Amikacin


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 was patented in 1971, and came into commercial use in 1976. It is on the World Health Organization's List of Essential Medicines. It is derived from kanamycin.

Medical uses

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 when first-line drugs fail to control the infection. It is rarely used alone.
It is often used in the following situations:
Amikacin may be combined with a beta-lactam antibiotic for empiric therapy for people with neutropenia and fever.

Available forms

A liposome inhalation suspension is also available and approved to treat Mycobacterium avium complex in the United States, and in the European Union.
Amikacin liposome inhalation suspension is the first drug approved under the US limited population pathway for antibacterial and antifungal drugs. It also was approved under the accelerated approval pathway. The US Food and Drug Administration granted the application for amikacin liposome inhalation suspension fast track, breakthrough therapy, priority review, and qualified infectious disease product 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.

Special populations

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.
In people with muscular disorders such as myasthenia gravis or Parkinson's disease, amikacin's paralytic effect on neuromuscular junctions can worsen muscle weakness.

Adverse effects

Side-effects of amikacin are similar to those of other aminoglycosides. Kidney damage and ototoxicity 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, 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, 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, glycosuria, decreased urine specific gravity, and oliguria. 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.
Amikacin can cause neuromuscular blockade and respiratory paralysis.
Rare side effects include allergic reactions, skin rash, fever, headaches, tremor, nausea and vomiting, eosinophilia, arthralgia, anemia, hypotension, and hypomagnesemia. In intravitreous injections, 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, bronchospasm, exacerbation of underlying lung disease and hemoptysis that have led to hospitalizations in some cases. Other common side effects in patients taking amikacin liposome inhalation suspension are dysphonia, cough, ototoxicity, upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.

Contraindications

Amikacin should be avoided in those who are sensitive to any aminoglycoside, as they are cross-allergenic. It should also be avoided in those sensitive to sulfite, 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 should not be used with neuromuscular blocking agents, as they can increase muscle weakness and paralysis.

Interactions

Amikacin can be inactivated by other beta-lactams, though not to the extent as other aminoglycosides, and is still often used with penicillins 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 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, the cholera vaccine, and the live typhoid vaccine by acting as a pharmacological antagonist.