Editing Macrolide

{{Short description|Class of natural products}}
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[[Image:Erythromycin A.svg|thumb|150px|[[Erythromycin]]. The macrolide ring is the [[lactone]] (cyclic [[ester]]) at upper left.]]
[[Image:Clarithromycin structure.svg|150px|thumb|[[Clarithromycin]]]]
[[Image:Roxithromycin.svg|150px|thumb|[[Roxithromycin]]]]

'''Macrolides''' are a class of mostly [[natural product]]s with a large [[macrocycle|macrocyclic]] [[lactone]] ring to which one or more [[deoxy sugar]]s, usually [[cladinose]] and [[desosamine]], may be attached. Macrolides belong to the [[polyketide]] class of natural products. Some macrolides have [[antibiotic]] or [[antifungal]] activity and are used as [[pharmaceutical drug]]s. [[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 [[Life extension|longevity therapeutic]].<ref>{{cite journal |last1=Arriola Apelo SI, Lamming DW |title=apamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island |journal=J Gerontol A Biol Sci Med Sci |date=July 2016 |volume=71 |issue=7 |pages=841–9 |doi=10.1093/gerona/glw090 |pmid=27208895 |url=https://academic.oup.com/biomedgerontology/article/71/7/841/2605206 |access-date=17 July 2022 |pmc=4906330}}</ref>

Macrolides are a diverse group with many members of very different properties:
* Macrolides with 14-, 15-, or 16-membered rings and two attached sugar molecules are antibiotics that bind to bacterial ribosomes, the key representative being [[erythromycin]]. The term "macrolide antibiotics" tend to refer to just this class.
* Some macrolides with very large (20+ membered) rings are immunosuppresants, the prototypical one being [[rapamycin]].
* Some 23-membered macrolides are also antibiotics that bind to the 50S part of the bacterial ribosome, see [[streptogramin A]].
* [[Polyene antimycotic]]s are also technically macrolides.

== Definition ==
In general, any macrocyclic lactone having greater than 8-membered rings are candidates for this class. The macrocycle may contain [[Amine|amino]] nitrogen, [[amide]] nitrogen (but should be differentiated from [[cyclopeptide]]s), an [[oxazole]] ring, or a [[thiazole]] ring. [[Benzene]] rings are excluded, in order to differentiate from [[tannin]]s. Also [[lactam]]s 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]].<ref>{{cite book|title=Macrolide Antibiotics: Chemistry, Biology, and Practice|publisher=Academic Press|year=2002|isbn=978-0-12-526451-8| edition=2nd | veditors = Omura S }}</ref>

== 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).<ref>{{cite journal | vauthors = Klein JO | title = History of macrolide use in pediatrics | journal = The Pediatric Infectious Disease Journal | volume = 16 | issue = 4 | pages = 427–31 | date = April 1997 | pmid = 9109154 | doi = 10.1097/00006454-199704000-00025 }}</ref>

==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.<ref>{{cite web|url=http://www.emedexpert.com/compare/macrolides.shtml|title=Macrolide Antibiotics Comparison: Erythromycin, Clarithromycin, Azithromycin|access-date=22 March 2017}}</ref> 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 [[Streptococcus|streptococci]], [[pneumococci]], [[Staphylococcus|staphylococci]], and [[Enterococcus|enterococci]] are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against ''[[Legionella pneumophila]]'', [[Mycoplasma]], [[Mycobacterium]], some [[Rickettsia]], and [[Chlamydia (bacterium)|Chlamydia]].

Macrolides are ''not'' to be used on non[[ruminant]] herbivores, such as horses and rabbits. They rapidly produce a reaction causing fatal digestive disturbance.<ref>{{cite book|title=Antimicrobial Therapy in Veterinary Medicine|publisher=Wiley-Blackwell|year=2006|isbn=978-0-8138-0656-3| edition=4th | veditors = Giguere S, Prescott JF, Baggot JD, Walker RD, Dowling PM }}</ref>  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.<ref>{{cite web|url=https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=macrolide|title=DailyMed|publisher=Food and Drug Administration (US)|access-date=22 March 2017}}</ref>

