Adverse effects of fluoroquinolones
|This article is being considered for deletion in accordance with Wikipedia's deletion policy.
Please share your thoughts on the matter at this article's entry on the Articles for deletion page.
Feel free to edit the article, but the article must not be blanked, and this notice must not be removed, until the discussion is closed. For more information, particularly on merging or moving the article during the discussion, read the Guide to deletion.
|Adverse effects of fluoroquinolones|
|Classification and external resources|
In general, fluoroquinolones are well tolerated, with most side effects being mild to moderate. On occasion, serious adverse effects occur. Common side effects include gastrointestinal effects such as nausea, vomiting and diarrhea, as well as headache and insomnia.
The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes. A U.S. Centers for Disease Control study found patients 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.
Post-marketing surveillance has revealed a variety of relatively rare but serious adverse effects that are 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. The most severe form of tendonopathy associated with fluoroquinolone administration is tendon rupture, which in the great majority of cases involves the Achilles tendon. Younger people typically experience good recovery, but permanent disability is possible, and is more likely in older patients. The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin is has been estimated at 17 per 100,000 treatments. Risk is substantially elevated in the elderly and in those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture. Tendon damage may manifest during, as well as up to a year after fluoroquinolone therapy has been completed.
FQs prolong the QT interval by blocking voltage-gated potassium channels. Prolongation of the QT interval can lead to torsades de pointes, a life threatening arrhythmia, but this appears relatively uncommon in part because the most widely prescribed fluoroquinolones (ciprofloxacin and levofloxacin) only minimally prolong the QT interval.
Clostridium difficile associated diarrhea 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 simlar to or less  than that associated with broad spectrum cephalosporins.
Studies examining nervous system effects have estimated that neurotoxicity occurs in approximately 1% to 4.4% of patients taking FQs, with serious adverse effects occurring less than 0.5% of the time. The most important of these may be peripheral neuropathy, which can be permanent. Other nervous system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis Other rare and serious adverse events have been observed with varying degrees of evidence for causation.
Events that may occur in acute overdose are rare, and include renal failure and seizure. Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.
Other quinolones have had their licensed indications restricted in certain countries due to toxicity issues. These include sparfloxacin in 1995, norfloxacin in 2008 and moxifloxacin in 2008.
- 1 Background
- 2 Risk factors and interactions
- 3 Adverse reactions and toxicities
- 4 DNA effects
- 5 References
- 6 External links
Fluoroquinolones are often effective as antibacterial agents. They are recommended for a number of serious bacterial infections, and, in some cases of life-threatening infections, they can be life-saving. The distinction between a quinolone drug and a fluoroquinolone drug is the addition of the fluorine atom to the basic pharmacophore, resulting in a fluorinated drug. The terms fluoroquinolone and quinolone are often used interchangeably, without regard to this distinction.
Risk factors and interactions
Certain patient groups are at increased risk of fluoroquinolone ADRs. A 1998 retrospective survey of the use of the fluoroquinolones in the pediatric population showed that the fluoroquinolones were oftentimes prescribed in children, and that numerous serious side effects had been recorded. Fluoroquinolones are not recommended in patient groups that are predisposed to adverse events (for example, because of diabetes, G6PD deficiency, renal impairment, myasthenia gravis, previous psychiatric, seizure disorder, or children (under 18)). An alternative antibiotic class should be used wherever possible in such patients, and,if used, special caution is advised; for example, possible dosage reduction may be required as well as extra vigilance for adverse reactions. There is also an increased risk of adverse events in the elderly, including tendon ruptures and seizures. Use in children or pregnant or breast-feeding women is not recommended and should be avoided. In the UK, the prescribing indications for fluoroquinolones for children is severely restricted. Only inhalant anthrax and pseudomonal infections in cystic fibrosis infections are licensed indications in the UK due to