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We performed a systematic review and meta\u2010analysis of randomized clinical trials that compared macrolides or tetracyclines with placeboes to provide long\u2010term safety information. We searched Medline and EMBASE from inception to October 2022 and identified studies that reported study drug\u2010related death, serious adverse events (SAEs), or withdrawal rates, and common adverse effects of each drug. Relative risk (RR) and number needed to harm were calculated. Of the 52 randomized clinical trials included, there are 3151 participants on doxycycline, 2519 participants on minocycline, 3049 participants on azithromycin, 763 participants on clarithromycin, 262 participants on erythromycin, and 100 participants on roxithromycin. There was no death related to any study drugs and rates of SAE were not significantly different from placebo in any drug. Overall withdrawal rates were slightly higher than placebo in doxycycline (RR, 1.30; 95% CI, 1.12\u20101.52) and minocycline (RR, 1.29; 95% CI, 1.15\u20101.46). Withdrawal rates due to adverse events were higher in doxycycline (RR, 2.82; 95% CI, 1.88\u20104.22), minocycline (RR, 1.48; 95% CI, 1.09\u20101.98), and azithromycin (RR, 1.53; 95% CI, 1.13\u20102.08). Gastrointestinal disturbances are the most common tolerable adverse effects for every drug. Photosensitivity and rash are the second most common adverse effects for doxycycline and minocycline. We found no evidence that long\u2010term use up to 2 years of macrolides or tetracyclines was associated with increased risk of SAEs.<\/jats:p>","DOI":"10.1002\/jcph.2358","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T20:43:51Z","timestamp":1695761031000},"page":"164-177","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Long\u2010Term Safety Profiles of Macrolides and Tetracyclines: A Systematic Review and Meta\u2010Analysis"],"prefix":"10.1002","volume":"64","author":[{"given":"Palapun","family":"Waitayangkoon","sequence":"first","affiliation":[{"name":"Department of Medicine MetroWest Medical Center Tufts University School of Medicine  Framingham MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Jin","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Medicine MetroWest Medical Center Tufts University School of Medicine  Framingham MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jai Juganya","family":"Tirupur Ponnusamy","sequence":"additional","affiliation":[{"name":"Department of Medicine MetroWest Medical Center Tufts University School of Medicine  Framingham MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Immunology Tufts University School of Medicine  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Driban","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Allergy &amp; Immunology Tufts Medical Center  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"McAlindon","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Allergy &amp; Immunology Tufts Medical Center  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,15]]},"reference":[{"issue":"8","key":"e_1_2_10_2_1","first-page":"14","article-title":"Nonantibiotic properties of tetracyclines in rosacea and their clinical implications","volume":"14","author":"Del Rosso JQ","year":"2021","journal-title":"J Clin Aesthet Dermatol"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.121.000300"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-2918(03)80095-4"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2165\/00151829-200504010-00004"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-4632.2008.03445.x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2005.04.069"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780370505"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200110)44:10<2235::AID-ART385>3.0.CO;2-A"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400510"},{"issue":"10","key":"e_1_2_10_11_1","first-page":"2112","article-title":"Should tetracycline treatment be used more extensively for rheumatoid arthritis? 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