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Azithromycin is the first macrolide antibiotic belonging to the azalide group. Azithromycin is derived from erythromycin by adding a nitrogen atom into the lactone ring of erythromycin A. Azithromycin is sold under the brand names Zithromax and Sumamed, and is one of the world's best-selling antibiotics.

Since the 1970s, PLIVA's (Croatian pharmaceutical company, based in Zagreb, Croatia) research team, led by Dr Slobodan Dokic, had been working in the area of macrolide antibiotics1. In 1981, his team of researchers, Gabrijela Kobrehel, Zrinka Tamburasev and Gorjana Radobolja-Lazarevski, synthesised a novel antibiotic named azithromycin, the first member of a new class of macrolide antibiotics, termed azalides. Azithromycin dihydrate was obtained from the erythromycin molecule and demonstrated superior properties.

It was patented in 1981, and was later found by Pfizer's scientists while going through patent documents. In 1986 Pliva and Pfizer signed a licensing agreement which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva brought their azithromycin on the market in Central and Eastern Europe under the brand name of Sumamed in 1988, and Pfizer under the brand name Zithromax in 1991.

Because of its exceptional therapeutic properties, azithromycin revolutionised antibiotic treatment and became one of the most successful drugs worldwide. From its early trials, it proved to be an extremely efficient antibiotic with expanded and enhanced antibacterial activity (particularly against gram-negative pathogens), prolonged and higher tissue concentration and a low incidence of gastrointestinal side effects compared to other similar antibiotics.

Azithromycin is indicated for the treatment of the following infections due to susceptible strains of sensitive organisms:

• Upper respiratory tract infections: pharyngitis/tonsillitis, sinusitis, otitis media
• Lower respiratory tract infections: bronchitis, acute exacerbation of chronic bronchitis, community acquired pneumonia of mild severity.
• Sexually transmitted diseases: uncomplicated urethritis, uncomplicated cervicitis due to Neisseria gonorrhoeae or Chlamydia trachomatis.
• Chancroid (genital ulcer disease in men).
• Skin and soft tissue infections: erysipelas, impetigo, secondary pyoderma, erythema migrans.
• Mycobacterial Infections.

Off-label and investigational uses of Azithromycin include:

Infectious diseases:

• Pelvic inflammatory disease (PID)
  PID comprises a spectrum of inflammatory disorders of the upper female genital tract, including any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. Sexually transmitted organisms, Neisseria gonorrhoeae and Chlamydia trachomatis are the major pathogens causing PID. Azithromycin provides a short simple treatment option for PID 3.
• Infectious diarrhoea
  Infectious diarrhoea is the most common cause of diarrhoea worldwide. Azithromycin is a good choice for pregnant women and children, for whom fluoroquinolones are not approved, and for patients who cannot otherwise tolerate fluoroquinolones 4.
• Dental infections
  Azithromycin is given to people allergic to penicillins and those who have abscesses and other dental infections, especially those extending into the sinuses, gums and bone, and for whom other antibiotics have proved ineffective.
• Acne
  Acne vulgaris is a common inflammatory disorder of the skin. Azithromycin is a safe and effective alternative in the treatment of inflammatory acne with few side effects and good compliance, even in adolescents.
  In 2004, researchers studied azithromycin in patients with moderate to severe papulopustular acne vulgaris 6. The researchers found that 83% of patients showed at least a 60% improvement in only 4 weeks and the majority achieved 80% clearance in 12 weeks.
• Pertussis
  Azithromycin is as effective as and better tolerated than erythromycin for the treatment of pertussis7.
• Prostatitis
  Azithromycin is used in the treatment of chronic prostatitis caused by Chlamydia trachomatis and Neisseria gonorrhoeae.
• Syphilis
  Azithromycin has been successfully used as a multidose treatment in persons who have early syphilis8.
• Mediterranean spotted fever (Rickettsiosis)
  Mediterranean spotted fever, also known as boutonneuse fever, is transmitted by the dog tick Rhipicephalus sanguineus and has a characteristic rash and a distinct mark, a tache noire (black spot) at the site of the tick bite. Azithromycin is effective treatment in children and can be used as alternatives to doxycycline in adults9.
• Endocarditis
  Azithromycin is used for prophylaxis of bacterial endocarditis in persons who are allergic to penicillin and undergoing surgical or dental procedures10.

Non-infectious diseases:

• Atherosclerosis
  Azithromycin appears to reduce the risk of Chlamydia pneumoniae-induced atherosclerosis11.
• Cystic fibrosis
  According to the studies2, azithromycin significantly improves quality of life, reduces the number of respiratory exacerbations, and reduces the rate of decline in lung function in persons with cystic fibrosis.
  While the exact mechanisms are unknown, anti-inflammatory rather than antimicrobial properties of macrolides seem to be responsible for the beneficial effects.

