Tetracyclines (30S inhibitors)

Tetracyclines (30S inhibitors)

Broad-spectrum antibiotics on the 30S subunit that stop bacteria growing, the first choice for rickettsiae, Lyme disease and chlamydia, which bind calcium wherever they meet it, in milk and antacids, and in a child's growing teeth.

Contents8 sections

At a glance

  1. Tetracyclines (doxycycline, minocycline, tetracycline, and the newer tigecycline) are four fused rings that bind calcium, magnesium, aluminium and iron. Antacids, iron and calcium tablets, and milk for tetracycline itself, cut their absorption; and they are laid down in teeth and bone as they calcify.
  2. They block the A site of the 30S subunit, so no aminoacyl-tRNA can bind and the chain stops growing. They stop bacteria growing rather than kill them.
  3. Their spectrum is broad and reaches inside cells: rickettsiae, Chlamydia, Mycoplasma, Borrelia, Treponema, Coxiella and Brucella, many gram-positives (some MRSA) and the malaria parasite, but not Pseudomonas or Proteus. Efflux pumps and ribosome protection make many bacteria resist; the newer drugs get past most of both.
  4. Doxycycline is the one used most: well absorbed, once or twice a day, and not changed in kidney failure. It is first choice for rickettsial infections at any age, Lyme disease and chlamydia, and treats acne, pneumonia and much else.
  5. Watch for an oesophageal ulcer if a capsule sticks, sunburn-like photosensitivity, raised pressure in the skull (never with isotretinoin), stained teeth in young children, and, with minocycline, dizziness, pigmentation and autoimmune reactions.
  6. In pregnancy they are avoided after about 13 weeks, for the baby's teeth; earlier use is not known to harm. A short course is compatible with breastfeeding. Their licences are stricter on both.

Drug classification

Tetracyclines are named for their four fused rings. The first, chlortetracycline, came from a soil Streptomyces in 1948; doxycycline and minocycline are semisynthetic, better absorbed and longer-acting, and tigecycline, eravacycline and omadacycline were built to get past the bacteria that resist the older ones.

Tetracyclines

Broad-spectrum and bacteriostatic, on the 30S subunit. The older drugs differ mostly in how they are absorbed and cleared; the newer three get past the efflux pumps and ribosome protection that defeat them.

  • Doxycyclineby mouth or injected, once or twice a day
  • Minocyclineby mouth, once or twice a day
  • Tetracyclineby mouth, four times a day
  • Oxytetracyclineby mouth, for acne
  • Lymecyclineby mouth, for acne
  • Demeclocyclineby mouth; also for the low sodium of SIADH
  • Tigecyclineinjected, a glycylcycline
  • Eravacyclineinjected, a fluorocycline
  • Omadacyclineby mouth or injected, approved in the US, not the EU

Pharmacokinetics

Tetracycline itself is absorbed only in part, about 70% (less with food or milk), doxycycline and minocycline more than 90%. All bind calcium, magnesium, aluminium, iron and zinc into complexes the gut can't absorb, so antacids, iron, calcium and zinc tablets and bismuth are taken two to three hours apart from them. Milk and food cut tetracycline's absorption most, doxycycline's and minocycline's little.

They spread widely, into most tissues and fluids and into cells, which is why they reach intracellular bacteria. Minocycline, the most fat-soluble, reaches the brain and cerebrospinal fluid best. They cross the placenta and are laid down wherever calcium is laid down, in growing teeth and bone.

DrugHalf-lifeHow it leaves
Tetracyclineabout 10 hoursin the urine, so it builds up in kidney failure
Doxycyclineabout 20 hoursin the urine and faeces, and more in the faeces as the kidneys fail, so its dose is not changed in kidney failure; inducers such as carbamazepine, phenytoin and rifampicin shorten its half-life
Minocyclineabout 20 hoursthrough the liver and bile, and the urine
Tigecyclineabout 40 hoursin bile and faeces; it spreads so widely into tissues that its blood levels stay low

Pharmacodynamics

On the ribosome

A tetracycline crosses the outer membrane of a gram-negative through its porins, and the inner membrane by an energy-dependent uptake that human cells lack, which is part of why they spare us. Inside, it binds the 16S ribosomal RNA of the 30S subunit, at the A site, and blocks each aminoacyl-tRNA from docking there, so no new amino acid is added. The binding is reversible, so the bacterium stops growing but isn't killed: tetracyclines are bacteriostatic, and their effect follows the drug's total exposure over the day.