ongoing safety concerns. At the first sign of psychiatric, neurological, peripheral neuropathy, tendonitis, or hypersensitivity reactions, fluoroquinolones should be discontinued. Quinolones are contraindicated in patients having had previous quinolone-related tendinopathy. Dose, length of time, and number of exposures to fluoroquinolones, as well as combination with corticosteroids, NSAIDs, or theophylline, increase the risk adverse reactions. Concurrent use of corticosteroids increases the risk of multiskeletal injury, manifesting as chronic tendonitis or spontaneous ruptures of tendons, and cartilage. Concurrent use of NSAIDs may in rare cases induce seizures. Most cases of fluoroquinolone-precipitated seizures occur in the elderly or those with severe cerebral arteriosclerosis, epilepsy, brain tumour, anoxia, and alcohol dependence, as well as those taking theophylline or the NSAIDs. Those who are benzodiazepine-dependent or in benzodiazepine withdrawal have a higher rate of adverse severe CNS effects possibly due to fluoroquinolones' displacement of benzodiazepines from their receptor site or pre-existing GABA underactivity due to withdrawal, thus leading to an increased sensitivity to fluoroquinolone toxicity. Articaine may worsen certain symptoms in an individual with fluoroquinolone toxicity. There have been persistent reports of unexplained paresthesia following the use of articaine (burning, tingling, and sometimes sharp shooting pains in tissues previously anesthetized with this anesthetic) during dental procedures involving patients having had adverse reactions to the fluoroquinolones. Broad spectrum antibacterials including cephalosporins, Fluoroquinolones (and clindamycin) have been associated with Clostridium difficile, a potentially life-threatening super-infection. Use of quinolones is also highly associated with colonisation with MRSA compared to some other antibiotic classes. Shigella toxin expression in EHEC infections has been shown to be upregulated following fluoroquinolone administration. Fluoroquinolones can have serious and potential fatal reaction when taken with certain other drugs. Some agents decrease theophylline clearance and thus increase toxicity. Warfarin is affected by many many drugs including fluoroquinolones and frequency of INR monitoring needs to be increased in those prescribed both agents.
Adverse reactions and toxicities
The most common adverse effects of the fluoroquinolones involve the gastrointestinal tract, skin, CNS, and PNS. They are for most patients mild and reversible. Severe adverse events such as hepatitis (trovafloxacin), hemolytic uremic syndrome (temafloxacin), and eosinophilic pneumonitis are thought to be specific to individual agents and as such not considered to be a class effect. Rare cases of liver failure have been reported in association with treatment with levofloxacin, ofloxacin, ciprofloxacin, and moxifloxacin. The incidence of liver failure associated with currently marketed fluoroquinolones is on the order of 1-5 cases per million treatments, and is similar to that associated with other antibacterial drugs.
Mechanism of toxicity
The mechanisms of the toxicity of fluoroquinolones has been attributed to their interactions with different receptor complexes such as blockade of the GABAa receptor complex within the central nervous system, leading to excitotoxic type effects and oxidative stress.
Nausea and vomiting are the most common side-effect of the fluoroquinolones. The group of side-effects includes nausea, vomiting, abdominal pain, diarrhea, and taste disturbance, which occur in about 2-20% of people taking fluoroquinolones. This rate is similar to those seen with azithromycin and cefixime. The highest rates occurred among older agents, which have been discontinued. Newer agents have lower rate of GI side-effects. C. difficile-associated diarrhea (CDAD) has been associated with all antibiotics. When compared to other antibiotics, however, the risk of CDAD was found to be 2.5 times greater with fluoroquinolones. Fluoroquinolones are associated with an increased risk of pseudomembranous colitis
The spectrum of this disease ranges from asymptomatic carrier state to life-threatening pseudomembranous colitis and toxic megacolon. Pathogenesis of pseudomembranous colitis results from the suppression of the natural microflora of the colon by broad spectrum antibiotics, which creates an environment favorable for C. difficile proliferation. A Clostridium difficile infection is the principal cause of nosocomial, antibiotic-associated diarrhea, and pseudomembranous colitis. C. difficile can be fatal if left untreated.
Like many antibiotics, fluoroquinolones increase the colonisation of Candida albicans, a yeast infection. Fluoroquinolones are associated with predisposing patients to an increased risk of C. difficile infections, and careful use, especially in acute hospitals, has been suggested.
