アミカシン硫酸塩 , BB K 8
EU APPROVED, 2020/10/27, Arikayce liposomal
Antibacterial, Protein biosynthesis inhibitor
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 disulfate is an aminoglycoside sulfate salt obtained by combining amikacin with two molar equivalents of sulfuric acid. It has a role as an antibacterial drug, an antimicrobial agent and a nephrotoxin. It contains an amikacin(4+).
Amikacin sulfate is semi-synthetic aminoglycoside antibiotic derived from kanamycin. It is C22H43N5O13•2H2SO4•O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[6-amino-6-deoxy-α-Dglucopyranosyl-( 1→6)]-N3-(4-amino-L-2-hydroxybutyryl)-2-deoxy-L-streptamine sulfate (1:2)
M.W. 585.61The dosage form is supplied as a sterile, colorless to light straw colored solution for intramuscular or intravenous use. Each mL contains 250 mg amikacin (as the sulfate), 0.66% sodium metabisulfite, 2.5% sodium citrate dihydrate with pH adjusted to 4.5 with sulfuric acid.
Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.
Amikacin, like other aminoglycoside antibiotics, can cause hearing loss, balance problems, and kidney problems. Other side effects include paralysis, resulting in the inability to breathe. If used during pregnancy it may cause permanent deafness in the baby. Amikacin works by blocking the function of the bacteria’s 30S ribosomal subunit, making it unable to produce proteins.
Amikacin is most often used for treating severe infections with multidrug-resistant, aerobic Gram-negative bacteria, especially Pseudomonas, Acinetobacter, Enterobacter, E. coli, Proteus, Klebsiella, and Serratia. The only Gram-positive bacteria that amikacin strongly affects are Staphylococcus and Nocardia. Amikacin can also be used to treat non-tubercular mycobacterial infections and tuberculosis (if caused by sensitive strains) when first-line drugs fail to control the infection. It is rarely used alone.
It is often used in the following situations:
- Bone and joint infections
- Granulocytopenia, when combined with ticarcillin, in people with cancer
- Intra-abdominal infections (such as peritonitis) as an adjunct to other medicines, like clindamycin, metronidazole, piperacillin/tazobactam, or ampicillin/sulbactam
- for meningitis by E. coli, as an adjunct to imipenem
- for meningitis caused by Pseudomonas, as an adjunct to meropenem
- for meningitis caused by Acetobacter, as an adjunct to imipenem or colistin
- for neonatal meningitis caused by Streptococcus agalactiae or Listeria monocytogenes, as an adjunct to ampicillin
- for neonatal meningitis caused by Gram negative bacteria such as E. coli, as adjunct to a 3rd-generation cephalosporin
- Mycobacterial infections, including as a second-line agent for active tuberculosis. It is also used for infections by Mycobacterium avium, M. abcessus, M. chelonae, and M. fortuitum.
- Rhodococcus equi, which causes an infection resembling tuberculosis
- Respiratory tract infections, including as an adjunct to beta-lactams or carbapenem for hospital-acquired pneumonia
- Sepsis, including that in neonates, as an adjunct to beta-lactams or carbapenem
- Skin and suture-site infections
- Urinary tract infections that are caused by bacteria resistant to less toxic drugs (often by Enterobacteriaceae or P. aeruginosa)
Amikacin may be administered once or twice a day and is usually given by the intravenous or intramuscular route, though it can be given via nebulization. There is no oral form available, as amikacin is not absorbed orally. In people with kidney failure, dosage must be adjusted according to the creatinine clearance, usually by reducing the dosing frequency. In people with a CNS infection such as meningitis, amikacin can be given intrathecally (by direct injection into the spine) or intraventricularly (by injection into the ventricles of brain).
An liposome inhalation suspension is also available and approved to treat Mycobacterium avium complex (MAC) in the United States. The application for Arikayce was withdrawn in the European Union because the Committee for Medicinal Products for Human Use (CHMP) was of the opinion that the benefits of Arikayce did not outweigh its risks.
