AMIKACIN SULFATE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Tuberculosis patients*
-Directly observed therapy (DOT) is recommended for all children, any adolescents living with HIV, and any regimen consisting of intermittent therapy.
Intravenous Administration
Dilution
-Dilute amikacin vial with a compatible solution to a concentration of 2.5 to 5 mg/mL.
-Compatible intravenous solutions include 5% Dextrose Injection, 5% Dextrose and 0.2% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, Lactated Ringer's Injection, Normosol M in 5% Dextrose Injection, Plasma-Lyte 56 in 5% Dextrose in water, Normosol R in 5% Dextrose Injection, and Plasma-Lyte 148 in 5% Dextrose in water.
-Storage: The diluted solution is stable for 24 hours at room temperature even after 60 days refrigerated (4 degrees C) or after 30 days frozen (-15 degrees C).

Intermittent IV Infusion

-Infuse over 30 to 60 minutes. The manufacturer recommends that infant doses should be diluted in sufficient volume to allow infusion over 1 to 2 hours; however, doses have been administered over 30 to 60 minutes in this population even with larger doses used in extended-interval dosing.

Intramuscular Administration
Intramuscular Injection
-Inject deeply into a large muscle (e.g., ventrogluteal, anterolateral thigh, or deltoid). The deltoid and ventrogluteal areas should be reserved for older children.

Nephrotoxicity (azotemia) is a well-known adverse reaction to amikacin and other aminoglycoside antibiotics. Aminoglycoside antibiotics are taken up by lysosomes in cells lining the proximal tubule, leading to necrosis and/or fibrosis. With continued exposure, interstitial fibrosis, renal tubular necrosis, and renal tubular acidosis (RTA) occur. If aminoglycoside therapy is discontinued before these events, renal dysfunction may be reversible. Worsening of creatinine clearance, hyposthenuria (loss of concentrating ability), pyuria (increased WBCs), proteinuria, and cylindruria (cells or casts in the urine) are all manifestations of nephrotoxicity; oliguria occurs rarely. Various studies have identified risk factors for developing nephrotoxicity from aminoglycosides: excessive trough serum concentrations, use of other nephrotoxic agents, total dose or treatment duration, and preexisting renal disease. Finally, new approaches to clinical dosing of amikacin also may reduce the incidence of nephrotoxicity.

Nausea and vomiting have been rarely reported with amikacin use.

Ototoxicity also can occur during amikacin therapy. This problem can be manifest as high-frequency hearing loss, tinnitus, vertigo, dizziness, or nausea because either cochlear or vestibular toxicity is possible. Uptake of drug into the inner ear may occur more readily in patients who develop ototoxicity. Factors that increase risk include the total duration of exposure to the aminoglycoside and concomitant use of ototoxic drugs such as ethacrynic acid. Audiograms should be performed in patients who receive repeated or prolonged courses of therapy with amikacin.

Neurotoxicity has been reported with amikacin therapy. Peripheral neuropathy or encephalopathy, paresthesias including numbness or skin tingling, muscle twitching, tetany (in neonates), convulsions (seizures), and a myasthenia gravis-like syndrome with muscle weakness, have been reported. Neuromuscular blockade and respiratory paralysis with apnea have been reported with aminoglycoside use.

Irritation after IM injection of amikacin has been reported. Patients should be observed for any injection site reaction after IM injection.

General adverse reactions that have been reported rarely with amikacin include rash (unspecified), drug fever, headache, arthralgia, and hypotension.

Eosinophilia and anemia have been reported rarely with the use of amikacin.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with amikacin. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate

Serious and potentially life-threatening hypersensitivity or anaphylactoid reactions, including anaphylaxis, have been reported in patients taking amikacin liposome inhalation suspension. Signs and symptoms include acute onset of skin and mucosal tissue hypersensitivity reactions (hives, pruritus, flushing, swollen lips/tongue/uvula), respiratory difficulty (shortness of breath, wheezing, stridor, cough), gastrointestinal symptoms (nausea, vomiting, diarrhea, crampy abdominal pain), and cardiovascular signs and symptoms of anaphylaxis (sinus tachycardia, low blood pressure, syncope, incontinence, dizziness). Evaluate for previous hypersensitivity reactions to aminoglycosides before therapy with amikacin liposome inhalation suspension is instituted. If anaphylaxis or a hypersensitivity reaction occurs, discontinue amikacin liposome inhalation suspension and institute appropriate supportive measures.

Patients receiving systemic aminoglycosides, such as amikacin, should be closely monitored for nephrotoxicity. Aminoglycosides are associated with major toxic effects on the renal tubules. In patients with pre-existing renal impairment or renal failure or in those with normal renal function who receive high doses or prolonged therapy, the risks of severe nephrotoxic adverse reactions are sharply increased. Nephrotoxicity can manifest as decreased creatinine clearance, the presence of cells or casts, oliguria, proteinuria, decreased urine specific gravity, or evidence of increasing nitrogen retention (increasing BUN, NPN, or serum creatinine). When monitoring amikacin serum concentrations during use of conventional dose regimens, the manufacturer states that peak concentrations above 35 mcg/mL and trough concentrations above 10 mcg/mL should be avoided. However, single-daily dosing regimens that produce higher peak serum concentrations have been used without additional toxicity noted; however, it is important to allow the trough concentration to decrease appropriately before redosing. Evidence of nephrotoxicity requires dosage adjustment or discontinuance of therapy. Hemodialysis may aid in amikacin removal in the event of overdose or toxic reactions, especially if renal function is or becomes impaired. In rare cases, nephrotoxicity may not be evident until soon after completion of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible. Avoid concurrent and/or sequential coadministration of aminoglycosides with other drugs that are potentially nephrotoxic and/or neurotoxic because toxicity may be additive. Use amikacin with caution in neonates and premature neonates due to renal immaturity and the prolongation of serum half-life of the drug, which increases the risk of amikacin-induced toxicity. Use caution and monitor urine output and laboratory values carefully in neonates being treated for patent ductus arteriosus with an NSAID. Patients with dehydration are at increased risk of developing toxicity. In the event of toxicity in newborns, exchange transfusions may be considered. Intravenous diuretics may also alter aminoglycoside concentrations in serum and tissue and thereby enhance aminoglycoside toxicity.

