Quinolone antibiotic#Third generation

File:Levofloxacin skeletal.svg]]

File:Trovafloxacin.svg]]

Fluoroquinolones are often used for genitourinary tract infections{{Cite journal |last1=Balch |first1=Jeremy |last2=Schoen |first2=Julia H. |last3=Patel |first3=Payal K. |date=2017-10-01 |title=Should Physicians Consider the Environmental Effects of Prescribing Antibiotics? |url=https://journalofethics.ama-assn.org/article/should-physicians-consider-environmental-effects-prescribing-antibiotics/2017-10 |journal=AMA Journal of Ethics |language=en |volume=19 |issue=10 |pages=957–965 |doi=10.1001/journalofethics.2017.19.10.peer1-1710 |pmid=29028464 |issn=2376-6980}} and are widely used in the treatment of hospital-acquired infections associated with urinary catheters. In community-acquired infections, they are recommended only when risk factors for multidrug resistance are present or after other antibiotic regimens have failed. However, for serious acute cases of pyelonephritis or bacterial prostatitis where the person may need to be hospitalised, fluoroquinolones are recommended as first-line therapy.{{cite journal | vauthors = Liu H, Mulholland SG | title = Appropriate antibiotic treatment of genitourinary infections in hospitalized patients | journal = The American Journal of Medicine | volume = 118 | issue = Suppl 7A | pages = 14S–20S | date = July 2005 | pmid = 15993673 | doi = 10.1016/j.amjmed.2005.05.009 }}

Due to people with sickle-cell disease being at increased risk for developing osteomyelitis from Salmonella, fluoroquinolones are the "drugs of choice" for this organism due to their ability to enter bone tissue without chelating it, as tetracyclines are known to do.{{citation needed|date=April 2023}}

In biofilm-associated infections, quinolones exhibit a good ability to penetrate the biofilm and target bacteria within it, especially during the early stages of biofilm formation. Their antibiofilm activity is generally higher than that of old beta-lactams and glycopeptides but remains lower compared to antibiotics such as tetracyclines, daptomycin, and fosfomycin, which demonstrate greater efficacy against biofilms.{{Cite journal |last1=Geremia |first1=Nicholas |last2=Giovagnorio |first2=Federico |last3=Colpani |first3=Agnese |last4=De Vito |first4=Andrea |last5=Botan |first5=Alexandru |last6=Stroffolini |first6=Giacomo |last7=Toc |first7=Dan-Alexandru |last8=Zerbato |first8=Verena |last9=Principe |first9=Luigi |last10=Madeddu |first10=Giordano |last11=Luzzati |first11=Roberto |last12=Parisi |first12=Saverio Giuseppe |last13=Di Bella |first13=Stefano |date=2024-12-11 |title=Fluoroquinolones and Biofilm: A Narrative Review |journal=Pharmaceuticals |language=en |volume=17 |issue=12 |pages=1673 |doi=10.3390/ph17121673 |doi-access=free |pmid=39770514 |issn=1424-8247|pmc=11679785 }}

Fluoroquinolones are featured prominently in guidelines for the treatment of hospital-acquired pneumonia.{{cite journal | title = Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia | journal = American Journal of Respiratory and Critical Care Medicine | volume = 171 | issue = 4 | pages = 388–416 | date = February 2005 | pmid = 15699079 | doi = 10.1164/rccm.200405-644ST | s2cid = 14907563 | author1 = American Thoracic Society | author2 = Infectious Diseases Society of America }}

In most countries, fluoroquinolones are approved for use in children only under narrowly defined circumstances, owing in part to the observation of high rates of musculoskeletal adverse events in fluoroquinolone-treated juvenile animals. In the UK, the prescribing indications for fluoroquinolones for children are severely restricted. Only inhalational anthrax and pseudomonal infections in cystic fibrosis infections are licensed indications in the UK due to ongoing safety concerns. In a study comparing the safety and efficacy of levofloxacin to that of azithromycin or ceftriaxone in 712 children with community-acquired pneumonia, serious adverse events were experienced by 6% of those treated with levofloxacin and 4% of those treated with comparator antibiotics. Most of these were considered by the treating physician to be unrelated or doubtfully related to the study drug. Two deaths were observed in the levofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the U.S. FDA Adverse Effects Reporting System at the time of the 20 September 2011 U.S. FDA Pediatric Drugs Advisory Committee included musculoskeletal events (39, including five cases of tendon rupture) and central nervous system events (19, including five cases of seizures) as the most common spontaneous reports between April 2005 and March 2008. An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients during that period.{{cite web |url=https://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4399s1-06%20%28Levofloxacin%29.pdf |archive-url=https://web.archive.org/web/20090712064114/http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4399s1-06%20(Levofloxacin).pdf |url-status=dead |archive-date=12 July 2009 |title=Adverse Event Review: Levaquin® (levofloxacin): Pediatric Advisory Committee Meeting |date=18 November 2008 |publisher=Food and Drug Administration }}

Meta-analyses conclude that fluoroquinolones pose little or no additional risk to children compared to other antibiotic classes.{{cite journal | vauthors = Sung L, Manji A, Beyene J, Dupuis LL, Alexander S, Phillips R, Lehrnbecher T | title = Fluoroquinolones in children with fever and neutropenia: a systematic review of prospective trials | journal = The Pediatric Infectious Disease Journal | volume = 31 | issue = 5 | pages = 431–435 | date = May 2012 | pmid = 22189521 | doi = 10.1097/INF.0b013e318245ab48 | s2cid = 52835801 }}{{cite journal | vauthors = Rosanova MT, Lede R, Capurro H, Petrungaro V, Copertari P | title = [Assessing fluoroquinolones as risk factor for musculoskeletal disorders in children: a systematic review and meta-analysis] | language = es | journal = Archivos Argentinos de Pediatria | volume = 108 | issue = 6 | pages = 524–531 | date = December 2010 | pmid = 21132249 | doi = 10.1590/S0325-00752010000600008 | doi-broken-date = 1 November 2024 }}{{cite journal | vauthors = Forsythe CT, Ernst ME | title = Do fluoroquinolones commonly cause arthropathy in children? | journal = CJEM | volume = 9 | issue = 6 | pages = 459–462 | date = November 2007 | pmid = 18072993 | doi = 10.1017/s1481803500015517 | doi-access = free }} Fluoroquinolone use in children may be appropriate when the infection is caused by multidrug-resistant bacteria, or when alternative treatment options require parenteral administration and oral therapy is preferred.{{cite journal | vauthors = Bradley JS, Jackson MA | title = The use of systemic and topical fluoroquinolones | journal = Pediatrics | volume = 128 | issue = 4 | pages = e1034–e1045 | date = October 2011 | pmid = 21949152 | doi = 10.1542/peds.2011-1496 | doi-access = free }}

