Linezolid and other protein synthesis inhibitors

01Drug classification

The remaining protein synthesis inhibitors fall into two groups. The "other antibiotics binding to the 50S subunit" are clindamycin and chloramphenicol, under Lincosamides and amphenicols, and quinupristin–dalfopristin and lefamulin, here. The "other protein synthesis inhibitors" are linezolid and mupirocin, with tedizolid, a newer oxazolidinone, and fusidic acid, used in Europe since the 1960s and not sold in the US.

02Pharmacokinetics

Linezolid spreads widely, into the cerebrospinal fluid at about 70% of the blood level. The dose isn't changed in kidney failure, but its two inactive metabolites build up, up to tenfold, and about 30% of a dose is lost in three hours of haemodialysis, so it is given after dialysis. Tedizolid is a phosphate prodrug, which phosphatases in the blood and tissues cleave to the active drug; kidney and liver failure don't change its dose. Lefamulin is taken an hour before or two hours after a meal, swallowed whole. Fusidic acid gets unusually well into tissues, bone and dead tissue among them, and leaves in the bile, so the dose isn't changed in kidney failure.

03Pharmacodynamics

Oxazolidinones at the peptidyl transferase centre

Linezolid and tedizolid bind the 23S ribosomal RNA of the 50S subunit, at the peptidyl transferase centre. The classic account is that they stop the initiation complex forming: the first tRNA, carrying N-formylmethionine, can't settle with the messenger RNA on the 70S ribosome, so a protein never starts. Later structures show the drug in the A site, where it puts the incoming tRNA out of place, and it stalls ribosomes partway along a protein, not only at its start. Linezolid stops staphylococci and enterococci growing and kills most streptococci; tedizolid only stops them growing.

They reach gram-positive bacteria: MRSA and other resistant staphylococci, vancomycin-resistant enterococci and penicillin-resistant pneumococci. Linezolid also reaches Nocardia and M. tuberculosis. Gram-negative bacteria are out of reach.

On the mitochondria, and on monoamine oxidase

Human mitochondria have ribosomes much like a bacterium's, and linezolid binds them at the same site and blocks their protein synthesis. That is the cause of its lactic acidosis, anaemia and optic and peripheral neuropathy, which grow with the length of the course.

Linezolid is also a reversible, non-selective inhibitor of monoamine oxidase. At antibacterial doses it is no antidepressant, but it slows the breakdown of serotonin, noradrenaline and tyramine: with serotonergic drugs it can bring on serotonin syndrome, and with sympathomimetics or a lot of tyramine, a rise in blood pressure. Tedizolid inhibits monoamine oxidase too; in studies it barely changed the response to pseudoephedrine or tyramine, though serotonin syndrome has been reported with it.

How bacteria resist the oxazolidinones

• Mutations in the 23S ribosomal RNA at the binding site (G2576U and T2500A the commonest), or in ribosomal proteins L3 and L4, which defeat both drugs.
• The cfr gene, on plasmids, which methylates a base nearby and defeats oxazolidinones, phenicols, lincosamides, pleuromutilins and streptogramin A at once. Tedizolid, which has a hydroxymethyl group where linezolid has an acetamide, still works against S. aureus that carry cfr without a mutation.
• The optrA and poxtA genes, also mostly on plasmids, which make proteins that shield the ribosome from oxazolidinones and phenicols. Tedizolid doesn't escape these.

Streptogramins: quinupristin–dalfopristin

Two streptogramins given as one, 30 parts quinupristin, a streptogramin B, to 70 parts dalfopristin, a streptogramin A. Dalfopristin blocks the early phase of protein synthesis at the peptidyl transferase centre, and quinupristin, which binds where the macrolides do, the late phase. Together they act more strongly than either alone: they kill staphylococci, MRSA among them, and streptococci, and stop vancomycin-resistant E. faecium growing. E. faecalis resists them. The erm methylation that defeats macrolides and clindamycin defeats quinupristin too. The combination blocks CYP3A4.

Pleuromutilins: lefamulin

Lefamulin binds the A and P sites of the peptidyl transferase centre, in domain V of the 23S ribosomal RNA, and stops the tRNAs settling in place. It kills pneumococci, H. influenzae and Mycoplasma pneumoniae, macrolide-resistant ones too, stops S. aureus and S. pyogenes growing, and reaches Legionella and Chlamydia pneumoniae. It misses the Enterobacterales, Pseudomonas and Acinetobacter. Resistance to β-lactams, macrolides, quinolones and tetracyclines leaves it working; cfr, ribosome-protecting proteins (vga) and mutations in ribosomal proteins L3 and L4 defeat it.

