Macrolides - Antimicrobials

Macrolides

Macrolide antibiotics possess a many-membered lactone ring to which are attached one or more deoxy sugars.

Examples

Azithromycin, clarithromycin, dirithromycin, erythromycin, miocamycin, roxithromycin and troleandomycin.

Uses

Erythromycin was first isolated in 1952 from Streptomyceserythreus. The other members of the group are semisyntheticderivatives.

The macrolides are effective mainly against aerobic gram-positive cocci and bacilli, and to a lesser extent, against gram-negative organisms such as H. Influenzae, N. meningitidis, N.gonorrhoeae, Campylobacter species, Pateurella multocida, Mycoplasma pneumoniae, and Legionella pneumophila.The macrolide antibiotics act as bacteriostatic agents at low concentrations, and (less frequently) bactericidal agents at high concentrations.

Toxicokinetics

Though erythromycin base is adequately absorbed on inges-tion, it is inactivated by gastric acids, and so it is usually administered as enteric-coated tablets or as capsules containing enteric-coated pellets. Esters of erythromycin (estolate, stearate, and ethyl succinate) improve acid stability and facilitate better absorption. Semi-synthetic macrolides are rapidly absorbed from the GI tract, though food can considerably delay absorp-tion.

The macrolides are widely distributed in all tissues and body fluids (except brain and CSF), and can also cross the placental barrier easily. Excretion is renal as well non-renal.

Mode of Action

Macrolides are bacteriostatic agents which inhibit protein synthesis by binding reversibly to 50s ribosomal subunits of sensitive micro-organisms.

Adverse and Clinical (Toxic) Features

·              In general, macrolide antibiotics are considered to have fewer, less severe toxic effects than most other antimicro- bial agents.

o     Allergic reactions are uncommon (fever, eosinophilia,and skin eruptions).

o     The most striking side-effect, especially associated with erytrhromycin estolate is cholestatic hepatitis, which is probably immune-mediated. Cholestasis is charac- terised by elevated liver enzymes, fever, abdominal pain, and jaundice. Patients without previous exposure to erythromycin generally develop symptoms after an average of 16 days of therapy. Patients who have received the drug previously may develop symptoms within less than 24 hours, and occasionally after a single dose. Discontinuation of the drug usually results in resolution of hepatotoxic effects.

o     Other effects include gastrointestinal irritation, ototox- icity, and thrombophlebitis (after IV administration). Candidal oesophagitis and gingival hyperplasia are uncommon adverse effects of treatment with various macrolides. Large doses of macrolides are also associ-ated with (reversible) high-frequency sensorineural hearing loss.

o     Rare instances of acute pancreatitis have been reported.

o     Exacerbation of myasthenia gravis may occur infre- quently following erythromycin administration.

o     Interstitial nephritis and glomerulonephritis have been reported with the administration of erythromycin, but are uncommon.

o     Rarely, erythromycin has been reported to cause cardiac arrhythmias (QT prolongation and torsades de pointes). In general, the risk of arrhythmias is increased when erythromycin is administered in combination with other drugs that prolong the QT interval.

o     Contact dermatitis, fixed drug eruptions, toxic pustulo- derma, and toxic epidermal necrolysis are uncommonside effects which may occur with macrolide use.

·              Acute oral overdoses of macrolide antibiotics are usually not life-threatening, and comprise mainly gastrointestinal manifestations. Seizures may occur. Treatment is the same as for penicillin overdose.

Drug Interactions

Macrolides (especially erythromycin) potentiate the effects of astemizole, carbamazepine, corticosteroids, cyclosporine, digoxin, ergot alkaloids, terfenadine, theophylline, triazolam, valproate, and warfarin, by interfering with P450-mediated metabolism of these drugs.

Treatment

·      Severe toxicity is unusual after ingestion; prehospital decon-tamination is generally not necessary. Discontinuation of the drug usually results in the resolution of the toxic effects.

·      Food, milk or an antacid may be administered for treatment of gastrointestinal distress.

·      CBC, electrolytes, and urinalysis are not generally needed unless the development of haematological disturbances (rare) or nephritis (rare) is suspected, or if the patient has experienced prolonged vomiting and diarrhoea.

·      Monitor ECG, vital signs, and fluid and electrolyte balances in massive overdoses.

·      Arrhythmias respond to magnesium sulphate, isoproterenol, phenytoin, or overdrive pacing.

·      Liver enzyme levels may aid in diagnosing or following a patient with evidence of cholestasis or hepatitis.