Ciprofloxacin: Difference between revisions
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{{Short description|Fluoroquinolone antibiotic}}
{{
{{distinguish|Ciproxifan}}
{{Use dmy dates|date=August 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 443526033
| image = Ciprofloxacin.svg
| width = 200
| alt = ciprofloxacin molecule
| caption = structure
| image2 = Ciprofloxacin-zwitterion-from-xtal-3D-balls.png
| width2 =
| alt2 = ciprofloxacin zwitterion molecule
| caption2 = 3D model of ciprofloxacin [[zwitterion]]
<!--
Clinical data
-->
| pronounce =
| tradename = Ciloxan, Cipro, Neofloxin, others
| Drugs.com = {{drugs.com|monograph|ciprofloxacin}}
| MedlinePlus = a688016
|
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name="Drugs.com Pregnancy">{{cite web |title=Ciprofloxacin Use During Pregnancy |website=Drugs.com |url=https://www.drugs.com/pregnancy/ciprofloxacin.html |date=7 January 2019 |access-date=19 December 2019}}</ref>
| pregnancy_category =
| routes_of_administration = [[By mouth]], [[intravenous therapy|intravenous]], [[topical]] ([[ear drop]]s, [[eye drop]]s)
| class = [[Fluoroquinolone]]
| ATCvet =
| ATC_prefix = J01
| ATC_suffix = MA02
| ATC_supplemental = {{ATC|S01|AE03}} {{ATC|S02|AA15}} {{ATC|S03|AA07}} {{ATC|J01|RA10}} {{ATC|J01|RA11}} {{ATC|J01|RA12}}
<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Cipro FDA label">{{cite web | title=Cipro- ciprofloxacin hydrochloride tablet, film coated; Cipro- ciprofloxacin kit | website=DailyMed | date=31 January 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=888dc7f9-ad9c-4c00-8d50-8ddfd9bd27c0 | access-date=9 February 2024}}</ref>
| legal_EU =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->
<!--
Pharmacokinetic data
-->
| bioavailability = 70%<ref name="pmid17154673">{{cite journal |vauthors=Zhanel GG, Fontaine S, Adam H, Schurek K, Mayer M, Noreddin AM, Gin AS, Rubinstein E, Hoban DJ |title=A Review of New Fluoroquinolones: Focus on their Use in Respiratory Tract Infections |journal=Treatments in Respiratory Medicine |volume=5 |issue=6 |pages=437–465 |year=2006 |pmid=17154673 |s2cid=26955572 |doi=10.2165/00151829-200605060-00009}}</ref>
| protein_bound = 30%<ref name="pmid17154673" />
| metabolism = [[Liver]]
|
| onset =
| elimination_half-life = 3.5 hours<ref name="pmid17154673" />
| duration_of_action =
| excretion = [[Kidney]]
<!--
Identifiers
-->
| index2_label = as HCl
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 85721-33-1
|
| PubChem = 2764
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00537
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
Line 41 ⟶ 78:
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00186
| KEGG2_Ref = {{keggcite|changed|kegg}}
| KEGG2 = D02216
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 100241
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 8
| NIAID_ChemDB = 001992
| PDB_ligand =
| synonyms =
<!--
Chemical
and physical data
-->
| IUPAC_name = 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid
| C=17 |H=18 |F=1 |N=3 |O=3
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H18FN3O3/c18-13-7-11-14(8-15(13)20-5-3-19-4-6-20)21(10-1-2-10)9-12(16(11)22)17(23)24/h7-10,19H,1-6H2,(H,23,24)
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MYSWGUAQZAJSOK-UHFFFAOYSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
<!-- Definition and medical uses -->
'''Ciprofloxacin''' is a [[fluoroquinolone]] [[antibiotic]] used to treat a number of [[bacterial infections]].<ref name=AHFS2015>{{cite web |title=Ciprofloxacin Hydrochloride |url=https://www.drugs.com/monograph/ciprofloxacin-hydrochloride.html |publisher=The American Society of Health-System Pharmacists |access-date=23 August 2015 |url-status=live |archive-url=https://web.archive.org/web/20150923232645/http://www.drugs.com/monograph/ciprofloxacin-hydrochloride.html |archive-date=23 September 2015}}</ref> This includes bone and [[joint infection]]s, intra-abdominal infections, certain types of [[Gastroenteritis|infectious diarrhea]], [[respiratory tract infection]]s, skin infections, [[typhoid fever]], and [[urinary tract infection]]s, among others.<ref name=AHFS2015/> For some infections it is used in addition to other antibiotics.<ref name=AHFS2015/> It can be taken by mouth, as eye drops, as ear drops, or intravenously.<ref name=AHFS2015/><ref name=":0">{{cite web |url=https://www.webmd.com/drugs/2/drug-91414-6093/ciprofloxacin-ophthalmic-eye/ciprofloxacin-drops-ophthalmic/details |title=Ciprofloxacin Hcl Drops |date=22 February 2018 |website=WebMD |access-date=22 February 2018}}</ref>
<!-- Side effects and mechanism-->
Common side effects include nausea, vomiting, and diarrhea.<ref name=AHFS2015/> Severe side effects include an increased risk of [[tendon rupture]], [[hallucinations]], and nerve damage.<ref name=AHFS2015/> In people with [[myasthenia gravis]], there is worsening muscle weakness.<ref name=AHFS2015/> Rates of side effects appear to be higher than some groups of antibiotics such as [[cephalosporin]]s but lower than others such as [[clindamycin]].<ref name=He2013>{{cite journal |vauthors=Heidelbaugh JJ, Holmstrom H |title=The perils of prescribing fluoroquinolones |url=http://www.jfponline.com/Pages.asp?AID=11235 |journal=The Journal of Family Practice |volume=62 |issue=4 |pages=191–197 |date=April 2013 |pmid=23570031}}</ref> Studies in other animals raise concerns regarding use in [[pregnancy]].<ref name=AG2015/> No problems were identified, however, in the children of a small number of women who took the medication.<ref name=AG2015>{{cite web |title=Prescribing medicines in pregnancy database |url=http://www.tga.gov.au/hp/medicines-pregnancy.htm |url-status=live |publisher=Government of Australia |date=23 August 2015 |archive-url=https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm |archive-date=8 April 2014}}</ref> It appears to be safe during [[breastfeeding]].<ref name=AHFS2015/> It is a second-generation fluoroquinolone with a [[Broad-spectrum antibiotic|broad spectrum of activity]] that usually results in the [[Bactericidal|death of the bacteria]].<ref name=AHFS2015/><ref name=":1">{{cite journal |vauthors=Ball P |title=Quinolone generations: natural history or natural selection? |journal=The Journal of Antimicrobial Chemotherapy |volume=46 Suppl T1 |pages=17–24 |date=July 2000 |pmid=10997595 |doi=10.1093/oxfordjournals.jac.a020889 |doi-access = free | title-link = doi }}</ref><ref>{{cite journal |vauthors=Oliphant CM, Green GM |title=Quinolones: a comprehensive review |url=http://www.aafp.org/link_out?pmid=11858629 |journal=American Family Physician |volume=65 |issue=3 |pages=455–464 |date=February 2002 |doi=10.1016/s0022-5347(17)67120-9 |pmid=1185862}}</ref>
<!-- History, society and culture -->
Ciprofloxacin was patented in 1980 and introduced in 1987.<ref>{{cite book |title=Oxford Handbook of Infectious Diseases and Microbiology |url=https://books.google.com/books?id=5W-WBQAAQBAJ&pg=PT56 |url-status=live |publisher=OUP Oxford |date=2009 |page=56 |archive-url=https://web.archive.org/web/20170908143257/https://books.google.com/books?id=5W-WBQAAQBAJ&pg=PT56 |archive-date=8 September 2017 |isbn=978-0-19-103962-1}}</ref><ref name=Fis2006>{{cite book |vauthors=Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA500 |publisher=[[John Wiley & Sons]] |date=2006 |page=500 |isbn=978-3-527-60749-5}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book |vauthors=((World Health Organization)) |author-link=World Health Organization |title=World Health Organization model list of essential medicines: 21st list 2019 |publisher=World Health Organization |location=Geneva |year=2019 |id=WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO |hdl=10665/325771 |hdl-access=free}}</ref><ref name="WHO22nd">{{cite book |vauthors=((World Health Organization)) |title=World Health Organization model list of essential medicines: 22nd list (2021) |publisher=World Health Organization |location=Geneva |year=2021 |id=WHO/MHP/HPS/EML/2021.02 |hdl=10665/345533 |hdl-access=free}}</ref> The World Health Organization classifies ciprofloxacin as critically important for human medicine.<ref>{{cite book |vauthors=((World Health Organization)) |title=Critically important antimicrobials for human medicine |edition=6th revision |publisher=World Health Organization |location=Geneva |year=2019 |hdl=10665/312266 |hdl-access=free |isbn=978-92-4-151552-8}}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/><ref name=Ric2014>{{cite book |vauthors=Hamilton RJ |title=Tarascon pharmacopoeia |url=https://books.google.com/books?id=F6YdAwAAQBAJ&pg=PA85 |url-status=live |publisher=Jones & Bartlett Publishers |edition=15th |date=2014 |page=85 |archive-url=https://web.archive.org/web/20170908143257/https://books.google.com/books?id=F6YdAwAAQBAJ&pg=PA85 |archive-date=8 September 2017 |isbn=978-1-284-05671-6}}</ref> In 2021, it was the 141st most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Ciprofloxacin - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Ciprofloxacin | access-date = 14 January 2024}}</ref>
==Medical uses==
Ciprofloxacin is used to treat a
Ciprofloxacin only treats bacterial infections; it does not treat viral infections such as the [[common cold]]. For certain uses including acute sinusitis, lower respiratory tract infections and uncomplicated [[gonorrhea]], ciprofloxacin is not considered a first-line agent.