Monitor patients receiving systemic and inhaled aminoglycosides, such as amikacin, for neurotoxicity, including ototoxicity and hearing impairment. Use aminoglycosides with caution in patients with preexisting hearing impairment, especially eighth-cranial-nerve impairment. Consider serial audiograms for high-risk patients. The risk of hearing loss increases with the degree of exposure (high or prolonged therapy), pre-existing renal impairment, concomitant or sequential nephrotoxic or ototoxic agents, dehydration, and advanced age. Patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant, may develop ototoxicity even when aminoglycoside serum concentrations are within the recommended range. These variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity, including severe cases, is unknown. If there is a known maternal history of ototoxicity due to aminoglycosides or a known mitochondrial DNA variant, consider alternative treatments unless the severity of the infection and lack of alternatives outweighs the risk of permanent hearing loss. Discontinue therapy if there is evidence of auditory or vestibular toxicity. In the event of toxicity in newborns, exchange transfusions may be considered. When monitoring amikacin serum concentrations during use of conventional dose regimens, avoid prolonged amikacin peak concentrations above 35 mcg/mL and trough concentrations above 10 mcg/mL. However, single-daily dosing schemes that produce higher peak serum concentrations have been used without additional toxicity noted. Aminoglycosides are associated with major toxic effects on the auditory and vestibular branches of the eighth nerve. Auditory changes are irreversible, usually bilateral, and may be partial or total. Symptoms of ototoxicity can include dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss and may manifest during therapy or after discontinuation. High-frequency hearing loss usually occurs before there is noticeable clinical hearing loss; clinical symptoms may not be present to warn of developing cochlear damage. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions.

Amikacin is contraindicated in patients with known aminoglycoside hypersensitivity. Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking amikacin liposome inhalation suspension. Evaluate for previous hypersensitivity reactions to aminoglycosides before therapy with amikacin liposome inhalation suspension is instituted. If anaphylaxis or a hypersensitivity reaction occurs, discontinue amikacin liposome inhalation suspension and institute appropriate supportive measures.

Systemic aminoglycosides, such as amikacin, are associated with neuromuscular blockade and may cause severe neuromuscular weakness lasting hours to days. Respiratory paralysis, respiratory insufficiency, or respiratory depression may occur when aminoglycosides are instilled after local irrigation and after topical application during surgical procedures. Neuromuscular blockade has also been reported with both oral and parenteral use of aminoglycosides. Clinicians should be aware of the possibility of neuromuscular blockade and respiratory paralysis if aminoglycosides are administered by any route, especially in patients receiving anesthetics, neuromuscular-blocking agents (e.g., tubocurarine, succinylcholine, decamethonium, or in patients receiving massive transfusions of citrate-anticoagulated blood). Corrective therapy is required for any electrolyte imbalance, which may aggravate risk for neuromuscular/neurological symptoms. During or after aminoglycoside therapy, paresthesias, tetany, positive Chvostek and Trousseau signs, and mental confusion have been described in patients with hypomagnesemia, hypocalcemia, and hypokalemia. In infants, tetany and muscle weakness have been described. Aminoglycosides may aggravate muscle weakness in patients with neuromuscular disease such as myasthenia gravis, botulism, or parkinsonism.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including amikacin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Use adjusted body weight (i.e., ideal body weight plus 40% of excess weight) for amikacin dosing in patients with marked obesity due to decreased distribution of extracellular fluids in adipose tissues. Dosing based on actual body weight will result in supratherapeutic concentrations.

Description: Amikacin is an aminoglycoside antibiotic that is active against aerobic gram-negative rods. It also possesses activity against certain Mycobacterium species, but is not active against any anaerobic bacteria. Amikacin is used as part of combination therapy for cystic fibrosis and as part of second-line therapy for tuberculosis and Mycobacterium avium complex (MAC). It is also used as part of combination treatment for gram-negative respiratory tract, abdominal, CNS infections. Amikacin is considered to be a narrow therapeutic index drug, and therefore, serum concentration monitoring is recommended for most regimens. The major toxicities include nephrotoxicity, ototoxicity, and neurotoxicity. Amikacin is FDA-approved for use in pediatric patients as young as neonates.