How a tetracycline stops a ribosome
A bacterial ribosome in section, reading a messenger RNA that runs across the picture: the small subunit below, holding the mRNA, with 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. The A site is empty, and a third tRNA, carrying its amino acid, comes in from the right. Step 1 of 6: A tRNA brings an amino acid. A tRNA carrying its amino acid comes to the empty A site, while the tRNA in the P site holds the growing chain.EPA

Step 1 of 6A tRNA brings an amino acid. A tRNA carrying its amino acid comes to the empty A site, while the tRNA in the P site holds the growing chain.

Point at a name or a part to light it.

A tetracycline binds the small subunit of the bacterial ribosome, where each new tRNA has to seat. Bacteria take it up with energy, which our cells hardly do, and the ribosomes in our cytoplasm bind it only weakly. Because it lets go, a tetracycline stops bacteria growing rather than killing them: it is bacteriostatic.

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; tetracycline drawn as its four rings and its main side groups; the magnesium it binds the ribosome with 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. Chopra I, Roberts M. Microbiol Mol Biol Rev 2001;65:232–60. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance
  7. Grossman TH. Cold Spring Harb Perspect Med 2016;6:a025387. Tetracycline antibiotics and resistance
  8. Arenz S, Wilson DN. Cold Spring Harb Perspect Med 2016;6:a025361. Bacterial protein synthesis as a target for antibiotic inhibition

What they reach

  • Intracellular and wall-less bacteria: rickettsiae, Coxiella (Q fever), Anaplasma and Ehrlichia, Chlamydia trachomatis, C. pneumoniae and C. psittaci (once Chlamydophila), Mycoplasma pneumoniae, Legionella.
  • Spirochaetes: Borrelia (Lyme disease, relapsing fever), Treponema pallidum, Leptospira.
  • Others: Brucella, Vibrio cholerae, Yersinia pestis, Francisella, Bacillus anthracis, Cutibacterium acnes (once Propionibacterium), Helicobacter pylori, many streptococci and staphylococci, community MRSA among them.
  • Parasites: the malaria parasite, so doxycycline protects travellers.

They don't reach Pseudomonas aeruginosa or Proteus, and tigecycline, for all its breadth, misses them too.

How bacteria resist

  • Efflux pumps of the Tet family, carried on plasmids and transposons, push the drug out: the commonest way in gram-negatives.
  • Ribosome protection proteins, such as Tet(M), knock the drug off the ribosome.
  • Enzymes, Tet(X), that break it down, a rarer way that reaches tigecycline too.

The genes spread between species; feeding tetracyclines to farm animals to make them grow faster has helped spread them round the world. Tigecycline, eravacycline and omadacycline bind the ribosome more tightly and get past most efflux pumps and ribosome protection.

Beyond killing bacteria

At doses too low to act on bacteria, doxycycline blocks the matrix metalloproteinases, collagenases among them, that break down connective tissue. Doxycycline 20 mg twice a day was licensed in the US and parts of Europe as an aid to scaling and root planing in periodontitis, but it is no longer suggested. Antibiotics placed in the pocket and released slowly there, doxycycline gel or minocycline microspheres, may be considered alongside subgingival instrumentation.

A modified-release dose of 40 mg once a day, also too low to act on bacteria, reduces the papules and pustules of rosacea, probably by damping inflammation.

Demeclocycline blunts the kidney's response to ADH, a reversible nephrogenic diabetes insipidus. Its UK licence turns this to use, for the low sodium of the syndrome of inappropriate ADH secretion (SIADH) caused by cancer when restricting water fails, but it is not recommended in Europe, for reports of acute kidney injury.