Ciprofloxacin occupies an important role in treatment guidelines issued by major medical societies for the treatment of serious infections, especially those likely to be caused by Gram-negative bacteria, including ''[[Pseudomonas aeruginosa]]''. For example, ciprofloxacin in combination with [[metronidazole]] is one of several first-line antibiotic regimens recommended by the [[Infectious Diseases Society of America]] for the treatment of community-acquired abdominal infections in adults.<ref>{{cite journal |vauthors = Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, O'Neill PJ, Chow AW, Dellinger EP, Eachempati SR, Gorbach S, Hilfiker M, May AK, Nathens AB, Sawyer RG, Bartlett JG |title = Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America |journal = Clinical Infectious Diseases |volume = 50 |issue = 2 |pages = 133–64 |date = January 2010 |pmid = 20034345 |doi = 10.1086/649554 |author-link11 = Sherwood Gorbach |doi-access = free | title-link = doi }}</ref> It also features prominently in treatment guidelines for acute pyelonephritis, complicated or hospital-acquired urinary tract infection, acute or chronic prostatitis,<ref name=uroweb2013>{{cite web |vauthors = Grabe M, Bjerklund-Johansen TE, Botto H, Çek M, Naber KG, Pickard RS, Tenke P, Wagenlehner F, Wullt B |title = Guidelines on Urological Infections |publisher = European Association of Urology |archive-url = https://web.archive.org/web/20131231000606/http://www.uroweb.org/gls/pdf/18_Urological%20infections_LR.pdf |archive-date=31 December 2013 |date=2013 |url=http://www.uroweb.org/gls/pdf/18_Urological%20infections_LR.pdf |url-status=dead}}</ref> certain types of endocarditis,<ref>{{cite journal |vauthors = Baddour LM, Wilson WR, Bayer AS, Fowler VG, Bolger AF, Levison ME, Ferrieri P, Gerber MA, Tani LY, Gewitz MH, Tong DC, Steckelberg JM, Baltimore RS, Shulman ST, Burns JC, Falace DA, Newburger JW, Pallasch TJ, Takahashi M, Taubert KA |title = Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America |journal = Circulation |volume = 111 |issue = 23 |pages = e394–434 |date = June 2005 |pmid = 15956145 |doi = 10.1161/CIRCULATIONAHA.105.165564 |author23 = Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia |author22 = Council on Cardiovascular Disease in the Young |author21 = Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease |author25 = Infectious Diseases Society of America |author24 = American Heart Association |doi-access = free | title-link = doi }}</ref> certain skin infections,<ref>{{cite journal |vauthors = Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan EL, Montoya JG, Wade JC |title = Practice guidelines for the diagnosis and management of skin and soft-tissue infections |journal = Clinical Infectious Diseases |volume = 41 |issue = 10 |pages = 1373–406 |date = November 2005 |pmid = 16231249 |doi = 10.1086/497143 |doi-access = free | title-link = doi }}</ref> and prosthetic joint infections.<ref>{{cite journal |vauthors = Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, Rao N, Hanssen A, Wilson WR |title = Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America |journal = Clinical Infectious Diseases |volume = 56 |issue = 1 |pages = e1–e25 |date = January 2013 |pmid = 23223583 |doi = 10.1093/cid/cis803 |author10 = Infectious Diseases Society of America. |doi-access = free | title-link = doi }}</ref>
In other cases, treatment guidelines are more restrictive, recommending in most cases that older, narrower-spectrum drugs be used as first-line therapy for less severe infections to minimize fluoroquinolone-resistance development. For example, the Infectious Diseases Society of America recommends the use of ciprofloxacin and other fluoroquinolones in urinary tract infections be reserved to cases of proven or expected resistance to narrower-spectrum drugs such as [[nitrofurantoin]] or [[trimethoprim/sulfamethoxazole]].<ref>{{cite journal |vauthors = Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE |title = International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases |journal = Clinical Infectious Diseases |volume = 52 |issue = 5 |pages = e103–20 |date = March 2011 |pmid = 21292654 |doi = 10.1093/cid/ciq257 |doi-access = free | title-link = doi }}</ref> The [[European Association of Urology]] recommends ciprofloxacin as an alternative regimen for the treatment of uncomplicated urinary tract infections, but cautions that the potential for "adverse events have to be considered".<ref name=uroweb2013/>
Although approved by regulatory authorities for the treatment of respiratory infections, ciprofloxacin is not recommended for respiratory infections by most treatment guidelines due in part to its modest activity against the common respiratory pathogen ''[[Streptococcus pneumoniae]]''.<ref name=cfaeocb>{{cite journal |vauthors=Hoogkamp-Korstanje JA, Klein SJ |title=Ciprofloxacin in acute exacerbations of chronic bronchitis |journal=The Journal of Antimicrobial Chemotherapy |volume=18 |issue=3 |pages=407–413 |date=September 1986 |pmid=3490468 |doi=10.1093/jac/18.3.407}}</ref><ref>{{cite journal |vauthors=Vardakas KZ, Siempos II, Grammatikos A, Athanassa Z, Korbila IP, Falagas ME |title=Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials |journal=[[Canadian Medical Association Journal]] |volume=179 |issue=12 |pages=1269–1277 |date=December 2008 |pmid= 19047608 |pmc=2585120 |doi=10.1503/cmaj.080358}}</ref><ref name="pmid8019264">{{cite journal |vauthors=Donaldson PM, Pallett AP, Carroll MP |title=Ciprofloxacin in general practice |journal=BMJ |volume=308 |issue=6941 |page=1437 |date=May 1994 |pmid=8019264 |pmc=2540361 |doi=10.1136/bmj.308.6941.1437}}</ref> "Respiratory quinolones" such as [[levofloxacin]], having greater activity against this pathogen, are recommended as first line agents for the treatment of community-acquired pneumonia in patients with important co-morbidities and in patients requiring hospitalization (Infectious Diseases Society of America 2007). Similarly, ciprofloxacin is not recommended as a first-line treatment for [[acute sinusitis]].<ref name="Karageorgopoulos-2008">{{cite journal |vauthors=Karageorgopoulos DE, Giannopoulou KP, Grammatikos AP, Dimopoulos G, Falagas ME |title=Fluoroquinolones compared with beta-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials |journal=Canadian Medical Association Journal |volume=178 |issue=7 |pages=845–854 |date=March 2008 |pmid=18362380 |pmc=2267830 |doi=10.1503/cmaj.071157}}</ref><ref>{{cite journal |vauthors=Chow AW, Benninger MS, Brook I, Brozek JL, Goldstein EJ, Hicks LA, Pankey GA, Seleznick M, Volturo G, Wald ER, File TM |title=IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults |journal=Clinical Infectious Diseases |volume=54 |issue=8 |pages=e72–e112 |date=April 2012 |s2cid=1946193 |pmid=22438350 |doi=10.1093/cid/cir1043|doi-access = free | title-link = doi }}</ref>