General Dosing Information
-Amikacin is a narrow therapeutic index drug. While initial doses can be recommended, maintenance dosing (except for low-dose regimens used for synergy) should be individualized based on pathogen, site of infection, and serum concentrations.
-Monitor renal function closely in all patients receiving amikacin. Measure serum concentrations if there is a decrease in urine output or a laboratory value that suggests a change in renal function.
-In overweight patients, a modified dosing body weight should be used to calculate the dosage. The equation used in adult patients is: Dosing Body Weight = [(total body weight - ideal body weight) x 0.4] + ideal body weight.
-Enterococcus species are generally resistant to therapeutic concentrations of aminoglycosides. Aminoglycosides are only effective in clinical cure of enterococcus infections when used to provide synergistic bactericidal activity to penicillins or vancomycin. The degree of synergy is related to the level of aminoglycoside resistance of the specific enterococcus strain.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Acinetobacter sp., Citrobacter freundii, Enterobacter sp., Escherichia coli, Klebsiella sp., Proteus sp., Providencia rettgeri, Providencia sp., Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas sp., Serratia marcescens, Serratia sp., Staphylococcus sp.
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Aeromonas sp., Bacillus anthracis, Citrobacter sp., Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Morganella sp., Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium intracellulare, Mycobacterium tuberculosis, Nocardia sp., Salmonella sp., Shigella sp.
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of meningitis and ventriculitis*:
Intravenous or Intramuscular dosage (extended-interval dosing)*:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours. An aminoglycoside plus ampicillin is recommended as a treatment option for initial empiric therapy for neonatal meningitis. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis or meningitis due to Listeria monocytogenes and a duration of at least 21 days is recommended for meningitis due to gram-negative bacilli.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours. An aminoglycoside plus ampicillin is recommended as a treatment option for initial empiric therapy for neonatal meningitis. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis or meningitis due to Listeria monocytogenes and a duration of at least 21 days is recommended for meningitis due to gram-negative bacilli.
Neonates 30 to 34 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 36 hours. An aminoglycoside plus ampicillin is recommended as a treatment option for initial empiric therapy for neonatal meningitis. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis or meningitis due to Listeria monocytogenes and a duration of at least 21 days is recommended for meningitis due to gram-negative bacilli.
Neonates 30 to 34 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours. An aminoglycoside plus ampicillin is recommended as a treatment option for initial empiric therapy for neonatal meningitis. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis or meningitis due to Listeria monocytogenes and a duration of at least 21 days is recommended for meningitis due to gram-negative bacilli.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours. An aminoglycoside plus ampicillin is recommended as a treatment option for initial empiric therapy for neonatal meningitis. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis or meningitis due to Listeria monocytogenes and a duration of at least 21 days is recommended for meningitis due to gram-negative bacilli.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM every 24 hours. An aminoglycoside plus ampicillin is recommended as a treatment option for initial empiric therapy for neonatal meningitis. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis or meningitis due to Listeria monocytogenes and a duration of at least 21 days is recommended for meningitis due to gram-negative bacilli.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/dose IV or IM every 24 hours. The IDSA recommends an aminoglycoside in combination with ampicillin as a treatment option for meningitis due to Streptococcus agalactiae (group B streptococcus), Listeria monocytogenes, and Enterococcus species. An aminoglycoside in combination with a third-generation cephalosporin is also recommended for meningitis due to Pseudomonas aeruginosa. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis and at least 3 weeks for meningitis due to Listeria monocytogenes or Pseudomonas aeruginosa.
Intravenous or Intramuscular dosage (conventional dosing):
Neonates 0 to 7 days: 15 to 20 mg/kg/day IV or IM divided every 12 hours is recommended by guidelines, with a smaller dose and longer dosing interval recommended in low birth-weight neonates (less than 2 kg). 10 mg/kg IV or IM loading dose, followed by 7.5 mg/kg/dose IV or IM every 12 hours is the FDA-approved dose. An aminoglycoside plus ampicillin is recommended as a treatment option for initial empiric therapy for neonatal meningitis. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis or meningitis due to Listeria monocytogenes and a duration of at least 21 days is recommended for meningitis due to gram-negative bacilli.
Neonates 8 days and older: 30 mg/kg/day IV or IM divided every 8 hours is recommended by guidelines, with a smaller dose and longer dosing interval recommended in low birth-weight neonates (less than 2 kg). 10 mg/kg IV or IM loading dose, followed by 7.5 mg/kg/dose IV or IM every 12 hours is the FDA-approved dose. An aminoglycoside plus ampicillin is recommended as a treatment option for initial empiric therapy for neonatal meningitis. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis or meningitis due to Listeria monocytogenes and a duration of at least 21 days is recommended for meningitis due to gram-negative bacilli.
Infants, Children, and Adolescents: 20 to 30 mg/kg/day IV or IM divided every 8 hours is recommended by guidelines. 15 mg/kg/day IV or IM divided every 8 to 12 hours (Max: 1.5 g/day) is the FDA-approved dosage. The IDSA recommends an aminoglycoside in combination with ampicillin as a treatment option for meningitis due to Streptococcus agalactiae (group B streptococcus), Listeria monocytogenes, and Enterococcus species. An aminoglycoside in combination with a third-generation cephalosporin is also recommended for meningitis due to Pseudomonas aeruginosa. The recommended duration of therapy is 14 to 21 days for group B streptococcal meningitis and at least 3 weeks for meningitis due to Listeria monocytogenes or Pseudomonas aeruginosa.
Intrathecal* or Intraventricular dosage* (preservative-free formulations only):
Neonates: 1 to 5 mg administered intraventricularly into the CSF has been studied in a small case series (n = 8) with the goal of maintaining a drug concentration at least 10 times the MIC of the infecting organism. In general, a 5 mg intraventricular dose achieved this goal in all patients studied.
Infants, Children, and Adolescents: 5 to 50 mg (with a usual dose of 30 mg) intraventricularly into the CSF once daily in combination with systemic therapy has been recommended in general without specific pediatric qualifications. Doses should be adjusted to maintain adequate CSF concentrations depending on the susceptibility of the infecting organism.

For the treatment of pulmonary exacerbations in patients with cystic fibrosis* (CF):
Intravenous dosage:
Infants, Children, and Adolescents: 30 to 35 mg/kg/dose IV every 24 hours. Amikacin has traditionally been administered as a 2 to 3 times daily regimen such as 30 mg/kg/day IV divided every 8 to 12 hours; however, high dose extended-interval aminoglycoside regimens are now preferred. Amikacin and tobramycin have comparable efficacy for the treatment of acute pulmonary exacerbations in CF patients and either agent is recommended as first-line therapy in conjunction with an antipseudomonal beta-lactam agent.

