View source for Ciprofloxacin

{{Redirect|Cipro|the Rome Metro station|Cipro (Rome Metro)}}
{{drugbox | Watchedfields = changed
| verifiedrevid = 322135456
| IUPAC_name = 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3-carboxylic acid
| image = Ciprofloxacin.svg
| image2 = Ciprofloxacin-zwitterion-from-xtal-3D-balls.png
| width = 200
| CASNo_Ref = {{cascite}}
| InChI = 1/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)
| InChIKey = MYSWGUAQZAJSOK-UHFFFAOYAL
| CAS_number = 85721-33-1
| ChemSpiderID = 2662
| ATC_prefix = J01
| ATC_suffix = MA02
| ATC_supplemental = {{ATC|S01|AX13}} {{ATC|S02|AA15}} {{ATC|S03|AA07}}
| PubChem = 2764
| DrugBank = DB00537
| C=17|H=18|F=1|N=3|O=3
| molecular_weight = 331.346
| smiles = O=C(O)\C2=C\N(c1cc(c(F)cc1C2=O)N3CCNCC3)C4CC4
| bioavailability = 69%<ref>{{cite journal |author=Drusano GL, Standiford HC, Plaisance K, Forrest A, Leslie J, Caldwell J |title=Absolute oral bioavailability of ciprofloxacin |journal=Antimicrob Agents Chemother. |volume=30 |issue=3 |pages=444–6 |year=1986 |month=September |pmid=3777908 |pmc=180577 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=3777908 |doi=10.1128/AAC. |first1=GL |first2=HC |first3=K |first4=A |first5=J |first6=J |issn=0066-4804}}</ref>
| protein_bound =
| metabolism = Hepatic, including [[CYP1A2]]
| elimination_half-life = 4 hours
| excretion = Renal
| pregnancy_AU = B3
| pregnancy_US = C
| legal_AU = S4
| legal_UK = POM
| routes_of_administration = [[Route of administration#Enteral|Oral]], [[intravenous therapy|intravenous]], [[topical]] ([[ear drop]]s, [[eye drop]]s)
}}

'''Ciprofloxacin''' ([[International Nonproprietary Name|INN]]) is a synthetic [[chemotherapeutic]] [[antibiotic]] of the [[fluoroquinolone]] drug class.<ref>{{Cite journal  | last1 = Nelson | first1 = JM. | last2 = Chiller | first2 = TM. | last3 = Powers | first3 = JH. | last4 = Angulo | first4 = FJ. | title = Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story. | journal = Clin Infect Dis | volume = 44 | issue = 7 | pages = 977–80 | month = Apr | year = 2007 | doi = 10.1086/512369 | pmid = 17342653 }}</ref><ref>{{Cite journal  | last1 = Kawahara | first1 = S. | title = [Chemotherapeutic agents under study] | journal = Nippon Rinsho | volume = 56 | issue = 12 | pages = 3096–9 | month = Dec | year = 1998 | pmid = 9883617 }}</ref>
It is a second-generation [[quinolone|fluoroquinolone]] antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops DNA and protein synthesis.

Ciprofloxacin is marketed worldwide with over three hundred different brand names. In the United States, Canada, and the UK, it is marketed as '''Baycip''', '''Ciloxan''', '''Ciflox''', '''Cipro''', '''Cipro XR''', '''Cipro XL''', '''Ciproxin''' and most recently, '''Proquin'''. In addition, ciprofloxacin is available as a generic drug under a variety of different brand names and is also available for limited use in [[veterinary medicine]].

Ciprofloxacin was first patented in 1983 by [[Bayer|Bayer A.G.]] and subsequently approved by the United States [[Food and Drug Administration (United States)|Food and Drug Administration]] (FDA) in 1987. Ciprofloxacin has 12 FDA-approved human uses and other veterinary uses, but it is often used for non-approved uses (off-label). Ciprofloxacin interacts with other drugs, herbal and natural supplements, and thyroid medications.<ref>{{cite journal |author=Cooper JG, Harboe K, Frost SK, Skadberg Ø |title=Ciprofloxacin interacts with thyroid replacement therapy |journal=BMJ |volume=330 |issue=7498 |page=1002 |year=2005 |month=April |pmid=15860826 |pmc=557149 |doi=10.1136/bmj.330.7498.1002 |url= |first1=JG |first2=K |first3=SK |issn=0959-8138}}</ref> 

==History==
[[Image:Cipro 250 mg.JPG|right|thumb|Ciprofloxacin 250mg tablets from Ukraine]]
The patent history for ciprofloxacin makes reference to a 1982 European Patent (patent number 0049355), as well a German patent dated 21 January 1986. Bayer introduced ciprofloxacin in 1987 and was later approved by the U.S. FDA on 22 October 22 1987 for use in the United States to treat specific bacterial infections. In 1991, the intravenous formulation was introduced. The current United States patent appears to be held by Bayer, being the assignee.<ref>{{cite web |author=Streuff, et al |title=United States Patent 5,286,754 |url=http://patft.uspto.gov/netacgi/nph-Parser?u=%2Fnetahtml%2Fsrchnum.htm&Sect1=PTO1&Sect2=HITOFF&p=1&r=1&l=50&f=G&d=PALL&s1=5286754.PN.&OS=PN/5286754&RS=PN/5286754 |publisher=uspto.gov |location=USA |date=15 February 1994 |accessdate=30 August 2009}}</ref> The United States patent was applied for in January 1987, but was not approved until 1996 according to the patent history.

In 2004, ciprofloxacin and [[levofloxacin]] together commanded 65% ($3.3 billion) of the global sales of the fluoroquinolone class.<ref>{{cite web |first= |last= |author= |authorlink= |title=Commercial Perspectives: Fluoroquinolones - Established Products Drive Market Growth |url=https://www.leaddiscovery.co.uk/reports/843/Commercial_Perspectives_Fluoroquinolones_Established_Products_Drive_Market_Growth |date=28 January 2004 |accessdate=30 August 2009}}</ref> The first nine months of 2008 sales for ciprofloxacin were $242 million, as compared to $324 million for Bayer [[aspirin]].<ref>{{cite web |author=Dr. Katrin Schneider |title=Stockholders’ Newsletter |url=http://www.stockholders-newsletter-q3-08.bayer.com/en/bayer_stockholders_newsletter_3Q_08.pdfx |publisher=Bayer AG |format=PDF |date=29 October 2008 |accessdate=30 August 2009}}</ref> Ciprofloxacin has proven to be a blockbuster drug for Bayer A. G., generating billions of dollars in additional revenue. "In 1999, Cipro was the eleventh most prescribed drug in the United States based on new prescriptions, and ranked twentieth in total United States sales. In 1999, Bayer's gross sales of Cipro in the United States were approximately $1.04 billion."<ref>{{cite web |title=Cipro |url=http://www.prescriptionaccess.org/lawsuitssettlements/past_lawsuits?id=0010 |publisher=Prescription Access |location=USA |accessdate=4 September 2009}}</ref> The sale of ciprofloxacin increased dramatically following the anthrax scare of 2001. On 24 October 2002, the Bush Administration (2001–2009) announced a deal between the government and Bayer Pharmaceuticals to purchase 100 million tablets of ciprofloxacin at a reduced price of $0.95 per pill. A full course of ciprofloxacin for postexposure prophylaxis (60 days) resulting from this arrangement costs the government $204 per person treated, compared with $12 per person treated with [[doxycycline]], the drug normally used to treat anthrax, a difference of $192.<ref>{{cite web |author=Bayer Corporation |authorlink=Bayer |title=HHS, BAYER AGREE TO CIPRO PURCHASE |url=http://www.hhs.gov/news/press/2001pres/20011024.html |publisher=U.S. Department of Health & Human Services |location=USA |date=24 October 2001 |accessdate=4 September 2009}} {{Dead link|date=September 2010|bot=H3llBot}}</ref>

*Generic equivalents:

On 24 October 2001, The Prescription Access Litigation (PAL), filed suit to dissolve an agreement between Bayer, Barr Laboratories, and two other generic drug companies that it 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 three of its competitors — Barr Laboratories, Rugby, and Hoechst-Marion Roussel — a total of $200 million to prevent cheaper, generic versions of ciprofloxacin from being brought to the market, as well as manipulating the price and supply of ciprofloxacin. Numerous other consumer advocacy groups joined this 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 generic defendants’ motion for summary judgment, holding that any anticompetitive effects caused by the settlement agreements between Bayer and the generic defendants 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 |format=PDF |year=2008 |accessdate=4 September 2009}} {{Dead link|date=September 2010|bot=H3llBot}}</ref> in effect upholding Bayer’s agreement to pay Barr Laboratories, Rugby, and Hoechst-Marion Roussel a total of $200 million to prevent the marketing a generic equivalent of ciprofloxacin.

==Licensed uses==

The licensed uses for ciprofloxacin in the United States are as follows: 

In the adult population, ciprofloxacin is limited to the treatment of proven bacterial infections such as:

*[[Urinary tract infection]]s (not recommended as a first-line antibiotic)<ref>{{cite web |title=Fluroquinolone Drug Class Review |url=http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/reviews/articles/fluroquinolone-lit.html |publisher=Oregon State University College of Pharmacy |year=2002 |accessdate=4 September 2009}}</ref>
*Acute uncomplicated [[cystitis]] in females
*[[Chronic bacterial prostatitis]] (not recommended as a first-line antibiotic choice)<ref>{{cite journal |pmid=15492337 |url=http://www.annals.org/cgi/content/full/141/8/581 |journal=Annals of Internal Medicine |title=Ciprofloxacin or Tamsulosin in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Double-Blind Trial |volume=141 |issue=8 |page=581 |date= October 19, 2004 |first1=RB |first2=KJ |first3=AJ |first4=JR |first5=JC |first6=MP |first7=MA |first8=M |first9=DA |issn=0003-4819 |author1=Alexander, Richard B |author2=Propert, Kathleen J |author3=Schaeffer, Anthony J |author4=Landis, J. Richard |author5=Nickel, J. Curtis |author6=O'Leary, Michael P |author7=Pontari, Michel A |author8=McNaughton-collins, Mary |author9=Shoskes, Daniel A |author=Alexander, Richard B.; Propert, Kathleen J; Schaeffer, Anthony J; Landis, J. Richard; Nickel, J. Curtis; O'Leary, Michael P; Pontari, Michel A; McNaughton-collins, Mary; Shoskes, Daniel A; Comiter, Craig V; Datta, Nand S; Fowler, Jackson E.; Nadler, Robert B; Zeitlin, Scott I; Knauss, Jill S; Wang, Yanlin; Kusek, John W; Nyberg, Leroy M.; Litwin, Mark S; Network*, and the Chronic Prostatitis Collaborative Research |quote=did not substantially reduce symptoms in men with long-standing CP/CPPS who had at least moderate symptoms. |first=Network |last2=Chronic Prostatitis Collaborative Research |last3=Nadler |last4=Zeitlin |last1=Litwin |authorsep=Network*, and the Chronic Prostatitis Collaborative Research }}</ref><ref>{{cite web |author=J. Dimitrakov |coauthors=J. Tchitalov, T. Zlatanov, D. Dikov |title=A Prospective, Randomized, Double-Blind, Placebo-Controlled Study Of Antibiotics For The Treatment Of Category Iiib Chronic Pelvic Pain Syndrome In Men |url=http://www.prostatitis.org/a92000.html |publisher=Third International Chronic Prostatitis Network |accessdate=4 September 2009}}</ref>
*[[Lower respiratory tract infection]]s (not recommended as a first-line antibiotic choice)<ref name=cfaeocb>{{cite journal |author=A Zuger |date=3 November 1998 |title=Ciprofloxacin for Acute Exacerbations of Chronic Bronchitis |journal=Journal Watch (General) |url=http://general-medicine.jwatch.org/cgi/content/citation/1998/1103/4 |quote=Because of its unpredictable activity against the pneumococcus, ciprofloxacin is not usually considered a first-line treatment for respiratory infections... |volume=1998 |issue=1103 |page=4 }}</ref><ref>{{Cite journal  | last1 = Vardakas | first1 = KZ. | last2 = Siempos | first2 = II. | last3 = Grammatikos | first3 = A. | last4 = Athanassa | first4 = Z. | last5 = Korbila | first5 = IP. | last6 = Falagas | first6 = ME. | title = Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials. | journal = CMAJ | volume = 179 | issue = 12 | pages = 1269–77 | month = December | year = 2008 | doi = 10.1503/cmaj.080358 | pmid = 19047608 |url=http://www.ecmaj.com/cgi/reprint/179/12/1269  | author2 = Siempos  | author3 = Grammatikos  | author4 = Athanassa  | author5 = Korbila  | author6 = Falagas  | pmc = 2585120 }}</ref><ref>{{cite journal |pmid=8019264 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2540361&blobtype=pdf |format=PDF |year=1994 |month=May |title=Ciprofloxacin in general practice. |volume=308 |issue=6941 |page=1437 |issn=0959-8138 |pmc=2540361 |journal=BMJ (Clinical research ed.) |first1=PM |first2=AP |first3=MP |author1=Donaldson, Pm |author2=Pallett, Ap |author3=Carroll, Mp}}</ref>
*[[Acute sinusitis]] (not recommended as a first-line antibiotic choice)<ref name="Karageorgopoulos-2008">{{Cite journal  | last1 = Karageorgopoulos | first1 = DE. | last2 = Giannopoulou | first2 = KP. | last3 = Grammatikos | first3 = AP. | last4 = Dimopoulos | first4 = G. | last5 = Falagas | first5 = ME. | title = Fluoroquinolones compared with beta-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials. | journal = CMAJ | volume = 178 | issue = 7 | pages = 845–54 | month = March | year = 2008 | doi = 10.1503/cmaj.071157 | pmid = 18362380 |url=http://www.cmaj.ca/cgi/content/full/178/7/845  | author2 = Giannopoulou  | author3 = Grammatikos  | author4 = Dimopoulos  | author5 = Falagas  | pmc = 2267830}}</ref>
*Skin and skin structure infections
*Bone and joint infections
*Infectious diarrhea
*[[Typhoid fever]] (enteric fever) caused by ''Salmonella typhi''
*Uncomplicated cervical and urethra gonorrhea (due to ''N. gonorrhoeae'') – however, this indication is no longer effective in some areas (e.g., Asian countries,<ref>(World Health Organization (WHO) Western Pacific Region Gonococcal Antimicrobial Susceptibility Programme (GASP) Report- 2000. Commun Dis Intell 2001; 25:274-277).
</ref> United States (including Hawaii), Canada ,<ref>{{cite web |author=DEPARTMENT OF HEALTH AND HUMAN SERVICES |authorlink=DEPARTMENT OF HEALTH AND HUMAN SERVICES |coauthors=[[Centers for Disease Control and Prevention]] |title=Gonococcal Isolate Surveillance Project (GISP) Annual Report - 2003 |url=http://www.cdc.gov/STD/gisp2003/GISP2003.pdf |publisher=Center for Disease Controlo |location=USA |format=PDF |month=November |year=2004 |accessdate=31 August 2009}}</ref> and Scotland)<ref>{{cite journal |author=Hugh Young |date=22 July 2003 |title=Ciprofloxacin resistant gonorrhoea: the situation in Scotland and implications for therapy |journal=SCIEH Weekly Report - SCOTTISH CENTRE FOR INFECTION AND ENVIRONMENTAL HEALTH |volume=37 |publisher=National Health Service |location=Scotland |issn=1357-4493 |doi= |url=http://www.documents.hps.scot.nhs.uk/ewr/pdf2003/0329.pdf |format=PDF }}</ref> due to bacterial resistance. Fluoroquinolones are no longer recommended in the USA for this indication.<ref>{{cite journal |date=13 April 2007 |title=Update to CDC's sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections.|journal=Morbidity and Mortality Weekly Report |volume=56  |issue=14 |pages=332–336 |publisher=Center for Disease Control |location=USA |url=Center for Disease Control |format=PDF |accessdate=31 August 2009 |pmid=17431378 |author1=Centers for Disease Control and Prevention (CDC) }}</ref>

Ciprofloxacin is not recommended for the treatment of [[tuberculosis]].<ref>{{cite journal |pmid=16034951 |year=2005 |month=July |title=Fluoroquinolones for treating tuberculosis. |volume= |issue=3 |pages=CD004795 |issn= |doi=10.1002/14651858.CD004795.pub2 |journal=Cochrane database of systematic reviews (Online) |first1=LE |first2=AA |first3=SB |author1=Ziganshina, Le |author2=Vizel, Aa |author3=Squire, Sb |last1=Ziganshina |last2=Vizel |last3=Squire |first4=Lilia |last4=Ziganshina }}</ref>

As well as in combination with other specific drugs:

*Complicated intra-abdominal infections (in combination with metronidazole);
*Empirical therapy for febrile neutropenic patients (in combination with piperacillin)

Oral and intravenous fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions as outlined below. Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of arthropathy was reported to be 9.3% at one month and 13.6% at one year.<ref name=dospidp>{{cite web |first=Joette |last=Meyer |author=Renata Albrecht |title=Division of Special Pathogen and Immunologic Drug Products - Summary of Clinical Review of Studies Submitted in Response to a Pediatric Written Request |url=http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4152b1_03_03_Cipro%20medical.pdf |publisher=FDA |location=USA |format=PDF |date=16 March 2004 |accessdate=31 August 2009}}</ref> As such the pediatric use of ciprofloxacin is restricted to proven complicated urinary tract infections and [[pyelonephritis]] due to ''E. coli '' and inhalation [[anthrax]].<ref name=ctcos>{{cite web |first= |last= |author=Bayer HealthCare Pharmaceuticals Inc |title=CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO,(ciprofloxacin*) ORAL SUSPENSION |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf |publisher=FDA |location=USA |format=PDF |month=September |year=2008 |accessdate=31 August 2009}}</ref> Although claimed to be effective, ciprofloxacin is not to be considered a first line agent for inhalation anthrax in the pediatric population.<ref name=dospidp/><ref>{{cite journal |issn= 0031-4005|pmid=12777590 |url=http://pediatrics.aappublications.org/cgi/reprint/111/6/e714 |format=PDF |doi= 10.1542/peds.111.6.e714 |title= Fluoroquinolone Safety in Pediatric Patients: A Prospective, Multicenter, Comparative Cohort Study in France |year= 2003 |author= Chalumeau, M. |journal= Pediatrics |volume= 111 |pages= e714 |month= June |first1= M |first2= S |first3= P |first4= JM |first5= D |first6= G |first7= G |first8= Investigators |issue= 6 Pt 1 |last2= Tonnelier |last3= D'athis |last4= Tréluyer |last5= Gendrel |last6= Bréart |last7= Pons |author8= Pediatric Fluoroquinolone Safety Study Investigators }}</ref><ref>62 Meeting of the Anti-Infective Drugs Advisory Committee</ref><ref>{{cite web |first=Evelyn R |last=Farinas |author=PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH |coauthors=DEPARTMENT OF HEALTH AND HUMAN |title=Consult: One-Year Post Pediatric Exclusivity Postmarketing Adverse Events Review |url=http://www.fda.gov/OHRMS/DOCKETS/AC/05/briefing/2005-4152b1_03_01_Cipro%20AE.pdf |publisher=FDA |location=USA |format=PDF |date=1 March 2005 |accessdate=31 August 2009}}</ref> The CDC revoked its recommendation regarding the use of ciprofloxacin as a first line agent in treating anthrax due to the unacceptable risk documented within the Antimicrobial Postexposure Prophylaxis for Anthrax study (aka Cipro 60 day study).<ref>{{cite journal |publisher=[[Center for Disease Control]] |location=USA |issn= 1080-6040|pmid=12396927 |url=http://www.cdc.gov/ncidod/EID/vol8no10/02-0349.htm |year=2002 |month=October |title=Antimicrobial postexposure prophylaxis for anthrax: adverse events and adherence. |volume=8 |issue=10 |pages=1124–32 |journal=Emerging infectious diseases |first1=CW |first2=M |first3=ER |first4=J |first5=S |first6=S |first7=S |first8=J |first9=R |author1=Shepard, Cw |author2=Soriano-gabarro, M |author3=Zell, Er |author4=Hayslett, J |author5=Lukacs, S |author6=Goldstein, S |author7=Factor, S |author8=Jones, J |author9=Ridzon, R |first=Group |last2=Cdc Adverse Events Working |author=Cdc, Adverse}}</ref> However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Current recommendations by the American Academy of Pediatrics note that the systemic use of ciprofloxacin in children should be restricted to infections caused by multidrug resistant pathogens or when no safe or effective alternatives are available.<ref name=c2009>{{cite web |author=Lexi-Comp |title=Ciprofloxacin |url=http://www.merck.com/mmpe/lexicomp/ciprofloxacin.html |publisher=Merk |month=February |year=2009 |accessdate=4 September 2009}}</ref>

Indications include:

*Complicated urinary tract infections and [[pyelonephritis]] due to ''Escherichia coli''<ref name=cipro2004>{{cite web |author=Renata Albrecht |title=NDA 19-537/S-049, NDA 19-857/S-031, NDA 19-847/S-027, NDA 20-780/S-013 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537s049,19857s031,19847s027,20780s013ltr.pdf |publisher=FDA |location=USA |format=PDF |date=25 March 2004 |accessdate=7 September 2009}}</ref>

