Macrolides and ketolides (50S inhibitors)

Macrolides and ketolides (50S inhibitors)

Large-ringed antibiotics that block the exit tunnel of the 50S subunit, for the bacteria of the airways, atypical ones among them, and a few of the gut and genitals; and the interactions and heart rhythm to watch for with them.

Contents8 sections

At a glance

  1. Macrolides (erythromycin, clarithromycin, azithromycin) are a large lactone ring with sugars attached. They bind the 23S ribosomal RNA in the exit tunnel of the 50S subunit, so most growing chains can't get past and protein synthesis stalls; they mostly stop bacteria growing.
  2. Erythromycin is broken by stomach acid and short-lived; clarithromycin is better absorbed, twice a day; azithromycin collects in tissues and cells and leaves slowly, a half-life of about 68 hours, so three to five days suffice.
  3. They reach the bacteria of the airways, the atypical ones (Mycoplasma, Chlamydia pneumoniae, Legionella) above all, and Bordetella pertussis, Chlamydia trachomatis, Campylobacter and Mycobacterium avium complex; clarithromycin also treats H. pylori. Pneumococci and streptococci resist them more and more, by methylating the ribosome (erm) or pumping the drug out (mef).
  4. Erythromycin and clarithromycin block CYP3A4 and raise the levels of simvastatin, carbamazepine, colchicine, ciclosporin and many more; azithromycin barely does.
  5. All can lengthen the QT interval and bring on torsades de pointes. Erythromycin stimulates motilin receptors: cramps, nausea and diarrhoea, and, given to newborns, pyloric stenosis (azithromycin too).
  6. In pregnancy erythromycin and azithromycin are used when a penicillin won't do, erythromycin after preterm rupture of the membranes; a small risk after use early in pregnancy can't be ruled out, and erythromycin is preferred to clarithromycin. In breastfeeding they are compatible, erythromycin after the baby's first month.

Drug classification

Erythromycin, the first macrolide used in medicine, came into use in 1952. It is made by Saccharopolyspora erythraea (once Streptomyces erythreus), found in a soil sample from the Philippines. Clarithromycin and azithromycin are semisynthetic, more acid-stable and better absorbed. The macrolides are grouped by the size of their ring: 14 atoms in erythromycin and clarithromycin, 15 in azithromycin (an azalide, with a nitrogen in the ring), 16 in spiramycin.

Macrolides

On the 50S subunit, for the bacteria of the airways and the atypical ones. Erythromycin and clarithromycin block CYP3A4; azithromycin barely does.

  • Erythromycinby mouth or injected, four times a day
  • Clarithromycinby mouth or injected, twice a day
  • Azithromycinby mouth or injected, once a day, an azalide
  • Roxithromycinby mouth, in parts of Europe
  • Spiramycinby mouth, for toxoplasmosis in pregnancy

Ketolides

Erythromycin with a keto group in place of one of its sugars and a side chain that binds the ribosome at a second place, so it gets past most macrolide resistance in pneumococci.

  • Telithromycinno longer sold in the EU or US

Pharmacokinetics

DrugBy mouthHalf-lifeDosing
Erythromycinbroken by stomach acid, so given as coated tablets or esters; absorption low and variableabout 2 hoursfour times a day, or twice
Clarithromycinacid-stable, about half absorbed; made into an active metabolite in the liverabout 5 hourstwice a day, or once as modified release
Azithromycinabout 37% absorbedabout 68 hoursonce a day, for 3 to 5 days

All are given by mouth, and erythromycin, clarithromycin and azithromycin also into a vein; erythromycin is used on the skin for acne and in the eye. They spread into tissues and cells and are carried in phagocytes to the infection, which suits the intracellular bacteria they treat; little reaches the cerebrospinal fluid.

Azithromycin is taken up into tissues so thoroughly that its level in the blood is low while tissue levels are high, and it leaves them slowly, unchanged in bile. Its half-life is sometimes given as 12 hours, that of its first fall in the blood; the 68 hours is its slow release from the tissues, which sets how long it acts. Erythromycin and clarithromycin are broken down by CYP3A4 in the liver, and leave in bile and, for clarithromycin, the urine too, so its dose is halved when the creatinine clearance is under 30 mL/min.

Interactions

Erythromycin and clarithromycin bind CYP3A4 and inactivate it, and block P-glycoprotein, so the levels of many drugs rise:

  • statins broken down by CYP3A4 (simvastatin, lovastatin, and atorvastatin less): muscle breakdown;
  • colchicine: fatal toxicity;
  • carbamazepine, ciclosporin, tacrolimus, theophylline and digoxin: toxicity;
  • ergot alkaloids: ergotism, with limbs left without blood;
  • direct oral anticoagulants and warfarin: bleeding;
  • drugs that lengthen the QT interval, such as pimozide and domperidone, whose levels rise as well.

