Macrolide Antibiotics

MACROLIDE ANTIBIOTICS

Structure

The macrolide antibiotics are those that consist of a large lactone ring to which sugars are attached. Antibiotics in this group include erythromycin (Ilotycin, E-mycin, Robimycin), clarithromycin (Biaxin), azithromycin (Zithromax), and oleandomycin (Matromycin). Erythro-mycin and its derivatives (clarithromycin, azithromycin) are the only macrolides in common use, although the acetylated derivative of oleandomycin (troleandomycin, TAO) is available for oral use.

Mechanism of Action

Macrolides bind to the 50S ribosomal subunit of bacte-ria but not to the 80S mammalian ribosome; this ac-counts for its selective toxicity. Binding to the ribosome occurs at a site near peptidyltransferase, with a resultant inhibition of translocation, peptide bond formation, and release of oligopeptidyl tRNA. However, unlike chlo-ramphenicol, the macrolides do not inhibit protein syn-thesis by intact mitochondria, and this suggests that the mitochondrial membrane is not permeable to erythro-mycin.

Antibacterial Spectrum

The macrolides are effective against a number of organ-isms, including Mycoplasma spp., H. influenzae, Strep-tococcus spp. (including S. pyogenes and S. pneumoniae), staphylococci, gonococci, Legionella pneumophila, and other Legionella spp. There has been increasing resist-ance of S. pneumoniae to macrolides worldwide. This is true especially if the strain is resistant to penicillin. This resistance includes not only erythromycin but also clar-ithromycin and azithromycin. Approximately 10 to 15% of S. pneumoniae in the United States show complete re-sistance to macrolides. Staphylococci resistant to erythro-mycin are resistant to all macrolides.The hemolytic strep-tococci also exhibit varying degrees of cross-resistance to the macrolides and to lincomycin and clindamycin, although the macrolides are chemically unrelated to the last two agents. There are only minor variations in the antibacterial spectrum of the newer macrolides. Clarithromycin is very active against H. influenzae, Legionella, and Mycobacterium avium-intracellulare, whereas azithromycin is superior against Branhamella, Neisseria, and H. influenzae but less active against my-cobacterial species. Clarithromycin and azithromycin have significant activity against Mycobacterium avium complex (MAC), and it is one of the drugs of choice in treating disseminated MAC. Both azithromycin and clar-ithromycin can be used prophylactically in HIV and AIDS patients to help prevent disseminated MAC.

Absorption, Distribution, Metabolism, and Excretion

The macrolides are absorbed from the intestinal tract, although the presence of food interferes with absorption and part of the dose is destroyed because of the relative acid lability of these antimicrobials. To minimize de-struction and enhance absorption, erythromycin is ad-ministered as a stearate or oleate salt or is enteric coated. Because stearate and estolate erythromycins are not acid labile, the administration of these formulations results in higher blood levels. The O-methyl substitution of erythromycin that results in clarithromycin also con-fers acid stability and better absorption with food.

The macrolides diffuse readily into tissues and cross placental membranes. CSF levels are about 20% of plasma levels, while biliary concentrations are about 10 times plasma levels. Although the serum levels of clar-ithromycin and azithromycin are low, these antibiotics concentrate in tissue and reach high levels.

Erythromycin and azithromycin are excreted prima-rily in active form in bile, with only low levels found in urine. Clarithromycin is metabolized to the biologically active 14-OH metabolite and is eliminated largely by the kidney. The half-life of erythromycin is approximately 1.4 hours, whereas the half-life of clarithromycin is 3 to 7 hours and that of azithromycin approaches 68 hours.

Clinical Uses

Although erythromycin is a well-established antibiotic, there are relatively few primary indications for its use. These indications include the treatment of Mycoplasma pneumoniae infections, eradication of Corynebacterium diphtheriae from pharyngeal carriers, the early preparox-ysmal stage of pertussis, chlamydial infections, and more recently, the treatment of Legionnaires’ disease, Campylobacter enteritis, and chlamydial conjunctivitis, and the prevention of secondary pneumonia in neonates.

Erythromycin is effective in the treatment and pre-vention of S. pyogenes and other streptococcal infec-tions, but not those caused by the more resistant fecal streptococci. Staphylococci are generally susceptible to erythromycin, so this antibiotic is a suitable alternative drug for the penicillin-hypersensitive individual. It is a second-line drug for the treatment of gonorrhea and syphilis. Although erythromycin is popular for the treat-ment of middle ear and sinus infections, including H. in-fluenzae, possible erythromycin-resistant S. pneumoniae is a concern.

The new macrolides have similar indications for use as erythromycin but with some additional areas of po-tential value. Clarithromycin has activity against Toxo-plasma gondii and Mycobacterium avium-intracellulare, and it has expanded coverage against untypable H. in-fluenzae strains that predominate in exacerbations of chronic bronchitis. Azithromycin has less coverage against these organisms, and because of its lower peak serum concentrations and prolonged protein binding, it partitions less well across bronchial membranes. The prolonged half-life and protein binding and the use of an abbreviated one-time dose of azithromycin appear to be extremely beneficial in the treatment of sexually transmitted diseases.

Adverse Effects

The incidence of side effects associated with erythro-mycin therapy is very low. Mild gastrointestinal upset with nausea, diarrhea, and abdominal pain are reported to occur more commonly when the propionate and es-tolate salts are used. Rashes are seen infrequently but may be a part of a general hypersensitivity reaction that includes fever and eosinophilia. Thrombophlebitis may follow intravenous administration, as may transient im-pairment of hearing.

Cholestatic hepatitis may occur when drug therapy lasts longer than 10 days or repeated courses are pre-scribed. The hepatitis is characterized by fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin, and elevated transaminase 1evels. Hepatitis has been associated with the estolate salt of erythromycin but not with other for-mulations. Although the hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can occur within hours in a patient who has had such a reaction in the past. The hepatitis is believed to be the result of both a hepatotoxic effect and a hypersensitivity reac-tion; this latter effect is reversible on withdrawal of the drug. Erythromycin and derivatives induce hepatic mi-crosomal enzymes and interfere with the actions of var-ious drugs, including theophylline and carbamazepine.