Editing Azithromycin (section)

==Research==
Azithromycin is researched for its supposed anti-inflammatory and immunomodulatory properties, which are believed to be exhibited through its suppression of proinflammatory [[cytokine]]s and enhancing the production of anti-inflammatory cytokines, which is important in dampening [[inflammation]]. Cytokines are small proteins that are secreted by immune cells and play a key role in the immune response. Studies suggest that azithromycin can decrease the release of pro-inflammatory cytokines such as [[TNF-alpha]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 6|IL-6]], and [[Interleukin 8|IL-8]] while increasing the levels of anti-inflammatory cytokine [[Interleukin 10|IL-10]]. By decreasing the number of pro-inflammatory cytokines, azithromycin probably controls potential tissue damage during inflammation. These effects are believed to be due to azithromycin's ability to suppress a [[transcription factor]] called [[NF-κB|nuclear factor-kappa B (NF-κB)]] resulting in blockade of inflammatory response pathways downstream from [[NF-κB]] activation leading to decreased chemokine receptor [[CXCR4]] signaling causing reduced inflammation.<ref name="pmid32725797">{{cite journal |vauthors=Lim DJ, Thompson HM, Walz CR, Ayinala S, Skinner D, Zhang S, Grayson JW, Cho DY, Woodworth BA |title=Azithromycin and ciprofloxacin inhibit interleukin-8 secretion without disrupting human sinonasal epithelial integrity in vitro |journal=Int Forum Allergy Rhinol |volume=11 |issue=2 |pages=136–143 |date=February 2021 |pmid=32725797 |pmc=7854841 |doi=10.1002/alr.22656 }}</ref><ref name="pmid37499396">{{cite journal |vauthors=Yadav S, Dalai P, Gowda S, Nivsarkar M, Agrawal-Rajput R |title=Azithromycin alters Colony Stimulating Factor-1R (CSF-1R) expression and functional output of murine bone marrow-derived macrophages: A novel report |journal=Int Immunopharmacol |volume=123 |issue= |pages=110688 |date=October 2023 |pmid=37499396 |doi=10.1016/j.intimp.2023.110688 |s2cid=260186900 }}</ref><ref name="pmid37778397">{{cite journal |vauthors=Wang Z, Chu C, Ding Y, Li Y, Lu C |title=Clinical significance of serum microRNA-146a and inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment |journal=J Pediatr (Rio J) |volume= 100|issue= 1|pages= 108–115|date=September 2023 |pmid=37778397 |doi=10.1016/j.jped.2023.06.004 |s2cid=263253426 | doi-access = free | title-link = doi |pmc=10751685 }}</ref><ref name="pmid37118704">{{cite journal |vauthors=Terpstra LC, Altenburg J, Doodeman HJ, ((Piñeros YSS)), Lutter R, ((Heijerman HGM)), Boersma WG |title=The effect of azithromycin on sputum inflammatory markers in bronchiectasis |journal=BMC Pulm Med |volume=23 |issue=1 |pages=151 |date=April 2023 |pmid=37118704 |pmc=10148509 |doi=10.1186/s12890-023-02444-1 | doi-access = free | title-link = doi }}</ref><ref name="pmid36691058">{{cite journal |vauthors=Wu S, Tian X, Mao Q, Peng C |title=Azithromycin attenuates wheezing after pulmonary inflammation through inhibiting histone H3K27me3 hypermethylation mediated by EZH2 |journal=Clin Epigenetics |volume=15 |issue=1 |pages=12 |date=January 2023 |pmid=36691058 |pmc=9872437 |doi=10.1186/s13148-023-01430-y | doi-access = free | title-link = doi }}</ref> Despite the efficiency of treating rosacea with azithromycin, the exact mechanism of why azithromycin is effective in treating rosacea are not completely understood.<ref name="pmid17244346">{{cite journal |vauthors=Bakar O, Demirçay Z, Yuksel M, Haklar G, Sanisoglu Y |title=The effect of azithromycin on reactive oxygen species in rosacea |journal=Clin Exp Dermatol |volume=32 |issue=2 |pages=197–200 |date=March 2007 |pmid=17244346 |doi=10.1111/j.1365-2230.2006.02322.x |s2cid=30016695 }}</ref> It is unclear whether its antibacterial or immunomodulatory properties or a combination of both mechanisms contribute to its efficacy. Azithromycin may prevent [[mast cell]] [[degranulation]] and thus can suppress inflammation of [[Dorsal root ganglion|dorsal root ganglia]] through various signaling pathways such as decreased numbers of [[CD4+ cells|CD4+]] [[T cell]]s which are particularly relevant since they mediate the response of [[hair follicle]] [[antigen]]s.