Mupirocin and isoleucine

Mupirocin, made by Pseudomonas fluorescens, resembles the amino acid isoleucine. It competes with isoleucine for isoleucyl-tRNA synthetase, so the bacterium can't load isoleucine onto its tRNA, and protein synthesis stops. No other antibiotic works this way. It reaches staphylococci, MRSA among them, and streptococci, S. pyogenes among them, stopping their growth at low levels and killing them at the high levels on the skin. Gram-negative bacteria such as E. coli resist it, probably because it can't get through their outer membrane.

Resistance is low-level, from mutations in the bacterium's own synthetase gene (ileS), or high-level, from a second synthetase carried on a plasmid (mupA). Both follow heavy use of mupirocin, and resistance, the high-level kind above all, makes clearing MRSA from the nose more likely to fail.

Fusidic acid and elongation factor G

Fusidic acid is a steroid antibiotic, the only fusidane in use. It locks elongation factor G (EF-G), with its GDP, onto the ribosome, so the chain can't move on to the next codon and the ribosome can't be released at the end. It reaches staphylococci, MRSA and S. epidermidis among them.

Resistance comes easily. Single mutations in fusA, the gene for EF-G, give high-level resistance; small proteins that shield EF-G (fusB, fusC), carried on plasmids or other mobile pieces of DNA and selected mostly by its use on the skin, give low-level resistance. So by mouth it is given with a second antibiotic for deep or long infections, and on the skin in short courses.

04Clinical indications

of linezolid taken by mouth, so the tablet does what the drip does

100%absorbedof linezolid taken by mouth, so the tablet does what the drip does

the longest course in linezolid's licence; most of its nerve damage came after longer ones

28daysthe longest course in linezolid's licence; most of its nerve damage came after longer ones

of tedizolid, once a day, for a skin infection

6daysof tedizolid, once a day, for a skin infection

05Adverse drug reactions

• Serious
  Marrow suppression with linezolid: thrombocytopenia and anaemia, both common, and leucopenia and pancytopenia, more the longer it is given, in older people, and in severe kidney disease or moderate to severe liver disease. The full blood count is checked weekly, whatever it was at the start; the counts usually recover when the drug is stopped. Tedizolid lowers them too, mostly when given for longer than its 6 days.
• Life-threatening
  Serotonin syndrome with linezolid, and reported with tedizolid, when given with serotonergic drugs: agitation, confusion, fever, sweating, tremor, clonus and hyperreflexia.
• Life-threatening
  Lactic acidosis with linezolid, from harm to the mitochondria: recurrent nausea or vomiting, abdominal pain, a low bicarbonate or fast breathing need attention at once.
• Life-threatening
  Optic neuropathy with linezolid, sometimes going on to loss of sight, mostly in courses longer than 28 days. Any change in sight or colour vision means an eye examination.
• Serious
  Peripheral neuropathy with linezolid, mostly in courses longer than 28 days.
• Serious
  Convulsions, low sodium (from inappropriate ADH secretion) and rhabdomyolysis have been reported with linezolid, the convulsions mostly in people with a history of seizures.
• Life-threatening
  A long QT interval with lefamulin, more when given into a vein, which with other drugs that lengthen it could bring on torsades de pointes; its own lowering of potassium adds to the risk. Atrial fibrillation is its commonest serious reaction.
• Serious
  Joint and muscle pain, some severe, and inflamed veins with quinupristin–dalfopristin, for which it may be infused through a central line; the bilirubin rises, at times over five times normal.
• Serious
  Liver injury with fusidic acid by mouth: raised enzymes, jaundice and cholestatic hepatitis, usually reversible, and uncommonly liver failure.
• Serious
  C. difficile colitis with any of the drugs given into the body, from mild diarrhoea to fatal colitis, even more than two months after the course.
• Life-threatening
  Severe skin reactions and anaphylaxis, rarely: DRESS, Stevens–Johnson syndrome and toxic epidermal necrolysis with fusidic acid by mouth; anaphylaxis, very rarely, even with mupirocin.

06Side effects

• Mild
  Diarrhoea, nausea and vomiting, common with the drugs given by mouth or into a vein, and headache with linezolid and tedizolid; with lefamulin the stomach upsets come mostly with the tablets.
• Mild
  A metallic taste, and staining of the tongue and the surface of the teeth, with linezolid.
• Mild
  Thrush, in the mouth or the vagina.
• Mild
  Pain and redness where the drip goes in, raised liver enzymes and insomnia, with lefamulin.
• Mild
  Stinging or irritation where mupirocin or fusidic acid is applied, in the nose or on the skin.