Advantages:

• Excellent efficacy. Many scientific studies have shown that azithromycin is better or equally effective compared to other antibiotics.
• Low potential for drug interactions. Azithromycin, unlike the majority of macrolides, does not bind to cytochrome P-450 in the liver, resulting in low potential for drug to drug interaction.
• Low rate of side effects. Side effects with azithromycin are mild to moderate, mostly gastrointestinal.
• Sustained antimicrobial activity. Azithromycin reaches high and sustained tissue concentrations that results in sustained antimicrobial activity.
• Active against intracellular bacteria (Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Legionella spp.). Since azithromycin is a weak base, it easily penetrates the cell membrane and stays within the cell.
• Targeted activity at the site of infection. Because of the transport with white blood cells, azithromycin possesses a unique property - targeted activity at the site of infection. In infected tissues, azithromycin achieves high and sustained therapeutic concentrations that last five to seven days after the last dose.
• Suitable choice for empirical therapy. Since azithromycin has a good activity against the most common pathogens it is used as a choice for empirical therapy.
• Good compliance: short once daily dosing regimen. Azithromycin's short dosing regimen is convenient and improves patient compliance. For the majority of infections, azithromycin is administered once daily for three days. In the treatment of sexually transmitted diseases, azithromycin is administered as a single dose.
• Active against most respiratory tract infections. Betalactams lack activity against atypical pathogens. Among macrolides, azithromycin shows the best activity against H. influenzae.

Disadvantages:

• Food reduces azithromycin absorption rate. Azithromycin capsules should not be mixed with or taken with food, however tablets may be taken without regard to food.

Azithromycin acts by interfering with bacterial protein synthesis. Although this mechanism is considered bacteriostatic, concentrations several times higher than minimum inhibitory concentrations (MIC) contribute to the bactericidal activity of azithromycin.

Non-antibiotic properties: immunomodulating effect

Data indicate that macrolides may have immunomodulatory activities: in vitro and ex vivo studies clearly show that macrolides can influence cytokine production by several cell types; furthermore, macrolides can alter polymorphonuclear cell functions in vitro and ex vivo. Although immunomodulation may serve as one explanation for the beneficial effects of macrolides in patients with chronic pulmonary inflammation, the effect of low-dose macrolide therapy on biofilm-formation may form a second explanation for the positive effects of long-term low-dose macrolide therapy.

The half-life of Azithromycin is about 68 hours. So it takes about 16-17 days to clear out of the system.

Chlamydia trachomatis is the most common sexually transmitted infection worldwide, especially among adolescents and young adults. Chlamydia is a very guileful infection because many cases of infection are asymptomatic. Untreated infection can progress to persistent infection, which may initiate pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, and chlamydia-induced arthritis.

The importance of azithromycin comes from its highly favorable pharmacokinetic properties: acid stability, high tissue penetration, low serum levels and a very long half-life. Anti-chlamydial levels of the drug are readily achieved inside cells or tissues. Adequate intracellular levels may be sustained for several days because of the slow efflux from cells.

According to the CDC Guidelines azithromycin is a first-line treatment for chlamydial genital infections. Azithromycin is also recommended by the CDC for the treatment of pregnant women.

The treatment consists of a single 1 gram dose.

Recurrent Chlamydia
Relapsing or persistent chlamydia is a common problem, even though patients are often treated appropriately. Azithromycin may be particularly effective against persistent infection4.

• Azithromycin (Zithromax) versus other medications

• 1. SUMAMED - success story, from sumamed.com.hr
• 2. Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax. 2002 Mar;57(3):212-6.
• 3. Bevan CD, Ridgway GL, Rothermel CD. Efficacy and safety of azithromycin compared with two standard multidrug regimens for the treatment of acute pelvic inflammatory disease. J Int Med Res. 2003 Jan-Feb;31(1):45-54. PubMed
• 4. Reveneau N, Crane DD, Fischer E, Caldwell HD. Bactericidal activity of first-choice antibiotics against gamma interferon-induced persistent infection of human epithelial cells by Chlamydia trachomatis. Antimicrob Agents Chemother. 2005 May;49(5):1787-93.
• 5. Khan WA, Seas C, Dhar U, Salam MA, Bennish ML. Treatment of shigellosis. Ann Intern Med. 1997 May 1;126(9):697-703. PubMed
• 6. Kapadia N, Talib A. Acne treated successfully with azithromycin. Int J Dermatol. 2004 Oct;43(10):766-7. PubMed
• 7. Langley JM, Halperin SA, Boucher FD, Smith B; Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC). Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics. 2004 Jul;114(1):e96-101.
• 8.Gruber F, Kastelan M, Cabrijan L, Simonić E, Brajac I. Treatment of early syphilis with azithromycin. J Chemother. 2000 Jun;12(3):240-3.
• 9. Dzelalija B, Petrovec M, Avsic-Zupanc T, Strugar J, Milic' TA. Randomized trial of Zithromax in the prophylaxis of Mediterranean spotted fever. Acta Med Croatica. 2002;56(2):45-7. PubMed
• 10. Rouse MS, Steckelberg JM, Brandt CM, Patel R, Miro JM, Wilson WR. Efficacy of azithromycin or clarithromycin for prophylaxis of viridans group streptococcus experimental endocarditis. Antimicrob Agents Chemother. 1997 Aug;41(8):1673-6.
• 11. Bouwman JJ, Visseren FL, Bevers LM, van der Vlist WE, Bouter KP, Diepersloot RJ. Azithromycin reduces Chlamydia pneumoniae-induced attenuation of eNOS and cGMP production by endothelial cells. Eur J Clin Invest. 2005 Sep;35(9):573-82. PubMed

Published: March 31, 2008
Last updated: January 21, 2012