Ciprofloxacin is approved for the treatment of gonorrhea in many countries, but this recommendation is widely regarded as obsolete due to resistance development.<ref>{{cite web |title=Gonococcal Isolate Surveillance Project (GISP) Annual Report – 2003 |url=https://www.cdc.gov/STD/gisp2003/GISP2003.pdf |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |date=November 2004 |access-date=31 August 2009 |url-status=live |archive-url=https://web.archive.org/web/20090424062831/http://www.cdc.gov/std/GISP2003/GISP2003.pdf |archive-date=24 April 2009}}</ref><ref>{{cite journal |vauthors = Young H, Palmer J, Winter A |date=22 July 2003 |title=Ciprofloxacin resistant gonorrhoea: the situation in Scotland and implications for therapy |journal=SCIEH Weekly Report |volume=37 |issn=1357-4493 |url=http://www.documents.hps.scot.nhs.uk/ewr/pdf2003/0329.pdf |url-status=dead |archive-url= https://web.archive.org/web/20110722204213/http://www.documents.hps.scot.nhs.uk/ewr/pdf2003/0329.pdf |archive-date=22 July 2011|access-date=30 August 2009}}</ref><ref>{{cite journal |title = Update to CDC's sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections |journal = MMWR. Morbidity and Mortality Weekly Report |volume = 56 |issue = 14 |pages = 332–336 |date = April 2007 |pmid = 17431378 |url = https://www.cdc.gov/mmwr/PDF/wk/mm5614.pdf |author1 = Centers for Disease Control and Prevention (CDC) }}</ref>
===Pregnancy===
An expert review of published data on experiences with ciprofloxacin use during pregnancy concluded therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state no risk exists.<ref>{{cite journal |vauthors = Barolin GS |title = [Illness, anxiety and the physician. An example from neurology and neurorehabilitation] |journal = Wiener Medizinische Wochenschrift |volume = 141 |issue = 22 |pages = 512–25 |date = May 1995 |pmid = 1801454 |pmc = 1801454 }}</ref> Exposure to quinolones, including levofloxacin, during the first-trimester is not associated with an increased risk of stillbirths, premature births, birth defects, or low birth weight.<ref>{{cite journal |vauthors=Ziv A, Masarwa R, Perlman A, Ziv D, Matok I |title=Pregnancy Outcomes Following Exposure to Quinolone Antibiotics – a Systematic-Review and Meta-Analysis |journal=Pharm. Res. |volume=35 |issue=5 |pages=109 |date=March 2018 |pmid=29582196 |doi=10.1007/s11095-018-2383-8 |s2cid=4724821 }}</ref>
Two small post-marketing epidemiology studies of mostly short-term, first-trimester exposure found that fluoroquinolones did not increase risk of major malformations, spontaneous abortions, premature birth, or low birth weight.<ref name="pmid9624471">{{cite journal |vauthors = Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, Schick B, Bonati M, Moretti M, Lalkin A, Pastuszak A, Koren G |title = Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study |journal = Antimicrobial Agents and Chemotherapy |volume = 42 |issue = 6 |pages = 1336–9 |date = June 1998 |pmid = 9624471 |pmc = 105599 |doi = 10.1128/AAC.42.6.1336 }}</ref><ref name="pmid8902438">{{cite journal |vauthors = Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, Rodriguez-Pinilla E, Pexieder T, Prapas N, Merlob P |title = Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS) |journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology |volume = 69 |issue = 2 |pages = 83–9 |date = November 1996 |pmid = 8902438 |doi = 10.1016/0301-2115(95)02524-3}}</ref>
===Breastfeeding===
Fluoroquinolones have been reported as present in a mother's milk and thus passed on to the nursing child.<ref>{{cite journal |vauthors = Shin HC, Kim JC, Chung MK, Jung YH, Kim JS, Lee MK, Amidon GL |title = Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats |journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology |volume = 136 |issue = 1 |pages = 95–102 |date = September 2003 |pmid = 14522602 |doi = 10.1016/j.cca.2003.08.004 }}</ref><ref>{{cite journal |vauthors = Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H |title = Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women |journal = Antimicrobial Agents and Chemotherapy |volume = 37 |issue = 2 |pages = 293–6 |date = February 1993 |pmid = 8452360 |pmc = 187655 |doi = 10.1128/AAC.37.2.293}}</ref>
===Children===
Oral and intravenous ciprofloxacin are approved by the FDA for use in children for only two indications due to the risk of permanent injury to the musculoskeletal system:
# Inhalational [[anthrax]] (postexposure)<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20780S08ltr.pdf |title=Cipro Labeling Revision Letter 08/30/2000 Supplement 008 New or Modified Indication |vauthors = Murphy D |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=30 August 2000 |url-status=live |archive-url=https://web.archive.org/web/20121018202604/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20780S08ltr.pdf |archive-date=18 October 2012}}</ref>
# Complicated urinary tract infections and [[pyelonephritis]] due to ''Escherichia coli'',<ref name=cipro2004>{{cite web |vauthors = Albrecht R |title=Cipro Labeling Revision Letter 03/25/2004 Supplement 049 Patient Population Altered |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537s049,19857s031,19847s027,20780s013ltr.pdf |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=25 March 2004 |access-date=7 September 2009 |url-status=live |archive-url=https://web.archive.org/web/20121018202556/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537s049,19857s031,19847s027,20780s013ltr.pdf |archive-date=18 October 2012}}</ref> but never as first-line agents.
