Amikacin

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Amikacin may be confused with Amicar®, anakinra
Amikin® may be confused with Amicar®, Kineret®

PHARMACOLOGIC CATEGORY
Antibiotic, Aminoglycoside

DOSING: ADULTS — Individualization is critical because of the low therapeutic index

Note: Use of ideal body weight (IBW) for determining the mg/kg/dose appears to be more accurate than dosing on the basis of total body weight (TBW)
In morbid obesity, dosage requirement may best be estimated using a dosing weight of IBW + 0.4 (TBW - IBW)
Initial and periodic peak and trough plasma drug levels should be determined, particularly in critically-ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (eg, cystic fibrosis, burns, or major surgery). Manufacturer recommends a maximum daily dose of 15 mg/kg/day (or 1.5 g/day in heavier patients). Higher doses may be warranted based on therapeutic drug monitoring or susceptibility information.

Usual dosage range: I.M., I.V.: 5-7.5 mg/kg/dose every 8 hours
Note: Some clinicians suggest a daily dose of 15-20 mg/kg for all patients with normal renal function. This dose is at least as efficacious with similar, if not less, toxicity than conventional dosing.

Indication-specific dosing:
Endophthalmitis, bacterial (unlabeled use): Intravitreal: 0.4 mg/0.1 mL NS in combination with vancomycin
Hospital-acquired pneumonia (HAP): I.V.: 20 mg/kg/day with antipseudomonal beta-lactam or carbapenem (American Thoracic Society/ATS guidelines)
Meningitis(Pseudomonas aeruginosa): I.V.: 5 mg/kg every 8 hours (administered with another bacteriocidal drug)
Mycobacterium fortuitum, M. chelonae, or M. abscessus: I.V.: 10-15 mg/kg daily for at least 2 weeks with high dose cefoxitin

DOSING: PEDIATRIC — Usual dosage range: Infants and Children: I.M., I.V.: 5-7.5 mg/kg/dose every 8 hours

(For additional information see "Amikacin: Pediatric drug information")

Note: Individualization is critical because of the low therapeutic index

Use of ideal body weight (IBW) for determining the mg/kg/dose appears to be more accurate than dosing on the basis of total body weight (TBW)
In morbid obesity, dosage requirement may best be estimated using a dosing weight of IBW + 0.4 (TBW - IBW)
Initial and periodic peak and trough plasma drug levels should be determined, particularly in critically-ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (eg, cystic fibrosis, burns, or major surgery). Manufacturer recommends a maximum daily dose of 15 mg/kg/day (or 1.5 g/day in heavier patients). Higher doses may be warranted based on therapeutic drug monitoring or susceptibility information.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — Some patients may require larger or more frequent doses if serum levels document the need (ie, cystic fibrosis or febrile granulocytopenic patients).
Clcr ≥ 60 mL/minute: Administer every 8 hours
Clcr 40-60 mL/minute: Administer every 12 hours
Clcr 20-40 mL/minute: Administer every 24 hours
Clcr <20 mL/minute: Loading dose, then monitor levels

Dialyzable (50% to 100%)

Administer dose postdialysis or administer 2/3 normal dose as a supplemental dose postdialysis and follow levels.

Peritoneal dialysis effects: Dose as for Clcr <20 mL/minute: Follow levels.

Continuous arteriovenous or venovenous hemodiafiltration effects: Dose as for Clcr 10-40 mL/minute: Follow levels.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution, as sulfate: 50 mg/mL (2 mL); 250 mg/mL (2 mL, 4 mL)

DOSAGE FORMS: CONCISE
Injection, solution: 50 mg/mL (2 mL); 250 mg/mL (2 mL, 4 mL)

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — Administer around-the-clock to promote less variation in peak and trough serum levels. Do not mix with other drugs, administer separately.

I.M.: Administer I.M. injection in large muscle mass.

I.V.: Infuse over 30-60 minutes.

Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.