While typical drug side effects reactions are mild to moderate, sometimes serious adverse effects, such as suicide, occur. With fluoroquinolones these effects are sometimes collectively called floxing.{{cite web | url=https://ncmedsoc.org/do-you-know-what-floxing-is-could-it-be-deadly-to-your-patients/ | title=Do You Know What 'Floxing' Is? Could It be Deadly to Your Patients? | date=11 April 2023 }}

Fluoroquinolones can increase the risk of psychiatric symptoms, including depression and psychotic reactions. These may potentially lead to thoughts of suicide or suicide attempts.Medicines and Healthcare products Regulatory Agency|title=Fluoroquinolone antibiotics: suicidal thoughts and behaviour|journal=Drug Safety Updates|year=2023|volume=17|issue=2|pages=5-6|url=https://assets.publishing.service.gov.uk/media/6512d31e3d3718000d6d0bdd/September-2023-DSU-PDF.pdf

For example, recent reports from senior coroners on two suicides show the risks of fluoroquinolones in everyday life. Neither victim had a history of depression or mental health problems. However, both men had been prescribed ciprofloxacin shortly before they killed themselves.=Bedford PJ (coroner). "Regulation 28 Report to Prevent Future Deaths." January 11, 2017. https://www.judiciary.uk/wp-content/uploads/2017/02/Rendell-2017-0006.pdf/Fleming HM (coroner). "Regulation 28 Report to Prevent Future Deaths." May 5, 2023. https://www.judiciary.uk/wp-content/uploads/2023/06/Robert-Stevenson-Prevention-of-future-deaths-report-2023-0180_Published.pdf

In a “Report to Prevent Future Deaths,” mandated by UK law, one of the coroners noted that there is no compelling reason why patients should expect to risk becoming suicidal from an antibiotic unless this fact and potential symptoms were brought to their attention by the prescriber.

A 2024 review from the UK’s Medicines & Healthcare Products Regulatory Agency examined the effectiveness of current measures to reduce these identified risks of fluoroquinolones. It concluded, “Systemic fluoroquinolones must now only be prescribed when other commonly recommended antibiotics are inappropriate.”

UK’s Medicines & Healthcare Products Regulatory Agency https://www.gov.uk/drug-safety-update/fluoroquinolone-antibiotics-must-now-only-be-prescribed-when-other-commonly-recommended-antibiotics-are-inappropriate

Nervous-system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis.{{cite journal | vauthors = Galatti L, Giustini SE, Sessa A, Polimeni G, Salvo F, Spina E, Caputi AP | title = Neuropsychiatric reactions to drugs: an analysis of spontaneous reports from general practitioners in Italy | journal = Pharmacological Research | volume = 51 | issue = 3 | pages = 211–216 | date = March 2005 | pmid = 15661570 | doi = 10.1016/j.phrs.2004.08.003 }} Other rare and serious adverse events have been observed with varying degrees of evidence for causation.{{cite journal | vauthors = Babar SM | title = SIADH associated with ciprofloxacin | journal = The Annals of Pharmacotherapy | volume = 47 | issue = 10 | pages = 1359–1363 | date = October 2013 | pmid = 24259701 | doi = 10.1177/1060028013502457 | s2cid = 36759747 }}{{cite journal | vauthors = Rouveix B | title = [Clinically significant toxicity and tolerance of the main antibiotics used in lower respiratory tract infections] | journal = Médecine et Maladies Infectieuses | volume = 36 | issue = 11–12 | pages = 697–705 | date = Nov–Dec 2006 | pmid = 16876974 | doi = 10.1016/j.medmal.2006.05.012 }}{{cite journal | vauthors = Mehlhorn AJ, Brown DA | title = Safety concerns with fluoroquinolones | journal = The Annals of Pharmacotherapy | volume = 41 | issue = 11 | pages = 1859–1866 | date = November 2007 | pmid = 17911203 | doi = 10.1345/aph.1K347 | s2cid = 26411679 }}{{cite journal | vauthors = Jones SE, Smith RH | title = Quinolones may induce hepatitis | journal = The BMJ | volume = 314 | issue = 7084 | pages = 869 | date = March 1997 | pmid = 9093098 | pmc = 2126221 | doi = 10.1136/bmj.314.7084.869 }}

In 2008, the U.S. FDA added black box warnings on all fluoroquinolones, advising of the increased risk of tendon damage.{{cite news|url=http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html|title=FDA orders 'black box' label on some antibiotics |access-date=8 July 2008 |publisher=CNN| date=8 July 2008}} In 2016, the FDA found that systemic use (by mouth or injection) of fluoroquinolones was associated with "disabling and potentially permanent serious side effects" involving the tendons, muscles, joints, nerves, and central nervous system, concluding that these side effects generally outweigh the benefits for people with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections when other treatment options are available.{{cite news|title=FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together|url=https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm|archive-url=https://web.archive.org/web/20160514121109/http://www.fda.gov/drugs/drugsafety/ucm500143.htm|url-status=dead|archive-date=14 May 2016|work=FDA|date=12 May 2016}} Concerns regarding low blood sugar and mental health problems were added in 2018.{{cite web |title=Safety Alerts for Human Medical Products – Fluoroquinolone Antibiotics: FDA Requires Labeling Changes Due to Low Blood Sugar Levels and Mental Health Side Effects |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm612979.htm |archive-url=https://web.archive.org/web/20180724202627/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm612979.htm |url-status=dead |archive-date=24 July 2018 |website=fda.gov |access-date=13 July 2018}} In December 2018, the FDA issued a warning regarding an increased risk of aortic aneurysms and aortic dissections associated with fluoroquinolone use. This warning specifically targeted older adults and patients with conditions such as hypertension, Marfan syndrome, Ehlers-Danlos syndrome, atherosclerosis, peripheral vascular disease, and a history of aneurysms.{{cite journal|first1=John G. |last1=Rizk |first2=Julia F. |last2=Slejko |first3=Emily L. |last3=Heil |first4=Dominique |last4=Seo |first5=Danya M. |last5=Qato |title=Impact of the US Food and Drug Administration warning regarding increased risk of aortic aneurysms or aortic dissections on fluoroquinolone prescribing trends|journal=BMJ Open Quality|year=2024|volume=13|issue=e002925|pages=e002925 |doi=10.1136/bmjoq-2024-002925|doi-access=free |pmid=39053916 |pmc=11733791 }}