Azithromycin hardly touches CYP3A4, so it is the macrolide for a patient on many drugs, though it still blocks P-glycoprotein, so digoxin and colchicine are watched, and its effect on the QT interval remains.

Pharmacodynamics

In the exit tunnel

A macrolide binds the 23S ribosomal RNA of the 50S subunit, in the tunnel through which the new protein leaves the ribosome, just past the peptidyl transferase centre. The first few amino acids of the chain are made, then the chain jams against the drug, the ribosome stalls, and the peptidyl-tRNA can fall off. This is the classic picture, simplified: the drug only narrows the tunnel, some proteins get past it, and the ribosome stalls at particular sequences in the growing chain. The block is reversible, so macrolides mostly stop bacteria growing, though at high levels they kill some streptococci. Their effect follows the time above the MIC, and for azithromycin its total exposure.

How a macrolide 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 the exit tunnel running up through it. The ribosome has just begun a protein: tRNAs stand in the E and P sites, the one in the P site holding a chain of three amino acids whose first lies just inside the tunnel, and a tRNA has docked in the A site with the fourth. Step 1 of 5: A protein is begun. The ribosome has joined the first three amino acids of a new protein, and a tRNA has docked with the fourth. The chain will leave through the exit tunnel.EPA

Step 1 of 5A protein is begun. The ribosome has joined the first three amino acids of a new protein, and a tRNA has docked with the fourth. The chain will leave through the exit tunnel.

Point at a name or a part to light it.

Macrolides such as erythromycin, clarithromycin and azithromycin bind the large subunit’s RNA inside the exit tunnel, just beyond the peptidyl transferase centre. A ribosome that has only just begun a protein stalls when the chain reaches the drug, and the tRNA, still holding the short chain, falls off the ribosome. Macrolides mostly stop bacteria growing rather than kill them.

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 macrolide drawn after erythromycin, its large ring, a few methyl groups and its two sugars; the drug drawn coming in down the tunnel from its exit, the way it is thought to reach its site; the chain drawn shorter than the six to eight amino acids erythromycin lets through before it stalls; the drug drawn as a plug, though it only narrows the tunnel: many proteins thread past it, and a ribosome stalls only at certain sequences.

9 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. Tenson T, Lovmar M, Ehrenberg M. The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J Mol Biol 2003;330:1005–14.
  7. PubChem. Erythromycin (CID 12560).
  8. Dinos GP. Br J Pharmacol 2017;174:2967–83. The macrolide antibiotic renaissance
  9. Arenz S, Wilson DN. Cold Spring Harb Perspect Med 2016;6:a025361. Bacterial protein synthesis as a target for antibiotic inhibition

What they reach

  • Respiratory bacteria: Streptococcus pyogenes and pneumococci (with rising resistance), H. influenzae and Moraxella (azithromycin and clarithromycin more than erythromycin, though for H. influenzae the evidence that they help is conflicting), Bordetella pertussis.
  • Atypical bacteria: Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella.
  • Genital and gut bacteria: Chlamydia trachomatis, Mycoplasma genitalium, Haemophilus ducreyi, Campylobacter, Shigella and Salmonella Typhi (azithromycin).
  • Others: Helicobacter pylori (clarithromycin), Mycobacterium avium complex, Bartonella, and Toxoplasma (spiramycin).

They miss most gram-negative bacilli, such as E. coli, Klebsiella and Pseudomonas (azithromycin's reach to Salmonella and Shigella is the exception), and most MRSA.

How bacteria resist

  • Methylating the ribosome. The erm genes add a methyl group to the 23S ribosomal RNA where macrolides bind. That blocks macrolides, lincosamides and streptogramin B together, the MLSB phenotype, and in some strains it switches on only when a macrolide is present, which is why a laboratory checks for inducible clindamycin resistance.
  • Pumping it out. The mef genes make an efflux pump for 14- and 15-membered macrolides only, a lower-level resistance.
  • Mutations in the ribosomal RNA, as in H. pylori and Mycoplasma.

Macrolide resistance in pneumococci differs widely across Europe, from under one in ten in some countries to a third or more in others, and in parts of East Asia most Mycoplasma pneumoniae resist.

Azithromycin is in the Watch group of antibiotics, those likelier to breed resistance, and the long, falling tail of its levels after a course favours it. Since 2025 its EU licence asks that it be started only when the preferred treatment won't do, and in the EU it is no longer licensed for acne, H. pylori or preventing asthma attacks.

