VA Class:AM300

AHFS Class:

• Aminoglycosides 8:12.02

Generic Name(s):

• Amikacin Sulfate

Associated Monographs

• Aminoglycosides General Statement

Amikacin is a semisynthetic aminoglycoside antibiotic derived from kanamycin A.1,2,3,4,11,12

Serious Bacterial Infections

Amikacin is used for the short-term treatment of serious infections caused by susceptible gram-negative bacteria, including Acinetobacter , Escherichia coli , Enterobacter , Klebsiella , Proteus , Providencia , Pseudomonas , or Serratia marcescens .1,2,3 Amikacin may be the preferred aminoglycoside for initial treatment of serious nosocomial gram-negative infections, especially in areas where resistance to gentamicin and tobramycin has been reported.4,11

Although amikacin and other aminoglycosides are not usually recommended for the treatment of staphylococcal infections, the manufacturers state that amikacin may be considered for the treatment of known or suspected staphylococcal infections in certain situations.1,2,3 This includes initial treatment of severe infections when the causative organisms may be either gram-negative bacteria or staphylococci, treatment of infections caused by susceptible staphylococci in patients hypersensitive to other more appropriate anti-infectives, and treatment of mixed infections that may involve both gram-negative bacteria and staphylococci.1,2,3

Intra-abdominal Infections

Amikacin is used for the treatment of serious intra-abdominal infections (including peritonitis) caused by susceptible gram-negative bacteria, including Acinetobacter , Enterobacter , E. coli , Klebsiella , Proteus , Providencia , Serratia , or Pseudomonas .1,2,5,57 Amikacin usually is used as an adjunct to other appropriate anti-infectives (e.g., clindamycin, metronidazole, piperacillin and tazobactam, ampicillin and sulbactam).5,57

The Infectious Diseases Society of America (IDSA) states that patients with community-acquired intra-abdominal infections of mild to moderate severity may receive initial treatment with an empiric regimen of the fixed combination of ampicillin and sulbactam, cefazolin or cefuroxime in conjunction with metronidazole, the fixed combination of ticarcillin and clavulanate, ertapenem monotherapy, or a fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin) in conjunction with metronidazole.57 Patients who are immunosuppressed or have more severe community-acquired intra-abdominal infections should receive a regimen that has a broader spectrum of activity such as meropenem monotherapy; imipenem and cilastatin monotherapy; a third or fourth generation cephalosporin (cefotaxime, ceftriaxone, ceftazidime, cefepime) in conjunction with metronidazole; ciprofloxacin in conjunction with metronidazole; the fixed combination of piperacillin and tazobactam; or aztreonam in conjunction with metronidazole.57

IDSA states that aminoglycosides are not recommended for routine use in community-acquired intra-abdominal infections; however, an aminoglycoside may be included in empiric regimens for the treatment of nosocomial intra-abdominal infections, depending on local patterns of in vitro susceptibility of nosocomial isolates.57 IDSA states that aminoglycosides generally should be reserved for when β-lactams and fluoroquinolones cannot be used.57 Other clinicians suggest that severely ill patients and those with prolonged hospitalization should receive an initial regimen that includes an antipseudomonal agent such as an antipseudomonal penicillin (ticarcillin and clavulanate, piperacillin and tazobactam), a carbapenem (imipenem or meropenem), ceftazidime, or cefepime used in conjunction with metronidazole.5 These clinicians state that an aminoglycoside also could be included in the empiric regimen.5

Meningitis and Other CNS Infections

Amikacin is used for the treatment of meningitis caused by susceptible gram-negative bacteria.1,2,3,4,5,15,33,37,38,39,64,77 Like other aminoglycosides, amikacin should not be used alone for the treatment of meningitis, but may be used in conjunction with other anti-infectives.4,33

Amikacin has been used in conjunction with ampicillin for initial empiric treatment of meningitis caused by Streptococcus agalactiae (group B streptococci) in neonates or for Listeria monocytogenes meningitis in children.6 Concomitant use of amikacin and a third-generation cephalosporin also has been used for the treatment of neonatal gram-negative bacterial meningitis, including infections caused by E. coli .15 In adults, amikacin has been used concomitantly with imipenem for the treatment of meningitis caused by E. coli ,33 concomitantly with meropenem for the treatment of meningitis caused by Pseudomonas , or concomitantly with imipenem or colistin (commercially available as colistimethate sodium) for the treatment of meningitis caused by Acinetobacter .37,38 To provide higher amikacin CSF concentrations for the treatment of meningitis, amikacin has been given intrathecally† or intraventricularly† concomitantly with IM or IV administration.4,19,33,34,35,38,39 Although concomitant parenteral and intrathecal or intraventricular therapy may result in higher anti-infective CSF concentrations, such therapy also may be associated with increased mortality in neonates.73

Mycobacterial Infections

Active Tuberculosis

Amikacin is used in conjunction with antituberculosis agents for the treatment of active tuberculosis†.218

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) recommend several possible multiple-drug regimens for the treatment of culture-positive pulmonary tuberculosis.218 These regimens have a minimum duration of 6 months (26 weeks), and consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).218

Amikacin is considered a second-line agent for use in multiple-drug regimens in patients with relapse, treatment failure, or Mycobacterium tuberculosis resistant to isoniazid and/or rifampin or when first-line drugs cannot be tolerated.218 If amikacin is added as a new drug to a regimen in patients experiencing treatment failure who have proven or suspected drug-resistant tuberculosis, at least 2 (preferably 3) new drugs known or expected to be active against the resistant strain should be added at the same time.218 After results of in vitro susceptibility testing are available, the regimen can be adjusted accordingly.218 Streptomycin-resistant M. tuberculosis may be susceptible to both amikacin and kanamycin;218 complete cross-resistance usually occurs between amikacin and kanamycin.4,218 Patients with treatment failure or drug-resistant M. tuberculosis should be managed in consultation with an expert in the treatment of tuberculosis.218

For information on general principles of antituberculosis therapy and recommendations regarding specific multiple-drug regimens and duration of therapy, see the Antituberculosis Agents General Statement 8:16.04.