Quinolones are associated with a small risk of tendonitis and tendon rupture; a 2013 review found the incidence of tendon injury among those taking fluoroquinolones to be between 0.08 and 0.20%.{{cite journal | vauthors = Stephenson AL, Wu W, Cortes D, Rochon PA | title = Tendon Injury and Fluoroquinolone Use: A Systematic Review | journal = Drug Safety | volume = 36 | issue = 9 | pages = 709–721 | date = September 2013 | pmid = 23888427 | doi = 10.1007/s40264-013-0089-8 | s2cid = 24948660 }} The risk appears to be higher among people older than 60 and those also taking corticosteroids; the risk also may be higher among people who are male, have a pre-existing joint or tendon issue, have kidney disease, or are highly active.{{cite journal | vauthors = Lewis T, Cook J | title = Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature | journal = Journal of Athletic Training | volume = 49 | issue = 3 | pages = 422–427 | date = 2014 | pmid = 24762232 | pmc = 4080593 | doi = 10.4085/1062-6050-49.2.09 }} Some experts have advised avoidance of fluoroquinolones in athletes. If tendonitis occurs, it generally appears within one month, and the most common tendon injured appears to be the Achilles tendon. The cause is not well understood.

Fluoroquinolones can increase the rate of rare but serious tears in the aorta by 31% compared to other antibiotics.{{cite journal | vauthors = Newton ER, Akerman AW, Strassle PD, Kibbe MR | title = Association of Fluoroquinolone Use With Short-term Risk of Development of Aortic Aneurysm | journal = JAMA Surgery | volume = 156 | issue = 3 | pages = 264–272 | date = March 2021 | pmid = 33404647 | pmc = 7788511 | doi = 10.1001/jamasurg.2020.6165 }} People at increased risk include those with aortic aneurysm, hypertension, certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and the elderly. For these people, fluoroquinolones should be used only when no other treatment options are available.{{cite web|title=FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients|url=https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm|archive-url=https://web.archive.org/web/20190207145027/https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm|url-status=dead|archive-date=7 February 2019|work=FDA|date=20 December 2018|access-date=9 February 2019}} One year after the warning announcement, prescribing behaviors were reported to have remained unchanged.

Clostridioides difficile colitis may occur in connection with the use of any antibacterial drug, especially those with a broad spectrum of activity such as clindamycin, cephalosporins, and fluoroquinolones. Fluoroquinoline treatment is associated with risk that is similar to{{cite journal | vauthors = Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Sferra TJ, Hernandez AV, Donskey CJ | display-authors = 6 | title = Community-associated Clostridium difficile infection and antibiotics: a meta-analysis | journal = The Journal of Antimicrobial Chemotherapy | volume = 68 | issue = 9 | pages = 1951–1961 | date = September 2013 | pmid = 23620467 | doi = 10.1093/jac/dkt129 | doi-access = free }} or less than{{cite journal | vauthors = Slimings C, Riley TV | title = Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis | journal = The Journal of Antimicrobial Chemotherapy | volume = 69 | issue = 4 | pages = 881–891 | date = April 2014 | pmid = 24324224 | doi = 10.1093/jac/dkt477 | doi-access = free }} that associated with broad spectrum cephalosporins. Fluoroquinolone administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridium strain.{{cite journal | vauthors = Vardakas KZ, Konstantelias AA, Loizidis G, Rafailidis PI, Falagas ME | title = Risk factors for development of Clostridium difficile infection due to BI/NAP1/027 strain: a meta-analysis | journal = International Journal of Infectious Diseases | volume = 16 | issue = 11 | pages = e768–e773 | date = November 2012 | pmid = 22921930 | doi = 10.1016/j.ijid.2012.07.010 | doi-access = free }}

More generally, fluoroquinolones are tolerated, with typical drug side effects being mild to moderate.{{cite journal | vauthors = Owens RC, Ambrose PG | title = Antimicrobial safety: focus on fluoroquinolones | journal = Clinical Infectious Diseases | volume = 41 | issue = Suppl 2 | pages = S144–S157 | date = July 2005 | pmid = 15942881 | doi = 10.1086/428055 | doi-access = free }} Common side effects include gastrointestinal effects such as nausea, vomiting, and diarrhea, as well as headache and insomnia. Postmarketing surveillance has revealed a variety of relatively rare but serious adverse effects associated with all members of the fluoroquinolone antibacterial class. Among these, tendon problems and exacerbation of the symptoms of the neurological disorder myasthenia gravis are the subject of "black box" warnings in the United States.{{Cite web |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126085.htm |title=Information for Healthcare Professionals: 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)] |website=Food and Drug Administration |access-date=16 December 2019 |archive-date=30 October 2017 |archive-url=https://web.archive.org/web/20171030105320/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126085.htm |url-status=dead }}{{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 = 371–384 | date = March 2001 | pmid = 11172695 | doi = 10.2174/0929867013373435 }}

A 2018 EU-wide review of fluoroquinolones concluded that they are associated with serious side effects including tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impaired hearing, vision, taste and smell. Tendon damage (especially to Achilles tendon but also other tendons) can occur within 48 hours of starting fluoroquinolone treatment but the damage may be delayed several months after stopping treatment.{{cite web |url=https://www.ema.europa.eu/en/medicines/human/referrals/quinolone-fluoroquinolone-containing-medicinal-products |title=Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics |date=11 March 2019 |website=European Medicines Agency}}

The overall rate of adverse events in people treated with fluoroquinolones is roughly similar to that seen in people treated with other antibiotic classes.{{cite web |vauthors = Levine JG, Szarfman A |date=15 December 2006 |url=https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4266s1-01-06-FDA-Levine.ppt |archive-url=https://web.archive.org/web/20081017065439/http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4266s1-01-06-FDA-Levine.ppt |url-status=dead |archive-date=17 October 2008 |title=Data Mining Analysis of Multiple Antibiotics in AERS |format=Microsoft PowerPoint |publisher= U.S. Food and Drug Administration }}{{cite journal | vauthors = Skalsky K, Yahav D, Lador A, Eliakim-Raz N, Leibovici L, Paul M | title = Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials | journal = Clinical Microbiology and Infection | volume = 19 | issue = 4 | pages = 370–378 | date = April 2013 | pmid = 22489673 | doi = 10.1111/j.1469-0691.2012.03838.x | doi-access = free }}{{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 = 1553–1566 | date = December 2006 | pmid = 17165634 | doi = 10.4065/81.12.1553 }}{{cite journal | vauthors = Van Bambeke F, Tulkens PM | title = Safety profile of the respiratory fluoroquinolone moxifloxacin: comparison with other fluoroquinolones and other antibacterial classes | journal = Drug Safety | volume = 32 | issue = 5 | pages = 359–378 | year = 2009 | pmid = 19419232 | doi = 10.2165/00002018-200932050-00001 | s2cid = 19026852 }} A U.S. Centers for Disease Control and Prevention study found people treated with fluoroquinolones experienced adverse events severe enough to lead to an emergency department visit more frequently than those treated with cephalosporins or macrolides, but less frequently than those treated with penicillins, clindamycin, sulfonamides, or vancomycin.{{cite journal | vauthors = Shehab N, Patel PR, Srinivasan A, Budnitz DS | title = Emergency department visits for antibiotic-associated adverse events | journal = Clinical Infectious Diseases | volume = 47 | issue = 6 | pages = 735–743 | date = September 2008 | pmid = 18694344 | doi = 10.1086/591126 | doi-access = free }}

