Macrolides

Erythromycin

Erythromycin (t1/, 2-4 h) binds to bacterial ribosomes and interferes with protein synthesis; it is bacteriostatic and exhibits time-dependent bacterial killing (see p. 203). It is effective against Grampositive organisms because these accumulate the drug more efficiently than Gram-negative organisms, and its antibacterial spectrum is similar, but not identical, to that of penicillin.

Absorption after oral administration is best with erythromycin estolate, even if there is food in the stomach. Hydrolysis of the estolate in the body releases the active erythromycin which diffuses readily into most tissues; the t/2 is dose-dependent and elimination is almost exclusively in the bile and faeces.

Uses. Erythromycin is the drug of choice for:

• Mycoplasma pneumoniae in children, although in adults a tetracycline may be preferred

• Legionella spp. (including Legionnaires' disease), with or without rifampicin

• Diphtheria (including carriers), pertussis and for some chlamydial infections.

In gastroenteritis caused by Campylobacter jejuni, erythromycin is effective in eliminating the organism from the faeces, although it does not reduce the duration of the symptoms unless given very early in the course of the illness.

Erythromycin is an effective alternative choice for penicillin-allergic patients infected with Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae or Treponema pallidum. Acne; see page 313.

Dose is 250 mg 6-hourly or twice this in serious infection and four times this for Legionnaires' disease. The ethylsuccinate and stearate esters of erythromycin produce lower plasma concentrations of the active drug than does the same dose of the estolate.

Adverse reactions. Erythromycin is remarkably nontoxic, but the estolate can cause cholestatic hepatitis with abdominal pain and fever which may be confused with viral hepatitis, acute cholecystitis or acute pancreatitis. This is probably an allergy, and recovery is usual but the estolate should not be given to a patient with liver disease. Other allergies are rare. Gastrointestinal disturbances occur frequently (up to 28%), particularly diarrhoea and nausea, but, with the antibacterial spectrum being narrower than with tetracycline, opportunistic infection is less troublesome.

Interactions. Erythromycin and the other macro-lides are enzyme inhibitors and interfere with the metabolic inactivation of some drugs, e.g. warfarin, carbamazepine, theophylline, disopyramide, increasing their effects. Reduced inactivation of terfena-dine may lead to serious cardiac arrhythmias, and of ergot alkaloids may cause ergotism.

Clarithromycin acts like erythromycin and has a similar spectrum of antibacterial activity, i.e. mainly against Gram-positive organisms, although it is usefully more active against Haemophilus influenzae. The usual dose is 250 mg 12-hourly or twice that for serious infections. It is rapidly and completely absorbed from the gastrointestinal tract, 60% of a dose is inactivated by metabolism which is saturable (note that the tV2 increases with dose: 3 h after 250 mg, 9 h after 1200 mg) and the remainder is eliminated in the urine. Clarithromycin is used for respiratory tract infections including atypical pneumonias and soft tissue infections. It is concentrated intracellularly, achieving concentrations which allow effective therapy in combination for mycobacterial infections such as Mycobacterium avium-intracellulare in patients with AIDS and with pyrimethamine for some Toxoplasma infections (see p. 275). It causes fewer gastrointestinal tract adverse effects (7%) than erythromycin. Interactions: see erythromycin (above).

Azithromycin is usefully active against a number of important Gram-negative organisms including Haemophilus influenzae and Neisseria gonorrhoeae, and also against Chlamydiae, but is a little less effective than erythromycin against Gram-positive organisms.

Azithromycin achieves high concentrations in tissues relative to those in plasma. It remains largely unmetabolised and is excreted in the bile and faeces (t'/2 50h). Azithromycin is used to treat respiratory tract and soft tissue infections, and sexually transmitted diseases, especially genital Chlamydia infections. Gastrointestinal effects (9%) are less than with erythromycin but diarrhoea, nausea and abdominal pain occur. In view of its high hepatic excretion use in patients with liver disease should be avoided. Interactions: see erythromycin (above).

Clindamycin, structurally a lincosamide rather than a macrolide, binds to bacterial ribosomes to inhibit protein synthesis. Its antibacterial spectrum is similar to that of erythromycin (with which there is partial cross-resistance) and benzylpenicillin (but includes penicillin-resistant staphylococci); it has the useful additional property of efficacy against anaerobes such as Bacteroides fragilis which are involved in gut-associated sepsis. Clindamycin is well absorbed from the gut and distributes to most body tissues including bone. The drug is metabolised by the liver and enterohepatic cycling occurs with bile concentrations 2-5 times those of plasma (t1/, 3h). Significant excretion of metabolites occurs via the gut.

Clindamycin is used for staphylococcal bone and joint infections, dental infections and serious intraabdominal sepsis (in the latter case, it is usually combined with an agent active against Gramnegative pathogens such as gentamicin). It is also a second choice in combination for some Toxoplasma infections (see p. 275). Topical preparations are used for therapy of severe acne and non-sexually transmitted infection of the genital tract in women. It is the antibiotic of choice for streptococcal necrotising fasciitis and other serious invasive Streptococcus pyogenes infections, although surgical resection of affected tissue plays a prime role.

The most serious adverse effect is antibiotic-associated (pseudomembranous) colitis (see p. 210) usually due to opportunistic infection of the bowel with Clostridium difficile which produces an entero-toxin; clindamycin should be stopped if any diarrhoea occurs.

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