Other Mycobacterial Infections

Amikacin has been used as an alternative agent in multiple-drug regimens used for the treatment of M. avium complex† (MAC) infections.5,9,58,59,60,61 A regimen of amikacin, ethambutol, rifampin, and ciprofloxacin and a regimen of amikacin, ethambutol, ciprofloxacin, and clarithromycin or azithromycin has been used with some success in HIV-infected patients.59,60 However, there was no evidence that addition of amikacin to a regimen of rifampin, ethambutol, clofazimine, and ciprofloxacin provided any additional benefit in HIV-infected patients.61

Amikacin is used in conjunction with other antimycobacterial anti-infectives for the treatment of nonpulmonary infections caused by M. abscessus †,6,9 M. chelonae †,4 and M. fortuitum †.4,5,6,9

Nocardia Infections

Amikacin is used in the treatment of infections caused by Nocardia †.4,5,6,41,42,65,66,67,68,69 Sulfonamides (usually co-trimoxazole) are the treatment of choice for most Nocardia infections;4,5,6,42,65,69 concomitant use of amikacin, imipenem, and/or ceftriaxone is recommended for initial treatment of severe or disseminated infections.6,65 When sulfonamides cannot be used, some clinicians recommend regimens containing amikacin, a carbapenem (imipenem or meropenem), a third-generation cephalosporin (ceftriaxone), a tetracycline (doxycycline, minocycline), fixed combination of amoxicillin and clavulanate, clarithromycin, cycloserine, or linezolid.4,5,6,65,69 In vitro susceptibility testing, if available, is recommended for Nocardia isolates from patients with invasive disease and those unable to tolerate a sulfonamide.6,65 Prolonged treatment is necessary.6,65,68,69

Rhodococcus Infections

Amikacin is used for the treatment of infections caused by Rhodococcus equi †.5 Optimum regimens for these infections have not been identified, but combination regimens have been recommended.40 Some clinicians suggest that the regimen of choice is vancomycin with or without a fluoroquinolone, rifampin, carbapenem (imipenem or meropenem), or amikacin.5

Empiric Therapy in Febrile Neutropenic Patients

Amikacin is used for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients†.4,5,8,62,63,75 Amikacin is used in conjunction with an appropriate antipseudomonal cephalosporin (e.g., ceftazidime, ceftriaxone, cefepime), extended-spectrum penicillin (e.g., piperacillin and tazobactam, ticarcillin and clavulanate), or carbapenem (e.g., imipenem, meropenem).5,8,62,63,75,75

Published protocols for the treatment of infections in febrile neutropenic patients should be consulted for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.8 Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also is advised.8

Administration

Amikacin sulfate is administered by IM injection or IV infusion.1,2,3

Amikacin sulfate has been given intrathecally† or intraventricularly† as an adjunct to IM or IV administration of the drug for the treatment of meningitis and other CNS infections.4,19,33,34,35,37,38,39

Although amikacin has been given intraperitoneally†,30,55,66 the risk of toxicity associated with this route should be considered.4 (See Cautions in the Aminoglycosides General Statement 8:12.02.)

Patients should be well hydrated prior to and during amikacin therapy to minimize chemical irritation of renal tubules which may occur as the result of high urine amikacin concentrations.1,2,3

Renal function should be assessed prior to and daily during amikacin therapy.1,2,3 Patients should be under close clinical observation because of the risk of ototoxicity and nephrotoxicity.1,2,3 (See Cautions in the Aminoglycosides General Statement 8:12.02.)

Prior to administration, amikacin solutions should be inspected visually for particulate matter or discoloration.1,2,3

IM Injection

For IM injection, the appropriate dose of commercially available injection containing amikacin in a concentration of 50 or 250 mg/mL should be given undiluted.1,2,3 IM injections of amikacin have been given into the upper outer quadrant of the buttocks.16

IV Infusion

IV infusions for adults are prepared by adding 500 mg of amikacin to 100-200 mL of compatible IV infusion fluid (e.g., 0.9% sodium chloride, 5% dextrose).1,2,3 (See Chemistry and Stability: Stability.) For pediatric patients, the volume of diluent depends on the dosage of amikacin prescribed and is chosen to provide the appropriate infusion rate.1,2,3

Amikacin should not be admixed with other drugs or infused simultaneously through the same tubing with other drugs.1,2,3,7 If a β-lactam anti-infective (e.g., cephalosporin, penicillin) is administered concomitantly with amikacin, the drugs should not be admixed and should be administered separately.1,2,3,7

Rate of Administration

In adults, IV infusions of amikacin should be given over 30-60 minutes.1,2,3

In pediatric patients, the volume of infusion fluid should be sufficient to provide an infusion period of 1-2 hours in infants or 30-60 minutes in older children.1,2,3

Dosage

Dosage of amikacin sulfate is expressed in terms of amikacin.1,2,3 IM and IV dosage is identical.1,2,3

Like other aminoglycosides, dosage of amikacin should be individualized taking into consideration the patient's pretreatment body weight, renal status, severity of the infection, and susceptibility of the causative organism.1,2,3,4,11,200,201,202,203,204,216 Many clinicians recommend that amikacin dosage be determined using appropriate pharmacokinetic methods for calculating dosage requirements and patient-specific pharmacokinetic parameters (e.g., elimination rate constant, volume of distribution) derived from serum concentration-time data.11,200,201,202,203,204,216

Whenever possible, especially in patients with life-threatening infections, suspected toxicity or nonresponse to treatment, decreased or varying renal function, and/or when increased aminoglycoside clearance (e.g., patients with cystic fibrosis, burns) or prolonged therapy is likely, peak and trough serum concentrations of amikacin should be determined periodically and dosage should be adjusted to maintain desired serum concentrations.4,11,207,216,219,222,223,228,236,237 (See Dosage and Administration: Dosage, in the Aminoglycosides General Statement 8:12.02.) A causal relationship between maintenance of certain peak or trough serum concentrations or other pharmacodynamic endpoints and clinical response or toxicity has not been established to date for amikacin dosing regimens.205,206,219,220,221 However, for amikacin administered in conventional dosage regimens (i.e., multiple daily doses), peak serum concentrations of 15-30 and trough concentrations less than 5-10 mcg/mL have been suggested.4,11,14,216,222,225,226,227,238,239 Amikacin serum concentrations greater than 30-35 mcg/mL may be associated with toxicity.14 The manufacturers recommend that peak serum concentrations (30-90 minutes after injection) greater than 35 mcg/mL and trough serum concentrations (just prior to the next dose) greater than 10 mcg/mL should be avoided.1,2,3

Parenteral aminoglycosides historically have been administered in dosage regimens that include multiple daily doses,4,11,216 and current prescribing information for IM or IV amikacin only includes dosage regimens that involve multiple daily doses (usually 2 or 3 doses daily).1,2,3 However, there is evidence that once-daily† (single-daily) aminoglycoside dosage regimens are at least as effective as, may provide superior pharmacokinetics, and may be less toxic than conventional dosage regimens employing multiple daily doses.11,48,49,50,52,56,62,74,75,76,205,206,207,208,209,210,211,212,213,214,215,216,217,228,229,230,231,232,233,234,235,243,245,246,247,248 Once-daily parenteral aminoglycoside regimens should not be used in all patients.11,252 Additional controlled studies in children, patients with renal dysfunction, and other appropriate patient groups are needed to fully define the optimal use of once-daily aminoglycoside dosing regimens.202,204,205,207,208,209,210,216,229,232,235,244,247,248,249,250,251,252,253 In addition, the most appropriate methods for optimizing dosage selection for once-daily regimens and monitoring serum aminoglycoside concentrations in patients receiving such regimens have not been clearly established.243,245,247,249,251,252,253,254,255,256,257,258 (See Dosage and Administration: Dosage, in the Aminoglycosides General Statement 8:12.02.)