Fluoroquinolones prolong the heart's QT interval by blocking voltage-gated potassium channels.{{cite journal | vauthors = Heidelbaugh JJ, Holmstrom H | title = The perils of prescribing fluoroquinolones | journal = The Journal of Family Practice | volume = 62 | issue = 4 | pages = 191–197 | date = April 2013 | pmid = 23570031 }} Prolongation of the QT interval can lead to torsades de pointes, a life-threatening arrhythmia, but in practice, this appears relatively uncommon in part because the most widely prescribed fluoroquinolones (ciprofloxacin and levofloxacin) only minimally prolong the QT interval.{{cite journal | vauthors = Rubinstein E, Camm J | title = Cardiotoxicity of fluoroquinolones | journal = The Journal of Antimicrobial Chemotherapy | volume = 49 | issue = 4 | pages = 593–596 | date = April 2002 | pmid = 11909831 | doi = 10.1093/jac/49.4.593 | doi-access = free }}

In 2019 study by Journal of the American College of Cardiology it was discovered that fluoroquinolones could increase the risk for heart valve diseases.{{Cite news | vauthors = Bakalar N |date=2019-09-17 |title=Antibiotics Tied to Heart Valve Problems|work=The New York Times |url=https://www.nytimes.com/2019/09/17/well/live/antibiotics-fluoroquinolones-cipro-levaquin-heart-valve-problems.html |access-date=2021-08-24 |issn=0362-4331}}

Events that may occur in acute overdose are rare, and include kidney failure and seizure.{{cite book |vauthors = Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA |title=Goldfrank's toxicologic emergencies |publisher=McGraw-Hill, Medical Pub. Division |location=New York |year=2006 |isbn=978-0-07-143763-9 |url=https://books.google.com/books?id=cvJuLqBxGUcC&q=goldfranks+Fluoroquinolone+toxicity&pg=PA849 }} Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.{{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 = 1403–1413 | date = June 2007 | pmid = 17559736 | doi = 10.1185/030079907X188099 | s2cid = 34091286 }}{{cite web| vauthors = Farinas ER |collaboration = Public Health Service Food and Drug Administration Center for Drug Evaluation and Research |title=Consult: One-Year Post Pediatric Exclusivity Postmarketing Adverse Events Review |url=https://www.fda.gov/OHRMS/DOCKETS/AC/05/briefing/2005-4152b1_03_01_Cipro%20AE.pdf |archive-url=https://web.archive.org/web/20090710194429/http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4152b1_03_01_Cipro%20AE.pdf |url-status=dead |archive-date=10 July 2009 |publisher=Food and Drug Administration |date=1 March 2005 |access-date=31 August 2009}}

The mechanisms of the toxicity of fluoroquinolones have been attributed to their interactions with different receptor complexes, such as blockade of the GABA_A receptor complex within the central nervous system, leading to excitotoxic type effects and oxidative stress.{{cite journal | vauthors = Saint F, Salomon L, Cicco A, de la Taille A, Chopin D, Abbou CC | title = [Tendinopathy associated with fluoroquinolones: individuals at risk, incriminated physiopathologic mechanisms, therapeutic management] | language = fr | journal = Progres en Urologie | volume = 11 | issue = 6 | pages = 1331–1334 | date = December 2001 | pmid = 11859676 }}

Products containing multivalent cations, such as aluminium- or magnesium-containing antacids, and products containing calcium, iron, or zinc invariably result in marked reduction of oral absorption of fluoroquinolones. Other drugs that interact with fluoroquinolones include sucralfate, probenecid, cimetidine, theophylline, warfarin, antiviral agents, phenytoin, cyclosporine, rifampin, pyrazinamide, and cycloserine.{{cite journal | vauthors = Fish DN | title = Fluoroquinolone adverse effects and drug interactions | journal = Pharmacotherapy | volume = 21 | issue = 10 Pt 2 | pages = 253S–272S | date = October 2001 | pmid = 11642691 | doi = 10.1592/phco.21.16.253S.33993 | s2cid = 29617455 }}

Administration of quinolone antibiotics to a benzodiazepine-dependent individual can precipitate acute benzodiazepine withdrawal symptoms due to quinolones displacing benzodiazepines from their binding sites.{{cite web | url = http://www.smmgp.org.uk/download/guidance/guidance025.pdf | title = Guidance for the use and reduction of misuse of benzodiazepines and other hypnotics and anxiolytics in general practice | vauthors = Ford C, Law F | date = July 2014 | publisher = SMMGP | access-date = 24 July 2017 | archive-date = 6 July 2017 | archive-url = https://web.archive.org/web/20170706085219/http://www.smmgp.org.uk/download/guidance/guidance025.pdf | url-status = dead }} Fluoroquinolones have varying specificity for cytochrome P450, so may have interactions with drugs cleared by those enzymes; the order from most P450-inhibitory to least, is enoxacin > ciprofloxacin > norfloxacin > ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin.

