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... ges of erythromycin estate in comparison to the other derivatives. Table 3. 1 compares erythromycin estate and ethyl succinate. Erythromycin estate Erythromycin ethyl succinate Plasma levels up to 6. 5 mg / l Plasma levels up to 2. 5 mg / l 2 doses per day 3 doses per day 250 mg per dose 400 mg per dose no bitter taste bitter taste pH range 3 & # 8211; 7. 5 pH range 6 & # 8211; 8. 5 no dependence on meals dependence on meals Table 3. 1 Comparison between erythromycin estate and ethyl succinate [ 2 ] Diagram 3. 1 shows the pharmacokinetics of erythromycin estate and ethyl succinate. The acid stability of the estate allows a much lower dose administration and a longer half-life due to the higher amounts of resorption. Diagram 3. 1 Pharmacokinetics of erythromycin estate and ethyl succinate [ 2 ] 3. 4 Comparison between erythromycin base and estate The improvement of erythromycin estate as both a salt and an ester showed a tremendous increase in plasma levels of erythromycin.
In addition the influence of food administration on the bioavailability were not as important for the estate. Diagram 3. 2 shows the plasma levels of the 2 '-propagate compared with the base. Diagram 3. 2 Plasma levels of erythromycin 2 '-propagate and erythromycin base following single doses of erythromycin estate capsules [ 11 ] The plasma levels for the major metabolite of erythromycin estate are much higher and therefore increase the half-life of the drug. As a result, erythromycin estate must be taken twice a day in a lower dose than erythromycin base, which must be taken three times a day with almost double the dose.
The advantages of erythromycin estate make it an optimal oral antibiotic in paediatrics. 4 Chemical derivatives of erythromycin The instability problems with erythromycin could be solved or reduced by different formulations or the formation of salts and esters. All these investigations have been made before 1984. However, erythromycin estate is still a great improvement in the oral treatment regimen. Since 1984, research and the improvement of erythromycin focused on the 14 -membered lactone ring. The goal was to increase the acid stability without any loss in antibiotic activity.
To achieve this goal, especially the formation of the hemiketal in position 9 of the lactone ring should be prevented. Figure 4. 1 Dehydration of erythromycin to 6, 9 -hemiketal [ 4 ] The lactone ring derivatives of erythromycin all show broader antibacterial spectra and / or good bioavailability through increased acid stability. The five most important derivatives are briefly discussed and compared with erythromycin base. 4. 1 Roxithromycin Figure 4. 2 Roxithromycin [ 4 ] Roxithromycin, a methoxyethoxymethyl ether oxime of erythromycin, is more stable in acidic media. Interestingly, roxithromycin showed less antibiotic activity than erythromycin in vitro. But after administration in vivo, the higher tissue distribution and the longer half-life due to its increased lipophilic character made it worth for the market. [ 7 ] 4. 2 Clarithromycin Figure 4. 3 Clarithromycin (left) and major metabolite (right) [ 4 ] Clarithromycin is more stable than erythromycin in gastric juices and is well absorbed after oral administration. The concentration in lungs was remarkably higher, causing less liver toxicity and providing an extended range for the treatment of respiratory tract infections.
One major metabolite in the urine was found to have almost the same in vitro activity and increased the in vivo activity of clarithromycin. At a pH of 1. 39, clarithromycin degraded with a t 50 of 17 min. while erythromycin kinetics corresponded to a t 50 of 3 sec. Therefore, clarithromycin was 340 -fold more stable at pH 1. 39 than erythromycin. [ 10 ] 4. 3 Azithromycin The subdivision of azide macrolide's is represented by the most famous representative azithromycin [ 9 ]. Besides the improvement of pharmacokinetics and bioavailability, it was another goal to achieve antibacterial activity against gram negative bacteria, while erythromycin shows only less activity. Azithromycin has a good pharmacokinetic profile.
Azithromycin decomposition occurs primarily via acid-catalyzed hydrolysis of the ether bond to the neutral cladinose sugar. In solution at 37 ^ 0 C and pH 2 with ionic strength u = 0. 02, azithromycin was degraded with t 90 of 20. 1 min. while erythromycin underwent 10 % decay in only 3. 7 sec. [ 9 ] It is used in H. influenzae infections because of its increased activity against gram negative bacteria.