For the empiric treatment of febrile neutropenia*:
Intravenous dosage (extended-interval dosing):
Infants, Children, and Adolescents: 15 to 20 mg/kg/dose IV every 24 hours. The efficacy of once daily amikacin for febrile neutropenia has been established in several studies in pediatric patients. A maximum single dose of 750 mg was reported in 1 study. The FDA-approved maximum daily dose is 1.5 g/day. Amikacin, in combination with an antipseudomonal penicillin or cephalosporin, has been successfully used for the empiric treatment of febrile neutropenia in children. Guidelines for the management of fever and neutropenia in cancer patients recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem as empiric treatment in high-risk patients; addition of a second gram-negative antimicrobial agent (i.e., aminoglycoside, aztreonam) is recommended for patients who are clinically unstable, when a resistant infection is suspected, or for centers with high rates of resistant pathogens.
Intravenous dosage (conventional dosing):
Infants, Children, and Adolescents: 15 to 20 mg/kg/day IV divided every 8 to 12 hours. The FDA-approved maximum daily dose is 1.5 g/day. Amikacin, in combination with an antipseudomonal penicillin or cephalosporin, has been successfully used for the empiric treatment of febrile neutropenia in children. Guidelines for the management of fever and neutropenia in cancer patients recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem as empiric treatment in high-risk patients; addition of a second gram-negative antimicrobial agent (i.e., aminoglycoside, aztreonam) is recommended for patients who are clinically unstable, when a resistant infection is suspected, or for centers with high rates of resistant pathogens.

For the treatment of Mycobacterium avium complex infection* (MAC) in HIV-infected patients:
Intravenous dosage:
Infants and Children: 15 to 30 mg/kg/day IV divided every 12 to 24 hours (Max: 1.5 g/day) plus clarithromycin or azithromycin and ethambutol. May consider addition of amikacin if rifabutin cannot be administered for severe disease or if a fourth drug is needed for patients with more severe symptoms or disseminated disease. Duration of treatment depends on clinical response but should continue for at least 12 months.
Adolescents: 10 to 15 mg/kg/dose IV once daily (Max: 1.5 g/day) plus clarithromycin or azithromycin and ethambutol. May consider addition of amikacin as a third or fourth drug (or rifabutin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Duration of treatment depends on clinical response but should continue for at least 12 months.

For the treatment of drug-susceptible tuberculosis infection* as part of combination therapy:
NOTE: Use adjusted body weight (i.e., ideal body weight plus 40% of excess weight) for dosing in patients with marked obesity.
-for the treatment of drug-susceptible tuberculosis* infection in persons without HIV as part of combination therapy:
Intravenous and Intramuscular dosage:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV or IM every 36 hours. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV or IM once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Infants, Children, and Adolescents: 15 to 20 mg/kg/dose (Max: 1 g/dose) IV or IM once daily or 5 days/week, or alternatively, 25 to 30 mg/kg/dose (Max: 1/dose) IV or IM twice weekly. Daily dosing is preferred and is defined as 5- or 7 days/week. Use adjusted body weight in obese patients. Amikacin is generally recommended as second-line therapy; duration is dependent on the site of involvement.
-for the treatment of drug-susceptible tuberculosis infection* in persons with HIV as part of combination therapy:
Intravenous and Intramuscular dosage:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV or IM every 36 hours. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV or IM once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Amikacin is generally recommended as part of the initial 2-month intensive phase of treatment for susceptible infections.
Infants, Children, and Adolescents: 15 to 20 mg/kg/dose (Max: 1 g/dose) IV or IM once daily or 5 days/week. Daily dosing is defined as 5- or 7 days/week. Use adjusted body weight in obese patients. Amikacin is generally recommended as second-line therapy; duration is dependent on the site of involvement.

For the treatment of drug-resistant tuberculosis infection* as part of combination therapy:
NOTE: Use adjusted body weight (i.e., ideal body weight plus 40% of excess weight) for dosing in patients with marked obesity.
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 15 to 30 mg/kg/dose (Max: 1 g /dose) IV or IM once daily or 5 days/week. Use adjusted body weight in obese patients. Daily dosing is defined as 5- or 7 days/week.

For the treatment of infective endocarditis*:
Intravenous dosage:
Children and Adolescents: 15 mg/kg/day IV divided every 8 to 12 hours. Clinical practice guidelines recommend an aminoglycoside, in combination with ampicillin, for 4 weeks as an alternative therapy for endocarditis due to HACEK organisms. An aminoglycoside in combination with a third or fourth generation cephalosporin (i.e., ceftazidime, cefepime, cefotaxime, ceftriaxone) for at least 6 weeks is recommended as preferred treatment for endocarditis due to other gram-negative microorganisms.

For the treatment of bacteremia and sepsis:
Intravenous or Intramuscular dosage (extended-interval dosing)*:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV or IM every 36 hours.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for de-escalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from the scope of the Surviving Sepsis Campaign guidelines.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM every 24 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for de-escalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from the scope of the Surviving Sepsis Campaign guidelines.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/dose IV or IM every 24 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for de-escalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.
Intravenous or Intramuscular dosage (conventional dosing):
Neonates: 10 mg/kg IV or IM loading dose, followed by 7.5 mg/kg/dose IV or IM every 12 hours is the FDA-approved dose; however, this dosing does not account for gestational age or birthweight. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for de-escalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from the scope of the Surviving Sepsis Campaign guidelines.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/day (Max: 1.5 g/day) IV or IM divided every 8 to 12 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for de-escalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.

