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| Clinical data | |
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| Trade names | Amikin, Amiglyde-V, Arikayce, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682661 |
| License data | |
| Pregnancy category | |
| Routes of administration | Intramuscular,intravenous,inhalation |
| Drug class | Aminoglycoside |
| ATC code | |
| Legal status | |
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| Pharmacokinetic data | |
| Bioavailability | >90%[7] |
| Protein binding | 0–11% |
| Metabolism | Mostly unmetabolized |
| Eliminationhalf-life | 2–3 hours |
| Excretion | Kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.048.653 |
| Chemical and physical data | |
| Formula | C22H43N5O13 |
| Molar mass | 585.608 g·mol−1 |
| 3D model (JSmol) | |
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Amikacin is anantibiotic medication used for a number ofbacterial infections.[8] This includesjoint infections,intra-abdominal infections,meningitis,pneumonia,sepsis, andurinary tract infections.[8] It is also used for the treatment ofmultidrug-resistant tuberculosis.[9] It is used by injectioninto a vein using an IV orinto a muscle.[8]
Amikacin, like otheraminoglycoside antibiotics, can causehearing loss, balance problems, andkidney problems.[8] Other side effects includeparalysis, resulting in the inability to breathe.[8] If used duringpregnancy it may cause permanent deafness in the baby.[8][1] Amikacin works by blocking the function of the bacteria's30S ribosomal subunit, making it unable to produceproteins.[8]
Amikacin was patented in 1971, and came into commercial use in 1976.[10][11] It is on theWorld Health Organization's List of Essential Medicines.[12] It is derived fromkanamycin.[8]
Amikacin is most often used for treating severe infections withmultidrug-resistant, aerobicGram-negative bacteria, especiallyPseudomonas,Acinetobacter,Enterobacter,E. coli,Proteus,Klebsiella, andSerratia.[13] The onlyGram-positive bacteria that amikacin strongly affects areStaphylococcus[13] andNocardia.[14] Amikacin can also be used to treat non-tubercularmycobacterial infections and tuberculosis (if caused by sensitive strains) when first-line drugs fail to control the infection.[8] It is rarely used alone.[15]
It is often used in the following situations:[8]
Amikacin may be combined with a beta-lactam antibiotic forempiric therapy for people withneutropenia andfever.[8]
A liposome inhalation suspension is also available and approved to treatMycobacterium avium complex (MAC) in the United States,[19][4] and in the European Union.[5]
Amikacin liposome inhalation suspension is the first drug approved under the USlimited population pathway for antibacterial and antifungal drugs (LPAD pathway).[19] It also was approved under theaccelerated approval pathway.[19] The USFood and Drug Administration (FDA) granted the application for amikacin liposome inhalation suspensionfast track,breakthrough therapy,priority review, andqualified infectious disease product (QIDP) designations.[19] The FDA granted approval of Arikayce to Insmed, Inc.[19]
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.[19] 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.[19] 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.[19]
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 consideredpregnancy category D in both the United States and Australia, meaning they have a probability of harming the fetus.[8] 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.[13] A pregnant woman taking amikacin with anotheraminoglycoside has a possibility of causingcongenital deafness in her child. While it is known to cross the placenta, amikacin is only partially secreted in breast milk.[8]
In general, amikacin should be avoided in infants.[20] Infants also tend to have a larger volume of distribution due to their higher concentration ofextracellular fluid, where aminoglycosides reside.[7]
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.[21]
Clearance is even higher in people withcystic fibrosis.[22]
In people with muscular disorders such asmyasthenia gravis orParkinson's disease, amikacin's paralytic effect on neuromuscular junctions can worsen muscle weakness.[8]
Side-effects of amikacin are similar to those of other aminoglycosides.Kidney damage andototoxicity (which can lead to hearing loss) are the most important effects, occurring in 1–10% of users.[16] The nephro- and ototoxicity are thought to be due to aminoglycosides' tendency to accumulate in the kidneys and inner ear.[7]
