Aminoglycoside

When treating infections brought on by organisms resistant to other aminoglycosides, amikacin has clear benefits. Relatively few enzymes that modify arninoglycosides have an impact on amikacin. Amikacin is effective in treating infections brought on by Mycobacterium avium-intracellulare, Nocardia asteroides, and a few species of "rapid-growing" mycobacteria, such as M. chelonae and M. fortuitumi[1].
With an LD50 value of 453 μM, amikacin (100-1500 μM) reliably causes a dose-dependent loss of lateral line zebrafish hair cells[3].

Treatment with amikacin (320 mg/kg; subcutaneous injection; daily; for 10 days; male Fischer rats) raises the risk of significant hearing loss in rats in vivo[3].

Animal Model: Male Fischer 344 rats (40-50-day-old)[3]
Dosage: 320 mg/kg
Administration: Subcutaneous injection; daily; for 10 days
Result: Induced hearing loss in rats.

Absorption, Distribution and Excretion
Rapidly absorbed after intramuscular administration. Rapid absorption occurs from the peritoneum and pleura. Poor oral and topical absorption. Poorly absorbed from bladder irrigations and intrathecal administration. The bioavailability of this drug is expected to vary primarily from individual differences in nebulizer efficiency and airway pathology. Following IM administration of a single dose of amikacin of 7.5 mg/kg in adults with normal renal function, peak plasma amikacin concentrations of 17-25 micrograms/mL are attained within 45 minutes to 2 hours. Following IV infusion of the same dose given over 1 hour peak plasma concentrations of the drug average 38 micrograms/mL immediately following the infusion, 5.5 micrograms/mL at 4 hours, and 1.3 micrograms/mL at 8 hours.
This drug is eliminated by the kidneys. In adults with normal renal function, 94-98% of a single IM or IV dose of amikacin is excreted unchanged by glomerular filtration in the kidney within 24 hours. Amikacin can be completely recovered within approximately 10-20 days in patients with normal, healthy renal function. In patients with impaired renal function, the clearance of amikacin is found to be decreased; the more severe the impairment, the slower the clearance. The interval between doses of amikacin should be adjusted according to the level of renal impairment. Endogenous creatinine clearance rate and serum creatinine which have a high correlation with serum half-life of amikacin, may be used as a guide for dosing.
24 L (28% of body weight healthy adult subjects). Following administration of usual dosages of amikacin, amikacin has been found in bone, heart, gallbladder, and lung tissue. Amikacin is also distributed into bile, sputum, bronchial secretions, and interstitial, pleural, and synovial fluids.
The mean serum clearance rate is about 100 mL/min and the renal clearance rate is 94 mL/min in subjects with normal renal function.
Emergence of a multiply drug resistant Enterobacter cloacae during a seven-week period in 1980 caused amikacin to become the aminoglycoside of choice in the initial management of suspected sepsis in a neonatal intensive care unit. Recommended doses (7.5-10 mg/kg loading; 15 mg/kg in two divided doses IV) were given to 5 infants < or = 1,000 gm and to 13 larger babies. Trough levels 11.5 hours after a dose were 16.6 +/- 11.9 ug/mL in infants < or = 1,000 gm and 6.5 +/- 4.3 ug/mL in the larger infants (P < 0.02). Peak levels one hour postinfusion exceeded 40 ug/mL in 3 of 5 < or = 1,000-gm babies and 4 of 12 > 1,000-gm infants (P = NS). Overall, 7 of 10 peak and/or trough levels in < or = 1,000-gm infants were in the range considered toxic in adults, versus 7 of 24 in larger babies (P = 0.03). These data show that ... excessive blood levels of amikacin are likely in infants < or = 1,000 gm and may also occur in larger infants using currently recommended dosage schedules. These ... findings emphasize the need to monitor drug levels and individualize therapy in very low birthweight infants.
Amikacin is poorly absorbed from the GI tract. Amikacin is rapidly absorbed following IM administration. 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 ug/mL; plasma concentrations 10 hours after the dose average 2.1 ug/mL.
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 ug/mL immediately following the infusion, 18 ug/mL at 1 hour, and 0.75 ug/mL at 10 hours. 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 ug/mL and trough concentrations (measured immediately before start of an infusion) were 1.8 ug/mL.
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.
For more Absorption, Distribution and Excretion (Complete) data for Amikacin (15 total), please visit the HSDB record page.