Beyond killing bacteria

Erythromycin, and less so the others, is an agonist at the motilin receptor, which sets off the gut's waves of contraction: the cause of its stomach upsets, and the reason it is given to empty the stomach. Taken for months, azithromycin calms inflammation in the airways and cuts exacerbations of bronchiectasis, chronic obstructive pulmonary disease and cystic fibrosis, partly through effects on the host and on how Pseudomonas behaves, which it doesn't kill.

Clinical indications

UseNotes
Community-acquired pneumoniaclarithromycin, or azithromycin, added to amoxicillin when atypical bacteria are suspected in moderate pneumonia and to co-amoxiclav in severe; alone, or doxycycline instead, in milder pneumonia with penicillin allergy; Legionella
Sore throat, otitis, sinusitiswhen a penicillin can't be given
Whooping coughazithromycin or clarithromycin, for the patient and close contacts
Chlamydia in pregnancy, chancroid, Mycoplasma genitalium without macrolide-resistance mutationsazithromycin; doxycycline is first choice for chlamydia outside pregnancy, and moxifloxacin for resistant M. genitalium
Gonorrhoeaazithromycin 2 g with ceftriaxone in Europe, with ceftriaxone alone only in well-controlled settings; ceftriaxone alone in the US
Campylobacter, travellers' diarrhoea, typhoidazithromycin
H. pyloriclarithromycin in triple therapy only where resistance is under 15% or the strain is tested; otherwise bismuth quadruple therapy
Mycobacterium avium complexclarithromycin or azithromycin, with ethambutol and rifampicin
Preventing exacerbationsazithromycin for months, in bronchiectasis, COPD and cystic fibrosis, after an ECG, liver tests and, where possible, a sputum test, as azithromycin alone would breed resistance in non-tuberculous mycobacteria
Emptying the stomacherythromycin into a vein before endoscopy for an upper gastrointestinal bleed
Toxoplasmosis in pregnancyspiramycin, to cut the chance of the infection passing to the baby
the half-life of azithromycin, so three days of tablets leave it in the tissues for about a week
68hours
of life, before which erythromycin or azithromycin given to a baby raises the risk of pyloric stenosis most
2weeks

Adverse drug reactions

  • Life-threatening
    A long QT interval and torsades de pointes. Macrolides block the potassium current that repolarises the ventricles. The risk is greatest with other drugs that lengthen the QT, low potassium or magnesium, a slow heart, heart failure, and with erythromycin or clarithromycin given with a CYP3A4 substrate that lengthens it too. In a large US study, azithromycin was linked to a small rise in cardiovascular deaths in the five days of treatment, mostly in patients already at risk.
  • Life-threatening
    Toxic levels of other drugs with erythromycin and clarithromycin: muscle breakdown with simvastatin, fatal colchicine poisoning, carbamazepine toxicity, ergotism.
  • Life-threatening
    Worsening of myasthenia gravis, which can stop breathing; with telithromycin it was sometimes fatal, one of the reasons its use was restricted.
  • Serious
    Liver injury, usually cholestatic hepatitis, with jaundice and itching, which usually recovers when the drug is stopped; rarely the liver fails. It is best known with erythromycin estolate.
  • Serious
    Pyloric stenosis in babies. Erythromycin or azithromycin given to a baby in the first weeks of life, most in the first two, raises the risk of infantile hypertrophic pyloric stenosis: projectile vomiting a few weeks later.
  • Serious
    Hearing loss and tinnitus, usually reversible, with high doses, such as erythromycin into a vein or azithromycin taken for months.
  • Serious
    C. difficile colitis, less often than with clindamycin, cephalosporins or quinolones.
  • Life-threatening
    Anaphylaxis and severe skin reactions, rarely.

Side effects

  • Mild
    Nausea, vomiting, cramps and diarrhoea, the commonest, worst with erythromycin, which stimulates motilin receptors; clarithromycin and azithromycin cause less.
  • Mild
    A bitter or metallic taste with clarithromycin.
  • Mild
    Pain and phlebitis along the vein with erythromycin infused.
  • Mild
    Headache and rash.

Contraindications

  • Contraindicated
    An allergy to any macrolide.
  • Contraindicated
    A long QT interval, inborn or acquired, a past ventricular arrhythmia such as torsades de pointes, or uncorrected low potassium or magnesium, for clarithromycin and erythromycin in their licences.
  • Contraindicated
    Drugs they would raise to toxic levels: with clarithromycin, simvastatin and lovastatin, colchicine, ergot alkaloids, oral midazolam, ticagrelor, ivabradine and ranolazine; with erythromycin, simvastatin and ergot alkaloids; with both, drugs that lengthen the QT such as pimozide and domperidone, among others in their licences.
  • Contraindicated
    Clarithromycin in severe liver failure with impaired kidney function.
  • Avoid
    Carbamazepine, ciclosporin and tacrolimus with erythromycin or clarithromycin. Azithromycin is used, or the levels are watched closely.
  • Caution
    Other drugs that lengthen the QT interval, such as citalopram, antipsychotics, methadone, ondansetron and quinolones, heart failure or a slow heart, and, for azithromycin, a long QT or low potassium or magnesium. An ECG is checked when the risk is high.
  • Caution
    Warfarin and the direct oral anticoagulants, whose effect can rise.
  • Caution
    Myasthenia gravis, which can worsen.
  • Caution
    Liver disease, and kidney failure with clarithromycin, whose dose is halved when the creatinine clearance is under 30 mL/min.
  • Caution
    Babies in their first weeks, because of pyloric stenosis; parents are told to watch for vomiting.