Amikacin can cause neurotoxicity if used at a higher dose or for longer than recommended. The resulting effects of neurotoxicity includevertigo,numbness,tingling of the skin (paresthesia), muscletwitching, andseizures.[8] Its toxic effect on the 8thcranial nerve causes ototoxicity, resulting in loss of balance and, more commonly, hearing loss.[7] Damage to thecochlea, caused by the forcedapoptosis of thehair cells, leads to the loss of high-frequency hearing and happens before any clinical hearing loss can be detected.[13][23] Damage to theear vestibules, most likely by creating excessive oxidativefree 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.[24]
Amikacin causes nephrotoxicity (damage to the kidneys), by acting on theproximal renal tubules. It easily ionizes to acation and binds to theanionic sites of the epithelial cells of the proximal tubule as part of receptor-mediatedpinocytosis. The concentration of amikacin in therenal cortex becomes ten times that of amikacin in the plasma;[20] it then most likely interferes with the metabolism ofphospholipids in thelysosomes, which causes lytic enzymes to leak into the cytoplasm.[7] Nephrotoxicity results in increased serumcreatinine,blood urea nitrogen,red blood cells, andwhite blood cells, as well asalbuminuria (increased output ofalbumin in the urine),glycosuria (excretion of glucose into the urine), decreased urinespecific gravity, andoliguria (decrease in overall urine output).[13][23] It can also causeurinary casts to appear.[7] The changes inrenal tubular function also change the electrolyte levels and acid-base balance in the body, which can lead tohypokalemia andacidosis oralkalosis.[24] Nephrotoxicity is more common in those with pre-existing hypokalemia,hypocalcemia,hypomagnesemia, acidosis, lowglomerular filtration rate,diabetes mellitus, dehydration, fever, andsepsis, as well as those takingantiprostaglandins.[8][20][7][24] The toxicity usually reverts once the antibiotic course has been completed,[7] and can be avoided altogether by less frequent dosing (such as once every 24 hours rather than once every 8 hours).[20]
Amikacin can cause neuromuscular blockade (including acute muscular paralysis) and respiratory paralysis (includingapnea).[8]
Rare side effects (occurring in fewer than 1% of users) include allergic reactions,skin rash,fever,headaches,tremor,nausea andvomiting,eosinophilia,arthralgia,anemia,hypotension, and hypomagnesemia. In intravitreous injections (where amikacin is injected into the eye), macularinfarction can cause permanent vision loss.[13][16]
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.[19][4] 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.[19][4]
Amikacin should be avoided in those who are sensitive toany 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 tosulfite (seen more among people with asthma),[13] since most amikacin usually comes withsodium metabisulfite, which can cause an allergic reaction.[8]
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 antiviralacyclovir; the antifungalamphotericin B; the antibioticsbacitracin,capreomycin, colistin,polymyxin B, andvancomycin; andcisplatin, which is used inchemotherapy.[8]
Amikacin should not be used withneuromuscular blocking agents, as they can increase muscle weakness and paralysis.[8]
Amikacin can be inactivated by other beta-lactams, though not to the extent as other aminoglycosides, and is still often used withpenicillins (a type of beta-lactam) to create an additive effect against certain bacteria, and carbapenems, which can have a synergistic effect against some Gram-positive bacteria. Another group of beta-lactams, the cephalosporins, can increase the nephrotoxicity of aminoglycoside as well as randomly elevatingcreatinine levels. The antibioticschloramphenicol, clindamycin, andtetracycline have been known to inactivate aminoglycosides in general by pharmacological antagonism.[8]
The effect of amikacin is increased when used with drugs derived from thebotulinum toxin,[16]anesthetics, neuromuscular blocking agents, or large doses of blood that containscitrate as ananticoagulant.[8]
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.[8]Quinidine also increases levels of amikacin in the body.[16] TheNSAIDindomethacin can increase serum aminoglycoside levels in premature infants.[8] Contrast mediums such asioversol increases the nephrotoxicity and otoxicity caused by amikacin.[16]
Amikacin can decrease the effect certain vaccines, such as the liveBCG vaccine (used for tuberculosis), thecholera vaccine, and the livetyphoid vaccine by acting as a pharmacological antagonist.[16]
Amikacin irreversibly binds to16S rRNA and the RNA-bindingS12 protein of the30S subunit of prokaryoticribosome and inhibits protein synthesis by changing the ribosome's shape so that it cannot read themRNAcodons correctly.[13][25] It also interferes with the region that interacts with thewobble base of thetRNA anticodon.[26] It works in a concentration-dependent manner, and has better action in an alkaline environment.[7]
