Amikacin
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Amikacin
Drug Class & Chemistry
Amikacin is a semisynthetic aminoglycoside antibiotic, derived from kanamycin. It is a polycationic, highly polar molecule. Its key structural feature is a modification that makes it resistant to many of the aminoglycoside-inactivating enzymes that destroy gentamicin and tobramycin, giving it a broader gram-negative spectrum.
- Katzung's Basic and Clinical Pharmacology, 16th Ed.
- Jawetz, Melnick & Adelberg's Medical Microbiology, 28th Ed.
Mechanism of Action
Aminoglycosides (including amikacin) act by binding to the 30S ribosomal subunit of bacteria. The steps:
- Attachment to a specific receptor protein on the 30S subunit
- Blocks the initiation complex (mRNA + formyl methionine + tRNA) for peptide formation
- mRNA misreading on the recognition region - wrong amino acids are inserted, producing nonfunctional proteins
- Breakup of polysomes into monosomes incapable of protein synthesis
The result is an irreversible bactericidal event. This is in contrast to 80S mammalian ribosomes, which are not significantly affected.
- Jawetz, Melnick & Adelberg's Medical Microbiology, 28th Ed.
Spectrum of Activity
| Category | Organisms |
|---|---|
| Gram-negative | Proteus, Pseudomonas, Enterobacter, Serratia, and other Enterobacterales |
| MDR organisms | Many strains resistant to gentamicin and tobramycin |
| Mycobacteria | MDR M. tuberculosis (including streptomycin-resistant strains); NTM (M. avium complex) |
- Many gram-negative bacteria are inhibited at 1-20 mcg/mL in vitro
- Kanamycin-resistant strains may be cross-resistant to amikacin
Pharmacokinetics
| Parameter | Details |
|---|---|
| Absorption | Not orally absorbed (highly polar); must be given IV or IM |
| Distribution | Poor CNS penetration (requires intrathecal/intraventricular for CNS infections); crosses placenta |
| Elimination | >90% excreted unchanged in urine; accumulates in renal failure |
| Special populations | Rapidly eliminated in cystic fibrosis, burns, febrile neutropenia |
- Lippincott Illustrated Reviews: Pharmacology
Dosing
Adult (Standard)
- 500 mg IM/IV every 12 hours (15 mg/kg/day)
- Peak serum levels: 10-30 mcg/mL after 500 mg IM dose
MDR Tuberculosis
- 10-15 mg/kg/day once daily or twice/thrice weekly injection, always in combination
Pediatric (Harriet Lane Handbook, 23rd Ed.)
Neonates:
| Postconceptional Age (wk) | Postnatal Age (days) | Dose (mg/kg/dose) | Interval (hr) |
|---|---|---|---|
| ≤29 | 0-7 | 18 | 48 |
| ≤29 | 8-28 | 15 | 36 |
| ≤29 | >28 | 15 | 24 |
| 30-34 | 0-7 | 18 | 36 |
| 30-34 | >7 | 15 | 24 |
| ≥35 | All | 15 | 24 |
Infants and children: 15-22.5 mg/kg/24 hr divided Q8h IV/IM
Cystic fibrosis (conventional): 30 mg/kg/24 hr Q8h IV
Cystic fibrosis (high-dose extended interval): 30-35 mg/kg/24 hr Q24h IV
Cystic fibrosis (conventional): 30 mg/kg/24 hr Q8h IV
Cystic fibrosis (high-dose extended interval): 30-35 mg/kg/24 hr Q24h IV
Obese patients: Use adjusted body weight: ABW = IBW + 0.4 (TBW - IBW)
Therapeutic Drug Monitoring (TDM)
TDM is imperative for all patients to ensure efficacy and limit toxicity.
| Dosing Method | Peak Target | Trough Target | Sampling Time |
|---|---|---|---|
| Conventional dosing | 20-30 mg/L (25-30 for CNS, pulmonary, Pseudomonas, febrile neutropenia) | 5-10 mg/L | Trough before 3rd dose; peak 30-60 min after 3rd dose |
| High-dose extended interval (CF, Q24h) | 80-120 mg/L | <10 mg/L | Before 2nd dose; peak after 2nd dose |
| Extended interval (NTM, Q84h) | 20-40 mg/L | <10 mg/L | Before 2nd dose; peak after 2nd dose |
- Harriet Lane Handbook, 23rd Ed.
Resistance Mechanisms
- Enzymatic inactivation (most common) - plasmid-mediated enzymes: phosphotransferases (APHs), adenyl-transferases (ANTs), acetyltransferases (AACs) that modify amino and hydroxyl groups. Amikacin is less vulnerable to these enzymes than gentamicin/tobramycin.
- Permeability defect - outer membrane change reduces active transport of the drug into the cell
- Modified ribosomal target - lack of specific receptor protein on 30S subunit (chromosomal resistance)
- Efflux pumps
- Medical Microbiology, 9th Ed.; Lippincott Illustrated Reviews: Pharmacology
Adverse Effects
1. Ototoxicity
- Affects both vestibular and auditory portions of the 8th cranial nerve
- Directly related to high peak concentrations and duration of treatment
- Aminoglycosides accumulate in endolymph and perilymph of the inner ear
- Deafness may be irreversible - can affect fetuses
- Risk increased with: loop diuretics, cisplatin (concurrent ototoxic drugs)
2. Nephrotoxicity
- Aminoglycosides are retained in proximal tubular cells, disrupting calcium-mediated transport
- Ranges from mild reversible impairment to severe acute tubular necrosis
- Risk correlates with trough concentration (accumulation)
- Dose adjustment required in all renal impairment
3. Neuromuscular Blockade
- Associated with rapid infusion or concurrent neuromuscular blockers
- Particularly dangerous in myasthenia gravis
- Reversed by prompt calcium gluconate administration
4. Other
- Rash (including contact dermatitis)
- Neuromuscular blockade with loop diuretics potentiates ototoxicity
Special Formulations
- Amikacin Liposome Inhalation Suspension (ALIS) - Arikayce: Approved in adults as part of multi-drug regimen for Mycobacterium avium complex (MAC) lung disease (refractory/treatment-limiting NTM)
- Intravitreal amikacin (400 mcg/0.1 mL): Used in ophthalmology for bacterial endophthalmitis
- Category in pregnancy: Crosses placenta; potential fetal ototoxicity (classified with caution)
Key Clinical Points
- Reserve amikacin for infections by organisms resistant to gentamicin/tobramycin - this preserves its utility
- Always monitor TDM - serum levels guide both efficacy and toxicity prevention
- Renal dose adjustment is mandatory; longer intervals in patients with reduced GFR
- Synergistic with beta-lactams and carbapenems for MDR gram-negatives
- For CNS infections, CSF penetration is poor - intrathecal/intraventricular routes needed
- Longer dosing intervals required if patient is receiving indomethacin (for PDA in neonates) or has poor cardiac output
Sources: Katzung's Basic and Clinical Pharmacology 16th Ed. | Jawetz Melnick & Adelberg's Medical Microbiology 28th Ed. | Lippincott Illustrated Reviews: Pharmacology | Harriet Lane Handbook 23rd Ed.
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