==Mechanism of action==
{{hatnote|This section specifically refers to macrolides with a 14&ndash;16-membered ring.}}
===Antibacterial===
Macrolides are [[protein synthesis inhibitor]]s. The [[mechanism of action]] of macrolides is [[enzyme inhibitor|inhibition]] of bacterial [[protein biosynthesis]], and they are thought to do this by preventing [[peptidyltransferase]] from adding the growing peptide attached to [[Transfer RNA|tRNA]] to the next amino acid<ref name="pharmamotion">[https://web.archive.org/web/20081226204524/http://pharmamotion.com.ar/protein-synthesis-inhibitors-macrolides-mechanism-of-action-animation-classification-of-agents/ 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</ref> (similarly to [[chloramphenicol]]<ref>{{cite journal | vauthors = Drainas D, Kalpaxis DL, Coutsogeorgopoulos C | title = Inhibition of ribosomal peptidyltransferase by chloramphenicol. Kinetic studies | journal = European Journal of Biochemistry | volume = 164 | issue = 1 | pages = 53–8 | date = April 1987 | pmid = 3549307 | doi = 10.1111/j.1432-1033.1987.tb10991.x }}</ref>) as well as inhibiting [[bacterial translation|bacterial ribosomal translation]].<ref name=pharmamotion/> Another potential mechanism is premature dissociation of the [[peptidyl-tRNA]] from the ribosome.<ref name="lovmar">{{cite journal | vauthors = Tenson T, Lovmar M, Ehrenberg M | title = The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome | journal = Journal of Molecular Biology | volume = 330 | issue = 5 | pages = 1005–14 | date = July 2003 | pmid = 12860123 | doi = 10.1016/S0022-2836(03)00662-4 }}</ref>

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 [[White blood cell|leukocytes]], and thus are transported into the site of infection.<ref>{{cite journal | vauthors = Bailly S, Pocidalo JJ, Fay M, Gougerot-Pocidalo MA | title = Differential modulation of cytokine production by macrolides: interleukin-6 production is increased by spiramycin and erythromycin | journal = Antimicrobial Agents and Chemotherapy | volume = 35 | issue = 10 | pages = 2016–9 | date = October 1991 | pmid = 1759822 | pmc = 245317 | doi = 10.1128/AAC.35.10.2016 }}</ref>

===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).<ref name="mac">{{cite journal | vauthors = Keicho N, Kudoh S | title = Diffuse panbronchiolitis: role of macrolides in therapy | journal = American Journal of Respiratory Medicine | volume = 1 | issue = 2 | pages = 119–31 | year = 2002 | pmid = 14720066 | doi = 10.1007/BF03256601 | s2cid = 7634677 }}</ref><ref name="mac08">{{cite journal | vauthors = López-Boado YS, Rubin BK | title = Macrolides as immunomodulatory medications for the therapy of chronic lung diseases | journal = Current Opinion in Pharmacology | volume = 8 | issue = 3 | pages = 286–91 | date = June 2008 | pmid = 18339582 | doi = 10.1016/j.coph.2008.01.010 }}</ref> The successful results of macrolides in DPB stems from controlling symptoms through [[Immunotherapy|immunomodulation]] (adjusting the immune response),<ref name=mac08/> with the added benefit of [[dosing|low-dose]] requirements.<ref name=mac/>

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 [[secretion]]s in airways.<ref name=mac/> The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB.<ref name="mac04">{{cite journal | vauthors = Schultz MJ | title = Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis | journal = The Journal of Antimicrobial Chemotherapy | volume = 54 | issue = 1 | pages = 21–8 | date = July 2004 | pmid = 15190022 | doi = 10.1093/jac/dkh309 | doi-access = free }}</ref> 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.<ref name=mac/>

==Examples==
===Antibiotic macrolides===
US FDA-approved:
*[[Azithromycin]]{{snd}} unique; does not extensively inhibit [[CYP3A4]]<ref name="pmid31628882"/>
*[[Clarithromycin]]
*[[Dirithromycin]]{{snd}} discontinued but was US FDA approved
*[[Erythromycin]]

[[File:Azithromycin 250mg.jpg|thumb|[[Azithromycin]] capsules]]
Not approved in the US by FDA but approved in the other countries by respective national authorities:
*[[Carbomycin|Carbomycin A]]
*[[Josamycin]]
*[[Kitasamycin]]
*[[Midecamycin]]/[[midecamycin acetate]]
*[[Oleandomycin]]
*[[Spiramycin]]{{snd}} approved in the EU, and in other countries
*[[Troleandomycin]]{{snd}} used in Italy and Turkey
*[[Tylosin]]/[[tylocine]]{{snd}} used in animals
*[[Roxithromycin]]

