Amikacin

Amikacin is an Antibiotic agent belonging to Aminoglycoside

Amikacin is used in the treatment of serious infections (eg, bloodstream infection, bone infection, respiratory tract infection, endocarditis) due to gram-negative organisms, including Pseudomonas, Escherichia coli, Proteus, Providencia, Klebsiella, Enterobacter, Serratia, and Acinetobacter. It is also used to treat Cystic fibrosis, acute pulmonary exacerbation; Mycobacterium avium complex infection; Mycobacterium (nontuberculous, rapidly growing) infection; Nocardiosis, severe; Plague (Yersinia pestis), treatment; Tuberculosis.

Amikacin is Rapidly absorbed (IM); variable (inhalation) and get readily diffuses into extracellular fluids (highly hydrophilic) but poorly penetrates the blood-brain barrier (even with inflamed meninges) and Crosses the placenta and enters breast milk. Volume of distribution: 0.25 L/kg (systemic); 5.0 L/kg (inhalation). Plasma protein binding: ≤20% (systemic); ≤10% (inhalation) and get excreted Via urine (94-98%, as unchanged drug [systemic]; 7.42% as unchanged drug [inhalation]). Elimination half-life: 2-3 hours (systemic); approx 5.9-19.5% (inhalation).

Amikacin shows common side effects like Headache, dizziness, Diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Amikacin is available in the form of injection

Amikacin is available in India, Germany, Canada, Italy.

Amikacin, an antibiotic with bactericidal activity, inhibits bacterial protein synthesis by irreversibly binding to 30S ribosomal subunits.

Amikacin is available in the form of injection.

• IM: Administer IM injection in large muscle mass.

• IV: Infuse over 30 to 60 minutes.

• Some penicillin (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.

• Intrathecal/Intraventricular (off-label route): Reconstitute with preservative-free diluent (NS) only to a final volume of 3 mL. When administered through a ventricular drain, clamp drain for 15 to 60 minutes before opening the drain to allow amikacin solution to equilibrate in the CSF.

• Inhalation (injection formulation; off-label route): Nebulization: Use with standard jet nebulizer connected to an air compressor or ultrasonic nebulizer; administer with mouthpiece or face mask . Dilute with NS up to total volume of 4 mL

Amikacin is used in the treatment of serious infections (eg, bloodstream infection, bone infection, respiratory tract infection, endocarditis) due to gram-negative organisms, including Pseudomonas, Escherichia coli, Proteus, Providencia, Klebsiella, Enterobacter, Serratia, and Acinetobacter. It is also used to treat Cystic fibrosis, acute pulmonary exacerbation; Mycobacterium avium complex infection; Mycobacterium (nontuberculous, rapidly growing) infection; Nocardiosis, severe; Plague (Yersinia pestis), treatment; Tuberculosis.

Amikacin is an antibiotic. It stops bacterial growth by preventing synthesis of essential proteins required by bacteria to carry out vital functions.

Amikacin is approved for use in the following clinical indications

Amikacin is used to treat serious bacterial infections in many different parts of the body.

Amikacin is available in various strengths as 500 mg/2 mL (2 mL); 1 g/4 mL (4 mL),1 g/4 mL (4 mL).

Amikacin is available in the form of injection.

• Dosage Adjustment in Kidney Patient

High-dose, extended-interval dosing: IV:

Note: Use with caution in patients with CrCl <40 mL/minute, although high-dose extended-interval dosing may still be considered, especially in patients with severe sepsis/shock or those infected with multidrug-resistant gram-negative organisms .

Initial dose: 15 to 20 mg/kg; up to 30 mg/kg once daily in critically ill patients. Subsequent doses and frequency of administration should be determined based on therapeutic drug monitoring. Regimens may vary; nomograms exist to guide dose adjustments, although individualized calculations may be necessary in patients with highly variable or altered aminoglycoside pharmacokinetics (ie, critical illness, pregnancy, etc)

CrCl ≥60 mL/minute: Administer every 24 hours; adjust dose and/or interval based on amikacin serum concentrations.

CrCl 40 to <60 mL/minute: Administer every 36 hours; adjust dose and/or interval based on amikacin serum concentrations.

CrCl 20 to <40 mL/minute: Administer every 48 hours; adjust dose and/or interval based on amikacin serum concentrations.

CrCl <20 mL/minute: Administer usual dose once, then determine subsequent dose and interval based on amikacin serum concentrations. Some published protocols would recommend conventional/traditional dosing in these patients.

Conventional/traditional dosing: IM, IV:

Note: High-dose, extended-interval dosing is generally preferred for treatment of gram-negative infections.

Regimens may vary based on individualized pharmacokinetic calculations and pharmacodynamic targets; also refer to institutional-specific policies.

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):

Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients.

High-dose, extended-interval dosing: IV: Initial: 20 to 30 mg/kg once daily for known/suspected sepsis; adjust dose and/or interval based on amikacin serum concentrations and individualized pharmacokinetic calculations and pharmacodynamic targets.