The usual duration of amikacin treatment is 7-10 days.1,2,3 The manufacturers state that safety of amikacin treatment for longer than 14 days has not been established.1,2,3 If a clinical response does not occur within 3-5 days, amikacin should be discontinued and in vitro susceptibility to the drug should be reassessed.1,2,3 In difficult and complicated infections, use of amikacin should be re-evaluated if treatment longer than 10 days is being considered.1,2,3 If the drug is continued, serum amikacin concentrations and renal, auditory, and vestibular functions should be monitored closely.1,2,3

The maximum dosage of amikacin recommended by the manufacturers is 15 mg/kg (up to 1.5 g) daily.1,2,3

Adult Dosage

General Adult Dosage

If IM or IV amikacin is used for the treatment of serious infections caused by susceptible bacteria in adults with normal renal function, the usual adult dosage recommended by the manufacturers is 15 mg/kg daily given in 2 or 3 equally divided doses (i.e., 5 mg/kg every 8 hours or 7.5 mg/kg every 12 hours).1,2,3

Adults have received amikacin in a once-daily† regimen of 15 mg/kg once daily.11,49

Active Tuberculosis

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that the usual dosage of IM or IV amikacin for use in conjunction with other antituberculosis agents for the treatment of active tuberculosis† in adults is 15 mg/kg daily (up to 1 g) given as a single daily dose (usually 750-1000 mg daily) 5-7 times weekly for the first 2-4 months or until culture conversion; dosage can then be reduced to 15 mg/kg daily (up to 1 g) given 2 or 3 times weekly, depending on efficacy of the other drugs in the regimen.218

The ATS, CDC, and IDSA recommend that adults older than 59 years of age receive a dosage of 10 mg/kg (up to 750 mg) daily.218

Other Mycobacterial Infections

Amikacin has been given IM or IV in a dosage of 7.5-15 mg/kg daily in conjunction with other antimycobacterial anti-infectives for the treatment of infections caused by Mycobacterium avium complex† (MAC).58,59,60,61

For the treatment of infections caused by M. abscessus † or M. fortuitum †, IV amikacin has been given in a dosage of 10-15 mg/kg daily in 2 divided doses in conjunction with other antimycobacterial anti-infectives.9

Meningitis

If amikacin is used for the treatment of meningitis, some clinicians recommend that adults receive 15 mg/kg daily given in 3 divided doses.77

In adults with meningitis caused by susceptible gram-negative bacteria, 4-20 mg of amikacin has been administered intrathecally† or intraventricularly† as a single daily dose4,19,33,35,37 in conjunction with IM or IV amikacin given in a dosage of 7.5 mg/kg every 12 hours.19,33,35,37

Nocardiosis

For the treatment of nocardiosis†, IM or IV amikacin has been given in a dosage of 5-7.5 mg/kg every 12 hours.69

Urinary Tract Infections

If amikacin is used for the treatment of uncomplicated urinary tract infections caused by susceptible bacteria when other less toxic anti-infectives cannot be used, the usual adult dosage is 250 mg twice daily.1,2,3

Empiric Therapy in Febrile Neutropenic Patients

For empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients†, adults have received IV amikacin in a dosage of 7.5 mg/kg twice daily in conjunction with IV ceftazidime or IV cefepime.63

Pediatric Dosage

General Dosage for Neonates

The manufacturers state that amikacin should be used with caution in premature and full-term neonates because renal immaturity in these patients may result in a prolonged serum half-life of the drug.1,2,3

When IM or IV amikacin is used in neonates, the manufacturers recommend an initial loading dose of 10 mg/kg followed by 7.5 mg/kg every 12 hours.1,2,3

The American Academy of Pediatrics (AAP) recommends that neonates younger than 1 week of age receive IM or IV amikacin in a dosage of 7.5 mg/kg every 18-24 hours if they weigh less than 1.2 kg, 7.5 mg/kg every 12 hours if they weigh 1.2-2 kg, or 7.5-10 mg/kg every 12 hours if they weigh more than 2 kg.6 For neonates 1-4 weeks of age, the AAP recommends a dosage of 7.5 mg/kg every 18-24 hours for those weighing less than 1.2 kg, 7.5-10 mg/kg every 8 or 12 hours for those weighing 1.2-2 kg, and 10 mg/kg every 8 hours for those weighing more than 2 kg.6 The AAP states that the drug is inappropriate for the treatment of mild to moderate infections.6

Full-term neonates have received amikacin in a once-daily† regimen of 15 mg/kg once daily.48,56,76

General Dosage for Infants and Children

The usual dosage of IM or IV amikacin recommended by the manufacturers for children and older infants with normal renal function is 15 mg/kg daily given in 2 or 3 equally divided doses (i.e., 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours).1,2,3

The AAP recommends that pediatric patients beyond the neonatal period receive IM or IV amikacin in a dosage of 15-22.5 mg/kg daily given in 3 equally divided doses for the treatment of severe infections.6 Some clinicians suggest a dosage of 30 mg/kg daily given in 3 equally divided doses in this age group.6 The AAP states that the drug is inappropriate for the treatment of mild to moderate infections.6

Children have received amikacin in a once-daily† regimen of 15-20 mg/kg once daily.50,54,62,74,76

Active Tuberculosis

For the treatment of active tuberculosis† in children younger than 15 years of age or weighing 40 kg or less, the ATS, CDC, and IDSA state that the usual dosage of IM or IV amikacin for use in conjunction with other antituberculosis agents is 15-30 mg/kg daily (up to 1 g) given once daily or twice weekly.218

For the treatment of active tuberculosis in children 15 years of age or older or weighing more than 40 kg, the ATS, CDC, and IDSA state that the usual dosage of IM or IV amikacin for use in conjunction with other antimycobacterial agents is 15 mg/kg daily (up to 1 g) given as a single daily dose (usually 750-1000 mg daily) 5-7 times weekly for the first 2-4 months or until culture conversion; dosage can then be reduced to 15 mg/kg daily (up to 1 g) given 2 or 3 times weekly, depending on efficacy of the other drugs in the regimen.218

When IM or IV amikacin is used for the treatment of drug-resistant tuberculosis, the AAP recommends that infants, children, or adolescents receive a dosage of 15-30 mg/kg daily (up to 1 g).6

Meningitis

If parenteral amikacin is used for the treatment of meningitis, some clinicians recommend that neonates 7 days of age or younger receive 15-20 mg/kg daily given in 2 divided doses and that older neonates and children receive 20-30 mg/kg daily given in 3 divided doses.64,77 Smaller doses and longer intervals between doses may be indicated in neonates weighing less than 2 kg.64,77

Empiric Therapy in Febrile Neutropenic Patients

For empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients†, children 1-17 years of age have received IV amikacin in a dosage of 20 mg/kg once daily or 6.5 mg/kg 3 times daily has been used in conjunction with IV ceftazidime.62

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of amikacin must be modified in response to serum concentrations of the drug and the degree of renal impairment.4,6,11,14,24 There are various methods to determine dosage and a wide variation in dosage recommendations for these patients.4,6,11,14,24 However, even when one of these methods is used, peak and trough serum concentrations of the drug should be monitored, especially in patients with changing renal function.4,6,11,14

The manufacturers recommend an initial amikacin loading dose of 7.5 mg/kg.1,2,3 For subsequent therapy, the manufacturers state that 7.5-mg/kg doses can be given at intervals (in hours) calculated by multiplying the patient's steady-state serum creatinine (in mg/dL) by 9.1,2,3 Alternatively, many clinicians recommend the dosing method of Sarubbi and Hull, which is based on corrected creatinine clearance. (See Dosage and Administration: Dosage in Renal Impairment, in the Aminoglycosides General Statement 8:12.02.)

