Aminoglycosides (Systemic)

This monograph includes information on the following:

1) Amikacin
2) Gentamicin
3) Kanamycin  
4) Neomycin  
5) Netilmicin
6) Streptomycin
7) Tobramycin

VA CLASSIFICATION
Amikacin
Primary: AM300

Gentamicin
Primary: AM300

Kanamycin
Primary: AM300

Neomycin
Primary: AM300

Netilmicin
Primary: AM300

Streptomycin
Primary: AM300
Secondary: AM500

Tobramycin
Primary: AM300


Commonly used brand name(s): Amikin1; G-Mycin2; Garamycin2; Jenamicin2; Kantrex3; Nebcin7; Netromycin5.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antibacterial (systemic)—Amikacin; Gentamicin; Kanamycin; Netilmicin; Streptomycin; Tobramycin;

Antibacterial (antimycobacterial)—Streptomycin;

Indications

General considerations
Aminoglycosides are indicated in the treatment of serious systemic infections for which less toxic antibacterials are ineffective or contraindicated. The spectrum of aminoglycosides covers aerobic gram-negative bacilli, and some gram-positive organisms. They are not active against anaerobic organisms.

The antibacterial activity of aminoglycosides against different strains of organisms varies among institutions and regions. However, aminoglycosides are generally active against most Enterobacteriaceae, including Escherichia coli , Proteus mirabilis , indole-positive Proteus , Citrobacter , Enterobacter , Klebsiella , Providencia , and Serratia species. Acinetobacter and Pseudomonas species are also usually susceptible. Although tobramycin is more potent in vitro against Pseudomonas aeruginosa , and gentamicin is more potent in vitro against Serratia species, neither has been shown to be more clinically effective than other aminoglycosides if the organism is susceptible. Aminoglycosides are used concurrently with antipseudomonal penicillins or certain cephalosporins in the treatment of serious Pseudomonas aeruginosa infections.

Bacterial resistance to gentamicin and tobramycin is very similar, although a few organisms resistant to gentamicin remain susceptible to tobramycin. The antibacterial activity and resistance pattern of netilmicin is very similar to those of both gentamicin and tobramycin, although there are a few gentamicin- and tobramycin-resistant strains that remain susceptible to netilmicin.

Amikacin is similar to gentamicin, tobramycin, and netilmicin in its spectrum of activity; however, amikacin has the advantage of not being inactivated by the same enzymes that render other aminoglycosides inactive against resistant organisms. Therefore, amikacin may remain active against strains of Pseudomonas aeruginosa that are resistant to tobramycin and netilmicin. Kanamycin use has declined over the years due to the emergence of a large number of resistant organisms. However, because of its disuse, resistance has decreased in some areas. {109} {121}

Streptomycin is used primarily as an antitubercular and is active against Mycobacterium tuberculosis and M. bovis . It is also considered the drug of choice for the treatment of infections caused by Francisella tularensis and Yersinia pestis , and is often used to treat Brucella infections. Because many other gram-negative bacilli are resistant, streptomycin is rarely used to treat those organisms.

Aminoglycosides are also active against Staphylococcus aureus , but are rarely used as sole therapy since other, less toxic, antibiotics are available. Amikacin, gentamicin, netilmicin, or tobramycin, administered concurrently with a penicillin, is synergistic against certain susceptible strains of Enterococcus faecalis . Streptomycin has been used, in combination with penicillin or vancomycin, in the treatment of endocarditis caused by Enterococcus faecalis or S. viridans . {109} {110}

Aminoglycosides are indicated for the treatment of serious infections caused by, or strongly suspected to be caused by, susceptible gram-negative bacilli. Some aminoglycosides, such as amikacin, gentamicin, and tobramycin, may also be given as an aerosol nebulization. This is usually as an adjunct to parenteral therapy in patients with cystic fibrosis with acute exacerbations of pulmonary infections. {120} Aminoglycosides are used to treat central nervous system (CNS) infections mainly in neonates due to better penetration across the blood-brain barrier in this age group; gentamicin may also be given intrathecally to treat CNS infections in adults. Aminoglycosides are also used in combination with other antibacterials for a possible synergistic effect.

Accepted

Biliary tract infections (treatment)—Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are indicated in the treatment of biliary tract infections caused by susceptible organisms.

Bone and joint infections (treatment)—Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are indicated in the treatment of bone and joint infections caused by susceptible organisms.

Brucellosis (treatment)—Streptomycin is indicated in the treatment of brucellosis caused by Brucella species.

Central nervous system infections (including meningitis and ventriculitis) (treatment)—Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are indicated in the treatment of central nervous system infections caused by susceptible organisms.

Granuloma inguinale (treatment)—Streptomycin is indicated in the treatment of granuloma inguinale.

Intra-abdominal infections (including peritonitis)(treatment)—Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are indicated in the treatment of intra-abdominal infections caused by susceptible organisms.

Plague (treatment)—Streptomycin is indicated in the treatment of plague.

Pneumonia, gram-negative, bacterial (treatment)—Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are indicated in the treatment of bacterial, gram-negative pneumonia caused by susceptible organisms.

Septicemia, bacterial (treatment)—Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are indicated in the treatment of bacterial septicemia caused by susceptible organisms.

Skin and soft tissue infections (including burn wound infections) (treatment)—Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are indicated in the treatment of skin and soft tissue infections caused by susceptible organisms.

Tuberculosis (treatment)—Streptomycin is indicated in the treatment of tuberculosis.

Tularemia (treatment)—Streptomycin is indicated in the treatment of tularemia.

Urinary tract infections (recurrent complicated)(treatment)—Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are indicated in the treatment of recurrent complicated urinary tract infections caused by susceptible organisms.

—Not all species or strains of a particular organism may be susceptible to a specific aminoglycoside.

Unaccepted
Aminoglycosides are not indicated routinely in the treatment of staphylococcal infections since less toxic antibacterials are available.

Aminoglycosides are not routinely indicated in the initial treatment of uncomplicated urinary tract infections unless the organism is resistant to other less toxic antibacterials.

Parenteral neomycin has been replaced by safer and more effective agents. Because of its potential toxicity, parenteral use of neomycin is not recommended for any indication.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Amikacin sulfate: 781.75 {76}
    Kanamycin sulfate: 582.58 {76}
    Netilmicin sulfate: 1441.54 {76}
    Tobramycin sulfate: 1425.39 {76}

Mechanism of action/Effect:

Actively transported across the bacterial cell membrane, irreversibly binds to one or more specific receptor proteins on the 30 S subunit of bacterial ribosomes, and interferes with an initiation complex between messenger RNA (mRNA) and the 30 S subunit. DNA may be misread, thus producing nonfunctional proteins; polyribosomes are split apart and are unable to synthesize protein. This results in accelerated aminoglycoside transport, increasing the disruption of bacterial cytoplasmic membranes, and eventual cell death. {79}

Note: Aminoglycosides are bactericidal, while most other antibiotics that interfere with protein synthesis are bacteriostatic.


Absorption:


All aminoglycosides:

Intramuscular: Rapidly and completely absorbed after intramuscular administration. {62} {70} {71} {72} {73} {74}

Local; topical: May also be absorbed in significant amounts from body surfaces (except urinary bladder) following local irrigation or topical application. Intraperitoneal and intrapleural administration results in rapid absorption. {78} {109}

Oral: Poorly absorbed from intact gastrointestinal tract after oral administration, but may accumulate in patients with renal failure. {78} {109} {122}


Distribution:


All aminoglycosides {78}:

Distributed to extracellular fluid, including serum, abscesses, ascitic, pericardial, pleural, synovial, lymphatic, and peritoneal fluids.

High concentrations found in urine.

Low concentrations found in bile, breast milk, aqueous humor {71}, bronchial secretions, sputum, and cerebral spinal fluid (CSF). In adults, does not cross the blood-brain barrier (BBB) in therapeutically adequate concentrations. Small improvement in penetration with inflamed meninges. Higher levels are achieved in the CSF of newborns than in adults. {109} {121}

Crosses the placenta.

Also distributed to all body tissues, where aminoglycosides accumulate intracellularly.

High concentrations found in highly perfused organs, such as the liver, lungs, and especially, the kidneys, where aminoglycosides accumulate in the renal cortex.

