Aminoglycosides (30S inhibitors)

Aminoglycosides (30S inhibitors)

Bactericidal antibiotics for aerobic gram-negatives, given by injection once a day for a high peak, whose levels are watched because they can harm the kidney and, often for good, the inner ear.

Contents8 sections

At a glance

  1. Aminoglycosides (gentamicin, tobramycin, amikacin) are amino sugars joined by glycosidic bonds, positively charged in the body. They are barely absorbed from the gut, so they are injected for infections beyond it, unless put on the skin, eye or ear, or inhaled; they stay in the fluid outside cells, reach the cerebrospinal fluid poorly and leave unchanged through the glomeruli.
  2. They bind the decoding site of the 30S subunit, on its 16S ribosomal RNA, so the ribosome misreads the message and makes faulty proteins. Unlike most drugs that act on the ribosome, they kill, and the higher the peak the faster: with a long post-antibiotic effect, that is why one dose a day is enough.
  3. They reach aerobic gram-negatives, Pseudomonas among them. Getting in takes oxygen, so anaerobes resist; given with a β-lactam or vancomycin, which opens the wall to them, they kill gram-positives such as enterococci and streptococci.
  4. Bacteria resist them mostly with enzymes that add an acetyl, phosphate or nucleotide to the drug. Amikacin, and plazomicin more so, resist most of these enzymes.
  5. They can harm the kidney, usually reversibly, and the inner ear, often for good; rarely they block the neuromuscular junction. Courses are kept short and levels watched, and carriers of mitochondrial variants such as m.1555A>G can go deaf after a single dose.
  6. In pregnancy they are given when a serious infection needs them, with levels watched; streptomycin has caused deafness in babies exposed in the womb. In breastfeeding they are compatible, as the baby barely absorbs them.

Drug classification

The antibiotics that block protein synthesis are grouped by the ribosome's subunit they bind: the aminoglycosides and tetracyclines the small, 30S subunit; the macrolides, lincosamides, chloramphenicol, streptogramins and pleuromutilins the large, 50S one; and linezolid and mupirocin apart (Linezolid and other protein synthesis inhibitors).

Aminoglycosides come from soil bacteria, and most of their names keep which: those ending in -mycin from Streptomyces, those in -micin from Micromonospora. Streptomycin, isolated in 1943 in Selman Waksman's laboratory, was the first effective drug against tuberculosis.

Aminoglycosides

Bactericidal on the 30S subunit, for aerobic gram-negatives. They differ mostly in which bacteria and which resistance enzymes they get past, and in where they are used.

  • Gentamicininjected, the most used
  • Tobramycininjected or inhaled, antipseudomonal
  • Amikacininjected or inhaled, resists most enzymes
  • Streptomycininto muscle, plague, tularaemia, sometimes tuberculosis
  • Plazomicininjected, resists nearly all enzymes
  • Neomycinby mouth or on the skin, too toxic to inject
  • Paromomycinby mouth for gut parasites, or injected

Pharmacokinetics

Charged and water-loving, aminoglycosides are almost unabsorbed by mouth, which is why neomycin and paromomycin given by mouth act mainly in the gut, though enough can be absorbed through a damaged gut or skin, or build up when the kidneys fail, to harm the ear. For any other infection they are given into a vein or a muscle, or put on the skin, in the eye or ear, or, for tobramycin and amikacin, inhaled.

They spread through the fluid outside cells and enter cells poorly, so they reach the cerebrospinal fluid, eye, bile and prostate badly, even when the meninges are inflamed. Their volume grows with fluid overload, burns, sepsis and cystic fibrosis, which need larger doses. Two places take them up and keep them: the cells of the proximal tubule and the hair cells of the inner ear, which is where they do harm.

They leave unchanged by glomerular filtration, so their clearance follows the creatinine clearance. Their half-life of 2 to 3 hours stretches to a day or more when the kidneys fail, and the dose is then given less often rather than made smaller. Haemodialysis removes them.