Figure 4. 4 Azithromycin [ 4 ] Surprisingly, azithromycin shows a very similar conformation of the lactone ring than erythromycin in X-ray crystallographic analyzes. Although the structure-activity relationships do not extremely alter, the alteration of hydrophilic ity and pKs by two ionizable nitrogen groups of azithromycin seem to have an effect on the antibacterial spectrum and pharmacokinetics. [ 9 ] Figure 4. 5 Crystalline structure of azithromycin [ 1 ] 4. 4 Dirithromycin Like roxithromycin, dirithromycin has a superior tissue distribution and prolonged serum half-life then erythromycin, reducing the dosage and frequency of administration. Its antibacterial activity is comparable to the other derivatives focusing on gram positive bacteria. Figure 4. 6 Dirithromycin [ 4 ] 4. 5 Flurithromycin The (8 S) - 8 -fluorinated derivatives of erythromycin, including flurithromycin, were found to be considerably stable in acidic solutions, although both erythronolide A and erythromycin base were unstable and proceeded to degrade along similar pathways. Flurithromycin shows the most promising features of antimicrobial activity in vivo, pharmacokinetics, and clinical efficacy among the fluorinated derivatives.
The in vitro activity against pathogens of respiratory tract infections was superior to that of erythromycin. Figure 4. 7 Flurithromycin [ 4 ] Interestingly, fermentation with streptomyces erythraeus is involved in the synthesis of flurithromycin. For the microbial glucosidation, fluorinated erythronolide A and B were added into the fermentation broth of streptomyces erythraeus ATCC 31772, a blocked mutant in erythromycin biosynthesis. Flurithromycin is formed by the conjugation of the fluorinated erythronolide A with sugars produced by the bacteria. Figure 4. 8 Biosynthesis of flurithromycin [ 4 ] 4. 6 Comparison of properties among the newer macrolide's The newer macrolide's and derivatives of erythromycin have been discovered after 1984. The advantages include increased acid stability, higher bioavailability, prolonged half-life, and wider range of antimicrobial activity including gram positive and gram negative pathogens.
The in vitro activity is shown in Table 4. 1. The MIC 50 was measured in ug / ml . Every macro lide antibiotic has his own advantages and increased activity spectrum against pathogens. One great advantage of azithromycin is his increased activity against H.
influenzae. Overall, clarithromycin has the lowest MIC 50 for almost all pathogens & # 8211; except H. influenzae. Organism Erythromycin Roxithromycin Clarithromycin Azithromycin S. aureus 0. 39 0. 78 0. 20 0. 78 S. epidermis 0. 39 0. 39 0. 20 0. 78 S.
pyogenes & # 8804; 0. 025 0. 10 & # 8804; 0. 025 0. 10 S. pneumoniae 0. 39 0. 39 0. 10 0. 39 E. faecalis 3. 13 6. 25 1. 56 6. 25 H. influenzae 3. 13 12. 5 6. 25 1. 56 Table 4. 1 MIC 50 for macro lide antibiotics, lowest MIC 50 for pathogen is printed bold [ 4 ] In regard ence of the differences of in vivo and in vitro activity, the ED 50 values for erythromycin, clarithromycin and azithromycin in Table 4. 2 gives another, more applicable impression.
Although clarithromycin has still the lowest ED 50 's, the differences between the macrolide's have increased. Due to the acid instability of erythromycin, much higher ED 50 's are necessary. S. aureus S. pyogenes S.
pneumoniae H. influenzae Erythromycin > 156 (0. 78) 41. 2 (0. 20) > 172 (0. 10) 189 (3. 13) Clarithromycin 19. 0 (0. 39) 6. 78 (0. 05) 69. 5 (0. 05) 113 (3. 13) Azithromycin 35. 8 (1. 56) 7. 23 (0. 39) 42. 2 (0. 20) 29. 1 (0. 78) Table 4. 2 ED 50 (mg / kg ) for macro lide antibiotics, parentheses indicate MIC (ug / ml ) [ 4 ] The effect of medium pH on the antibacterial activity of these newer macrolide's is shown in Table 4. 3 and Diagrams 4. 1 to 4. 3. The MIC of azithromycin is much affected by a change of pH, particularly with gram positive bacteria (150 - 200 times) compared with gram negative bacteria (30 times). The changes in MIC's of roxithromycin and clarithromycin were less than that of azithromycin (10 - 20 times) against three species at pH 6. 0 - 8. 0. Macrolide pH S. aureus E.
