Macrolide antibiotics inactivation

A major aim of enteric coating is protection of drugs that are sensitive or unstable at acidic pH. This is particularly important for drugs such as enzymes and proteins, because these macromolecules are rapidly hydrolyzed and inactivated in acidic medium. Antibiotics, especially macrolide antibiotics like erythromycin, are also rapidly degraded by gastric juices. Others, such as acidic drugs like NSAID s (e.g., diclofenac, valproic acid, or acetylsalicylic acid) need to be enteric coated to prevent local irritation of the stomach mucosa. 

Mechanism-based inhibitors or suicide substrates seem to be particularly prevalent with CYP3A4. Such compounds are substrates for the enzyme, but metabolism is believed to form products that deactivate the enzyme. Several macrolide antibiotics, generally involving a tertiary amine function, are able to inhibit CYP3A4 in this manner (147,148). Erythromycin is one of the most widely used examples of this type of interaction, although there are other commonly prescribed agents that inactivate CYP3A4 (149-151), and a consideration of this phenomenon partially explains a number of interactions that are not readily explained by the conventional in vitro data (152). 

In connection to mechanism 3, inactivation of macrolide antibiotics by pathogenic Nocardia spp. was not described in this review. For example, we did not consider the inactivation due to phosphorylation (class EC 3), glycosylation (EC 3), reduction (EC 1), deacylation (EC 3), or a combination of phosphorylation and reduction [209]. The organisms are usually found in soil and water, and most cases are opportunistic, occurring in immunosuppressed patients. 

Yazawa, K., Mikami, Y, Sakamoto, T., Ueno, Y., Morisaki, N., Iwasaki, S., and Furihata, K. (1994). Inactivation of the macrolide antibiotics erythromycin, midecamycin, and rokitamycin by pathogenic Nocardia species. Antimicrob. Agents Chemothen 38, 2197—2199. 

Fig. 5.6 Macrolide antibiotics and other therapeutic amine drugs documented to inactivate certain P450 isoforms via MIcomplexation. Following cointake of these therapeutic amines with other therapeutic drugs, in vivo...

Resistance to Lincomycin. Resistance to lincomycin is developed slowly, and is usually caused by modification of 23S ribosomal RNA, which leads to co-resistance to macroHde, lincosaminide, and streptogramin B antibiotics (25). Inactivation of lincomycin by clinical isolates of strains of Staphjlococcus aureus and Staphjlococcus haemoljticus, though retention of sensitivity to macroHdes (see Antibiotics, macrolides) and streptogramins (see Antibiotics, peptides), has been found to be the consequence of the conversion of the antibiotic into its 3-(5 -adenylate) (26). 

Another group of antibiotics that can be inactivated by hydrolysis are 14- and 15- membered macrolides [2]. Esterases cleave the lactone ring. The plasmid encoded ere genes are found in members of the Enter-obacteriaceae and increase the intrinsic resistance. Furthermore, these esterases can also be found in some isolates of erythromycin resistant staphylococci. 

The resistance mechanisms that cause the inactivation of penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not apply to fluoroquinolones, and there is therefore no cross-resistance between quinolones and other antibiotics. 

The macrolides form an important group of clinically useful antibiotics. Older members include erythromycin (6), oleandomycin, triacetyloleando-mycin and spiramycin, now joined by clarithromycin (44), roxithromycin (45) and azithromycin (46) [196]. Enterobacteria which show a high level of insusceptibility to erythromycin can inactivate the antibiotic by plasmid-encoded esterases that hydrolyse the lactone ring [197],... 

Plasmid (or transposon)-encoded enzymes are thus responsible for the degradation of several different types of antibiotics. The inactivation of several /J-lactams, AGACs, 14-membered macrolides, other macrolides, lin-cosamides and streptogramis (MLS) and chloramphenicol is a major resistance mechanism it has yet to be shown that inactivation of other antibiotics falls into this category. 

As shown in Table IV the enzymes that are capable of inactivation of macrolide, lincosamide, or streptogramin type B antibiotics can specifically distinguish only one or a class of the drugs as a corresponding substrate in acquired resistance bacteria. 

The resistance mechanisms are divided into three major groups (1) target modification, (2) decreased macrolide accumulation due to enhanced drug efflux, and (3) inactivation of the antibiotics. 

Chloramphenicol is a bacteriostatic agent that binds to the 508 ribosomal subunit and inhibits the transpeptidation in protein synthesis. While this agent is not widely used to treat staphylococcal infection, resistance to chloramphenicol is due to inactivation of the antibiotic by chloramphenicol acetyltransferase enzyme (CA7). Macrolides, such as erythromycin and oleandomycin lincosamides, such as lincomycin and clindamycin and streptogramin antibiotics also have a bacteriostatic effect on Staphylococcus spp. by binding to their 508 ribosomal subunit, arresting protein synthesis, but resistance to these antibiotics is also prevalent. Rifampin has also been used to treat staphylococcal infections, but when used alone, resistant strains quickly arise. 

The mechanisms of microbial resistance to antibiotics are generally due to alterations of the antibiotic s target site, enzymatic inactivation of the antibiotic, cell impermeability, reduced cellular uptake, or increased efflux of antibiotic from cells [218]. The occurrence of these mechanisms in macrolide-resistant organisms has been reviewed [219-221]. The most widespread mechanism is modification of the macrolide s ribosomal... 

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