===Spectrum of activity===
Its spectrum of activity includes most strains of bacterial pathogens responsible for [[community-acquired pneumonia]]s, [[bronchitis]], [[urinary tract infection]]s, and gastroenteritis.<ref>{{cite book |title=Pharmcards review cards for medical students |vauthors = Johannsen EC, Sabatine MS |date=2010 |publisher=Wolters Kluwer{{!}}Lippincott Williams & Wilkins |isbn=978-0-7817-8741-3 |edition=4th |location= Philadelphia |oclc=893525059 }}{{page needed|date=July 2018}}</ref> Ciprofloxacin is particularly effective against [[Gram-negative bacteria]] (such as ''[[Escherichia coli]]'', ''[[Haemophilus influenzae]]'', ''[[Klebsiella pneumoniae]]'', ''[[Legionella pneumophila]]'', ''[[Moraxella catarrhalis]]'', ''[[Proteus mirabilis]]'', and ''[[Pseudomonas aeruginosa]]''), but is less effective against [[Gram-positive bacteria]] (such as methicillin-sensitive ''[[Staphylococcus aureus]]'', ''[[Streptococcus pneumoniae]]'', and ''[[Enterococcus faecalis]]'') than newer fluoroquinolones.<ref>{{cite web |url=https://www.uptodate.com/contents/fluoroquinolones |title=Fluoroquinolones |vauthors = Hooper D |date=12 February 2018 |website=UpToDate |access-date=26 February 2018}}</ref>
===Bacterial resistance===
{{see also|Antibiotic abuse|Antibiotic resistance}}
As a result of its widespread use to treat minor infections readily treatable with older, narrower-spectrum antibiotics, many bacteria have developed resistance to this drug, leaving it significantly less effective than it would have been otherwise.<ref name="pmid10341191">{{cite journal |vauthors = Vatopoulos AC, Kalapothaki V, Legakis NJ |title = Bacterial resistance to ciprofloxacin in Greece: results from the National Electronic Surveillance System. Greek Network for the Surveillance of Antimicrobial Resistance |journal = Emerging Infectious Diseases |volume = 5 |issue = 3 |pages = 471–6 |date = 1999 |pmid = 10341191 |pmc = 2640758 |doi = 10.3201/eid0503.990325 }}</ref><ref>{{cite web |url = http://www.health.state.mn.us/news/pressrel/2009/bacterial022609.html |title=Bacterial resistance prompts concern among health officials |publisher= Minnesota Department of Health |date=26 February 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090305232555/http://www.health.state.mn.us/news/pressrel/2009/bacterial022609.html |archive-date=5 March 2009 }}</ref>
[[Antibiotic resistance|Resistance]] to ciprofloxacin and other [[fluoroquinolone]]s may evolve rapidly, even during a course of treatment. Numerous [[pathogen]]s, including [[enterococci]], ''[[Streptococcus pyogenes]]'' , and ''[[Klebsiella pneumoniae]]'' (quinolone-resistant) now exhibit resistance.<ref>M Jacobs, Worldwide Overview of Antimicrobial Resistance. International Symposium on Antimicrobial Agents and Resistance 2005.</ref> Widespread veterinary usage of fluoroquinolones, particularly in Europe, has been implicated.<ref>{{cite press release |title=Update on Extra-Label Use of Fluoroquinolones |url=https://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm127657.htm |publisher=[[Center for Veterinary Medicine]] (CVM) |date=16 July 1996 |access-date=12 August 2009 |url-status=live |archive-url=https://web.archive.org/web/20100309003153/https://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm127657.htm |archive-date=9 March 2010}}</ref> Meanwhile, some ''[[Burkholderia cepacia]]'', ''[[Clostridium innocuum]]'', and ''[[Enterococcus faecium]]'' strains have developed resistance to ciprofloxacin to varying degrees.<ref>{{cite web |title=Ciprofloxacin Data Sheet |url=http://www.toku-e.com/Upload/Products/PDS/20120618005735.pdf |date=1 December 2010 |publisher=Toku-E |url-status=dead |archive-url=https://web.archive.org/web/20131009014110/http://www.toku-e.com/Upload/Products/PDS/20120618005735.pdf |archive-date=9 October 2013 |access-date=20 June 2012}}</ref>
Fluoroquinolones had become the class of antibiotics most commonly prescribed to adults in 2002.<ref name="pmid15745724">{{cite journal |vauthors = Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS |title = Fluoroquinolone prescribing in the United States: 1995 to 2002 |journal = The American Journal of Medicine |volume = 118 |issue = 3 |pages = 259–68 |date = March 2005 |pmid = 15745724 |doi = 10.1016/j.amjmed.2004.09.015 }}</ref> Nearly half (42%) of those prescriptions in the US were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection.<ref name="pmid15745724"/>
==Contraindications==
Contraindications include:<ref name="Cipro FDA label" />
* Taking [[tizanidine]] at the same time
* Use by those who are hypersensitive to any member of the [[quinolone]] class of antimicrobial agents
* Use by those who are diagnosed with myasthenia gravis, as muscle weakness may be exacerbated<ref>{{cite book |vauthors=Thai T, Salisbury BH, Zito PM |chapter=Ciprofloxacin |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK535454/ |title=StatPearls |publisher=StatPearls Publishing |location=Treasure Island, FL |date=2022 |pmid=30571075 |access-date=31 January 2022}}</ref>
Ciprofloxacin is also considered to be contraindicated in children (except for the indications outlined above), in [[pregnancy]], to nursing mothers, and in people with [[epilepsy]] or other [[seizure]] disorders.
Caution may be required in people with [[Marfan syndrome]] or [[Ehlers-Danlos syndrome]].<ref>{{cite journal |vauthors=LeMaire SA, Zhang L, Zhang NS, Luo W, Barrish JP, Zhang Q, Coselli JS, Shen YH |title=Ciprofloxacin accelerates aortic enlargement and promotes dissection and rupture in Marfan mice |journal=[[The Journal of Thoracic and Cardiovascular Surgery]] |volume=163 |issue=3 |pages=e215–e226 |date=March 2022 |s2cid=224937717 |pmid=34586071 |doi=10.1016/j.jtcvs.2020.09.069|doi-access=free }}</ref>
==Adverse effects==
Adverse effects can involve the tendons, muscles, joints, nerves, and the central nervous system.<ref name=FDA2018>{{cite web |title=Drug Safety and Availability – FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects |url=https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm |publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=10 January 2018}}</ref><ref name="Fluoroquinolones increase the risk">{{cite journal |vauthors=Liu X, Ma J, Huang L, Zhu W |title=Fluoroquinolones increase the risk of serious arrhythmias: A systematic review and meta-analysis |journal=Medicine (Baltimore) |volume=96 |issue=44 |pages=e8273 |date=November 2017 |pmid=29095256 |pmc=5682775 |doi=10.1097/MD.0000000000008273}}</ref>
Rates of adverse effects appear to be higher than with some groups of antibiotics such as [[cephalosporin]]s but lower than with others such as [[clindamycin]].<ref name=He2013/> Compared to other antibiotics some studies find a higher rate of adverse effects<ref name=Br2013>{{cite journal |vauthors = Brown KA, Khanafer N, Daneman N, Fisman DN |title = Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection |journal = Antimicrobial Agents and Chemotherapy |volume = 57 |issue = 5 |pages = 2326–32 |date = May 2013 |pmid = 23478961 |pmc = 3632900 |doi = 10.1128/AAC.02176-12 }}</ref><ref name=Fal2006>{{cite journal |vauthors = Falagas ME, Matthaiou DK, Vardakas KZ |title = Fluoroquinolones vs beta-lactams for empirical treatment of immunocompetent patients with skin and soft tissue infections: a meta-analysis of randomized controlled trials |journal = Mayo Clinic Proceedings |volume = 81 |issue = 12 |pages = 1553–66 |date = December 2006 |pmid = 17165634 |doi = 10.4065/81.12.1553 }}</ref> while others find no difference.<ref name=Kn2012>{{cite journal |vauthors = Knottnerus BJ, Grigoryan L, Geerlings SE, Moll van Charante EP, Verheij TJ, Kessels AG, ter Riet G |title = Comparative effectiveness of antibiotics for uncomplicated urinary tract infections: network meta-analysis of randomized trials |journal = Family Practice |volume = 29 |issue = 6 |pages = 659–70 |date = December 2012 |pmid = 22516128 |doi = 10.1093/fampra/cms029 |doi-access = free | title-link = doi }}</ref>
In clinical trials most of the adverse events were described as mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment.<ref name="Cipro FDA label" /> Some adverse effects may be permanent.<ref name=FDA2018/> Ciprofloxacin was stopped because of an adverse event in 1% of people treated with the medication by mouth. The most frequently reported drug-related events, from trials of all formulations, all dosages, all drug-therapy durations, and for all indications, were nausea (2.5%), diarrhea (1.6%), abnormal liver function tests (1.3%), vomiting (1%), and rash (1%). Other adverse events occurred at rates of <1%.<ref name=CiproIV>{{cite web |title=Cipro IV Meta-analysis |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019847s046,019857s053lbl.pdf |archive-url=https://web.archive.org/web/20170218081012/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019847s046,019857s053lbl.pdf |archive-date=18 February 2017 |url-status=live |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=November 2011}}</ref>
