/kg | Q36h |
| ≤29 wk | >28 days | 15 mg/kg | Q24h |
| 30-34 wk | 0-7 days | 18 mg/kg | Q36h |
| 30-34 wk | >7 days | 15 mg/kg | Q24h |
| ≥35 wk | All | 15 mg/kg | Q24h |
Infants and Children
- General: 15-22.5 mg/kg/24 hr Q8h IV/IM
- Cystic fibrosis (conventional): 30 mg/kg/24 hr Q8h IV
- Cystic fibrosis (high-dose extended interval): 30-35 mg/kg Q24h IV
- NTM (infant/child): 15-30 mg/kg/dose Q24h IV (max 1500 mg/24 hr)
Obesity
Use adjusted body weight: ABW = IBW + 0.4 × (TBW - IBW)
Therapeutic Drug Monitoring (TDM)
| Dosing Regimen | Target Peak | Target Trough | Sampling Time |
|---|---|---|---|
| Conventional dosing | 20-30 mg/L (25-30 for CNS, bone, Pseudomonas, febrile neutropenia) | 5-10 mg/L | Trough 30 min pre-dose 3; peak 30-60 min post-dose 3 |
| High-dose extended interval Q24h (CF) | 80-120 mg/L | <10 mg/L | Trough 30 min pre-dose 2; peak 30-60 min post-dose 2 |
| Extended interval Q24h (NTM) | 20-40 mg/L | <10 mg/L | Same as above |
TDM is mandatory in all patients due to narrow therapeutic index and variability in renal clearance. - Harriet Lane, 23rd Ed.
Clinical Uses
- Serious gram-negative infections - including MDR organisms resistant to gentamicin/tobramycin (Pseudomonas, Acinetobacter, Enterobacteriaceae)
- MDR/XDR tuberculosis - second-line injectable agent for streptomycin-resistant or multidrug-resistant TB; must always be used in a combination regimen
- Nontuberculous mycobacteria (NTM/MAC) - part of multi-drug regimen
- Cystic fibrosis - chronic Pseudomonas infection management
- Febrile neutropenia - empirical gram-negative coverage
- Intravitreal injection (400 mcg/0.1 mL) - bacterial endophthalmitis (Wills Eye Manual)
- Amikacin Liposome Inhalation Suspension (ALIS / Arikayce) - approved in adults for MAC lung disease refractory to guideline-based therapy
ALIS (Arikayce) - Key Clinical Data
The phase 3 CONVERT study showed that adding ALIS to guideline-based therapy in MAC patients with persistent positive cultures produced a 4-fold improvement in culture conversion rates vs. standard care alone. Benefits were seen only when amikacin MIC was ≤64 mcg/mL. Adverse effects were common (>90% had treatment-related events): dysphonia, cough, hemoptysis, dyspnea - leading to ALIS discontinuation in ~17% of patients.
- Fishman's Pulmonary Diseases and Disorders; Harriet Lane, 23rd Ed.
Adverse Effects
1. Nephrotoxicity
- Proximal tubular injury - dose- and duration-dependent
- Risk factors: prolonged therapy, elevated trough levels, concurrent NSAIDs, amphotericin B, cisplatin, cyclosporine, or dehydration
- Monitor SCr and drug levels throughout
2. Ototoxicity
- Primarily cochlear (auditory) - irreversible high-frequency hearing loss that can progress to deafness
- Vestibular toxicity also possible
- Loop diuretics (furosemide, ethacrynic acid) markedly potentiate ototoxicity - avoid concurrent use when possible
- Pre-existing auditory/vestibular impairment is a strong risk factor
3. Neuromuscular Blockade
- Rare but potentially fatal respiratory paralysis
- Highest risk: concurrent neuromuscular blocking agents, anesthesia, myasthenia gravis, hypocalcemia
- Reversible with IV calcium gluconate or neostigmine
4. Other
-
Rash (uncommon)
-
Sulfite sensitivity (injectable contains sodium bisulfite)
-
Katzung's 16th Ed.; Harriet Lane, 23rd Ed.; Cummings Otolaryngology
Resistance Mechanisms
| Mechanism | Detail |
|---|---|
| Enzymatic inactivation (most common) | Plasmid-encoded phosphorylases, adenylases, acetylases modify hydroxyl/amino groups; amikacin is substrate for very few of these |
| Impermeability | Reduced active transport across cytoplasmic membrane (slowly increasing in clinical isolates) |
| Ribosomal binding site mutation | Low-affinity 30S subunit; less common |
Amikacin's structural modifications make it resistant to most inactivating enzymes, but kanamycin resistance typically predicts amikacin resistance because they share key enzyme targets. - Goodman & Gilman's
Key Summary
| Feature | Detail |
|---|---|
| Class | Semisynthetic aminoglycoside |
| Origin | Derived from kanamycin |
| Killing | Concentration-dependent bactericidal |
| Target | 30S ribosomal subunit |
| Unique advantage | Resistant to most aminoglycoside-modifying enzymes |
| Requires TDM | Yes - peak and trough in all patients |
| Main toxicities | Nephrotoxicity, ototoxicity, neuromuscular blockade |
| Key interaction | Loop diuretics (furosemide) - potentiate ototoxicity |
| CNS use | Requires intrathecal/intraventricular for meningitis |
| Role in TB | Second-line injectable for MDR-TB |
| Novel formulation | ALIS (Arikayce) - inhaled, for MAC lung disease |
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