*Inhalational [[anthrax]] (postexposure)<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20780S08ltr.pdf |title=NDA 19-537/S-038, NDA 19-847/S-024, NDA 19-857/S-027, NDA 19-858/S-021, NDA 20-780/S-008 |author=Dianne Murphy |publisher=FDA |location=USA |format=PDF }}</ref>

Ciprofloxacin is not recommended to treat CAP (community acquired pneumonia) as a stand-alone first-line agent.  The current guidelines (Infectious Diseases Society of America 2007) state that, in very limited circumstances, ciprofloxacin or levofloxacin should be combined with other drugs such as a b-lactam drug to treat specific CAP infections, but neither drug is recommended to be used separately as a stand-alone first-line agent. In addition, the current guidelines state that: “Data exist suggesting that resistance to macrolides and older fluoroquinolones (ciprofloxacin and levofloxacin) results in clinical failure. Other studies have shown that repeated use of fluoroquinolones predicts an increased risk of infection with fluoroquinolone-resistant pneumococci....”<ref>{{Cite journal | last1 = Mandell | first1 = LA. | last2 = Wunderink | first2 = RG. | last3 = Anzueto | first3 = A. | last4 = Bartlett | first4 = JG. | last5 = Campbell | first5 = GD. | last6 = Dean | first6 = NC. | last7 = Dowell | first7 = SF. | last8 = File | first8 = TM. | last9 = Musher | first9 = DM. | title = Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. | journal = Clin Infect Dis | volume = 44 Suppl 2 | url = http://www.thoracic.org/sections/publications/statements/resources/idsaats-cap.pdf | format = PDF | pages = S27–72 | month = Mar | year = 2007 | doi = 10.1086/511159 | pmid = 17278083 }}</ref>

As such, the general opinion stated in 1994 that ciprofloxacin “is not to be considered a suitable agent for use in general practice for the blind initial treatment of chest infections....”<ref>{{Cite journal | last1 = Donaldson | first1 = PM. | last2 = Pallett | first2 = AP. | last3 = Carroll | first3 = MP. | title = Ciprofloxacin in general practice. | journal = BMJ | volume = 308 | issue = 6941 | pages = 1437 | month = May | year = 1994 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2540361/pdf/bmj00442-0061a.pdf | format = PDF | pmid = 8019264 | pmc = 2540361 }}</ref><ref>{{Cite journal | last1 = Körner | first1 = RJ. | last2 = Reeves | first2 = DS. | last3 = MacGowan | first3 = AP. | title = Dangers of oral fluoroquinolone treatment in community acquired upper respiratory tract infections. | journal = BMJ | volume = 308 | issue = 6922 | pages = 191–2 | month = Jan | year = 1994 | url = http://www.bmj.com/cgi/content/extract/308/6922/191 | pmid = 8312775 | pmc = 2542530 }}</ref> does not appear to have changed within these current guidelines.

Antibiotics may not improve the long-term clinical outcome for sinusitis.<ref>{{cite journal | author=van Buchem, F. L. | journal=The Lancet | volume=349 | issue=9053 | pages=683–687 | date= March 8, 1997 |   doi=10.1016/S0140-6736(96)07585-X | title=Primary-care-based randomised placebo-controlled trial of antibiotic treatment in acute maxillary sinusitis}}</ref>
When prescribed for chronic bronchitis and acute bacterial sinusitis, the use of the fluoroquinolone class offers no compelling advantages over established treatment.<ref>{{cite journal |pmid=15310155 |url=http://dtb.bmj.com/cgi/content/abstract/42/8/61 |doi=10.1136/dtb.2004.42861 |title= Moxifloxacin - a new fluoroquinolone antibacterial |year=2004 |journal=Drug and Therapeutics Bulletin |volume=42 |page=61 |month=August |issue=8 |issn=0012-6543 }}</ref> Nor does antibiotic treatment help sore throats.<ref>{{cite journal |pmid=9270442 |url= http://www.bmj.com/archive/7104/7104e1.htm |year=1997 |month=August |title=Acute otitis media in children. |volume=315 |issue=7104 |pages=321–2 |issn=0959-8138 |pmc=2127258 |journal=BMJ (Clinical research ed.) |first1=A |first2=T |author1=Majeed, A |author2=Harris, T}}</ref> The use of antibiotics such as ciprofloxacin to  treat bronchitis is to be considered unnecessary and as such exposes the patient to an unacceptable risk of suffering a severe adverse reaction.<ref>{{cite journal |pmid=9071245 |year=1997 |month=March |author=Hueston, Wj |title=Antibiotics: neither cost effective nor 'cough' effective. |volume=44 |issue=3 |pages=261–5 |journal=The Journal of family practice |url= http://www.nlm.nih.gov/medlineplus/antibiotics.html|format=Free full text |first1=WJ |issn=0094-3509}}</ref> Additionally, antibiotics have no effect upon viral infections, such as the common head cold or viral respiratory infections.

Note: Ciprofloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.

==Availability==
Ciprofloxacin is available as:
* tablets (250&nbsp;mg, 500&nbsp;mg, 750&nbsp;mg or 1000&nbsp;mg)
* intravenous solutions (5% and 10%, 100 mL)
* eye and ear drops

In most countries, all formulations require a prescription.

See the latest package insert for ciprofloxacin (Cipro) for additional details.<ref name="accessdata.fda.gov">{{cite web |author=Bayer HealthCare Pharmaceuticals |authorlink=Bayer HealthCare Pharmaceuticals |title=CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO (ciprofloxacin*) ORAL SUSPENSION |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s69,19847s43,19857s50,20780s27lbl.pdf |publisher=FDA |location=USA |format=PDF |date=12 February 2009 |accessdate=1 September 2009}}</ref>

==Mode of action==
Ciprofloxacin is a [[broad-spectrum antibiotic]] that is active against both
[[Gram-positive]] and [[Gram-negative]] bacteria. It functions by inhibiting [[DNA gyrase]], a type II [[topoisomerase]], and topoisomerase IV,<ref>{{cite journal |author=Drlica K, Zhao X |title=DNA gyrase, topoisomerase IV, and the 4-quinolones |journal=Microbiol Mol Biol Rev. |volume=61 |issue=3 |pages=377–92 |pmid=9293187 |pmc=232616 |url=http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=9293187 |date= September 1, 1997 |first1=K |first2=X |issn=1092-2172}}</ref> enzymes necessary to separate bacterial DNA, thereby inhibiting cell division.

This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine)<ref>{{cite journal |author=Robinson MJ, Martin BA, Gootz TD, McGuirk PR, Osheroff N |title=Effects of novel fluoroquinolones on the catalytic activities of eukaryotic topoisomerase II: Influence of the C-8 fluorine group |journal=Antimicrob. Agents Chemother. |volume=36 |issue=4 |pages=751–6 |year=1992 |month=April |pmid=1323952 |pmc=189387 |doi= |url=http://aac.asm.org/cgi/reprint/36/4/751.pdf |format=PDF |first1=MJ |first2=BA |first3=TD |first4=PR |first5=N |issn=0066-4804}}</ref> display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and ''in vivo'' tumor models.<ref name="pmid14529452">{{cite journal |author=Sissi C, Palumbo M |title=The quinolone family: from antibacterial to anticancer agents |journal=Curr Med Chem Anticancer Agents |volume=3 |issue=6 |pages=439–50 |year=2003 |month=November |pmid=14529452 |doi= 10.2174/1568011033482279|url=http://openurl.ingenta.com/content/nlm?genre=article&issn=1568-0118&volume=3&issue=6&spage=439&aulast=Sissi |quote=The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent. Indeed, a distinctive feature of drugs based on the quinolone structure is their remarkable ability to target different type II topoisomerase enzymes. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. |first1=C |first2=M |issn=1568-0118}}</ref>
Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al.).<ref>{{cite journal |author=Hussy P, Maass G, Tümmler B, Grosse F, Schomburg U |title=Effect of 4-quinolones and novobiocin on calf thymus DNA polymerase alpha primase complex, topoisomerases I and II, and growth of mammalian lymphoblasts |journal=Antimicrob. Agents Chemother. |volume=29 |issue=6 |pages=1073–8 |year=1986 |month=June |pmid=3015015 |pmc=180502 |doi= |url=http://aac.asm.org/cgi/reprint/29/6/1073.pdf |format=PDF|first1=P |first2=G |first3=B |first4=F |first5=U |issn=0066-4804}}</ref> 

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.<ref>{{cite journal |last= |first= |author=Hosomi JA |year=1988 |title=Mutagenicity of norfloxacin and AM-833 in bacteria and mammalian cells |journal=Rev. Infect |volume=10 |series=1 |pages=S148–S149 |publisher=jstor.org |url=http://www.jstor.org/pss/4454399 |first2= . |first3= . |first4= . |author5= Yokota |author2= Hosomi, J |author3= Maeda, A |author4= Oomori, Y }}</ref><ref>{{cite journal |author=Forsgren A, Bredberg A, Pardee AB, Schlossman SF, Tedder TF |title=Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide biosynthesis and cell growth |journal=Antimicrob. Agents Chemother. |volume=31 |issue=5 |pages=774–9 |year=1987 |month=May |pmid=3606077 |pmc=174831 |doi= |url=http://aac.asm.org/cgi/reprint/31/5/774.pdf |format=PDF |first1=A |first2=A |first3=AB |first4=SF |first5=TF |issn=0066-4804}}</ref><ref>{{cite journal |author=Gootz TD, Barrett JF, Sutcliffe JA |title=Inhibitory effects of quinolone antibacterial agents on eucaryotic topoisomerases and related test systems |journal=Antimicrob. Agents Chemother. |volume=34 |issue=1 |pages=8–12 |year=1990 |month=January |pmid=2158274 |pmc=171510 |doi= |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=171510&blobtype=pdf |first1=TD |first2=JF |first3=JA |issn=0066-4804}}</ref><ref>{{cite journal |author=Lawrence JW, Darkin-Rattray S, Xie F, Neims AH, Rowe TC |title=4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210 leukemia cells |journal=J. Cell. Biochem. |volume=51 |issue=2 |pages=165–74 |year=1993 |month=February |pmid=8440750 |doi=10.1002/jcb.240510208 |url= |first1=JW |first2=S |first3=F |first4=AH |first5=TC |issn=0730-2312 |format=Free full text}}</ref>
As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.<ref>{{cite journal |author=Elsea SH, Osheroff N, Nitiss JL |title=Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast |journal=J. Biol. Chem. |volume=267 |issue=19 |pages=13150–3 |year=1992 |month=July |pmid=1320012 |doi= |url=http://www.jbc.org/cgi/reprint/267/19/13150 |first1=SH |first2=N |first3=JL |issn=0021-9258}}</ref><ref>{{cite journal |author=Suto MJ, Domagala JM, Roland GE, Mailloux GB, Cohen MA |title=Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity |journal=J. Med. Chem. |volume=35 |issue=25 |pages=4745–50 |year=1992 |month=December |pmid=1469702 |doi= 10.1021/jm00103a013|url= |first1=MJ |first2=JM |first3=GE |first4=GB |first5=MA |issn=0022-2623}}</ref><ref>{{cite journal |author=Enzmann H, Wiemann C, Ahr HJ, Schlüter G |title=Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver |journal=Mutat. Res. |volume=425 |issue=2 |pages=213–24 |year=1999 |month=April |pmid=10216214 |doi= 10.1016/S0027-5107(99)00044-5|url= |first1=H |first2=C |first3=HJ |first4=G |issn=0027-5107}}</ref><ref>{{cite journal |author=Kashida Y, Sasaki YF, Ohsawa K |title=Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice |journal=Toxicol. Sci. |volume=69 |issue=2 |pages=317–21 |year=2002 |month=October |pmid=12377980 |doi= 10.1093/toxsci/69.2.317|url=http://toxsci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12377980 |first1=Y |first2=YF |first3=K |first4=N |first5=A |first6=T |first7=K |issn=1096-6080}}</ref><ref>{{cite journal |author=Thomas A, Tocher J, Edwards DI |title=Electrochemical characteristics of five quinolone drugs and their effect on DNA damage and repair in ''Escherichia coli'' |journal=J. Antimicrob. Chemother. |volume=25 |issue=5 |pages=733–44 |year=1990 |month=May |pmid=2165050 |doi= 10.1093/jac/25.5.733|url=http://jac.oxfordjournals.org/cgi/reprint/25/5/733 |first1=A |first2=J |first3=DI |issn=0305-7453}}</ref><ref>{{cite web | url = http://www.academy.org.uk/pharmacy/fluoroq.htm| title = Fluoroquinolones and Quinolones| accessdate = 29 January 2009| publisher = The American Academy of Optometry (British Chapter) }}</ref>