===Tendon problems===
Ciprofloxacin includes a [[boxed warning]] in the United States due to an increased risk of [[tendinitis]] and tendon rupture, especially in people who are older than 60 years, people who also use corticosteroids, and people with kidney, lung, or heart transplants.<ref>{{cite journal |vauthors=Stephenson AL, Wu W, Cortes D, Rochon PA |title=Tendon Injury and Fluoroquinolone Use: A Systematic Review |journal=Drug Saf |volume=36 |issue=9 |pages=709–21 |date=September 2013 |pmid=23888427 |doi=10.1007/s40264-013-0089-8 |s2cid=24948660}}</ref> Tendon rupture can occur during therapy or even months after discontinuation of the medication.<ref>{{cite journal |vauthors = Saint F, Gueguen G, Biserte J, Fontaine C, Mazeman E |title = [Rupture of the patellar ligament one month after treatment with fluoroquinolone] |language = fr |journal = Revue de Chirurgie Orthopedique et Reparatrice de l'Appareil Moteur |volume = 86 |issue = 5 |pages = 495–7 |date = September 2000 |pmid = 10970974 |url = http://www.masson.fr/masson/MDOI-RCO-09-2000-86-5-0035-1040-101019-ART7 |trans-title = Rupture of the patellar ligament one month after treatment with fluoroquinolone }}</ref> One study found that fluoroquinolone use was associated with a 1.9-fold increase in tendon problems. The risk increased to 3.2 in those over 60 years of age and to 6.2 in those over the age of 60 who were also taking corticosteroids. Among the 46,766 quinolone users in the study, 38 (0.08%) cases of Achilles tendon rupture were identified.<ref>{{cite journal |vauthors = Corrao G, Zambon A, Bertù L, Mauri A, Paleari V, Rossi C, Venegoni M |title = Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study |journal = Drug Safety |volume = 29 |issue = 10 |pages = 889–96 |year = 2006 |pmid = 16970512 |doi = 10.2165/00002018-200629100-00006 |s2cid = 21513856 }}</ref>
===Cardiac arrhythmia===
The fluoroquinolones, including ciprofloxacin, are associated with an increased risk of cardiac toxicity, including [[QT interval]] prolongation, ''[[torsades de pointes]]'', ventricular arrhythmia, and [[sudden cardiac death|sudden death]].<ref>{{cite journal |vauthors=Gorelik E, Masarwa R, Perlman A, Rotshild V, Abbasi M, Muszkat M, Matok I |title=Fluoroquinolones and Cardiovascular Risk: A Systematic Review, Meta-analysis and Network Meta-analysis |journal=Drug Saf |volume= 42|issue= 4|pages= 529–538|date=October 2018 |pmid=30368737 |doi=10.1007/s40264-018-0751-2 |s2cid=53105534 }}</ref><ref name="Fluoroquinolones increase the risk"/>
===Nervous system===
Because Ciprofloxacin is lipophilic, it has the ability to cross the [[blood–brain barrier]].<ref name="babar2013">{{cite journal |vauthors = Babar SM |title = SIADH associated with ciprofloxacin |journal = The Annals of Pharmacotherapy |volume = 47 |issue = 10 |pages = 1359–63 |date = October 2013 |pmid = 24259701 |doi = 10.1177/1060028013502457 |s2cid = 36759747 }}</ref> The 2013 FDA label warns of nervous system effects. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold, and may cause other central nervous system adverse effects. Headache, dizziness, and insomnia have been reported as occurring fairly commonly in postapproval review articles, along with a much lower incidence of serious CNS adverse effects such as tremors, psychosis, anxiety, hallucinations, paranoia, and suicide attempts, especially at higher doses.<ref name=He2013/> Like other fluoroquinolones, it is also known to cause peripheral neuropathy that may be irreversible, such as weakness, burning pain, tingling or numbness.<ref>{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/ucm365050.htm |title=FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection |publisher=U.S. [[Food and Drug Administration]] (FDA) |url-status=dead |archive-url=https://web.archive.org/web/20160528231716/https://www.fda.gov/Drugs/DrugSafety/ucm365050.htm |archive-date=28 May 2016}}</ref>
Fluoroquinolones have already been reported for movement disorders.<ref name=":0" /> In this context, ciprofloxacin is especially associated with [[myoclonus]], which derives the term "ciproclonus."<ref name=":1" />
===Cancer===
Ciprofloxacin is active in six of eight ''in vitro'' assays used as rapid screens for the detection of genotoxic effects, but is not active in ''in vivo'' assays of genotoxicity.<ref name="Cipro FDA label" /> Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (about 1.7 and 2.5 times the highest recommended therapeutic dose based upon mg/m<sup>2</sup>). Results from photo co-carcinogenicity testing indicate ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control.<ref name="Cipro FDA label" />
===Other===
The other black box warning is that ciprofloxacin should not be used in people with [[myasthenia gravis]] due to possible exacerbation of muscle weakness which may lead to breathing problems resulting in death or ventilator support. Fluoroquinolones are known to block neuromuscular transmission.<ref name="Cipro FDA label" /> There are concerns that fluoroquinolones including ciprofloxacin can affect cartilage in young children.<ref name="Cipro FDA label" />
''[[Clostridium difficile (bacteria)|Clostridium difficile]]''-associated diarrhea is a serious adverse effect of ciprofloxacin and other fluoroquinolones; it is unclear whether the risk is higher than with other broad-spectrum antibiotics.<ref name="pmid18067688">{{cite journal |vauthors = Deshpande A, Pant C, Jain A, Fraser TG, Rolston DD |title = Do fluoroquinolones predispose patients to Clostridium difficile associated disease? A review of the evidence |journal = Current Medical Research and Opinion |volume = 24 |issue = 2 |pages = 329–33 |date = February 2008 |pmid = 18067688 |doi = 10.1185/030079908X253735 |s2cid = 280563}}</ref>
A wide range of rare but potentially fatal adverse effects reported to the US FDA or the subject of case reports includes [[aortic dissection]],<ref>{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm |title=Drug Safety and Availability – FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients |publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=4 January 2019}}</ref> [[toxic epidermal necrolysis]], [[Stevens–Johnson syndrome]], low blood pressure, allergic pneumonitis, bone marrow suppression, hepatitis or liver failure, and sensitivity to light.<ref name="Cipro FDA label" /><ref name="pmid24352180">{{cite journal |vauthors=Alshammari TM, Larrat EP, Morrill HJ, Caffrey AR, Quilliam BJ, LaPlante KL |title=Risk of hepatotoxicity associated with fluoroquinolones: a national case-control safety study |journal=American Journal of Health-System Pharmacy |volume=71 |issue=1 |pages=37–43 |date=January 2014 |pmid=24352180 |doi=10.2146/ajhp130165}}</ref> The medication should be discontinued if a rash, jaundice, or other sign of hypersensitivity occurs.<ref name="Cipro FDA label" />
Children and the elderly are at a much greater risk of experiencing adverse reactions.<ref name="autogenerated1403">{{cite journal |vauthors = Iannini PB |title = The safety profile of moxifloxacin and other fluoroquinolones in special patient populations |journal = Current Medical Research and Opinion |volume = 23 |issue = 6 |pages = 1403–13 |date = June 2007 |pmid = 17559736 |doi = 10.1185/030079907X188099 |s2cid = 34091286 }}</ref><ref>{{cite journal |vauthors = Owens RC, Ambrose PG |title = Antimicrobial safety: focus on fluoroquinolones |journal = Clinical Infectious Diseases |volume = 41 |pages = S144–57 |date = July 2005 |issue = Suppl 2 |pmid = 15942881 |doi = 10.1086/428055 |doi-access = free | title-link = doi }}</ref>
==Overdose==
Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach by induced vomiting or [[gastric lavage]], as well as administration of antacids containing magnesium, aluminium, or calcium to reduce drug absorption. Renal function and urinary pH should be monitored. Important support includes adequate hydration and urine acidification if necessary to prevent crystalluria. [[Hemodialysis]] or [[peritoneal dialysis]] can only remove less than 10% of ciprofloxacin.<ref name="FDA 81532304, R.1">{{cite web |title=Cipro Labeling Revision 04/06/2009 Supplement 073 |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s073,020780s030lbl.pdf |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=6 April 2009 |access-date=8 September 2009 |url-status=live |archive-url=https://web.archive.org/web/20100705053513/http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s073,020780s030lbl.pdf |archive-date=5 July 2010}}</ref> Ciprofloxacin may be quantified in plasma or serum to monitor for drug accumulation in patients with hepatic dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.<ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 313–315. {{ISBN|978-0-9626523-7-0}}.</ref>
== Interactions ==
Ciprofloxacin interacts with certain foods and several other drugs leading to undesirable increases or decreases in the serum levels or distribution of one or both drugs.