COMPATIBILITY — Stable in dextran 75 6% in NS, D5LR, D51/4NS, D51/3NS, D51/2NS, D5NS, D10NS, D5W, D10W, D20W, mannitol 20%, 1/4NS, 1/2NS, NS; variable stability (consult detailed reference) in peritoneal dialysis solutions.

Y-site administration: Compatible: Acyclovir, alatrofloxacin, amifostine, amiodarone, amsacrine, aztreonam, cefpirome, cisatracurium, cyclophosphamide, dexamethasone sodium phosphate, diltiazem, docetaxel, enalaprilat, esmolol, etoposide, filgrastim, fluconazole, fludarabine, foscarnet, furosemide, gatifloxacin, gemcitabine, granisetron, idarubicin, IL-2, labetalol, levofloxacin, linezolid, lorazepam, magnesium sulfate, melphalan, midazolam, morphine, ondansetron, paclitaxel, perphenazine, remifentanil, sargramostim, teniposide, thiotepa, vinorelbine, warfarin, zidovudine. Incompatible: Allopurinol, amphotericin B cholesteryl sulfate complex, hetastarch, propofol.

Compatibility in syringe: Compatible: Clindamycin, doxapram. Incompatible: Heparin.

Compatibility when admixed: Compatible: Amobarbital, ascorbic acid injection, bleomycin, calcium chloride, calcium gluconate, cefepime, cefoxitin, chloramphenicol, chlorpheniramine, cimetidine, ciprofloxacin, clindamycin, colistimethate, dimenhydrinate, diphenhydramine, epinephrine, ergonovine, fluconazole, furosemide, hyaluronidase, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, lincomycin, metaraminol, metronidazole, metronidazole with sodium bicarbonate, norepinephrine, pentobarbital, phenobarbital, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine, ranitidine, sodium bicarbonate, succinylcholine, vancomycin, verapamil. Incompatible: Amphotericin B, ampicillin, cefazolin, chlorothiazide, heparin, phenytoin, thiopental, vitamin B complex with C. Variable (consult detailed reference): Aminophylline, dexamethasone sodium phosphate, oxacillin, penicillin G potassium, potassium chloride.

USE — Treatment of serious infections (bone infections, respiratory tract infections, endocarditis, and septicemia) due to organisms resistant to gentamicin and tobramycin, including Pseudomonas, Proteus, Serratia, and other gram-negative bacilli; documented infection of mycobacterial organisms susceptible to amikacin

USE - UNLABELED / INVESTIGATIONAL — Bacterial endophthalmitis

ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Neurotoxicity
Otic: Ototoxicity (auditory), ototoxicity (vestibular)
Renal: Nephrotoxicity

<1% (Limited to important or life-threatening): Allergic reaction, dyspnea, eosinophilia

CONTRAINDICATIONS — Hypersensitivity to amikacin sulfate or any component of the formulation; cross-sensitivity may exist with other aminoglycosides

WARNINGS / PRECAUTIONS
Boxed Warnings: Nephrotoxicity: . Neuromuscular blockade and respiratory paralysis: . Neurotoxicity: .

Concerns related to adverse effects: Nephrotoxicity: [U.S. Boxed Warning]: May cause nephrotoxicity; usual risk factors include pre-existing renal impairment, concomitant nephrotoxic medications, advanced age and dehydration. Discontinue treatment if signs of nephrotoxicity occur; renal damage is usually reversible. Neuromuscular blockade and respiratory paralysis: [U.S. Boxed Warning]: May cause neuromuscular blockade and respiratory paralysis; especially when given soon after anesthesia or muscle relaxants. Neurotoxicity: [U.S. Boxed Warning]: May cause neurotoxicity; usual risk factors include pre-existing renal impairment, concomitant neuro-/nephrotoxic medications, advanced age and dehydration. Ototoxicity is proportional to the amount of drug given and the duration of treatment. Tinnitus or vertigo may be indications of vestibular injury and impending bilateral irreversible damage. Discontinue treatment if signs of ototoxicity occur. Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns: Hearing impairment: Use with caution in patients with pre-existing vertigo, tinnitus, or hearing loss. Hypocalcemia: Use with caution in patients with hypocalcemia. Neuromuscular disorders: Use with caution in patients with neuromuscular disorders, including myasthenia gravis. Renal impairment: Use with caution in patients with pre-existing renal insufficiency; dosage modification required.