Pregnancy and lactation

  • Compatible
    Erythromycin after preterm rupture of the membranes, the antibiotic given to prevent infection of the womb.
  • Compatible
    Erythromycin and azithromycin in pregnancy. They are given when a penicillin won't do, such as in penicillin allergy, and azithromycin treats chlamydia in pregnancy, when doxycycline is avoided. There is no sign that they harm the baby. A large UK study linked use in the first trimester to birth defects, of the heart in particular, and the UK regulator found the evidence too weak to confirm or rule out a small rise in birth defects or miscarriage. The regulator and the licences are therefore more cautious, using a macrolide early in pregnancy only when no suitable alternative will do, and erythromycin is preferred when one is needed.
  • Caution
    Clarithromycin in pregnancy. There is no sign that it affects the baby's development; some studies linked it to miscarriage, which the infections treated may explain. Its licence is more cautious: animal studies gave mixed results, and it is used in pregnancy only after weighing benefit against risk, particularly in the first trimester. Erythromycin is preferred when a macrolide is needed in pregnancy.
  • Compatible
    Spiramycin for toxoplasmosis in pregnancy, given to cut the chance of the parasite passing to the baby.
  • Compatible
    Azithromycin and clarithromycin in breastfeeding. Very little passes into milk; the baby may get loose stools or thrush. Their licences are more cautious, azithromycin's asking for the benefit of breastfeeding to be weighed against that of the drug.
  • Caution
    Erythromycin in breastfeeding, in the baby's first month. Little passes into milk, but a link with pyloric stenosis, when the mother takes a macrolide in the baby's first two weeks, has been found in some studies and not others, so another macrolide is preferred in the first month and parents watch for vomiting. After the first month it is compatible.

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

1A man on simvastatin needs clarithromycin for pneumonia. What is done about the simvastatin?

2Which change on the ECG can macrolides cause?

3Why does erythromycin cause cramps and diarrhoea, and how is the same effect put to use?

4What is the antibiotic of choice for whooping cough?

5Why is three days of azithromycin enough for many respiratory infections?

6What happened to telithromycin, the ketolide?

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

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Pneumonia

Clarithromycin or azithromycin add cover for atypical bacteria.

Helicobacter pylori

Clarithromycin is used where resistance to it is low.

  • PenicillinsAntimicrobials and chemotherapeuticsAmoxicillin is a mainstay of eradication regimens.
  • Antiprotozoal drugsAntimicrobials and chemotherapeuticsNot written yetMetronidazole, a nitroimidazole that also kills protozoa, is a common partner.
  • Tetracyclines (30S inhibitors)Antimicrobials and chemotherapeuticsTetracycline is part of bismuth quadruple therapy.
  • 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.

Cytochrome P450

Clarithromycin and erythromycin inhibit CYP3A4.

  • Drug metabolismPharmacokineticsNot written yetPhase I reactions, most of them by CYP enzymes.
  • Drug interactions at pharmacokinetic levelPharmacodynamicsNot written yetInducers lower other drugs’ levels; inhibitors raise them.
  • Factors on the part of the body influencing the kinetics and the action of the drugsPharmacodynamicsNot written yetGene variants make some people slow or fast metabolisers.
  • Antituberculosis drugs. Antileprosy drugsAntimicrobials and chemotherapeuticsRifampicin is a strong inducer: it can make the pill or warfarin fail.
  • Antiepileptic drugs (AEDs)Central and peripheral nervous systemNot written yetCarbamazepine and phenytoin are inducers.
  • Antimycotics (antifungal drugs)Antimicrobials and chemotherapeuticsNot written yetAzoles such as itraconazole and voriconazole inhibit CYP3A4.
  • AnticoagulantsHematologic drugsNot written yetDrugs that inhibit or induce CYP2C9, such as fluconazole or rifampicin, shift warfarin’s effect.
  • Antidepressants: types, mechanism of action, clinical effects, adverse effects, indications, and monitoringPsychiatryFluoxetine and paroxetine inhibit CYP2D6, raising the levels of other drugs it breaks down.

Bacterial ribosome

Bind the 50S subunit and block the growing chain.