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Metabolism / Metabolites
Amikacin's structure has been altered to reduce the possible route of enzymatic deactivation, thus reducing bacterial resistance. Many strains of Gram-negative organisms resistant to gentamicin and tobramycin have shown to be sensitive to amikacin in vitro.
Aminoglycosides are not metabolized and are excreted unchanged in the urine primarily by glomerular filtration. /Aminoglycosides/

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Biological Half-Life
The plasma elimination half-life of amikacin is usually 2-3 hours in adults with normal renal function and is reported to range from 30-86 hours in adults with severe renal impairment.
The plasma elimination half-life of amikacin usually is 2-3 hours in adults with normal renal function and is reported to range from 28-86 hours in adults with severe renal impairment. 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. In preterm neonates, half-life is inversely related to postconceptional age and has ranged from 4.5-15.6 hours. 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.

Hepatotoxicity
Intravenous and intramuscular therapy with amikacin has not been linked to serum alkaline phosphatase or aminotransferase elevations, and no convincing cases of symptomatic or icteric hepatotoxicity due to amikacin have been published. Other aminoglycosides have been linked to very rare cases of cholestatic hepatitis, that typically arise within 1 to 3 weeks of starting therapy, often associated with skin rash, fever and sometimes eosinophilia. Recovery typically occurs within 1 to 2 months and chronic injury has not been described. Amikacin as well as other aminoglycosides are not mentioned in large case series of drug induced liver disease and acute liver failure; thus, hepatic injury due to amikacin is very rare if it occurs at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Amikacin is poorly excreted into breastmilk. Newborn infants apparently absorb small amounts of other aminoglycosides, but serum levels with typical three times daily dosages are far below those attained when treating newborn infections and systemic effects of amikacin are unlikely. Older infants would be expected to absorb even less amikacin. Because there is little variability in the milk amikacin levels during multiple daily dose regimens, timing breastfeeding with respect to the dose is of little or no benefit in reducing infant exposure. Data are not available with single daily dose regimens. Monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (e.g., thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
The protein binding of amikacin in serum is ≤ 10%.

[1]. Edson, R.S. and C.L. Terrell, The aminoglycosides. Mayo Clin Proc, 1999. 74(5): p. 519-28.

[2]. An overview of amikacin. Ther Drug Monit. 1985;7(1):12-25.

[3]. ORC-13661 Protects Sensory Hair Cells From Aminoglycoside and Cisplatin Ototoxicity. JCI Insight. 2019 Aug 8;4(15):e126764.