At normal doses, amikacin-sensitive bacteria respond within 24–48 hours.[13]
Amikacin evades attacks by all antibiotic-inactivating enzymes that are responsible forantibiotic resistance in bacteria, except for aminoacetyltransferase andnucleotidyltransferase.[27] This is accomplished by theL-hydroxyaminobuteroyl amide (L-HABA) moiety attached to N-1 (compare tokanamycin, which simply has a hydrogen), which blocks the access and decreases the affinity of aminoglycoside-inactivating enzymes.[27][28][29] Amikacin ends up with only one site where these enzymes can attack, while gentamicin and tobramycin have six.[15]
Bacteria that are resistant tostreptomycin 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.[30]
Resistance to amikacin and kanamycin inMycobacterium tuberculosis, the causative agent of tuberculosis, is due to a mutation in therrs gene, which codes for the 16S rRNA. Mutations such as these reduce the binding affinity of amikacin to the bacteria's ribosome.[31] Variations of aminoglycosideacetyltransferase (AAC) and aminoglycosideadenylyltransferase (AAD) also confer resistance: resistance inPseudomonas aeruginosa is caused by AAC(6')-IV, which also confers resistance to kanamycin, gentamicin, and tobramycin, and resistance inStaphylococcus aureus andS. epidermidis is caused by AAD(4',4),which also confers resistance to kanamycin, tobramycin, and apramycin.[28] Some strains ofS. aureus can also inactivate amikacin by phosphorylating it.[17]
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 theheart,gallbladder,lungs, andbones, as well as inbile,sputum,interstitial fluid,pleural fluid, andsynovial fluids. It is usually found at low concentrations in thecerebrospinal fluid, except when administered intraventricularly.[8] 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.[13] It does not easily cross theblood–brain barrier or enter ocular tissue.[7]
While the half-life of amikacin is normally two hours, it is 50 hours in those with end-stage renal disease.[15]
The majority (95%) of amikacin from an intramuscular or intravenous dose is secreted unchanged viaglomerular filtration and into the urine within 24 hours.[8][15] Factors that cause amikacin to be excreted via urine include its relatively low molecular weight, high water solubility, and unmetabolized state.[20]
Amikacin is derived fromkanamycin A:[32][33]
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,[34] and has been used in dogs, cats,guinea pigs,chinchillas,hamsters,rats,mice,prairie dogs,cattle,birds,snakes,turtles andtortoises,crocodilians,bullfrogs, andfish.[7][35][36] It is often used for respiratory infections in snakes, bacterial shell disease in turtles, andsinusitis inmacaws. It is generally contraindicated inrabbits andhares (though it has still been used) because it harms the balance ofintestinal microflora.[7]
In dogs and cats, amikacin is commonly used as a topical antibiotic forear infections and forcorneal ulcers, especially those that are caused byPseudomonas aeruginosa. The ears are often cleaned before administering the medication, sincepus and cellular debris lessen the activity of amikacin.[34] Amikacin is administered to the eye when prepared as an ophthalmic ointment or solution, or when injectedsubconjunctivally.[37] Amikacin in the eye can be accompanied bycephazolin. Despite its use there amikacin (and all aminoglycosides) are toxic to intraocular structures.[38]
In horses, amikacin is FDA-approved for uterine infections (such asendometriosis andpyometra) when caused by susceptible bacteria.[39] It is also used in topical medication for the eyes andarthroscopic lavage; when combined with a cephalosporin, is used to treatsubcutaneous infections that are caused byStaphylococcus. For infections in the limbs or joints, it is often administered with a cephalosporin vialimb perfusion directly into the limb orinjected into the joint.[34][40] Amikacin is also injected into the joints with the anti-arthritic medicationAdequan in order to prevent infection.[41]
Side effects in animals include nephrotoxicity, ototoxicity, andallergic 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, facialedema, andperipheral neuropathy.[7][34]
The half-life in most animals is one to two hours.[42]
Treating overdoses of amikacin requireskidney dialysis orperitoneal dialysis, which reduce serum concentrations of amikacin, and/or penicillins, some of which can form complexes with amikacin that deactivate it.[7]
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