Clinical indications

InfectionThe usual choice
Rickettsial infections (spotted fevers, typhus), Q fever, anaplasmosisdoxycycline, first choice at any age
Lyme disease: erythema migrans, and much neuroborreliosis in Europedoxycycline
Chlamydia, lymphogranuloma venereum, pelvic inflammatory disease (with other drugs)doxycycline
Community-acquired pneumoniadoxycycline, an alternative to amoxicillin, and for atypical bacteria
Moderate to severe acnelymecycline or doxycycline, with a topical treatment
Rosacea, papules and pustulesdoxycycline 40 mg modified-release, alone or with a topical treatment
Brucellosis, cholera, plague, tularaemia, anthraxdoxycycline, in brucellosis with rifampicin or an aminoglycoside
Malariadoxycycline to prevent it in travellers; with artesunate or quinine to treat it
H. pyloritetracycline, in bismuth quadruple therapy
Community MRSA skin infectionsdoxycycline
Complicated skin and abdominal infections when other drugs are not suitabletigecycline
of pregnancy, after which tetracyclines are avoided, for the baby's teeth
13weeks
apart from antacids, iron, calcium or zinc
2 to 3hours
of doxycycline twice a day for 7 days treats chlamydia
100mg

Adverse drug reactions

  • Serious
    Oesophageal ulcers. A capsule or tablet that sticks in the oesophagus can burn an ulcer, with pain on swallowing. Doxycycline is taken sitting or standing, with a full glass of water, and not just before lying down.
  • Serious
    Stained teeth. In children whose teeth are still calcifying, tetracyclines stain them for good and can thin the enamel, which is why they are kept from young children, under eight in most guidance and under twelve in most UK licences.
  • Serious
    Idiopathic intracranial hypertension: headache, blurred or double vision, and swelling of the optic discs, which can threaten sight. The drug is stopped. It is likelier with isotretinoin, which is never given with them.
  • Life-threatening
    Severe immune reactions with minocycline: DRESS, autoimmune hepatitis and a lupus-like syndrome, the last mostly after months of treatment for acne. They are rarer with doxycycline.
  • Serious
    Blue-grey pigmentation with minocycline, of skin, scars, nails, gums or teeth, mostly after long use. The drug is stopped, and the colour fades slowly, sometimes not at all.
  • Serious
    Liver injury, rare, mostly with high intravenous doses. Pregnant women given large doses of intravenous tetracycline developed acute fatty liver, sometimes fatally, one more reason to avoid them in pregnancy.
  • Serious
    Kidney. Tetracycline, unlike doxycycline, builds up in kidney failure and raises the urea further, and tetracyclines add to the harm other drugs do to the kidney, such as aminoglycosides. Out-of-date tetracycline, broken down, once caused Fanconi syndrome, a failure of the proximal tubule.
  • Serious
    More deaths with tigecycline. In trials, more patients died on tigecycline than on comparison antibiotics. The cause isn't known, but poorer efficacy can't be ruled out, so it is kept for when other antibiotics are not suitable. It can also cause pancreatitis and a low fibrinogen.
  • Life-threatening
    Anaphylaxis and severe skin reactions, rarely.

Side effects

  • Mild
    Nausea, vomiting, heartburn and diarrhoea, the commonest. Food eases them with doxycycline. Tigecycline causes nausea in about one patient in five.
  • Mild
    Photosensitivity, a reaction like exaggerated sunburn on skin exposed to sunlight, and sometimes lifting of the nails; doxycycline does it more than minocycline, and demeclocycline most of all. Patients avoid strong sun and use sunscreen while on it, and the drug is stopped if the skin reddens.
  • Mild
    Dizziness and vertigo with minocycline, commoner in women.
  • Mild
    A Jarisch–Herxheimer reaction when doxycycline treats Lyme disease, syphilis, leptospirosis or relapsing fever: within hours of starting, fever, chills, aches and headache flare as the bacteria die. It passes within a day or two and doesn't usually mean stopping.
  • Mild
    Thrush, in the mouth or vagina.

