Macrolides

MACROLIDES

The macrolide antibiotics are large molecules comprising 12–16-membered lactone rings linked through glycosidic bonds with amino sugars. Erythromycin was the first member of the group to be discovered in 1952 and it is still an important antibiotic today. It was quickly followed 2 years later by spiramycin and oleandomycin but, although still available in certain countries, these last two are now little used. Erythromycin suffers from several disadvantages: its antimicrobial spectrum is largely restricted to Gram-positive species, it has poor acid stability so its absorption is erratic, it commonly exhibits gastrointestinal side effects and bacteria acquire resistance to it relatively easily. These shortcomings prompted the search for new macrolides, and several semisynthetic derivatives were forthcoming: roxithromycin was marketed in 1987, clarithromycin and azithromycin in 1991 and the most recent, telithromycin, in 2001. Erythromycin (Figure 11.8) and roxithromycin are chemically similar in possessing a 14-membered ring structure. A distinction is sometimes drawn between them and both azithromycin which, strictly speaking, is an azalide (a 15-membered ring containing an additional nitrogen atom) and telithromycin which is a ketolide (a 14-membered ring with an additional keto group). The term macrolide, however, is commonly used to describe all five antibiotics, and that terminology will be used here.

The macrolides are active against most Gram-positive bacteria, Neisseria and H. influenzae but, with the excep tion of azithromycin, not against the Enterobacteriaceae. Because their antibacterial spectrum is similar to those of the early penicillins, the macrolides were, and still are, considered alternatives for patients with penicillin allergy. They are commonly used for respiratory, skin and soft tissue infections, but one of the factors that stimulated the development of the more recent macrolides was their activity against emerging pathogens like species of Legionella, Campylobacter, Helicobacter and Chlamydia, as well as some mycoplasmas and rickettsias and the Mycobacterium avium complex to which AIDS/HIV patients are susceptible. The semisynthetic macrolides do not afford a significant advantage over erythromycin in terms of their activity against staphylococci, streptococci and enterococci, but they represent an advantage in several other respects: they are generally more active against the other organisms mentioned above; they exhibit better stability and pharmacokinetics, thus permitting less frequent dosage and better tissue penetration; they generally have fewer side effects; and, particularly in the case of telithromycin and other ketolides, they may be active against some strains that have acquired resistance to erythromycin, and they are, themselves, less vulnerable to resistance development.

The macrolides all act by inhibiting protein synthesis in bacteria and they are regarded as bacteristatic drugs, although bactericidal activity may be achieved at high concentrations. The antimicrobial activity of erythromycin is pH-dependent, increasing with pH up to about 8.5, and the same effect occurs to varying degrees with other members of the group. The macrolides are extremely bitter and their tablets are often coated, both to disguise the taste and to protect the antibiotic from stomach acid. Erythromycin exhibits particularly poor acid stability and erratic oral absorption, and a variety of esters have been used to minimize these problems which, although present, are much less evident in the semisynthetic molecules.

All the macrolides are orally active and they are concentrated intracellularly, particularly into neutrophils by which they are transported to infection sites. The longer elimination half-lives of the newer drugs permit less frequent dosing than that required for erythromycin. The group as a whole are regarded as relatively safe antibiotics which do not exhibit severe adverse reactions, although gastrointestinal disturbances (nausea, vomiting, abdominal pain and, infrequently, diarrhoea) are relatively common with erythromycin and much reduced or absent in the others. These and other characteristics are summarized in Table 11.4.