Lower concentrations are seen in muscle, fat, and bone.



Vol D:

Adults—0.26 L per kg (range, 0.20 to 0.40 L per kg). {73} {78} {79}

Children—0.2 to 0.4 L per kg. {111} {119}

Neonates—

< 1 week old, < 1500 grams: up to 0.68 L per kg.

< 1 week old, > 1500 grams: up to 0.58 L per kg. {106} {119}

Cystic fibrosis patients—0.30 to 0.39 L per kg. {112} {113} {114} {115}




Protein binding:

All aminoglycosides—Low (0 to 10%). {78}

Biotransformation:

Not metabolized. {70} {71} {72} {73} {74}

Half-life:


All aminoglycosides:


Distribution half-life—

5 to 15 minutes. {78}



Elimination half-life—


Adults—

Normal renal function: 2 to 4 hours. {78}

Impaired renal function: Varies with degree of dysfunction; up to 100 hours. {105}

Cystic fibrosis patients: 1 to 2 hours. {112} {113} {114} {115} {116}

Burn patients and febrile patients: May have a shorter half-life than average due to increased clearance of the drug. {71}



Pediatrics—

Neonates: 5 to 8 hours. {49} {107}

Children: 2.5 to 4 hours. {78}




Terminal half-life—

> 100 hours (release of intracellularly bound aminoglycoside). {78}



Time to peak concentration:


All aminoglycosides:

Intramuscular: 0.5 to 1.5 hours. {62} {71} {72} {73} {74}

Intravenous (time to post-distributional peak level): 30 minutes after end of 30 minute infusion, or 15 minutes after end of 1 hour infusion. {106} {119}


Time to peak bile concentration

Kanamycin—Approximately 6 hours (intramuscular). {81}

Peak serum concentrations


In adults with normal renal function:


Amikacin {70}

Intramuscular—7.5 mg per kg of body weight (mg/kg): 21 mcg per mL.

Intravenous over 30 minutes—7.5 mg/kg: 38 mcg per mL.



Gentamicin—

Intramuscular or intravenous—1.5 mg/kg: 6 mcg per mL. {71}



Kanamycin—

Intramuscular or intravenous—7.5 mg/kg: 22 mcg per mL. {72}



Netilmicin {51}

Intramuscular—2 mg/kg: 5.5 mcg per mL.

Intravenous over 30 minutes—2 mg/kg: 11.8 mcg per mL.



Streptomycin—

Intramuscular—1 gram: 25 to 50 mcg per mL. {62}



Tobramycin—

Intramuscular or intravenous—1 mg/kg: 4 mcg per mL. {74}



Bile concentration

Netilmicin—10% of serum concentrations; may vary up to 25% of serum concentrations with abnormal hepatic function.

Elimination:
    Renal; excreted unchanged by glomerular filtration. 70 to 95% of aminoglycoside dose recovered in urine over 24 hours. Small amount excreted in bile. {46}
    Hemodialysis—Each 4 to 6 hour hemodialysis period decreases plasma aminoglycoside concentrations by up to 50%. {78}
    Peritoneal dialysis—Less effective than hemodialysis. Removes approximately 25% of a dose in 48 to 72 hours. {78}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to one aminoglycoside may be hypersensitive to other aminoglycosides also. {70} {71} {72} {73} {74}

Carcinogenicity/Mutagenicity/Tumorigenicity

Amikacin and kanamycin—Studies on the carcinogenic or mutagenic effects in humans have not been done. {56} {58} {70} {72}

Netilmicin—Lifetime carcinogenicity studies in mice and rats have not shown any netilmicin-related tumors. Mutagenicity studies in mice and rats have shown negative results. {73}

Pregnancy/Reproduction
Fertility—
Amikacin: Reproduction studies in rats and mice have not shown that amikacin causes impaired fertility. {56} {70}

Gentamicin: Reproduction studies in rats and rabbits have not shown that gentamicin causes impaired fertility. {49} {57}

Kanamycin: Studies in rats and rabbits have not shown that kanamycin causes impaired fertility. {72}

Netilmicin: Reproduction studies in rats and rabbits given intramuscular and subcutaneous doses of netilmicin approximately 13 to 15 times the highest adult human dose have not shown that netilmicin impairs fertility or causes adverse effects on the fetus. {73}

Pregnancy—
All aminoglycosides cross the placenta, sometimes resulting in significant concentrations in the cord blood and/or amniotic fluid. Aminoglycosides may be nephrotoxic in the human fetus. In addition, some aminoglycosides (e.g., streptomycin, tobramycin) have been reported to cause total irreversible, bilateral congenital deafness in children whose mothers received aminoglycosides during pregnancy. {56} {70} {71} {72} {73} {74}

Amikacin: Adequate and well-controlled studies in humans have not been done. Amikacin has not been shown to cause adverse effects on the fetus, even though peak fetal serum concentrations of amikacin average approximately 16% of peak maternal serum concentrations and amikacin may be concentrated in the fetal kidneys. However, since other aminoglycosides have been reported to cause deafness in the fetus, risk-benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective. {56} {70}

FDA Pregnancy Category D.


Gentamicin: Adequate and well-controlled studies in humans have not been done. Since other aminoglycosides have been reported to cause deafness in the fetus, risk-benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective. {57} {71}

Studies in rats and rabbits have not shown that gentamicin causes adverse effects on the fetus.

FDA Pregnancy Category C.


Kanamycin: Fetal serum concentrations average approximately 16 to 50% of maternal serum concentrations. Adequate and well-controlled studies in humans have not been done. {72}

Studies in rats and rabbits have not shown that kanamycin is teratogenic. However, studies in rats and guinea pigs given doses of 200 mg/kg daily have shown that kanamycin causes hearing impairment in the fetus.

FDA Pregnancy Category D.


Netilmicin: Netilmicin has been detected in cord blood and in the human fetus. Therefore, risk-benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective. {73}

Studies in rats given netilmicin subcutaneously during pregnancy have not shown that netilmicin causes ototoxicity in the fetus.

FDA Pregnancy Category D.


Streptomycin: Adequate and well-controlled studies in humans have not been done. Fetal serum concentrations are usually less than 50% of maternal serum concentrations. Streptomycin has been shown to cause deafness in infants whose mothers received streptomycin during pregnancy. Therefore, risk-benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective. {108}

FDA Pregnancy Category D.


Tobramycin: Tobramycin concentrates in the fetal kidneys and has been shown to cause total irreversible bilateral congenital deafness in the human fetus. Therefore, risk-benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective. {74}

FDA Pregnancy Category D.


Breast-feeding

Aminoglycosides are excreted in breast milk in small but variable amounts (e.g., up to 18 mcg per mL for kanamycin). However, aminoglycosides are poorly absorbed from the gastrointestinal tract and problems in nursing infants have not been documented. {108}

Pediatrics

All aminoglycosides—CNS depression, characterized by stupor, flaccidity, coma, or deep respiratory depression, has been reported in very young infants receiving streptomycin at doses that exceeded the maximum recommended amount. However, all aminoglycosides have this potential to cause neuromuscular blockade. {62}

Amikacin, gentamicin, kanamycin, netilmicin, and tobramycin—These aminoglycosides {61} should be used with caution in premature infants and neonates because of these patients' immature renal capability, which may result in prolonged elimination half-life and aminoglycoside-induced toxicity {61} {70} {72} {73} {74}. Dosage adjustments may be required in pediatric patients. See also Patient monitoring and General Dosing Information .


