Amikacin drug profile: By RxVichuZ!

This word document deals with the drug profile of amikacin. Important headings, with respect to its pharmacology, along with a note on important dosage regimens and antimicrobial spectrum, have also been mentioned, with reference to standard textbooks, guidelines and relevant articles.

1. AMIKACIN:

A. CLASS: Aminoglycoside

B. MECHANISM OF ACTION: (Ref.: Katzung, 14
th
ed., Pg.: 826; Antibiotics
manual: A guide to commonly used antimicrobials, 2
nd
ed., Pg.: 9;
Antibiotics simplified, 4
th
ed., Pg.: 98; Goodman & Gilman, 13
th
ed., Pg.:
1039-40)

- Major principle involved: “Irreversible inhibition of protein synthesis  produces
bactericidal effects”
- Amikacin  passively diffuses (via porin channels) across outer membrane of
susceptible organism  drug is actively transported across cell membrane into
cytoplasm (with help of oxygen-dependent process)  drug enters into bacterial cell
 binds to 30S ribosomal protein  produces inhibition of protein synthesis.

- Role of gradient in drug mechanism:

a. Transmembrane electrochemical gradient  supplies energy for oxygen-
dependent process
b. Through above gradient  transport is coupled to a protein pump
c. In the following conditions  electrochemical gradient is blocked, which can
result in inhibition of drug transport:
i. Low extracellular PH (hyperosmolar acidic urine)
ii. Presence of anaerobes.

- Drug transport  enhanced by concurrent usage of cell-wall synthesis inhibitors
(Penicillin/ vancomycin)  justifies co-usage of aforesaid drugs with amikacin!

- Drug  inhibits protein synthesis in 3 ways:

a. Blockage of initiation complex of peptide formation
b. Drug  causes misreading of m-RNA  incorporates incorrect amino acid into
peptide  tantamounts to formation of non-functional protein
c. Polysomes  disintegrates into non-functional monosomes

- Above effects  leads to cell death (bactericidal outcome).

2. C. PHARMACOKINETIC PROFILE: (Ref.: Katzung, 14
th
ed., Pg.: 828-29;
Goodman & Gilman, 13
th
ed., Pg.: 1041-42)

1. ABSORPTION:

- Drug  polar cation  thus, poorly absorbed from GIT
- In cases of GI disease (ulcerations, IBD)  drug absorption increases
- If amikacin is administered into body cavities with serosal surfaces  results in rapid
absorption  high risk of toxicities, like NMB (Neuromuscular blockade)!
- Absorbed rapidly from i.m route
- Peak plasma concentration:
a. Observed within 30-90 mins. of drug administration
b. Usual value is 20-35 µg/ml (with a 7.5 mg/kg dose)

2. DISTRIBUTION:

- Drug  shows polar nature  does not penetrate well into most tissues
- Drug poorly distributed into adipose tissue  demands dosage individualization in
obese patients
- High drug concentration  found at:
a. Renal cortex  results in nephrotoxicity
b. Endolymph & perilymph of inner ear  results in ototoxicity!

- Amikacin is not much efficacious when given for CSF infections (especially via i.v
route) [Kearney and Aweeka, 1999]
- Amikacin  if given to women in late pregnancy  can cause accumulation of drug
in fetal plasma & amniotic fluid!

3. METABOLISM & EXCRETION:

- Minimal metabolism observed
- Excreted via glomerular filtration
- In normal renal function  drug half-life is 2-3 hours
- Drug half-life has been shown to be reduced in patients with Cystic Fibrosis (Mann
et al, 1985)
- In patients with burns  drug loss may occur through burn tissue  warrants
increased drug dosing!

3. - Penicillins with non-renal elimination(piperacillin)  does not inactivate amikacin,
when admixed together in solution (thus, combination can be safely used)

D. ADVERSE EFFECTS (Ref.: Goodman & Gilman, 13
th
ed., Pg.: 1043-44;
Antibiotics manual: A guide to commonly used antimicrobials, 2
nd
ed., Pg.:
9)

1. OTOTOXICITY:

- With amikacin use  vestibular & auditory dysfunction can occur (Guthrie, 2008)
- Amikacin  causes degeneration of hair cells & neurons in cochlea  leads to
hearing loss
- Devastating effects of amikacin in ear  attributed to it higher half-life in otic fluids
(5-6 times greater than that of plasma!)
- Amikacin (along with kanamycin & neomycin)  mainly affects auditory function
- Deafness may occur even weeks after amikacin treatment is discontinued!
- High-pitched tinnitus  first symptom of cochlear toxicity
- If amikacin is not discontinued even after first symptom of cochlear toxicity 
auditory impairment can occur after a few days.
- Tinnitus may continue for several days to weeks, even after treatment cessation
- Initially  sound perception in high-frequency range is lost (thus individuals might
be unaware of symptoms)  later, low-frequency range sound perception is lost.

