Continuing Education Activity

Amikacin is an antimicrobial with 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 sp. and some Mycobacterium spp. (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. This activity covers amikacin, its mechanism, activity spectrum, and its place in an infectious disease regimen. Members of the interprofessional team need to review its indications, coverage, contraindications, and adverse event profile to optimally manage patients with infectious disease.

Objectives:

• Summarize the mechanism of action of amikacin.
• Identify the bacterial coverage and indications for amikacin.
• Review the adverse events of amikacin, including proper monitoring procedures.
• Explain amikacin's place in infectious disease management as it pertains to improving care coordination amongst the interprofessional team and in the context of antimicrobial stewardship.

Indications

Amikacin's niche is because 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 sp. and some Mycobacterium spp. (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 antimicrobials.

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 to the 30 S bacterial ribosome subunit, resulting in interference with a reading of the genetic code and inhibition of protein synthesis, e.g., elicits premature protein termination and incorporation of incorrect amino acid.  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. Aminoglycosides demonstrate bacterial killing that is concentration-dependent and also have a post-antibiotic effect.

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.

Amikacin may retain activity against tobramycin- and gentamicin-resistant strains because of reduced inactivation by bacterial acetylase, adenylase, and phosphorylase. Thus, its routine clinical use should be reserved for difficult to treat serious nosocomial infections.[4]

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 concentrations in the cerebrospinal fluid immediately.[5][6][7]

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 a 12 hr dosing 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 plasma concentrations 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 50 mg/day, usual dose is 30 mg (preservative-free formulation, OFF LABEL)

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

There is also liposomal amikacin undergoing clinical trials to treat respiratory infections in patients with cystic fibrosis and bronchiectasis. In the trials, the liposomal dosage form is being used to treat nontuberculous bacteria and Pseudomonas aeruginosa. Liposomal amikacin is FDA indicated for the treatment of Mycobacterium avium complex (MAC), which is inhaled using a nebulizer for 14 to 20 minutes.

Special Populations

Amikacin use requires great caution in the elderly population who tend to have decreased 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.[8]

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 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 drug formulation.

Amikacin can pass through breast milk and the placenta. Hence it is not recommended in pregnant women 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 systemic 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 receiving neuromuscular blockers because it can prolong muscle paralysis and weakness.[4]

Monitoring

Monitor renal function (BUN/Cr every 1 to 2 days based on the stability of renal function), Ins and Outs (daily), hearing parameters (baseline and weekly audiograms), symptoms of vertigo/dizziness (daily), peak concentrations (conventional dosing, no need in once-daily dosing) and trough concentrations (both conventional and once-daily dosing, repeat every 2 to 3 days and prolong if plasma concentrations are stable.[9]

Conventional Dosing Concentrations

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

Goal Concentrations

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 Concentrations:

• Monitor after the initial dose, no need to wait for four half-lives
• Clinicians can use the Hartford nomogram (multiply drug concentration scale by a factor of 2 to use) to estimate the appropriateness of the once-daily dosing (ODD) regimen.
• Recommend confirmatory trough concentration 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. Avoid potentially toxic prolonged peak concentrations above 35 mcg/mL.

Drug Interactions

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

High-ceiling diuretics like furosemide increase ototoxicity and have the potential to increase the concentration of amikacin, thereby worsening the ototoxicity.

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

Enhancing Healthcare Team Outcomes

Amikacin is a beneficial drug to treat aerobic gram-negative infections. Healthcare workers, including the 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 all clinicians, specialists, nurses, and pharmacists, should all be responsible for assessing treatment effectiveness and monitoring for side effects. [Level 5]