Joint pain and swelling occurs in approximately 1% of people taking fluoroquinolones and usually remits within days of stopping treatment. A rare but serious adverse reaction with fluoroquinolones involves spontaneous tendon ruptures. Such injury to the patient potentially include ruptures the Achilles or other tendons. The risk of tendon disorders with fluoroquinolone use is 0.1% to 0.4% or 3 cases per 1000 patient-years of exposure. These problems usually start 13 days after treatment was started and may possibly persist for a month. Risk of tendon rupture is even less with only 38 of 46,000 people treated with fluoroquinolone suffering a rupture of the Achilles. This is 1.9 times the rate seen in the general population. The achilles is the most common tendon affected. This risk is greatest in those older than 60, in those taking corticosteroid drugs, and in kidney, heart, and lung transplant recipients. Because of their possible negative effect on cartilage, they are not recommended for use in pregnant women or children. The FDA recommends stopping treatment, contacting a physician and resting affected limbs if these adverse events occur. Achjilles tendon rupture has been observed up to a year post-treatment. Tendinitis, arthralgia, myalgia, as well as joint, muscle, and tendon pain, are found to be the top-three adverse reactions reported to the FDA via the Adverse Event Reporting System (AERS) for all the drugs within this class.
The odds ratios (ORs) of suffering a spontaneous rupture of the achilles tendon are 4.3, for current exposure 2.4, recent exposure and 1.4 for past exposure to a fluoroquinolone drug, respectively, compared with non-exposure. The incidence of spontaneous tendon rupture within the kidney recipient population is even more common. In the renal transplant population, a tendonopathy incidence of 12.2%–15.6% is reported, compared with 0.6%–3.6% for transplant recipients not receiving fluoroquinolones. In one study of 149 heart transplant patients, fourteen (9.5%) patients developed Achilles tendinopathy, which in three patients (2.25%) progressed to tendon rupture.
Any CNS side-effect occurs with an incidence of 1–2%. Adverse event reporting for antibiotics found that 12.2% of adverse reaction reports concerning fluoroquinolones involved the CNS versus 3.6% for other antibiotics. Newer agents to have a lower risk of side-effects have been found. Seizures are rare, and usually occur when they do in those with an underlying CNS disorder. However, caution use in patient with epilepsy is still advised. Suicidal behavior and other psychiatric effects including anxiety, panic attacks, depression, anhedonia, cognitive dysfunction (or brain fog), depersonalization, paranoia, hallucinations, toxic psychosis have been reported, with varying levels of evidence supporting causation.
Photosensitivity reactions have been reported with the fluoroquinolone class. The phototoxic potentials of fluoroquinolones are influenced not only by the substituent at position 8 (Halogenation at position C8) but also by those at position 1. Drugs such as Lomefloxacin and Sparfloxcacin, with a C8-fluorine substituent, and Clinafloxacin, with a C8-chlorine substituent, exhibit a greater incidence of phototoxic reactions than drugs without this substituent. Clinafloxacin was subsequently removed from clinical use due to severe phototoxicity reactions and in June 1995 The Medicines Agency restricted the use of Sparfloxacin due to the large number of reports of phototoxicity associated with its use.
Extremely rare cases of cutaneous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. One review estimated the incidence of fluoroquinolone-associated Stevens-Johnson syndrome at less than 0.5 cases per million patients treated.
Peripheral neuropathy has been rarely reported. Symptoms may include paresthesia (tingling), hypoesthesia (numbness), dysesthesia (pain), and weakness. Therapy should be discontinued if any neurological symptoms develop in order to prevent the occurrence of a possible irreversible condition. Rare cases of sensory impairment involving taste or smell have been reported with a number of fluoroquinolones and may last for up to several months.
In 2004, the FDA added warnings to the package inserts about the possibility of irreversible fluoroquinolone-innduced peripheral neuropathy.
Fluoroquinolones can cause QT prolongation and, thus, predispose a person to Torsades de Pointes which is sometimes fatal. Some members of the quinolone family are more likely to causes an increased QT than others. Grepafloxacin was removed from the market due to frequent QT prolongation. Of the currently available agents, moxifloxacin causes the greatest QT prolongation, while ciprofloxacin is associated with a lowest risk of QT prolongation.
Blood abnormalities are believed to occur in less than one percent of patients. However, Temafloxacin was removed from clinical use in 1992 due to its side-effects of hemolytic anemia (destruction of red blood cells) and other blood cell abnormalities; kidney dysfunction requiring renal dialysis (in 50% of patients affected); and severe liver dysfunction.
Blood sugar abnormalities
Changes in blood sugar levels may occur with fluoroquinolones. Risks for this complication includes diabetes, old age, renal failure, and sepsis. Gatifloxacin was removed from the market in the US and Canada partly due to its negative effects on blood sugar. Temafloxacin was removed from clinical use in 1992 partially due to several cases of low blood sugar as well.
