Gentamicin
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| Pronunciation | /ˌdʒɛntəˈmaɪsən/ |
| Trade names | Cidomycin, Genticyn, Garamycin, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682275 |
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IV, eye drop, IM, topical, ear drop |
| Drug class | Aminoglycoside antibiotic |
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| Pharmacokinetic data | |
| Bioavailability | limited bioavailability by mouth |
| Protein binding | 0–10% |
| Elimination half-life | 2 h |
| Excretion | Kidney |
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| ECHA InfoCard | 100.014.332  |
| Chemical and physical data | |
| Formula | C21H43N5O7 |
| Molar mass | 477.603 g·mol−1 |
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Gentamicin, sold under brand name Garamycin among others, is an antibiotic used to treat several types of bacterial infections.[2] This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis among others.[2] It is not effective for gonorrhea or chlamydia infections.[2] It can be given intravenously, by injection into a muscle, or topically.[2] Topical formulations may be used in burns or for infections of the outside of the eye.[3] In the developed world, it is often only used for two days until bacterial cultures determine what specific antibiotics the infection is sensitive to.[4] The dose required should be monitored by blood testing.[2]
Gentamicin can cause inner ear problems and kidney problems.[2] The inner ear problems can include problems with balance and hearing loss.[2] These problems may be permanent.[2] If used during pregnancy, it can cause harm to the developing baby.[2] However, it appears to be safe for use during breastfeeding.[5] Gentamicin is a type of aminoglycoside.[2] It works by disrupting the ability of the bacteria to make proteins, which typically kills the bacteria.[2]
Gentamicin was patented in 1962 and approved for medical use in 1964.[6] It is made from the bacterium Micromonospora purpurea.[2] It is on the World Health Organization’s List of Essential Medicines.[7] The World Health Organization classifies gentamicin as critically important for human medicine.[8] It is available as a generic medication.[9]
Medical uses[edit]
Gentamicin is active against a wide range of bacterial infections, mostly Gram-negative bacteria including Pseudomonas, Proteus, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Serratia, and the Gram-positive Staphylococcus.[10] Gentamicin is used in the treatment of respiratory tract infections, urinary tract infections, blood, bone and soft tissue infections of these susceptible bacteria.[11]
There is insufficient evidence to support gentamicin as the first line treatment of Neisseria gonorrhoeae infection.[12] Gentamicin is not used for Neisseria meningitidis or Legionella pneumophila bacterial infections (because of the risk of the person going into shock from lipid A endotoxin found in certain Gram-negative organisms). Gentamicin is also useful against Yersinia pestis (responsible for plague), its relatives, and Francisella tularensis (the organism responsible for tularemia often seen in hunters and trappers).[13]
Some Enterobacteriaceae, Pseudomonas spp., Enterococcus spp., Staphylococcus aureus and other Staphylococcus spp. have varying degrees of resistance to gentamicin.[14]
Adverse effects[edit]
Adverse effects of gentamicin can range from less severe reactions, such as nausea and vomiting, to more severe reactions including:[10]
- Low blood cell counts
- Allergic reactions
- Neuromuscular problems
- Nerve damage (neuropathy)
- Kidney damage (nephrotoxicity)
- Ear disorders (ototoxicity)
Nephrotoxicity and ototoxicity are thought to be dose related with higher doses causing greater chance of toxicity.[10] These two toxicities may have delayed presentation, sometimes not appearing until after completing treatment.[10]
Kidney damage[edit]
Kidney damage is a problem in 10-25% of people who receive aminoglycosides, and gentamicin is one of the most nephrotoxic drugs of this class.[15] Oftentimes, acute nephrotoxicity is reversible, but it may be fatal.[10] The risk of nephrotoxicity can be affected by the dose, frequency, duration of therapy, and concurrent use of certain medications, such as NSAIDs, diuretics, cisplatin, ciclosporin, cephalosporins, amphotericin, iodide contrast media, and vancomycin.[15]
Factors that increase risk of nephrotoxicity include:[15]
- Increased age
- Reduced renal function
- Pregnancy
- Hypothyroidism
- Hepatic dysfunction
- Volume depletion
- Metabolic acidosis
- Sodium depletion
Kidney dysfunction is monitored by measuring creatinine in the blood, electrolyte levels, urine output, presence of protein in the urine, and concentrations of other chemicals, such as urea, in the blood.[15]
Inner ear[edit]
About 11% of the population who receives aminoglycosides experience damage to their inner ear.[16] The common symptoms of inner ear damage include tinnitus, hearing loss, vertigo, trouble with coordination, and dizziness.[17] Chronic use of gentamicin can affect two areas of the ears. First, damage of the inner ear hair cells can result in irreversible hearing loss. Second, damage to the inner ear vestibular apparatus can lead to balance problems.[17] To reduce the risk of ototoxicity during treatment, it is recommended to stay hydrated.[10]
Factors that increase the risk of inner ear damage include:[10][11]
- Increased age
- High blood uric acid levels
- Kidney dysfunction
- Liver dysfunction
- Higher doses
- Long courses of therapy
- Also taking strong diuretics (e.g., furosemide)
Mechanism of action[edit]