Dosage form specific issues: Sulfite: Solution contains sodium metabisulfate; use caution in patients with sulfite allergy.

DRUG INTERACTIONS
Amphotericin B: May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy

Bisphosphonate Derivatives: Aminoglycosides may enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy

Capreomycin: May enhance the neuromuscular-blocking effect of Aminoglycosides. Risk C: Monitor therapy

CARBOplatin: Aminoglycosides may enhance the ototoxic effect of CARBOplatin. Especially with higher doses of carboplatin. Risk C: Monitor therapy

CISplatin: May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy

Colistimethate: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Risk D: Consider therapy modification

CycloSPORINE: Aminoglycosides may enhance the nephrotoxic effect of CycloSPORINE. Risk C: Monitor therapy

Gallium Nitrate: Aminoglycosides may enhance the nephrotoxic effect of Gallium Nitrate. Risk X: Avoid combination

Loop Diuretics: May enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity and ototoxicity. Risk C: Monitor therapy

Neuromuscular-Blocking Agents: Aminoglycosides may enhance the respiratory depressant effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May decrease the excretion of Aminoglycosides. Data only in premature infants. Risk C: Monitor therapy

OnabotulinumtoxinA: Aminoglycosides may enhance the neuromuscular-blocking effect of OnabotulinumtoxinA. Risk C: Monitor therapy

Penicillins: May decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Exceptions: Amoxicillin; Ampicillin; Cloxacillin; Dicloxacillin; Methicillin; Nafcillin; Oxacillin; Penicillin G (Parenteral/Aqueous); Penicillin G Benzathine; Penicillin G Procaine; Penicillin V Potassium. Risk D: Consider therapy modification

RimabotulinumtoxinB: Aminoglycosides may enhance the neuromuscular-blocking effect of RimabotulinumtoxinB. Risk C: Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Risk D: Consider therapy modification

Vancomycin: May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy

PREGNANCY RISK FACTOR — D (show table)

PREGNANCY IMPLICATIONS — Amikacin crosses the placenta, produces detectable serum levels in the fetus, and concentrates in the fetal kidneys. Because of several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy, the manufacturer classifies amikacin as pregnancy risk factor D. Renal toxicity has been observed in animals, but fetal toxicity in humans has not been reported. No adequate and well-controlled studies have been conducted in pregnant women and it is not known whether amikacin can cause fetal harm. Although the manufacturer considers amikacin pregnancy risk factor D, amikacin-specific clinical data would suggest pregnancy risk factor C.

Due to pregnancy-induced physiologic changes, some pharmacokinetic parameters of amikacin may be altered. Pregnant women have an average-to-larger volume of distribution which may result in lower peak serum levels than for the same dose in nonpregnant women. Serum half-life is also shorter.

LACTATION — Enters breast milk/compatible

BREAST-FEEDING CONSIDERATIONS — Amikacin is excreted into breast milk in trace amounts; however, it is not absorbed when taken orally. This limited oral absorption may minimize exposure to the nursing infant. Nondose-related effects could include modification of bowel flora.

DIETARY CONSIDERATIONS — Sodium content of 1 g: 29.9 mg (1.3 mEq)

MONITORING PARAMETERS — Urinalysis, BUN, serum creatinine, appropriately timed peak and trough concentrations, vital signs, temperature, weight, I & O, hearing parameters

Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro. This may be clinically-significant for certain penicillin (ticarcillin, piperacillin, carbenicillin) and aminoglycoside (gentamicin, tobramycin) combination therapy in patients with significant renal impairment. Close monitoring of aminoglycoside levels is warranted.

