37517-28-5

Amikacin is made semisynthetically from kanamycin A. Interestingly, the L-hydroxyaminobutyryl amide (HABA) moiety attached to N-3 inhibits adenylation and phosphorylation in the distant amino sugar ring (at C-2′and C-3′), even though the HABA substituent is not where the enzymatic reaction takes place. This effect is attributed to decreased binding to the R factor–mediated enzymes.

white crystalline powder

Amikin,Bristol,US,1976

Antibacterial;Ribosomal protein synthesis inhibitor

ChEBI: An amino cyclitol glycoside that is kanamycin A acylated at the N-1 position by a 4-amino-2-hydroxybutyryl group.

Preparation of L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyric acid: L-(-)-γ- amino-α-hydroxybutyric acid (7.4 g, 0.062 mol) was added to a solution of 5.2 grams (0.13 mol) of sodium hydroxide in 50 ml of water. To the stirred solution was added dropwise at 0-5°C over a period of 0.5 hour, 11.7 grams (0.068 mol) of carbobenzoxy chloride and the mixture was stirred for another hour at the same temperature. The reaction mixture was washed with 50 ml of ether, adjusted to pH 2 with dilute hydrochloric acid and extracted with four 80 ml portions of ether. The ethereal extracts were combined, washed with a small amount of saturated sodium chloride solution, dried with anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuum and the resulting residue was crystallized from benzene to give 11.6 grams (74%) of colorless plates; MP 78.5°C to 79.5°C.
Preparation of N-Hydroxysuccinimide Ester of L-(-)-γ-Benzyloxycarbonylamino- α-hydroxybutyric acid: A solution of 10.6 grams (0.042 mol) of L-(-)-γ- benzyloxycarbonylamino-α-hydroxybutyric acid and 4.8 grams (0.042 mol) of N-hydroxysuccinimide in 200 ml of ethyl acetate was cooled to 0°C and then 8.6 grams (0.042 mol) of dicyclohexylcarbodiimide was added. The mixture was kept overnight in a refrigerator. The dicyclohexylurea which separated was filtered off and the filtrate was concentrated to about 50 ml under reduced pressure to give colorless crystals of L-(-)-γ-benzyloxycarbonylamino- α-hydroxybutyric acid which were collected by filtration; 6.4 grams, MP 121- 122.5°C. The filtrate was evaporated to dryness in vacuum and the crystalline residue was washed with 20 ml of a benzene-n-hexane mixture to give an additional amount of L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyric acid. The total yield was 13.4 grams (92%).
Preparation of 1-[L-(-)-γ-Benzyloxycarbonylamino-α-Hydroxybutyryl]-6'- Carbobenzoxykanamycin A: A solution of 1.6 grams (4.6 mmol) of L-(-)-γ- benzyloxycarbonylamino-α-hydroxybutyric acid in 40 ml of ethylene glycol dimethyl ether (DME) was added dropwise to a stirred solution of 2.6 grams (4.2 mmol) of 6'-monobenzyloxycarbonylkanamycin A in 40 ml of 50% aqueous ethylene glycol dimethyl ether and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure to give a brown residue 1-[L-(-)-γ-benzyloxycarbonylarnino-α-hydroxybutyryl]-6'- carbobenzoxykanamycin A which was used for the next reaction without further purification.
Preparation of 1-[L-(-)-γ-Amino-α-Hydroxybutyryl] Kanamycin A: The crude product 1-[L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyryl]-6'- carbobenzoxykanamycin A was dissolved in 40 ml of 50% aqueous dioxane and a small amount of insoluble material was removed by filtration. To the filtrate was added 0.8 ml of glacial acetic acid and 1 gram of 10% palladiumon- charcoal and the mixture was hydrogenated at room temperature for 24 hours in a Parr hydrogenation apparatus. The reaction mixture was filtered to remove the palladium catalyst and the filtrate was evaporated to dryness in vacuum.
The residue was dissolved in 30 ml of water and chromatographed on a column of CG-50 ion exchange resin (NH4 + type, 50 cm x 1.8 cm). The column was washed with 200 ml of water and then eluted with 800 ml of 0.1 N NH4OH, 500 ml of 0.2 N NH4OH and finally 500 ml of 0.5 N NH4OH. Ten milliliter fractions were collected and fractions 146 to 154 contained 552 mg (22%. based on carbobenzoxykanamycin A, 6'- monobenzyloxycarbonylkanamycin A) of the product which was designated BB-K8 lot 2. MP 187°C (dec). Relative potency against B. subtilis (agar plate) = 560 mcg/mg (standard: kanamycin A free base).
A solution of 250 mg of BB-K8 lot 2 in 10 ml of water was subjected to chromatography on a column of CG-50 (NH4 + type, 30 cm x 0.9 cm). The column was washed with 50 ml of water and then eluted with 0.2 N NH4OH. Ten milliliter fractions were collected. Fractions 50 to 63 were combined and evaporated to dryness under reduced pressure to give 98 mg of the pure product base.
Preparation of the Monosulfate Salt of 1-[L-(-)-γ-Amino-α-Hydroxybutyryl] Kanamycin A: One mol of 1-[L-(-)-γ-amino-α-hydroxybutyryl] kanamycin A is dissolved in 1 to 3 liters of water. The solution is filtered to remove any undissolved solids. To the chilled and stirred solution is added one mol of sulfuric acid dissolved in 500 ml of water. The mixture is allowed to stir for 30 minutes, following which cold ethanol is added to the mixture till precipitation occurs. The solids are collected by filtration and are determined to be the desired monosulfate salt.