Oral use and I.V. use of the fluoroquinolones are associated with a rare reports of serious visual disturbances. Patients receiving fluoroquinolones have been reported to have developed visual disturbances, which include color distortion and diplopia (double vision). Such disturbances may present as blurred and dim vision, disturbed vision, flashing lights, diplopia, floaters,as well as decreased visual acuity and cataracts. Norfloxacin, ProQuin XR and Ciprofloxacin have also been associated with diplopia., as well as Iquix (levofloxacin ophthalmic solution).
The fluoroquinolones exert their therapeutic effects by interfering with bacterial DNA replication by inhibiting an enzyme complex called DNA gyrase. Research has indicated that fluoroquinolones at therapeutically used doses have little effect on enzymes involved in DNA replication in mammalian cells including human cells; however, not all subtypes of eucaryotic topoisomerases have been routinely studied in clinical studies. In vitro studies in human fibroblast cells have shown that nalidixic acid can impair repair type DNA synthesis at a relatively low dosage (5 ug/ml), but this effect is seen only at very high doses (at least 50 ug/ml) of other quinolones (ciprofloxacin, norfloxacin, and ofloxacin) tested. Fluoroquinolones increase the uptake of deoxyuridine, uridine, and thymidine into the DNA of human lymphocytes and decrease pyrimidine production. A reduction in leucine occurs. With some quinolones, these effects appear to occur at therapeutic dose levels. Quinolones also appear to effect the growth of eucaryotic cells and HeLa cells. However, relatively high doses of quinolones (20 ug/ml) are required to impair eucaryotic cell growth. At doses that are achievable in therapeutic dosing of (5 ug/ml), a 50% reduction in lymphocyte immunogloblin production occurs. DNA damage such as strand breaks, occurs only at extremely high doses of fluoroquinolones (above 100 ug/ml). DNA polymerase a, topoisomerase I, topoisomerase II, and mitochondrial function are inhibited only at high doses of quinolones above the dosages that would be seen in clinical practice. Some quinolones have been shown to be capable of causing injury to the chromosome of eukaryotic cells. As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells. There is some debate in the medical literature as to whether these DNA effects are to be considered one of the mechanisms of action concerning some of the severe ADRs and toxicities experienced by some patients following fluoroquinolone therapy. It has been speculated that the effects of fluoroquinolones on human eukaryotic topoisomerases have potential to cause cytotoxicity. Fluoroquinolones may have the potential to cause clastogenicity and the induction of micronuclei. Retinal pigment epithelial cells are critical to the functioning of the eye and are involved in many eye diseases. In one study, DNA damage to RPE cells was observed with Sparfloxacin.
- Owens RC, Ambrose PG (July 2005). "Antimicrobial safety: focus on fluoroquinolones". Clin. Infect. Dis. 41 Suppl 2: S144–57. doi:10.1086/428055. PMID 15942881.
- De Sarro A, De Sarro G (March 2001). "Adverse reactions to fluoroquinolones. an overview on mechanistic aspects". Curr. Med. Chem. 8 (4): 371–84. doi:10.2174/0929867013373435. PMID 11172695.
- Skalsky K, Yahav D, Lador A, Eliakim-Raz N, Leibovici L, Paul M (April 2013). "Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials". Clin. Microbiol. Infect. 19 (4): 370–8. doi:10.1111/j.1469-0691.2012.03838.x. PMID 22489673.
- Falagas ME, Matthaiou DK, Vardakas KZ (December 2006). "Fluoroquinolones vs beta-lactams for empirical treatment of immunocompetent patients with skin and soft tissue infections: a meta-analysis of randomized controlled trials". Mayo Clin. Proc. 81 (12): 1553–66. PMID 17165634.
- Van Bambeke F, Tulkens PM (2009). "Safety profile of the respiratory fluoroquinolone moxifloxacin: comparison with other fluoroquinolones and other antibacterial classes". Drug Saf 32 (5): 359–78. PMID 19419232.
- Shehab N, Patel PR, Srinivasan A, Budnitz DS (September 2008). "Emergency department visits for antibiotic-associated adverse events". Clin. Infect. Dis. 47 (6): 735–43. doi:10.1086/591126. PMID 18694344.