Ciprofloxacin should not be taken with antacids containing magnesium or aluminum, highly buffered drugs ([[sevelamer]], [[lanthanum carbonate]], [[sucralfate]], [[didanosine]]), or with supplements containing calcium, iron, or zinc. It should be taken two hours before or six hours after these products. Magnesium or aluminum antacids turn ciprofloxacin into insoluble salts that are not readily absorbed by the intestinal tract, reducing peak serum concentrations by 90% or more, leading to therapeutic failure. Additionally, it should not be taken with dairy products or calcium-fortified juices alone, as peak serum concentration and the area under the serum concentration-time curve can be reduced up to 40%. However, ciprofloxacin may be taken with dairy products or calcium-fortified juices as part of a meal.<ref name="FDA 81532304, R.1"/><ref>{{cite journal |vauthors = Rodvold KA, Piscitelli SC |title = New oral macrolide and fluoroquinolone antibiotics: an overview of pharmacokinetics, interactions, and safety |journal = Clinical Infectious Diseases |volume = 17 |pages = S192–9 |date = August 1993 |issue = Suppl 1 |pmid = 8399914 |doi = 10.1093/clinids/17.supplement_1.s192 }}</ref><ref name="Bolhuis MS, Panday PN, Pranger AD, Kosterink JG, Alffenaar JW 2011 865–913">{{cite journal |vauthors = Bolhuis MS, Panday PN, Pranger AD, Kosterink JG, Alffenaar JW |title = Pharmacokinetic drug interactions of antimicrobial drugs: a systematic review on oxazolidinones, rifamycines, macrolides, fluoroquinolones, and Beta-lactams |journal = Pharmaceutics |volume = 3 |issue = 4 |pages = 865–913 |date = November 2011 |pmid = 24309312 |pmc = 3857062 |doi = 10.3390/pharmaceutics3040865 |doi-access = free | title-link = doi }}</ref>
Ciprofloxacin inhibits the drug-metabolizing enzyme [[CYP1A2]] and thereby can reduce the clearance of drugs metabolized by that enzyme. CYP1A2 substrates that exhibit increased serum levels in ciprofloxacin-treated patients include [[tizanidine]], [[theophylline]], [[caffeine]], [[methylxanthines]], [[clozapine]], [[olanzapine]], and [[ropinirole]]. Co-administration of ciprofloxacin with the CYP1A2 substrate tizanidine (Zanaflex) is contraindicated due to a 583% increase in the peak serum concentrations of tizanidine when administered with ciprofloxacin as compared to administration of tizanidine alone. Use of ciprofloxacin is cautioned in patients on theophylline due to its narrow therapeutic index. The authors of one review recommended that patients being treated with ciprofloxacin reduce their caffeine intake. Evidence for significant interactions with several other CYP1A2 substrates such as [[cyclosporine]] is equivocal or conflicting.<ref name="Bolhuis MS, Panday PN, Pranger AD, Kosterink JG, Alffenaar JW 2011 865–913"/><ref name="Cipro FDA label" /><ref>{{cite journal |vauthors = Janknegt R |title = Drug interactions with quinolones |journal = The Journal of Antimicrobial Chemotherapy |volume = 26 Suppl D |pages = 7–29 |date = November 1990 |pmid = 2286594 |doi = 10.1093/jac/26.suppl_D.7 }}</ref>
The [[Committee on Safety of Medicines]] and the FDA warn that [[central nervous system]] adverse effects, including seizure risk, may be increased when [[NSAID]]s are combined with quinolones.<ref name="Cipro FDA label" /><ref>{{cite book |title=British National Formulary (BNF 57) |author=Royal Pharmaceutical Society of Great Britain |author-link=Royal Pharmaceutical Society of Great Britain |publisher=BMJ Group and RPS Publishing |chapter=5 Infections |year=2009 |isbn=978-0-85369-845-6 |title-link=British National Formulary }}</ref> The mechanism for this interaction may involve a [[Synergy|synergistic]] increased antagonism of GABA neurotransmission.<ref name="pmid11172695">{{cite journal |vauthors = De Sarro A, De Sarro G |title = Adverse reactions to fluoroquinolones. an overview on mechanistic aspects |journal = Current Medicinal Chemistry |volume = 8 |issue = 4 |pages = 371–84 |date = March 2001 |pmid = 11172695 |doi = 10.2174/0929867013373435 }}</ref><ref>{{cite journal |vauthors = Brouwers JR |title = Drug interactions with quinolone antibacterials |journal = Drug Safety |volume = 7 |issue = 4 |pages = 268–81 |year = 1992 |pmid = 1524699 |doi = 10.2165/00002018-199207040-00003 |s2cid = 6701544 }}</ref>
Altered serum levels of the antiepileptic drugs [[phenytoin]] and [[carbamazepine]] (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.<ref name="Cipro FDA label" /><ref>{{cite journal |vauthors = Shahzadi A, Javed I, Aslam B, Muhammad F, Asi MR, Ashraf MY |title = Therapeutic effects of ciprofloxacin on the pharmacokinetics of carbamazepine in healthy adult male volunteers |journal = [[Pakistan Journal of Pharmaceutical Sciences]] |volume = 24 |issue = 1 |pages = 63–8 |date = January 2011 |pmid = 21190921 }}</ref><ref>{{cite journal |vauthors = Springuel P |title = Risk of seizures from concomitant use of ciprofloxacin and phenytoin in patients with epilepsy |journal = Canadian Medical Association Journal |volume = 158 |issue = 1 |pages = 104–5, 108–9 |date = January 1998 |pmid = 9475922 }}</ref>
Ciprofloxacin is a potent inhibitor of [[CYP1A2]], [[CYP2D6]], and [[CYP3A4]].<ref name="HaddadDavis2006">{{cite journal |vauthors = Haddad A, Davis M, Lagman R |title = The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions |journal = Supportive Care in Cancer |volume = 15 |issue = 3 |pages = 251–7 |date = March 2007 |pmid = 17139496 |doi = 10.1007/s00520-006-0127-5 |s2cid = 9186457 }}</ref>
==Mechanism of action==
Ciprofloxacin is a [[broad-spectrum antibiotic]] of the [[Quinolone antibiotic|fluoroquinolone]] class. It is active against some [[Gram-positive]] and many [[Gram-negative]] bacteria.<ref>{{cite book |title=First aid for the USMLE step 2 CK |url=https://archive.org/details/firstaidcasesfor00taol |url-access=registration |publisher=McGraw-Hill Medical |isbn=978-0-07-148795-5 |edition=6th |date=June 2007 }}</ref> It functions by inhibiting a type II [[topoisomerase]] ([[DNA gyrase]]) and topoisomerase IV,<ref>{{cite journal |vauthors = Drlica K, Zhao X |title = DNA gyrase, topoisomerase IV, and the 4-quinolones |journal = Microbiology and Molecular Biology Reviews |volume = 61 |issue = 3 |pages = 377–92 |date = September 1997 |doi = 10.1128/mmbr.61.3.377-392.1997 |pmid = 9293187 |pmc = 232616 }}</ref><ref>{{cite journal |vauthors = Pommier Y, Leo E, Zhang H, Marchand C |title = DNA topoisomerases and their poisoning by anticancer and antibacterial drugs |journal = Chemistry & Biology |volume = 17 |issue = 5 |pages = 421–33 |date = May 2010 |pmid = 20534341 |doi = 10.1016/j.chembiol.2010.04.012 |pmc = 7316379 |doi-access = free | title-link = doi }}</ref> necessary to separate bacterial DNA, thereby inhibiting cell division. Bacterial DNA fragmentation will occur as a result of inhibition of the enzymes.