For the treatment of lower respiratory tract infections (LRTIs), including community-acquired pneumonia (CAP):
-for the treatment of nonspecific lower respiratory tract infections (LRTIs):
Intravenous or Intramuscular dosage (conventional dosing):
Neonates: 10 mg/kg IV or IM loading dose, followed by 7.5 mg/kg/dose IV or IM every 12 hours. This dosing does not account for gestational age or birthweight.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/day IV or IM divided every 8 to 12 hours (Max: 1.5 g/day).
Intravenous or Intramuscular dosage (extended-interval dosing)*:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 30 to 34 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 36 hours.
Neonates 30 to 34 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM every 24 hours.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/dose IV or IM every 24 hours.
-for the treatment of community-acquired pneumonia (CAP):
Intravenous dosage (conventional dosing):
HIV-Infected Adolescents: 15 to 22.5 mg/kg/day IV divided every 8 to 12 hours (Max: 1.5 g/day) for 5 to 7 days as an alternative in combination therapy for hospitalized patients at risk for P. aeruginosa.
Intravenous dosage (extended-interval dosing)*:
HIV-Infected Adolescents: 15 to 22.5 mg/kg/dose IV every 24 hours for 5 to 7 days as an alternative in combination therapy for hospitalized patients at risk for P. aeruginosa.

For the treatment of intraabdominal infections (i.e., peritonitis):
Intravenous or Intramuscular dosage (extended-interval dosing)*:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV or IM every 36 hours.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM every 24 hours.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/dose IV or IM every 24 hours.
Intravenous or Intramuscular dosage (conventional dosing):
Neonates: 10 mg/kg IV or IM loading dose, followed by 7.5 mg/kg/dose IV or IM every 12 hours is the FDA-approved dose; however, this dosing does not account for gestational age or birthweight.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/day IV or IM divided every 8 to 12 hours (Max: 1.5 g/day).
-for the treatment of peritoneal dialysis-associated peritonitis in patients with end-stage renal disease:
Intraperitoneal dosage*:
Infants, Children, and Adolescents: 25 mg/L intraperitoneal (IP) loading dose followed by a maintenance dose of 12 mg/L of peritoneal dialysate. Treat for 2 to 3 weeks depending on infecting organism and the patient's clinical status.

For the treatment of complicated urinary tract infection (UTI) and pyelonephritis:
Intravenous or Intramuscular dosage (extended-interval dosing)*:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV or IM every 36 hours. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV or IM every 24 hours. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM every 24 hours. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants younger than 2 months: 15 to 22.5 mg/kg/dose IV or IM every 24 hours. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants, Children, and Adolescents 2 months to 17 years: 15 to 22.5 mg/kg/dose IV or IM every 24 hours. Treat for 24 to 48 hours or until patient is clinically stable and afebrile, followed by oral antibiotics for a total duration of 7 to 14 days.
Intravenous or Intramuscular dosage (conventional dosing):
Neonates: 10 mg/kg IV or IM loading dose, followed by 7.5 mg/kg/dose IV or IM every 12 hours is the FDA-approved dosage; however, this dosing does not account for gestational age or birthweight. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants younger than 2 months: 15 to 22.5 mg/kg/day IV or IM divided every 8 to 12 hours. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants, Children, and Adolescents 2 months to 17 years: 15 to 22.5 mg/kg/day (Max: 1.5 g/day) IV or IM divided every 8 to 12 hours. Treat for 24 to 48 hours or until patient is clinically stable and afebrile, followed by oral antibiotics for a total duration of 7 to 14 days.

For the treatment of bone and joint infections, including osteomyelitis and infectious arthritis:
-for the treatment of osteomyelitis:
Intravenous dosage (extended-interval dosing)*:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV every 48 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV every 36 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants 1 to 2 months: 15 to 22.5 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 22.5 mg/kg/dose IV every 24 hours. Treat for 2 to 4 days or until clinically improved, followed by oral step-down therapy for a total duration of 3 to 4 weeks for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for severe or complicated infections.
Intravenous dosage (conventional dosing):
Neonates: 10 mg/kg IV loading dose, followed by 7.5 mg/kg/dose IV every 12 hours is the FDA-approved dosage; however, this dosing does not account for gestational age or birthweight. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants 1 to 2 months: 15 to 22.5 mg/kg/day IV divided every 8 to 12 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 22.5 mg/kg/day (Max: 1.5 g/day) IV divided every 8 to 12 hours. Treat for 2 to 4 days or until clinically improved, followed by oral step-down therapy for a total duration of 3 to 4 weeks for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for severe or complicated infections.
-for the treatment of infectious arthritis:
Intravenous dosage (extended-interval dosing)*:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV every 48 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV every 36 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants 1 to 2 months: 15 to 22.5 mg/kg/dose IV every 24 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 22.5 mg/kg/dose IV every 24 hours. Treat for 2 to 4 days or until clinically improved, followed by oral step-down therapy for a total duration of 2 to 3 weeks for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for septic hip arthritis or severe or complicated infections.
Intravenous dosage (conventional dosing):
Neonates: 10 mg/kg IV loading dose, followed by 7.5 mg/kg/dose IV every 12 hours is the FDA-approved dosage; however, this dosing does not account for gestational age or birthweight. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants 1 to 2 months: 15 to 22.5 mg/kg/day IV divided every 8 to 12 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 22.5 mg/kg/day (Max: 1.5 g/day) IV divided every 8 to 12 hours. Treat for 2 to 4 days or until clinically improved, followed by oral step-down therapy for a total duration of 2 to 3 weeks for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for septic hip arthritis or severe or complicated infections.

