Macrolide

Last updated August 07, 2024

Roxithromycin Roxithromycin.svg — Roxithromycin

Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the polyketide class of natural products. Some macrolides have antibiotic or antifungal activity and are used as pharmaceutical drugs. Rapamycin is also a macrolide and was originally developed as an antifungal, but has since been used as an immunosuppressant drug and is being investigated as a potential longevity therapeutic.^[1]

Definition

In general, any macrocyclic lactone having greater than 8-membered rings are candidates for this class. The macrocycle may contain amino nitrogen, amide nitrogen (but should be differentiated from 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 Gram-positive bacteria (e.g., Streptococcus pneumoniae ) and limited Gram-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 of penicillin, and, therefore, macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic streptococci, pneumococci, staphylococci, and enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against Legionella pneumophila , Mycoplasma, Mycobacterium, some Rickettsia, and 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 protein synthesis inhibitors. The mechanism of action of macrolides is inhibition of bacterial protein biosynthesis, and they are thought to do this by preventing peptidyltransferase from adding the growing peptide attached to tRNA to the next amino acid^[7] (similarly to chloramphenicol ^[8]) as well as inhibiting bacterial ribosomal translation.^[7] Another potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.^[9]

Macrolide antibiotics bind reversibly to the P site on the 50S subunit of the bacterial ribosome. This action is considered to be 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 – unique; does not extensively inhibit CYP3A4 ^[14]
Clarithromycin
Dirithromycin – discontinued but was US FDA approved
Erythromycin

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

Carbomycin A
Josamycin
Kitasamycin
Midecamycin/midecamycin acetate
Oleandomycin
Spiramycin – approved in the EU, and in other countries
Troleandomycin – used in Italy and Turkey
Tylosin/tylocine – used in animals
Roxithromycin

Not approved as a drug for medical use:

Boromycin ^[15]

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:

Telithromycin – the first and only approved ketolide^[16]
Cethromycin
Solithromycin

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 so far only fluoroketolide (not yet approved)

Non-antibiotic macrolides

The drugs tacrolimus, pimecrolimus, and sirolimus, which are used as 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 British Medical Journal article highlights that the combination of some macrolides and statins (used for lowering cholesterol) is not advisable and can lead to debilitating myopathy.^[25] This is because some macrolides (clarithromycin and erythromycin, not azithromycin) are potent inhibitors of the cytochrome P450 system, particularly of CYP3A4. Macrolides, mainly erythromycin and clarithromycin, also have a class effect of QT prolongation, which can lead to torsades de pointes. Macrolides exhibit 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 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

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]

Related Research Articles

Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn, and to improve delayed stomach emptying. It can be given intravenously and by mouth. An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.

Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, H. pylori infection, and Lyme disease, among others. Clarithromycin can be taken by mouth as a tablet or liquid or can be infused intravenously.

<span class="mw-page-title-main">Drug resistance</span> Pathogen resistance to medications

Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.

This is the timeline of modern antimicrobial (anti-infective) therapy. The years show when a given drug was released onto the pharmaceutical market. This is not a timeline of the development of the antibiotics themselves.

<span class="mw-page-title-main">Clindamycin</span> Antibiotic

Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media, and endocarditis. It can also be used to treat acne, and some cases of methicillin-resistant Staphylococcus aureus (MRSA). In combination with quinine, it can be used to treat malaria. It is available by mouth, by injection into a vein, and as a cream or a gel to be applied to the skin or in the vagina.

Azithromycin, sold under the brand names Zithromax and Azasite, is an antibiotic medication used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumonia, traveler's diarrhea, and certain other intestinal infections. Along with other medications, it may also be used for malaria. It is administered by mouth, into a vein, or into the eye.