faecalis H. influenzae Erythromycin 6. 0 1. 87 5. 66 7. 46 7. 2 0. 35 0. 62 2. 00 8. 0 0. 18 0. 35 0. 81 Roxithromycin 6. 0 6. 06 24. 25 19. 70 7. 2 0. 81 3. 48 5. 30 8. 0 0. 35 1. 41 1. 90 Clarithromycin 6. 0 1. 15 3. 25 7. 46 7. 2 0. 25 0. 61 2. 30 8. 0 0. 11 0. 25 1. 00 Azithromycin 6. 0 64. 00 111. 43 6. 50 7. 2 1. 41 4. 59 0. 76 8. 0 0. 31 0. 76 0. 23 Table 4. 3 Influence of medium pH on antibacterial activity of newer macrolide's [ 4 ] The acid stability has a great influence on the bioavailability and antibacterial activity of the macrolide's. Clarithromycin has the highest acid stability within the range of pH 6. 0 - 8. 0 and is therefore used as a wide-range antibiotic for the treatment of respiratory tract infections. Diagrams 4. 1 to 4. 3 Antibacterial activity of newer macrolide's at pH 6. 0, 7. 2, and 8. 0 5 Discussion and conclusions Erythromycin is one of the most common antibiotics used in the treatment for gram positive pathogens.
First discovered in 1952, investigations have been made to improve the stability and bioavailability of the drug. Before 1984, mainly the formation of salts and esters resulted in an improved delivery. Especially erythromycin estate is still a favorite in paediatric emulsions due to its non-bitter taste. After 1984, the focus switched to the variation within the lactone ring of the erythronolide to avoid an inactivation by dehydration. As a result, not only the stability in acidic media increased, but also the antibacterial spectrum of azithromycin covered now gram negative pathogens. Besides that, the dose could be decreased due to a higher tissue distribution and a prolonged half-life of clarithromycin.
Recent modifications still try to improve the stability by combining different methods like forming salts and modify the lactone ring. There's still research to do and room for improvements & # 8211; making the macro lide antibiotics a modern an up-to-date treatment opportunity. References [ 1 ] Molecular Expressions; web [ 2 ] Seminar arbeit 'Erythromycin-Zubereitungen'; ; Lukassowitz, St " ober-Masslinski, St " obits ch; West " alice Wilhelms-Universit " at M"user, Institut f"ur pharmazeutische Technologie, 1994 / 1995 [ 3 ] Grinning Graphics; web [ 4 ] Chemical Modification of Macrolide's; T. Sunazuka, S. Omura, S. Iwasaki, S.
Omura; Kitasato University, Japan; Macrolide antibiotics, 2 nd Edition, Academic Press, 2002 [ 5 ] Solid-state investigations of Erythromycin A dehydrate: Structure, NMR spectroscopy, and Hygrosopicity; G. Stephenson, J. Stowell, P. Toma, R.
Pfeiffer, S. Bryn; Lilly Research Laboratory and Department of Medicinal Chemistry, Purdue University; Journal of Pharmaceutical Sciences, Vol. 86, No. 11, November 1997, 1239 [ 6 ] Antibiotics, Actions, Origins, Resistance; C. Walsh; ASM Press, 2001 [ 7 ] Pharmacokinetics and Metabolism of Macrolide's; Y. Kong; Taisho Pharmaceutical Co. , Japan; Macrolide antibiotics, 2 nd Edition, Academic Press, 2002 [ 8 ] Novel Activity of Erythromycin and Its Derivatives; J.
Tamaoki, K. Nakata, H. Takizawa, H. Goto; University of Tokyo, International Medical Center of Japan; Macrolide antibiotics, 2 nd Edition, Academic Press, 2002 [ 9 ] Comparison of the acid stability of azithromycin and erythromycin A; Free EF, Steffen SH; J Antimicrob Chemother. , 1990 Jan; 25 Suppl A: 39 - 47 [ 10 ] Physicochemical properties and stability in the acidic solution of a new macro lide antibiotic, clarithromycin, in comparison with erythromycin; Nakagawa Y, It S, Yoshida T, Nagai T; Chem Pharm Bull (Tokyo), 1992 Mar; 40 (3): 725 - 8 [ 11 ] J.
Pharm. Sci. , 1979, 68, 150
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Research essay sample on Stability And Bioavailability Of Different Erythromycin Derivatives