In adults with renal failure undergoing hemodialysis, some clinicians recommend supplemental doses of 50-75% of the initial loading dose at the end of each dialysis period.14 Others suggest that supplemental amikacin doses may not be necessary in patients undergoing short-term hemodialysis.51 Serum amikacin concentrations should be monitored in dialysis patients and dosage adjusted as needed to maintain desired serum concentrations.14,51

For the treatment of active tuberculosis† in adults with renal impairment, the ATS, CDC, and IDSA recommend that usual doses be given at less frequent intervals since use of lower doses may reduce efficacy of the drug.218 These experts recommend that adults with renal impairment receive amikacin in a dosage of 12-15 mg/kg daily given 2 or 3 times weekly.218 In addition, if the patient is receiving hemodialysis, the dose should be given after the procedure is finished and serum concentrations of the drug monitored to avoid toxicity.218

Pharmacokinetics

The pharmacokinetics of amikacin are similar to those of the other aminoglycosides.4 In all studies described in the Pharmacokinetics section, amikacin was administered as the sulfate salt; dosages and concentrations of the drug are expressed in terms of amikacin.

Absorption

Amikacin is poorly absorbed from the GI tract.4,11

Amikacin is rapidly absorbed following IM administration.1,2,3,11 Following IM administration of a single 7.5-mg/kg dose of amikacin in adults with normal renal function, peak plasma amikacin concentrations are attained within about 0.5-2 hours and average 17-25 mcg/mL;1,2,3,13,16 plasma concentrations 10 hours after the dose average 2.1 mcg/mL.1,2,3

When a 7.5-mg/kg dose of amikacin is administered by IV infusion over 30 minutes, peak plasma concentrations of the drug average 38 mcg/mL immediately following the infusion, 18 mcg/mL at 1 hour, and 0.75 mcg/mL at 10 hours.1,2,3 In adults receiving 15 mg/kg once daily by IV infusion over 30 minutes, peak serum concentrations (measured 30 minutes after completion of an infusion) were 40.9 mcg/mL and trough concentrations (measured immediately before start of an infusion) were 1.8 mcg/mL.4,230

In a study in neonates, peak serum amikacin concentrations of 17-20 mcg/mL were attained 30 minutes after a single 7.5-mg/kg IM dose of the drug.18 In a study in infants (mean age 3.5 months) with serious infections, serum amikacin concentrations after a single 7.5-mg/kg dose ranged from 11.8-23 mcg/mL at 30-60 minutes after the dose, averaged 4.2 mcg/mL 4 hours after the dose, and were undetectable (less than 0.8 mcg/mL) 12 hours after the dose.36 When this same dose was given to children up to 6 years of age (mean age 3.1 years), peak serum amikacin concentrations were attained 30-60 minutes after the dose and ranged from 9-29 mcg/mL; serum concentrations 4 hours after the dose averaged 3.7 mcg/ml and the drug was undetectable (less than 0.8 mcg/mL) 12 hours after the dose.36

Plasma concentrations of amikacin may be lower in pregnant women than in nonpregnant patients, probably because of an increased volume of distribution and increased glomerular filtration rate.4

Accumulation of amikacin does not appear to occur in adult or pediatric patients with normal renal function receiving usual dosages of the drug twice daily for 4-10 days.1,2,3,23,36

Distribution

Following administration of usual dosages of amikacin, therapeutic concentrations of the drug are achieved in bone,1,2,3 heart,1,2,3 gallbladder,1,2,3,4 and lung tissue.1,2,3 Amikacin also is well distributed into urine,1,2,3,4 bile,1,2,3,4,31,32 sputum,1,2,3,27,43 bronchial secretions,1,2,3,26,44,45 and interstitial,1,2,3 pleural,1,2,3 and synovial fluids.1,2,3,46,99

In a study in adults with bronchopneumonia who received IV amikacin in a dosage of 15 mg/kg once daily or 7.5 mg/kg twice daily, mean concentrations of amikacin in bronchial secretions (3 hours after initiation of the IV infusion on day 1) were 13.6 or 4.8 mcg/mL, respectively.26 In the group that received the once-daily regimen, mean concentrations in bronchial secretions remained above 8 mcg/mL for 12 hours after a dose while mean concentrations in bronchial secretions remained at 3-4 mcg/mL for a 24-hour period in those receiving the twice-daily regimen.26

Amikacin is distributed into CSF in low concentrations following IM or IV administration.1,2,3,4,25 In infants, CSF concentrations may be 10-20% of concurrent serum concentrations, but may be 50% of concurrent serum concentrations in those with inflamed meninges.1,2,3 In a study in children 4 months to 8 years of age with bacterial meningitis who received 7.5 mg/kg of amikacin twice daily by IV infusion over 30 minutes in conjunction with IV ceftriaxone (amikacin infusions were started 1 hour after ceftriaxone infusions were completed), CSF concentrations 3 hours after the third amikacin dose averaged 1.65 mcg/mL.25

In one adult with meningitis, intrathecal administration of 4 mg of amikacin daily in conjunction with IM administration of 15 mg/kg daily for 2 weeks resulted in CSF concentrations of the drug ranging from 7-40 mcg/mL 12 hours after an intrathecal dose and 1-19 mcg/mL 24 hours after an intrathecal dose.19

The apparent volume of distribution of amikacin in healthy adults averages about 24 L (28% of body weight).1,2,3,16 The apparent volume of distribution of the drug in neonates indicates that amikacin is distributed principally into the extracellular fluid volume in this age group.1,2,3

Amikacin crosses the placenta and is distributed into amniotic fluid.1,2,3,4 Peak fetal serum concentrations are about 16% of peak maternal serum concentrations.1,2,3

Amikacin is distributed into milk in low concentrations.259

Elimination

The plasma elimination half-life of amikacin usually is 2-3 hours in adults with normal renal function1,2,3,4,13,14,16,17,20 and is reported to range from 28-86 hours in adults with severe renal impairment.4,14,21,22,24

