Lincosamides. Amphenicols (50S inhibitors)

01Drug classification

Clindamycin and chloramphenicol, with quinupristin–dalfopristin and lefamulin, are "other antibiotics binding to the 50S subunit". The syllabus groups the first two by their chemistry: the lincosamides, an amino acid joined to an amino sugar, and the amphenicols, a benzene ring with a dichloroacetyl tail; chloramphenicol's ring carries a nitro group, which its relative thiamphenicol's lacks. Quinupristin–dalfopristin and lefamulin are under Linezolid and other protein synthesis inhibitors.

Lincomycin came from Streptomyces lincolnensis, found in soil from Lincoln, Nebraska, and clindamycin was made from it in the 1960s. Chloramphenicol came from Streptomyces venezuelae in 1947, and was the first antibiotic made wholly by chemical synthesis.

02Pharmacokinetics

Clindamycin is about 90% absorbed by mouth, with or without food; the capsule is swallowed with a full glass of water, as it can ulcer the oesophagus. Into a vein it is given as clindamycin phosphate, by infusion, never as a bolus. It spreads well into tissues, bone, joints and abscesses, and into neutrophils and macrophages, but not usefully into the cerebrospinal fluid. The liver breaks it down, by CYP3A4, and its metabolites leave in urine and bile; its half-life is about 2 to 3 hours, so it is given three or four times a day. The dose is not changed in kidney failure.

Chloramphenicol is well absorbed by mouth, and into a vein is given as the succinate, which the body cleaves to the active drug. It is small and fat-soluble, and reaches the cerebrospinal fluid and brain even when the meninges are not inflamed, and the eye. The liver conjugates it with glucuronic acid and the kidneys excrete it; its half-life is about 3 hours. Newborns, whose glucuronyl transferase is still immature, clear it far more slowly. Its levels are measured in newborns, in liver or kidney failure and with drugs that interact, as over 25 mg/L is often toxic. It inhibits the liver's CYP enzymes, CYP2C19 and CYP3A4 in studies of human liver, and raises the levels of phenytoin, warfarin and sulfonylureas such as tolbutamide.

03Pharmacodynamics

At the peptidyl transferase centre

Both bind the 23S ribosomal RNA of the 50S subunit where the peptide bond is made. Chloramphenicol sits in the A site and blocks the amino acid of the incoming tRNA from being joined to the chain; clindamycin overlaps the A and P sites and blocks the chain's first steps and its move along. Because macrolides bind next to them, the three compete, and one bacterial change, the erm methylation, defeats macrolides and clindamycin together. Both mostly stop bacteria growing; chloramphenicol kills H. influenzae, meningococci and pneumococci.

What clindamycin reaches

• Gram-positive cocci: streptococci and staphylococci, some MRSA among them, if the laboratory finds them susceptible; it isn't given blind when MRSA is suspected.
• Anaerobes: those of the mouth (Prevotella, Fusobacterium, Peptostreptococcus, Actinomyces), Clostridium perfringens, and Bacteroides fragilis, though resistance in Bacteroides is now common.
• Parasites, with a partner: Toxoplasma (with pyrimethamine), malaria (with quinine or artesunate), Pneumocystis (with primaquine), Babesia (with quinine).

It misses aerobic gram-negatives, enterococci and C. difficile.

Switching off toxins

Because it stops protein synthesis, clindamycin stops streptococci and staphylococci making their toxins: the superantigens of toxic shock, and the Panton–Valentine leukocidin. A β-lactam needs bacteria to be growing, and in a dense infection most have stopped; clindamycin doesn't. So in necrotising fasciitis and toxic shock it is given with the β-lactam.

Resistance

• erm methylation of the 23S ribosomal RNA, which defeats macrolides, lincosamides and streptogramin B (MLSB). In some strains it is switched on only when a macrolide is present: such a strain resists erythromycin and looks susceptible to clindamycin, but can turn resistant during treatment, so the laboratory reports it resistant; it may still do for a short course in a minor skin infection. In the D-test, an erythromycin disc set beside a clindamycin disc flattens the clindamycin zone into a D.
• Enzymes that inactivate lincosamides (the lnu genes) and, for chloramphenicol, chloramphenicol acetyltransferase, carried on plasmids.
• The cfr gene, which methylates a nearby base and defeats chloramphenicol, clindamycin, linezolid, streptogramin A and the pleuromutilins at once.

What chloramphenicol reaches

Most gram-positives and gram-negatives, H. influenzae, Neisseria, Salmonella Typhi among them, anaerobes, rickettsiae, Chlamydia and Mycoplasma, but not Pseudomonas. It also binds the ribosomes of human mitochondria, much like bacterial ones, which is why, at high levels, it suppresses the marrow. The rare aplastic anaemia is a separate reaction, probably to metabolites of its nitro group.