==Pharmacokinetics==
Ciprofloxacin for systemic administration is available as immediate-release tablets, extended-release tablets, an oral suspension, and as a solution for intravenous administration. When administered over one hour as an intravenous infusion,<ref name="Cipro FDA label" /> ciprofloxacin rapidly distributes into the tissues, with levels in some tissues exceeding those in the serum. Penetration into the central nervous system is relatively modest, with cerebrospinal fluid levels normally less than 10% of peak serum concentrations. The serum half-life of ciprofloxacin is about 4–6 hours, with 50–70% of an administered dose being excreted in the urine as unmetabolized drug. An additional 10% is excreted in urine as metabolites. Urinary excretion is virtually complete 24 hours after administration. Dose adjustment is required in the elderly and in those with renal impairment.<ref name="Cipro FDA label" />
Ciprofloxacin is weakly bound to serum proteins (20–40%). It is an inhibitor of the drug-metabolizing enzyme [[CYP1A2|cytochrome P450 1A2]], which leads to the potential for clinically important drug interactions with drugs metabolized by that enzyme.<ref name=AHFS2015 /> Ciprofloxacin is about 70% available when administered orally.<ref name="Cipro FDA label" />
The extended release tablets<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/21554_ciproXR_lbl.pdf |title=Cipro XR Prescribing Information |publisher=U.S. [[Food and Drug Administration]] (FDA) |url-status=live |archive-url=https://web.archive.org/web/20131230232923/http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/21554_ciproXR_lbl.pdf |archive-date=30 December 2013}}</ref> allow once-daily administration by releasing the drug more slowly in the gastrointestinal tract. These tablets contain 35% of the administered dose in an immediate-release form and 65% in a slow-release matrix. Maximum serum concentrations are achieved between 1 and 4 hours after administration. Compared to the 250- and 500-mg immediate-release tablets, the 500-mg and 1000-mg XR tablets provide higher C<sub>max</sub>, but the 24‑hour AUCs are equivalent.
Ciprofloxacin immediate-release tablets contain ciprofloxacin as the hydrochloride salt, and the XR tablets contain a mixture of the hydrochloride salt and the free base.<ref name="Cipro FDA label" />
==Chemical properties==
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C<sub>17</sub>H<sub>18</sub>FN<sub>3</sub>O<sub>3</sub> and its molecular weight is 331.4 g/mol. It is a faintly yellowish to light yellow crystalline substance.<ref name="FDA 81532304, R.1" />
Ciprofloxacin hydrochloride ([[United States Pharmacopeia|USP]]) is the monohydrochloride monohydrate salt of ciprofloxacin. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8 g/mol. Its empirical formula is C<sub>17</sub>H<sub>18</sub>FN<sub>3</sub>O<sub>3</sub>HCl•H<sub>2</sub>O.<ref name="FDA 81532304, R.1" />
==Usage==
Ciprofloxacin is the most widely used of the second-generation quinolones.<ref>{{cite journal |vauthors = Goossens H, Ferech M, Coenen S, Stephens P |title = Comparison of outpatient systemic antibacterial use in 2004 in the United States and 27 European countries |journal = Clinical Infectious Diseases |volume = 44 |issue = 8 |pages = 1091–5 |date = April 2007 |pmid = 17366456 |doi = 10.1086/512810 |doi-access = free | title-link = doi }}</ref><ref>{{cite web |url=http://www.bccdc.ca/NR/rdonlyres/BC629780-7E03-4153-B67B-5CFD4F521DAC/0/Full2010AntibioticConsumptionReport_aug2012.pdf |title=British Columbia Annual Summary of Antibiotics Utilization 2010 |url-status=dead |archive-url=https://web.archive.org/web/20131230232309/http://www.bccdc.ca/NR/rdonlyres/BC629780-7E03-4153-B67B-5CFD4F521DAC/0/Full2010AntibioticConsumptionReport_aug2012.pdf |archive-date=30 December 2013}}</ref> In 2010, over 20 million prescriptions were written, making it the 35th-most-commonly prescribed generic drug and the 5th-most-commonly prescribed antibacterial in the US.<ref>{{cite web |title = 2010 Top 200 generic drugs by total prescriptions |url=http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard/drugtopics/252011/727243/article.pdf |access-date = 2 November 2012 |archive-date= 15 December 2012 |archive-url=https://web.archive.org/web/20121215070930/http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252011/727243/article.pdf}}</ref>
==History==
[[
The first members of the quinolone antibacterial class were relatively low-potency drugs such as [[nalidixic acid]], used mainly in the treatment of urinary tract infections owing to their renal excretion and propensity to be concentrated in urine.<ref>{{cite journal |vauthors = Mayrer AR, Andriole VT |title = Urinary tract antiseptics |journal = The Medical Clinics of North America |volume = 66 |issue = 1 |pages = 199–208 |date = January 1982 |pmid = 7038329 |doi = 10.1016/s0025-7125(16)31453-5 }}</ref> In 1979, the publication of a patent<ref>{{cite web |url=https://www.google.com/patents/US4146719 |title=Patent US4146719 - Piperazinyl derivatives of quinoline carboxylic acids - Google Patents}}</ref> filed by the pharmaceutical arm of Kyorin Seiyaku Kabushiki Kaisha disclosed the discovery of [[norfloxacin]], and the demonstration that certain structural modifications including the attachment of a fluorine atom to the quinolone ring leads to dramatically enhanced antibacterial potency.<ref>{{cite journal |vauthors = Khan MY, Gruninger RP, Nelson SM, Klicker RE |title = Comparative in vitro activity of norfloxacin (MK-0366) and ten other oral antimicrobial agents against urinary bacterial isolates |journal = Antimicrobial Agents and Chemotherapy |volume = 21 |issue = 5 |pages = 848–51 |date = May 1982 |pmid = 6213200 |pmc = 182027 |doi = 10.1128/AAC.21.5.848 }}</ref> In the aftermath of this disclosure, several other pharmaceutical companies initiated research and development programs with the goal of discovering additional antibacterial agents of the fluoroquinolone class.