Quinolones are not recommended in people with epilepsy, Marfan's syndrome, Ehlers-Danlos Syndrome,{{cite web | url=https://edsinfo.wordpress.com/2013/08/28/fluoroquinolones-antibiotic-alert-especially-with-eds/ | title=Fluoroquinolones Antibiotic Alert – especially with EDS| date=2013-08-29}} QT prolongation, pre-existing CNS lesions, or CNS inflammation, or who have had a stroke. They are best avoided in the athlete population.[http://www.levaquinadversesideeffect.com/wp-content/uploads/Documents/Hall-2011.pdf 2011 Document] levaquinadversesideeffect.com {{Webarchive|url=https://web.archive.org/web/20210617084159/https://www.levaquinadversesideeffect.com/wp-content/uploads/Documents/Hall-2011.pdf |date=17 June 2021 }} Safety concerns exist for fluoroquinolone use during pregnancy, so they are contraindicated unless no other safe alternative antibiotic exists.{{cite journal | vauthors = Nardiello S, Pizzella T, Ariviello R | title = [Risks of antibacterial agents in pregnancy] | journal = Le Infezioni in Medicina | volume = 10 | issue = 1 | pages = 8–15 | date = March 2002 | pmid = 12700435 }} However, one meta-analysis looking at the outcome of pregnancies involving quinolone use in the first trimester found no increased risk of malformations.{{cite journal | vauthors = Bar-Oz B, Moretti ME, Boskovic R, O'Brien L, Koren G | title = The safety of quinolones--a meta-analysis of pregnancy outcomes | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 143 | issue = 2 | pages = 75–78 | date = April 2009 | pmid = 19181435 | doi = 10.1016/j.ejogrb.2008.12.007 }} They are also contraindicated in children due to the risks of damage to the musculoskeletal system.{{cite journal | vauthors = Noel GJ, Bradley JS, Kauffman RE, Duffy CM, Gerbino PG, Arguedas A, Bagchi P, Balis DA, Blumer JL | display-authors = 6 | title = Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders | journal = The Pediatric Infectious Disease Journal | volume = 26 | issue = 10 | pages = 879–891 | date = October 2007 | pmid = 17901792 | doi = 10.1097/INF.0b013e3180cbd382 | s2cid = 26457648 }} Their use in children is not absolutely contraindicated, however for certain severe infections where other antibiotics are not an option, their use can be justified.{{cite journal | vauthors = Leibovitz E | title = The use of fluoroquinolones in children | journal = Current Opinion in Pediatrics | volume = 18 | issue = 1 | pages = 64–70 | date = February 2006 | pmid = 16470165 | doi = 10.1097/01.mop.0000192520.48411.fa | s2cid = 37437573 }} Quinolones should also not be given to people with a known hypersensitivity to the drug class.{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021721s020_020635s57_020634s52_lbl.pdf |archive-url=https://web.archive.org/web/20100602045827/http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021721s020_020635s57_020634s52_lbl.pdf |url-status=dead |archive-date=2 June 2010 |title=Highlights of Prescribing Information |author=Janssen Pharmaceutica |author-link=Janssen Pharmaceutica |publisher=Food and Drug Administration |date=September 2008 }}{{cite journal | vauthors = Scherer K, Bircher AJ | title = Hypersensitivity reactions to fluoroquinolones | journal = Current Allergy and Asthma Reports | volume = 5 | issue = 1 | pages = 15–21 | date = January 2005 | pmid = 15659258 | doi = 10.1007/s11882-005-0049-1 | s2cid = 31447696 }}

The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon the quinoline ring system.{{cite journal |vauthors=Schaumann R, Rodloff AC |date=January 2007 |title=Activities of Quinolones Against Obligately Anaerobic Bacteria |journal=Anti-Infective Agents in Medicinal Chemistry |volume=6 |issue=1 |pages=49–56 |url=http://www.bentham.org/cmcaia/sample/cmcaia%206-1/0004Y.pdf |doi=10.2174/187152107779314179 |access-date=6 May 2011 |archive-date=16 June 2010 |archive-url=https://web.archive.org/web/20100616120431/http://bentham.org/cmcaia/sample/cmcaia%206-1/0004Y.pdf |url-status=dead }} The addition of the fluorine atom at C6 distinguishes the successive-generation fluoroquinolones from the first-generation of quinolones. The addition of the C6 fluorine atom has since been demonstrated not to be required for the antibacterial activity of this class (circa 1997).{{cite journal | vauthors = Hong CY, Kim SH, Kim YK |doi=10.1016/S0960-894X(97)00324-7 |title=Novel 5-amino-6-methylquinolone antibacterials: A new class of non-6-fluoroquinolones |date=22 July 1997 |journal=Bioorganic & Medicinal Chemistry Letters |volume=7 |issue=14 |pages=1875–1878 }}

{{See also|Antibiotic misuse|Antibiotic resistance}}

Because the use of broad-spectrum antibiotics encourages the spread of multidrug-resistant strains and the development of Clostridioides difficile infections, treatment guidelines often recommend minimizing the use of fluoroquinolones and other broad-spectrum antibiotics in less severe infections and in those in which risk factors for multidrug resistance are not present. It has been recommended that fluoroquinolones not be used as a first-line agent for community-acquired pneumonia,{{cite journal | vauthors = Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG | display-authors = 6 | title = Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults | journal = Clinical Infectious Diseases | volume = 44 | issue = Suppl 2 | pages = S27–S72 | date = March 2007 | pmid = 17278083 | pmc = 7107997 | doi = 10.1086/511159 }} instead recommending macrolide or doxycycline as first-line agents. The Drug-Resistant Streptococcus pneumoniae Working Group recommends fluoroquinolones be used for the ambulatory treatment of community-acquired pneumonia only after other antibiotic classes have been tried and failed, or in cases with demonstrated drug-resistant Streptococcus pneumoniae.{{cite journal | vauthors = MacDougall C, Guglielmo BJ, Maselli J, Gonzales R | title = Antimicrobial drug prescribing for pneumonia in ambulatory care | journal = Emerging Infectious Diseases | volume = 11 | issue = 3 | pages = 380–384 | date = March 2005 | pmid = 15757551 | pmc = 3298265 | doi = 10.3201/eid1103.040819 }}

Resistance to quinolones can evolve rapidly, even during a course of treatment. Numerous pathogens, including Escherichia coli, commonly exhibit resistance.{{cite book | vauthors = Jacobs M | chapter = Worldwide overview of antimicrobial Resistance. | title = International Symposium on Antimicrobial Agents and Resistance. Drugs. | date = 2005 | pages = 542–546 }} Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.{{cite journal | vauthors = Nelson JM, Chiller TM, Powers JH, Angulo FJ | title = Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story | journal = Clinical Infectious Diseases | volume = 44 | issue = 7 | pages = 977–980 | date = April 2007 | pmid = 17342653 | doi = 10.1086/512369 | doi-access = free }}

Fluoroquinolones had become the class of antibiotics most commonly prescribed to adults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the U.S. FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study supported in part by the Agency for Healthcare Research and Quality.{{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 = 259–268 | date = March 2005 | pmid = 15745724 | doi = 10.1016/j.amjmed.2004.09.015 }}K08 HS14563 and HS11313 In addition, they are commonly prescribed for medical conditions, such as acute respiratory illness, that are usually caused by viral infections.{{cite journal | vauthors = Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP | title = Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use | journal = JAMA | volume = 289 | issue = 7 | pages = 885–888 | date = February 2003 | pmid = 12588273 | doi = 10.1001/jama.289.7.885 | quote = From 1995 to 2002, inappropriate antibiotic prescribing for acute respiratory infections, which are usually caused by viruses and thus are not responsive to antibiotics, declined from 61 to 49 percent. However, the use of broad-spectrum antibiotics such as the fluoroquinolones, jumped from 41 to 77 percent from 1995 to 2001. Overuse of these antibiotics will eventually render them useless for treating antibiotic-resistant infections, for which broad-spectrum antibiotics are supposed to be reserved. | doi-access = free }}

