Macrolide antibiotics belong to the family of macrocyclic antibiotics and are a well-established class of antibacterial agents for both human and veterinary applications. They have been used for the treatment of various bacterial infections in both out-patient and in-patient settings for more than 40 years, and as a result of their very good safety profile, they are extensively prescribed to children. The term macrolide means large macrocyclic lactone and was first used by R. B. Woodward for the class of natural products produced by Strepto-myces species (129). Macrolide antibiotics are generally lipophilic and consist of a central highly substituted lactone ring (termed an aglycone) functionalized with various carbohydrate residues. This chapter covers antibacterial macrolides of clinical significance having aglycone of 12-16 atoms, with one or more sugars (or aminosugars) attached to the lactone core. The currently marketed macrolide antibiotics play a very important role in treating bacterial infections and have gained wide acceptance for the treatment of both upper and lower respiratory tract infections, as well as cutaneous infections. Because of the extensive medical use of this class of antibiotics,* the term macrolides is now generally synonymous with macrolide antibiotics in the medical-related scientific communities. A book on the chemistry, pharmacology, and clinical uses of approved macrolides was published in 1993 (130); this chapter therefore presents a brief summary of information on these three areas.
Naturally occurring macrolide antibiotics are grouped into three major groups of 12-, 14-, and 16-membered macrolides with the aglycone consisting of 12-, 14-, and 16-atom cyclic lactone rings, respectively. For example, erythromycin A (20) is a 14-membered macrolide (a 14-atom cyclic lactone ring) and possesses desosamine and cladinose glycosidically linked to C-5 and C-3, respectively.
In addition to natural macrolides, many semisynthetic macrolides have been made and developed for clinical use. A 15-membered macrolide, the azalide azithromycin (21), that incorporates an additional nitrogen atom in
the aglycone has been successfully synthesized and developed for human use.
Among the 14-membered naturally occurring macrolides, erythromycin A is by far the most useful and possesses excellent antibacterial activity against Gram-positive bacteria and mycoplasmas. Erythromycin was developed initially for the treatment of staphylococcal infections for patients allergic to penicillin; however, after more than 40 years of use, most of the staphylococci isolated in hospitals are erythromycin resistant. Erythromycin and its semisynthetic derivatives are now used to treat lower and upper respiratory infections as well as skin and soft tissue infections, and are administered either orally or parenterally. Some of the disadvantages of erythromycin A are low bioavailability, a narrow spectrum of activity, and high gastrointestinal side effects.
These liabilities have prompted research laboratories throughout the world to search for better semisynthetic erythromycin derivatives. These derivatives possess improved therapeutic properties such as enhanced antibacterial activity and/or broadened spectrum (including Gram-negative bacteria such as Haemophilus influenzae), or improved pharmacokinetic properties as well as reducing gastrointestinal side effects.
Several semisynthetic derivatives of erythromycin A, including clarithromycin (22), di-rithromycin (23), flurithromycin (24), and roxithromycin (25), have been successfully developed and are currently in clinical use. These semisynthetic newer macrolides are used for the following indications: community acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, acute bacterial sinusitis, tonsillitis/pharyngitis, otitis media, skin and soft-tissue infections, and ophthalmologic infections. They possess good antibacterial activity against the common respiratory pathogens such as Streptococcus pyogenes, Streptococcus pneumoniae, H. influenzae, and M catarrhalis as well as atypical bacteria such as L. pneumophila, M. pneumoniae, and C. pneumoniae. In addition to these derivatives of erythromycin A, an oleandomycin (26) analog called triacetyloleandomycin (27) has also been developed for limited clinical use.
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