04Clinical indications

of clindamycin taken by mouth

90%absorbedof clindamycin taken by mouth

exposed to chloramphenicol develop aplastic anaemia

1 in 20,000 to 40,000patientsexposed to chloramphenicol develop aplastic anaemia

the chloramphenicol level above which it is often toxic

25mg/Lthe chloramphenicol level above which it is often toxic

05Adverse drug reactions

• Life-threatening
  C. difficile colitis with clindamycin, from mild diarrhoea to pseudomembranous colitis and toxic megacolon, which can kill. It can start during the course or weeks after it. Marked or lasting diarrhoea means stopping clindamycin and testing for C. difficile.
• Life-threatening
  Aplastic anaemia with chloramphenicol, idiosyncratic, unrelated to the dose, and often fatal, in about 1 in 20,000 to 40,000 patients exposed, even weeks or months after the course. Very rare cases have followed eye drops.
• Serious
  Dose-related marrow suppression with chloramphenicol: anaemia, and low white cells and platelets, as it blocks the mitochondrial ribosomes of the marrow's cells and their use of iron for heme. It is common at high levels and recovers when the drug is stopped. The blood count is checked about every two days during the course and the drug stopped at the first fall, though the counts don't warn of aplastic anaemia.
• Life-threatening
  The grey baby syndrome: in newborns, chloramphenicol builds up and causes vomiting, a swollen abdomen, grey skin, a low temperature and circulatory collapse, sometimes fatally.
• Serious
  Optic and peripheral neuritis with long courses of chloramphenicol.
• Life-threatening
  Severe skin reactions with clindamycin, rarely: Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS and acute generalised exanthematous pustulosis. Anaphylaxis is rare with both drugs.
• Serious
  Liver injury and acute kidney injury with clindamycin, rarely.

06Side effects

• Mild
  Diarrhoea, common with clindamycin, nausea and abdominal pain. Marked or lasting diarrhoea may be C. difficile (above).
• Mild
  Rash, a maculopapular rash, among the commoner effects of clindamycin.
• Mild
  A metallic taste with clindamycin into a vein, and stinging with chloramphenicol eye drops.

07Contraindications

• Contraindicated
  An allergy to clindamycin or lincomycin, which cross-react.
• Contraindicated
  A past allergic or toxic reaction to chloramphenicol, in its licence, marrow suppression among them.
• Contraindicated
  A personal or family history of a blood disorder, aplastic anaemia among them, for chloramphenicol eye drops too.
• Avoid
  Chloramphenicol by mouth or into a vein for a minor infection or as prophylaxis, or when a safer antibiotic would work. Its licence keeps it for serious infections where less toxic drugs fail or can't be used.
• Avoid
  Chloramphenicol with other drugs that suppress the marrow, which its licence says to avoid.
• Avoid
  Clindamycin after C. difficile colitis, or in inflammatory bowel disease, if another antibiotic will do. Its licence is less strict, asking for caution in gut disease, colitis above all.
• Avoid
  Clindamycin with erythromycin, which competes with it on the ribosome; they are not given together.
• Caution
  Chloramphenicol in newborns, whose doses are cut and levels measured.
• Caution
  Chloramphenicol with phenytoin, warfarin or a sulfonylurea, whose levels it raises, so their doses may need cutting.
• Caution
  Clindamycin with warfarin, whose effect it can raise, so the INR is checked more often, or with rifampicin, which speeds its breakdown.
• Caution
  Clindamycin with neuromuscular blockers, or in myasthenia gravis, as it can deepen neuromuscular blockade.
• Caution
  Clindamycin into a vein, only diluted and infused, never as a bolus, which has caused low blood pressure and cardiac arrest.
• Caution
  Severe liver disease. Chloramphenicol builds up, so its dose is cut and its levels measured; clindamycin is cleared more slowly too, but its dose isn't usually changed.

08Pregnancy and lactation

• Compatible
  Clindamycin in pregnancy. It crosses the placenta. Most human studies have not found more birth defects (one large cohort found a small rise, not confirmed), animal studies found harm only at doses toxic to the mother, and it is used for bacterial vaginosis, malaria with quinine, and other infections in pregnancy. Its licence asks that it be used only if clearly needed.
• Compatible
  Chloramphenicol eye or ear drops in pregnancy, which leave too little in the blood to harm the baby; the eye drops are the usual first choice for an eye infection in pregnancy. Their licences don't recommend them in pregnancy, as safety hasn't been established.
• Avoid
  Chloramphenicol by mouth or into a vein in pregnancy. It is given for a serious infection when the benefit is likely to outweigh the risk, but there are few data, it can harm the mother's marrow, and near delivery it can reach the newborn, who can't clear it. Its licence contraindicates it in pregnancy.
• Compatible
  Clindamycin in breastfeeding. Small amounts pass into milk. The baby may get diarrhoea or a rash, and rarely blood in the stool, which is worth watching for. Its licence says it is no reason to stop breastfeeding, though another drug may be preferred.
• Caution
  Chloramphenicol eye or ear drops in breastfeeding. Very little reaches the milk, and they are probably compatible, with the baby watched for poor feeding, vomiting or unusual bruising. In the UK fusidic acid or gentamicin drops are preferred where they will do, and the drops are ruled out if the mother or her family has had a blood disorder. Their licences don't recommend them in breastfeeding.
• Avoid
  Chloramphenicol by mouth or into a vein in breastfeeding, because it passes into milk and could suppress the baby's marrow; another antibiotic is used, or breastfeeding is paused. Its licence contraindicates it in breastfeeding.