Geriatrics


Because of their toxicity, aminoglycosides should be used with caution in elderly patients, only after less toxic alternatives have been considered and/or found ineffective. Elderly patients are more likely to have an age-related decrease in renal function. {71} Recommended doses should not be exceeded, and the patient's renal function should be carefully monitored during therapy. Geriatric patients may require smaller daily doses of aminoglycosides in accordance with their increased age, decreased renal function, and, possibly, decreased weight. {61} In addition, loss of hearing may result even in patients with normal renal function.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Aminoglycosides, 2 or more concurrently or
» Capreomycin{52}{62}{70}{71}{72}{73}{74}{99}    (concurrent and/or sequential use of 2 or more aminoglycosides by any route or concurrent use of capreomycin with aminoglycosides should be avoided since the potential for ototoxicity, nephrotoxicity, and neuromuscular blockade may be increased; hearing loss may occur and may progress to deafness even after discontinuation of the drug; loss of hearing may be reversible, but usually is permanent; neuromuscular blockade may result in skeletal muscle weakness and respiratory depression or paralysis [apnea]. Also, concurrent use of 2 or more aminoglycosides may result in reduced bacterial uptake of each one since the medications compete for the same uptake mechanism)


Antimyasthenics{84}{85}    (concurrent use of medications with neuromuscular blocking action may antagonize the effect of antimyasthenics on skeletal muscle; temporary dosage adjustments of antimyasthenics may be necessary to control symptoms of myasthenia gravis during and following use of medications with neuromuscular blocking action)


Beta-lactam antibiotics{55}{109}{120}    (aminoglycosides can be inactivated by many beta-lactam antibiotics [cephalosporins, penicillins] in vitro and in vivo in patients with significant renal failure. Degradation depends on the concentration of the beta-lactam, storage time, and temperature)


Indomethacin, intravenous{54}    (when aminoglycosides are administered concurrently with intravenous indomethacin in the premature neonate, renal clearance of aminoglycosides may be decreased, leading to increased plasma concentrations, elimination half-lives, and risk of aminoglycoside toxicity; dosage adjustment of aminoglycosides based on measurement of plasma concentrations and/or evidence of toxicity may also be required)


» Methoxyflurane or{102}
» Polymyxins, parenteral{62}{70}{71}{72}{73}{74}    (concurrent and/or sequential use of these medications with aminoglycosides should be avoided since the potential for nephrotoxicity and/or neuromuscular blockade may be increased; neuromuscular blockade may result in skeletal muscle weakness and respiratory depression or paralysis [apnea]; caution is also recommended when methoxyflurane or polymyxins are used concurrently with aminoglycosides during surgery or in the postoperative period)


» Nephrotoxic medications, other(See Appendix II ) or
» Ototoxic medications, other (See Appendix II ){70}{71}{72}{73}{74}{83}{87}{88}    (concurrent or sequential use of these medications with aminoglycosides may increase the potential for ototoxicity or nephrotoxicity; hearing loss may occur and may progress to deafness even after discontinuation of the drug and may be reversible, but usually is permanent; serial audiometric function determinations may be required with concurrent or sequential use of other ototoxic antibacterials; renal function determinations may be required)

    (vancomycin and aminoglycosides must often be administered concurrently in the prophylaxis of bacterial endocarditis, in the treatment of endocarditis caused by streptococci and Corynebacteria species, in the treatment of resistant staphylococcal infections, or in penicillin-allergic patients; appropriate monitoring will help to reduce the risk of nephrotoxicity or ototoxicity; renal function determinations, serum aminoglycoside and vancomycin concentrations, dosage reductions, and/or dosage interval adjustments, or alternate antibacterials, may be required)


» Neuromuscular blocking agents or medications with neuromuscular blocking activity, other{03}    (concurrent use of medications with neuromuscular blocking activity, including halogenated hydrocarbon inhalation anesthetics, opioid analgesics, and massive transfusions with citrate anticoagulated blood, with aminoglycosides should be carefully monitored since neuromuscular blockade may be enhanced, resulting in skeletal muscle weakness and respiratory depression or paralysis [apnea]; caution is recommended when these medications and aminoglycosides are used concurrently during surgery or in the postoperative period, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively; treatment with anticholinesterase agents or calcium salts may help reverse the blockade)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum and
Alkaline phosphatase, serum and
Aspartate aminotransferase (AST [SGOT]), serum and
Bilirubin, serum and
Lactate dehydrogenase (LDH), serum    (values may be increased {46} {47} {48} {49} {50} {51} {52} {53} {71})


Blood urea nitrogen (BUN) and
Creatinine, serum    (concentrations may be increased {46} {47} {48} {49} {50} {51} {52} {53} {71})


Calcium, serum and
Magnesium, serum and
Potassium, serum and
Sodium, serum    (concentrations may be decreased {47} {48} {49} {71} {73})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Botulism, infant or{72}
» Myasthenia gravis or{47}{48}{49}{51}{70}{72}{74}{84}
» Parkinsonism    (aminoglycosides may cause neuromuscular blockade, resulting in further skeletal muscle weakness)


Dehydration or{70}
» Renal function impairment{46}{47}{48}{49}{50}{51}{52}{53}{70}{71}{72}{73}{74}    (possible increased risk of toxicity because of elevated serum concentrations; it is recommended that aminoglycosides be administered in a reduced dosage at a fixed interval, or in normal doses at prolonged intervals, to patients with impaired renal function)


» Eighth-cranial-nerve impairment{46}{47}{48}{49}{50}{51}{52}{53}{70}{72}{74}    (aminoglycosides may cause auditory and vestibular toxicity)


» Previous allergic reaction to aminoglycosides{70}{71}{72}{73}{74}    (hypersensitivity reaction to one aminoglycoside may contraindicate the use of other aminoglycosides due to known cross-sensitivity)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For all aminoglycosides {70} {71} {72} {73} {74}
» Aminoglycoside concentrations, serum    (aminoglycoside levels should be monitored in all patients, especially neonates and the elderly, even without renal function impairment, to avoid potentially toxic concentrations from accumulation of the drug; peak levels should be drawn 30 minutes after a 30-minute aminoglycoside infusion, to allow for drug distribution, and trough levels, immediately prior to the next dose; see General Dosing Information)


» Audiograms and
» Renal function determinations and
» Vestibular function determinations    (may be required prior to, periodically during, and following treatment in patients with pre-existing renal or eighth-cranial-nerve impairment; twice-weekly or weekly audiometric testing to detect high-frequency hearing loss in patients old enough to be tested and daily renal function determinations may be required in patients on high-dose therapy or therapy continued for longer than 10 days, especially if renal function is changing; renal function determinations may be required to detect nephrotoxicity and to help prevent severe neurotoxic reactions; audiometric testing may also be required with concurrent or sequential administration of other ototoxic antibacterials; if renal, vestibular, or auditory function impairment occurs, reduction in dose or discontinuation of the aminoglycoside may be required)


» Urinalyses    (may be required prior to treatment and daily during treatment to detect albumin, casts, and cells in the urine, as well as decreased specific gravity {56} {70})


For streptomycin
» Caloric stimulation tests    (may also be required prior to, periodically during, and following prolonged therapy to detect vestibular toxicity)




Side/Adverse Effects

Note: Leg cramps, skin rash, fever, and seizures have been reported when gentamicin was administered concurrently by the systemic and intrathecal routes.
Endotoxin-like reactions (shaking, chills, and fever) have been reported with once-daily dosing regimens of gentamicin, possibly due to elevated endotoxin levels in certain brands of the drug{126}{127}.
Neuromuscular blockade, respiratory paralysis, ototoxicity, and nephrotoxicity may occur following local irrigation and following topical application of aminoglycosides during surgery.
Because of its potential toxicity, use of parenteral neomycin is not recommended.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Nephrotoxicity (greatly increased or decreased frequency of urination or amount of urine; increased thirst; loss of appetite; nausea; vomiting )
    
neurotoxicity ( muscle twitching; numbness; seizures; tingling)
    
ototoxicity, auditory (any loss of hearing; ringing or buzzing, or a feeling of fullness in the ears)
    
ototoxicity, vestibular (clumsiness; dizziness; nausea; vomiting; unsteadiness )
    
peripheral neuritis (burning of face or mouth; numbness; tingling)— streptomycin only

Incidence less frequent
    
Hypersensitivity (skin itching, redness, rash, or swelling)
    
optic neuritis (any loss of vision)—streptomycin only

Incidence rare
    
Endotoxin-like reaction{126}{127} (shaking; chills; fever)—gentamicin only
neuromuscular blockade (difficulty in breathing; drowsiness; weakness)



Those indicating possible ototoxicity, vestibular toxicity, or nephrotoxicity and the need for medical attention if they occur and/or progress after medication is discontinued
    
Any loss of hearing
    
clumsiness or unsteadiness
    
dizziness
    
greatly increased or decreased frequency of urination or amount of urine
    
increased thirst
    
loss of appetite
    
nausea or vomiting
    
ringing or buzzing or a feeling of fullness in the ears




Overdose
For more informatin on the management of overdose or unintentional ingestion, contact a Poison Control Center (See Poison Control Center Listing).