The plasma elimination half-life of amikacin is reported to be 4-5 hours in full-term infants 7 days of age or older and 7-8 hours in low birth-weight infants 1-3 days of age.18,23,53 In preterm neonates, half-life is inversely related to postconceptional age and has ranged from 4.5-15.6 hours.47 In one study in infants and children 20 days to 6 years of age, mean plasma half-life after a single 7.5-mg/kg IM dose was about 2 hours.36

In adults with normal renal function, 94-98% of a single IM or IV dose of amikacin is excreted unchanged by glomerular filtration within 24 hours.1,2,3,4,17 Urine concentrations of amikacin average 563 mcg/mL for 6 hours following a single 250-mg IM dose and 832 mcg/mL following a single 500-mg IM dose in adults with normal renal function.1,2,3

Amikacin is removed by hemodialysis.4,28 The drug also is removed by peritoneal dialysis, including continuous ambulatory peritoneal dialysis.4,30

Chemistry and Stability

Chemistry

Amikacin is a semisynthetic aminoglycoside antibiotic derived from kanamycin A.1,2,3,4,11,12 The drug is commercially available as the sulfate salt.1,2,3 Amikacin sulfate occurs as a white, crystalline powder and is freely soluble in water.10 Commercially available amikacin sulfate injection is a colorless to light straw-colored solution;1,2 sulfuric acid is added during the manufacturing process to adjust the pH to 3.5-5.5.1,2

Stability

Amikacin sulfate injection should be stored at 15-30°C.1,2,3 Although amikacin sulfate solutions may become light straw-colored during storage, this does not indicate loss of potency.1,2,3

Amikacin sulfate is stable for 24 hours at room temperature at concentrations of 0.25 and 5 mg/mL in most IV infusion fluids, including 0.9% sodium chloride, 5% dextrose injection, 5% dextrose in 0.2 or 0.45% sodium chloride injection, lactated Ringer's injection, Normosol-M^® or Normosol-R^® in 5% dextrose injection, Plasma-Lyte 56 or 148 in 5% dextrose injection.1,2,3 The above solutions also are stable for 24 hours at room temperature after being refrigerated at 4°C for 60 days or after being frozen for 30 days at -15°C.2 Amikacin sulfate injection should not be mixed with other drugs.1,2,3

Additional Information

For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, and dosage and administration of amikacin, see the Aminoglycosides General Statement 8:12.02.

1. Hospira. Amikacin sulfate injection, USP fliptop vial prescribing information. Lake Forest, IL; 2004 Apr.

2. Bedford. Amikacin sulfate injection, USP prescribing information. Bedford, OH; 2004 Jan.

3. Sicor. Amikacin sulfate injection USP. Irvine, CA; 2005 Jun.

4. Kucers A, Crowe S, Grayson ML et al, eds. The use of antibiotics. A clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Jordan Hill, Oxford: Butterworth-Heinemann; 1997: 504-21.

5. Anon. The choice of antibacterial drugs. Med Lett Treat Guid . 2004; 2:13-26.

6. American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

7. Trissel LA. Handbook on injectable drugs. 13th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2005:39-50.

8. Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis . 2002; 34:730-51. [PubMed 11850858]

9. American Thoracic Society. Supplement: American Thoracic Society—Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med . 1997; 156(2 Part 2):S1-19.

10. The United States pharmacopoeia, 29th rev, and The national formulary, 24th ed. Rockville, MD: The United States Pharmacopeial Convention; 2005:127-8,3192.

11. Chambers HF. Aminoglycosides. In: Brunton LL, Lazo JS, Parker KL et al, eds. Goodman and Gillman's the pharmacological basis of therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006:1155-71.

12. Kawaguchi H. Discovery, chemistry, and activity of amikacin. J Infect Dis . 1978; 134(Suppl):242-8.

13. Kaplan MA, Coppola WP, Nunning BC et al. Pharmaceutical properties and stability of amikacin. Curr Ther Res Clin Exp . 1976; 20:352-8. [PubMed 12916]

14. Barza M, Scheife RT. Drug therapy reviews: antimicrobial spectrum, pharmacology and therapeutic use of antibiotics, part 4: aminoglycosides. Am J Hosp Pharm . 1977; 34:723-37. [PubMed 407790]

15. Dellagrammaticas HD, Christodoulou C, Megaloyanni E et al. Treatment of gram-negative bacterial meningitis in term neonates with third generation cephalosporins plus amikacin. Biol Neonate . 2000; 77:139-46. [PubMed 10729716]

16. Clarke JR, Libke RD, Regamey C et al. Comparative pharmacokinetics of amikacin and kanamycin. Clin Pharmacol Ther . 1974; 15:610-6. [PubMed 4210297]

17. Lode H, Grunert K, Koeppe P et al. Pharmacokinetic and clinical studies with amikacin, a new aminoglycoside antibiotic. J Infect Dis . 1976; 134(Suppl):316-22.

18. Howard JB, McCracken GH, Trujillo H et al. Amikacin in newborn infants: comparative pharmacology with kanamycin and clinical efficacy in 45 neonates with bacterial diseases. Antimicrob Agents Chemother . 1976; 10:205-10. [PubMedCentral][PubMed 984762]

19. Hamory B, Ignatiadis P, Sande MA. Intrathecal amikacin administration-use in the treatment of gentamicin-resistant Klebsiella pneumoniae meningitis. J AMA . 1976; 236:1973-4.

20. Bodey GP, Valdivieso M, Feld R et al. Pharmacology of amikacin in humans. Antimicrob Agents Chemother . 1974; 5:508-12. [PubMedCentral][PubMed 4462465]

21. Appel GB, Neu HC. The nephrotoxicity of antimicrobial agents, part 2. N Engl J Med . 1977; 296:722-8. [PubMed 190540]

22. Bennett WM, Muther RS, Parker RA et al. Drug therapy in renal failure: dosing guidelines for adults. Ann Intern Med . 1980; 93:62-89. [PubMed 6994534]

23. Howard JB, McCracken GH. Pharmacological evaluation of amikacin in neonates. Antimicrob Agents Chemother . 1975; 8:86-90. [PubMedCentral][PubMed 1164009]

24. Pijck J, Hallynck T, Soep H et al. Pharmacokinetics of amikacin in patients with renal insufficiency: relation of half-life and creatinine clearance. J Infect Dis . 1976; 134(Suppl):S331-41.