- LABYRINTHE DYSFUNCTION:

a. Earlier sign: Moderately intense headache (lasting for 1-2 days)
b. Earliest sign  followed by acute stage, in which the following symptoms may
occur:

i. Nausea & vomiting (develop & persist for 1-2 weeks)
ii. Difficulty with equilibrium (develop & persist for 1-2 weeks)
iii. Vertigo in upright position
iv. Reduced ability to perceive termination of movement
v. Difficulty in standing/sitting without visual indication

4. c. Acute stage  followed rapidly & unwarned by chronic labyrinthitis, in which
the following may occur:
i. Ataxia
ii. Difficulty in walking
iii. Difficulty in making sudden movements

d. Chronic form  persists for approx. 2 months
e. Recovery can be expected in 12-18 months (even then, some patients may have
permanent residual damage)
f. With early drug discontinuation  progression into irreversible ototoxicity may
be prevented.

2. NEPHROTOXICITY:

- Reversible renal damage observed in 8-26% of patients
- Amikacin  accumulates & persists in proximal tubular cells results in toxicity
- Reversible damage is observed, since proximal tubular cells have propensity to
regenerate! (Lietman and Smith, 1983).

- Nephrotoxicity is directly proportional to the following:

a. Total amount of drug administered
b. Duration of treatment (de Jager and van Altena, 2002)

- With high, extended interval dosing  reduced nephrotoxicity observed (compared
to that of divided doses)


3. NEUROMUSCULAR BLOCKADE:

- Amikacin  causes acute neuromuscular blockade and apnea (especially in patients
with myasthenia gravis)
- Usually occurs with concurrent administration of anesthetics or other
neuromuscular blocking agents
- Principal features include numbness, skin tingling, convulsions, etc.

5. 4. MISCELLANEOUS ADRs:

- Rare hypersensitivity reactions (skin rashes, eosinophilia, fever, blood dyscrasias,
angioedema, exfoliative dermatitis, etc.)
- Hypomagnesemia
- Hypotension
- Anemia
- Drug (when given intravitreously)  can lead to macular infarction leads to
permanent loss of vision!
- Tremor
- Seizures.



E. MECHANISMS OF RESISTANCE: (Ref.: Katzung, 14
th
ed., Pg.: 827-28)

Include:

1. Bacteria  produces enzyme “transferase”  inactivates the drug, via acetylation,
adenylylation, phosphorylation (very common!)
2. Mutation/ deletion of porin protein  hampers electrochemical gradient 
hampers drug transport process  drug can’t enter into the cell
3. Mutation  causes alteration/ deletion of receptor protein on 30S ribosomal
subunit  drug can’t bind to it.




F. ANTIMICROBIAL SPECTRUM: (Antibiotics simplified, 4
th
ed., Pg.: 98)

1. Good coverage: Gram negative organisms (E. Coli, Klebsiella, Pseudomonas,
Acinetobacter, etc)
2. Moderate coverage(In combination with a beta-lactam/ glycopeptide):
Staphylococci(including MRSA), streptococcus viridans
3. Poor coverage: Atypicals, anaerobes, Gram (+) organisms (as monotherapy).

6. G. THERAPEUTIC DRUG MONITORING: ITS RELEVANCE: (Ref.: Goodman &
Gilman, 13
th
ed., Pg.: 1042)

- Since plasma concentration of amikacin after a given dose varies among patients 
TDM of amikacin is warranted! (Bartel et al, 2003)
- Optimal steady-state concentration: < 10 µg/ml
- Optimal peak plasma concentration: 20-35 µg/ml

- METHOD OF ASSAY:

a. Take 2 plasma samples at long time intervals (e.g.: 2 hours & 12 hours after a
given dose)
b. Calculate clearance
c. Adjust dose as required to achieve therapeutic range.

H. DRUG INTERACTIONS: (Ref.: Goodman & Gilman, 13
th
ed., Pg.: 1044)

1. Amikacin + AMB, vancomycin, ACE-I, cyclosporine, cisplatin  potentiation of
nephrotoxicity of former! (Wood et al, 1986)
2. Amikacin + anesthetics, neuromuscular blocking agents  potentiation of
neuromuscular blocking property of former!
3. Amikacin + ethacrynic acid  potentiation of ototoxicity of former!