Treatment of overdose
Specific treatment—

Hemodialysis or peritoneal dialysis to remove aminoglycosides from the blood of patients with impaired renal function. {71} {73}

Anticholinesterase agents, calcium salts, or mechanical respiratory assistance to treat neuromuscular blockade, resulting in prolonged skeletal muscle weakness and respiratory depression or paralysis (apnea), that may occur when two or more aminoglycosides are given concurrently. {74}

Supportive care—Since there is no specific antidote, treatment of aminoglycoside overdose or toxic reactions should be symptomatic and supportive. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Aminoglycosides (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to aminoglycosides

Pregnancy—May be nephrotoxic in the fetus or cause irreversible deafness in children whose mothers received aminoglycosides during pregnancy





Use in children—Premature infants and neonates may be more susceptible to renal toxicity because of their immature renal capability






Use in the elderly—Geriatric patients may be at risk of renal toxicity because of an age-related decrease in renal function
Other medications, especially 2 or more aminoglycosides used together, capreomycin, other nephrotoxic or ototoxic medications, or other neuromuscular blocking agents
Other medical problems, especially eighth-cranial-nerve impairment, infant botulism, myasthenia gravis, parkinsonism, or renal function impairment

Proper use of this medication
» Importance of receiving medication for full course of therapy and on regular schedule

» Proper dosing


Side/adverse effects
Signs of potential side effects, especially hypersensitivity, endotoxin-like reaction, optic neuritis, neuromuscular blockade, nephrotoxicity, neurotoxicity, auditory and vestibular ototoxicity, and peripheral neuritis, which are more likely to occur in children and the elderly


General Dosing Information
Because of the low therapeutic index of aminoglycosides, it is best to base dosage calculations on ideal body weight (IBW) as follows:

• IBW (males) = 50 kg + (2.3 kg × inches over 5 feet)


• IBW (females) = 45 kg + (2.3 kg × inches over 5 feet)


Serum concentrations should be monitored, especially in neonates and the elderly, even without renal function impairment, and in patients with impaired renal function to ensure adequate concentrations and to avoid potentially toxic concentrations. Therapeutic concentrations are shown in the table below. Prolonged peak (post-distributional) concentrations(measured 15 to 30 minutes after injection) and trough concentrations (measured immediately prior to the next dose) {56} {70} greater than those shown below should be avoided {62} {70} {71} {72} {73}.



Drug
Therapeutic
Concentration
(mcg/mL)
Maximum
Peak
Concentration
(mcg/mL)
Maximum
Trough
Concentration
(mcg/mL)
Amikacin
15–25
35
5
Gentamicin
4–10
10
2
Kanamycin
15–30
30–35
5
Netilmicin
6–12
16
2
Streptomycin

20–25 *

Tobramycin
4–10
10
2
* In patients with renal damage. Peak concentrations greater than 50 mcg per mL are associated with increased risk of toxicity.


Because of their larger volume of distribution and reduced renal development, infants may require larger doses, given at less frequent intervals, for achievement of therapeutic serum concentrations. Cystic fibrosis patients and burn patients may also require larger doses, but because they eliminate the aminoglycoside faster than average, the dosing interval may need to be decreased too.

Serum concentrations should be used whenever possible to monitor aminoglycoside therapy. Creatinine clearance may be used to help monitor therapy, in conjunction with serum levels. Creatinine clearance (in mL per minute) may be calculated as follows: {73}

Adult males: Creatinine clearance

= [(140 - age) × (ideal body weight in kg)]/[72 × serum creatinine (mg per dL)]

Adult females: Creatinine clearance

= [(140 - age) × (ideal body weight in kg)]/[72 × serum creatinine (mg per dL)] × 0.85

Creatinine clearance may also be calculated in SI units (as mL per second) as follows:

Adult males: Creatinine clearance

= [(140 - age) × (ideal body weight in kg)]/[50 × serum creatinine (micromoles per L)]

Adult females: Creatinine clearance

= [(140 - age) × (ideal body weight in kg)]/[50 × serum creatinine (micromoles per L)] × 0.85

The following dosing chart by Sarubbi and Hull (Ann Intern Med 1978; 89: 612-8) may be used to provide the clinician with an initial loading dose and maintenance dosage regimen in adult patients. Further dosage adjustments should be individualized and based on peak and trough serum concentrations, which should be drawn after the third maintenance dose.

1. Select loading dose based on the patient's ideal body weight (in mg per kg of body weight [mg/kg]) to provide peak serum concentration in the range listed below for the desired aminoglycoside.

Aminoglycoside
Usual Loading
Dose
(mg/kg)
Expected Peak Serum
Concentrations
(mcg/mL)
Gentamicin
Tobramycin
1.5 to 2
4 to 10
Amikacin
Kanamycin
5 to 7.5
15 to 30
Netilmicin
1.3 to 3.25
4 to 12


2. Select maintenance dose (as percentage of chosen loading dose) to maintain peak serum concentrations indicated above according to desired dosing interval and the patient's corrected creatinine clearance. This chart is not applicable to neonates and children.



CrCl
(mL/min)/
(mL/sec)
Half-life
(hours)
Percentage of Loading Dose Required
for Dosage Interval Selected
8 hours
12 hours
24 hours
90/1.50
3.1
84%


80/1.33
3.4
80
91%

70/1.17
3.9
76
88

60/1.00
4.5
71
84

50/0.83
5.3
65
79

40/0.67
6.5
57
72
92%
30/0.50
8.4
48
63
86
25/0.42
9.9
43
57
81
20/0.33
11.9
37
50
75
17/0.28
13.6
33
46
70
15/0.25
15.1
31
42
67
12/0.20
17.9
27
37
61
10 */0.17 *
20.4
24
34
56
7/0.12
25.9
19
28
47
5/0.08
31.5
16
23
41
2/0.03
46.8
11
16
30
0/0
69.3
8
11
21
* Dosing for patients with CrCl <10 mL/min (<0.17 mL/sec) should be assisted by measured serum levels.


After an initial full therapeutic loading dose, neonates or patients with impaired renal, vestibular, or auditory function may require (1) a reduction in the maintenance dose administered either (a) by administration of the usual dose at prolonged intervals or (b) by administration of reduced dose at fixed intervals or (2) discontinuation of the aminoglycoside. Since aminoglycosides are not metabolized and are excreted primarily in the urine, toxic concentrations may accumulate in patients with impaired renal function. {71} {74}

Because of the high concentrations of aminoglycosides in the urine and excretory system, patients should be well hydrated to prevent or minimize chemical irritation of the renal tubules. {73} Therapeutic serum aminoglycoside levels are usually not needed to effectively treat urinary tract infections.

If a dose of this medication is missed, give it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

AMIKACIN


Additional Dosing Information
For initial dosing guidelines for patients with renal function impairment, see the Sarubbi and Hull nomogram in General Dosing Information.

Burn and certain other patients may require a dose of 5 to 7.5 mg per kg of body weight (mg/kg) every four to six hours because of the shorter half-life (1 to 1.5 hours) in these patients.

Amikacin sulfate injection may also be administered as an aerosol nebulization.


Parenteral Dosage Forms

AMIKACIN SULFATE INJECTION USP

Usual adult and adolescent dose
Antibacterial (systemic)
Intramuscular or intravenous infusion, 5 mg per kg of body weight every eight hours; or 7.5 mg per kg of body weight every twelve hours for seven to ten days. {56}


Note: Urinary tract infections, bacterial (uncomplicated)—Intramuscular or intravenous infusion, 250 mg every twelve hours. {56}
Following hemodialysis, a supplemental dose of 3 to 5 mg per kg of body weight may be administered.


Usual adult prescribing limits
Up to 15 mg per kg of body weight daily, but not to exceed 1.5 grams daily for more than ten days.

Usual pediatric dose
Antibacterial (systemic):


Intramuscular or intravenous infusion:


Premature neonates—
—Initially, 10 mg per kg of body weight, then 7.5 mg per kg of body weight every eighteen to twenty-four hours for seven to ten days.