Not approved as a drug for medical use:
*[[Boromycin]] (not a member of the classical 14&ndash;16-membered class)<ref name="pmid17991498">{{cite journal | vauthors = Rezanka T, Sigler K | title = Biologically active compounds of semi-metals | journal = Phytochemistry | volume = 69 | issue = 3 | pages = 585–606 | date = February 2008 | pmid = 17991498 | doi = 10.1016/j.phytochem.2007.09.018 | bibcode = 2008PChem..69..585R }}</ref>

===Ketolides===
[[Ketolide]]s 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]]{{snd}} the first and only approved ketolide<ref>{{cite journal | vauthors = Nguyen M, Chung EP | title = Telithromycin: the first ketolide antimicrobial | journal = Clinical Therapeutics | volume = 27 | issue = 8 | pages = 1144–63 | date = August 2005 | pmid = 16199242 | doi = 10.1016/j.clinthera.2005.08.009 }}</ref>
*[[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]]{{snd}} the first and so far only fluoroketolide (not yet approved)

===Non-antibiotic macrolides===
The drugs [[tacrolimus]], [[pimecrolimus]], and [[sirolimus]], which are used as [[immunosuppressant]]s or immunomodulators, are also macrolides. They have similar activity to [[ciclosporin]].

===Antifungal drugs===
[[Polyene antimycotic]]s, such as [[amphotericin B]], [[nystatin]] etc., are a subgroup of macrolides.<ref>{{cite journal | vauthors = Hamilton-Miller JM | title = Chemistry and biology of the polyene macrolide antibiotics | journal = Bacteriological Reviews | volume = 37 | issue = 2 | pages = 166–96 | date = June 1973 | doi = 10.1128/br.37.3.166-196.1973 | pmid = 4578757 | pmc = 413810 }}</ref> [[Cruentaren]] is another example of an antifungal macrolide.<ref>{{cite journal | vauthors = Kunze B, Sasse F, Wieczorek H, Huss M | title = Cruentaren A, a highly cytotoxic benzolactone from Myxobacteria is a novel selective inhibitor of mitochondrial F1-ATPases | journal = FEBS Letters | volume = 581 | issue = 18 | pages = 3523–7 | date = July 2007 | pmid = 17624334 | doi = 10.1016/j.febslet.2007.06.069 | doi-access = free | bibcode = 2007FEBSL.581.3523K }}</ref>

===Toxic macrolides===
A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as the [[mycolactone]]s.

==Resistance==
The primary means of [[Antimicrobial resistance|bacterial resistance]] to macrolides occurs by post-transcriptional methylation of the [[23S ribosomal RNA|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 [[streptogramin]]s (an MLS-resistant phenotype).<ref>{{cite journal | vauthors = Munita JM, Arias CA | title = Mechanisms of Antibiotic Resistance | journal = Microbiology Spectrum | volume = 4 | issue = 2 | pages = 481–511 | date = April 2016 | pmid = 27227291 | pmc = 4888801 | doi = 10.1128/microbiolspec.VMBF-0016-2015 | isbn = 978-1-55581-927-9 }}</ref>