Three mechanisms of resistance are known.{{cite journal | vauthors = Robicsek A, Jacoby GA, Hooper DC | title = The worldwide emergence of plasmid-mediated quinolone resistance | journal = The Lancet. Infectious Diseases | volume = 6 | issue = 10 | pages = 629–640 | date = October 2006 | pmid = 17008172 | doi = 10.1016/S1473-3099(06)70599-0 }} Some types of efflux pumps can act to decrease intracellular quinolone concentration.{{cite journal | vauthors = Morita Y, Kodama K, Shiota S, Mine T, Kataoka A, Mizushima T, Tsuchiya T | title = NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli | journal = Antimicrobial Agents and Chemotherapy | volume = 42 | issue = 7 | pages = 1778–1782 | date = July 1998 | pmid = 9661020 | pmc = 105682 | doi = 10.1128/AAC.42.7.1778 }} In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drugs' effectiveness.{{citation needed|date=April 2023}}

File:GyraseCiproTop.png

Quinolones are chemotherapeutic bactericidal drugs. They interfere with DNA replication by preventing bacterial DNA from unwinding and duplicating. Specifically, they inhibit the ligase activity of the type II topoisomerases, DNA gyrase and topoisomerase IV, which cut DNA to introduce supercoiling, while leaving nuclease activity unaffected. With the ligase activity disrupted, these enzymes release DNA with single- and double-strand breaks that lead to cell death.{{cite journal | vauthors = Aldred KJ, Kerns RJ, Osheroff N | title = Mechanism of quinolone action and resistance | journal = Biochemistry | volume = 53 | issue = 10 | pages = 1565–1574 | date = March 2014 | pmid = 24576155 | pmc = 3985860 | doi = 10.1021/bi5000564 }} The majority of quinolones in clinical use are fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-8 position. Most of them are named with the -oxacin suffix. First and second generation quinolones are largely active against Gram-negative bacteria, whereas third and fourth generation quinolones have increased activity against Gram-positive and anaerobic bacteria.{{cite journal | vauthors = Andriole VT | title = The quinolones: past, present, and future | journal = Clinical Infectious Diseases | volume = 41 | issue = S2 | pages = S113–S119 | date = July 2005 | pmid = 15942877 | doi = 10.1086/428051 | doi-access = free }} Some quinolones containing aromatic substituents at their C-7 positions are highly active against eukaryotic type II topoisomerase.{{cite journal | vauthors = 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 = The Journal of Biological Chemistry | volume = 267 | issue = 19 | pages = 13150–13153 | date = July 1992 | pmid = 1320012 | doi = 10.1016/S0021-9258(18)42185-0 | doi-access = free }}

It has also been proposed that quinolone antibiotics cause oxidation of guanine nucleotides in the bacterial nucleotide pool, and that this process contributes to the cytotoxicity of these agents.{{cite journal | vauthors = Foti JJ, Devadoss B, Winkler JA, Collins JJ, Walker GC | title = Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics | journal = Science | location = New York, N.Y. | volume = 336 | issue = 6079 | pages = 315–9 | date = April 2012 | pmid = 22517853 | pmc = 3357493 | doi = 10.1126/science.1219192 | bibcode = 2012Sci...336..315F }} The incorporation of oxidized guanine nucleotides into DNA could be bactericidal. Bacterial cytotoxicity could arise from incomplete repair of closely spaced 8-oxo-2'-deoxyguanosine in the DNA resulting in double-strand breaks.

Fluoroquinolones can enter in cells easily via porins, so are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many Gram-negative bacteria, DNA gyrase is the target, whereas topoisomerase IV is the target for many Gram-positive bacteria.{{citation needed|date=April 2023}}

Eukaryotic cells are not believed to contain DNA gyrase or topoisomerase IV. However, debate exists concerning whether the quinolones still have such an adverse effect on the DNA of healthy cells. Some compounds in this class have been shown to inhibit the synthesis of mitochondrial DNA.{{cite book | vauthors = Bergan T |year=1988 | chapter = Pharmacokinetics of fluorinated quinolones | title = The quinolones |publisher=Academic Press |pages=119–154 }}{{cite book| vauthors = Bergan T, Dalhoff A, Thorsteinsson SB | date = July 1985 | chapter = A review of the pharmacokinetics and tissue penetration of ciprofloxacin. | title = Ciprofloxacin A new 4–quinolone. |pages=23–36 | publisher = Sieber and McIntyre | location = Hong Kong }}{{cite journal | vauthors = Castora FJ, Vissering FF, Simpson MV | title = The effect of bacterial DNA gyrase inhibitors on DNA synthesis in mammalian mitochondria | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 740 | issue = 4 | pages = 417–427 | date = September 1983 | pmid = 6309236 | doi = 10.1016/0167-4781(83)90090-8 }}{{cite journal | vauthors = Suto MJ, Domagala JM, Roland GE, Mailloux GB, Cohen MA | title = Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity | journal = Journal of Medicinal Chemistry | volume = 35 | issue = 25 | pages = 4745–4750 | date = December 1992 | pmid = 1469702 | doi = 10.1021/jm00103a013 }}

The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon the quinoline ring system.{{cite journal | vauthors = Schaumann R, Rodloff AC |date=January 2007 |title=Activities of Quinolones Against Obligately Anaerobic Bacteria |journal=Anti-Infective Agents in Medicinal Chemistry |volume=6 |issue=1 |pages=49–56 |url=http://www.bentham.org/cmcaia/sample/cmcaia%206-1/0004Y.pdf |access-date=6 May 2011 |archive-url=https://web.archive.org/web/20100616120431/http://bentham.org/cmcaia/sample/cmcaia%206-1/0004Y.pdf |archive-date=16 June 2010 |url-status=live |doi=10.2174/187152107779314179}} Various substitutions made to the quinoline ring resulted in the development of numerous fluoroquinolone drugs. The addition of the fluorine atom at C-6 distinguishes the successive-generation fluoroquinolones from the first-generation quinolones, although examples are known that omit the atom while retaining antibacterial activity.

File:Nalidixic acid.png, it is considered the predecessor of all subsequently developed quinolone antibiotics.]]

