Rokitamycin

These compounds are shown in Figure 2. More recendy, >"- and 4 -0-substituted derivatives of spiramycin were synthesized which showed similar in vivo improvements in activity (325—327). Rokitamycin and miokamycin have been commercially launched in Japan (116). 

Fig. 2. Semisynthetic derivatives of I6-membered macroHdes rokitamycin (62, R = R " = H, R = butyryl, R" = propionyl) miokamycin (62,...

Braga, E C. Bovio, C. Culici, M. Dal Sasso, M. Flow cytometric assessment of susceptibilities of Streptococcus pyogens to erythromycin and rokitamycin. Antimicrob. Agents Chemother. 2003, 47, 408-412. 

Semisynthetic Derivatives. 3 -O-Acyl derivatives have not been found via fermentation, but chemical acylation of the 3/ -hydroxyl group yields products having good antibiotic activity and better pharmacokinetics than the parent macrolides. Two such compounds have been developed 3r/-O-propionyl-leucomycin Af (rokitamycin) C42H 9N015, formerly TMS-19-Q, and 9,3 -di-O-acetylmidecamyein (miokamycin) C HtiNOi . At least part of the in viva improvement was attributed to slower elimination of active metabolites from serum. 

Rokitamycin (6) is a semi-synthetic derivative of leucomycin Aj (5), another of the individual factors found in the leucomycin complex along with josamycin (leucomycin Aj). Initially referred to as TMS-19-Q, rokitamycin is the 3"-0-propionyl derivative of leucomycin A5 Figure 5.2) [32, 33]. 

Since the lung is among the tissues into which macrolides penetrate well, they are used to treat infections in the respiratory tract, including those caused by intracellular pathogens such as Legionella, Chlamydia, and Mycoplasma [241]. Bronchoalveolar lavage was used as a convenient method to measure high intrapulmonary concentrations of josamycin [242]. Rokitamycin achieved sufficient concentrations of antibiotic in bronchial secretions to treat lower respiratory tract infections [243]. 

Several 16-membered macrolides form metabolites which retain antimicrobial activity. As discussed above, 3"-esters such as rokitamycin and miokamycin produce prolonged concentrations of antibiotic in vivo due to the facile 3"- to 4"-0-acyl migration that follows enzymatic removal of the original 4 -ester [34, 269, 270], Following a different approach to overcome the lability of 4"-esters, specific 4"-0-acyl derivatives of tylosin were selected from the series of esters (15) based upon their greater stability toward liver enzymes [80], Although esterases play the most prominent role in metabolism of 16-membered macrolides, other mechanisms such as oxidative hydroxylation, A-demethylation, reduction, and hydrolysis of sugars have been reported for various compounds [91, 96, 115, 259, 270-272]. 

An 18-year-old woman with childhood asthma, using inhaled glucocorticoids and zafirlukast, developed Churg-Strauss syndrome 10 days after starting to use rokitamycin (12). 

The following macrohdes are covered in separate monographs azithromycin, clarithromycin, dirithromycin, erythromycin, josamycin, midecamycin, rokitamycin, roxithromycin, spiramycin, and troleandomycin (all rINNs). 

Rokitamycin is a semisjmthetic 16-membered ring macro-Ude. It is more hydrophobic, and has better bacterial uptake and slower release, more cohesive ribosomal binding, and a longer post-antibiotic effect than other 14-, 15-and 16-membered ring macroUdes (1). 

Braga PC. Rokitamycin bacterial resistance to a 16-membered ring macrolide differs from that to 14- and 15-membered ring macrolides. J Chemother 2002 14(2) 115-31. 

Recently, 3"-0-acyl derivatives have been synthesized and were found to have a strong antibacterial activity in vitro and in vivo. Among them, miokamycin and rokitamycin have been launched (Fig. 30). 

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