Two other forms of acquired resistance include the production of drug-inactivating enzymes (esterases<ref>{{cite journal |last1=Morar |first1=Mariya |last2=Pengelly |first2=Kate |last3=Koteva |first3=Kalinka |last4=Wright |first4=Gerard D. |date=2012-02-28 |title=Mechanism and diversity of the erythromycin esterase family of enzymes |url=https://pubmed.ncbi.nlm.nih.gov/22303981/#:~:text=Our%20analysis%20reveals%20that%20erythromycin,dimensional%20structures%20have%20been%20determined. |journal=Biochemistry |volume=51 |issue=8 |pages=1740–1751 |doi=10.1021/bi201790u |issn=1520-4995 |pmid=22303981}}</ref><ref>{{cite journal |last1=Dhindwal |first1=Poonam |last2=Thompson |first2=Charis |last3=Kos |first3=Daniel |last4=Planedin |first4=Koa |last5=Jain |first5=Richa |last6=Jelinski |first6=Murray |last7=Ruzzini |first7=Antonio |date=2023-02-21 |title=A neglected and emerging antimicrobial resistance gene encodes for a serine-dependent macrolide esterase |journal=Proceedings of the National Academy of Sciences |language=en |volume=120 |issue=8 |pages=e2219827120 |doi=10.1073/pnas.2219827120 |pmid=36791107 |pmc=9974460 |bibcode=2023PNAS..12019827D |issn=0027-8424}}</ref> or kinases<ref>{{cite journal |last1=Fong |first1=Desiree H. |last2=Burk |first2=David L. |last3=Blanchet |first3=Jonathan |last4=Yan |first4=Amy Y. |last5=Berghuis |first5=Albert M. |date=2017-05-02 |title=Structural Basis for Kinase-Mediated Macrolide Antibiotic Resistance |journal=Structure  |volume=25 |issue=5 |pages=750–761.e5 |doi=10.1016/j.str.2017.03.007 |issn=1878-4186 |pmid=28416110|doi-access=free }}</ref>), as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.<ref>{{cite journal | title=Mechanisms of Resistance to Macrolides and Lincosamides: Nature of the Resistance Elements and Their Clinical Implications | author=Roland Leclercq | date=15 February 2002 |journal=Clinical Infectious Diseases | volume=34 | issue=4 | pages=482–492 |doi=10.1086/324626| pmid=11797175 | doi-access=free }}</ref>

Azithromycin has been used to treat strep throat ([[Group A streptococcal infection|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.<ref>{{cite journal |url=https://www.aafp.org/pubs/afp/issues/2009/0301/p383.html|title=Diagnosis and Treatment of Streptococcal Pharyngitis |journal=American Family Physician |year=2009 |volume=79 |issue=5 |pages=383–390 |access-date=2024-01-25 | vauthors = Choby BA |pmid=19275067 }}</ref>

==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]].<ref>{{cite journal | vauthors = Sathasivam S, Lecky B | title = Statin induced myopathy | journal = BMJ | volume = 337 | pages = a2286 | date = November 2008 | pmid = 18988647 | doi = 10.1136/bmj.a2286 | s2cid = 3239804 }}</ref> This is because some macrolides (clarithromycin and erythromycin, not azithromycin) are potent [[enzyme inhibitor|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.<ref>{{cite journal | vauthors = SanFilippo A | title = Infantile hypertrophic pyloric stenosis related to ingestion of erythromycine estolate: A report of five cases | journal = Journal of Pediatric Surgery | volume = 11 | issue = 2 | pages = 177–80 | date = April 1976 | pmid = 1263054 | doi = 10.1016/0022-3468(76)90283-9 }}</ref><ref>{{cite journal | vauthors = Honein MA, Paulozzi LJ, Himelright IM, Lee B, Cragan JD, Patterson L, Correa A, Hall S, Erickson JD | title = Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromcyin: a case review and cohort study | journal = Lancet | volume = 354 | issue = 9196 | pages = 2101–5 | year = 1999 | pmid = 10609814 | doi = 10.1016/S0140-6736(99)10073-4 | s2cid = 24160212 }}</ref>

Some macrolides are also known to cause [[cholestasis]], a condition where bile cannot flow from the liver to the duodenum.<ref>{{cite journal | vauthors = Hautekeete ML | title = Hepatotoxicity of antibiotics | journal = Acta Gastro-Enterologica Belgica | volume = 58 | issue = 3–4 | pages = 290–6 | year = 1995 | pmid = 7491842 }}</ref> A study reported in 2019 found an association between erythromycin use during infancy and developing IHPS (Infantile hypertrophic pyloric stenosis) in infants.<ref name=":0">{{cite journal | vauthors = Abdellatif M, Ghozy S, Kamel MG, Elawady SS, Ghorab MM, Attia AW, Le Huyen TT, Duy DT, Hirayama K, Huy NT | title = Association between exposure to macrolides and the development of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis | journal = European Journal of Pediatrics | volume = 178 | issue = 3 | pages = 301–314 | date = March 2019 | pmid = 30470884 | doi = 10.1007/s00431-018-3287-7 | s2cid = 53711818 }}</ref> However, no significant association was found between macrolides use during pregnancy or breastfeeding.<ref name=":0" />