<ref name="pmid29888693">{{cite journal |vauthors=Ersoy B, Aktan B, Kilic K, Sakat MS, Sipal S |title=The anti-inflammatory effects of erythromycin, clarithromycin, azithromycin and roxithromycin on histamine-induced otitis media with effusion in guinea pigs |journal=J Laryngol Otol |volume=132 |issue=7 |pages=579–583 |date=July 2018 |pmid=29888693 |doi=10.1017/S0022215118000610 |s2cid=47010752 }}</ref> Inflammation in rosacea is thought to be associated with increased production of [[reactive oxygen species]] (ROS) by inflammatory cells. The ability of azithromycin to decrease [[Reactive oxygen species|ROS]] production can help reduce [[oxidative stress]] and inflammation, but this remains speculation.<ref name="pmid17244346"/>

The therapeutic role of azithromycin has been explored in various diseases such as [[cystic fibrosis]] exacerbation, burn injury-induced lung injury, [[asthma]], [[chronic obstructive pulmonary disease]], and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in COVID-19 infection.<ref name="pmid37524191">{{cite journal |vauthors=Durán-Álvarez JC, Prado B, Zanella R, Rodríguez M, Díaz S |title=Wastewater surveillance of pharmaceuticals during the COVID-19 pandemic in Mexico City and the Mezquital Valley: A comprehensive environmental risk assessment |journal=Sci Total Environ |volume=900 |issue= |pages=165886 |date=November 2023 |pmid=37524191 |doi=10.1016/j.scitotenv.2023.165886 |bibcode= 2023ScTEn.90065886D|s2cid=260323001 }}</ref><ref name="pmid15516680">{{cite journal |vauthors=Southern KW, Barker PM |title=Azithromycin for cystic fibrosis |journal=Eur Respir J |volume=24 |issue=5 |pages=834–8 |date=November 2004 |pmid=15516680 |doi=10.1183/09031936.04.00084304 |s2cid=17778741 | doi-access = free | title-link = doi }}</ref><ref name="pmid35853636">{{cite journal |vauthors= |title=Azithromycin and cystic fibrosis |journal=Arch Dis Child |volume=107 |issue=8 |pages=739 |date=August 2022 |pmid=35853636 |doi=10.1136/archdischild-2022-324569 |s2cid=250624603 }}</ref><ref name="pmid35202621">{{cite journal |vauthors=Ghimire JJ, Jat KR, Sankar J, Lodha R, Iyer VK, Gautam H, Sood S, Kabra SK |title=Azithromycin for Poorly Controlled Asthma in Children: A Randomized Controlled Trial |journal=Chest |volume=161 |issue=6 |pages=1456–1464 |date=June 2022 |pmid=35202621 |doi=10.1016/j.chest.2022.02.025 |s2cid=247074537 }}</ref><ref name="pmid28687413">{{cite journal |vauthors=Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, Marks GB, Baraket M, Powell H, Taylor SL, ((Leong LEX)), Rogers GB, Simpson JL |title=Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial |journal=Lancet |volume=390 |issue=10095 |pages=659–668 |date=August 2017 |pmid=28687413 |doi=10.1016/S0140-6736(17)31281-3 |s2cid=4523731 |url=http://handle.unsw.edu.au/1959.4/unsworks_46370 }}</ref> Despite early evidence showing azithromycin slowed down coronavirus multiplication in laboratory settings, further research indicates it to be ineffective as a treatment for [[COVID-19]] in humans.<ref>{{cite journal |journal=Cochrane Database of Systematic Reviews |title=Intervention Antibiotics for the treatment of COVID-19 |vauthors=Popp M, Stegemann M, Riemer M, Metzendorf M, Romero CS, Mikolajewska A, Kranke P, Meybohm P, Skoetz N, Weibel S |date=22 October 2021 |volume=10 |issue=10 |pages=CD015025 |doi=10.1002/14651858.CD015025|pmid=34679203 |pmc=8536098 }}</ref> Azithromycin in conjunction with [[chloroquine]] or [[hydroxychloroquine]] has been associated with deleterious outcomes in COVID-19 patients, including [[drug-induced QT prolongation]].