Once a day, by levels

Most adults now have one large dose a day, gentamicin 5 to 7 mg/kg, rather than the three daily doses once standard. A blood level some hours after the dose, read against a chart, or a trough just before the next dose, sets the interval: the level should fall almost to zero between doses, which limits how much builds up in the kidney and ear. When gentamicin is given only to help a β-lactam kill gram-positives, as in endocarditis, the dose is lower, about 3 mg/kg a day.

of gentamicin, once a day, for an adult with normal kidneys
5 to 7mg/kg
the usual target trough of gentamicin given once a day
under 1mg/L
carried m.1555A>G in a large British study, the commonest variant that makes the ear sensitive to aminoglycosides
1 in 500children

Pharmacodynamics

Getting in

An aminoglycoside first crosses the outer membrane of a gram-negative through its porins and by pushing aside the magnesium and calcium that hold the lipopolysaccharide together. Crossing the inner membrane then takes the electrical potential that oxygen-using respiration builds. Strict anaerobes don't build it, and neither do facultative bacteria in the acid, airless pus of an abscess, so they take up too little.

A drug that damages the wall, a β-lactam or vancomycin, lets far more in. That is the synergy behind giving gentamicin with a penicillin to kill enterococci and streptococci, which resist an aminoglycoside alone.

On the ribosome

Inside, the drug binds the A site of the 16S ribosomal RNA in the 30S subunit, where the ribosome checks each codon against its tRNA. The ribosome then lets the wrong tRNAs through, and makes misread proteins with the wrong amino acids in them; some end up in the membrane, let more drug in, and the damage feeds on itself. They also disturb the start of translation. The result is death of the bacterium, not just a pause, unlike most drugs that act on the ribosome.

How an aminoglycoside makes a ribosome misread
A bacterial ribosome in section, reading a messenger RNA that runs across the picture: the small subunit below, holding the mRNA, with the decoding centre just under its A site and its E, P and A sites marked from left to right, and the large subunit above, with an exit tunnel running up through it. Two tRNAs stand on their codons in the E and P sites, the one in the P site holding the growing chain of amino acids, which runs up the tunnel and out of the ribosome. A third tRNA, one base of its anticodon not pairing with the codon, has come to the A site with the wrong amino acid, its body still leaning out. Step 1 of 5: A mismatched tRNA comes. A tRNA whose anticodon is one base off the codon brings the wrong amino acid to the A site, and the decoding centre checks the pairing.EPA

Step 1 of 5A mismatched tRNA comes. A tRNA whose anticodon is one base off the codon brings the wrong amino acid to the A site, and the decoding centre checks the pairing.

Point at a name or a part to light it.

Normally the ribosome turns away a tRNA that doesn’t match its codon. An aminoglycoside binds the decoding centre in the small subunit’s RNA and lets such tRNAs through, so wrong amino acids get into the bacterium’s proteins. Some of the faulty proteins lodge in its membrane and let more drug in, and unlike most drugs that act on the ribosome, aminoglycosides kill.

Simplified: not to scale, the drug drawn larger than it is; the tRNAs drawn as flat cloverleaves, though each is folded in three dimensions; the elongation factors that bring each tRNA and move the ribosome along left out; the peptide bond and the move along the mRNA drawn as one step, the mRNA moving rather than the ribosome; one ribosome and one drug molecule; the aminoglycoside drawn as gentamicin, three linked rings, an aminocyclitol between two amino sugars, with their amino and hydroxyl groups; the decoding centre drawn as a patch under the codon, though the drug binds deep in a helix of the small subunit’s RNA; their block of the start of protein synthesis left out.

