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Macrolide

From Wikipedia, the free encyclopedia
Erythromycin.The macrolide ring is thelactone(cyclicester) at upper left.
Clarithromycin
Roxithromycin

Macrolidesare a class of mostlynatural productswith a largemacrocycliclactonering to which one or moredeoxy sugars,usuallycladinoseanddesosamine,may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to thepolyketideclass of natural products. Some macrolides haveantibioticorantifungalactivity and are used aspharmaceutical drugs.Rapamycinis also a macrolide and was originally developed as an antifungal, but has since been used as animmunosuppressant drugand is being investigated as a potentiallongevity therapeutic.[1]

Macrolides arebacteriostaticin that they suppress or inhibit bacterial growth rather than killing bacteria completely.

Definition[edit]

In general, any macrocyclic lactone having greater than 8-membered rings are candidates for this class. The macrocycle may containaminonitrogen,amidenitrogen (but should be differentiated fromcyclopeptides), anoxazolering, or athiazolering.Benzenerings are excluded, in order to differentiate fromtannins.Alsolactamsinstead of lactones (as in theansamycinfamily) are excluded. Included are not only 12-16 membered macrocycles but also larger rings as intacrolimus.[2]

History[edit]

The first macrolide discovered waserythromycin,which was first used in 1952. Erythromycin was widely used as a substitute topenicillinin cases where patients were allergic to penicillin or had penicillin-resistant illnesses. Later macrolides developed, includingazithromycinandclarithromycin,stemmed from chemically modifying erythromycin; these compounds were designed to be more easily absorbed and have fewer side-effects (erythromycin caused gastrointestinal side-effects in a significant proportion of users).[3]

Uses[edit]

Antibiotic macrolides are used to treat infections caused byGram-positive bacteria(e.g.,Streptococcus pneumoniae) and limitedGram-negative bacteria(e.g.,Bordetella pertussis,Haemophilus influenzae), and some respiratory tract and soft-tissue infections.[4]The antimicrobial spectrum of macrolides is slightly wider than that ofpenicillin,and, therefore, macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolyticstreptococci,pneumococci,staphylococci,andenterococciare usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective againstLegionella pneumophila,Mycoplasma,Mycobacterium,someRickettsia,andChlamydia.

Macrolides arenotto be used on nonruminantherbivores, such as horses and rabbits. They rapidly produce a reaction causing fatal digestive disturbance.[5]It can be used in horses less than one year old, but care must be taken that other horses (such as a foal's mare) do not come in contact with the macrolide treatment.

Macrolides can be administered in a variety of ways, including tablets, capsules, suspensions, injections and topically.[6]

Mechanism of action[edit]

Antibacterial[edit]

Macrolides areprotein synthesis inhibitors.Themechanism of actionof macrolides isinhibitionof bacterialprotein biosynthesis,and they are thought to do this by preventingpeptidyltransferasefrom adding the growing peptide attached totRNAto the next amino acid[7](similarly tochloramphenicol[8]) as well as inhibitingbacterial ribosomal translation.[7]Another potential mechanism is premature dissociation of thepeptidyl-tRNAfrom the ribosome.[9]

Macrolide antibiotics bind reversibly to the P site on the50Ssubunit of the bacterialribosome.This action is considered to bebacteriostatic.Macrolides are actively concentrated withinleukocytes,and thus are transported into the site of infection.[10]

Immunomodulation[edit]

Diffuse panbronchiolitis[edit]

The macrolide antibiotics erythromycin, clarithromycin, and roxithromycin have proven to be an effective long-term treatment for theidiopathic,Asian-prevalent lung diseasediffuse panbronchiolitis(DPB).[11][12]The successful results of macrolides in DPB stems from controlling symptoms throughimmunomodulation(adjusting the immune response),[12]with the added benefit oflow-doserequirements.[11]

With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not onlyneutrophil granulocyteproliferation but alsolymphocyteactivity and obstructivesecretionsin airways.[11]The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB.[13]This is evident, as the treatment dosage is much too low to fight infection, and in DPB cases with the occurrence of the macrolide-resistant bacteriumPseudomonas aeruginosa,macrolide therapy still produces substantial anti-inflammatory results.[11]

Examples[edit]

Antibiotic macrolides[edit]

US FDA-approved:

Azithromycincapsules

Not approved in the US by FDA but approved in the other countries by respective national authorities:

Not approved as a drug for medical use:

Ketolides[edit]

Ketolidesare a class of antibiotics that are structurally related to the macrolides. They are used to treat respiratory tract infections caused by macrolide-resistant bacteria. Ketolides are especially effective, as they have two ribosomal binding sites.

Ketolides include:

Fluoroketolides[edit]

Fluoroketolides are a class of antibiotics that are structurally related to the ketolides. The fluoroketolides have three ribosomal interaction sites.