Contraindications

  • Contraindicated
    An allergy to any tetracycline.
  • Contraindicated
    Isotretinoin or another oral retinoid, which raise the pressure inside the skull as tetracyclines can.
  • Contraindicated
    Tetracycline, oxytetracycline, lymecycline or demeclocycline in kidney failure. They build up and can worsen it, so doxycycline is used instead; the licences of lymecycline, oxytetracycline and demeclocycline rule them out. Minocycline needs a lower dose in severe failure and isn't given in complete failure.
  • Avoid
    Children under eight, because of their teeth, and under twelve for most tetracyclines in UK licences. Doxycycline is the exception for serious infections, such as rickettsial disease or anthrax, for which it is given at any age; from eight to twelve, its licence asks that its use be justified.
  • Caution
    Antacids, iron, calcium, zinc, magnesium and bismuth, taken two to three hours apart.
  • Caution
    Warfarin. Tetracyclines can raise its effect, so the INR is checked.
  • Caution
    Carbamazepine, phenytoin, rifampicin, barbiturates and heavy drinking, which speed doxycycline's breakdown and can make it fail.
  • Caution
    Liver disease, lupus and myasthenia gravis, which tetracyclines can worsen.

Pregnancy and lactation

  • Compatible
    Early pregnancy, up to about 13 weeks. Use is not known to harm the baby, so a course taken before the pregnancy was known is no cause for concern. Licences are more cautious: doxycycline's, minocycline's and lymecycline's rule out the whole pregnancy, and oral tetracyclines for acne are not used in pregnancy or when planning one.
  • Avoid
    After about 13 weeks. The baby's milk teeth are forming, and tetracyclines can stain them. A course is still considered when it is the only suitable treatment for a serious infection.
  • Compatible
    Breastfeeding, a short course, up to about three weeks. Doxycycline passes into milk in modest amounts, tetracycline itself very little, and the calcium in milk is thought to bind much of it, so the baby absorbs little. The baby may get diarrhoea or thrush. Licences are more cautious, and doxycycline's, minocycline's and lymecycline's rule out breastfeeding.
  • Avoid
    Breastfeeding, long or repeated courses, such as for acne, because in theory they could reach the baby's teeth and bones.

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

1A patient's chest infection doesn't improve on doxycycline. She takes it with her calcium and iron tablets and an antacid. Why might it be failing?

2Why are tetracyclines avoided after about 13 weeks of pregnancy?

3How should doxycycline be taken to avoid an oesophageal ulcer?

4A 4-year-old back from southern France has fever, a rash and a black scab where a tick bit. Mediterranean spotted fever is suspected. What is the treatment?

5A teenager on lymecycline for acne is to start isotretinoin. What happens to the lymecycline?

6What is the first choice for uncomplicated genital chlamydia in current European guidance?

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Helicobacter pylori

Tetracycline is part of bismuth quadruple therapy.

  • PenicillinsAntimicrobials and chemotherapeuticsAmoxicillin is a mainstay of eradication regimens.
  • Macrolides and ketolides (50S inhibitors)Antimicrobials and chemotherapeuticsClarithromycin is used where resistance to it is low.
  • Antiprotozoal drugsAntimicrobials and chemotherapeuticsNot written yetMetronidazole, a nitroimidazole that also kills protozoa, is a common partner.
  • Antiulcer drugsGastrointestinal, metabolic and hormonal drugsNot written yetEvery regimen has an acid blocker, usually a proton pump inhibitor; bismuth is added in bismuth quadruple therapy.
  • Helicobacter pylori infectionInternal medicineNot written yetHow the infection is found and eradicated.
  • Peptic ulcerInternal medicineNot written yetIt causes most duodenal and many gastric ulcers; eradication largely stops them coming back.
  • Gastric carcinomaInternal medicineNot written yetLong infection raises the risk of gastric adenocarcinoma.
  • Non-Hodgkin’s lymphomasInternal medicineGastric MALT lymphoma can regress once the bacterium is eradicated.

Bacterial ribosome

Bind the 30S subunit and stop new tRNAs docking.