For the treatment of skin and skin structure infections, including burn wound infection and necrotizing infections:
-for the general treatment of skin and skin structure infections:
Intravenous or Intramuscular dosage (extended-interval dosing)*:
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV or IM every 36 hours.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM every 24 hours.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/dose IV or IM every 24 hours.
Intravenous or Intramuscular dosage (conventional dosing):
Neonates: 10 mg/kg IV or IM loading dose, followed by 7.5 mg/kg/dose IV or IM every 12 hours is the FDA-approved dosage; however, this dosing does not account for gestational age or birthweight.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/day (Max: 1.5 g/day) IV or IM divided every 8 to 12 hours.
-for the treatment of necrotizing infections of the skin, fascia, and muscle:
Intravenous or Intramuscular dosage (extended-interval dosing):
Neonates younger than 30 weeks gestation and 0 to 14 days: 15 mg/kg/dose IV or IM every 48 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.
Neonates younger than 30 weeks gestation and 15 days and older: 15 mg/kg/dose IV or IM every 24 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.
Neonates 30 to 34 weeks gestation and 0 to 10 days: 15 mg/kg/dose IV or IM every 36 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.
Neonates 30 to 34 weeks gestation and 11 days and older: 15 mg/kg/dose IV or IM every 24 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.
Neonates 35 weeks gestation and older and 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.
Neonates 35 weeks gestation and older and 8 days and older: 18 mg/kg/dose IV or IM every 24 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/dose IV or IM every 24 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.
Intravenous or Intramuscular dosage (conventional dosing):
Neonates: 10 mg/kg IV or IM loading dose, followed by 7.5 mg/kg/dose IV or IM every 12 hours is the FDA-approved dosage; however, this dosing does not account for gestational age or birthweight. Treat until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.
Infants, Children, and Adolescents: 15 to 22.5 mg/kg/day (Max: 1.5 g/day) IV or IM divided every 8 to 12 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin or metronidazole for mixed necrotizing infections.

For the treatment of bartonellosis*, including severe Oroya fever*:
Intravenous or Intramuscular dosage (conventional dosing):
Infants, Children, and Adolescents: 7.5 mg/kg/dose IV or IM every 12 hours for 7 to 10 days plus ciprofloxacin as second-line therapy.

For the treatment of plague* infection:
-for the treatment of bubonic or pharyngeal plague*:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours for 10 to 14 days as an alternative therapy. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients infected after intentional release of Y. pestis.
Neonates 8 days and older: 17.5 mg/kg/dose IV or IM every 24 hours for 10 to 14 days as an alternative therapy. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients infected after intentional release of Y. pestis.
Infants, Children, and Adolescents: 15 to 20 mg/kg/dose IV or IM every 24 hours for 10 to 14 days as an alternative therapy. Monotherapy is recommended for stable patients with naturally occurring plague, although dual therapy can be considered for patients with large buboes. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients infected after intentional release of Y. pestis.
-for the treatment of pneumonic or septicemic plague*:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 15 mg/kg/dose IV or IM every 24 hours for 10 to 14 days as an alternative therapy. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients with severe disease and patients infected after intentional release of Y. pestis.
Neonates 8 days and older: 17.5 mg/kg/dose IV or IM every 24 hours for 10 to 14 days as an alternative therapy. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients with severe disease and patients infected after intentional release of Y. pestis.
Infants, Children, and Adolescents: 15 to 20 mg/kg/dose IV or IM every 24 hours for 10 to 14 days as an alternative therapy. Monotherapy can be considered for mild-to-moderate disease in patients with naturally occurring plague. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients with severe disease and patients infected after intentional release of Y. pestis.

Therapeutic Drug Monitoring:
Conventional Dosing
Usual target peak concentration: 25 to 40 mcg/mL depending on site of infection and pathogen.
Usual target trough concentration: Less than 5 mcg/mL.

Extended-Interval Dosing
Usual target peak concentration: Not established by the literature, but depends on site of infection and pathogen; some experts would suggest targets of 80 to 120 mcg/mL in patients with cystic fibrosis.
Usual target trough concentration: less than 5 mcg/mL; some would suggest troughs of less than 1 mcg/mL.
-Optimal serum concentration monitoring has not been determined in pediatric patients; various methods have been developed and are often institution-specific. In general, the goal is to obtain a significant peak concentration, often in the range of 45 to 60 mcg/mL, and then allow sufficient time for the serum concentration to become undetectable. One method that has been used is to obtain 2 serum concentrations at least one half-life apart (e.g., 2 and 6 hours after the dose) and use those concentrations to calculate a peak and trough and ensure that the serum concentration is not undetectable for significantly longer than the estimated post-antibiotic effect (e.g., 4 to 7 hours). Once an extended interval dose has been determined to be appropriate by measuring serum concentrations, follow-up concentrations are often trough-only to ensure no accumulation is occurring.

General Therapeutic Drug Monitoring Information
-Dosing of injectable aminoglycosides is highly variable. Factors such as patient size, renal function, site of infection, and organism susceptibility should all be considered. In patients who are overweight, use the following equation to determine the appropriate weight for dosage calculations: [(total body weight - ideal body weight) x 0.4] + ideal body weight.
-Traditional dosing regimens of amikacin are designed to achieve serum peak concentrations of 25 to 35 mcg/mL and trough concentrations of less than 5 mcg/mL. However, correlation with MIC data was not used in determining these serum concentrations.
-The importance of achieving peak concentrations in several-fold excess of the organism's MIC has been established. Both time-kill studies as well as studies in humans have shown that a peak:MIC of more than 8 to 12:1 is associated with successful regimens for systemic infections. Consideration must also be given to the site of infection as antimicrobial tissue penetration is also a factor. These data have led to the development of extended interval aminoglycoside therapy (often referred to as 'single-daily dosing' or 'once-daily dosing'), with amikacin given 15 to 20 mg/kg IV once daily to achieve the peak:MIC goals. In adults with these doses, peak concentrations of amikacin often reach 45 to 60 mcg/mL. While study results are mixed as to improved clinical outcomes as compared to traditional dosing, a likely confounding factor is the concomitant use of beta-lactams in the studies; therefore, evaluating the impact of the of only the aminoglycoside dosing is difficult.
-Because elevated serum trough concentrations are associated with an increased risk of toxicity, trough values for conventional dosing should fall below 5 mcg/mL and trough values for extended-interval dosing regimens are designed to fall below the MIC for an extended period of time and are often undetectable. The post-antibiotic effect of aminoglycosides against gram-negative organisms is also used to justify the low trough concentrations. Since actual trough concentrations are often undetectable, most aminoglycoside single-daily dose regimens suggest obtaining a serum concentration at 8 to 12 hours postdose and using a dosing nomogram to assess the dose
-Most urinary tract infections may be adequately treated with lower peak serum concentrations as aminoglycosides are mainly renally eliminated; therefore, drug accumulation in the urine is higher than in the serum.