Amikacin should be used in smaller doses in the elderly, who often have age-related decreases in kidney function, and children, whose kidneys are not fully developed yet. It is considered pregnancy category D in both the United States and Australia, meaning they have a probability of harming the fetus. Around 16% of amikacin crosses the placenta; while the half-life of amikacin in the mother is 2 hours, it is 3.7 hours in the fetus. A pregnant woman taking amikacin with another aminoglycoside has a possibility of causing congenital deafness in her child. While it is known to cross the placenta, amikacin is only partially secreted in breast milk.
In general, amikacin should be avoided in infants. Infants also tend to have a larger volume of distribution due to their higher concentration of extracellular fluid, where aminoglycosides reside.
The elderly tend to have amikacin stay longer in their system; while the average clearance of amikacin in a 20-year-old is 6 L/hr, it is 3 L/hr in an 80-year-old.
Clearance is even higher in people with cystic fibrosis.
Side-effects of amikacin are similar to those of other aminoglycosides. Kidney damage and ototoxicity (which can lead to hearing loss) are the most important effects, occurring in 1–10% of users. The nephro- and ototoxicity are thought to be due to aminoglycosides’ tendency to accumulate in the kidneys and inner ear.
Amikacin can cause neurotoxicity if used at a higher dose or for longer than recommended. The resulting effects of neurotoxicity include vertigo, numbness, tingling of the skin (paresthesia), muscle twitching, and seizures. Its toxic effect on the 8th cranial nerve causes ototoxicity, resulting in loss of balance and, more commonly, hearing loss. Damage to the cochlea, caused by the forced apoptosis of the hair cells, leads to the loss of high-frequency hearing and happens before any clinical hearing loss can be detected. Damage to the ear vestibules, most likely by creating excessive oxidative free radicals. It does so in a time-dependent rather than dose-dependent manner, meaning that risk can be minimized by reducing the duration of use.
Amikacin causes nephrotoxicity (damage to the kidneys), by acting on the proximal renal tubules. It easily ionizes to a cation and binds to the anionic sites of the epithelial cells of the proximal tubule as part of receptor-mediated pinocytosis. The concentration of amikacin in the renal cortex becomes ten times that of amikacin in the plasma; it then most likely interferes with the metabolism of phospholipids in the lysosomes, which causes lytic enzymes to leak into the cytoplasm. Nephrotoxicity results in increased serum creatinine, blood urea nitrogen, red blood cells, and white blood cells, as well as albuminuria (increased output of albumin in the urine), glycosuria (excretion of glucose into the urine), decreased urine specific gravity, and oliguria (decrease in overall urine output). It can also cause urinary casts to appear. The changes in renal tubular function also change the electrolyte levels and acid-base balance in the body, which can lead to hypokalemia and acidosis or alkalosis. Nephrotoxicity is more common in those with pre-existing hypokalemia, hypocalcemia, hypomagnesemia, acidosis, low glomerular filtration rate, diabetes mellitus, dehydration, fever, and sepsis, as well as those taking antiprostaglandins. The toxicity usually reverts once the antibiotic course has been completed, and can be avoided altogether by less frequent dosing (such as once every 24 hours rather than once every 8 hours).
Rare side effects (occurring in fewer than 1% of users) include allergic reactions, skin rash, fever, headaches, tremor, nausea and vomiting, eosinophilia, arthralgia, anemia, hypotension, and hypomagnesemia. In intravitreous injections (where amikacin is injected into the eye), macular infarction can cause permanent vision loss.
The amikacin liposome inhalation suspension prescribing information includes a boxed warning regarding the increased risk of respiratory conditions including hypersensitivity pneumonitis (inflamed lungs), bronchospasm (tightening of the airway), exacerbation of underlying lung disease and hemoptysis (spitting up blood) that have led to hospitalizations in some cases. Other common side effects in patients taking amikacin liposome inhalation suspension are dysphonia (difficulty speaking), cough, ototoxicity (damaged hearing), upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.