Neonates—
—Initially, 10 mg per kg of body weight, then 7.5 mg per kg of body weight every twelve hours for seven to ten days.



Older infants and children—
See Usual adult and adolescent dose. {56}




Strength(s) usually available
U.S.—


50 mg per mL (Rx) [Amikin (sodium bisulfite 0.13%)][Generic]


250 mg per mL (Rx) [Amikin (sodium bisulfite 0.66%)][Generic]

Canada—


250 mg per mL (Rx) [Amikin (sodium bisulfite 0.66%)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
To prepare initial dilution for intravenous use, add the contents of each 500-mg vial to 100 to 200 mL of 0.9% sodium chloride injection, 5% dextrose injection, or other suitable diluent. The resulting solution should be administered slowly over a 30- to 60-minute period to help avoid neuromuscular blockade. Pediatric patients may require a proportionately smaller volume of diluent. {70}

Stability:
Intravenous infusions of amikacin retain their potency for 24 hours at room temperature at concentrations of 0.25 and 5 mg per mL in dextrose injection, dextrose and sodium chloride injection, 0.9% sodium chloride injection, lactated Ringer's injection, and other electrolyte-containing solutions (see manufacturer's package insert). {70}

Intravenous infusions of amikacin retain their potency for 60 days at 4 °C (39 °F) at concentrations of 0.25 and 5 mg per mL in the above-listed diluents. When these solutions are then stored at 25 °C (77 °F), they retain their potency for 24 hours. {56} {70}

Intravenous infusions of amikacin retain their potency for 30 days when frozen at -15 °C (5 °F) at concentrations of 0.25 and 5 mg per mL in the above-listed diluents. When these solutions are thawed and stored at 25 °C (77 °F), they retain their potency for 24 hours. {56} {70}

Solutions may vary in color from colorless to light straw or very pale yellow; this variation does not affect their potency. Discard dark-colored solutions.

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle. {70} {91}

Amikacin is incompatible with amphotericin B, cephalothin sodium, nitrofurantoin sodium, sulfadiazine sodium, and tetracyclines (in some solutions).

Since complexes form with a number of other drugs also, extemporaneous admixtures with Amikacin Sulfate Injection USP are not recommended. {70}

Additional information:
Commercially available amikacin sulfate injection contains sodium bisulfite, an antioxidant, but no preservatives.


GENTAMICIN


Additional Dosing Information
Surgical, obstetrical, gynecological, or burn patients receiving gentamicin doses adjusted on the basis of serum concentrations may require less than the minimum recommended dose or greater than the maximum recommended dose of gentamicin because of wide interpatient variability. In patients receiving gentamicin intrathecally, CSF concentrations should also be monitored.

For initial dosing guidelines for patients with renal function impairment, see the Sarrubi and Hull nomogram in General Dosing Information.

Subcutaneous administration is not recommended and may be painful.

Commercially available gentamicin piggyback injections should be administered by intravenous infusion only.

Preservative-free gentamicin may also be administered directly into the subdural space, directly into the ventricles, or by means of an implanted reservoir.

Gentamicin sulfate injection may also be administered as an aerosol nebulization.


Parenteral Dosage Forms

Note: The dosing and dosage forms available are expressed in terms of gentamicin base.


GENTAMICIN SULFATE INJECTION USP

Usual adult and adolescent dose
Antibacterial (systemic) {71}
Intramuscular or intravenous infusion, 1 to 1.7 mg (base) per kg of body weight every eight hours for seven to ten days or more.

Note: Urinary tract infections, bacterial (uncomplicated)—Intramuscular or intravenous infusion: {49}
Adults less than 60 kg of body weight—3 mg (base) per kg of body weight once a day; or 1.5 mg per kg of body weight every twelve hours.
Adults 60 kg of body weight and over—160 mg (base) once a day; or 80 mg every twelve hours.
Following hemodialysis, a supplemental dose of 1 to 1.7 mg (base) per kg of body weight may be administered, depending on the severity of the infection. {71}


Intralumbar or intraventricular, 4 to 8 mg (base) once a day.


Usual adult prescribing limits
Up to 8 mg (base) per kg of body weight daily in severe, life-threatening infections.

Note: Doses up to 15 mg (base) per kg of body weight daily have been used in the treatment of intraocular infections.


Usual pediatric dose
Antibacterial (systemic)


Intramuscular or intravenous infusion:


Premature or full-term neonates up to 1 week of age—
2.5 mg (base) per kg of body weight every twelve to twenty-four hours for seven to ten days or more. {71}



Older neonates and infants—
2.5 mg (base) per kg of body weight every eight to sixteen hours for seven to ten days or more. {71}



Children—
2 to 2.5 mg (base) per kg of body weight every eight hours for seven to ten days or more. {71}

Note: The dosing interval of gentamicin in pediatric patients may vary from every four hours to every twenty-four hours, depending on the medical condition of the patient (cystic fibrosis, burns, renal dysfunction); serum levels must be monitored.
Following hemodialysis, a supplemental dose of 2 to 2.5 mg (base) per kg of body weight may be administered, depending on the severity of the infection. {71}





Intralumbar or intraventricular:


Infants up to 3 months of age—
Dosage has not been established.



Infants and children 3 months of age and over—
1 to 2 mg (base) once a day.

Note: Doses up to 8 mg (base) daily have been used in infants with functioning ventricular shunts.





Strength(s) usually available
U.S.—



Intramuscular and intravenous


10 mg per mL (base) (Rx) [Garamycin][Generic]( sodium bisulfite 3.2 mg)


40 mg per mL (base) (Rx) [Garamycin] [G-Mycin] [Jenamicin][Generic](sodium bisulfite 3.2 mg)



Intrathecal


2 mg per mL (base) (Rx) [Garamycin]

Canada—



Intramuscular and intravenous


10 mg per mL (base) (Rx) [Garamycin (sodium bisulfite)]


40 mg per mL (base) (Rx) [Garamycin (sodium bisulfite)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
Intravenous—To prepare initial dilution for intravenous use, add each dose to 50 to 200 mL of 0.9% sodium chloride injection or 5% dextrose injection to provide a concentration not exceeding 1 mg (base) per mL (0.1%). The resulting solution should be administered slowly over a 30- to 60-minute period to help decrease the chance of neuromuscular blockade. Pediatric patients may require a proportionately smaller volume of diluent. {71}

Intralumbar and/or intraventricular (2 mg per mL)—To prepare initial dilution for intralumbar use, each dose should be drawn up into a 5- or 10-mL sterile syringe. Following lumbar puncture and the removal of a specimen of cerebrospinal fluid (CSF) for laboratory analysis, the syringe containing gentamicin is inserted into the hub of the spinal needle. A quantity of CSF equal to approximately 10% of the total estimated CSF volume is allowed to flow into the syringe and mix with the gentamicin. The resulting solution should be administered over a 3- to 5-minute period with the bevel of the spinal needle directed upward. Gentamicin may also be diluted with sodium chloride injection (without preservatives) if the CSF is grossly purulent or unobtainable. Since the 2-mg-per-mL concentration contains no preservatives, it should be used promptly after being opened; unused portions should be discarded. {71}

Stability:
Do not use if injection is discolored or contains a precipitate.

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle. {91}

Since complexes form with a number of other drugs also, extemporaneous admixtures with Gentamicin Sulfate Injection USP are not recommended. {91}

Additional information:
Intrathecal gentamicin is commercially available as a preservative-free injection.


GENTAMICIN SULFATE IN SODIUM CHLORIDE INJECTION

Usual adult and adolescent dose
Antibacterial (systemic)
Intravenous infusion, 1 to 1.7 mg (base) per kg of body weight every eight hours for seven to ten days or more. {71}

Note: Urinary tract infections, bacterial (uncomplicated)—Intravenous infusion: {49}
Adults less than 60 kg of body weight—3 mg (base) per kg of body weight once a day; or 1.5 mg per kg of body weight every twelve hours.
Adults 60 kg of body weight and over—160 mg (base) once a day; or 80 mg every twelve hours.
Following hemodialysis, a supplemental dose of 1 to 1.7 mg (base) per kg of body weight may be administered, depending on the severity of the infection. {71}



Usual adult prescribing limits
Up to 8 mg (base) per kg of body weight daily in severe, life-threatening infections.