- Kim GK (April 2010). "The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture: What Does The Clinician Need To Know?". J Clin Aesthet Dermatol 3 (4): 49–54. PMC 2921747. PMID 20725547.
- Sode J, Obel N, Hallas J, Lassen A (May 2007). "Use of fluroquinolone and risk of Achilles tendon rupture: a population-based cohort study". Eur. J. Clin. Pharmacol. 63 (5): 499–503. doi:10.1007/s00228-007-0265-9. PMID 17334751.
- Owens RC, Ambrose PG (July 2005). "Antimicrobial safety: focus on fluoroquinolones". Clin. Infect. Dis. 41 Suppl 2: S144–57. doi:10.1086/428055. PMID 15942881.
- Khaliq Y, Zhanel GG (October 2005). "Musculoskeletal injury associated with fluoroquinolone antibiotics". Clin Plast Surg 32 (4): 495–502, vi. doi:10.1016/j.cps.2005.05.004. PMID 16139623.
- Saint F, Gueguen G, Biserte J, Fontaine C, Mazeman E (September 2000). "[Rupture of the patellar ligament one month after treatment with fluoroquinolone]". Rev Chir Orthop Reparatrice Appar Mot (in French) 86 (5): 495–7. PMID 10970974.
- Heidelbaugh JJ, Holmstrom H (April 2013). "The perils of prescribing fluoroquinolones". J Fam Pract 62 (4): 191–7. PMID 23570031.
- Rubinstein E, Camm J (April 2002). "Cardiotoxicity of fluoroquinolones". J. Antimicrob. Chemother. 49 (4): 593–6. PMID 11909831.
- Deshpande A, Pasupuleti V, Thota P, et al. (September 2013). "Community-associated Clostridium difficile infection and antibiotics: a meta-analysis". J. Antimicrob. Chemother. 68 (9): 1951–61. doi:10.1093/jac/dkt129. PMID 23620467.
- Slimings C, Riley TV (December 2013). "Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis". J. Antimicrob. Chemother. doi:10.1093/jac/dkt477. PMID 24324224.
- "Data Mining Analysis of Multiple Antibiotics in AERS".
- "FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection".
- Galatti L, Giustini SE, Sessa A, et al. (March 2005). "Neuropsychiatric reactions to drugs: an analysis of spontaneous reports from general practitioners in Italy". Pharmacol. Res. 51 (3): 211–6. doi:10.1016/j.phrs.2004.08.003. PMID 15661570.
- Babar, S. (October 2013). "SIADH Associated With Ciprofloxacin.". The Annals of Pharmacotherapy (Sage Publishing) 47 (10): 1359–1363. doi:10.1177/1060028013502457. ISSN 1060-0280. Retrieved November 139,2013.
- Rouveix, B. (Nov–Dec 2006). "[Clinically significant toxicity and tolerance of the main antibiotics used in lower respiratory tract infections]". Med Mal Infect 36 (11–12): 697–705. doi:10.1016/j.medmal.2006.05.012. PMID 16876974.
- Mehlhorn AJ, Brown DA (November 2007). "Safety concerns with fluoroquinolones". Annals of Pharmacotherapy 41 (11): 1859–66. doi:10.1345/aph.1K347. PMID 17911203.
- Jones SF, Smith RH (March 1997). "Quinolones may induce hepatitis". BMJ 314 (7084): 869. doi:10.1136/bmj.314.7084.869. PMC 2126221. PMID 9093098.
- Nelson, Lewis H.; Flomenbaum, Neal; Goldfrank, Lewis R.; Hoffman, Robert Louis; Howland, Mary Deems; Neal A. Lewin (2006). Goldfrank's toxicologic emergencies. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-143763-0.
- Iannini PB (June 2007). "The safety profile of moxifloxacin and other fluoroquinolones in special patient populations". Curr Med Res Opin 23 (6): 1403–13. doi:10.1185/030079907X188099. PMID 17559736.
- Farinas, Evelyn R; PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH (1 March 2005). "Consult: One-Year Post Pediatric Exclusivity Postmarketing Adverse Events Review" (PDF). USA: FDA. Retrieved 31 August 2009.
- "Consolidated List of Products" (PDF). United Nations. 2005.
- The European Medicines Agency (24 July 2008). "EMEA Restricts Use of Oral Norfloxacin Drugs in UTIs". United Kingdom: Doctor's Guide.