Amikacin should be avoided in those who are sensitive to any aminoglycoside, as they are cross-allergenic (that is, an allergy to one aminoglycoside also confers hypersensitivity to other aminoglycosides). It should also be avoided in those sensitive to sulfite (seen more among people with asthma), since most amikacin usually comes with sodium metabisulfite, which can cause an allergic reaction.
In general, amikacin should not be used with or just before/after another drug that can cause neurotoxicity, ototoxicity, or nephrotoxicity. Such drugs include other aminoglycosides; the antiviral acyclovir; the antifungal amphotericin B; the antibiotics bacitracin, capreomycin, colistin, polymyxin B, and vancomycin; and cisplatin, which is used in chemotherapy.
Amikacin can be inactivated by other beta-lactams, though not to the extent as other aminoglycosides, and is still often used with penicillins (a type of beta-lactam) to create an additive effect against certain bacteria, and carbapenems, which can have a synergistic against some Gram-positive bacteria. Another group of beta-lactams, the cephalosporins, can increase the nephrotoxicity of aminoglycoside as well as randomly elevating creatinine levels. The antibiotics chloramphenicol, clindamycin, and tetracycline have been known to inactivate aminoglycosides in general by pharmacological antagonism.
The effect of amikacin is increased when used with drugs derived from the botulinum toxin, anesthetics, neuromuscular blocking agents, or large doses of blood that contains citrate as an anticoagulant.
Potent diuretics not only cause ototoxicity themselves, but they can also increase the concentration of amikacin in the serum and tissue, making the ototoxicity even more likely. Quinidine also increases levels of amikacin in the body. The NSAID indomethacin can increase serum aminoglycoside levels in premature infants. Contrast mediums such as ioversol increases the nephrotoxicity and otoxicity caused by amikacin.
Amikacin can decrease the effect certain vaccines, such as the live BCG vaccine (used for tuberculosis), the cholera vaccine, and the live typhoid vaccine by acting as a pharmacological antagonist.
Mechanism of action
Amikacin irreversibly binds to 16S rRNA and the RNA-binding S12 protein of the 30S subunit of prokaryotic ribosome and inhibits protein synthesis by changing the ribosome’s shape so that it cannot read the mRNA codons correctly. It also interferes with the region that interacts with the wobble base of the tRNA anticodon. It works in a concentration-dependent manner, and has better action in an alkaline environment.
At normal doses, amikacin-sensitive bacteria respond within 24–48 hours.
Amikacin evades attacks by all antibiotic-inactivating enzymes that are responsible for antibiotic resistance in bacteria, except for aminoacetyltransferase and nucleotidyltransferase. This is accomplished by the L-hydroxyaminobuteroyl amide (L-HABA) moiety attached to N-1 (compare to kanamycin, which simply has a hydrogen), which blocks the access and decreases the affinity of aminoglycoside-inactivating enzymes. Amikacin ends up with only one site where these enzymes can attack, while gentamicin and tobramycin have six.
Bacteria that are resistant to streptomycin and capreomycin are still susceptible to amikacin; bacteria that are resistant to kanamycin have varying susceptibility to amikacin. Resistance to amikacin also confers resistance to kanamycin and capreomycin.
Resistance to amikacin and kanamycin in Mycobacterium, the causative agent of tuberculosis, is due to a mutation in the rrs gene, which codes for the 16S rRNA. Mutations such as these reduce the binding affinity of amikacin to the bacteria’s ribosome. Variations of aminoglycoside acetyltransferase (AAC) and aminoglycoside adenylyltransferase (AAD) also confer resistance: resistance in Pseudomonas aeruginosa is caused by AAC(6′)-IV, which also confers resistance to kanamycin, gentamicin, and tobramycin, and resistance in Staphylococcus aureus and S. epidermidis is caused by AAD(4′,4), which also confers resistance to kanamycin, tobramycin, and apramycin. Some strains of S. aureus can also inactivate amikacin by phosphorylating it.
