Amikacin

Article Author:
Omeed Sizar
Article Editor:
Vidya Sundareshan
Updated:
10/12/2019 4:59:37 PM
PubMed Link:
Amikacin

Indications

Amikacin's niche is that it also has activity against more resistant gram-negative bacilli such as Acinetobacter baumanii and Pseudomonas aeruginosa. It also has excellent activity against most aerobic gram-negative bacilli from the Enterobacteriaceae family, including Nocardia and some Mycobacterium (M. avium-intracellulare, M. chelonae, and M. fortuitum). Unlike gentamicin, amikacin does not provide synergistic activity against Enterococcus faecium when combined with beta-lactam antibiotics.[1][2][3]

Amikacin is rarely used alone and often combined with other antibiotics.

Indications Include

  • Hospital-Acquired/Ventilator-Associated/Healthcare-Associated Pneumonia
  • Endophthalmitis, bacterial (intravitreal injection, OFF LABEL)
  • Meningitis (IV) or (Intrathecal/Intraventricular, OFF LABEL)
  • Wound infections caused by susceptible organisms
  • Urinary tract infections (Generally only if caused by resistant organisms, OFF LABEL)
  • Gram-negative Bacteremia/Sepsis (OFF LABEL)

Mechanism of Action

Amikacin binds irreversibly to the 30 S bacterial ribosome subunit, resulting in interference with a reading of the genetic code and inhibition of protein synthesis. Amikacin, as well as the rest of the aminoglycosides, are generally bacteriocidal and probably have an additional mechanism of action, which as yet remains undetermined.

Administration

Amikacin can be administered parenterally or via nebulization. There is no oral formulation of the drug available because the drug is not absorbed from the gastrointestinal tract. Amikacin can be administered intramuscularly when intravenous access is not available. In some patients with meningitis, it can be administered intrathecally and reaches high levels in the cerebrospinal fluid immediately.[4][5][6]

Dosing based on weight (Kg):

  • Underweight or nonobese: dose on ACTUAL body weight (ABW)
  • Obese (ABW/IBW* > or = to 1.25): dose on DOSING body weight (DBW= IBW + 0.4(ABW - IBW)

Adult Dosing:

  • Conventional Dosing: 5mg/kg IV every 8 hours - the elderly often require only each 12 hr interval
  • Adjustment for renal impairment (assuming every 8-hr dosing)

Greater than 50 mL/min (CrCL): no adjustment

30 to 50 mL/min: every 12 to 18 hrs

10 to 29 mL/min: every 18 to 24 hr

Less than 10 mL/min: dose based on levels or consult a pharmacist.

Once Daily Dosing:

Not to be used in patients with ascites, over 20% BSA burns, pregnant patients, or patients on dialysis. (Use conventional dosing or consult a pharmacist.)

15 mg/kg per dose once daily

Adjustment for renal impairment:

60 mL/min (CrCL) and above: every 24 hours

40 to 59 mL/min: every 36 hours

30 to 39 mL/min: every 48 hours

Less than 30mL/min: Use conventional dosing method

Intravitreal: 0.4 mg/0.1 mL of normal saline (preservative-free formulation, OFF LABEL)

Intrathecal/intraventricular: 5 to 50mg/day, usual dose is 30mg (preservative-free formulation, OFF LABEL)

*IBW: Ideal body weight, ABW: Actual body weight, DBW: Dosing body weight, CrCL: creatinine clearance (not GFR)

There is also liposomal amikacin undergoing clinical trials for the treatment of respiratory infections in patients with cystic fibrosis and bronchiectasis. In the trials, the liposomal formula is being used to treat nontuberculous bacteria and pseudomonas aeruginosa.

Special Populations

Amikacin use requires great caution in the elderly population who tend to have a marginal renal function. Also, young children do not have a fully developed renal system, and hence smaller doses are necessary.

Adverse Effects

Major Adverse Effects

Nephrotoxicity is the most common, occurring in 1% to 10% of patients. The nephrotoxicity is reversible if detected early, and the drug discontinued. Renal damage is more likely to occur in dehydrated patients, have a low glomerular filtration rate, have diabetes, sepsis, fever, or are on NSAIDs.[7]

Ototoxicity, vestibular, and auditory (4% to 6%), can occur when using high doses. The patient may complain of loss of balance and hearing loss, which can be permanent if drug therapy continues for prolonged periods. The ototoxicity is believed to be due to the generation of oxidative free radicals which damage the hair cells in the cochlea. Many hospitals now routinely monitor hearing before, during, and after therapy in infants.

Neuromuscular blockade is less common.

Minor Effects

Increase in BUN/Cr (5% to 25%), drug fever, and rash (less common).

Neurotoxicity may present in some patients with paresthesias, tingling, and numbness. 

Contraindications

Patients may demonstrate hypersensitivity to amikacin, other aminoglycosides, or any component of the formulation.

Amikacin can pass through breast milk and the placenta. Hence it is not recommended in women who are pregnant as the drug may cause congenital deafness in the infant. Even though only small amounts pass into breast milk, experts do not recommend breastfeeding while on amikacin.

In general, amikacin is not used in infants. Further, since infants and small children tend to have a large volume of distribution, the drug remains in the circulation for prolonged periods.