- The European Medicines Agency (EMEA); Danish Medicines Agency (24 July 2008). "EMEA recommends restricting the use of oral moxifloxacin-containing medicines".
- de Castro FR, Torres A (2003). "Optimizing treatment outcomes in severe community-acquired pneumonia". Am J Respir Med 2 (1): 39–54. PMID 14720021.
- Niyogi SK (April 2005). "Shigellosis". J. Microbiol. 43 (2): 133–43. PMID 15880088.
- R. Schaumann; A.C. Rodloff (2007). "Activities of Quinolones Against Obligately Anaerobic Bacteria" (PDF). Anti-Infective Agents in Medicinal Chemistry 6: 49–56.
- Pariente-Khayat, A.; Vauzelle-Kervroedan, F.; d'Athis, P.; Bréart, G.; Gendrel, D.; Aujard, Y.; Olive, G.; Pons, G. (May 1998). "[Retrospective survey of fluoroquinolone use in children]". Arch Pediatr 5 (5): 484–8. doi:10.1016/S0929-693X(99)80311-X. PMID 9759180.
- Owens RC, Ambrose PG (July 2005). "Antimicrobial safety: focus on fluoroquinolones". Clin. Infect. Dis. 41 (Suppl 2): S144–57. doi:10.1086/428055. PMID 15942881.
- Committee on Safety of Medicines; Medicines and Healthcare products Regulatory Agency (2008). "Quinolones". United Kingdom: British National Formulary. Retrieved 16 February 2009.
- Bayer HealthCare Pharmaceuticals Inc (September 2008). "CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO,(ciprofloxacin*) ORAL SUSPENSION" (PDF). USA: FDA. Retrieved 31 August 2009.
- Kushner JM, Peckman HJ, Snyder CR (October 2001). "Seizures associated with fluoroquinolones". Annals of Pharmacotherapy 35 (10): 1194–8. doi:10.1345/aph.10359. PMID 11675843.
- "(WO/2002/093162) INDIVIDUALIZATION OF THERAPY WITH ANTIBIOTIC AGENTS". World Health Organisation. 21 November 2002.
- Professor Heather Ashton (2002). "Benzodiazepines: How They Work and How to Withdraw".
- McConnell JG (May 2008). "Benzodiazepine tolerance, dependency, and withdrawal syndromes and interactions with fluoroquinolone antimicrobials". British Journal of General Practice (Royal College of General Practitioners) 58 (550): 365–366. doi:10.3399/bjgp08X280317. PMC 2435654. PMID 18482496.
- Unseld E; Ziegler G, Gemeinhardt A, Janssen U, Klotz U (July 1990). "Possible interaction of fluoroquinolones with the benzodiazepine-GABAA-receptor complex". Br J Clin Pharmacol 30 (1): 63–70. doi:10.1111/j.1365-2125.1990.tb03744.x. PMC 1368276. PMID 2167717.
- Sternbach H, State R (1997). "Antibiotics: neuropsychiatric effects and psychotropic interactions". Harv Rev Psychiatry 5 (4): 214–26. doi:10.3109/10673229709000304. PMID 9427014.
- Martin S. Spiller, D.M.D. "The Local Anesthetics". Archived from the original on 18 January 2009. Retrieved 30 January 2009.
- Dr Ralf-Peter Vonberg. "Clostridium difficile: a challenge for hospitals". European Center for Disease Prevention and Control. Institute for Medical Microbiology and Hospital Epidemiology: IHE. Archived from the original on 11 June 2009. Retrieved 27 July 2009.
- Muto, CA.; Jernigan, JA.; Ostrowsky, BE.; Richet, HM.; Jarvis, WR.; Boyce, JM.; Farr, BM. (May 2003). "SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and enterococcus.". Infect Control Hosp Epidemiol 24 (5): 362–86. doi:10.1086/502213. PMID 12785411.
- Tacconelli, E.; De Angelis, G.; Cataldo, MA.; Pozzi, E.; Cauda, R. (Jan 2008). "Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) isolation? A systematic review and meta-analysis.". J Antimicrob Chemother 61 (1): 26–38. doi:10.1093/jac/dkm416. PMID 17986491.
- "Toxin Gene Expression by Shiga Toxin-Producing Escherichia coli: the Role of Antibiotics and the Bacterial SOS Response". Cdc.gov. 2009-03-05. Retrieved 2011-03-29.