There continues to be debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapy.<ref name="pmid14529452"/><ref>{{cite journal |title=A new class of dihaloquinolones bearing N'-aldehydoglycosylhydrazides, mercapto-1,2,4-triazole, oxadiazoline and a-amino ester precursors: synthesis and antimicrobial activity |journal=J. Braz. Chem. Soc |volume=14 |issue=5 |pages= |year=2003 |month=|doi=10.1590/S0103-50532003000500014 |url=http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532003000500014&lng=es&nrm=iso&tlng=es |quote=Nevertheless, some quinolones cause injury to the chromosome of eukaryotic cells.21,22 These findings prompted us to optimize the substituent at C-3, by... |author1=Al-soud, Yaseen A |author2=Al-masoudi, Najim A |last1=Al-Soud |first1=Yaseen A.}}</ref><ref>{{cite journal |author=Yaseen A. Al-Soud a and Najim A. Al-Masoudi |title=A New Class of Dihaloquinolones Bearing N’-Aldehydoglycosylhydrazides, Mercapto-1,2,4-triazole, Oxadiazoline and α-Amino Ester Precursors: Synthesis and Antimicrobial Activity |journal=J. Braz. Chem. Soc |volume=14 |issue=5 |pages=790–796 |year=2003 |url=http://jbcs.sbq.org.br/jbcs/2003/v14_n5/13-048-02.pdf |format=PDF|quote=Although the current quinolones are not considered to be potent inhibitors of eucaryotic topoisomerases, some effects on these and other enzymes involved with DNA replication have been observed}}</ref>

==Contraindications==
As noted above, under licensed use, ciprofloxacin is also now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.<ref name="nycms.org">{{cite web |author=Susan Blank |coauthors=Julia Schillinger |title=DOHMH ALERT #8:Fluoroquinolone-resistant gonorrhea, NYC |url=http://www.nycms.org/article_view.php3?view=947&part=1 |publisher=New York County Medical Society |location=USA |date=14 May 2004 |accessdate=22 July 2009}}</ref>

There are only four contraindications found within the 2009 package insert:<ref name="accessdata.fda.gov"/>

*“Coadministration of ciprofloxacin with other drugs primarily metabolized by [[CYP1A2]] results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug.”

*“Concomitant administration with [[tizanidine]] is contraindicated”

*“Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components.”

*“Local I.V. site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions that resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.”'

Due to growing prevalence of antibiotic resistance to the fluoroquinolones in southeast Asia, the use of ciprofloxacin in patients having been to southeast Asia is increasingly being discouraged.<ref>{{cite journal |title=Fluoroquinolone resistance in Neisseria gonorrhoeae—Colorado and Washington, 1995 |journal=MMWR Morb Mortal Wkly Rep. |volume=44 |issue=41 |pages=761–4 |year=1995 |month=October |pmid=7565558 |url=http://www.cdc.gov/mmwr/preview/mmwrhtml/00039305.htm |issn=0149-2195 |author1=Centers for Disease Control and Prevention (CDC)}}</ref>

Ciprofloxacin is also considered to be contraindicated within the pediatric population (except for the indications outlined under licensed use above), [[pregnancy]], nursing mothers, and in patients with [[epilepsy]] or other seizure disorders.

*'''Pregnancy'''
The fluoroquinolones rapidly cross the blood-placenta and blood-milk barriers, and are extensively distributed into the fetal tissues. For this reason, the fluoroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The fluoroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child, which may increases the risk of the child suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.<ref>{{cite journal |author=Shin HC, Kim JC, Chung MK |title=Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats |journal=Comp. Biochem. Physiol. C Toxicol. Pharmacol. |volume=136 |issue=1 |pages=95–102 |year=2003 |month=September |pmid=14522602 |doi= 10.1016/j.cca.2003.08.004|url= |first1=HC |first2=JC |first3=MK |first4=YH |first5=JS |first6=MK |first7=GL |issn=1532-0456}}</ref><ref>{{cite journal |author=Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H |title=Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women |journal=Antimicrob. Agents Chemother. |volume=37 |issue=2 |pages=293–6 |year=1993 |month=February |pmid=8452360 |pmc=187655 |doi= |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=8452360 |first1=M |first2=E |first3=R |first4=R |first5=H |issn=0066-4804}}</ref>

*'''Pediatric population'''
Fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of fatalities<ref name="pmid1592498">{{cite journal |author=Karande SC, Kshirsagar NA |title=Adverse drug reaction monitoring of ciprofloxacin in pediatric practice |journal=Indian Pediatr |volume=29 |issue=2 |pages=181–8 |year=1992 |month=February |pmid=1592498 |doi= |url= |first1=SC |first2=NA |issn=0019-6061 |format=Free full text}}</ref> as well as permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin is being licensed for the treatment of complicated urinary tract infections and pyelonephritis due to ''Escherichia coli'', and inhalational anthrax (postexposure), and levofloxacin was recently licensed for the treatment of inhalational anthrax (postexposure). However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004), the rate of atrophy was reported to be 9.3%.<ref name=dospaidos>{{cite web  |author=Joette Meyer |coauthors=Renata Albrecht |title=Division of Special Pathogen and Immunologic Drug Products Summary of Clinical Review of Studies Submitted in Response to a Pediatric Written Request |url=http://www.fda.gov/ohrms/dockets/AC/05/briefing/2005-4152b1_03_03_Cipro%20medical.pdf |publisher=FDA |location=USA |format=PDF |date=16 March 2004 |accessdate=22 July 2009}}</ref>  
Within the BPCA Pediatric Studies Summary for ciprofloxacin<ref name=dospaidos/>, it was stated that the overall incidence of adverse events at six weeks was 41%. This would be consistent with the safety profile found with the other fluoroquinolones studied in the pediatric population. As such, the current ban on the use of the fluoroquinolones in the pediatric population is both reasonable and supported by various clinical studies. The most recent long term study, ''BAY 0 9867 Cipro Pediatric Use Study (QUIP)'', which followed pediatric patients from 1999–2008,<ref>[http://clinicaltrials.gov/ct2/show/results/NCT00761462?show_out=all#all BAY 0 9867 Cipro Pediatric Use Study (QUIP) - Study Results - ClinicalTrials.gov<!-- Bot generated title -->]</ref> supports the current expert opinion that the risk of permanent injury continues to outweigh the potential benefits of ciprofloxacin therapy in the pediatric population.

Within the United States, the FDA has stated it is their intention to pursue the licensing of the fluoroquinolones for pediatric use in spite of the evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee that the fluoroquinolones cause irreversible joint damage in the pediatric population.<ref>62 Meeting of the Anti-Infective Drugs Advisory Committee  [http://fqresearch.org/pdf_files/62nd_fda_meeting.pdf FQresearch.org]</ref>


*'''Depression and Anxiety Disorders'''
Ciprofloxacin has highly pronounced side effects in people suffering from [[panic disorder]] or/and [[Major depressive disorder|depression]].
There have been reported cases of psychosis, suicide attempts, panic attacks and acute anxiety, all occurring during or shortly after ciprofloxacin treatment. {{Citation needed|date=August 2010}} Patients with previous or current psychiatric conditions, are prone to experiencing this type of side effect.
Caution is highly advised.