Fluoroketolides include:

  • Solithromycin– the first and so far only fluoroketolide (not yet approved)

Non-antibiotic macrolides[edit]

The drugstacrolimus,pimecrolimus,andsirolimus,which are used asimmunosuppressantsor immunomodulators, are also macrolides. They have similar activity tociclosporin.

Antifungal drugs[edit]

Polyene antimycotics,such asamphotericin B,nystatinetc., are a subgroup of macrolides.[17]Cruentarenis another example of an antifungal macrolide.[18]

Toxic macrolides[edit]

A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as themycolactones.

Resistance[edit]

The primary means ofbacterial resistanceto macrolides occurs by post-transcriptional methylation of the23Sbacterial ribosomal RNA. This acquired resistance can be eitherplasmid-mediated or chromosomal, i.e., through mutation, and results incross-resistanceto macrolides,lincosamides,andstreptogramins(an MLS-resistant phenotype).[19]

Two other forms of acquired resistance include the production of drug-inactivating enzymes (esterases[20][21]or kinases[22]), as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.[23]

Azithromycin has been used to treat strep throat (Group A streptococcal (GAS) infectioncaused byStreptococcus pyogenes) in penicillin-sensitive patients; however, macrolide-resistant strains of GAS occur with moderate frequency.Cephalosporinis another option for these patients.[24]

Side-effects[edit]

A 2008British Medical Journalarticle highlights that the combination of some macrolides andstatins(used for lowering cholesterol) is not advisable and can lead to debilitatingmyopathy.[25]This is because some macrolides (clarithromycin and erythromycin, not azithromycin) are potentinhibitorsof thecytochrome P450system, particularly ofCYP3A4.Macrolides, mainly erythromycin and clarithromycin, also have a class effect ofQT prolongation,which can lead totorsades de pointes.Macrolides exhibitenterohepatic recycling;that is, the drug is absorbed in the gut and sent to the liver, only to be excreted into theduodenumin bile from the liver. This can lead to a buildup of the product in the system, thereby causing nausea. In infants the use of erythromycin has been associated with pyloric stenosis.[26][27]

Some macrolides are also known to causecholestasis,a condition where bile cannot flow from the liver to the duodenum.[28]A study reported in 2019 found an association between erythromycin use during infancy and developing IHPS (Infantile hypertrophic pyloric stenosis) in infants.[29]However, no significant association was found between macrolides use during pregnancy or breastfeeding.[29]

A Cochrane review showed gastrointestinal symptoms to be the most frequent adverse event reported in literature.[30]

Interactions[edit]

CYP3A4is an enzyme that metabolizes many drugs in the liver. Macrolides inhibit CYP3A4, which means they reduce its activity and increase the blood levels of the drugs that depend on it for elimination. This can lead to adverse effects or drug-drug interactions.[31]

Macrolides have cyclic structure with alactonering and sugar moieties. They can inhibit CYP3A4 by a mechanism called mechanism-based inhibition (MBI), which involves the formation of reactive metabolites that bind covalently and irreversibly to the enzyme, rendering it inactive. MBI is more serious and long-lasting than reversible inhibition, as it requires the synthesis of new enzyme molecules to restore the activity.[14]

The degree of MBI by macrolides depends on the size and structure of their lactone ring.Clarithromycinanderythromycinhave a 14-membered lactone ring, which is more prone to demethylation by CYP3A4 and subsequent formation of nitrosoalkenes, the reactive metabolites that cause MBI.Azithromycin,on the other hand, has a 15-membered lactone ring, which is less susceptible to demethylation and nitrosoalkene formation. Therefore, azithromycin is a weak inhibitor of CYP3A4, while clarithromycin and erythromycin are strong inhibitors which increase the area under the curve (AUC) value of co-administered drugs more than five-fold.[14]AUC it is a measure of the drug exposure in the body over time. By inhibiting CYP3A4, macrolide antibitiotics, such aserythromycinandclarithromycin,but not azithromycin, can significantly increase the AUC of the drugs that depend on it for clearance, which can lead to higher risk of adverse effects or drug-drug interactions. Azithromycin stands apart from other macrolide antibiotics because it is a weak inhibitor of CYP3A4, and does not significantly increase AUC value of co-administered drugs.[32]

The difference in CYP3A4 inhibition by macrolides has clinical implications, for example, for patients who takestatins,which are cholesterol-lowering drugs that are mainly metabolized by CYP3A4. Co-administration of clarithromycin or erythromycin with statins can increase the risk of statin-induced myopathy, a condition that causes muscle pain and damage. Azithromycin, however, does not significantly affect the pharmacokinetics of statins and is considered a safer alternative. Another option is to use fluvastatin, a statin that is metabolized by CYP2C9, an enzyme that is not inhibited by clarithromycin.[14]

Macrolides, including azithromycin, should not be taken withcolchicineas it may lead to colchicine toxicity. Symptoms of colchicine toxicity include gastrointestinal upset, fever, myalgia, pancytopenia, and organ failure.[33][34]

References[edit]

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Further reading[edit]

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