7. I. DOSAGE ADJUSTMENTS FOR SPECIAL POPULATIONS: (Ref.:Antibiotics
manual: A guide to commonly used antimicrobials, 2
nd
ed., Pg.: 10)

1. For renal impairment:
- Adjust dose, either by increasing dosage interval or by lowering the dose
- Adjusted dose can be calculated as:

Adjusted dose = (Dose) ×
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- For hemodialysis  give loading dose of 10 mg/kg  follow it up with 2.5-3.75
mg/kg after hemodialysis
- For peritoneal dialysis  2.5 mg/kg/day, i.v
- For CRRT  10 mg/kg loading dose  follow it up with 7.5 mg/kg, every 24-48
hours.

2. For hepatic impairment: Not necessary
3. For children: Use with caution in children
4. In pregnancy: Category “D” (Use only in life-threatening emergencies when no safer
drug alternatives available; positive evidence of human fetal risk!)


J. CLINICAL USES: (Ref.:Antibiotics manual: A guide to commonly used
antimicrobials, 2
nd
ed., Pg.: 10; Goodman & Gilman, 13
th
ed., Pg.: 1045)

- Amikacin is the broadest-spectrum aminoglycoside!
- Since amikacin is resistant to most of aminoglycoside-inactivating enzymes  drug
can be used for initial management of serious nosocomial gram negative bacillary
infections in hospitals (resistant to tobramycin & gentamicin)!
- Effective against Enterobacter, Klebsiella & E. Coli (resistant to gentamicin &
tobramycin)

8. - Used in the treatment of Gram-negative infections in the following:

a. Bacteremia
b. Pneumonia
c. Osteomyelitis
d. Arthritis
e. Meningitis
f. Skin & soft tissue infections
g. Intra-abdominal infections
h. In burns & post-operative infections
i. UTIs

- Other uses include:

a. M.tuberculosis
b. M.avium intracellulare lung disease
c. Nocardia
d. For Gram-positive endovascular infections (in combination with beta-lactams)


K. DOSAGES: (Ref.:Antibiotics manual: A guide to commonly used
antimicrobials, 2
nd
ed., Pg.: 10; Goodman & Gilman, 13
th
ed., Pg.: 1045)

1. Total dose: 15 mg/kg/day (i.v/i.m), OD, or in divided doses, every 8-12 hours
2. Intrathecal dose: 10-40 mg every 24 hours
3. Dose for UTI: 250 mg i.v/i.m; every 12 hours
4. Dose for hospital acquired pneumonia: 20 mg/kg/day, i.v (May add an
antipseudomonal beta-lactam or a carbapenem)
5. Dose for M.avium lung disease(orphan indication): 590 mg/8.4 ml(liposomal
suspension), inhaled orally every day.

9. L. IMPORTANT TIPS FOR HEALTH-CARE PROFESSIONALS: (Ref.:Antibiotics
manual: A guide to commonly used antimicrobials, 2
nd
ed., Pg.: 10;
Antibiotics simplified, 4
th
ed., Pg.: 99; Goodman & Gilman, 13
th
ed., Pg.:
1044)

1. Amikacin is more active against Gram negative rods compared to that of other
aminoglycosides
2. Amikacin  requires oxygen to be active  thus inactive in anaerobic
environments (abscess/ infected bone)
3. Amikacin  shows reduced activity in low PH environments (abscess, respiratory
secretions, etc.)
4. When scheduling dosing for amikacin  focus on IDEAL BODY WEIGHT (and not
TRUE BODY WEIGHT, since overdosing can result in case of obesity)
5. Amikacin is concentration dependent  thus more effective if given at higher doses
for longer intervals

For example, a dose of 15 mg/kg/day is much more worthwhile, as compared to 5
mg/kg/day, TID)

6. i.v dose  should be infused over 60 minutes in order to avoid neuromuscular
blockade

7. Monitoring parameters include:

a. RFT
b. Eighth cranial nerve function
8. For amikacin-induced neuromuscular blockade  use i.v administration of calcium
salt (Sarkar et al, 1992)
9. Amikacin has post antibiotic effect  thus can be used once-daily
10. For Pseudomonas infections  amikacin is preferred over tobramycin &
gentamicin.


VISHNU.R. NAIR,
PHARM.D INTERN,
NATIONAL COLLEGE OF PHARMACY.