REFERENCE RANGE
Sample size: 0.5-2 mL blood (red top tube) or 0.1-1 mL serum (separated)

Therapeutic levels:
Peak:
Life-threatening infections: 25-40 mcg/mL
Serious infections: 20-25 mcg/mL
Urinary tract infections: 15-20 mcg/mL
Trough: <8 mcg/mL
The American Thoracic Society (ATS) recommends trough levels of <4-5 mcg/mL for patients with hospital-acquired pneumonia.

Toxic concentration: Peak: >40 mcg/mL; Trough: >10 mcg/mL

Timing of serum samples: Draw peak 30 minutes after completion of 30-minute infusion or at 1 hour following initiation of infusion or I.M. injection; draw trough within 30 minutes prior to next dose

CANADIAN BRAND NAMES — Amikacin Sulfate Injection, USP; Amikin®

INTERNATIONAL BRAND NAMES — Acemycin (TW); Agnicin (MX); Akacin (MX, TH); Akicin (TH); Alostil (ID); Amicasil (IT); Amicin (IN); Amikabiot (PE); Amikacin Fresenius (DE); Amikacina (CN); Amikacina Medical (ES); Amikacina Normon (ES, PT); Amikacine Aguettant (FR); Amikacine Dakota Pharm (FR); Amikacine Panpharma (FR); Amikafur (MX); Amikan (IT); Amikaxing (CL); Amikayect (MX); Amikin (AU, BF, BG, BJ, BR, CH, CI, CO, CZ, EE, ET, GB, GH, GM, GN, HK, HN, HU, ID, IE, KE, KP, LR, MA, ML, MR, MU, MW, MY, NE, NG, PE, PH, PK, PL, SC, SD, SG, SL, SN, TH, TN, TZ, UG, ZA, ZM, ZW); Amikin. (MX); Amiklin (FR); Amikozit (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Amukin (BE, LU, NL); Biclin (ES, MX, PT); Biklin (AR, AT, DE, FI, PH, SE, VE); Biodacyna (PL); Biokacin (MX, PY); Briclin (UY); Briklin (GR); Chemacin (IT); Cidacid (PH); Cinmik (PH); Eukacin (TW); Gamikal (MX); Glukamin (EC); Kacinth-A (ZA); Kamin (PH); Kamina (PT); Kanbine (ES); Karmikin (MX); Kormakin (PH); Lanomycin (GR); Likacin (AE, BH, CY, EG, HU, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Lisobac (MX); Lukadin (IT); Miacin (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Mikasul (PH); Nica (PH); Novamin (BR); Oprad (MX); Orlobin (GR); Panmikin (PH); Riklinak (AR); Savox (TW); Selaxa (GR); Selemycin (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Sikacin (TW); Tybikin (TH); Vijomikin (GT, HN, PA, SV); Yectamid (MX)

MECHANISM OF ACTION — Inhibits protein synthesis in susceptible bacteria by binding to 30S ribosomal subunits

PHARMACODYNAMICS / KINETICS
Absorption:
I.M.: Rapid
Oral: Poorly absorbed

Distribution: Primarily into extracellular fluid (highly hydrophilic); penetrates blood-brain barrier when meninges inflamed
Relative diffusion of antimicrobial agents from blood into CSF: Good only with inflammation (exceeds usual MICs)
CSF:blood level ratio: Normal meninges: 10% to 20%; Inflamed meninges: 15% to 24%

Protein-binding: 0% to 11%

Half-life elimination (renal function and age dependent):
Infants: Low birth weight (1-3 days): 7-9 hours; Full-term >7 days: 4-5 hours
Children: 1.6-2.5 hours
Adults: Normal renal function: 1.4-2.3 hours; Anuria/end-stage renal disease: 28-86 hours

Time to peak, serum: I.M.: 45-120 minutes

Excretion: Urine (94% to 98%)

PATIENT INFORMATION — Report loss of hearing, ringing or roaring in the ears, or feeling of fullness in head