==Special precautions==
The status of the patient’s renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to an overdose and the development of toxicity. Ciprofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver and the intestine. Modification of the dosage is ''recommended'' using the table found within the package insert for those with impaired liver or kidney function. However, since the drug is known to be substantially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The duration of treatment depends upon the severity of infection and is usually 7 to 14 days.<ref name=ctcos/>

==Adverse effects==
{{See also|Adverse effects of fluoroquinolones}}
Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. In most, adverse reactions are mild to moderate; however, occasionally serious adverse effects occur.<ref>{{cite journal |pmid=15942881 |year=2005 |month=July |last1=Owens Rc |first1=Jr |last2=Ambrose |first2=PG |title=Antimicrobial safety: focus on fluoroquinolones. |volume=41 Suppl 2 |pages=S144–57 |issn=1058-4838 |doi=10.1086/428055 |journal=Clinical infectious diseases : an official publication of the Infectious Diseases Society of America |author2=Ambrose }}</ref><ref name="pmid11172695">{{cite journal |author=De Sarro A, De Sarro G |title=Adverse reactions to fluoroquinolones. an overview on mechanistic aspects |journal=Curr. Med. Chem. |volume=8 |issue=4 |pages=371–84 |year=2001 |month=March |pmid=11172695 |doi= |url=http://www.fqresearch.org/pdf_files/cmc.pdf |format=PDF}}</ref> There have been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings,<ref>{{cite web |author=U S Food and Drug Administration |authorlink=US Food and Drug Administration |title=FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116919.htm |publisher=FDA |location=USA |format=PDF |date=8 July 2008 |accessdate=5 September 2009}}</ref><ref>{{cite web |author=US Food and Drug Administration |authorlink=US Food and Drug Administration |title=Fluoroquinolone Antimicrobial Drugs [ciprofloxacin (marketed as Cipro and generic ciprofloxacin), ciprofloxacin extended release (marketed as Cipro XR and Proquin XR), gemifloxacin (marketed as Factive), levofloxacin (marketed as Levaquin), moxifloxacin (marketed as Avelox), norfloxacin (marketed as Noroxin), and ofloxacin (marketed as Floxin and generic ofloxacin)] |url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm084316.htm |publisher= |location=USA |year=2008 |accessdate=5 September 2009}} {{Dead link|date=September 2010|bot=H3llBot}}</ref> additional warnings and safety information added to the package inserts<ref>{{cite web |author=US Food and Drug Administration |authorlink=US Food and Drug Administration |title=Drugs at FDA: FDA Approved Drug Products |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist |publisher=FDA |location=USA |accessdate=5 September 2009}}</ref> together with the issuance of "Dear Doctor Letters"<ref>{{cite web |author=Paul MacCarthy |title=Important Change in the Avelox (moxifloxacin hydrochloride) and Cipro (ciprofloxacin) Complete Prescribing Information – Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture |url=http://www.avelox.com/html/pdf/dhpl.pdf |publisher=Bayer healthcare pharmaceuticals |format=PDF |date=22 October 2008 |accessdate=5 September 2009}}</ref> concerning the recent addition of Black Box Warnings. In 2004, the U.S. FDA requested new warning labels to be added to all of the fluoroquinolones, including ciprofloxacin, regarding [[peripheral neuropathy]] (irreversible nerve damage), tendon damage, heart problems (prolonged QT Interval / [[torsades de pointes]]), [[pseudomembranous colitis]], [[rhabdomyolysis]] (muscle breakdown), [[Stevens-Johnson syndrome]], as well as concurrent usage of [[NSAIDs]] contributing to the severity of these reactions.

Subsequent to this, on June 25, 2007, the U.S. FDA required the manufacturer to add an additional warning to the package inserts that stated that “Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin.”<ref>{{cite web |author=Renata Albrecht |title=NDA 19-537/S-062, NDA 20-780/S-023, NDA 19-847/S-037, NDA 19-857/S-042, NDA 21-473/S-016 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/019537s62,020780s23,019847s37,019857s42,021473s16LTR.pdf |publisher=FDA |location=USA |format=PDF |date=19 June 2006 |accessdate=5 September 2009}}</ref> It was not until 2008, (four years later) that the label revisions for ciprofloxacin included any warnings concerning heart problems (prolonged QT Interval / torsades de pointes). Warnings concerning rhabdomyolysis and Stevens-Johnson syndrome are still conspicuously absent from the package inserts as of September 2009.

The serious adverse effects that may occur as a result of ciprofloxacin therapy include irreversible peripheral neuropathy,<ref>{{cite web |author=Renata Albrecht |title=NDA 19-537/S-053, S-054, NDA 20-780/S-017, S-018 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537s053,054,20780s017,018ltr.pdf |publisher= |location=USA |format=PDF |date=14 July 2004 |accessdate=5 September 2009}}</ref><ref>{{cite journal |pmid=7488901 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2551120&blobtype=pdf |quote=One case of peripheral neuropathy has been reported. We report two cases of generalised painful dysaesthesia due to ciprofloxacin, a reaction not previously associated with this particular fluoroquinolone |year=1995 |month=November |last1=Zehnder |first1=D |last2=Hoigné |first2=R |last3=Neftel |first3=KA |last4=Sieber |first4=R |title=Painful dysaesthesia with ciprofloxacin. |volume=311 |issue=7014 |page=1204 |issn=0959-8138 |journal=BMJ (Clinical research ed.) |author2=Hoigné |author3=Neftel |author4=Sieber |pmc=2551120 }}</ref> spontaneous [[tendon rupture]] and [[tendonitis]],<ref name=FDA1996/><ref>{{cite web |author=Renata Albrecht |title=NDA 19-537/S-048, S-050, S-051, NDA 20-780/S-012, S-014, S-015 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537slr048,050,051,20780slr012,014,015ltr.pdf |publisher=FDA |location=USA |format=PDF |date=15 March 2004 |accessdate=5 September 2009}}</ref><ref>[http://www.fqresearch.org/text_documents/FDA_Medical_Bulletin_1996.doc FQresearch.org]</ref><ref>{{cite web |author=Renata Albrecht |title=NDA 19-537/S-068, NDA 19-847/S-042, NDA 19-857/S-049, NDA 20-780/S-026, NDA 21-473/S-024 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/019537s068,019847s042ltr.pdf |publisher=FDA |location=USA |format=PDF |date=3 October 2008 |accessdate=5 September 2009}}</ref> acute [[liver failure]] or serious liver injury ([[hepatitis]]),<ref>{{cite journal |pmid=7841570 |year=1994 |month=October |last1=Sherman |first1=O |last2=Beizer |first2=JL |title=Possible ciprofloxacin-induced acute cholestatic jaundice. |volume=28 |issue=10 |pages=1162–4 |issn=1060-0280 |journal=The Annals of pharmacotherapy |url=http://www.nlm.nih.gov/medlineplus/bileductdiseases.html |format=Free full text |author2=Beizer }}</ref><ref>{{cite journal |pmid=14994731 |year=2004 |month=January |last1=Zimpfer |first1=A |last2=Propst |first2=A |last3=Mikuz |first3=G |last4=Vogel |first4=W |last5=Terracciano |first5=L |last6=Stadlmann |first6=S |title=Ciprofloxacin-induced acute liver injury: case report and review of literature. |volume=444 |issue=1 |pages=87–9 |issn=0945-6317 |journal=Virchows Archiv : an international journal of pathology |doi=10.1007/s00428-003-0917-9 |author2=Propst |author3=Mikuz |author4=Vogel |author5=Terracciano |author6=Stadlmann }}</ref> QTc prolongation/torsades de pointes,<ref name=ctcos/> [[toxic epidermal necrolysis]] (TEN),<ref>{{cite journal |pmid=14735388 |year=2003 |month=December |last1=Jongen-Lavrencic |first1=M |last2=Schneeberger |last3=Van Der Hoeven |title=Ciprofloxacin-induced toxic epidermal necrolysis in a patient with systemic lupus erythematosus. |volume=31 |issue=6 |pages=428–9 |issn=0300-8126 |doi=10.1007/s15010-003-2128-3 |journal=Infection |author2=Schneeberger |author3=Van Der Hoeven }}</ref><ref>{{cite journal |pmid=8305780 |year=1993 |month=December |last1=Moshfeghi |first1=M |last2=Mandler |title=Ciprofloxacin-induced toxic epidermal necrolysis. |volume=27 |issue=12 |pages=1467–9 |issn=1060-0280 |journal=The Annals of pharmacotherapy |url= |format= |author2=Mandler}}</ref><ref>{{cite journal |pmid=8305780 |year=1993 |month=December |last1=Moshfeghi |first1=M |last2=Mandler |title=Ciprofloxacin-induced toxic epidermal necrolysis. |volume=27 |issue=12 |pages=1467–9 |issn=1060-0280 |journal=The Annals of pharmacotherapy |url= |format= |author2=Mandler }}</ref> and Stevens-Johnson syndrome, severe central nervous system disorders (CNS)<ref name=cipro2004/> and [[Clostridium difficile]] associated disease (CDAD: [[pseudomembranous colitis]]),<ref>{{cite journal |pmid=18067688 |year=2008 |month=February |last1=Deshpande |first1=A |last2=Pant |last3=Jain |last4=Fraser |last5=Rolston |title=Do fluoroquinolones predispose patients to Clostridium difficile associated disease? A review of the evidence. |volume=24 |issue=2 |pages=329–33 |issn=0300-7995 |doi=10.1185/030079908X253735 |journal=Current medical research and opinion |author2=Pant |author3=Jain |author4=Fraser |author5=Rolston }}</ref><ref>{{cite web |author=Renata Albrecht |title=NDA 19-537/S-065, NDA 19-847/S-039, NDA 19-857/S-046, NDA 20-780/S-024, NDA 21-473/S-022 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/019537s65,19847s39,19857s46,20780s24,21473s22ltr.pdf |publisher=FDA |location=USA |format=PDF |date=25 June 2007 |accessdate=4 September 2009}}</ref> as well as photosensitivity/[[phototoxicity]] reactions.

