Azithromycin Drug Use - Essay Example

? Azithromycin Drug - Azithromycin Drug Introduction: Discovery of microscope revealed a whole new world of small notorious pathogens, invisible to naked eye and responsible for most of the human diseases. With the advent of technology, much was revealed about these microbial organisms and efforts were made to combat their virulence properties. But it was Fleming’s accidental discovery of Penicillin that initiated and revolutionized the development of potent antibiotic drugs. Since then many different drugs have been discovered and modified in an attempt to aid human health. A Brief History: Azithromycin is a relatively newer antibiotic and is a macrolide derivative (Ballow & Amsden 1253). Most of the drugs are designed based on a lead compound which remains constant but its structure is modified a little to produce various classes of more potent drugs. In the case of azithromycin and related drugs, the common skeletal structure is macrolide. The prototype drug from the macrolide group is erythromycin. It was first isolated in 1952, from the culture broth of Saccharopolyspora erythrae, a soil bacterium, as a secondary metabolite. It has a complex structure with 3 major components. The core is the 14 member lactone ring with a neutral sugar and amino group attached to it (Scho?Nfeld & Kirst, 1). Azithromycin is a 15 member macrolide drug and has a very similar molecular structure as erythromycin. The only difference between two drugs is the substitution of methyl group with nitrogen on a 15 member macrolide ring (James 215). Moreover, azithromycin is the first among macrolide drugs to have nitrogen on the lactone ring so it is also considered as the first ‘azalide’ antibiotic, a new class of antimicrobials. (Ballow & Amsden 1253). Following figure summarizes the semi synthetic derivatives of erythromycin A. Source: (Scho?Nfeld & Kirst 5). Synthesis: Interestingly, azithromycin is the only 15-membered macrolide derived drug in the market with nitrogen present on the macrocyclic ring. As mentioned earlier, its structure is very similar to erythromycin so the starting compound used for its synthesis is erythromycin oxime. Development of erythromycin oxime was itself a breakthrough achievement and initial trials showed that erythromycin oxime had same antimicrobial activity on gram positive microbes as erythromycin with some promising additional effect on gram negative bacteria. In subsequent experiments, with catalytic reduction oxime was transformed into an amine that also showed similar properties. Investigations were carried to produce various substituted derivatives of these two compounds. The main driving ideology behind was to combine the properties of both sulfonamides and erythromycin compounds. Therefore, sulfonyl derivatives of oximes were produced with subsequent transformation into amides. This led to the formation of erythromycin-6,9-imino-ether. This product, however, had no antimicrobial activity so the process of its derivation was further continued and catalytic dehydrgoenation reaction produced 15-membered cyclic amine. This compound showed promising gram positive and negative activity and it was further derived until the best activity was achieved. This final new product 9-dihydo-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin was named as ‘azithromycin’ (Scho?Nfeld & Kirst 74-76). Spectrum: Azithromycin is an effective drug for all the gram positive bacteria that are covered by erythromycin. Surveys were conducted in United States to determine the effectiveness of azithmromycin against the erythromycin susceptible gram positive pathogens. The susceptibility rates for both these drugs were virtually identical against the most common pathogens; streptococcus pneumonia, S. pyogenes, S. agalactiae and methicilin susceptible staph aureus. Moreover, azithromycin has shown additional antimicrobial activity against clinically important gram negative organisms such as haemophilis influenza, mycoplasma pneumoniae and moraxella catarrhalis. Syphilis: Syphilis is sexually transmitted disease caused by a spirochete called ‘Treponema Pallidum’. The disease has four stages named primary, secondary, latent and tertiary. Tertiary stage is feared because it involves nervous system and has a high mortality rate. Emphasis is given on treating the patients as early as possible when the cure is easy and simple. Studies have shown that azithromycin is effective for the treatment of primary and secondary syphilis as it has antitreponemal activity. This activity was first observed in vitro in rabbit model but further studies have supported these findings (Bowden et al 196-197). Occular Toxoplasmosis: Toxoplasmosis is a parasitic infection with multiorgan involvement. Occular toxoplasmosis is a serious condition if untreated as it results in tragic loss of eyesight. Traditional management regimes consisted of pyrimethamine, clindamycin and the sulphonamides. Although, these drugs helped by inhibiting the proliferation of parasites during the active stage of retinitis they were not effective against