Hemodialysis, intermittent (thrice weekly):

Dialyzable (~20% to 65% dependent on filter and duration): Note: Post-dialysis concentrations should be drawn ≥2 and up to 4 hours after hemodialysis to allow for redistribution

IM, IV: 5 to 12.5 mg/kg/dose 3 times weekly after dialysis on dialysis days (Heintz 2009; expert opinion). Redose when prehemodialysis amikacin concentration <10 mg/L or when posthemodialysis amikacin concentration <6 to 8 mg/L.

Peritoneal dialysis: IM, IV: Initial: 5 to 12.5 mg/kg/dose (depending on infection site, severity, and susceptibility of infecting organisms) every 48 to 72 hours; adjust dose and/or interval based on amikacin serum concentrations.

CRRT :

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, nephrotoxicity) due to drug accumulation is important.

CVVH/CVVHD/CVVHDF: IV: Initial: 15 to 25 mg/kg (depending on infection site, severity, and susceptibility of infecting organisms) every 48 hours. Adjust dose and/or interval, as needed, based upon amikacin serum concentrations.

PIRRT (eg, sustained, low-efficiency diafiltration):

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, nephrotoxicity) due to drug accumulation is important. The following dosing assumes daily use of PIRRT.

IV: Initial: 15 to 25 mg/kg (depending on infection site, severity, and susceptibility of infecting organisms) every 48 hours. Adjust dose and/or interval, as needed, based upon amikacin serum concentrations. Note: Administer each dose 30 to 60 minutes prior to PIRRT session on PIRRT days.

● Dosage Adjustment for Pediatric Patients:-

CNS infection:

Meningitis, including health care-associated meningitis: Limited data available: Infants, Children, and Adolescents: IV: 20 to 30 mg/kg/day divided every 8 hours; individualize duration based on patient characteristics, infecting bacteria, and response.

Ventriculitis (including health care-associated ventriculitis and cerebrospinal fluid [CSF] shunt infections): Limited data available:

Intraventricular/intrathecal (use a preservative-free preparation): Infants, Children, and Adolescents: 5 to 50 mg/day; usual dose: 30 mg/day ; Due to the smaller CSF volume in infants, some guidelines recommend decreasing the infant dose; dosage and administration interval can also be adjusted based on CSF amikacin concentrations, ventricle size, and daily output from ventricular drain. Duration is individualized according to clinical and microbiological response

Cystic fibrosis, acute pulmonary exacerbation:

Note: Extended-interval dosing is preferred over traditional dosing. Use as part of appropriate combination therapy . Treatment duration varies and is dependent on patient-specific factors including response to therapy; typical duration is 10 to 21 days.

Extended-interval dosing: Infants, Children, and Adolescents: IV, IM: 30 to 35 mg/kg/dose every 24 hours Higher doses (eg, 40 mg/kg/dose every 24 hours) may be necessary when MIC is ≥8 mg/L.

Traditional dosing: Infants, Children, and Adolescents: IV, IM: 10 mg/kg/dose every 8 hours.

Endocarditis, treatment:

Children and Adolescents: IV: 15 mg/kg/day divided every 8 to 12 hours; use in combination with other antibiotics dependent upon pathogen and source of infection

Intra-abdominal infection, complicated:

Infants, Children, and Adolescents: IV: 15 to 22.5 mg/kg/day divided every 8 to 24 hours

Mycobacterial (nontuberculous) infection: Limited data available:

Mycobacterium avium complex infection in persons that are HIV-exposed/-infected (adjunct therapy):

Infants and Children: IV: 15 to 30 mg/kg/day divided every 12 to 24 hours as part of an appropriate combination regimen; maximum daily dose: 1,500 mg/day; total duration of therapy for M. avium complex infection is ≥12 months .

Adolescents: IV: 10 to 15 mg/kg/dose every 24 hours as part of an appropriate combination regimen; maximum daily dose: 1,500 mg/day; total duration of therapy for M. avium complex infection is ≥12 months .

Pulmonary infection in patients with cystic fibrosis (eg, Mycobacterium abscessus, M. avium complex ): Note: Use as part of an appropriate combination regimen. The duration of parenteral therapy is generally 3 to 12 weeks depending on clinical response, followed by transition to oral and/or inhaled therapy; total treatment duration is ≥12 months after culture conversion.

Infants and Children: IV: 15 to 30 mg/kg/dose every 24 hours; maximum dose: 1,500 mg/dose.

Adolescents: IV: 10 to 15 mg/kg/dose every 24 hours; maximum dose: 1,500 mg/dose.

Tuberculosis, active (drug-resistant); treatment (alternative agent):Limited data available:

Note: Use as part of an appropriate combination regimen; duration should be individualized based on extent of disease, rapidity of culture conversion, clinical response, and toxicity.

Peritonitis (CAPD):

Infants, Children, and Adolescents: Intraperitoneal: Continuous: Loading dose: 25 mg per liter of dialysate; maintenance dose: 12 mg per liter.

Hypersensitivity to amikacin and other aminoglycoside antibiotics. Myasthenia gravis. Concomitant or sequential administration of oral or topical drugs that are neurotoxic, ototoxic or nephrotoxic; concomitant use with potent diuretics.