Amikacin is not absorbed orally and thus must be administered parenterally. It reaches peak serum concentrations in 0.5–2 hours when administered intramuscularly. Less than 11% of the amikacin actually binds to plasma proteins. It is distributed into the heart, gallbladder, lungs, and bones, as well as in bile, sputum, interstitial fluid, pleural fluid, and synovial fluids. It is usually found at low concentrations in the cerebrospinal fluid, except when administered intraventricularly. In infants, amikacin is normally found at 10–20% of plasma levels in the spinal fluid, but the amount reaches 50% in cases of meningitis. It does not easily cross the blood-brain barrier or enter ocular tissue.
While the half-life of amikacin is normally two hours, it is 50 hours in those with end-stage renal disease.
The vast majority (95%) of amikacin from an IM or IV dose is secreted unchanged via glomerular filtration and into the urine within 24 hours. Factors that cause amikacin to be excreted via urine include its relatively low molecular weight, high water solubility, and unmetabolized state.
While amikacin is only FDA-approved for use in dogs and for intrauterine infection in horses, it is one of the most common aminoglycosides used in veterinary medicine, and has been used in dogs, cats, guinea pigs, chinchillas, hamsters, rats, mice, prairie dogs, cattle, birds, snakes, turtles and tortoises, crocodilians, bullfrogs, and fish. It is often used for respiratory infections in snakes, bacterial shell disease in turtles, and sinusitis in macaws. It is generally contraindicated in rabbits and hares (though it has still been used) because it harms the balance of intestinal microflora.
In dogs and cats, amikacin is commonly used as a topical antibiotic for ear infections and for corneal ulcers, especially those that are caused by Pseudomonas aeruginosa. The ears are often cleaned before administering the medication, since pus and cellular debris lessen the activity of amikacin. Amikacin is administered to the eye when prepared as an ophthalmic ointment or solution, or when injected subconjunctivally. Amikacin in the eye can be accompanied by cephazolin. Despite its use there amikacin (and all aminoglycosides) are toxic to intraocular structures.
In horses, amikacin is FDA-approved for uterine infections (such as endometriosis and pyometra) when caused by susceptible bacteria. It is also used in topical medication for the eyes and arthroscopic lavage; when combined with a cephalosporin, is used to treat subcutaneous infections that are caused by Staphylococcus. For infections in the limbs or joints, it is often administered with a cephalosporin via limb perfusion directly into the limb or injected into the joint. Amikacin is also injected into the joints with the anti-arthritic medication Adequan in order to prevent infection.
Side effects in animals include nephrotoxicity, ototoxicity, and allergic reactions at IM injection sites. Cats tend to be more sensitive to the vestibular damage caused by ototoxicity. Less frequent side effects include neuromuscular blockade, facial edema, and peripheral neuropathy.
The half-life in most animals is one to two hours.
Treating overdoses of amikacin requires kidney dialysis or peritoneal dialysis, which reduce serum concentrations of amikacin, and/or penicillins, some of which can form complexes with amikacin that deactivate it.
Liposome inhalation suspension
Amikacin liposome inhalation suspension was the first drug approved under the US limited population pathway for antibacterial and antifungal drugs (LPAD pathway). It also was approved under the accelerated approval pathway. The U.S. Food and Drug Administration (FDA) granted the application for amikacin liposome inhalation suspension fast track, breakthrough therapy, priority review, and qualified infectious disease product (QIDP) designations. The FDA granted approval of Arikayce to Insmed, Inc.
The safety and efficacy of amikacin liposome inhalation suspension, an inhaled treatment taken through a nebulizer, was demonstrated in a randomized, controlled clinical trial where patients were assigned to one of two treatment groups. One group of patients received amikacin liposome inhalation suspension plus a background multi-drug antibacterial regimen, while the other treatment group received a background multi-drug antibacterial regimen alone. By the sixth month of treatment, 29 percent of patients treated with amikacin liposome inhalation suspension had no growth of mycobacteria in their sputum cultures for three consecutive months compared to 9 percent of patients who were not treated with amikacin liposome inhalation suspension.