Clinicians should not use amikacin in combination with other drugs that have the potential to cause renal and auditory toxicity. The list of medications that should be avoided includes amphotericin B, acyclovir, capreomycin, bacitracin, vancomycin, and cisplatin. Also, amikacin should not be used in patients who are receiving neuromuscular blockers because it can prolong muscle paralysis and weakness.

Monitoring

Monitor renal function (BUN/Cr every 1 to 2 days based on stability of renal function), Ins and Outs (daily), hearing parameters (baseline and weekly audiograms), symptoms of vertigo/dizziness (daily), peak levels (conventional dosing, no need in once-daily dosing) and trough levels (both conventional and once-daily dosing, repeat every 2 to 3 days and prolong if levels are stable.

Conventional Dosing Levels

  • Obtain peak levels (1 hr after the start of a 30 min infusion) after 24 hrs or four half-lives
  • Obtain trough levels (30 min before the next scheduled dose) again after

Goal levels

Peak:

  • Serious infection: 20 to 25 mg/dL
  • Life-Threatening infection: 25 to 30 mg/dL

Trough:

  • Serious infection: 1 to 4 mg/dL
  • Life-Threatening infection: 4 to 8 mg/dL

Once Daily Dosing Levels:

  • Monitor after the initial dose, no need to wait for four half-lives
  • Can use Hartford nomogram (multiply drug level scale by a factor of 2 to use) to estimate appropriateness of once-daily dosing (ODD) regimen.
  • Recommend confirmatory trough level 30 min before the next scheduled dose if using the nomogram: less than 2.5 mg/dL (goal trough with ODD)

Toxicity

No antidote for toxicity is available, only 20% dialyzable; however, this is variable based on hemodialysis filter.

Drug Interactions

Amikacin, when combined with penicillins, can have an additive effect on specific microorganisms.

Amikacin, when combined with carbapenems, can have a synergistic effect against some gram-positive organisms.

Clindamycin, chloramphenicol, and tetracycline can inactivate amikacin and other aminoglycosides.

High-ceiling diuretics like furosemide not only increase ototoxicity themselves, but they also have the potential to increase the concentration of amikacin, thereby worsening the ototoxicity.

Other medications that can increase levels of amikacin in the blood include NSAIDs (especially indomethacin) and quinidine.

Enhancing Healthcare Team Outcomes

Amikacin is a beneficial drug to treat gram-negative infections. Healthcare workers, including nurse practitioners and clinicians who prescribe it, should always check renal function regularly as the drug is nephrotoxic. In many inpatient facilities, the clinician or infectious disease specialist will initiate amikacin as part of the antimicrobial regimen, and then allow the clinical pharmacist to handle dosing and subsequent dose adjustment. Nursing will perform drug administration and should have open access to both the clinicians and the pharmacists. If problems arise, the nurse or pharmacist must reach out to the clinician to adjust therapy. The interprofessional team, including the clinician, specialist, nurse, and pharmacist, should all be responsible for assessing treatment effectiveness and monitoring for side effects. [Level V]


References

[1] Endo A,Nemoto A,Hanawa K,Maebayashi Y,Hasebe Y,Kobayashi M,Naito A,Kobayashi Y,Yamamoto S,Isobe K, Relationship between amikacin blood concentration and ototoxicity in low birth weight infants. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2019 Jan     [PubMed PMID: 30539740]
[2] Nolt VD,Pijut KD,Autry EB,Williams WC,Burgess DS,Burgess DR,Arora V,Kuhn RJ, Amikacin target achievement in adult cystic fibrosis patients utilizing Monte Carlo simulation. Pediatric pulmonology. 2018 Dec 3     [PubMed PMID: 30507069]
[3] Kulengowski B,Clark JA,Burgess DS, Killing activity of meropenem in combination with amikacin against VIM- or KPC-producing Enterobacteriaceae that are susceptible, intermediate, or resistant to amikacin. Diagnostic microbiology and infectious disease. 2018 Nov 10     [PubMed PMID: 30514595]
[4] Sturkenboom MGG,Simbar N,Akkerman OW,Ghimire S,Bolhuis MS,Alffenaar JC, Amikacin Dosing for MDR Tuberculosis: A Systematic Review to Establish or Revise the Current Recommended Dose for Tuberculosis Treatment. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018 Nov 28     [PubMed PMID: 30496466]
[5] Illamola SM,Huynh HQ,Liu X,Bhakta ZN,Sherwin CM,Liou TG,Carveth H,Young DC, Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis. Antimicrobial agents and chemotherapy. 2018 Oct     [PubMed PMID: 30061295]
[6] Liu X,Smits A,Wang Y,Renard M,Wead S,Kagan RJ,Healy DP,De Cock P,Allegaert K,Sherwin C, Impact of Disease on Amikacin Pharmacokinetics and Dosing in Children. Therapeutic drug monitoring. 2018 Oct 15     [PubMed PMID: 30299427]
[7] Arnold A,Cooke GS,Kon OM,Dedicoat M,Lipman M,Loyse A,Chis Ster I,Harrison TS, Adverse Effects and Choice between the Injectable Agents Amikacin and Capreomycin in Multidrug-Resistant Tuberculosis. Antimicrobial agents and chemotherapy. 2017 Sep     [PubMed PMID: 28696239]