Amikacin is an amino cyclitol glycoside that is kanamycin A acylated at the N-1 position by a 4-amino-2-hydroxybutyryl group. It has a role as an antimicrobial agent, an antibacterial drug and a nephrotoxin. It is an alpha-D-glucoside, an aminoglycoside, a carboxamide and an amino cyclitol glycoside. It is functionally related to a kanamycin A. It is a conjugate base of an amikacin(4+).
Amikacin is a semi-synthetic aminoglycoside antibiotic that is derived from kanamycin A. Amikacin is synthesized by acylation with the l-(-)-γ-amino-α-hydroxybutyryl side chain at the C-1 amino group of the deoxystreptamine moiety of kanamycin A. Amikacin's unique property is that it exerts activity against more resistant gram-negative bacilli such as Acinetobacter baumanii and Pseudomonas aeruginosa. Amikacin also exerts excellent activity against most aerobic gram-negative bacilli from the Enterobacteriaceae family, including Nocardia and some Mycobacterium (M. avium-intracellulare, M. chelonae, and M. fortuitum). M. avium-intracellulare (MAC) is a type of nontuberculous mycobacteria (NTM) found in water and soil. Symptoms of this disease include a persistent cough, fatigue, weight loss, night sweats, and shortness of breath and the coughing up of blood. Several forms of amikacin are used currently, including an intravenous (IV) or intramuscular (IM) injection. In September 2018, a liposomal inhalation suspension of this drug was approved by the FDA for the treatment of lung disease caused by Mycobacterium avium complex (MAC) bacteria in a small population of patients with the disease who do not respond to traditional treatment.
Amikacin is an Aminoglycoside Antibacterial.
Amikacin is a parenterally administered, broad spectrum aminoglycoside antibiotic typically used for severe gram negative infections. Despite widespread use, amikacin has not been associated with instances of acute liver injury.
Amikacin has been reported in Stachybotrys chartarum, Streptomyces hygroscopicus, and Liquidambar formosana with data available.
Amikacin Sulfate is the sulfate salt of amikacin, a broad-spectrum semi-synthetic aminoglycoside antibiotic, derived from kanamycin with antimicrobial property. Amikacin irreversibly binds to the bacterial 30S ribosomal subunit, specifically in contact with 16S rRNA and S12 protein within the 30S subunit. This leads to interference with translational initiation complex and misreading of mRNA, thereby hampering protein synthesis and resulting in bactericidal effect. This agent is usually used in short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria.
Amikacin is a broad-spectrum semi-synthetic aminoglycoside antibiotic, derived from kanamycin with antimicrobial property. Amikacin irreversibly binds to the bacterial 30S ribosomal subunit, specifically locking 16S rRNA and S12 protein within the 30S subunit. This leads to interference with translational initiation complex and misreading of mRNA, thereby hampering protein synthesis and resulting in bactericidal effect. This agent is usually used in short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria.
A broad-spectrum antibiotic derived from KANAMYCIN. It is reno- and oto-toxic like the other aminoglycoside antibiotics.

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Drug Indication
The amikacin sulfate injection is indicated in the short-term treatment of serious bacterial infections due to susceptible strains of gram-negative bacteria, including Pseudomonas species, Escherichia coli, species of indole-positive and indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, as well as Acinetobacter (Mima-Herellea) species. Clinical studies have shown amikacin sulfate injection to be effective in bacterial septicemia (including neonatal sepsis); in serious infections of the respiratory tract, bones and joints, central nervous system (including meningitis) and skin and soft tissue; intra-abdominal infections (including peritonitis); and in burns and postoperative infections (including post-vascular surgery). Clinical studies have shown amikacin also to be effective in serious, complicated, and recurrent urinary tract infections due to the above organisms. Aminoglycosides, including amikacin, are not indicated in uncomplicated first-time episodes of urinary tract infections unless the causative organisms are not susceptible to antibiotics which are less toxic. In September 2018, a new indication with a new dosage route was approved for this drug. Amikacin liposome inhalation suspension was approved for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex (MAC) in a limited population of patients with the disease who do not respond to conventional treatment (refractory disease). This indication is approved under accelerated approval based on achieving sputum culture conversion (defined as 3 consecutive negative monthly sputum cultures) by Month 6 of treatment. Clinical benefit has not yet been established. **Important notes regarding Staphylococcus and Sensitivity testing:** Staphylococcus aureus, including methicillin-resistant strains, is the principal Gram-positive organism sensitive to amikacin. The use of amikacin in the treatment of staphylococcal infections should be restricted only to second-line therapy, and should be limited to only those patients suffering from severe infections caused by susceptible strains of staphylococcus species who have failed to show sensitivity to other available antibiotics. Bacteriologic studies should be performed to identify causative organisms and their susceptibilities to amikacin. Amikacin may be used as initial therapy in suspected gram-negative infections and therapy may be initiated before obtaining the results of susceptibility testing.
Arikayce liposomal is indicated for the treatment of non-tuberculous mycobacterial (NTM) lung infections caused by Mycobacterium avium Complex (MAC) in adults with limited treatment options who do not have cystic fibrosis.
Treatment of nontuberculous mycobacterial lung infection, Treatment of Pseudomonas aeruginosa lung infection/colonisation in cystic fibrosis patients