- Ball P, Mandell L, Niki Y, Tillotson G (November 1999). "Comparative tolerability of the newer fluoroquinolone antibacterials". Drug Saf 21 (5): 407–21. doi:10.2165/00002018-199921050-00005. PMID 10554054.
- Borcherding SM, Stevens R, Nicholas RA, Corley CR, Self T (January 1996). "Quinolones: a practical review of clinical uses, dosing considerations, and drug interactions". J Fam Pract 42 (1): 69–78. PMID 8537808.
- Bayer Schering Pharma, Bayer plc (February 2008). "IMPORTANT INFORMATION REGARDING SERIOUS ADVERSE REACTIONS AND SAFETY MEASURES" (PDF). United Kingdom: Medicines and Healthcare products Regulatory Agency (MHRA).
- Zimpfer, Annette; Propst, Albert; Mikuz, Gregor; Vogel, Wolfgang; Terracciano, Luigi; Stadlmann, Sylvia (2004). "Ciprofloxacin-induced acute liver injury: case report and review of literature". Virchows Archiv. 1 444 (1): 87–9. doi:10.1007/s00428-003-0917-9. ISSN 0945-6317. PMID 14994731.
- Renata Albrecht (19 June 2007). "NDA 20-634/S-045, NDA 20-635/S-048, NDA 21-721/S-013" (PDF). USA: FDA.
- Paterson JM, Mamdani MM, Manno M, Juurlink DN (October 2012). "Fluoroquinolone therapy and idiosyncratic acute liver injury: a population-based study". CMAJ 184 (14): 1565–70. doi:10.1503/cmaj.111823. PMC 3470619. PMID 22891208.
- Saint F, Salomon L, Cicco A, de la Taille A, Chopin D, Abbou CC (December 2001). "[Tendinopathy associated with fluoroquinolones: individuals at risk, incriminated physiopathologic mechanisms, therapeutic management]". Prog. Urol. (in French) 11 (6): 1331–4. PMID 11859676.
- Fashner J, Garcia M, Ribble L, Crowell K (September 2011). "Clinical inquiry: what risk factors contribute to C difficile diarrhea?". J Fam Pract 60 (9): 545–7. PMID 21901182.
- McCusker ME, Harris AD, Perencevich E, Roghmann MC (June 2003). "Fluoroquinolone Use and Clostridium difficile–Associated Diarrhea". Emerging Infect. Dis. 9 (6): 730–3. doi:10.3201/eid0906.020385. PMC 3000134. PMID 12781017.
- Deshpande A, Pant C, Jain A, Fraser TG, Rolston DD (February 2008). "Do fluoroquinolones predispose patients to Clostridium difficile associated disease? A review of the evidence". Curr Med Res Opin 24 (2): 329–33. doi:10.1185/030079908X253735. PMID 18067688.
- Walbrown MA, Aspinall SL, Bayliss NK, et al. (2008). "Evaluation of Clostridium difficile-associated diarrhea with a drug formulary change in preferred fluoroquinolones". J Manag Care Pharm 14 (1): 34–40. PMID 18240880.
- Muto CA, Pokrywka M, Shutt K, et al. (March 2005). "A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use". Infect Control Hosp Epidemiol 26 (3): 273–80. doi:10.1086/502539. PMID 15796280.
- Cain DB, O'Connor ME (October 1990). "Pseudomembranous colitis associated with ciprofloxacin". Lancet 336 (8720): 946. doi:10.1016/0140-6736(90)92320-H. PMID 1976960.
- Pérez-Calvo JI, Matamala C, Sanjoaquín I, Amores M, Castillo J, Bueno-Gómez J (1993). "[Diarrhea following antibiotic treatment, Clostridium difficile, and quinolones]". Enferm. Infecc. Microbiol. Clin. (in Spanish; Castilian) 11 (6): 345. PMID 8347715.
- Ozawa TT, Valadez T (March 2002). "Clostridium difficile infection associated with levofloxacin treatment". Tenn Med 95 (3): 113–5. PMID 11898264.
- Ortiz-de-Saracho J, Pantoja L, Romero MJ, López R (March 2003). "Moxifloxacin-induced Clostridium difficile diarrhea". Annals of Pharmacotherapy 37 (3): 452–3. doi:10.1345/aph.1C325. PMID 12639182.