Amikacin is a semi-synthetic aminoglycoside antibiotic with a broad antibacterial spectrum and strong antibacterial activity against a variety of bacteria; its sulfate has become a clinically commonly used first-line anti-infective drug in the world and continues to Develop new dosage forms and uses.
 Amikacin sulfate is suitable for Pseudomonas aeruginosa and other Pseudomonas, Escherichia coli, Proteus, Klebsiella, Enterobacter, Serratia, Acinetobacter Severe infections caused by other sensitive gram-negative bacilli and Staphylococcus (methicillin-sensitive strains), such as bacteremia or sepsis, bacterial endocarditis, lower respiratory tract infections, bone and joint infections, biliary tract infections, abdominal infections, Complex urinary tract infections, skin and soft tissue infections, etc. Because it is stable to most aminoglycoside inactivating enzymes, it is especially suitable for the treatment of serious infections caused by gram-negative bacilli against kanamycin, gentamicin or tobramycin-resistant strains.
 Amikacin, also known as amikacin, has a molecular weight of 585. The most commonly used synthetic route is a silyl protecting routes, such as the document “amikacin by New Method” (Author: Jiangzhong Liang, Wang Yu; Fine & Specialty Chemicals, 2004, 12 (10), 26- 28) The main process recorded is: (1) Using kanamycin A (KMA) as a raw material to protect the 11 amino groups and hydroxyl groups of kanamycin to obtain methylsilyl kanamycin; (2) ) Using YN-phthalimido-α-hydroxybutyric acid (PHBA) and N-hydroxy-phthalimide (NOP) as raw materials in dicyclohexylcarbodiimide (DCC) The active ester compound is prepared in the presence; (3) acylation (transesterification reaction) with methylsilyl kanamycin and active ester, and then acidolysis and hydrazinolysis reactions to obtain amikacin. As shown in the following route:
 1. Silanization protection reaction:
 2. Preparation of Living King®:
 3. Acylation reaction:
 4. Acidolysis reaction:
 5. Hydrazine reaction:
 The acylation reaction in the above route adopts a transesterification reaction between a silyl group protection reactant and an independently prepared active ester. Due to the active transesterification reaction, a large excess of reactant active ester is needed to improve the reaction yield, and there is an independent unit reaction for preparing active ester, and the raw material N-hydroxy-phthalimide is used. (NOP), increasing the usage amount of reaction solvent, the solvent in the process is volatile, the loss is large, the environment is affected, and the production cost is increased.
 How to find a direct one-step acylation reaction between the silyl group protection and YN-phthalimido-α-hydroxybutyric acid (PHBA), which can not only ensure the synthesis yield, but also reduce the synthesis The steps are easy to operate, and the N-hydroxy-phthalimide (NOP), the raw material for preparing active esters, is no longer used, and the acylation reaction conditions that reduce solvent consumption are a very beneficial synthetic process line.
 600mL of acetonitrile was put into the silanization reaction flask, and 0.1 billion kanamycin A (KMA) was added. After the feeding port was closed and stirred for 10 minutes, hexamethyldisilazane (HMDS) was added. 400mL, heated to reflux, refluxed at 75~80°C for 7hr. Use drinking water to cool the outside of the reaction flask to lower the temperature to below 35°C, and let it stand for natural layering. Separate and collect the lower layer to obtain a silyl group protected product.
 Add 1000mL acetone to the silyl group protection product, start stirring, add 60g γ-N-phthalimido-α-hydroxybutyric acid (PHBA), and then add 2.5g catalyst 4-N, N -Lutidine (DMAP), cooled to -15~-1 (TC〇
 Dissolve 60gN, N-bicyclohexylcarbodiimide with 300mL of acetone, add its flow to the above-mentioned reactant, control the flow rate of 5mL/min, and control the temperature of the reactant to -15~-10°C; the flow is completed Continue the reaction for 1 hour.
 After the completion of the acylation reaction, the material was transferred to the acidolysis bottle, the stirring was turned on, and 400mL of 4.0mol/L hydrochloric acid was added for acidolysis, and the feed solution was pH 3.0 and allowed to stand for 60 minutes. The lower acid hydrolysis solution was collected by suction filtration, and the filter cake (DCU) was washed three times with 150 mL of deionized water, and the washing water was incorporated into the acid hydrolysis solution.