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Mechanism of Action
The primary mechanism of action of amikacin is the same as that for all aminoglycosides. It binds to bacterial 30S ribosomal subunits and interferes with mRNA binding and tRNA acceptor sites, interfering with bacterial growth. This leads to disruption of normal protein synthesis and production of non-functional or toxic peptides. Other actions have been postulated for drugs of this class. Amikacin, as well as the rest of the aminoglycosides, are generally bacteriocidal against gram-positive and gram-negative bacteria.
Aminoglycosides are usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/
... Aminoglycosides are aminocyclitols that kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane. Aminoglycoside resistance mechanisms include: (a) the deactivation of aminoglycosides by N-acetylation, adenylylation or O-phosphorylation, (b) the reduction of the intracellular concentration of aminoglycosides by changes in outer membrane permeability, decreased inner membrane transport, active efflux, and drug trapping, (c) the alteration of the 30S ribosomal subunit target by mutation, and (d) methylation of the aminoglycoside binding site. ... /Aminoglycosides/

C22H47N5O21S2

781.7595

781.22

C, 33.80; H, 6.06; N, 8.96; O, 42.98; S, 8.20

39831-55-5

Amikacin hydrate;1257517-67-1;Amikacin sulfate;149022-22-0;Amikacin;37517-28-5

37768

White to off-white crystalline powder.

981.8ºC at 760 mmHg

220-230ºC

13

17

10

40

819

16

S(=O)(=O)(O[H])O[H].S(=O)(=O)(O[H])O[H].O([C@]1([H])[C@]([H])([C@]([H])([C@@]([H])([C@]([H])(C([H])([H])O[H])O1)O[H])N([H])[H])O[H])[C@]1([H])[C@]([H])([C@]([H])([C@]([H])(C([H])([H])[C@@]1([H])N([H])C([C@]([H])(C([H])([H])C([H])([H])N([H])[H])O[H])=O)N([H])[H])O[C@]1([H])[C@]([H])([C@]([H])([C@@]([H])([C@]([H])(C([H])([H])N([H])[H])O1)O[H])O[H])O[H])O[H]

FXKSEJFHKVNEFI-GCZBSULCSA-N

InChI=1S/C22H43N5O13.2H2O4S/c23-2-1-8(29)20(36)27-7-3-6(25)18(39-22-16(34)15(33)13(31)9(4-24)37-22)17(35)19(7)40-21-14(32)11(26)12(30)10(5-28)38-21;2*1-5(2,3)4/h6-19,21-22,28-35H,1-5,23-26H2,(H,27,36);2*(H2,1,2,3,4)/t6-,7+,8-,9+,10+,11-,12+,13+,14+,15-,16+,17-,18+,19-,21+,22+;;/m0../s1

(S)-4-amino-N-((1R,2S,3S,4R,5S)-5-amino-2-(((2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-4-(((2R,3R,4S,5S,6R)-6-(aminomethyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxycyclohexyl)-2-hydroxybutanamide bis(sulfate)

BAY-416651 sulfate; BAY416651 sulfate; BAY416651 sulfate; Amikacin sulfate; Amitrex; Antibiotic BB-K8 sulfate; BB-K8; Biklin; Biodacyn; Chemacin; Fabianol; Kaminax; Kancin-Gap; Likacin; Lukadin; BB K8; BBK8

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~127.92 mM)
DMSO : ~1 mg/mL (~1.28 mM)

Solubility in Formulation 1: 50 mg/mL (63.96 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)