<ref name="pmid38425958">{{cite journal |vauthors=Nag K, Tripura K, Datta A, Karmakar N, Singh M, Singh M, Singal K, Pradhan P |title=Effect of Hydroxychloroquine and Azithromycin Combination Use in COVID-19 Patients - An Umbrella Review |journal=Indian J Community Med |volume=49 |issue=1 |pages=22–27 |date=2024 |pmid=38425958 |pmc=10900474 |doi=10.4103/ijcm.ijcm_983_22 | doi-access = free | title-link = doi }}</ref> After a large-scale trial showed no benefit of using azithromycin in treating COVID-19, the UK's [[National Institute for Health and Care Excellence]] (NICE) updated its guidance and no longer recommends the medication for COVID-19.<ref>{{cite journal | vauthors = Butler CC, Yu LM, Dorward J, Gbinigie O, Hayward G, Saville BR, Van Hecke O, Berry N, Detry MA, Saunders C, Fitzgerald M, Harris V, Djukanovic R, Gadola S, Kirkpatrick J, de Lusignan S, Ogburn E, Evans PH, Thomas NP, Patel MG, Hobbs FD | title = Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial | journal = The Lancet. Respiratory Medicine | volume = 9 | issue = 9 | pages = 1010–1020 | date = September 2021 | pmid = 34329624 | pmc = 8315758 | doi = 10.1016/S2213-2600(21)00310-6 }}</ref><ref>{{cite journal |date=31 May 2022 |title=Platform trial rules out treatments for COVID-19 |url=https://evidence.nihr.ac.uk/alert/platform-trial-rules-out-covid-treatments/ |website=National Institute for Health and Care Research (NIHR) |doi=10.3310/nihrevidence_50873 |access-date=1 June 2022 |archive-date=1 June 2022 |archive-url=https://web.archive.org/web/20220601095141/https://evidence.nihr.ac.uk/alert/platform-trial-rules-out-covid-treatments/ |url-status=live |url-access=subscription }}</ref>

Azithromycin has been studied in the treatment of [[chronic fatigue syndrome]] (CFS) and has been reported to improve or even resolve symptoms in some cases.<ref name="KlimasKoneru2007">{{cite journal | vauthors = Klimas NG, Koneru AO | title = Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions | journal = Curr Rheumatol Rep | volume = 9 | issue = 6 | pages = 482–487 | date = December 2007 | pmid = 18177602 | doi = 10.1007/s11926-007-0078-y | url = }}</ref><ref name="KavyaniLidburySchloeffel2022">{{cite journal | vauthors = Kavyani B, Lidbury BA, Schloeffel R, Fisher PR, Missailidis D, Annesley SJ, Dehhaghi M, Heng B, Guillemin GJ | title = Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle? | journal = Cell Mol Life Sci | volume = 79 | issue = 8 | pages = 412 | date = July 2022 | pmid = 35821534| pmc = 9276562 | doi = 10.1007/s00018-022-04380-5 | url = }}</ref><ref name="VanHoudenhovePaeLuyten2010">{{cite journal | vauthors = Van Houdenhove B, Pae CU, Luyten P | title = Chronic fatigue syndrome: is there a role for non-antidepressant pharmacotherapy? | journal = Expert Opin Pharmacother | volume = 11 | issue = 2 | pages = 215–223 | date = February 2010 | pmid = 20088743 | doi = 10.1517/14656560903487744 | url = }}</ref><ref name="VermeulenScholte2006">{{cite journal | vauthors = Vermeulen RC, Scholte HR | title = Azithromycin in chronic fatigue syndrome (CFS), an analysis of clinical data | journal = J Transl Med | volume = 4 | issue = | pages = 34 | date = August 2006 | pmid = 16911783 | doi = 10.1186/1479-5876-4-34 | doi-access = free | pmc = 1562448 | url = }}</ref><ref name="ChiaChia1999">{{cite journal | vauthors = Chia JK, Chia LY | title = Chronic Chlamydia pneumoniae infection: a treatable cause of chronic fatigue syndrome | journal = Clin Infect Dis | volume = 29 | issue = 2 | pages = 452–453 | date = August 1999 | pmid = 10476765 | doi = 10.1086/520239 | url = }}</ref> However, these studies have been described as being of very low [[quality of evidence|quality]].<ref name="VanHoudenhovePaeLuyten2010" /> In any case, the beneficial effects might be by eradication of chronic bacterial infections that are possibly contributing to or causing CFS or by the immunomodulatory effects of azithromycin.<ref name="KlimasKoneru2007" /><ref name="KavyaniLidburySchloeffel2022" /><ref name="VanHoudenhovePaeLuyten2010" /><ref name="VermeulenScholte2006" /><ref name="ChiaChia1999" />