Note: Doses up to 15 mg (base) per kg of body weight daily have been used in the treatment of intraocular infections.


Usual pediatric dose
Antibacterial (systemic)


Intravenous infusion:


Premature or full-term neonates up to 1 week of age—
2.5 mg (base) per kg of body weight every twelve to twenty-four hours for seven to ten days or more. {71}



Older neonates and infants—
2.5 mg (base) per kg of body weight every eight to sixteen hours for seven to ten days or more. {71}



Children—
2 to 2.5 mg (base) per kg of body weight every eight hours for seven to ten days or more. {71}

Note: The dosing interval of gentamicin in pediatric patients may vary from every four hours to every twenty-four hours, depending on the medical conditions of the patient (cystic fibrosis, burns, renal dysfunction); serum levels must be monitored.
Following hemodialysis, a supplemental dose of 2 to 2.5 mg (base) per kg of body weight may be administered, depending on the severity of the infection. {71}





Strength(s) usually available
U.S.—


40 mg in 50 mL (base) (Rx)[Generic]


40 mg in 100 mL (base) (Rx)[Generic]


60 mg in 50 mL (base) (Rx)[Generic]


60 mg in 100 mL (base) (Rx)[Generic]


70 mg in 50 mL (base) (Rx)[Generic]


80 mg in 50 mL (base) (Rx)[Generic]


80 mg in 100 mL (base) (Rx)[Generic]


90 mg in 100 mL (base) (Rx)[Generic]


100 mg in 50 mL (base) (Rx)[Generic]


100 mg in 100 mL (base) (Rx)[Generic]


120 mg in 100 mL (base) (Rx)[Generic]


160 mg in 100 mL (base) (Rx)[Generic]


180 mg in 100 mL (base) (Rx)[Generic]

Canada—


60 mg in 50 mL (base) (Rx)[Generic]


70 mg in 50 mL (base) (Rx)[Generic]


80 mg in 100 mL (base) (Rx)[Generic]

Packaging and storage:
Store between 2 and 30 °C (36 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. {03} {71}

Preparation of dosage form:
Commercially available gentamicin piggyback injections require no further dilution prior to administration (see manufacturer's labeling for instructions). Since these injections contain no preservatives, they should be used promptly after being opened; unused portions should be discarded.

Stability:
Do not use if injection is discolored or contains a precipitate.

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle. {91}

Since complexes form with a number of other drugs also, extemporaneous admixtures with gentamicin in sodium chloride injection are not recommended. {91}

Additional information:
The sodium content is approximately 19.6 mEq (450 mg) per 50 mL. This must be considered in patients on a restricted sodium intake when calculating total daily sodium intake.


KANAMYCIN


Additional Dosing Information
For initial dosing guidelines for patients with renal function impairment, see the Sarubbi and Hull nomogram in General Dosing Information.
For intravenous use only:

   • Direct intravenous administration of undiluted kanamycin sulfate injection is not recommended because of the possibility of neuromuscular blockade.
For intramuscular use only:

   • Inject kanamycin sulfate injection deeply into the upper outer quadrant of the gluteal muscle.
For other routes:

   • Kanamycin sulfate injection may also be administered as an irrigation in a concentration of 0.25%.
   • Kanamycin sulfate injection may also be administered as an aerosol nebulization.
   • Kanamycin sulfate injection may also be administered intraperitoneally in a concentration of 2.5%.


Parenteral Dosage Forms

KANAMYCIN SULFATE INJECTION USP

Usual adult and adolescent dose
Antibacterial (systemic)
Inhalation treatment, 250 mg two to four times a day. {07}

Intramuscular, 3.75 mg per kg of body weight every six hours; 5 mg per kg of body weight every eight hours; or 7.5 mg per kg of body weight every twelve hours for seven to ten days. {07}

Intraperitoneal, 500 mg. {07}

Intravenous infusion, 5 mg per kg of body weight every eight hours; or 7.5 mg per kg of body weight every twelve hours for seven to ten days. {07}


Usual adult prescribing limits
Up to 15 mg per kg of body weight daily, but not to exceed 1.5 grams daily. {07}

Note: The total daily dose should take into account the amounts given by all routes, including intraperitoneal, inhalation, and irrigation. In intraocular infections, initial intramuscular doses of 2 grams, followed by 1 gram every twelve hours, have been used.


Usual pediatric dose
Antibacterial (systemic)—Intramuscular or intravenous infusion: See Usual adult and adolescent dose.

Note: Doses up to 30 mg per kg of body weight daily have been used in children.


Strength(s) usually available
U.S.—


37.5 mg per mL (Rx) [Kantrex][Generic]( sodium bisulfite 0.099%)


250 mg per mL (Rx) [Kantrex][Generic]( sodium bisulfite 0.66%)


333.3 mg per mL (Rx) [Kantrex][Generic]( sodium bisulfite 0.45%)

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
Intraperitoneal—To prepare dilution for intraperitoneal use, add the contents of each 500-mg vial to 20 mL of sterile water for injection. The resulting solution may be instilled postoperatively through a polyethylene catheter sutured into the wound at closure. {07} To help prevent or minimize neuromuscular blockade, instillation of kanamycin should be postponed until the patient has fully recovered from the effects of anesthesia or neuromuscular blocking agents.

Intravenous—To prepare initial dilution for intravenous use, add the contents of each 500-mg vial to 100 to 200 mL or the contents of each 1-gram vial to 200 to 400 mL of 0.9% sodium chloride injection, 5% dextrose injection, or other suitable diluent. The resulting solution should be administered over a 30- to 60-minute period. Pediatric patients may require a proportionately smaller volume of diluent. {07}

Stability:
Solutions may darken during storage; this darkening does not affect their potency. {07}

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle. {07} {91}

Since complexes form with a number of other drugs also, extemporaneous admixtures with kanamycin sulfate injection are not recommended.


NEOMYCIN




NEOMYCIN SULFATE STERILE USP

Note: Parenteral neomycin has been replaced by safer and more effective agents. Because of its potential toxicity, the parenteral use of neomycin is not recommended for any indication.


Size(s) usually available:
U.S.—


500 mg (Rx)[Generic]

Canada—
Not commercially available.


NETILMICIN


Additional Dosing Information
Serum concentrations of netilmicin in febrile patients may be lower than in afebrile patients receiving the same dose because of shorter half-life. The half-life may also be shorter in anemic patients. However, when the body temperature returns to normal in febrile patients, serum concentrations may increase. Dosage adjustments are not usually necessary.

For initial dosing guidelines for patients with renal function impairment, see the Sarubbi and Hull nomogram in General Dosing Information.

In severely burned patients, serum concentrations of netilmicin may be lower than expected from a particular dose. Serum determinations are especially important in these patients for dosage adjustment. {73}


Parenteral Dosage Forms

Note: The dosing and dosage forms available are expressed in terms of netilmicin base.


NETILMICIN SULFATE INJECTION USP

Usual adult and adolescent dose
Antibacterial (systemic)


Intramuscular or intravenous:


Systemic infections (serious)—
1.3 to 2.2 mg (base) per kg of body weight every eight hours; or 2 to 3.25 mg (base) per kg of body weight every twelve hours for seven to fourteen days. {73}



Urinary tract infections, bacterial (complicated)—
1.5 to 2 mg (base) per kg of body weight every twelve hours for seven to fourteen days. {73}




Note: Following hemodialysis, a supplemental dose of 1 mg (base) per kg of body weight may be administered.


Usual adult prescribing limits
Up to 7.5 mg (base) per kg of body weight daily.

Note: Doses up to 12 mg (base) per kg of body weight daily have been used in cystic fibrosis patients.