Although not formally a quinolone, nalidixic acid is considered the first quinolone drug. It was introduced in 1962 for treatment of urinary tract infections (UTIs) in humans.{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/014214s058lbl.pdf |archive-url=https://web.archive.org/web/20121016134755/http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/014214s058lbl.pdf |url-status=dead |archive-date=16 October 2012 |title=NegGram Caplets (nalidixic acid, USP) |author=Sanofi-Aventis U.S. LLC |author-link=Sanofi-Aventis |publisher=Food and Drug Administration |date=September 2008 }} Nalidixic acid was discovered by George Lesher and coworkers in a distillate during an attempt at chloroquine synthesis.{{cite book | vauthors = Wentland MP | chapter = In memoriam: George Y. Lesher, PhD | veditors = Hooper DC, Wolfson JS | title = Quinolone antimicrobial agents | edition = 2nd | location = Washington DC | publisher = American Society for Microbiology | volume = XIII-XIV | date = 1993 }} Nalidixic acid is thus considered to be the predecessor of all members of the quinolone family, including the second, third and fourth generations commonly known as fluoroquinolones. Since the introduction of nalidixic acid, more than 10,000 analogs have been synthesized, but only a handful have found their way into clinical practice. The first generation also included other quinolone drugs, such as pipemidic acid, oxolinic acid, and cinoxacin, which were introduced in the 1970s. They proved to be only marginal improvements over nalidixic acid.{{cite book| vauthors = Norris S, Mandell GL |title=The quinolones: history and overview |year=1988 |publisher=Academic Press Inc |location=San Diego |pages=1–22 }}

These drugs were widely used as a first-line treatment for many infections, including very commons ones such as acute sinusitis, acute bronchitis, and uncomplicated UTIs.{{cite news|title=FDA updates warnings for fluoroquinolone antibiotics|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513183.htm|archive-url=https://web.archive.org/web/20160727142005/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513183.htm|url-status=dead|archive-date=27 July 2016|work=FDA|date=26 July 2016}} Reports of serious adverse events began emerging, and the FDA first added a black-box warning to fluoroquinolones in July 2008 for the increased risk of tendinitis and tendon rupture. In February 2011, the risk of worsening symptoms for those with myasthenia gravis was added to the warning. In August 2013, the agency required updates to the labels to describe the potential for irreversible peripheral neuropathy (serious nerve damage).{{citation needed|date=April 2023}}

In November 2015, an FDA Advisory Committee discussed the risks and benefits of fluoroquinolones for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated UTIs based on new safety information. The new information focused on two or more side effects occurring at the same time and causing the potential for irreversible impairment. The advisory committee concluded that the serious risks associated with the use of fluoroquinolones for these types of uncomplicated infections generally outweighed the benefits for patients with other treatment options.{{cite web|title=Fluoroquinolone Safety Labeling Changes|url=https://www.fda.gov/downloads/AboutFDA/WorkingatFDA/FellowshipInternshipGraduateFacultyPrograms/PharmacyStudentExperientialProgramCDER/UCM550259.pdf|publisher=FDA|archive-url=https://web.archive.org/web/20170509132217/https://www.fda.gov/downloads/AboutFDA/WorkingatFDA/FellowshipInternshipGraduateFacultyPrograms/PharmacyStudentExperientialProgramCDER/UCM550259.pdf|archive-date=9 May 2017|date=4 April 2017}}{{cite web|title = Briefing Information for the November 5, 2015 Joint Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM)|url = https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm467380.htm |publisher=Food and Drug Administration |access-date = 2015-10-19|archive-url=https://web.archive.org/web/20151020194411/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm467380.htm|archive-date=20 October 2015}}{{cite web|title=FDA Briefing Document Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, November 5, 2015 |url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM467383.pdf|publisher=FDA|archive-url=https://web.archive.org/web/20151117040645/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM467383.pdf|archive-date=17 November 2015}}{{cite web|title=Transcript: Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, November 5, 2015 |url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM477657.pdf|publisher=FDA|archive-url=https://web.archive.org/web/20160208032716/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM477657.pdf|archive-date=8 February 2016}} The 21-member joint committee overwhelmingly recommended stronger label warnings on the containers because of rare but sometimes devastating side effects.{{cite news|url=https://www.wsj.com/article_email/fda-panel-seeks-tougher-antibiotic-labels-1446784061-lMyQjAxMTE1MDAyNjAwODY4Wj | title=FDA Panel Seeks Tougher Antibiotic Labels | vauthors = Burton TM | access-date=6 November 2015 |newspaper=The Wall Street Journal| date=6 November 2015}}

On 12 May 2016, the FDA issued a drug safety communication advising that fluoroquinolones should be reserved for these conditions only when no other options are available due to potentially permanent, disabling side effects occurring together. The drug safety communication also announced the required labeling updates to reflect this new safety information. The FDA put out another label change in July 2017, strengthening the warnings about potentially disabling adverse effects and limiting use of these drugs to second-line treatments for acute sinusitis, acute bronchitis, and uncomplicated UTIs.

The first generation of the quinolones began following introduction of the related, but structurally distinct naphthyridine-family nalidixic acid in 1962 for treatment of UTIs in humans.{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/014214s058lbl.pdf |archive-url=https://web.archive.org/web/20121016134755/http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/014214s058lbl.pdf |url-status=dead |archive-date=16 October 2012 |title=NegGram® Caplets (nalidixic acid, USP) |author=Sanofi-Aventis U.S. LLC |author-link=Sanofi-Aventis |publisher=FDA |location=USA |date=September 2008 | access-date=6 May 2011 }} Nalidixic acid was discovered by George Lesher and coworkers in a chemical distillate during an attempt at synthesis of the chloroquinoline antimalarial agent, chloroquine.Wentland MP: In memoriam: George Y. Lesher, PhD, in Hooper DC, Wolfson JS (eds): Quinolone antimicrobial agents, ed 2., Washington DC, American Society for Microbiology : XIII – XIV, 1993. Naphthyridone and quinolone classes of antibiotics prevent bacterial DNA replication by inhibition of DNA unwinding events, and can be both bacteriostatic and bacteriocidal.{{cite journal | vauthors = Hooper DC | title = Emerging mechanisms of fluoroquinolone resistance | journal = Emerging Infectious Diseases | volume = 7 | issue = 2 | pages = 337–341 | date = Mar–Apr 2001 | pmid = 11294736 | pmc = 2631735 | doi = 10.3201/eid0702.010239 }} (See Mechanism of Action earlier.) The majority of quinolones in clinical use belong to the second generation class of "fluoroquinolones", which have a true quinoline framework, maintain the C-3 carboxylic acid group, and add a fluorine atom to the all-carbon containing ring, typically at the C-6 or C-8 positions.