Amikin (Apothecon).

Antibacterial

Among other organisms, Acinetobacter, Alkaligenes, Campylobacter, Citrobacter, Hafnia, Legionella, Pasteurella, Providencia, Serratia and Yersinia spp. are usually susceptible in vitro. Stenotrophomonas maltophilia, many nonaeruginosa pseudomonads and Flavobacterium spp. are resistant. M. tuberculosis (including most streptomycin-resistant strains) and some other mycobacteria (including M. fortuitum and the M. avium complex) are susceptible; most other mycobacteria, including M. kansasii, are resistant. Nocardia asteroides is susceptible.
It exhibits typical aminoglycoside characteristics, including an effect of divalent cations on its activity against Ps. aeruginosa analogous to that seen with gentamicin and synergy with β-lactam antibiotics.

Amikacin is unaffected by many of the modifying enzymes that inactivate gentamicin and tobramycin and is consequently active against staphylococci, enterobacteria and Pseudomonas that owe their resistance to the production of those enzymes. However, AAC(6′), ANT(4′) and some forms of APH(3′) can confer resistance; because these enzymes generally do not confer gentamicin resistance, amikacin-resistant strains can be missed in routine susceptibility tests when gentamicin is used as the representative aminoglycoside.
There have been reports of resistance arising during treatment of infections due to Serratia spp. and Ps. aeruginosa. Outbreaks of infection with multiresistant strains of enterobacteria and Ps. aeruginosa have occurred after extensive use, particularly in burns units. Bacteria that owe their resistance to the expression of ANT(4′) have been described in Staph. aureus, coagulase-negative staphylococci, Esch. coli, Klebsiella spp. and Ps. aeruginosa. In E. faecalis, resistance to penicillin– aminoglycoside synergy has been associated with plasmidmediated APH(3′). Resistance in Gram-negative organisms is usually caused by either reduced accumulation of the drug or, more commonly, by the aminoglycoside-modifying enzymes AAC(6′) or AAC(3)-VI. The latter enzyme is usually found in Acinetobacter spp., but has also been found, encoded by a transposon, in Prov. stuartii. One type of AAC(6) is chromosomally encoded by Ser. marcescens, though not usually expressed.
The prevalence of resistance to amikacin remains low (<5%) in many countries but can change rapidly with increased usage of the drug. However, the spread of extended spectrum β-lactamases belonging to the TEM and SHV families may result in an increase in amikacin resistance that is not associated with use, since most strains that produce such enzymes also produce AAC(6′).

Amikacin was synthesized by Kawaguchi et al. of the Bristol-Banyu Research Institute in 1970 starting with kanamycin and the acyl moiety of butirosin. Its design is based on knowledge of the mechanisms of bacterial resistance to kanamycin and related compounds in which the 3 -hydroxyl group of the antibiotic is phosphorylated enzymatically. The acyl moiety in butirosin prevents this enzymatic inactivation.

Aminoglycoside antibiotic derived from kanamycin A. Effective against Gram-negative and Gram-positive bacteria.

C_{max 7.5 mg/kg intramuscular： c. 30 mg/L after 1 h
500 mg 30-min infusion： 35–50 mg/L end infusion
15 mg/kg 30-min infusion： >50 mg/L after 1 h
Plasma half-life： 2.2 h
Volume of distribution： 0.25–0.3 L/kg
Plasma protein binding： 3–11%
It is readily absorbed after intramuscular administration. Rapid intravenous injection of 7.5 mg/kg produced concentrations in excess of 60 mg/L shortly after injection.
Most pharmacokinetic parameters follow an almost linear correlation when the once-daily doses (15 mg/kg) are compared with the traditional 7.5 mg/kg twice daily. In patients on CAPD, there was no difference in mean peak plasma concentration or volume of distribution whether the drug was given intravenously or intraperitoneally. However, in patients with significant burn injuries, doses should be increased to 20 mg/kg.
In infants receiving 7.5 mg/kg by intravenous injection, peak plasma concentrations were 17–20 mg/L. No accumulation occurred on 12 mg/kg per day for 5–7 days. There was little change in the plasma concentration or the half-life (1.7 and 1.9 h) on the third and seventh days of a period over which 150 mg/m2 was infused over 30 min every 6 h. When the dose was raised to 200 mg/m2 the concentration never fell below 8 mg/L. The plasma half-life was longer in babies of lower birth weight and was still 5–5.5 h in babies aged 1 week or older. The importance of dosage control in the neonate is emphasized by the findings that there is an inverse relationship between post-conception age and plasma elimination half-life, though in extremely premature babies the weight of the child is also a significant predictor of half-life.}