Psychotic reactions and confusional states, [[acute pancreatitis]],<ref>{{cite journal |pmid=11129278 |year=2000 |month=December |last1=Mann |first1=S |last2=Thillainayagam |title=Is ciprofloxacin a new cause of acute pancreatitis? |volume=31 |issue=4 |page=336 |issn=0192-0790 |journal=Journal of clinical gastroenterology |doi=10.1097/00004836-200012000-00014 |author2=Thillainayagam }}</ref> [[bone marrow depression]], [[interstitial nephritis]] and [[hemolytic anemia]] may also occur during ciprofloxacin therapy.<ref>{{cite journal |pmid=10616701 |year=1999 |month=September |last1=Dutta |first1=TK |last2=Badhe |title=Ciprofloxacin-induced bone marrow depression. |volume=75 |issue=887 |pages=571–3 |issn=0032-5473 |journal=Postgraduate medical journal |author2=Badhe |pmc=1741342 }}</ref><ref>{{cite journal |pmid=12911170 |year=2003 |month=July |last1=Lim |first1=S |last2=Alam |title=Ciprofloxacin-induced acute interstitial nephritis and autoimmune hemolytic anemia. |volume=25 |issue=4 |pages=647–51 |issn=0886-022X |journal=Renal failure |doi=10.1081/JDI-120022557 |author2=Alam }}</ref> Additional serious adverse reactions include temporary, as well as permanent, [[loss of vision]],<ref>{{cite journal |pmid=2374675 |year=1990 |month=June |last1=Vrabec |first1=TR |last2=Sergott |last3=Jaeger |last4=Savino |last5=Bosley |title=Reversible visual loss in a patient receiving high-dose ciprofloxacin hydrochloride (Cipro) |volume=97 |issue=6 |pages=707–10 |issn=0161-6420 |journal=Ophthalmology |url= |format= |author2=Sergott |author3=Jaeger |author4=Savino |author5=Bosley }}</ref><ref>{{cite journal |pmid=17300586 |year=2007 |month=January |last1=Samarakoon |first1=N |last2=Harrisberg |last3=Ell |title=Ciprofloxacin-induced toxic optic neuropathy. |volume=35 |issue=1 |pages=102–4 |issn=1442-6404 |doi=10.1111/j.1442-9071.2007.01427.x |journal=Clinical & experimental ophthalmology |author2=Harrisberg |author3=Ell }}</ref> irreversible [[double vision]],<ref name=pmid19643481>{{cite journal |pmid=19643481 |year=2009 |month=September |last1=Fraunfelder |first1=FW |last2=Fraunfelder |title=Diplopia and fluoroquinolones |volume=116 |issue=9 |pages=1814–7 |issn=0161-6420 |doi=10.1016/j.ophtha.2009.06.027 |journal=Ophthalmology |author2=Fraunfelder }}</ref> drug induced psychosis<ref>{{ cite journal |pmid=7604468 |year=1995 |month=July |last1=Mulhall |first1=JP |last2=Bergmann |title=Ciprofloxacin-induced acute psychosis. |volume=46 |issue=1 |pages=102–3 |issn=0090-4295 |doi=10.1016/S0090-4295(99)80171-X |journal=Urology |author2=Bergmann }}</ref><ref>{{cite journal |pmid=1504404 |year=1992 |month=July |last1=Reeves |first1=RR |title=Ciprofloxacin-induced psychosis. |volume=26 |issue=7-8 |pages=930–1 |issn=1060-0280 |journal=The Annals of pharmacotherapy |url= |format= }}</ref> and [[chorea]] (involuntary muscle movements),<ref>{{cite journal |pmid=15739219 |year=2005 |month=April |last1=Azar |first1=S |last2=Ramjiani |last3=Van Gerpen |title=Ciprofloxacin-induced chorea. |volume=20 |issue=4 |pages=513–4; author reply 514 |issn=0885-3185 |doi=10.1002/mds.20425 |journal=Movement disorders : official journal of the Movement Disorder Society |author2=Ramjiani |author3=Van Gerpen }}</ref> impaired [[color vision]], [[exanthema]], abdominal pain, [[malaise]], [[drug fever]], [[dysaesthesia]] and [[eosinophilia]].<ref>{{cite journal |pmid=3053554 |year=1988 |month=August |title=Therapy of acute and chronic gram-negative osteomyelitis with ciprofloxacin. Report from a Swedish Study Group. |volume=22 |issue=2 |pages=221–8 |issn=0305-7453 |journal=The Journal of antimicrobial chemotherapy |doi=10.1093/jac/22.2.221 }}</ref><ref>{{cite journal |pmid=7488901 |quote=One case of peripheral neuropathy has been reported. We report two cases of generalised painful dysaesthesia due to ciprofloxacin, a reaction not previously associated with this particular fluoroquinolone. |year=1995 |month=November |last1=Zehnder |first1=D |last2=Hoigné |last3=Neftel |last4=Sieber |title=Painful dysaesthesia with ciprofloxacin. |volume=311 |issue=7014 |page=1204 |issn=0959-8138 |journal=BMJ (Clinical research ed.) |author2=Hoigné |author3=Neftel |author4=Sieber |pmc=2551120 }}</ref> [[Pseudotumor cerebri]], commonly known as idiopathic intracranial hypertension (IIH), (also referred to as increased intracranial pressure), has been reported to occur as a serious adverse reaction to ciprofloxacin.<ref>{{cite journal |pmid=2248512 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1792342&blobtype=pdf |format=PDF |year=1990 |month=October |last1=Winrow |first1=AP |last2=Supramaniam |title=Benign intracranial hypertension after ciprofloxacin administration. |volume=65 |issue=10 |pages=1165–6 |issn=0003-9888 |journal=Archives of disease in childhood |doi=10.1136/adc.65.10.1165 |author2=Supramaniam |pmc=1792342 }}</ref>

Children and the elderly are at a much greater risk of experiencing such adverse reactions.<ref name="autogenerated1403">{{cite journal |pmid=17559736 |year=2007 |month=June |last1=Iannini |first1=PB |title=The safety profile of moxifloxacin and other fluoroquinolones in special patient populations. |volume=23 |issue=6 |pages=1403–13 |issn=0300-7995 |doi=10.1185/030079907X188099 |journal=Current medical research and opinion }}</ref><ref>{{cite journal |pmid=15942881 |year=2005 |month=July |last1=Owens Rc |first1=Jr |last2=Ambrose |title=Antimicrobial safety: focus on fluoroquinolones. |volume=41 Suppl 2 |pages=S144–57 |issn=1058-4838 |doi=10.1086/428055 |journal=Clinical infectious diseases : an official publication of the Infectious Diseases Society of America |author2=Ambrose }}</ref> Such reactions may manifest during fluoroquinolone therapy, and long after it had been discontinued.<ref>{{cite journal |pmid=10970974 |year=2000 |month=September |last1=Saint |first1=F |last2=Gueguen |last3=Biserte |last4=Fontaine |last5=Mazeman |title=Rupture of the patellar ligament one month after treatment with fluoroquinolone |volume=86 |issue=5 |pages=495–7 |issn=0035-1040 |journal=Revue de chirurgie orthopedique et reparatrice de l'appareil moteur |author2=Gueguen |author3=Biserte |author4=Fontaine |author5=Mazeman }}</ref>

Serious visual complications have also been reported to occur with [[ophthalmic]] fluoroquinolone therapy, which may also occur with ciprofloxacin eye drops, especially [[corneal perforation]], but also [[evisceration]] and [[enucleation]]. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in [[stromal]] [[collagen]], leading to a reduction in [[tectonic]] strength.<ref>{{cite journal |pmid=10729294 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1723447&blobtype=pdf |format=PDF |year=2000 |month=April |last1=Gangopadhyay |first1=N |last2=Daniell |last3=Weih |last4=Taylor |title=Fluoroquinolone and fortified antibiotics for treating bacterial corneal ulcers. |volume=84 |issue=4 |pages=378–84 |issn=0007-1161 |journal=The British journal of ophthalmology |author2=Daniell |author3=Weih |author4=Taylor |pmc=1723447 |doi=10.1136/bjo.84.4.378 }}</ref><ref>{{cite journal |pmid=17068466 |year=2006 |month=August |last1=Walter |first1=K |last2=Tyler |title=Severe corneal toxicity after topical fluoroquinolone therapy: report of two cases. |volume=25 |issue=7 |pages=855–7 |issn=0277-3740 |journal=Cornea |author2=Tyler |doi=10.1097/01.ico.0000224642.43601.14 }}</ref> As noted previously permanent double vision (diplopia) has also been reported.<ref name=pmid19643481/>
An unusual case of seizures has also been reported with ciprofloxacin ear drops in an elderly patient.<ref>{{cite journal |issn= 0025-729X|pmid=12670280 |url=http://www.mja.com.au/public/issues/178_07_070403/orr10717_fm.html |year= 2003 |month= April |title= Eardrop attacks: seizures triggered by ciprofloxacin eardrops. |volume= 178 |issue= 7 |page= 343 |journal= The Medical journal of Australia |author1= Orr, Cf |author2= Rowe, Db }}</ref>
  
Some groups refer to these adverse events as "[[fluoroquinolone toxicity]]". These groups of people claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones, as well as legal action by the consumer advocate group [[Public Citizen]].<ref>{{cite web |title=Public Citizen Warns of Cipro Dangers |url=http://www.consumeraffairs.com/news04/2006/08/pubcit_cipro.html |publisher=Consumer affairs |location=USA |date=30 August 2006 |accessdate=7 September 2009}}</ref> Partly as a result of the efforts of the State of Illinois and Public Citizen, the FDA ordered black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.<ref>{{cite news |url=http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html|title=FDA orders 'black box' label on some antibiotics |accessdate=2008-07-08 | work=CNN | date=8 July 2008}}</ref>

==Interactions==
The toxicity of drugs that are metabolised by the [[cytochrome P450]] system is enhanced by concomitant use of some quinolones. Coadministration may dangerously increase coumarin ([[warfarin]]) activity; INR should be monitored closely. They may also interact with the [[GABA A receptor]] and cause neurological symptoms; this effect is augmented by certain [[nonsteroidal anti-inflammatory drug]]s.<ref>{{cite journal |author=Brouwers JR |title=Drug interactions with quinolone antibacterials |journal=Drug Saf |volume=7 |issue=4 |pages=268–81 |year=1992 |pmid=1524699 |doi=10.2165/00002018-199207040-00003 |month=July |first1=JR |issn=0114-5916 }}</ref> [[Quercetin]], a flavonol, occasionally used as a [[dietary supplement]], may interact with fluoroquinolones, as quercetin competitively binds to bacterial DNA gyrase. Some foods, such as [[garlic]] and [[apple]]s, contain high levels of quercetin; whether this inhibits or enhances the effect of fluoroquinolones is not entirely clear.<ref>{{cite journal |author=Hilliard JJ, Krause HM, Bernstein JI |title=A comparison of active site binding of 4-quinolones and novel flavone gyrase inhibitors to DNA gyrase |journal=Adv Exp Med Biol. |volume=390 |pages=59–69 |year=1995 |pmid=8718602 |first1=JJ |first2=HM |first3=JI |first4=JA |first5=V |first6=KA |first7=JF |issn=0065-2598 }}</ref> Ciprofloxacin can reduce [[phenytoin]] plasma levels, which may, in some cases, result in seizures.<ref>{{cite web |url=http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v8n1-eng.pdf |title=Risk of seizures from concomitant use of ciprofloxacin and phenytoin in patients with epilepsy |accessdate= 2009-01-30 |author=Carol Langlois |coauthors=Pascale Springuel |year=1998 |month=January |format=PDF |publisher=Canadian Adverse Drug Reaction Newsletter |location=Canada}}</ref> Ciprofloxacin may interfere with the levels of thyroid medications resulting in [[hypothyroidism]].<ref>{{cite journal |author=Cooper JG, Harboe K, Frost SK, Skadberg Ø |title=Ciprofloxacin interacts with thyroid replacement therapy |journal=BMJ |volume=330 |issue=7498 |page=1002 |year=2005 |month=April |pmid=15860826 |pmc=557149 |doi=10.1136/bmj.330.7498.1002 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15860826 |first1=JG |first2=K |first3=SK |issn=0959-8138}}</ref>

On 9 November 2005, the U.S. FDA required the manufacturers to provide additional warnings within the package inserts concerning ciprofloxacin being an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. The new warning stated: <blockquote>"Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug."<ref>{{cite web |author=Renata Albrecht |title=NDA 19-537/S-060, NDA 19-847/S-036, NDA 19-857/S-041, NDA 20-780/S-020, NDA 21-473/S-013 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019537s60,019847s36,019857s41,020780s20,021473s13ltr.pdf |publisher=FDA |location=USA |format=PDF |date=2005-11-09 |accessdate=2009-09-08}}</ref></blockquote>

Concurrent administration of ciprofloxacin with magnesium or aluminum antacids, sucralfate or products containing calcium, iron, or zinc (including multivitamins or other dietary supplements) may substantially decrease the absorption of ciprofloxacin, resulting in serum and urine levels considerably lower than desired.<ref name="FDA 81532304, R.1"/>  

===Significant drug interactions===
Ciprofloxacin can alter and be altered by the metabolism and effects of other drugs, resulting in some significant drug-drug interactions that may affect the [[musculoskeletal]], [[central nervous system|central nervous]], [[renal]], and other systems.