File:Quinolone.svg group, the R substituent in blue is a piperazine moiety, and the remaining substitution sites (R groups) are hydrogen atoms.]]

Quinolones can be classified into generations based on their antibacterial spectrums.{{cite journal | vauthors = Ball P | title = Quinolone generations: natural history or natural selection? | journal = The Journal of Antimicrobial Chemotherapy | volume = 46 | issue = Supplement 3 | pages = 17–24 | date = July 2000 | pmid = 10997595 | doi = 10.1093/oxfordjournals.jac.a020889 | doi-access = free }}{{cite journal |url=http://www.aafp.org/afp/20000501/2741.html |title=New Classification and Update on the Quinolone Antibiotics – May 1, 2000 – American Academy of Family Physicians |journal=American Family Physician |volume=61 |issue=9 |pages=2741–2748 |access-date=18 March 2008 |date=May 2000 |vauthors=Lilley SH, Malone R, King DE |archive-date=6 June 2011 |archive-url=https://web.archive.org/web/20110606041802/http://www.aafp.org/afp/20000501/2741.html |url-status=dead }} The earlier-generation agents are, in general, more narrow-spectrum than the later ones, but no standard is employed to determine which drug belongs to which generation. The only universal standard applied is the grouping of the non-fluorinated drugs found within this class (quinolones) within the first-generation heading. As such, a wide variation exists within the literature dependent upon the methods employed by the authors.{{citation needed|date=April 2023}}

The first generation is rarely used. Frequently prescribed drugs are moxifloxacin, ciprofloxacin, levofloxacin.

• flumequine (veterinary use)
• oxolinic acid
• rosoxacin

Structurally related first-generation drugs, but formally not 4-quinolones, include cinoxacin,{{cite journal | vauthors = Oliphant CM, Green GM | title = Quinolones: a comprehensive review | journal = American Family Physician | volume = 65 | issue = 3 | pages = 455–464 | date = February 2002 | pmid = 11858629 | url = http://www.aafp.org/afp/20020201/455.html | access-date = 6 May 2011 | url-status = live | archive-url = https://web.archive.org/web/20070929110523/http://www.aafp.org/afp/20020201/455.html | archive-date = 29 September 2007 }} nalidixic acid, and piromidic acid, pipemidic acid

The second-generation class is sometimes subdivided into "Class 1" and "Class 2".

• ciprofloxacin{{cite journal | vauthors = Ambrose PG, Owens Jr RC |date=1 March 2000 |title=Clinical Usefulness of Quinolones |journal=Seminars in Respiratory and Critical Care Medicine |url=http://www.medscape.com/viewarticle/410872_6 |access-date=6 May 2011 |archive-url=https://web.archive.org/web/20110623081143/http://www.medscape.com/viewarticle/410872_6 |archive-date=23 June 2011 |url-status=live}}
• fleroxacin
• lomefloxacin
• nadifloxacin
• norfloxacin
• ofloxacin
• pefloxacin
• rufloxacin

A structurally related second-generation drug, but formally not a 4-quinolone, is enoxacin.

Unlike the first and second generations, the third generation is active against streptococci.

• balofloxacin
• grepafloxacin
• levofloxacin
• pazufloxacin
• sparfloxacin{{cite web|url=http://www.un.org/esa/coordination/CL12.pdf |title=Consolidated list of products – Pharmaceuticals 12th issue |year=2005 |publisher=United Nations | access-date=6 May 2011 }}
• temafloxacin

A structurally related third-generation drug, but formally not a 4-quinolone, is tosufloxacin (Ozex, Tosacin).

Fourth-generation fluoroquinolones act at DNA gyrase and topoisomerase IV.{{cite book|author=Gupta|title=Clinical Ophthalmology: Contemporary Perspectives, 9/e|url=https://books.google.com/books?id=__GWFXs2IuwC&pg=PA112|access-date=20 September 2010|year=2009|publisher=Elsevier India|isbn=978-81-312-1680-4|pages=112–}} This dual action slows development of resistance.{{dubious|reason=Article previously states drugs of this larger class generally do both|date=October 2021}}

• clinafloxacin
• gatifloxacin{{cite news | vauthors = Schmid RE |url=http://www.sfgate.com/cgi-bin/article.cgi?file=/news/archive/2006/05/01/national/w120748D88.DTL&type=health |title=Drug Company Taking Tequin Off Market |agency=Associated Press |date=1 May 2006 |access-date=1 May 2006 |archive-url=https://web.archive.org/web/20071125104959/http://www.sfgate.com/cgi-bin/article.cgi?file=%2Fnews%2Farchive%2F2006%2F05%2F01%2Fnational%2Fw120748D88.DTL&type=health |archive-date=25 November 2007 |url-status=dead }}
• moxifloxacin
• sitafloxacin
• prulifloxacin
• besifloxacin
• delafloxacin

Two structurally related fourth-generation drugs, but formally not 4-quinolones, are gemifloxacin and trovafloxacin (removed from clinical use).

In development:

• ozenoxacin

Quinolones have been widely used in animal husbandry, and several agents have veterinary-specific applications.

• danofloxacin – 2nd gen, related to ciprofloxacin
• difloxacin – 2nd/3rd gen, related to temafloxacin
• enrofloxacin – 2nd gen, metabolizes into ciprofloxacin
• ibafloxacin – 3rd gen, related to levofloxacin
• marbofloxacin – 3rd gen, related to levofloxacin
• orbifloxacin – 3rd gen, related to sparfloxacin
• sarafloxacin – 2nd/3rd gen, related to difloxacin
• pradofloxacin – 3rd gen

{{HHS content|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513183.htm|title=FDA updates warnings for fluoroquinolone antibiotics}}

{{Reflist}}

• [https://www.cdc.gov/HAI/settings/lab/Quinolones-Clinical-Laboratory.html Healthcare-associated Infections (HAIs)- Quinolones and the Clinical Laboratory] CDC
• [https://web.archive.org/web/20090603060516/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126085.htm Information for Healthcare Professionals: Fluoroquinolone Antimicrobial Drugs] from the U.S. Food and Drug Administration
• [http://fpnotebook.com/ID160.htm Fluoroquinolones] ({{Webarchive|url=https://web.archive.org/web/20060617042701/http://fpnotebook.com/ID160.htm |date=17 June 2006 }}) "Family Practice Notebook" entry page for Fluoroquinolones
• [https://web.archive.org/web/20060304094439/http://www.infectio-lille.com/diaporamas/invites/struct-act-duatb05-bryskier.pdf Structure Activity Relationships] "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD

{{Nucleic acid inhibitors}}

{{Authority control}}