<span class="mw-page-title-main">Ketolide</span>

Ketolides are antibiotics belonging to the macrolide group. Ketolides are derived from erythromycin by substituting the cladinose sugar with a keto-group and attaching a cyclic carbamate group in the lactone ring. These modifications give ketolides much broader spectrum than other macrolides. Moreover, ketolides are effective against macrolide-resistant bacteria, due to their ability to bind at two sites at the bacterial ribosome as well as having a structural modification that makes them poor substrates for efflux-pump mediated resistance.

<span class="mw-page-title-main">Telithromycin</span> Chemical compound

Telithromycin is the first ketolide antibiotic to enter clinical use and is sold under the brand name of Ketek. It is used to treat community acquired pneumonia of mild to moderate severity. After significant safety concerns, the US Food and Drug Administration sharply curtailed the approved uses of the drug in early 2007.

<span class="mw-page-title-main">CYP3A4</span> Enzyme that metabolizes substances by oxidation

Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

Clavulanic acid is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

<span class="mw-page-title-main">Lincosamides</span> Group of antibiotics

Lincosamides are a class of antibiotics, which include lincomycin, clindamycin, and pirlimycin.

Azalides such as azithromycin are a class of macrolide antibiotics that were originally manufactured in response to the poor acid stability exhibited by original macrolides (erythromycin). Following the clinical overuse of macrolides and azalides, ketolides have been developed to combat surfacing macrolide-azalide resistance among streptococci species. Azalides have several advantages over erythromycin such as more potent gram negative antimicrobial activity, acid stability, and side effect tolerability. Although there are few drug interactions with azithromycin, it weakly inhibits the CYP3A4 enzyme.

<span class="mw-page-title-main">Oleandomycin</span> Chemical compound

Oleandomycin is a macrolide antibiotic. It is synthesized from strains of Streptomyces antibioticus. It is weaker than erythromycin.

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">Desosamine</span> Chemical compound

Desosamine is a 3-(dimethylamino)-3,4,6-trideoxyhexose found in certain macrolide antibiotics such as the commonly prescribed erythromycin, azithromycin, clarithroymcin, methymycin, narbomycin, oleandomycin, picromycin and roxithromycin. As the name suggests, these macrolide antibiotics contain a macrolide or lactone ring and they are attached to the ring Desosamine which is crucial for bactericidal activity. The biological action of the desosamine-based macrolide antibiotics is to inhibit the bacterial ribosomal protein synthesis. These antibiotics which contain Desosamine are widely used to cure bacterial-causing infections in human respiratory system, skin, muscle tissues, and urethra.

Diffuse panbronchiolitis (DPB) is an inflammatory lung disease of unknown cause. It is a severe, progressive form of bronchiolitis, an inflammatory condition of the bronchioles. The term diffuse signifies that lesions appear throughout both lungs, while panbronchiolitis refers to inflammation found in all layers of the respiratory bronchioles. DPB causes severe inflammation and nodule-like lesions of terminal bronchioles, chronic sinusitis, and intense coughing with large amounts of sputum production.

Streptogramin A is a group of antibiotics within the larger family of antibiotics known as streptogramins. They are synthesized by the bacteria Streptomyces virginiae. The streptogramin family of antibiotics consists of two distinct groups: group A antibiotics contain a 23-membered unsaturated ring with lactone and peptide bonds while group B antibiotics are depsipeptides. While structurally different, these two groups of antibiotics act synergistically, providing greater antibiotic activity than the combined activity of the separate components. These antibiotics have until recently been commercially manufactured as feed additives in agriculture, although today there is increased interest in their ability to combat antibiotic-resistant bacteria, particularly vancomycin-resistant bacteria.

<span class="mw-page-title-main">Solithromycin</span> Chemical compound

Solithromycin is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia and other infections.

<span class="mw-page-title-main">Antibiotic resistance in gonorrhea</span>

Neisseria gonorrhoeae, the bacterium that causes the sexually transmitted infection gonorrhea, has developed antibiotic resistance to many antibiotics. The bacteria was first identified in 1879.

Anti-ulcer agents are medications or supplements used to cure the damage of mucosal layer on organs to prevent the damage from further extending to deeper regions to cause complications.

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