8 sources
  1. Parker N et al. Microbiology. OpenStax, 2016. 10.3 Structure and function of RNA
  2. Parker N et al. Microbiology. OpenStax, 2016. 11.4 Protein synthesis (translation)
  3. Parker N et al. Microbiology. OpenStax, 2016. 14.3 Mechanisms of antibacterial drugs
  4. Stevens CW. Brenner and Stevens' Pharmacology, 6th edition. Elsevier, 2023. Chapter 39, Antibiotics that inhibit bacterial protein synthesis
  5. Vázquez-Laslop N, Mankin AS. Trends Biochem Sci 2018;43:668–84. How macrolide antibiotics work
  6. PubChem. Gentamicin (CID 3467).
  7. Krause KM, Serio AW, Kane TR, Connolly LE. Cold Spring Harb Perspect Med 2016;6:a027029. Aminoglycosides: an overview
  8. Arenz S, Wilson DN. Cold Spring Harb Perspect Med 2016;6:a025361. Bacterial protein synthesis as a target for antibiotic inhibition

Their killing is concentration-dependent: the higher the peak above the MIC, the faster and more complete it is, and a peak of eight to ten times the MIC is the aim. They also have a long post-antibiotic effect, suppressing growth for hours after the level has fallen.

What they reach

Aerobic gram-negative bacilli: Enterobacterales, Pseudomonas aeruginosa (tobramycin is the most active, amikacin reaches many resistant strains) and Acinetobacter; also staphylococci, Yersinia pestis, Francisella tularensis and mycobacteria (streptomycin and amikacin). Not anaerobes, and not streptococci or enterococci on their own.

How bacteria resist

  • Enzymes that change the drug, the main way: acetyltransferases, phosphotransferases and nucleotidyltransferases, often carried on plasmids. Amikacin's side chain shields it from most of them, and plazomicin from nearly all.
  • Methylases of the 16S ribosomal RNA, which change the binding site and defeat gentamicin, tobramycin, amikacin and plazomicin alike, though not streptomycin, which is built differently.
  • Less getting in, more pumped out, as in Pseudomonas.
  • A changed ribosome, which makes Mycobacterium tuberculosis resist streptomycin.

Enterococci with high-level resistance to gentamicin lose the synergy, so laboratories test for it before relying on the combination.

Clinical indications

Aminoglycosides are kept for serious infections, mostly in hospital, and for short courses, because their harm grows with time.

DrugTypical uses
Gentamicinsevere sepsis and pyelonephritis, often a dose or a few days beside a β-lactam until cultures are back; suspected sepsis in newborns, with benzylpenicillin; endocarditis, with a β-lactam or vancomycin; plague and tularaemia; brucellosis, with doxycycline; listeria, sometimes beside amoxicillin or ampicillin; eye and ear drops
TobramycinPseudomonas, inhaled in cystic fibrosis to hold back chronic infection
Amikacingram-negatives that resist gentamicin; nontuberculous mycobacteria, inhaled for M. avium lung disease; some regimens for drug-resistant tuberculosis
Streptomycinplague and tularaemia; brucellosis, with doxycycline; tuberculosis, now rarely
Neomycinin ear, eye and skin preparations, often with polymyxin B or a steroid; by mouth, to clear the gut before bowel surgery in some countries
Paromomycinby mouth for amoebae in the gut; injected for visceral leishmaniasis

Adverse drug reactions

  • Serious
    Kidney injury. Taken up by the cells of the proximal tubule, aminoglycosides can cause acute tubular necrosis, usually after five to seven days: a rising creatinine, often with the urine output kept, and losses of magnesium and potassium. It is more likely with long courses, high troughs, older age, dehydration, advanced liver disease and other drugs that harm the kidney, and usually recovers once the drug is stopped. Neomycin is the most toxic to the kidney, which is why it is never injected.
  • Serious
    Damage to the inner ear. The hair cells of the cochlea and vestibule die, causing tinnitus and hearing loss, high tones first, or vertigo, unsteadiness and a blurred view when the head moves. It is often permanent and can begin or worsen after the course ends. Amikacin harms hearing more, gentamicin and streptomycin balance. Their licences ask for hearing, balance and kidney function to be checked before, during and after every course; formal hearing tests are mostly kept for long courses.
  • Life-threatening
    Deafness with a mitochondrial variant. In carriers of variants of the mitochondrial MT-RNR1 gene, m.1555A>G above all, an aminoglycoside can cause profound, lasting deafness even after one dose and with levels in range. The variant passes from mother to child, so deafness on the mother's side of the family, above all after an aminoglycoside, is a warning.
  • Life-threatening
    Neuromuscular blockade. Aminoglycosides block the release of acetylcholine, which can cause weakness and stop breathing, mostly in myasthenia gravis, with neuromuscular blockers given in anaesthesia, after a fast infusion, with a low calcium, or with magnesium given into a vein, as in pre-eclampsia. Calcium given into a vein can reverse it, though breathing may need support for a while.
  • Life-threatening
    Anaphylaxis and severe skin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, rarely. Gentamicin is stopped at the first rash or mouth sores.