Amikacin, 1-N-amino-α-hydroxybutyrylkanamycin A(Amikin), is a semisynthetic aminoglycoside first preparedin Japan. The synthesis formally involves simple acylationof the 1-amino group of the deoxystreptamine ring ofkanamycin A with L-AHBA. This particular acyl derivativeretains about 50% of the original activity of kanamycin Aagainst sensitive strains of Gram-negative bacilli. The LAHBAderivative is much more active than the D-isomer.The remarkable feature of amikacin is that it resists attackby most bacteria-inactivating enzymes and, therefore, is effectiveagainst strains of bacteria that are resistant to otheraminoglycosides, including gentamicin and tobramycin.In fact, it is resistant to all known aminoglycoside-inactivatingenzymes, except the aminotransferase that acetylates the6 amino group and the 4'-nucleotidyl transferase thatadenylylates the 4'-hydroxyl group of aminoglycosides.
Preliminary studies indicate that amikacin may be lessototoxic than either kanamycin or gentamicin. Higherdosages of amikacin are generally required, however, for the treatment of most Gram-negative bacillary infections. Forthis reason, and to discourage the proliferation of bacterialstrains resistant to it, amikacin currently is recommended forthe treatment of serious infections caused by bacterialstrains resistant to other aminoglycosides.

Severe infection (including septicemia, neonatal sepsis, osteomyelitis, septic arthritis, respiratory tract, urinary tract, intra-abdominal, peritoneal and soft tissue infections) caused by susceptible micro-organisms Sepsis of unknown origin (combined with a β-lactam or anti-anaerobe agent as appropriate).
Mycobacterial infection
Amikacin is principally used for the treatment of infections caused by organisms resistant to other aminoglycosides because of their ability to degrade them. Peak concentrations on 15 mg/kg once daily administration should exceed 45 mg/L, and trough concentration of <5 mg/L should be maintained to achieve therapeutic effects.

Distribution
The apparent volume of distribution indicates distribution throughout the extracellular water. Following an intravenous bolus of 0.5 g, peak concentrations in blister fluid were around 12 mg/L, with a mean elimination half-life of 2.3 h. In patients with impaired renal function, penetration and peak concentration increased linearly with decrease in creatinine clearance.
In patients with purulent sputum, a loading dose of 4 mg/kg intravenously plus 8 h infusions of 7–12 mg/kg produced sputum concentrations around 2 mg/L, with a mean sputum:serum ratio of 0.15. With brief infusions over 10 min for 7 days, sputum concentrations of around 9% of the simultaneous serum values have been found.
Concentrations in the CSF of adult volunteers receiving 7.5 mg/kg intramuscularly were less than 0.5 mg/L and virtually the same in patients with meningitis. Rather higher, but variable, concentrations up to 3.8 mg/L have been found in neonatal meningitis.
Amikacin crosses the placenta, and concentrations of 0.5–6 mg/L have been found in the cord blood of women receiving 7.5 mg/kg in labor. Concentrations of 8 mg/L and 16.8 mg/L were reached in the fetal lung and kidney, respectively, after a standard dose of 7.5 mg/kg given to healthy women before therapeutic abortion.
Excretion
Only 1–2% of the administered dose is excreted in the bile, with the remainder excreted in the urine, producing urinary concentrations of 150–3000 mg/L. Renal clearance is 70–84 mL/min, and this, with the ratio of amikacin to creatinine clearance (around 0.7), indicates that it is filtered and tubular reabsorption is insignificant. Accumulation occurs in proportion to reduction in renal function, although there may be some extrarenal elimination in anephric patients. The mean plasma half-life in patients on hemodialysis was around 4 h, while that on peritoneal dialysis was 28 h.
In patients receiving 500 mg/kg preoperatively, concentrations in gallbladder wall reached 34 mg/L and in bile 7.5 mg/L in some patients. In patients given 500 mg intravenously 12 h before surgery and 12 hourly for four doses thereafter, the mean bile:serum ratio 1 h after the dose was around 0.4.
Ototoxicity
Neurosensory hearing loss (mainly high-tone deafness) and labyrinthine injury have been detected, but have seldom been severe. High-frequency hearing loss and vestibular impairment have been described in about 5% of patients and conversational loss in about 0.5%; more in patients monitored audiometrically (29%) and by caloric testing (19%).
Patients with high-tone hearing loss have generally received more drug and for longer than patients without; in patients receiving long-term treatment for tuberculosis no other factors were associated with the development of ototoxicity. On multiple daily dosing, over half the patients with peak serum concentrations exceeding 30 mg/L or trough concentrations exceeding 10 mg/L developed cochlear damage; here, the main contributory factor was previous treatment with other aminoglycosides.
Nephrotoxicity
Impairment of renal function, usually mild or transient, has been observed in 3–13% of patients, notably in the elderly or those with pre-existing renal disorders or treated concurrently or previously with other potentially nephrotoxic agents.
Other reactions
Adverse effects common to aminoglycosides occur, including hypersensitivity, gastrointestinal disturbances, headache, drug fever, peripheral nervous manifestations, eosinophilia, mild hematological abnormalities and disturbed liver function tests without other evidence of hepatic derangement.