Current or past treatment with oral [[corticosteroids]] is associated with an increased risk of [[achilles tendon]] rupture, especially in elderly patients who are also taking the [[fluoroquinolones]].<ref>{{cite journal |author=van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH |title=Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids |journal=Arch. Intern. Med. |volume=163 |issue=15 |pages=1801–7 |year=2003 |pmid=12912715 |doi=10.1001/archinte.163.15.1801 |url=http://archinte.ama-assn.org/cgi/content/full/163/15/1801 |month=August |first1=PD |first2=MC |first3=RM |first4=HM |first5=S |first6=BH |issn=0003-9926}}</ref> This is the subject of [[Black box warning]]s in FDA and [[BNF]] labeling for quinolones.

The [[Committee on the Safety of Medicines]] and the FDA warn that [[central nervous system]] adverse effects, including seizure risk, may be increased when NSAIDs are combined with quinolones.<ref name=ctcos/><ref>{{cite book |title=[[British National Formulary]] (BNF 57) |author=Royal Pharmaceutical Society of Great Britain |authorlink=Royal Pharmaceutical Society of Great Britain |publisher=BMJ Group and RPS Publishing |chapter=5 Infections |year=2009 |isbn=9780853698456 }}</ref> The interaction between quinolones and NSAIDs is important, because it has the potential for considerable CNS toxicity. The mechanism for this interaction is believed to be due to a [[synergistic]] increased antagonism of GABA neurotransmission.<ref name="pmid11172695"/>

Ciprofloxacin's renal clearance may affect other drugs subject to renal clearance or otherwise affecting the kidney.  The use of ciprofloxacin concomitantly with [[cyclosporine]] has also been associated with transient elevations in serum [[creatinine]]. Renal tubular transport of [[methotrexate]] may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and risk of methotrexate toxicity. [[Probenecid]] interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in serum.<ref name=ctcos/>

Some quinolones, including ciprofloxacin, exert an inhibitory effect on the cytochrome P-450 enzyme CYP1A2, thereby reducing clearance, and thus increasing blood levels of [[tizanidine]] and [[methylxanthines]] (e.g., [[theophylline]] and [[caffeine]]).<ref>{{cite journal |author=Harder S, Fuhr U, Staib AH, Wolff T |title=Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations |journal=Am. J. Med. |volume=87 |issue=5A |pages=89S–91S |year=1989 |month=November |pmid=2589393 |doi= 10.1016/0002-9343(89)90031-4|url= |first1=S |first2=U |first3=AH |first4=T |issn=0002-9343 |format=Free full text}}</ref><ref>{{cite journal |author=Janknegt R |title=Drug interactions with quinolones |journal=J. Antimicrob. Chemother. |volume=26 Suppl D |issue= |pages=7–29 |year=1990 |month=November |pmid=2286594 |doi= |url= |first1=R |issn=0305-7453}}</ref> The quinolones have also been reported to enhance the effects of [[warfarin]] or its derivatives.<ref name=ctcos/> Such interactions can augment the effects of the co-administered drug, including adverse effects. Ciprofloxacin can reduce effects of other drugs; for example, it has been shown to interact with thyroid medications ([[levothyroxine]]), resulting in unexplained [[hypothyroidism]].<ref>{{cite journal |author=Cooper JG, Harboe K, Frost SK, Skadberg Ø |title=Ciprofloxacin interacts with thyroid replacement therapy |journal=BMJ |volume=330 |issue=7498 |page=1002 |month=April |date=2005-04 |pmid=15860826 |pmc=557149 |doi=10.1136/bmj.330.7498.1002 |url=http://www.bmj.com/cgi/content/full/330/7498/1002 |first1=JG |first2=K |first3=SK |issn=0959-8138}}</ref> Altered serum levels of [[phenytoin]] (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.<ref name=ctcos/>

==Overdose==
Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach via induced vomiting or by [[gastric lavage]]. Careful monitoring and supportive treatment, monitoring of renal function and maintaining adequate hydration is recommended by the manufacturer. Administration of magnesium, aluminum, or calcium containing antacids can reduce the absorption of ciprofloxacin. [[Hemodialysis]] or [[peritoneal dialysis]] removes only less than 10 percent of ciprofloxacin.<ref name="FDA 81532304, R.1">{{cite web |author=Bayer HealthCare Pharmaceutucals |title=CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO (ciprofloxacin*) ORAL SUSPENSION |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s073,020780s030lbl.pdf |publisher=FDA |location=USA |format=PDF |date=12 February 2009 |accessdate=8 September 2009}}</ref> Ciprofloxacin may be quantitated 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.</ref>

==Chemistry==
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" />

==Pharmacokinetics==
The effects of 200–400&nbsp;mg of ciprofloxacin given intravenously are linear; drug accumulation does not occur when administered at 12 hour intervals. [[Bioavailability]] is approximately 70-80%, with no significant first pass effect. [[IV administration]] produces a similar [[serum]] levels as those achieved with administration of 500&nbsp;mg administered orally. IV administration over 60 minutes given every 8 hours produces similar serum levels of the drug as 750&nbsp;mg administered orally every 12 hours.<ref name="FDA 81532304, R.1" /> Biotransformation is hepatic. The [[elimination half life]] is 4 hours.<ref name=ctcos/>

==History of the black box warnings==
{{See also|Quinolone#Black box warnings}}
Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to [[nalidixic acid]].<ref name="autogenerated604">{{cite journal |author=Bailey RR, Natale R, Linton AL |title=Nalidixic acid arthralgia |journal=Can Med Assoc J |volume=107 |issue=7 |pages=604 passim |year=1972 |month=October |pmid=4541768 |pmc=1940945 |first1=RR |first2=R |first3=AL |issn=0008-4409}}</ref> Rheumatic disease after use of a fluoroquinolone ([[norfloxacin]]) was first reported eleven years later.<ref name="autogenerated590">{{cite journal |author=Bailey RR, Kirk JA, Peddie BA |title=Norfloxacin-induced rheumatic disease |journal=N Z Med J |volume=96 |issue=736 |page=590 |year=1983 |month=July |pmid=6223241 |first1=RR |first2=JA |first3=BA |issn=0028-8446 |url= |format=}}</ref> In response to a 1995 letter published in the ''[[New England Journal of Medicine]]'', representatives of the [[U.S. Food and Drug Administration]] (FDA) stated that the agency would "update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."<ref name="autogenerated193">{{cite journal |author=Szarfman A, Chen M, Blum MD |title=More on fluoroquinolone antibiotics and tendon rupture |journal=N Engl J Med |volume=332 |issue=3 |page=193 |year=1995 |month=January |pmid=7800023 |format=letter |doi=10.1056/NEJM199501193320319 |first1=A |first2=M |first3=MD |issn=0028-4793}}</ref> 

By August 1996, the FDA had not taken action, and the consumer advocacy group [[Public Citizen]] filed a petition with the FDA prompting the agency to act.<ref>{{cite web |title=Petition to Require a Warning on All Fluoroquinolone Antibiotics (HRG Publication #1399) |date=August 1, 1996 |publisher=[[Public Citizen]] |url=http://www.citizen.org/publications/release.cfm?ID=6595}} Retrieved on December 27, 2008.</ref> Two months later, the FDA published an alert in the ''FDA Medical Bulletin'' and requested that fluoroquinolone package inserts be amended to include information on this risk.<ref name=FDA1996>{{cite journal |title=Reports of adverse events with fluoroquinolones |journal=FDA Medical Bulletin |month=October | year=1996 |volume=26 |issue=3 |url=http://www.fqresearch.org/text_documents/FDA_Medical_Bulletin_1996.doc |format=Doc}}</ref>

Nine years later, in 2005, the [[Illinois Attorney General]] filed a second petition with the FDA again seeking [[Black Box Warning]]s and "Dear Doctor" letters emphasizing the risk of tendon rupture; the FDA responded that it had not yet been able to reach a decision on the matter.<ref name=Madigan>{{cite press release |title=Madigan, Public Citizen, petition FDA for "Black Box" warning regarding potential adverse effects of certain popular antibiotics |date=August 29, 2006 |publisher=Office of the Illinois Attorney General |url=http://www.illinoisattorneygeneral.gov/pressroom/2006_08/20060829.html | accessdate = 2008-12-27}} Full text of the [http://fqresearch.org/pdf_files/fda_response.pdf 2005 petition] and [http://fqresearch.org/pdf_files/illinois.pdf FDA response] available from the Fluoroquinolone Toxicity Research Foundation, a U.S. consumer advocacy group.</ref> In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for  Black Box Warnings by filing a third petition requesting such changes  be made.<ref name=Madigan/><ref>{{cite web |title=Public Citizen Petitions the FDA to Include a Black Box Warning on Fluoroquinolone Antibiotics (HRG Publication #1781) |date=August 29, 2006 |publisher=Public Citizen |url=http://www.citizen.org/publications/release.cfm?ID=7453 | accessdate = 2008-12-27}}</ref> When the FDA failed to respond to these two petitions as required by law Public Citizen, in January 2008,  filed suit to compel the FDA to respond to their 2006 petition.<ref>{{cite web |url=http://www.citizen.org/litigation/forms/cases/CaseDetails.cfm?cID=444 |title=Public Citizen v. Food and Drug Administration (FDA) (Fluoroquinolone) |date=January 3, 2008 |publisher=Public Citizen | accessdate = 2008-12-27}}</ref><ref>{{cite news |last=Ravn |first=Karen |title=Behind the FDA’s ‘black box’ warnings |date=August 18, 2008 |publisher=[[Los Angeles Times]] |url=http://articles.latimes.com/2008/aug/18/health/he-closer18 | accessdate = 2008-12-27}}</ref> On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding spontaneous tendon ruptures, and to develop a Medication Guide for patients.<ref name=FDA>{{cite press release |url=http://www.fda.gov/bbs/topics/NEWS/2008/NEW01858.html |title=FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs |publisher=[[U.S. Food and Drug Administration]] |date= 2008-07-08 | accessdate = 2008-10-11}}</ref> The package inserts for Ciprofloxacin, Avelox ([[moxifloxacin]]), Proquin XR, Factive ([[gemifloxacin]]), Floxin ([[ofloxacin]]), Noroxin ([[norfloxacin]]) and Levaquin ([[levofloxacin]]) were amended on September 8, 2008 to include these new warnings.<ref>The complete labeling history of each drug is available from [http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Drugs@FDA]. Medication Guides are available from the FDA's [http://www.fda.gov/medwatch MedWatch] system.</ref> [[Bayer]], which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.<ref>{{cite web |last=MacCarthy |first=Paul |title=Important Change in the Avelox (moxifloxacin hydrochloride) and Cipro (ciprofloxacin) Complete Prescribing Information&nbsp;– Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture |date=October 22, 2008 |publisher=Bayer HealthCare Pharmaceuticals |url=http://www.cipro.com/html/pdf/dhpl.pdf |format=PDF| accessdate= 2008-12-27}}</ref> [[Ortho-McNeil]], the manufacturers of Levaquin, issued a similar letter in November.<ref>{{cite web |last=Rosenthal |first=Norman |title=Important Change in the LEVAQUIN (Ievofloxacin) Complete Prescribing Information&nbsp;-Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture |month=November | year=2008 |publisher=Ortho-McNeil Janssen Scientific Affairs, LLC |url=http://www.fqresearch.org/pdf_files/Levaquin_11_2008_ortho_mcneil_dear_dr_letter.pdf |format=PDF| accessdate= 2008-12-27}}</ref> through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals.