Maximum Dosage Limits:
-Neonates
Aminoglycoside dosing is highly variable and dependent on several factors. The FDA-approved maximum dose is 15 mg/kg/day IV/IM; however, this dosing does not account for gestational age or birthweight and may be excessive in some patients. Usual maximum doses in neonates are as follows:
Younger than 30 weeks gestation: 15 mg/kg/dose IV/IM every 24 to 48 hours, depending on postnatal age.
30 to 34 weeks gestation: 15 mg/kg/dose IV/IM every 24 to 36 hours, depending on postnatal age.
35 weeks gestation and older: 15 to 18 mg/kg/dose IV/IM every 24 hours, depending on postnatal age.
-Infants
Aminoglycoside dosing is highly variable and dependent on several factors. The FDA-approved maximum dose is 15 mg/kg/day IV/IM; however, doses up to 22.5 mg/kg/day are used off-label; up to 35 mg/kg/day is used off-label for cystic fibrosis patients.
-Children
Aminoglycoside dosing is highly variable and dependent on several factors. The FDA-approved maximum dose is 15 mg/kg/day IV/IM (Max: 1.5 g/day); however, doses up to 22.5 mg/kg/day IV/IM are used off-label; up to 35 mg/kg/day is used off-label for cystic fibrosis patients.
-Adolescents
Aminoglycoside dosing is highly variable and dependent on several factors. The FDA-approved maximum dose is 15 mg/kg/day IV/IM (Max: 1.5 g/day); however, doses up to 22.5 mg/kg/day IV/IM are used off-label; up to 35 mg/kg/day is used off-label for cystic fibrosis patients.

Patients with Hepatic Impairment Dosing
Amikacin does not undergo hepatic metabolism. Specific guidelines for dosage adjustment in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Conventional Dosing
Dosing adjustments are recommendations based on a usual dose of 5 to 7.5 mg/kg/dose IV/IM every 8 hours.
GFR more than 50 mL/minute/1.73 m2: No initial adjustment; monitor serum concentrations.
GFR 30 to 50 mL/minute/1.73 m2: 5 to 7.5 mg/kg/dose IV every 12 to 18 hours; monitor serum concentrations.
GFR 10 to 29 mL/minute/1.73 m2: 5 to 7.5 mg/kg/dose IV every 18 to 24 hours; monitor serum concentrations.
GFR less than 10 mL/minute/1.73 m2: 5 to 7.5 mg/kg/dose IV every 48 to 72 hours; monitor serum concentrations.

Extended-Interval Dosing
Give a single dose and monitor serum concentrations. If significant impairment is present, consider reducing the initial dose and then evaluate serum concentrations.

Intermittent hemodialysis
A dose of 5 mg/kg/dose IV/IM after the initial hemodialysis session. Subsequent doses should be guided by serum amikacin concentrations. Factors such as patient size, site of infection, and organism susceptibility should also be considered.

Continuous ambulatory peritoneal dialysis (CAPD)
5 mg/kg/dose IV/IM as indicated by serum concentrations.

Continuous renal replacement therapy (CRRT)
7.5 mg/kg/dose IV/IM every 12 hours; monitor serum concentrations.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Amikacin is bactericidal in action. Similar to other aminoglycosides, it works by inhibiting bacterial protein synthesis through irreversible binding to the 30 S ribosomal subunit of susceptible bacteria. Amikacin is actively transported into the bacterial cell where it binds to receptors present on the 30 S ribosomal subunit. This binding interferes with messenger RNA (mRNA). As a result, abnormal, nonfunctional proteins are formed due to a misreading of the bacterial DNA. Eventually, susceptible bacteria die because of the lack of functional proteins. One aspect essential to aminoglycoside lethality is the need to achieve intracellular concentrations in excess of extracellular. Anaerobic bacteria are not susceptible to aminoglycosides due, at least in part, to a lack of an active transport mechanism for aminoglycoside uptake. The uptake of aminoglycosides may be facilitated by the presence of inhibitors of the bacterial cell wall (i.e., beta-lactams, vancomycin).

Against gram-negative aerobic rods, aminoglycosides exhibit 'concentration-dependent killing' and a 'post-antibiotic effect' (PAE). 'Concentration-dependent killing' describes the principle that bactericidal effects increase as the concentration increases. PAE is where suppression of bacterial growth continues after the antibiotic concentration falls below the bacterial MIC. The post-antibiotic effect can be bacteria specific, as well as drug specific. The PAE of aminoglycosides is short for most gram-positive organisms (less than 2 hours) and longer for gram-negative organisms (2 to 7 hours), such as E. coli, K. pneumoniae, and P. aeruginosa. Both these phenomena are being exploited in designing dosage regimens that employ higher doses administered at longer intervals. The major pharmacodynamic parameter that determines efficacy of aminoglycosides is the serum peak concentration to MIC ratio (peak to MIC ratio). Both time-kill studies as well as studies in humans have shown that a peak to MIC ratio of more than 8 to 1 to 1 to1 is associated with successful regimens.

The mechanism of renal toxicity with aminoglycosides is associated with accumulation in the renal tubule, which is a saturable process. Elevated serum trough concentrations are associated with an increased risk of toxicity.