25. Gaillard JL, Silly C, Le Masne A et al. Cerebrospinal fluid penetration of amikacin in children with community-acquired bacterial meningitis. Antimicrob Agents Chemother . 1995; 39:253-5. [PubMedCentral][PubMed 7695318]

26. Santre C, Georges H, Jacquier JM et al. Amikacin levels in bronchial secretions of 10 pneumonia patients with respiratory support treated once daily versus twice daily. Antimicrob Agents Chemother . 1995; 39:264-7. [PubMedCentral][PubMed 7695320]

27. Canis F, Husson MO, Turck D et al. Pharmacokinetics and bronchial diffusion of single daily dose amikacin in cystic fibrosis patients. J Antimicrob Chemother . 1997; 39:431-3. [PubMed 9096197]

28. Kihara M, Ikeda Y, Takagi N et al. Pharmacokinetics of single-dose intravenous amikacin in critically ill patients undergoing slow hemodialysis. Intensive Care Med . 1995; 21:348-51. [PubMed 7650258]

30. Smeltzer BD, Schwartzman MS, Bertino JS. Amikacin pharmacokinetics during continuous ambulatory peritoneal dialysis. Antimicrob Agents Chemother . 1988; 32:236-40. [PubMedCentral][PubMed 3364945]

31. Bermudez RH, Lugo A, Ramirez-Ronda CH et al. Amikacin sulfate levels in human serum and bile. Antimicrob Agents Chemother . 1981; 19:352-4. [PubMedCentral][PubMed 7347566]

32. Hansbrough JF, Clark JE, Reimer LG. Concentrations of kanamycin and amikacin in human gallbladder bile and wall. Antimicrob Agents Chemother . 1981; 20:515-7. [PubMedCentral][PubMed 7342877]

33. Preston SL, Briceland LL. Intrathecal administration of amikacin for treatment of meningitis secondary to cephalosporin-resistant Escherichia coli . Ann Pharmacother . 1993; 27:870-3. [PubMed 8364266]

34. Wright PF, Kaiser AB, Bowman CM et al. The pharmacokinetics and efficacy of an aminoglycoside administered into the cerebral ventricles in neonates: implications for further evaluation of this route of therapy in meningitis. J Infect Dis . 1981; 143:141-7. [PubMed 7012246]

35. Block CS, Cassel R, Koornhof HJ. Klebsiella meningitis treated with intrathecal amikacin. Lancet . 1977; 1:1371-2. [PubMed 69095]

36. Kafetzis DA, Sinaniotis CA, Papadatos CJ et al. Pharmacokinetics of amikacin in infants and pre-school children. Acta Paediatr Scand . 1979; 68:419-22. [PubMed 443042]

37. Fulnecky EJ, Wright D, Scheld WM et al. Amikacin and colistin for treatment of Acinetobacter baumannii meningitis. J Infect . 2005; 51:e249-51. [PubMed 15913780]

38. Nguyen MH, Harris SP, Muder RR et al. Antibiotic-resistant Acinetobacter meningitis in neurosurgical patients. Neurosurgery . 1994; 35:851-5. [PubMed 7838333]

39. Corpus KA, Weber KB, Zimmerman CR. Intrathecal amikacin for the treatment of pseudomonal meningitis. Ann Pharmacother . 2004; 38:992-5. [PubMed 15122005]

40. Torres-Tortosa M, Arrizabalaga J, Villanueva JL et al. Prognosis and clinical evaluation of infection caused by Rhodococcus equi in HIV-infected patients. Chest . 2003; 123:1970-6. [PubMed 12796176]

41. Kashima M, Kano R, Mikami Y et al. A successfully treated case of mycetoma due to Nocardia veterana . Br J Dermatol . 2005; 142:1349-52.

42. Hitti W, Wolff M. Two cases of multidrug-resistant Nocardia farcinica infection in immunosuppressed patients and implications for empiric therapy. Eur J Clin Microbiol Infect Dis . 2005; 24:142-4. [PubMed 15692815]

43. Autret E, Marchand S, Breteau M et al. Pharmacokinetics of amikacin in cystic fibrosis: a study of bronchial diffusion. Eur J Clin Pharmacol . 1986; 31:79-83. [PubMed 3780832]

44. Mombelli G, Coppens L, Thys JP et al. Anti- Pseudomonas activity in bronchial secretions of patients receiving amikacin or tobramycin as a continuous infusion. Antimicrob Agents Chemother . 1981; 19:72-5. [PubMedCentral][PubMed 7247362]

45. Dull WL, Alexander MR, Kasik JE. Bronchial secretion levels of amikacin. Antimicrob Agents Chemother . 1979; 16:767-71. [PubMedCentral][PubMed 533258]

46. Honda DH, Adams HG, Barriere SL. Amikacin penetration into synovial fluid during treatment of septic arthritis. Drug Intell Clin Pharm . 1981; 15:284-6. [PubMed 7023898]

47. Kenyon CF, Knoppert DC, Lee SK et al. Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant. Antimicrob Agents Chemother . 1990; 34:265-8. [PubMedCentral][PubMed 2327775]

48. Langhendries JP, Battisti O, Bertrand JM et al. Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity. Dev Pharmacol Ther . 1993; 20:220-30. [PubMed 7828457]

49. Karachalios GN, Houpas P, Tziviskou E et al. Prospective randomized study of once-daily versus twice-daily amikacin regimens in patients with systemic infections. Int J Clin Pharmacol Ther . 1998; 36:561-4. [PubMed 9799062]

50. Krivoy N, Postovsky S, Elhasid R et al. Pharmacokinetic analysis of amikacin twice and single daily dosage in immunocompromised pediatric patients. Infection . 1998; 26:396-8. [PubMed 9861567]

51. Armstrong DK, Hodgman T, Visconti JA et al. Hemodialysis of amikacin in critically ill patients. Crit Care Med . 1988; 16:517-20. [PubMed 3359790]

52. Vic P, Ategbo S, Turck D et al. Tolerance, pharmacokinetics and efficacy of once daily amikacin for treatment of Pseudomonas aeruginosa pulmonary exacerbations in cystic fibrosis patients. Eur J Pediatr . 1996; 155:948-53. [PubMed 8911895]

53. Izquierdo M, Lanao JM, Cervero L et al. A comparative study of the population pharmacokinetics of gentamicin and amikacin in newborn patients. J Clin Pharmacol Ther . 1993; 18:411-3,

54. El Desoky ES, Shoreit AH. Once- versus twice-daily administration of amikacin in pediatric patients with bronchopneumonia: plasma drug concentration and Bayesian pharmacokinetics estimation. Ann Pharmacother . 1999; 33:749-50. [PubMed 10410192]

55. O'Brien MA, Mason NA. Systemic absorption of intraperitoneal antimicrobials in continuous ambulatory peritoneal dialysis. Clin Pharm . 1992; 11:246-54. [PubMed 1611814]

56. Kotze A, Bartel PR, Sommers DK. Once versus twice daily amikacin in neonates: prospective study on toxicity. J Paediatr Child Health . 1999; 35:283-6. [PubMed 10404451]

57. Solomkin JS, Mazuski JE, Baron EJ et al. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis . 2003; 37:997-1005. [PubMed 14523762]

58. Horsburgh CR. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med . 1991; 324:1332-8. [PubMed 2017230]

59. Roger PM, Carles M, Agussol-Foin I et al. Efficacy and safety of an intravenous induction therapy for treatment of disseminated Mycobacterium avium complex infection in AIDS patients: a pilot study. J Antimicrob Chemother . 1999; 44:129-31. [PubMed 10459822]