Azithromycin therapy in cystic fibrosis patients yields a modest respiratory function improvement, reduces exacerbation risk, and extends time to exacerbation up to six months; still, long-term efficacy data is a subject of ongoing research. Potential benefits of azithromycin therapy is azithromycin's good safety profile, minimal treatment burden, and cost-effectiveness, but the drawbacks are gastrointestinal side effects with weekly dosing, which are ameliorated by a split dose regimen.<ref name="pmid38411248">{{cite journal |vauthors=Southern KW, Solis-Moya A, Kurz D, Smith S |title=Macrolide antibiotics (including azithromycin) for cystic fibrosis |journal=Cochrane Database Syst Rev |volume=2024 |issue=2 |pages=CD002203 |date=February 2024 |pmid=38411248 |doi=10.1002/14651858.CD002203.pub5 |pmc=10897949 }}</ref><ref name="pmid35411400">{{cite journal |vauthors=Ong JJ, Aguirre I, Unemo M, Kong FY, Fairley CK, Hocking JS, Chow EP, Tieosapjaroen W, Ly J, Chen MY |title=Comparison of gastrointestinal side effects from different doses of azithromycin for the treatment of gonorrhoea |journal=J Antimicrob Chemother |volume=77 |issue=7 |pages=2011–2016 |date=June 2022 |pmid=35411400 |pmc=9244214 |doi=10.1093/jac/dkac118 }}</ref> The potential role of azithromycin in inhibiting the autophagic destruction of non-tuberculous mycobacteria (NTM) within macrophages has garnered significant attention. This mechanism may contribute to the observed correlation between long-term macrolide monotherapy and an increased risk of NTM infection and the emergence of macrolide-resistant strains. Azithromycin's interference with autophagy could potentially predispose patients with cystic fibrosis to mycobacterial infections. Despite repeated refutations of a direct association between azithromycin use and NTM infection, there remains a high level of concern regarding the potential for the development of NTM strains resistant to macrolides.<ref name="pmid38104098">{{cite journal |vauthors=Gramegna A, Misuraca S, Lombardi A, Premuda C, Barone I, Ori M, Amati F, Retucci M, Nazzari E, Alicandro G, Ferrarese M, Codecasa L, Bandera A, Aliberti S, Daccò V, Blasi F |title=Treatable traits and challenges in the clinical management of non-tuberculous mycobacteria lung disease in people with cystic fibrosis |journal=Respir Res |volume=24 |issue=1 |pages=316 |date=December 2023 |pmid=38104098 |pmc=10725605 |doi=10.1186/s12931-023-02612-1| doi-access = free | title-link = doi }}</ref>

Azithromycin has been shown to be an effective preventive measure against many postpartum infections in mothers following planned vaginal births; still, its impact on neonatal outcomes remains inconclusive and is the subject of ongoing research.<ref name="pmid37724021">{{cite journal |vauthors=Crosara LF, Orsini PV, Eskandar K, Khalil SM, Castilhos GS, Strahl PA, Milbradt TL, Philip CE |title=Single-dose oral azithromycin prophylaxis in planned vaginal delivery for sepsis prevention: A systematic review and meta-analysis of randomized controlled trials |journal=Int J Gynaecol Obstet |volume=165 |issue=1 |pages=107–116 |date=April 2024 |pmid=37724021 |doi=10.1002/ijgo.15124}}</ref><ref name="pmid38486177">{{cite journal |vauthors=Ye H, Hu J, Li B, Yu X, Zheng X |title=Can the use of azithromycin during labour reduce the incidence of infection among puerperae and newborns? A systematic review and meta-analysis of randomized controlled trials |journal=BMC Pregnancy Childbirth |volume=24 |issue=1 |pages=200 |date=March 2024 |pmid=38486177 |pmc=10938810 |doi=10.1186/s12884-024-06390-6 | doi-access = free | title-link = doi }}</ref>