The mechanism of ototoxicity relates to the aminoglycoside-induced destruction of sensory hair cells of the inner ear. The cochlear sensory cells that are most vulnerable are in the basal end, thereby leading to high-frequency hearing loss first. As ototoxicity ascends toward the apex of the cochlea, the lower frequencies are affected. Sensory cells that deal with vestibular function may also be affected. Aminoglycosides may cause free-radical damage to sensory cells and neurons. Biochemically, aminoglycosides may bind to polyphosphoinositides, which are part of the transmembrane signaling system mediating physiological effects of hormones, neurotransmitters, and neuromodulators which may interfere with essential mechanisms of cell physiology. Neural destruction without any cochlear hair cell damage has also been described. There may also be a genetic mitochondrial RNA mutation that may predispose some patients to aminoglycoside ototoxicity. Aminoglycosides enter the inner ear rapidly, but it is suggested that concentrations do not correlate with the development of ototoxicity. Likely, the concentrations in the inner ear dissipate slowly, which is consistent with the possibility of developing ototoxicity days to weeks after drug discontinuation.

The susceptibility interpretive criteria for amikacin are delineated by pathogen. The MICs are defined for S. aureus, Acinetobacter sp., other non-Enterobacterales, Bacillus sp. (excluding B. anthracis) and related genera, Aeromonas sp., and Vibrio sp. as susceptible at 16 mcg/mL or less, intermediate at 32 mcg/mL, and resistant at 64 mcg/mL or more. The breakpoints for S. aureus, Acinetobacter sp., and other non-Enterobacterales are based on a dosage of 15 mg/kg every 24 hours. The Clinical and Laboratory Standards Institute (CLSI) and the FDA differ on MIC interpretation for Enterobacterales and P. aeruginosa. The MICs are defined for Enterobacterales by the FDA as susceptible at 16 mcg/mL or less, intermediate at 32 mcg/mL, and resistant at 64 mcg/mL or more; however, the MICs are defined for Enterobacterales by CLSI as susceptible at 4 mcg/mL or less, intermediate at 8 mcg/mL, and resistant at 16 mcg/mL or more based on a dosage of 15 mg/kg every 24 hours. The MICs are defined for P. aeruginosa by the FDA as susceptible at 16 mcg/mL or less, intermediate at 32 mcg/mL, and resistant at 64 mcg/mL or more; however, CLSI only recognizes these MICs in urinary isolates and based on a dosage regimen of 15 mg/kg every 24 hours.

Aminoglycoside resistance is well documented. There are a variety of resistance mechanisms employed by different pathogens. Enzymatic inhibition by gram-negative pathogens and Enterococcus sp. via aminoglycoside-modifying enzymes is achieved by modification of the aminoglycoside as it is transported across the cytoplasmic membrane. Alterations in the inner membrane porin channels by P. aeruginosa decrease antimicrobial penetration to the site of activity within the bacterial cell. Some gram-negative organisms and Enterococcus sp. can alter the ribosomal target sites of the aminoglycosides to decrease binding, thereby decreasing antimicrobial activity.

Pharmacokinetics: Amikacin is administered intravenously or intramuscularly. Amikacin distributes into extracellular fluid. Volume of distribution approximates extracellular space; therefore, peak serum concentrations may be lower in patients with a large volume of extracellular fluid. The volume of distribution may be higher in patients with sepsis, fever, severe burns, congestive cardiac failure, and peritonitis which may result in lower peak concentrations. Protein binding ranges from 0% to 11%. After administration, amikacin can be detected in bone, heart, gallbladder, and lung tissues as well as in the urine, sputum, bronchial secretions, and interstitial fluid, pleural fluid, and synovial fluid. Concentrations in the cerebrospinal fluid (CSF) in normal infants are approximately 10% to 20% of the serum concentrations, but may reach 50% with inflamed meninges. Amikacin is not metabolized. Elimination is almost exclusively via glomerular filtration. Thus, elimination half-life varies according to renal function. Reabsorption of a small amount of the drug by the proximal tubule results in accumulation in the renal cortex, which may be responsible for nephrotoxicity. Animal models suggest that amikacin and tobramycin have a diminished affinity for the proximal tubule. In patients with normal renal function 94% to 98% of the dose is recovered in the urine within 24 hours. In children with normal renal function, the serum half-life is approximately 1 to 2 hours; however, there is considerable interpatient variation.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
After IV administration, there is an acute distribution phase, followed by a linear elimination phase.

Intramuscular Route
Amikacin is rapidly absorbed after intramuscular administration with peak serum concentrations occurring about 1 hour after administration.


-Special Populations
Pediatrics
Neonates
Pharmacokinetics are highly variable in neonates, with factors such as renal maturation and postmenstrual age playing a significant role. Neonates have a larger volume of distribution (Vd) and a reduced clearance compared with children and adults. In an analysis of pharmacokinetic studies of amikacin in neonates with varying gestational ages and postnatal days, the Vd ranged from 0.34 to 0.72 L/kg, clearance ranged from 0.36 to 1.71 mL/kg/minute, and elimination half-life ranged from approximately 2.8 to 16.4 hours. Clearance increases with increasing gestational age (GA). In one study (n = 715), the clearance increased from 0.84 L/hour/70 kg at a postmenstrual age (PMA) of 28 weeks to 1.23 L/hour/70 kg by a PMA of 34 weeks and 1.56 L/hour/70 kg by a PMA of 40 weeks. In another study (n = 177), The clearance increased from 0.73 mL/kg/minute at a GA younger than 28 weeks to 1.15 mL/kg/minute at a GA of 37 to 41 weeks. The half-life decreased from 12.2 hours to 5.55 hours in the same populations.

Infants, Children, and Adolescents
Volume of distribution (Vd) is approximately 0.25 L/kg in children and adolescents. In children and adolescents with normal renal function, the serum half-life is approximately 1 to 2 hours, which is similar to adults. Infants may have a slightly longer half life. However, there is considerable interpatient variation.

Renal Impairment
In patients with impaired renal function, the amikacin serum elimination half-life can be 24 hours or longer. Aminoglycosides are removed efficiently by hemodialysis.