 The acid hydrolysate was transferred to a distillation flask. Turn on the vacuum, the degree of vacuum: <0.07Mpa, the distillation temperature is controlled at 40~68°C, the distillation time: 2.5 hours after the distillation is complete; transfer the PKS concentrate in the distillation flask into the hydrazinolysis flask, and add 7.Omol/ L ammonia water 200mL, so that the pH of the material solution reaches 8.0; add 180mL hydrazine hydrate, increase the temperature, the temperature is 85~95°C, hydrazinolysis 3.5 hours, use drinking water to cool outside the hydrazinolysis bottle, and cool to 40 °C.
 Add 4.0111〇1/1 hydrochloric acid 12001^ to the hydrazinolysis bottle, adjust? !1 is 4.0. Turn on the vacuum filtration. With 5001 ^ deionized water top washing filter, 1510mL of amikacin synthetic solution, amikacin content 5.8% (g/mL), relative to the synthetic yield of kanamycin A is 72.5 %.
 Example 2
 600mL of acetonitrile was put into the silanization reaction flask, 0.1 billion kanamycin A (KMA) was added, the feeding port was closed and stirred for 10 minutes, and hexamethyldisilazane (HMDS) was added 500mL, heated to reflux, refluxed at 75~80°C for 8hr. After the reaction is completed, cool down to 40°C with drinking water and let stand for natural layering. Separate and collect the lower layer to obtain a silyl group protected product.
 Add 1000mL acetone to the silyl group protection product, start stirring, add 70g Y-N-phthalimido-α-hydroxybutyric acid (PHBA), and add 3.0g catalyst 1-hydroxybenzo Triazole (HOBT), after the material is dissolved, the temperature is reduced to -15~-10°C.
 Dissolve 70g of N,N-bicyclohexylcarbodiimide with 300mL of acetone, add its flow to the above-mentioned reactants, control the flow rate of 6mL/min, and control the temperature of the reactants from -15 to -10°C; the flow is completed Continue the reaction for 1.5 hours.
 After the acylation reaction is completed, the material is transferred to the acidolysis bottle, the stirring is turned on, and 6.0m〇l/L hydrochloric acid 300mL is added for acidolysis, the feed solution is pH 2.0, and the acidolysis is completed, and it is allowed to stand for 50 minutes. The lower acid hydrolysis solution was collected by suction filtration, the filter cake (DCU) was washed three times with 200 mL of deionized water, and the washing water was incorporated into the acid hydrolysis solution.
 Transfer the acid hydrolysate into a distillation flask. Turn on the vacuum, vacuum degree: <-0.07Mpa, the distillation temperature is controlled at 40~68°C, the distillation time is 3.0 hours, except for acetone. After the distillation is completed, transfer the PKS concentrate in the distillation flask into the hydrazinolysis flask, add 150 mL of 10.0 mol/L ammonia water, the pH of the feed solution is 8.5; add 200 mL of hydrazine hydrate, increase the temperature at 85~95 °C, hydrazinolysis 4 After hours, use drinking water to cool down outside the hydrazinolysis bottle to 45°C.
 Add 6.0111〇1/1 hydrochloric acid 10001^ to the hydrazinolysis bottle, adjust? !1 is 3.0. Turn on the vacuum filtration, use 8001^ deionized water to wash and filter the fish, to obtain 1620 mL of amikacin synthetic solution, and the amikacin content is 5.5% (g/mL). The synthetic yield relative to kanamycin A was 73.7%.
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|Trade names||Amikin, Amiglyde-V, Arikayce, others|
|Elimination half-life||2–3 hours|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||585.608 g·mol−1|
|3D model (JSmol)|
/////////Amikacin sulfate, Arikayce liposomal, EU 2020, 2020 APPROVALS, Antibacterial, Protein biosynthesis inhibitor, アミカシン硫酸塩 , BB K 8, AMIKACIN