Erythromycin antibacterial activity

Isothiazole substituents have been attached to /3-lactam antibiotics and to macrocyclic antibiotics such as erythromycin. The sulfa drug, Sulfasomizole (244) also has good antibacterial activity. Thiosemicarbazones of 5-formyl- and 5-acetylisothiazoles show high activity against the pox group of viruses (65AHC(4)107). 

Gindamydn has antibacterial activity similar to that of erythromycin. It exerts a bacteriostatic effect mainly on gram-positive aerobic, as well as on anaerobic pathogens. Gindamycin is a semisynthetic chloro analogue of lin-comycin, which derives from a Streptomyces species. Taken orally, clindamycin is better absorbed than lincomycin, has greater antibacterial efficacy and is thus preferred. Both penetrate well into bone tissue. 

Antibacterial activity of macrolides depends on the acidity of the medium. High activity is observed in neutral and basic media in comparison with acid. In particular, erythromycin is inactivated in the acidic medium of the stomach. Macrolides have a relatively broad spectrum of use, and they are active with respect to Gram-positive and Gram-negative microorganisms, achiomycetes, mycoplasma, spirochaeta, chlamydia. Bacteria Rickettsia, certain mycobacteria. Colon bacillus, blue-pus bacillus, shigella, salmonella, and so on. 

Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47). Clarithromycin also has activity against M leprae and Toxoplasma gondii. Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin. 

Clarithromycin is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin, which also has antibacterial activity. A portion of active drug and this major metabolite is eliminated in the urine, and dosage reduction (eg, a 500-mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min. Clarithromycin has drug interactions similar to those described for erythromycin. 

Flurithromycin (120), a fluorinated erythromycin macrolide, has been isolated from a mutant strain of Streptomyces erythraeus. It shows antibacterial activity against Streptococcus pneumoniae (MIC 0.0015-... 

Godin, B., and E. Touitou. 2005. Erythromycin ethosomal systems Physicochemical characterization and enhanced antibacterial activity. Curr Drug Deliv 2 269. 

Erythromycin and the other macrolides exhibit a very broad spectrum of antibacterial activities and are active against many gram-positive bacteria, as well as some gram-negative bacteria. These agents are often used as the primary or alternative drug in a variety of clinical conditions (see Table 33-5). Macrolides may be especially useful in patients who are allergic to penicillin. 

Clarithromycin has a spectrum of antibacterial activity similar to that of erythromycin, but is also effective against Haemophilus influenzae. Its activity against intracellular pathogens such as Chlamydia. Legionella and Ureaplasma is higher than that of erythromycin (Figure 31.9). 

Erythromycin is active against gram-positive cocci with the exception of enterococci. Erythromycin is also active against Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia pneumoniae, and Borrelia burgdorferi. Clarithromycin and azithromycin have antibacterial spectra similar to that of erythromycin except that they have enhanced activity against H. influenzae. 

Macrolides e.g. erythromycin. Clindamycin, structurally a lincosamide, has a similar action and overlapping antibacterial activity. 

Morimoto, S., Takahashi, Y, Watanabe, Y, Omura, S. Chemical modification of erythromycins. 1. Synthesis and antibacterial activity of 6-O-methylerythromycins A. J. Antibiot. (Tokyo) 1984, 37, 187-189. 

Ester derivatives of erythromycin, shown in Table 4, were synthesized soon after its discovery (124—126). They are readily prepared by acylation of the 2-hydroxyl group the neighboring 3r-dimethylamino group directs acylation to this site. Commonly used esters of erythromycin are propionate, acetate, ethyl succinate, and ethyl carbonate (30). 2r-Esters do not bind bacterial ribosomes, however, and consequently must be hydrolyzed back to the parent to exert antibacterial activity (127). Ester derivatives are still being prepared (128,129). 2,-0-Acetylerythromycin stearate, also known as erythromycin acistrate, is an example undergoing clinical trial (11,130,131). Two salts of 2,-0-propionyl-erythromycin, N-acetylcysteinate (erythromycin stinoprate) and mercaptosuccinate, were prepared to combine antibiotic and mucolytic properties in a single agent (132—134). 

A few bioconversions of erythromycin have been reported (149). Certain modifications of erythromycin at both its 9-ketone and 11-hydroxyl groups inhibited hydrolysis of the lactone ring by an esterase isolated from Escherichia coli which might be involved in bacterial resistance to macrolides (150). The 9-methoxime-11-[(2-dimethylaminoethyl)oxymethyl] derivative of erythromycin, ER 42859, showed good antibacterial activity and pharmacokinetics in animals, but it gave lower blood levels than erythromycin when administered to humans (151). Other 9,11-cydic derivatives of erythromycin have been synthesized (152,153). Series of 9-A/-alkyl derivatives of both 9(5)- and 9(R)-eiythromycylamine have been prepared which improved activity in vivo over erythromycin (154,155). 

Erythromycin diffuses readily into intracellular fluids, achieving antibacterial activity in essentially all sites except the brain and CSF. Erythromycin penetrates into prostatic fluid, achieving concentrations approximately 40% of those in plasma. Concentrations in middle ear exudate reach only 50% of serum concentrations, and thus may be inadequate for the treatment of otitis media caused by H. influenzae. Protein binding is approximately 70 to 80% for erythromycin base and even higher, 96%, for the estolate. Erythromycin traverses the placenta, and drug concentrations in fetal plasma are about 5 to 20% of those in the maternal circulation. Concentrations in breast milk are 50% of those in serum. 

Chantot, J. F., Case, J. C., Gouin D Ambrieres, S., and Lutz, A. (1983). New ether oxime derivatives of erythromycin A Preparation and antibacterial activities. Presented at 23rd Intersci. Conf. Antimicrob. Agents Chemother. (Las Vegas, NV). Abstr. No. 447. 

Lartey, P. A., Deninno, S. L., Faghih, R., Clement, J. J., and Plattner, J. J. (1991). Effect of C-21 modifications on the antibacterial activity of (9R)-9-deoxo-9-dimethylamino erythromycin A. Presented at 31st Intersci. Conf. Antimicrob. Agents Chemother. (Sept. 29-Oct. 2, Chicago). Abstr. No. 382. 

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