Macrolide

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Erythromycin. The macrolide ring is the lactone (cyclic ester) at upper left.
Clarithromycin
Roxithromycin

Macrolides are a class of mostly

immunosuppressant drug and is being investigated as a potential longevity therapeutic.[1]

Macrolides are

bacteriostatic
in that they suppress or inhibit bacterial growth rather than killing bacteria completely.

Definition

In general, any macrocyclic lactone having greater than 8-membered rings are candidates for this class. The macrocycle may contain

cyclopeptides), an oxazole ring, or a thiazole ring. Benzene rings are excluded, in order to differentiate from tannins. Also lactams instead of lactones (as in the ansamycin family) are excluded. Included are not only 12-16 membered macrocycles but also larger rings as in tacrolimus.[2]

History

The first macrolide discovered was erythromycin, which was first used in 1952. Erythromycin was widely used as a substitute to penicillin in cases where patients were allergic to penicillin or had penicillin-resistant illnesses. Later macrolides developed, including azithromycin and clarithromycin, 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

Antibiotic macrolides are used to treat infections caused by

Chlamydia
.

Macrolides are not to be used on nonruminant herbivores, 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

Antibacterial

Macrolides are

peptidyl-tRNA from the ribosome.[9]

Macrolide antibiotics bind reversibly to the P site on the

bacteriostatic. Macrolides are actively concentrated within leukocytes, and thus are transported into the site of infection.[10]

Immunomodulation

Diffuse panbronchiolitis

The macrolide antibiotics erythromycin, clarithromycin, and roxithromycin have proven to be an effective long-term treatment for the

idiopathic, Asian-prevalent lung disease diffuse panbronchiolitis (DPB).[11][12] The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation (adjusting the immune response),[12] with the added benefit of low-dose requirements.[11]

With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only

neutrophil granulocyte proliferation but also lymphocyte activity and obstructive secretions in 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 bacterium Pseudomonas aeruginosa, macrolide therapy still produces substantial anti-inflammatory results.[11]

Examples

Antibiotic macrolides

US FDA-approved:

Azithromycin capsules

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

Ketolides are 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

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 currently the only fluoroketolide (not yet approved)

Non-antibiotic macrolides

The drugs

immunosuppressants or immunomodulators, are also macrolides. They have similar activity to ciclosporin
.

Antifungal drugs

Polyene antimycotics, such as amphotericin B, nystatin etc., are a subgroup of macrolides.[17] Cruentaren is another example of an antifungal macrolide.[18]

Toxic macrolides

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

Resistance

The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S bacterial ribosomal RNA. This acquired resistance can be either plasmid-mediated or chromosomal, i.e., through mutation, and results in cross-resistance to macrolides, lincosamides, and streptogramins (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) infection caused by Streptococcus pyogenes) in penicillin-sensitive patients; however, macrolide-resistant strains of GAS occur with moderate frequency. Cephalosporin is another option for these patients.[24]

Side-effects

A 2008

enterohepatic recycling; that is, the drug is absorbed in the gut and sent to the liver, only to be excreted into the duodenum in 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 cause cholestasis, a condition where bile cannot flow from the liver to the duodenum.[28] A new study 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

CYP3A4 is 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 a lactone ring 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. Clarithromycin and erythromycin have 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 as erythromycin and clarithromycin, 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 take statins, 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 with colchicine as it may lead to colchicine toxicity. Symptoms of colchicine toxicity include gastrointestinal upset, fever, myalgia, pancytopenia, and organ failure.[33][34]

References

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  4. ^ "Macrolide Antibiotics Comparison: Erythromycin, Clarithromycin, Azithromycin". Retrieved 22 March 2017.
  5. ISBN 978-0-8138-0656-3
    .
  6. ^ "DailyMed". Food and Drug Administration (US). Retrieved 22 March 2017.
  7. ^ a b Protein synthesis inhibitors: macrolides mechanism of action animation. Classification of agents Pharmamotion. Author: Gary Kaiser. The Community College of Baltimore County. Retrieved on July 31, 2009
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Further reading

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