The fluoroquinolone program at [[Bayer]] focused on examining the effects of very minor changes to the norfloxacin structure.<ref>{{cite web |url=https://www.google.com/patents/US4547503 |title=Patent US4547503 – 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(oxo-alkyl)-1-piperazinyl ... – Google Patents}}</ref><ref>{{cite web |url=https://www.google.com/patents/US4544658?pg=PA1 |title=Patent US4544658 – 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(alkyl-1-piperazinyl)quinoline-3 ... – Google Patents}}</ref> In 1983, the company published ''in vitro'' potency data for ciprofloxacin, a fluoroquinolone antibacterial having a chemical structure differing from that of norfloxacin by the presence of a single carbon atom.<ref>{{cite journal |vauthors = Wise R, Andrews JM, Edwards LJ |title = In vitro activity of Bay 09867, a new quinoline derivative, compared with those of other antimicrobial agents |journal = Antimicrobial Agents and Chemotherapy |volume = 23 |issue = 4 |pages = 559–64 |date = April 1983 |pmid = 6222695 |pmc = 184701 |doi = 10.1128/aac.23.4.559 }}</ref> This small change led to a two- to 10-fold increase in potency against most strains of Gram-negative bacteria. Importantly, this structural change led to a four-fold improvement in activity against the important [[Gram-negative]] pathogen ''[[Pseudomonas aeruginosa]]'', making ciprofloxacin one of the most potent known drugs for the treatment of this intrinsically antibiotic-resistant pathogen.{{Medical citation needed|date=September 2015}}
The oral tablet form of ciprofloxacin was approved in October 1987,<ref>{{cite web |url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019537&TABLE1=OB_Rx |title=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations N019537 |publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=5 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20140106040918/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019537&TABLE1=OB_Rx |archive-date=6 January 2014}}</ref> just one year after the approval of norfloxacin.<ref>{{cite web |url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019384&TABLE1=OB_Rx |title=Orange Book Detail Record Search |publisher=U.S. [[Food and Drug Administration]] (FDA) |url-status=live |archive-url=https://web.archive.org/web/20140106040606/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019384&TABLE1=OB_Rx |archive-date=6 January 2014}}</ref> In 1991, the intravenous formulation was introduced. Ciprofloxacin sales reached a peak of about 2 [[billion]] euros in 2001, before Bayer's patent expired in 2004, after which annual sales have averaged around €200 million.<ref>{{cite web |url= https://www.sec.gov/Archives/edgar/data/1144145/000115697302000306/f00360e20vf.txt |title=www.sec.gov |url-status=live |archive-url= https://web.archive.org/web/20170709045332/https://www.sec.gov/Archives/edgar/data/1144145/000115697302000306/f00360e20vf.txt |archive-date=9 July 2017}}</ref><ref>Dan Prochilo for Law360 18 November 2013 [http://www.law360.com/articles/489579/bayer-s-74m-cipro-pay-for-delay-deal-approved-in-calif Bayer's $74M Cipro Pay-For-Delay Deal Approved In Calif.] {{webarchive |url=https://web.archive.org/web/20150318093001/http://www.law360.com/articles/489579/bayer-s-74m-cipro-pay-for-delay-deal-approved-in-calif |date=18 March 2015 }}</ref>
The name probably originates from the International Scientific Nomenclature: ci- (alteration of cycl-) + propyl + fluor- + ox- + az- + -mycin.<ref>{{cite dictionary |url=https://www.merriam-webster.com/dictionary/ciprofloxacin|access-date=10 April 2022 |entry=Ciprofloxacin |dictionary=Merriam-Webster.com Dictionary |publisher=Meriam-Webster|title=Definition of CIPROFLOXACIN }}</ref>
==
===Economics===
It is available as a generic medication and not very expensive.<ref name=AHFS2015/><ref name=Ric2014/>
===Generic equivalents===
In October 2001, the Prescription Access Litigation (PAL) project filed suit to dissolve an agreement between Bayer and three of its competitors which produced [[Generic drugs|generic versions of drugs]] ([[Barr Pharmaceuticals|Barr Laboratories]], [[Actavis|Rugby Laboratories]], and [[Marion Merrell Dow|Hoechst-Marion-Roussel]]) that PAL claimed was blocking access to adequate supplies and cheaper, generic versions of ciprofloxacin. The plaintiffs charged that Bayer Corporation, a unit of Bayer AG, had unlawfully paid the three competing companies a total of $200 million to prevent cheaper, generic versions of ciprofloxacin from being brought to the market, as well as manipulating its price and supply. Numerous other consumer advocacy groups joined the lawsuit. On 15 October 2008, five years after Bayer's patent had expired, the United States District Court for the Eastern District of New York granted Bayer's and the other defendants' motion for summary judgment, holding that any anticompetitive effects caused by the settlement agreements between Bayer and its codefendants were within the exclusionary zone of the patent and thus could not be redressed by federal antitrust law,<ref>{{cite web |author=United States Court of Appeals for the Federal Circuit |title=United States Court of Appeals for the Federal Circuit |url=http://www.cafc.uscourts.gov/opinions/08-1097.pdf |location=USA |year=2008 |access-date=4 September 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090827080527/http://www.cafc.uscourts.gov/opinions/08-1097.pdf |archive-date=27 August 2009 }}</ref> in effect upholding Bayer's agreement with its competitors.
===Available forms===
Ciprofloxacin for systemic administration is available as immediate-release tablets, as extended-release tablets, as an oral suspension, and as a solution for intravenous infusion. It is available for local administration as eye drops and ear drops. It is available in combination with [[Ciprofloxacin/dexamethasone|dexamethasone]], with [[Ciprofloxacin/celecoxib|celecoxib]], with [[Ciprofloxacin/hydrocortisone|hydrocortisone]], and with [[Ciprofloxacin/fluocinolone acetonide|fluocinolone acetonide]].<ref>{{cite web | title=Otovel (- ciprofloxacin and fluocinolone acetonide solution | website=DailyMed | date=12 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a7e4806-3138-4b7a-b798-a99e163ee846 | access-date=9 February 2024}}</ref>
===Litigation===
A class action was filed against Bayer AG on behalf of employees of the Brentwood Post Office in Washington, D.C., and workers at the U.S. Capitol, along with employees of American Media, Inc. in Florida and postal workers in general who alleged they developed serious adverse effects from taking ciprofloxacin in the aftermath of the [[2001 anthrax attacks|anthrax attacks in 2001]]. The action alleged Bayer failed to warn class members of the potential side effects of the drug, thereby violating the Pennsylvania Unfair Trade Practices and Consumer Protection Laws. The class action was defeated and the litigation abandoned by the plaintiffs.<ref>{{cite web |title=Legal Brief of Postal Employees Cases (EEOC, MSPB, District Courts) |url=http://www.lunewsviews.com/legal_briefs_archives.htm#cipro |archive-url=https://web.archive.org/web/20071021073109/http://www.lunewsviews.com/legal_briefs_archives.htm#cipro |archive-date=21 October 2007 |publisher=Postal Reporter |location=USA |access-date=9 September 2009}}</ref> A similar action was filed in 2003 in New Jersey by four New Jersey postal workers but was withdrawn for lack of grounds, as workers had been informed of the risks of ciprofloxacin when they were given the option of taking the drug.<ref>Los Angeles Times, from wire service reports. 19 October 2003 [http://articles.latimes.com/2003/oct/19/nation/na-briefs19.2 Postal Workers Sue Over Anthrax Scare Antibiotic] {{webarchive |url=https://web.archive.org/web/20141205014829/http://articles.latimes.com/2003/oct/19/nation/na-briefs19.2 |date=5 December 2014 }}</ref><ref>Bill Lewis, President of Trenton Metro Area Local, American Postal Workers Union, AFL-CIO. 7 December 2003 [http://trentonmetroarealocal.com/president_page.html Trenton Metro Area Local: Welcome to Bill's Corner] {{webarchive |url=https://web.archive.org/web/20141023131440/http://trentonmetroarealocal.com/president_page.html |date=23 October 2014 }} Page accessed 23 October 2014</ref>
==Research==
As resistance to ciprofloxacin has grown since its introduction, research has been conducted to discover and develop analogs that can be effective against resistant bacteria; some have been looked at in antiviral models as well.<ref>{{cite journal |vauthors = Zhang GF, Liu X, Zhang S, Pan B, Liu ML |title = Ciprofloxacin derivatives and their antibacterial activities |journal = European Journal of Medicinal Chemistry |volume = 146 |pages = 599–612 |date = February 2018 |pmid = 29407984 |doi = 10.1016/j.ejmech.2018.01.078 }}</ref>
== References ==
{{reflist}}
== External links ==
{{Commons category}}
* {{cite web |title=Ciprofloxacin Ophthalmic |url=https://medlineplus.gov/druginfo/meds/a605005.html |website=MedlinePlus}}
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