60. Chiu J, Nussbaum J, Bozzette S et al. Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. Ann Intern Med . 1990; 113:358-61. [PubMed 2382918]

61. Parenti DM, Williams PL, Hafner R et al. A phase II/III trial of antimicrobial therapy with or without amikacin in the treatment of disseminated Mycobacterium avium infection in HIV-infected individuals. AIDS . 1998; 12:2439-46. [PubMed 9875582]

62. Charnas R, Luthi AR, Ruch W et al. Once daily ceftriaxone plus amikacin vs. three times daily ceftazidime plus amikacin for treatment of febrile neutropenic children with cancer. Pediatr Infect Dis J . 1997; 16:346-53. [PubMed 9109134]

63. Cordonnier C, Herbrecht R, Pico JL et al et al. Cefepime/amikacin versus ceftazidime/amikacin as empirical therapy for febrile episodes in neutropenic patients: a comparative study. Clin Infect Dis . 1997; 24:41-51. [PubMed 8994754]

64. Feigin RD, McCracken GH, Klein JO. Diagnosis and management of meningitis. Pediatr Infect Dis J . 1992; 11:785-814. [PubMed 1448332]

65. Sorrell TC, Iredell JR, Mitchell DH. Nocardia species. In: Mandell GL, Bennett JE, Dolin R eds. Principles and practices of infectious diseases. 5th ed. New York: Churchill Livingstone; 2000:2637-45.

66. Ortiz AM, Rabagliati R, Machuca E. Successful treatment of Nocardia asteroides peritonitis in a patient undergoing automated peritoneal dialysis and receiving immunosuppressive therapy. Adv Perit Dial . 2005; 21:66-8. [PubMed 16686287]

67. Tripodi MF, Adinolfi LE, Andreana A et al. Treatment of pulmonary nocardiosis in heart-transplant patients: importance of susceptibility studies. Clin Transp . 2001; 15:415-20.

68. Kilincer C, Hamamcioglu MK, Simsek O et al. Nocardial brain abscess: review of clinical management. J Clin Neurosci . 2006; 13:481-5. [PubMed 16678731]

69. Filice GA. Nocardiosis. In: Kasper DL, Braunwald E, Fauci AS et al, eds. Harrison's principles of internal medicine. 16th ed. New York: McGraw-Hill; 2006.

70. Kirby WMM, Clarke JT, Libke RD et al. Clinical pharmacology of amikacin and kanamycin. J Infect Dis . 1976; 134(Suppl):s312-5. [PubMed 993624]

71. Matsuda S, Mori S, Tanno M et al. Evaluation of amikacin in the obstetric and gynecologic fields. Jpn J Antibiot . 1974; 27:633-6. [PubMed 4617009]

73. Shah S, Ohlsson A, Shah V. Intraventricular antibiotics for bacterial meningitis in neonates (review). Cochrane Database Syst Rev . 2004; CD004496.

74. Forsyth NB, Botha JH, Hadley GP. A comparison of two amikacin dosing regimens in paediatric surgical patients. Ann Trop Paediatr . 1997; 17:253-61. [PubMed 9425382]

75. Ariffin H, Arasu A, Mahfuzah M et al. Single-daily ceftriaxone plus amikacin versus thrice-daily ceftazidime plus amikacin as empirical treatment of febrile neutropenia in children with cancer. J Paediatr Child Health . 2001; 37:38-43. [PubMed 11168867]

76. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV et al. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics . 2004; 114:111-8.

77. Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis . 2004; 39:1267-84. [PubMed 15494903]

99. Dee TH, Kozin F. Gentamicin and tobramycin penetration into synovial fluid. Antimicrob Agents Chemother . 1977; 12:548-9. [PubMedCentral][PubMed 921252]

200. Schentag JJ. Aminoglycosides. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied pharmacokinetics: principles of therapeutic drug monitoring. San Francisco: Applied Therapeutics, Inc.; 1980:174-209.

201. Zaske DE. Aminoglycosides: counterpoint discussion. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied pharmacokinetics: principles of therapeutic drug monitoring. San Francisco: Applied Therapeutics, Inc.; 1980:210-39.

202. Barclay ML, Begg EJ, Hickling KG. What is the evidence for once-daily aminoglycoside therapy? Clin Pharmacokinet . 1994; 27:32-48.

203. Rotschafer JC, Rybak MJ. Single daily dosing of aminoglycosides: a commentary. Ann Pharmacother . 1994; 28:797-801. [PubMed 7919572]

204. Klotz U, Godel A. Once-daily dosing of gentamicin: experience with therapeutic drug monitoring and Bayesian pharmacokinetics. Ther Drug Monit . 1994; 16:534-5. [PubMed 7846756]

205. Hustinx WN, Hoepelman IM. Aminoglycoside dosage regimens. Is once a day enough? Clin Pharmacokinet . 1993; 25:427-32.

206. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. Ann Intern Med . 1993; 119:584-93. [PubMed 8363169]

207. Rodman DP, Maxwell AJ, McKnight JT. Extended dosage intervals for aminoglycosides. Am J Hosp Pharm . 1994; 51:2016-21. [PubMed 7977422]

208. Bates RD, Nahata MC. Once-daily administration of aminoglycosides. DICP . 1994; 28:757-66.

209. Levison ME. New dosing regimens for aminoglycoside antibiotics. Ann Intern Med . 1992; 117:693-4. [PubMed 1530203]

210. Zhanel GG. Changing strategies in aminoglycoside dosing; the result of research on antimicrobial pharmacodynamics. Int J Med Microbiol Virol Parasitol Infect Dis . 1993; 279:447-9.

211. Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother . 1991; 35:399-405. [PubMedCentral][PubMed 2039189]

212. Prins JM, Buller HR, Kuijper EJ et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet . 1993; 341:335-9. [PubMed 8094114]

213. Parker SE, Davey PG. Once-daily aminoglycoside dosing. Lancet . 1993; 341:346-7. [PubMed 8094120]

214. Craig WA. Post-antibiotic effects in experimental infection models: relationship to in-vitro phenomena and to treatment of infections in man. J Antimicrob Chemother . 1993; 31(Suppl D):149-58. [PubMed 8335516]

215. Vanhaeverbeek M, Siska G, Douchamps J et al. Comparison of the efficacy and safety of amikacin once or twice-a-day in the treatment of severe gram-negative infections in the elderly. Int J Clin Pharmacol Ther Toxicol . 1993; 31:153-6. [PubMed 8468114]

216. Gilbert DN. Aminoglycosides. In: Mandell GL, Bennett JE, Dolin R eds. Principles and practices of infectious diseases. 5th ed. New York: Churchill Livingstone; 2000:307-36.