Side effects

  • Mild
    Pain where it is injected into a muscle.
  • Mild
    An itchy rash where neomycin is put on the skin, an allergic contact dermatitis, as neomycin is a common cause of contact allergy.
  • Mild
    Nausea and diarrhoea with neomycin or paromomycin by mouth.

Contraindications

  • Contraindicated
    An allergy to the drug, or to any aminoglycoside, as some licences have it, since they can cross-react.
  • Contraindicated
    Myasthenia gravis, in gentamicin's licence, because of the neuromuscular blockade.
  • Contraindicated
    Aminoglycoside ear drops with a perforated eardrum or a grommet, which let the drug reach the inner ear.
  • Avoid
    A mitochondrial variant that raises the risk of deafness, or deafness on the mother's side of the family. Unless the infection is severe and there is no safe alternative. In the UK testing is advised before a first dose when there is time, above all before long or repeated courses, but testing should never delay an urgent dose.
  • Caution
    Kidney failure. The dose is given less often, by its levels, and kidney function is checked during the course.
  • Caution
    Other drugs that harm the kidney or the ear: vancomycin, amphotericin B, ciclosporin, cisplatin, loop diuretics such as furosemide, NSAIDs, ACE inhibitors and contrast media. Their licences advise avoiding them together; when a regimen needs both, as with vancomycin in some, levels, kidney function and hearing are watched.
  • Caution
    Neuromuscular blockers in anaesthesia, and magnesium given into a vein, whose block at the neuromuscular junction an aminoglycoside deepens and prolongs.
  • Caution
    Hearing or balance already impaired, and older age, when a further loss matters more and the kidneys clear the drug more slowly.
  • Caution
    A penicillin or cephalosporin in the same bag or syringe. Mixed with a β-lactam, an aminoglycoside is inactivated, so the two are given separately.

Pregnancy and lactation

  • Caution
    Pregnancy. Aminoglycosides are not known to cause birth defects, and are given for serious infections, such as sepsis or an infection of the membranes, when the benefit outweighs the risk, with levels watched. They cross the placenta. Most babies exposed in the womb are unaffected, and in the few reports of babies with hearing problems the mother's hearing was harmed too. A woman who needs one could be offered the test for the variant linked to deafness, though treatment often can't wait for it. Gentamicin's licence is stricter, keeping it for life-threatening infections and asking for the baby's hearing and kidneys to be checked.
  • Avoid
    Streptomycin in pregnancy. It is the aminoglycoside best known to have caused deafness in babies exposed in the womb, so another drug is used. US tuberculosis guidance goes further, listing it, with amikacin, as contraindicated in pregnancy.
  • Compatible
    Eye and ear drops in pregnancy. Too little enters the blood to reach the baby.
  • Compatible
    Breastfeeding. Little passes into milk, and the baby barely absorbs it from the gut, though a premature or newborn baby may absorb more. The baby may get diarrhoea or thrush. Some licences are more cautious, asking to weigh stopping breastfeeding.

Check yourselfAnswer, then say how sure you were: a lucky guess still counts as a weak point.

1Why is gentamicin usually given once a day rather than in three smaller doses?

2Why do aminoglycosides not work against anaerobes?

3Why is gentamicin given with ampicillin in enterococcal endocarditis?

4A woman needs gentamicin for pyelonephritis. Her mother went deaf after an aminoglycoside. What does her mother's history most likely point to?

5Which condition does gentamicin's licence list as a contraindication?

6Which harm from an aminoglycoside is most often permanent?

Linked topicsThe concepts this topic shares, and the topics they tie it to.

See on the map

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Bind the 30S subunit and make it misread the code.

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