Poison by intravenous,intraperitoneal, and intramuscular routes. Moderately toxicby intraperitoneal route. An experimental teratogen. Whenheated to decomposition it emits toxic fumes of NOx.

Amikacin, O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[6-amino-6- deoxy-α-D-glucopyranosyl-(1→6)]-N3 -(4-amino-L-2-hydroxybutyryl)-2-deoxy-L-streptamine (3.4.10), is a semisynthetic antibiotic that is synthesized from kanamycin (3.4.6). The primary amino group in this molecule is previously protected by acylating it with N- (benzoyloxycarbonyloxy) succinimide in dimethylformamide, after which the resulting product (32.4.9) is treated with an ester synthesized from N-hydroxysuccinimide and benzyloxycarbonylamino-α-l-(?) hydroxybutyric acid, and as a result the 4-amino group of the streptamine region of the molecule is selectively acylated. Further removal of two benzyloxycarbonylamine protective groups in the traditional manner, via hydrogen reduction using a palladium on carbon catalyst, forms the desired amikacin (32.4.10).

This aminoglycoside-class antibiotic (FW = 585.60 g/mol; CAS 37517-28- 5) is a broad-spectrum semisynthetic derivative of kanamycin A that has become a go-to drug for treating hospital-acquired infections by multidrug- resistant, Gram-negative bacteria (e.g., Pseudomonas aeruginosa, Acinetobacter, Enterobacter, as well as Serratia marcescens and Providencia stuartii). (For additional mechanistic details, See Neomycins) Because amikacin is not absorbed orally, it must be delivered intravenously or by an intranasal using liposomes as carriers. Test results revealed that 60.5% of the isolates were resistant to tobramycin (at 8 μg/mL), 67.1% to gentamicin (at 8 μg/mL), 86.2% to kanamycin A (at 20 μg/mL), but only 8.6% to amikacin (at 20 μg/mL). Amikacin’s broad spectrum comports with the fact that it is a poor substrate for most enzymes that inactivate other aminoglycosides through O-phosphorylation, O-adenylylation, or N- acetylation. Pharmacokinetics: A dose of 300 mg/m2 intramuscularly produced a highest mean serum concentration of 25.4 μg/mL with a mean serum concentration of 3.1 μg/mL at 8 hours. The same dose intravenously produced a mean serum concentration of 52 μg/mL with a mean serum concentration of 2 μg/mL at 8 hours. The mean urinary excretion during the first 6 hours was 75 and 66%, respectively. When administered at 150 mg/m2 every 6 hours, there was evidence of some drug accumulation. A loading dose of 150 mg/m2 administered IV over 30 min, followed by a continuous infusion at 200 mg/m2 every 6 hours to maintain serum concentrations of 8 μg/mL. No major toxicity was observed with any of these drug regimens. Key Pharmacokinetic Parameters: See Appendix II in Goodman & Gilman’s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 12th Edition (Brunton, Chabner & Knollmann, eds.) McGraw-Hill Medical, New York.

Potentially hazardous interactions with other drugs
Antibacterials: increased risk of nephrotoxicity with colistimethate or polymyxins and possibly cephalosporins; increased risk of ototoxicity and nephrotoxicity with capreomycin or vancomycin.
Ciclosporin: increased risk of nephrotoxicity.
Cytotoxics: increased risk with platinum compounds of nephrotoxicity and possibly of ototoxicity
Diuretics: increased risk of ototoxicity with loop diuretics.
Muscle relaxants: enhanced effects of nondepolarising muscle relaxants and suxamethonium.
Parasympathomimetics: antagonism of effect of neostigmine and pyridostigmine.
Tacrolimus: increased risk of nephrotoxicity.

Amikacin diffuses readily through extracellular fluids and has been found in cerebrospinal fluid, pleural fluid, amniotic fluid and in the peritoneal cavity following parenteral administration. It is excreted in the urine unchanged, primarily by glomerular filtration.