the tissue cysts. With the increase in the incidence rates of AIDS worldwide, frequency of severe toxoplasmosis was on the rise and prompted for the search of an alternative solution. Various studies were conducted to determine the effectiveness of azithromycin that showed promising results. One of the studies demonstrated that azithromycin is an effective alternative for patients of ocular toxoplasmosis who cannot tolerate standard therapy (Rothova et al 1306-1307). Trachoma: Repeated ocular infection with Chlamydia trochomatis leads to Trachoma (Kuper et al 566). Traditionally, these infections were treated with antichlamydial drugs such as tetracycline. But this practice was associated with certain adverse effects. Firstly, tetracycline cannot be given to children below 12 years of age due to its effect on the growing teeth. Secondly, tetracycline eye ointments were unpleasant to apply that lead to decrease compliance in patients. With the advent of azithromycin, studies were carried out to determine its affectivity in treating trachoma. Fortunately, it showed very encouraging results as a single dose treatment was proved sufficient for the treatment of trachoma patients (Solomon & Burton 54), (West 55). Other Sexually Transmitted Diseases: Chlamydia and N. gonorrhoeae infection are the two most common STDs. It was observed that these patients are also likely to be suffering from syphilis. Therefore, a single dose azithromycin treatment was beneficial not only in eradicating the Chlamydia and Gonorrhoeae infections but also reduced the transmission of syphilis. (Omura 371). Pelvic Inflammatory Disease: PID is most commonly associated with STD causing pathogens such as Chlamydia and gonorrhoeae. Therefore, azitromycin has proven effective in treating patients with PID (Omura 371). Chancroid: It is an infectious disease caused by haemophilus ducreyi. Standard regime for the treatment of this infection includes 7 days of erythromycin or a single dose IM ceftriaxone. Studies have shown that a single dose oral azithrmocyin is equally effective in treating this disease. . (Omura 371). Respiratory Tract Infection: Azithrmycin is now widely used an alternative for beta lactam drugs, such as penicillin, in the treatment of both upper and lower respiratory tract infections. Various studies have compared its effectiveness with other antibiotic drugs for the treatment of LRTI. Not only had it proved to be equally effective but also more potent as compared to other antibiotics. . (Omura 372). Mechanism of Action: Azithormycin has similar mechanism of action as other macrolide derived drugs. Its antimicrobial activity is due to the ability of inhibiting bacterial protein synthesis. Ribosome is an important organelle required for the translation of messenger RNA and formation of protein molecule. Bacterial ribosomes have two separate components called 50S and 30S subunits. Azithromycin and similar drugs inhibit the 50S subunit of ribosome, strangling their ability of protein synthesis. (James 215). The effect cause by the drug on the human body is called pharmacodynamics and body’s response to the drug is called pharmacokinteics. Azithromycin has a unique cellular kinetics that distinguishes it from other similar drugs such as erythromycin. It has an ability to penetrate into tissues and achieve higher intracellular concentration. As a result it has low serum concentration. Azithromycin has relatively more rapid absorption rates and from serum it is immediately distributed in tissues. Bioavailability of 37% is also superior to erythromycin. Initial studies demonstrated higher acid stability and first pass metabolism for azithromycin resulting in higher bioavailability. Elimination half life is about 36-40h, almost 10 folds better than other macrolides (James 216). Azithromycin higher potency and unique cellular kinetics can be explained by exploring various factors. Firstly, due to its higher cellular penetrating ability, phagocytes get loaded up with the drug. These phagocytes act as carriers and transport drug at the site of infection where it is required the most (Amrol 9). Review of various studies has revealed that polymorphonuclear leukocytes (PMLs) uptake of azithromycin is about 10 folds greater as compared to erythromycin. Not only the uptake rate is superior, relatively, drug remains inside for a longer duration. All these attributes sum up and is reflected in the dosage schedule of azithromycin. A single 1-g dose is sufficient for treating most of the uncomplicated infectious diseases under the covered spectrum including cervicitis and urethritis. For other diseases, dose requirement and duration is significantly less as compared to other macrolides (Amrol 9) Drug Formulation and Delivery: Azithromycin is available in various forms to be used according to the circumstances. In adult patients, capsular formulation is most commonly used. Powder form of azithromycin is provided for pediatric patients that can be used to form oral suspension. One of the advantages of azithromcyin over other macrolide is its acid stable property. This property prevents the breakdown of drug in the stomach and more is available for absorption. Presence of food interferes with the absorption rate of azithromycin. This effect is more pronounced with capsular formulation and presence of food may even increase the rate of absorption if taken as oral suspension. However, the extent of absorption and bioavailability is not affected. 