Usual pediatric dose
Antibacterial (systemic)


Intramuscular or intravenous:


Neonates up to 6 weeks of age—
2 to 3.25 mg (base) per kg of body weight every twelve hours for seven to fourteen days. {73}



Infants and children 6 weeks to 12 years of age—
1.83 to 2.67 mg (base) per kg of body weight every eight hours; or 2.75 to 4 mg (base) per kg of body weight every twelve hours for seven to fourteen days. {73}




Strength(s) usually available
U.S.—


100 mg per mL (base) (Rx) [Netromycin (benzyl alcohol 10 mg, sodium metabisulfite 2.4 mg, sodium sulfite 0.8 mg)]

Canada—


25 mg per mL (base) (Rx) [Netromycin (sodium metabisulfite 2.1 mg, sodium sulfite 1.2 mg)]


50 mg per mL (base) (Rx) [Netromycin (sodium metabisulfite 2.1 mg, sodium sulfite 1.2 mg)]


100 mg per mL (base) (Rx) [Netromycin (benzyl alcohol 10 mg, sodium metabisulfite 2.4 mg, sodium sulfite 0.8 mg)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. {73}

Preparation of dosage form:
To prepare initial dilution for intravenous use, each dose should be diluted in 50 to 200 mL of a suitable diluent (see manufacturer's package insert). The resulting solution should be administered slowly over a 30- to 60-minute period to help avoid neuromuscular blockade. Pediatric patients may require a proportionately smaller volume of diluent. {73}

Stability:
Intravenous infusions of netilmicin retain their potency for up to 72 hours at room temperature or when refrigerated and stored in glass containers at concentrations of 2.1 to 3 mg per mL in suitable diluents (see manufacturer's package insert). {73}

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle. {73} {91}


STREPTOMYCIN

Summary of Differences
Indications: Used for the treatment of brucellosis, granuloma inguinale, plague, tuberculosis, and tularemia.

Pregnancy/Reproduction: Has been shown to cause deafness in humans.

Patient monitoring: Caloric stimulation tests may also be required.


Additional Dosing Information
Tuberculosis therapy may have to be continued for 1 to 2 years, and may even be required for up to several years or indefinitely, although in some patients shorter treatment regimens may also be effective. However, streptomycin should be discontinued when toxicity or toxic symptoms appear or are impending, when organisms have become resistant, or when the full therapeutic effect has been achieved. {62}

Injection sites should be alternated and concentrations greater than 500 mg per mL are not recommended. {62}


Parenteral Dosage Forms

Note: The dosing and dosage forms available are expressed in terms of streptomycin base.


STREPTOMYCIN INJECTION USP

Usual adult dose
Antibacterial (antimycobacterial)


Tuberculosis:


Intramuscular—
   • Daily dosing—In combination with other antimycobacterials, 15 milligrams (base) per kilogram of body weight, up to a maximum dose of 1 gram, given by intramuscular injection once daily. {128}
   • Twice weekly dosing—In combination with other antimycobacterials, 25 to 30 milligrams (base) per kilogram of body weight, up to a maximum dose of 1.5 grams, given by intramuscular injection twice weekly. {128}
   • Three times-a-week dosing—In combination with other antimycobacterials, 25 to 30 milligrams (base) per kilogram of body weight, up to a maximum dose of 1.5 grams, given by intramuscular injection three times-a-week. {128}



Antibacterial (systemic)


Other infections:


Intramuscular—
In combination with other antibacterials, 250 to 500 mg (base) every six hours; or 500 mg to 1 gram every twelve hours for moderate to severe infections. Do not exceed doses of 2 grams per day. {128}



Note: Endocarditis (penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis)—Intramuscular: 1 gram twice daily for first week, 500 milligrams twice daily for second week, given concomitantly with penicillin. Sensitivity: Penicillin MIC £ 0.1 microgram/milliliter.
Endocarditis (enterococcal)—Intramuscular: 1 gram twice daily for 2 weeks, then 500 milligrams twice daily for 4 weeks, given concomitantly with penicillin. Termination of streptomycin therapy prior to completion of the 6-week course of treatment may be necessary if ototoxicity occurs. {128}
Plague—Intramuscular: 1 gram every twelve hours for a minimum of 10 days of therapy. {128}
Tularemia—Intramuscular: 250 to 500 mg (base) every six hours; or 500 mg to 1 gram every twelve hours for seven to fourteen days until patient is afebrile for 5 to 7 days.{128}



Usual adult prescribing limits
Tuberculosis
1 gram daily or 1.5 grams two or three times weekly. {128}The total dose over the course of therapy should not exceed 120 grams unless there are no other therapeutic options. {128}

Other infections
Intramuscular doses should not exceed 2 grams per day. {128}


Usual pediatric and adolescent dose
Antibacterial (antimycobacterial)


Tuberculosis:


Intramuscular—
   • Daily dosing—In combination with other antimycobacterials, 20 to 40 milligrams (base) per kilogram of body weight, up to a maximum dose of 1 gram, given by intramuscular injection once daily. {128}
   • Twice weekly dosing—In combination with other antimycobacterials, 25 to 30 milligrams (base) per kilogram of body weight, up to a maximum dose of 1.5 grams, given by intramuscular injection twice weekly. {128}
   • Three times-a-week dosing—In combination with other antimycobacterials, 25 to 30 milligrams (base) per kilogram of body weight, up to a maximum dose of 1.5 grams, given by intramuscular injection three times-a-week. {128}



Antibacterial (systemic)


Other infections:


Intramuscular—
In combination with other antibacterials, 5 to 10 mg (base) per kg of body weight every six hours; or 10 to 20 mg per kg of body weight every twelve hours. Avoid excessive dosage in children. {128}




Usual geriatric dose
Antibacterial (antimycobacterial)


Tuberculosis:


Intramuscular—
In combination with other antimycobacterials, 500 to 750 mg (base) once a day.




Other bacterial infections:


Intramuscular—
Endocarditis (penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis)—Intramuscular: 500 milligrams twice daily, given concomitantly with penicillin for two weeks in patients over 60 years of age. {128}. Sensitivity: Penicillin MIC £ 0.1 micrograms/milliliter.




Strength(s) usually available
U.S.—


1 gram per ampule (base) (Rx)[Generic](Pfizer—may contain sodium metabisulfite {128})

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Solutions may vary in color from colorless to yellow and may darken on exposure to light. This variation does not affect their potency.

Solutions should not be autoclaved since loss of potency may result.


STREPTOMYCIN FOR INJECTION USP

Usual adult dose
Antibacterial (antimycobacterial)


Tuberculosis:


Intramuscular—
   • Daily dosing—In combination with other antimycobacterials, 15 milligrams (base) per kilogram of body weight, up to a maximum dose of 1 gram, given by intramuscular injection once daily. {129}
   • Twice weekly dosing—In combination with other antimycobacterials, 25 to 30 milligrams (base) per kilogram of body weight, up to a maximum dose of 1.5 grams, given by intramuscular injection twice weekly. {129}
   • Three times-a-week dosing—In combination with other antimycobacterials, 25 to 30 milligrams (base) per kilogram of body weight, up to a maximum dose of 1.5 grams, given by intramuscular injection three times-a-week. {129}



Antibacterial (systemic)


Other infections:


Intramuscular—
In combination with other antibacterials, 250 to 500 mg (base) every six hours; or 500 mg to 1 gram every twelve hours for moderate to severe infections. Do not exceed doses of 2 grams per day. {129}



Note: Endocarditis (penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis)—Intramuscular: 1 gram twice daily for first week, 500 milligrams twice daily for second week, given concomitantly with penicillin. Sensitivity: Penicillin MIC £ 0.1 microgram/milliliter.
Endocarditis (enterococcal)—Intramuscular: 1 gram twice daily for 2 weeks, then 500 milligrams twice daily for 4 weeks, given concomitantly with penicillin. Termination of streptomycin therapy prior to completion of the 6-week course of treatment may be necessary if ototoxicity occurs. {129}
Plague—Intramuscular: 1 gram every twelve hours for a minimum of 10 days of therapy. {129}
Tularemia—Intramuscular: 250 to 500 mg (base) every six hours; or 500 mg to 1 gram every twelve hours for seven to fourteen days until patient is afebrile for 5 to 7 days.{129}



Usual adult prescribing limits
Tuberculosis
1 gram daily or 1.5 grams two or three times weekly. {129} The total dose over the course of therapy should not exceed 120 grams unless there are no other therapeutic options. {129}

Other infections
Intramuscular doses should not exceed 2 grams per day. {129}


Usual pediatric and adolescent dose
Antibacterial (antimycobacterial)


Tuberculosis:


Intramuscular—
   • Daily dosing—In combination with other antimycobacterials, 20 to 40 milligrams (base) per kilogram of body weight, up to a maximum dose of 1 gram, given by intramuscular injection once daily. {129}
   • Twice weekly dosing—In combination with other antimycobacterials, 25 to 30 milligrams (base) per kilogram of body weight, up to a maximum dose of 1.5 grams, given by intramuscular injection twice weekly. {129}
   • Three times-a-week dosing—In combination with other antimycobacterials, 25 to 30 milligrams (base) per kilogram of body weight, up to a maximum dose of 1.5 grams, given by intramuscular injection three times-a-week. {129}



Antibacterial (systemic)


Other infections:


Intramuscular—
In combination with other antibacterials, 5 to 10 mg (base) per kg of body weight every six hours; or 10 to 20 mg per kg of body weight every twelve hours. Avoid excessive dosage in children. {129}




Usual geriatric dose
Antibacterial (antimycobacterial)


Tuberculosis:


Intramuscular—
In combination with other antimycobacterials, 500 to 700 mg (base) once a day. {129}




Other bacterial infections:


Intramuscular—
Endocarditis (penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis)—Intramuscular: 500 milligrams twice daily, given concomitantly with penicillin for two weeks in patients over 60 years of age. {129}. Sensitivity: Penicillin MIC £ 0.1 micrograms/milliliter.




Size(s) usually available:
U.S.—


1 gram per vial (base) (Rx){129}[Generic]

Canada—


1 gram per vial (base) (Rx){130}[Generic]

Packaging and storage:
Prior to reconstitution, store dry powder under controlled room temperature 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. {129}

Preparation of dosage form:
To prepare initial dilution for intramuscular use, add 4.2 mL of sterile water for injection to each 1-gram vial, according to the manufacturer, to provide a concentration of 200 mg (base) per mL, 3.2 mL of diluent to provide a concentration of 250 mg per mL or 1.8 mL of diluent to provide a concentration of 400 mg per mL. {129}

Stability:
After reconstitution, sterile solutions should be protected from light and may be stored at room temperature for 1 week without significant loss of potency. {129}


TOBRAMYCIN

Summary of Differences
Pregnancy/Reproduction: Has been shown to cause deafness in humans.


Additional Dosing Information
Commercially available tobramycin piggyback injections should be administered by intravenous infusion only.

Tobramycin sulfate injection may also be administered as an aerosol nebulization.


Parenteral Dosage Forms

Note: The dosing and dosage forms available are expressed in terms of tobramycin base.


TOBRAMYCIN SULFATE INJECTION USP

Usual adult and adolescent dose
Antibacterial (systemic)
Intramuscular or intravenous infusion, 0.75 mg to 1.25 mg (base) per kg of body weight every six hours; or 1 to 1.7 mg per kg of body weight every eight hours for seven to ten days or more. {74}


Usual adult prescribing limits
Up to 8 mg (base) per kg of body weight daily in severe, life-threatening infections.

Usual pediatric dose
Antibacterial (systemic)


Intramuscular or intravenous infusion:


Premature or full-term neonates up to 1 week of age—
Up to 2 mg (base) per kg of body weight every twelve to twenty-four hours. {60} {74}



Older infants and children—
—1.5 to 1.9 mg (base) per kg of body weight every six hours; or 2 to 2.5 mg per kg of body weight every eight to sixteen hours. {74}



Note: The dosing interval of tobramycin in pediatric patients may vary from every four hours to every twenty-four hours, depending on the medical condition of the patient (cystic fibrosis, burns, renal dysfunction); serum levels must be monitored.



Strength(s) usually available
U.S.—


10 mg per mL (base) (Rx) [Nebcin (sodium bisulfite 3.2 mg)][Generic]


20 mg per mL (base) (Rx)[Generic]


40 mg per mL (base) (Rx) [Nebcin (sodium bisulfite 3.2 mg)][Generic]


60 mg per mL (base) (Rx)[Generic]


80 mg per mL (base) (Rx)[Generic]

Canada—


10 mg per mL (base) (Rx) [Nebcin (sodium bisulfite)]


40 mg per mL (base) (Rx) [Nebcin (sodium bisulfite)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
To prepare initial dilution for intravenous use, add each dose to 50 to 200 mL of 0.9% sodium chloride injection or 5% dextrose injection to provide a concentration not exceeding 1 mg (base) per mL (0.1%). The resulting solution should be administered slowly over a 30- to 60-minute period to avoid neuromuscular blockade. In addition, infusion periods of less than 20 minutes are not recommended since peak serum concentrations may exceed 12 mcg per mL. Pediatric patients may require a proportionately smaller volume of diluent. {52} {74}

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle. {74} {91}

Since complexes form with a number of other drugs also, extemporaneous admixtures with tobramycin sulfate injection are not recommended. {74}

Additional information:
Subcutaneous administration is not recommended and may be painful.


TOBRAMYCIN SULFATE STERILE USP

Usual adult and adolescent dose
Antibacterial (systemic)
Intravenous infusion, 0.75 mg to 1.25 mg (base) per kg of body weight every six hours; or 1 to 1.7 mg per kg of body weight every eight hours for seven to ten days or more. {74}


Usual adult prescribing limits
Up to 8 mg (base) per kg of body weight daily in severe, life-threatening infections.

Usual pediatric dose
Antibacterial (systemic)


Intravenous infusion:


Premature or full-term neonates up to 1 week of age—
Up to 2 mg (base) per kg of body weight every twelve to twenty-four hours. {60} {74}



Older infants and children—
—1.5 to 1.9 mg (base) per kg of body weight every six hours; or 2 to 2.5 mg per kg of body weight every eight to sixteen hours. {74}



Note: The dosing interval of tobramycin in pediatric patients may vary from every four hours to every twenty-four hours, depending on the medical condition of the patient (cystic fibrosis, burns, renal dysfunction); serum levels must be monitored.



Size(s) usually available:
U.S.—


1.2 grams (base) (Rx) [Nebcin][Generic]

Canada—


1.2 grams (base) (Rx) [Nebcin]

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. {74}

Preparation of dosage form:
To prepare initial dilution for intravenous use, add 30 mL of sterile water for injection to each 1.2-gram vial to provide 40 mg (base) per mL. Withdraw each dose from the pharmacy bulk vial and add it to 50 to 200 mL of 0.9% sodium chloride injection or 5% dextrose injection to provide a final concentration not exceeding 1 mg per mL (0.1%). The resulting solution should be administered slowly over a 30- to 60-minute period to avoid neuromuscular blockade. In addition, infusion periods of less than 20 minutes are not recommended since peak serum concentrations may exceed 12 mcg per mL. Pediatric patients may require a proportionately smaller volume of diluent.

Stability:
After reconstitution, solutions retain their potency for 24 hours at room temperature or for 96 hours if refrigerated. {74}

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle. {74} {91}

Since complexes form with a number of other drugs also, extemporaneous admixtures with Sterile Tobramycin Sulfate USP are not recommended. {74}

Additional information:
Sterile Tobramycin Sulfate USP is available only in a pharmacy bulk vial (multiple-dose) and is intended for use in the extemporaneous preparation of intravenous admixtures.


TOBRAMYCIN SULFATE IN SODIUM CHLORIDE INJECTION

Usual adult and adolescent dose
See Tobramycin Sulfate Injection USP .

Usual adult prescribing limits
See Tobramycin Sulfate Injection USP .

Usual pediatric dose
See Tobramycin Sulfate Injection USP .

Strength(s) usually available
U.S.—


60 mg in 50 mL (base) (Rx)[Generic]


80 mg in 100 mL (base) (Rx)[Generic]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 30 °C (36 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
Commercially available tobramycin piggyback injections require no further dilution prior to administration (see manufacturer's labeling for instructions).

Stability:
Do not use if injection is discolored or contains a precipitate.

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle. {91}

Since complexes form with a number of other drugs also, extemporaneous admixtures with tobramycin in sodium chloride injection are not recommended. {91}

Additional information:
The sodium content is approximately 19.6 mEq (450 mg) per 50 mL. This must be considered in patients on a restricted sodium intake when calculating total daily sodium intake.



Revised: 09/11/2002



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