Concerns related to adverse effects:

Hypersensitivity: Cross-sensitivity to other aminoglycosides may occur.

• Nephrotoxicity: [US Boxed Warning]: May cause nephrotoxicity; usual risk factors include preexisting renal impairment, concomitant nephrotoxic medications, advanced age and dehydration. Discontinue treatment if signs of nephrotoxicity occur; renal damage is usually reversible.

• Neuromuscular blockade and respiratory paralysis: [US Boxed Warning]: May cause neuromuscular blockade and respiratory paralysis; especially when given soon after anesthesia or muscle relaxants.

• Neurotoxicity: [US Boxed Warning]: May cause neurotoxicity; usual risk factors include preexisting renal impairment, concomitant neuro-/nephrotoxic medications, advanced age and dehydration. Ototoxicity is proportional to the amount of drug given and the duration of treatment. Tinnitus or vertigo may be indications of vestibular injury and impending bilateral irreversible damage. Discontinue treatment if signs of ototoxicity occur.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Hearing impairment: Use with caution in patients with preexisting vertigo, tinnitus, or hearing loss.

• Hypocalcemia: Use with caution in patients with hypocalcemia.

• Neuromuscular disorders: Use with caution in patients with neuromuscular disorders, including myasthenia gravis or parkinsonism.

• Renal impairment: Use with caution in patients with preexisting renal insufficiency; dosage modification required.

Amikacin may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Amikacin is present in breast milk

Following a single IM dose of amikacin 100 mg given on days 5 to 7 postpartum, only trace amounts of amikacin were seen in breast milk after 4 and 6 hours. Amikacin was not detectable at 1 and 2 hours postdose

In general, antibiotics that are present in breast milk may cause nondose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush and diarrhea.

Immediate release: Food delays rate, but not extent of absorption; Extended release: Food increases Amikacin AUC by ~30% relative to fasting conditions. Management: Administer immediate release products without regard to meals. Administer extended release products with food.

• Common Adverse effects

Headache, Ototoxicity, Gastrointestinal disturbance, Anaphylactic reaction, Hypersensitivity reaction

• Less Common Adverse effects:

CNS effects including seizures, increased intracranial pressure, lightheadedness, dizziness, tremor; psychotic reactions (e.g. hallucinations, nervousness, delirium), sensory or sensorimotor peripheral neuropathy, prolonged QT interval, blood glucose disturbances (hypo-/hyperglycaemia), phototoxicity, superinfection (prolonged use), bronchospasm

• Rare Adverse effects

Hepatitis, jaundice. Injury, poisoning and procedural complications: Infusion site reaction (e.g. pain, reddening), phlebitis. Investigations: Increased hepatic enzymes (ALT/AST, alkaline phosphatase, GGT), decreased forced expiratory volume.

Additive neurotoxic, ototoxic or nephrotoxic effects with amphotericin B, bacitracin, cisplatin, ciclosporin, cephaloridine, paromomycin, polymyxin B, colistin, tacrolimus, vancomycin, viomycin, IV mannitol, or other aminoglycosides. Increased risk of ototoxicity with potent diuretics (e.g. ethacrynic acid or furosemide); may increase risk of toxicity with IV diuretics. May increase risk of respiratory paralysis with anaesthetics or neuromuscular blocking agents (e.g. tubocurarine, succinylcholine, decamethonium, atracurium, rocuronium, vecuronium, opioid analgesic, massive transfusions with citrated anticoagulated blood). Increased risk of nephrotoxicity and may increase serum creatinine levels with cephalosporins. May reduce antibacterial activity with penicillins. Increased risk of hypocalcaemia with bisphosphonates. Increased risk of nephrotoxicity and ototoxicity with platinum drugs. May increase serum concentration with indomethacin in neonates.

The common side effects of Amikacin include the following Nausea, vomiting ; twitching or weakness ; diarrhea that doesn’t stop, abdominal or stomach pain.

Pharmacodynamic

Amikacin is an aminoglycoside antibiotic. Aminoglycosides bind to the bacteria, causing misreading of t-RNA, leaving bacteria unable to synthesize proteins vital to their growth. Aminoglycosides are useful mainly in the treatment infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. In addition, some mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. Infections caused by Gram-positive bacteria can also be treated with aminoglycosides, however, other antibiotics may be more potent and less toxic to humans.

Pharmacokinetics

• Absorption: Rapidly absorbed (IM); variable (inhalation). Time to peak plasma concentration: 1 hour (IM); within 30 minutes (IV).
• Distribution: Readily diffuses into extracellular fluids (highly hydrophilic) but poorly penetrates the blood-brain barrier (even with inflamed meninges). Crosses the placenta and enters breast milk. Volume of distribution: 0.25 L/kg (systemic); 5.0 L/kg (inhalation). Plasma protein binding: ≤20% (systemic); ≤10% (inhalation).
• Excretion: Via urine (94-98%, as unchanged drug [systemic]; 7.42% as unchanged drug [inhalation]). Elimination half-life: 2-3 hours (systemic); approx 5.9-19.5% (inhalation).

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Amikacin -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Amikacin
• https://europepmc.org/article/med/6988203