Macrolides

5.3.2.1 Historical Development Macrolides are a group of antibiotics characterized by a large lactonic structure of 12, 14, or 16 atoms. The lactone ring has hydroxyl, alkyl, and ketone groups in various positions. In the 16-membered ring macrolides, an aldehydic group can also be present. Sometimes two of three hydroxyl groups are substituted by sugars, which can be neutral (6-deoxy-hexoses), bound through a a-glycosidic linkage, or basic (3-amino-sugars) bound through a j3-glyco-sidic linkage.

The first derivative introduced in therapy was erythromycin, which was isolated in 1952 from the fermentation broths of Streptomyces erythreus and followed by other natural deriv-

atives, such as spiramycin and oleandomycin, produced by other Streptomyces species. For some decades no other derivative was added to this antibiotic family until the 1980s, when josamycin and myocamycin, a semi-synthetic product, entered clinical use. Since then, new semi-synthetic derivatives have become available, namely roxithromycin, dirithromycin, flurithromycin, clarithromycin, and azithromycin. They belong to the 14-membered ring derivatives except the last one, which has a ring with an N-methyl group betweenC9 and CIO; for this reason, the name "azalides" has been proposed for azithromycin and other 15-membered ring macrolides (444).

Macrolides are usually administered by oral route, but because of their physico-chemical properties, they are poorly and erratically absorbed. Passage through the stomach can result in degradation and loss of activity. To obviate to this inconvenience, different salts and esters as well as adequate pharmaceutical formulations have been prepared (445). Once absorbed, they diffuse well in tissues and penetrate cells, so that they can be active in intracellular infections (446).They are metabolized in liver to a different extent according to derivatives, and because of their inducing activity on cytochrome P-450, they can interfere in the activity of other drugs metabolized by the same enzyme such as teophylline, antipyrine, and methylprednisolone (447). Macrolides are eliminated mainly by gastrointestinal route.

Among side effects, gastrointestinal disturbances prevail, and some derivatives show a certain degree of hepatotoxicity. However they are considered to be among the best-tolerated antibiotics (448).

5.3.2.1.1 Antimycobacterial Activity. The general spectrum of activity of macrolides in-eludes Gram-positive cocci, some Gram-negative species, and intracellular pathogens (449).

The most recent macrolide derivatives show better pharmacokinetic characteristics, particularly longer half-life, and higher tissue and intracellular concentration than old derivatives. In addition, they show better activity against some Gram-negative species, such as H. influenzae, and in addition, clarithro-mycin and azithromycin have some action against mycobacteria (449).

It was known that erythromycin could be active in infections caused by rapidly growing mycobacteria, M. fortuitum and M. chelonae, and probably also in M. smegmatis infection. New macrolides (clarithromycin, azithromy-and roxithromycin) have a similar or higher activity (416,450).

At present, the interest is focused on determining which derivatives can have some clinically exploitable activity against MAC and M.

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