Azalide antibiotics

Azithromycin is an azalide antibiotic, a sub-class of the macrolides. Azithromycin differs chemically from erythromycin in that a methyl substituted nitrogen atom is incorporated into the lactone ring. 

Amacher DE, Schomaker SJ, Retsema JA. Comparison of the effects of the new azalide antibiotic, azithromycin, and erythromycin estolate on rat liver cytochrome P-450. Antimicrob Agents Chemother 1991 35(6) 1186-90. 

Azithromycin, an azalide antibiotic and derivative of erythromycin, is a safe and effective alternate treatment of moderate to severe inflammatory acne. With a half-life of 68 hours, it may be intermittently dosed three times a week. One study using pulse therapy, 500 mg daily for 3 to 4 consecutive days every week for 4 weeks, demonstrated efficacy similar to other systemic antibacterial agents. Adherence is high with this regimen, and phototoxicity and resistance have not been reported. ... 

The comorbid conditions that can affect therapy and outcomes in patients with CAP include diabetes mellitus, COPD, congestive heart failure, and renal failure.27,28 If the patient has not received antibiotics in the past 3 months, then clarithromycin or azithromycin is the recommended first-line therapy by the IDSA. If the patient has received antibiotics in the last 3 months, then the IDSA recommends using either a respiratory fluoroquinolone alone or a combination of an oral P-lactam and an advanced macrolide/azalide (e.g., clarithromycin/azithromydn). The ATS recommends combination therapy or monotherapy with a respiratory fluoroquinolone for all patients with comorbidities. The p-lactam agents recommended include high-dose amoxicillin, high-dose amoxicillin-clavulanate, cefpodoxime, cefprozil, and cefuroxime. 

Several structural modifications of the C-9 ketone of erythromycin have been explored oximes and hydrazones are less prone to intramolecular cydization, but they often have less antibiotic activity than erythromycin (140). Synthesis of more complex oxime derivatives resulted in the development of roxithromycin, the 9-[0-(2-methoxyethoxy)methyl]oxime (33) (141). Reduction of the oximes and hydrazones produced 9(S)-erythromycylamine (34) as the principal product, with minor amounts of the 9(R)-isomer (140) however, clinical studies showed that 9(5)-erythromycyclamine and its N-benzylidene derivative were poody absorbed in humans (142). Evaluation of more complex oxazine derivatives of erythromycylamine led to dirithromycin, the 2-(2-methoxyethoxy)ethylidene oxazine derivative (35) (143). A third route to modification of the ketone utilized a Beckmann rearrangement of the 9-oxime to expand the 14-membered ring to a 15-membered intermediate, which was subsequently reduced and AT-methylated to yield azithromycin (36) (144,145). The term azalide was proposed to denote these 15-membered azalactones (10,145). 

Azithromycin, an azalide macrolide antibiotic (500 mg p.o. as a single dose on day 1, followed by 250 mg daily on days 2 to 5 total accumulation dose is 1.5 g), is indicated in the treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease caused by Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, or Streptococcus pneumoniae mild community-acquired pneumonia caused by H. influenzae or S. pneumoniae uncomplicated skin and skin-structure infections caused by Staphylococcus aureus, Streptococcus pyogenes, or S. agalactiae second-line therapy of pharyngitis or tonsillitis caused by S. pyogenes and in nongonococcal urethritis or cervicitis caused by Chlamydia trachomatis. 

A study on the macrolide antibiotic Idjaniniycin, whidi contains the tetrasaccharide residue 41, by antr. spectrosot uid HSEA fi)rce fidd calculations on the caibol drate nKxety, showed that the a-(1 3)4inlred d oxose residues are severdy restricted in their confi>rniationai fieedom. The predominant solution conformation of the synthetic intermediates, such as macrocyde 42, of IS-membered azalides have been established by similar tedmiques. Molecular dynamics studies on calidiean ns are r rred to in Chapto 19. 

Erythromycin, from the actinomycete Saccharo-polyspora (formerly Streptomyces) erythraea, is the first member of this family of antibiotics to be marketed and successfully used clinically to treat infections in humans. It has an antimicrobial spectrum at least as wide as the penicillins, and interestingly, from our perspective, it is often used as a replacement for patients allergic to that group of drags. Besides erythromycin, other members of the macrolide family of antibiotics that are clinically useful include azithromycin, clarithromycin, dirithromycin, roxithromycin, telithromycin (these six are approved by the FDA), oleandomycin, and spiramycin. Clarithromycin, dirithromycin, and roxithromycin and the azalide azithromycin are more recent members of the group and can be regarded as newer generation macrolide antibiotics. 

Fig. 6.1 Structure of the macrolide antibiotic erythromycin (a) which contains a 14-membeied lactone ring. The azalide, azithromycin (b), derived from erythromycin, has an iV-methyl group incorporated into the lactone ring, making it a 15-membered ring (compare highlighted sections)...

---