07Contraindications

• Contraindicated
  An allergy to the drug, and for lefamulin to any pleuromutilin, for quinupristin–dalfopristin to another streptogramin.
• Caution
  Tedizolid after an allergy to linezolid, as the two can cross-react.
• Contraindicated
  Linezolid with a monoamine oxidase inhibitor, or within two weeks of one: phenelzine, isocarboxazid, selegiline, moclobemide.
• Avoid
  Linezolid with serotonergic or pressor drugs, or in conditions that a rise in serotonin or noradrenaline would worsen, unless the patient's blood pressure and state can be watched closely: SSRIs, tricyclics, triptans, pethidine, buprenorphine and buspirone; pseudoephedrine and other sympathomimetics, adrenaline, noradrenaline, dopamine and dobutamine; uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder and acute confusion.
• Caution
  Linezolid with much tyramine-rich food, such as aged cheese, which can raise the blood pressure.
• Caution
  Linezolid for more than 10 to 14 days, with low counts already, with other drugs that lower them, or in severe kidney disease or moderate to severe liver disease, only where the blood count can be watched closely; in severe kidney failure its metabolites build up too. Its licence hasn't established courses beyond 28 days, though the tuberculosis regimens give it for 26 weeks.
• Contraindicated
  Lefamulin with a long QT or a risk of one: a known long QT, uncorrected low potassium, a slow heart rate that matters, unstable heart failure, past symptomatic ventricular arrhythmias; drugs that lengthen the QT, such as class IA and III antiarrhythmics; and drugs broken down by CYP3A that lengthen it, such as some antipsychotics, erythromycin and tricyclic antidepressants.
• Contraindicated
  Lefamulin with drugs that change its levels or that it raises: rifampicin, phenytoin, carbamazepine, efavirenz and St John's wort lower it; with the tablets, clarithromycin, itraconazole, ritonavir and grapefruit juice raise it; and it raises repaglinide.
• Caution
  Lefamulin tablets with other drugs broken down by CYP3A, such as midazolam, whose level they triple.
• Contraindicated
  Fusidic acid by mouth with a statin, which has caused rhabdomyolysis, some of it fatal. The statin is stopped for the course and restarted seven days after the last dose; only in exceptional cases, under close supervision, are the two given together.
• Avoid
  Fusidic acid by mouth with other drugs broken down by CYP3A4, ritonavir and saquinavir among them, as each may raise the other's level; with those two the liver may be harmed.
• Caution
  Fusidic acid by mouth in liver or biliary disease, or with other drugs that harm the liver, with liver tests during the course; and with warfarin, whose effect it raises.
• Caution
  Fusidic acid by mouth for newborns, or with jaundice, as it displaces bilirubin from albumin, with a theoretical risk of kernicterus.
• Caution
  Quinupristin–dalfopristin with drugs broken down by CYP3A4, such as ciclosporin, midazolam and nifedipine, whose levels it raises.

08Pregnancy and lactation

• Avoid
  Linezolid in pregnancy. There are no adequate human data, and animal studies showed harm to reproduction, so its licence keeps it for when it is clearly needed.
• Caution
  Linezolid in breastfeeding. It passes into milk in moderate amounts, under a tenth of the dose given to newborns, and it is probably compatible, with the baby watched. Its licence is more cautious, and says to stop breastfeeding.
• Avoid
  Tedizolid in pregnancy. There are no human data, and studies in mice and rats showed effects on development; its licence prefers to avoid it. In breastfeeding, too little is known, and either the drug or breastfeeding is stopped.
• Avoid
  Lefamulin in pregnancy and breastfeeding. There are no human data, and stillbirths rose in animals, so it is not recommended in pregnancy, and breastfeeding is stopped during the course. Women who could become pregnant use effective contraception, adding a barrier method to the pill.
• Compatible
  Mupirocin in pregnancy and breastfeeding. Barely any is absorbed, and it is safe in breastfeeding; its licence, with no experience in pregnancy, asks that it be used when the benefit outweighs the risk.
• Compatible
  Fusidic acid cream or eye drops in pregnancy and breastfeeding, which leave a negligible amount in the blood; the cream is not put on the breast.
• Avoid
  Fusidic acid by mouth in pregnancy. There are few data; animal studies showed no harm, but its licence prefers to avoid it as a precaution.
• Compatible
  Fusidic acid by mouth in breastfeeding. Very little passes into milk, and it is compatible, with the baby watched for jaundice in the first month, and more in a premature baby. Its licence asks that the benefit be weighed.