217. Powell SH, Thompson WL, Luthe MA et al. Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin. J Infect Dis . 1983; 147:918-32. [PubMed 6860416]

218. Centers for Disease Control and Prevention. Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep . 2003; 52(No. RR-11):1-77. [Fulltext MMWR][PubMed 12549898]

219. McCormack JP, Jewesson PJ. A critical reevaluation of the therapeutic range of aminoglycosides. Clin Infect Dis . 1992; 14:320-39. [PubMed 1571447]

220. Viscoli C, Dudley M, Ferrea G et al. Serum concentrations and safety of single daily dosing of amikacin in children undergoing bone marrow transplantation. J Antimicrob Chemother 1991; 27 (Suppl C):113-20.

221. Tulkens PM. Efficacy and safety of aminoglycosides once-a-day: experimental and clinical data. Scand J Infect Dis . 1991; 74:249-57.

222. Reviewers' comments (personal observations).

223. Zhanel GG, Craig WA. Pharmacokinetic contributions to postantibiotic effects. Clin Pharmacokinet . 1994; 27:377-92. [PubMed 7851055]

224. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis . 1987; 155:93-9. [PubMed 3540140]

225. Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis . 1984; 149:443-8. [PubMed 6715900]

226. Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med . 1984; 77:657-62. [PubMed 6385693]

227. Sarubbi FA Jr, Hull JH. Amikacin serum concentrations: prediction of levels and dosage guidelines. Ann Intern Med . 1978; 89:612-8. [PubMed 717929]

228. Parker SE, Davey PG. Serum monitoring and practicalities of once-daily aminoglycoside dosing. J Antimicrob Chemother . 1994; 33:351.

229. Hansen M, Achen F, Carstensen C et al. Once- versus thrice-daily dosing of netilmicin in febrile immunocompromised patients: a randomized, controlled study of efficacy and safety. J Drug Dev . 1988; 1(Suppl 3):119-24.

230. Maller R, Ahrne H, Holmen C et al. Once- versus twice-daily amikacin regimen: efficacy and safety in systemic Gram-negative infections. J Antimicrob Chemother . 1993; 31:939-48. [PubMed 8360131]

231. Marik PE, Lipman J, Kobilski S et al. A prospective randomized study comparing once- versus twice-daily amikacin dosing in critically ill adult and paediatric patients. J Antimicrob Chemother . 1991; 28:753-64. [PubMed 1778878]

232. Norström L, Lerner SA. Single daily dose therapy with aminoglycosides. J Hosp Infect . 1991; 18(Suppl A):117-29. [PubMed 1679774]

233. Parker SE, Davey PG. Practicalities of once-daily aminoglycoside dosing. J Antimicrob Chemother . 1993; 31:4-8. [PubMed 8018114]

234. Pechère JC, Craig WA, Meunier F. Once daily dosing of aminoglycoside: one step forward. J Antimicrob Chemother . 1991; 27(Suppl C):149-52. [PubMed 1856144]

235. Viganò A, Principi N, Brivio L et al. Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children. Antimicrob Agents Chemother . 1992; 36:1499-1503. [PubMedCentral][PubMed 1510446]

236. MacGowan AP, Reeves DS. Serum monitoring and practicalities of once-daily aminoglycoside dosing. J Antimicrob Chemother . 1994; 33:349-50. [PubMed 8182018]

237. O'Shaughnessy EM, Das SS. Serum monitoring and practicalities of once-daily aminoglycoside dosing. J Antimicrob Chemother . 1994; 33:350. [PubMed 8182019]

238. Smith CR, Maxwell RR, Edwards CQ et al. Nephrotoxicity induced by gentamicin and amikacin. Johns Hopkins Med J . 1978; 142:85-90. [PubMed 342789]

239. Konrad F, Wagner R, Neumeister B et al. Studies on drug monitoring in thrice and once daily treatment with aminoglycosides. Intensive Care Med . 1993; 19:215-20. [PubMed 8366230]

242. .

243. Nicolau DP, Freeman CD, Belliveau PP et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother . 1995; 39:650-5. [PubMedCentral][PubMed 7793867]

244. Skopnik H, Heimann G. Once daily aminoglycoside dosing in full term neonates. Pediatr Infect Dis J . 1995; 14:71-2. [PubMed 7715998]

245. Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med . 1996; 124:717-25. [PubMed 8633831]

246. Barza M, Ioannidis JPA, Cappelleri JC et al. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ . 1996; 312:338-45. [PubMedCentral][PubMed 8611830]

247. Ferriols-Lisart R, Alòs-Almiñana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health-Syst Pharm . 1996; 53:1141-50. [PubMed 8734674]

248. McLean AJ, Ioannides-Demos LL, Spicer WJ et al. Aminoglycoside dosing: one, two or three times a day? Med J Aust . 1996; 164:39-42.

249. Garrelts JC. Exploration of once-daily dosing of aminoglycosides through Bayesian simulation. Pharmacotherapy . 1996; 16:286-94. [PubMed 8820474]

250. Gilbert DN, Meta-analyses are no longer required for determining the efficacy of single daily dosing of aminoglycosides. Clin Infect Dis . 1997; 24:816-9. Editorial.

251. Barclay ML, Kirkpatrick CMJ, Begg EJ. Once daily aminoglycoside therapy. Is it less toxic than multiple daily doses and how should it be monitored? Clin Pharmacokinet . 1999; 36:89-98.

252. Freeman CD, Nicolau DP, Belliveau PP et al. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother . 1997; 39:677-86. [PubMed 9222035]

253. Tod MM, Padoin C, Petitjean O. Individualising aminoglycoside dosage regimens after therapeutic drug monitoring: simple or complex pharmacokinetic methods? Clin Pharmacokinet . 2001; 40:803-14.

254. Reimann IR, Meier-Hellmann A, Traut T et al. Monitoring of a single post-infusion blood sample to estimate the actual peak and trough concentration of tobramycin in critically ill patients. Exp Toxicol Pathol . 2003; 54:493-8. [PubMed 12877363]

255. Wallace AW, Jones M, Bertino JS. Evaluation of four once-daily aminoglycoside dosing nomograms. Pharmacotherapy . 2002; 22:1077-83. [PubMed 12222541]

256. Coulthard KP, Peckham DG, Conway SP et al. Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis-caution with trough concentrations. J Cyst Fibros . 2006; epub.

257. Prins JM, Weverling GJ, de Block K et al. Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing schedule and guidelines for monitoring therapy. Antimicrob Agents Chemother . 1996; 40:2494-9. [PubMedCentral][PubMed 8913452]

258. Boyle EM, Brookes I, Nye K et al. Random gentamicin concentrations do not predict trough levels in neonates receiving once daily fixed dose regimens. BMC Pediatrics . 2006; 6:1-17. [PubMedCentral][PubMed 16457711]

259. Matsuda S. Transfer of antibiotics into maternal milk. Biol Res Pregnancy Perinatol . 1984;5:57-60. [PubMed 6743732]