Gentamicin is a bactericidal antibiotic that works by binding the 30S subunit of the bacterial ribosome, negatively impacting protein synthesis. The primary mechanism of action is generally accepted to work through ablating the ability of the ribosome to discriminate on proper transfer RNA and messenger RNA interactions.[18] Typically, if an incorrect tRNA pairs with an mRNA codon at the aminoacyl site of the ribosome, adenosines 1492 and 1493 are excluded from the interaction and retract, signaling the ribosome to reject the aminoacylated tRNA::Elongation Factor Thermo-Unstable complex.[19] However, when gentamicin binds at helix 44 of the 16S rRNA, it forces the adenosines to maintain the position they take when there is a correct, or cognate, match between aa-tRNA and mRNA.[20] This leads to the acceptance of incorrect aa-tRNAs, causing the ribosome to synthesize proteins with wrong amino acids placed throughout (roughly every 1 in 500).[21] The non-functional, mistranslated proteins misfold and aggregate, eventually leading to death of the bacterium. A secondary mechanism has been proposed based on crystal structures of gentamicin in a secondary binding site at helix 69 of the 23S rRNA, which interacts with helix 44 and proteins that recognize stop codons. At this secondary site, gentamicin is believed to preclude interactions of the ribosome with ribosome recycling factors, causing the two subunits of the ribosome to stay complexed even after translation completes. This creates a pool of inactive ribosomes that can no longer re-initiate and translate new proteins.[22]
Components[edit]
Gentamicin is composed of a number of related gentamicin components and fractions which have varying degrees of antimicrobial potency.[23] The main components of gentamicin include members of the gentamicin C complex: gentamicin C1, gentamicin C1a, and gentamicin C2 which compose approximately 80% of gentamicin and have been found to have the highest antibacterial activity. Gentamicin A, B, X, and a few others make up the remaining 20% of gentamicin and have lower antibiotic activity than the gentamicin C complex.[24] The exact composition of a given sample or lot of gentamicin is not well defined, and the level of gentamicin C components or other components in gentamicin may differ from lot-to-lot depending on the gentamicin manufacturer or manufacturing process. Because of this lot-to-lot variability, it can be difficult to study various properties of gentamicin including pharmacokinetics and microorganism susceptibility if there is an unknown combination of chemically related but different compounds.[25]
Contraindications[edit]
Gentamicin should not be used if a person has a history of hypersensitivity, such as anaphylaxis, or other serious toxic reaction to gentamicin or any other aminoglycosides.[11] Greater care is required in people with myasthenia gravis and other neuromuscular disorders as there is a risk of worsening weakness.[2]
Special populations[edit]
Pregnancy and breastfeeding[edit]
Gentamicin is not recommended in pregnancy unless the benefits outweigh the risks for the mother. Gentamicin can cross the placenta and several reports of irreversible bilateral congenital deafness in children have been seen. Intramuscular injection of gentamicin in mothers can cause muscle weakness in the newborn.[11]
The safety and efficacy for gentamicin in nursing mothers has not been established. Detectable gentamicin levels are found in human breast milk and in nursing babies.[11]
Elderly[edit]
In the elderly, renal function should be assessed before beginning therapy as well as during treatment due to a decline in glomerular filtration rate. Gentamicin levels in the body can remain higher for a longer period of time in this population. Gentamicin should be used cautiously in persons with renal, auditory, vestibular, or neuromuscular dysfunction.[10]
Children[edit]
Gentamicin may not be appropriate to use in children, including babies. Studies have shown higher serum levels and a longer half-life in this population.[26] Kidney function should be checked periodically during therapy. Long-term effects of treatment can include hearing loss and balance problems. Hypocalcemia, hypokalemia, and muscle weakness have been reported when used by injection.[10]
History[edit]
Gentamicin for injection
Gentamicin is produced by the fermentation of Micromonospora purpurea. It was discovered in 1963 by Weinstein, Wagman et al. at Schering Corporation in Bloomfield, N.J. while working with source material (soil samples) provided by Rico Woyciesjes.[27] Subsequently, it was purified and the structures of its three components were determined by Cooper, et al., also at the Schering Corporation. It was initially used as a topical treatment for burns at burn units in Atlanta and San Antonio and was introduced into IV usage in 1971. It remains a mainstay for use in sepsis.
It is synthesized by Micromonospora, a genus of Gram-positive bacteria widely present in the environment (water and soil). To highlight their specific biological origins, gentamicin and other related antibiotics produced by this genus (verdamicin, mutamicin, sisomicin, netilmicin, and retymicin) generally have their spellings ending in ~micin and not in ~mycin.
Research[edit]
Gentamicin is also used in molecular biology research as an antibacterial agent in tissue and cell culture, to prevent contamination of sterile cultures. Gentamicin is one of the few heat-stable antibiotics that remain active even after autoclaving, which makes it particularly useful in the preparation of some microbiological growth media.[citation n