Review of the FDA website indicates that the majority of the generic versions of the fluoroquinolones have ''not'' been updated to include this Black Box Warning as of September 2009. Additionally there are numerous reports that this information has not been dessiminated to the pharmacist, the name brand products continue to contain the previous labels that are absent of this warning, and the Medication Guide has not been made available to the pharmicist or physician for distribution.

===FDA warning letters===
Additionally the manufacturers of ciprofloxacin (Bayer A.G.) received numerous warning letters from the United States [[Food and Drug Administration (United States)|Food and Drug Administration]] regarding false advertising and failure to provide adequate warnings within their promotional materials.<ref>{{cite web |title=NDA #19-537 Cipro (ciprofloxacin) Tablets Macmis ID #7451 |accessdate=30 January 2009 |author=FDA |authorlink=Food and Drug Administration (United States) |date=2 April 1999 |format=PDF |publisher=Food and Drug Administration |location=USA |url=http://www.fqresearch.org/pdf_files/040299_bayer.pdf}}</ref><ref>{{cite web  |title=RE: Cipro HC Otic Suspension (Ciprofloxacin Hydrochloride and Hydrocortisone Otic Suspension) NDA 20-805 Ciloxan (ciprofloxacin ophthalmic) Solution NDA 19-992 MACMIS ID# 11015 |date=18 July 2003 |accessdate=30 January 2009 |author=FDA |authorlink=Food and Drug Administration (United States) |format=PDF |publisher=Food and Drug Administration |location=USA |url=http://www.fqresearch.org/pdf_files/11015.pdf}}</ref>

==Overprescribing and bacterial resistance==
{{See also|Antibiotic abuse|Antibiotic resistance}}
Ciprofloxacin is commonly used for urinary tract and intestinal infections (traveler's diarrhea) and
was once considered a powerful antibiotic of last resort,<ref>Biosecurity requires drug reform. Jan 1, 2002 World Watch ISSN: 0896-0615</ref><ref>{{Cite journal  | last1 = Nawaz | first1 = H. | last2 = Rauf | first2 = S. | last3 = Akhtar | first3 = K. | last4 = Khalid | first4 = AM. | title = Electrochemical DNA biosensor for the study of ciprofloxacin-DNA interaction. | journal = Anal Biochem | volume = 354 | issue = 1 | pages = 28–34 | month = July | year = 2006 | doi = 10.1016/j.ab.2006.04.004 | pmid = 16707087  | author2 = Rauf  | author3 = Akhtar  | author4 = Khalid }}</ref><ref>{{cite book |title=The Resistance Phenomenon in Microbes and Infectious Disease Vectors: Implications for Human Health and Strategies for Containment, Workshop Summary|url=http://books.google.com/?id=90F3Q6MnkcAC |publisher=National Academies Press |isbn=978-0309088541 |page=34 |chapter= |chapterurl= |author=Stacey L. Knobler ... |year=2003 }}</ref> used to treat especially tenacious infections. Not all physicians agreed with this assessment, as evidenced by its wide spread use to treat minor infections as well as non-approved uses. As a result in recent years many bacteria have developed resistance to this drug, leaving it significantly less effective than it would have been otherwise.<ref>{{Cite web |url=http://www.cdc.gov/ncidod/eid/vol5no3/pdf/vatopoulos.pdf |title=Bacterial Resistance to Ciprofloxacin in Greece: Results from the National Electronic Surveillance System |author=A.C. Vatopoulos |coauthors=V. Kalapothaki |format=PDF |year=1997 }}</ref><ref>{{Cite web |url=http://www.health.state.mn.us/news/pressrel/2009/bacterial022609.html |title=Bacterial resistance prompts concern among health officials |first= |last= |author= |publisher= |location= |date=26 February 2009 }}</ref>

[[Antibiotic resistance|Resistance]] to ciprofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous [[pathogen]]s, including ''[[Staphylococcus aureus]]'', [[enterococci]], and ''[[Streptococcus pyogenes]]'' now exhibit resistance worldwide.<ref>M Jacobs, Worldwide Overview of Antimicrobial Resistance. International Symposium on Antimicrobial Agents and Resistance 2005.</ref> Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated.<ref>{{cite web |author=FDA |title=Update On Extra-Label Use Of Fluoroquinolones |url=http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm127657.htm |publisher=FDA |location=USA |date=16 July 1999 |accessdate=12 August 2009}}</ref>

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002.<ref name="pmid15745724">{{cite journal |author=Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS |title=Fluoroquinolone prescribing in the United States: 1995 to 2002 |journal=Am. J. Med. |volume=118 |issue=3 |pages=259–68 |year=2005 |month=March |pmid=15745724 |doi=10.1016/j.amjmed.2004.09.015 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(04)00711-9}}</ref> Nearly half (42%) of these prescriptions were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study that was supported in part by the Agency for Healthcare Research and Quality.<ref name="pmid15745724"/><ref>K08 HS14563 and HS11313</ref> Additionally they are commonly prescribed for medical conditions that are not even bacterial to begin with, such as viral infections, or those to which no proven benefit exist.

==Current litigation==
'''Bayer AG'''
A class action had been 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 allege that they have suffered serious adverse effects from taking the antibiotic ciprofloxacin (Cipro) in the aftermath of the anthrax attacks in 2001. The adverse effects included; tendon rupture, seizures, intestinal problems, tendonitis, anxiety, insomnia, muscle aches, depression and meniscus tears. The action alleged that 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. According to the allegations within the complaint, exposed individuals were not informed of the true safety profile of ciprofloxacin, the high rate of adverse events associated with its use, or the availability of safer and equally effective alternative drugs. The complaint further alleged that, as a result of taking Cipro, many individuals suffered severe and debilitating injuries. The action sought funding for a medical monitoring program and compensatory damages for those workers who have suffered side effects. In 2004, the law firm of Goodell, DeVries, Leech & Dann, LLP were retained as national counsel in this litigation. The class action was defeated and the litigation abandoned by the plaintiffs.<ref>{{cite web |title=Anthrax Scare Leaves Trail of Cipro Victims - Class Actions filed in Two States |url=http://www.sheller.com/NewsDetails.asp?NewsID=72 |publisher=Sheller Ludwig & Sheller |location=USA |date=17 October 2003 |accessdate=9 September 2009}} {{Dead link|date=September 2010|bot=H3llBot}}</ref><ref>{{cite web |title=Legal Brief of Postal Employees Cases (EEOC, MSPB, District Courts) |url=http://www.lunewsviews.com/legal_briefs_archives.htm#cipro |archiveurl=http://web.archive.org/web/20071021073109/http://www.lunewsviews.com/legal_briefs_archives.htm#cipro |archivedate=2007-10-21 |publisher=Postal Reporter |location=USA |accessdate=9 September 2009}}</ref><ref>{{cite web |author=Charles P. Goodell, Jr |title=Profile |url=http://www.gdldlaw.com/content/bio_goodell.htm |publisher=Goodell, DeVries, Leech &amp; Dann, LLP |location=USA |accessdate=9 September 2009}}</ref>
A similar action had been filed in New Jersey that covers New Jersey postal workers. Final disposition of that lawsuit is unknown. Following the addition of the Black Box Warning in 2008, regarding tendon damage, a significant number of product liability law firms began soliciting clients who have suffered a spontaneous tendon rupture following fluoroquinolone therapy.<ref>{{cite web |url=http://www.prlog.org/10088464-legalview-reveals-details-of-the-fda-mandated-black-box-warning-for-fluoroquinolone-antibiotics.html |title=LegalView Reveals Details of the FDA Mandated Black Box Warning For Fluoroquinolone Antibiotics |date=11 July 2008 |publisher=PRlog }}</ref><ref>{{cite web |url=http://www.zimbio.com/Shocking+Sports+Injuries/articles/W6tlqlrajER/Levaquin+Litigation+Moving+Ahead |title=Levaquin Litigation Moving Ahead |author=Cynthia Diaz |date=6 July 2009 |publisher=Zimbio |quote=In May we wrote that most litigation specialists expected thousands of people to file lawsuits against the makers of Levaquin and similar drugs...}}</ref><ref>{{cite web |url=http://www.reuters.com/article/pressRelease/idUS199242+03-Sep-2009+BW20090903 |title=Carey and Danis LLC Announces Four Lawsuits against the Makers of Levaquin |author=Carey and Danis LLC |publisher=Reuters |date=3 September 2009 }}</ref>

==See also==
*[[Adverse effects of fluoroquinolones]]
*[[Fluoroquinolone toxicity]]
*[[Quinolone]]

==Package insert links==
*[http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s073,020780s030lbl.pdf Ciprofloxacin Package Insert]
*[http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021744s008lbl.pdf Proquin XR Package Insert]
*[http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019992s020lbl.pdf  Ciloxan Package Insert]

==References==
{{reflist|colwidth=30em}}

==External links==
{{Commons category}}
* [http://health.howstuffworks.com/cipro.htm How Stuff Works - Cipro]
*{{DMOZ|Society/Issues/Health/Drugs/Medical}}
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Ciprofloxacin U.S. National Library of Medicine: Drug Information Portal - Ciprofloxacin] 

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{{Piperazines}}
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[[Category:Fluoroquinolone antibiotics]]
[[Category:Piperazines]]
[[Category:World Health Organization essential medicines]]
[[Category:Otologicals]]
[[Category:Ophthalmology]]

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[[fa:سیپروفلوکساسین]]
[[fr:Ciprofloxacine]]
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[[ja:シプロフロキサシン]]
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[[Category:2Fix]]