A Cochrane review showed gastrointestinal symptoms to be the most frequent adverse event reported in literature.<ref>{{cite journal |last1=Hansen |first1=Malene Plejdrup |last2=Scott |first2=Anna M |last3=McCullough |first3=Amanda |last4=Thorning |first4=Sarah |last5=Aronson |first5=Jeffrey K |last6=Beller |first6=Elaine M |last7=Glasziou |first7=Paul P |last8=Hoffmann |first8=Tammy C |last9=Clark |first9=Justin |last10=Del Mar |first10=Chris B |title=Adverse events in people taking macrolide antibiotics versus placebo for any indication |journal=Cochrane Database of Systematic Reviews |volume=1 |pages=CD011825 |date=18 January 2019 |issue=1 |doi=10.1002/14651858.CD011825.pub2|pmid=30656650 |pmc=6353052 }}</ref>

== 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.<ref name="pmid32807049">{{cite journal |vauthors=Zhang L, Xu X, Badawy S, Ihsan A, Liu Z, Xie C, Wang X, Tao Y |title=A Review: Effects of Macrolides on CYP450 Enzymes |journal=Curr Drug Metab |volume=21 |issue=12 |pages=928–937 |date=2020 |pmid=32807049 |doi=10.2174/1389200221666200817113920 |s2cid=221162650 |url=}}</ref> 

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.<ref name="pmid31628882">{{cite journal |vauthors=Hougaard Christensen MM, Bruun Haastrup M, Øhlenschlaeger T, Esbech P, Arnspang Pedersen S, Bach Dunvald AC, Bjerregaard Stage T, Pilsgaard Henriksen D, Thestrup Pedersen AJ |title=Interaction potential between clarithromycin and individual statins-A systematic review |journal=Basic Clin Pharmacol Toxicol |volume=126 |issue=4 |pages=307–317 |date=April 2020 |pmid=31628882 |doi=10.1111/bcpt.13343}}</ref>

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.<ref name="pmid31628882"/> 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.<ref name="pmid11012550">{{cite journal |vauthors=Westphal JF |title=Macrolide - induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin |journal=Br J Clin Pharmacol |volume=50 |issue=4 |pages=285–95 |date=October 2000 |pmid=11012550 |pmc=2015000 |doi=10.1046/j.1365-2125.2000.00261.x |url=}}</ref>

The difference in CYP3A4 inhibition by macrolides has clinical implications, for example, for patients who take [[statin]]s, 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.<ref name="pmid31628882"/>

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.<ref>{{cite web | url = http://www.hanstenandhorn.com/hh-article05-06.pdf | archive-url = https://web.archive.org/web/20060904085801/http://www.hanstenandhorn.com/hh-article05-06.pdf | url-status = usurped | archive-date = September 4, 2006 |author1=John R. Horn  |author2=Philip D. Hansten  | title = Life Threatening Colchicine Drug Interactions. Drug Interactions: Insights and Observations | date = 2006}}</ref><ref name="pmid36104598">{{cite journal |vauthors=Tan MS, Gomez-Lumbreras A, Villa-Zapata L, Malone DC |title=Colchicine and macrolides: a cohort study of the risk of adverse outcomes associated with concomitant exposure |journal=Rheumatol Int |volume=42 |issue=12 |pages=2253–2259 |date=December 2022 |pmid=36104598 |pmc=9473467 |doi=10.1007/s00296-022-05201-5 |url=}}</ref>

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | vauthors = Ōmura S | title = Macrolide antibiotics: chemistry, biology, and practice | publisher = Academic Press | location = Boston | year = 2002 | edition = 2nd | isbn = 978-0-12-526451-8 }}
* {{cite web | url = http://www.infectio-lille.com/diaporamas/invites/struct-act-duatb05-bryskier.pdf | archive-url = https://web.archive.org/web/20060304094439/http://www.infectio-lille.com/diaporamas/invites/struct-act-duatb05-bryskier.pdf | url-status = dead | archive-date = 2006-03-04 | title = Antibacterial Agents; Structure Activity Relationships | first = André | last = Bryskier | page = 143 }}
{{refend}}

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[[Category:Macrolides| ]]