1 gram single dose capsular formulation of azithromycin is used frequently to treat various infectious diseases. One of the problems with such formulation is the gastrointestinal disturbances due to rapid absorption of this relatively high dose (Ericsson et al 249). To overcome this disadvantage, pharmaceutical companies came up with extended release formulations. In this formulation, drug was packed in sustained release microspheres which contain small pores (200 µm). The drug is slowly released from these pores over time preventing a rapid concentration build up in tissues and prolonging the half life (King & Brucker 267). Moreover, the drug is released in the distal part of GI tract, decreasing the GI side effects and allowing a larger dose to be administered in a single dose (Amrol 9) Side Effects: Azithromycin is a relatively safer drug with mild to moderate side effects. The most common side effects associated with azithromycin are related to gastrointestinal tract (Bartlett & Jaanus 192). These effects are more pronounced when the drug is administered as a 1 gram single dose. When compared with adults, no additional side effects were seen in children. Diarrhea was the most common symptom of gastrointestinal disturbance with studies showing incidence rate of about 11-12% (Amrol 10-11). Other side effects of azithromycin include nausea, vomiting and vaginitis. To counter these side effects, extended release formulations have been developed which showed significant reduction in GI symptoms and a far superior bioavailability. In rare cases, where immediate release formulations were used, side effects such as hearing loss, photosensitivity, angioedema and cholestatic jaundice were also reported. (Amrol 11). Erythromycin and other related macrolides were known for their interaction with liver enzyme, cytochrome P450. Various drug interactions were reported with the use of these macrolides. Drug interaction with Theophylline and carbamazepine were clinically important. Fortunately, azithromycin does not interact with cytochrome P450 enzyme and studies have demonstrated no drug interactions with Theophylline or carbamazepine. Summary: Azithromycin is a relatively newer macrolide derived antibiotic. Because of the unique addition of nitrogen on the major ring, it is also considered as the first azalide drug. Azithromycin has many major advantages over other structurally similar drugs. It covers a broad spectrum of both gram positive and gram negative bacteria. Its mechanism of action is similar to other macrolides as it also disrupts bacterial protein synthesis by inhibiting the 50S subunit of ribosome. Unlike other macrolides, it can be used as a single dose drug therapy for treating various medical conditions. The side effects of this drug are very limited and with the advent of extended release formulation side effects are further reduced with significant increase in potency. Reference: AMROL D. (2007). Single-dose azithromycin microsphere formulation: a novel delivery system for antibiotics. International Journal of Nanomedicine. 2, 9-12. BALLOW CH, & AMSDEN GW. (1992). Azithromycin: the first azalide antibiotic. The Annals of Pharmacotherapy. 26, 1253-61. BARTLETT, J. D., & JAANUS, S. D. (2008). Clinical ocular pharmacology. Saint Louis, Butterworth Heinemann - Elsevier. BOWDEN, F J, FARMER, B, BULLEN, J, CHAMBERLAIN, V, & BASTIAN, I. (n.d.). Azithromycin and syphilis. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1195500. ERICSSON, C. D., DUPONT, H. L., & STEFFEN, R. (2003). Travelers' diarrhea. Hamilton, Ont, B C Decker. http://search.ebscohost.com/login.aspx?direct=true&scope=site&db=nlebk&db=nlabk&AN=102424. JAMES M. MCCARTY. (1996). Azithromycin (Zithromax®). Infectious Diseases in Obstetrics and Gynecology. http://dx.doi.org/10.1155/S1064744996000415. KING, T. L., & BRUCKER, M. C. (2011). Pharmacology for women's health. Sudbury, Mass, Jones and Bartlett Publishers. KUPER, HANNAH, & WORMALD, RICHARD. (n.d.). Topical azithromycin: new evidence? BMJ Group. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1954780 OMURA, S. (2010). Macrolide antibiotics: chemistry, biology, and practice. [S.l.], General Books ROTHOVA, A., BOSCH-DRIESSEN, L. E. H., LOON, N. H. V., & TREFFERS, W. F. (1998). Azithromycin for ocular toxoplasmosis. BJO. 82, 1306. SCHO?NFELD, W., & KIRST, H. A. (2002). Macrolide antibiotics. Basel, Birkha?user Verlag. SOLOMON ANTHONY & BURTON MATTHEW. (2004). what’s new in azithromycin? International Centre for Eye Health. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1705739. WEST, SHEILA K. (1999). Azithromycin for Control of Trachoma. International Centre for Eye Health. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1706032 Read More