- Mavromanolakis E, Maraki S, Cranidis A, Tselentis Y, Kontoyiannis DP, Samonis G (2001). "The impact of norfloxacin, ciprofloxacin and ofloxacin on human gut colonization by Candida albicans". Scand. J. Infect. Dis. 33 (6): 477–8. doi:10.1080/00365540152030006. PMID 11450873.
- Yip C, Loeb M, Salama S, Moss L, Olde J (September 2001). "Quinolone use as a risk factor for nosocomial Clostridium difficile-associated diarrhea". Infect Control Hosp Epidemiol 22 (9): 572–5. doi:10.1086/501954. PMID 11732787.
- Meyers JS, Ehrenpreis ED, Craig RM (February 2001). "Small Intestinal Bacterial Overgrowth Syndrome". Curr Treat Options Gastroenterol 4 (1): 7–14. doi:10.1007/s11938-001-0042-2. PMID 11177677.
- Cottrell WC, Pearsall AW, Hollis MJ (June 2002). "Simultaneous tears of the Achilles tendon and medial head of the gastrocnemius muscle". Orthopedics 25 (6): 685–7. PMID 12083581.
- "UpToDate Inc.".
- van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HG, Stricker BH (June 2002). "Fluoroquinolones and risk of Achilles tendon disorders: case-control study". BMJ 324 (7349): 1306–7. doi:10.1136/bmj.324.7349.1306. PMC 113766. PMID 12039823.
- Muzi F, Gravante G, Tati E, Tati G (June 2007). "Fluoroquinolones-induced tendinitis and tendon rupture in kidney transplant recipients: 2 cases and a review of the literature". Transplant. Proc. 39 (5): 1673–5. doi:10.1016/j.transproceed.2007.01.077. PMID 17580216.
- "FDA News Release". Food and Drug Administration (United States).
- Lipsky BA, Baker CA (February 1999). "Fluoroquinolone toxicity profiles: a review focusing on newer agents". Clin. Infect. Dis. 28 (2): 352–64. doi:10.1086/515104. PMID 10064255.
- Bailey RR, Natale R, Linton AL (October 1972). "Nalidixic acid arthralgia". Can Med Assoc J 107 (7): 604 passim. PMC 1940945. PMID 4541768.
- Harrell RM (June 1999). "Fluoroquinolone-induced tendinopathy: what do we know?". South. Med. J. 92 (6): 622–5. doi:10.1097/00007611-199906000-00014. PMID 10372859.
- Casparian JM, Luchi M, Moffat RE, Hinthorn D (May 2000). "Quinolones and tendon ruptures". South. Med. J. 93 (5): 488–91. PMID 10832946.
- Khaliq Y, Zhanel GG (June 2003). "Fluoroquinolone-associated tendinopathy: a critical review of the literature". Clin. Infect. Dis. 36 (11): 1404–10. doi:10.1086/375078. PMID 12766835.
- Summaries received from the FDA under the Freedom of Information Act. Accessed November of 2001
- "Avoiding Achilles Tendon Ruptures in the Elderly". Clinical Reviews. Retrieved 22 February 2009.
- Donck JB, Segaert MF, Vanrenterghem YF (September 1994). "Fluoroquinolones and Achilles tendinopathy in renal transplant recipients". Transplantation 58 (6): 736–7. doi:10.1097/00007890-199409270-00021. PMID 7940700.
- Leray H, Mourad G, Chong G, Marcelli C, Borderie P, Mion C (November 1993). "[Spontaneous ruptures of the Achilles tendon after kidney transplantation: use of fluoroquinolones]". Presse Med (in French) 22 (36): 1834. PMID 8309916.
- Barge-Caballero E, Crespo-Leiro MG, Paniagua-Martín MJ, et al. (January 2008). "Quinolone-related Achilles tendinopathy in heart transplant patients: incidence and risk factors". J. Heart Lung Transplant. 27 (1): 46–51. doi:10.1016/j.healun.2007.09.021. PMID 18187086.
- "Tavanic SPC". Sanofi-aventis.
- Lamarine RJ (December 1994). "Selected health and behavioral effects related to the use of caffeine". J Community Health 19 (6): 449–66. doi:10.1007/BF02260326. PMID 7844249.
- Harder S, Fuhr U, Staib AH, Wolff T (November 1989). "Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations". Am. J. Med. 87 (5A): 89S–91S. doi:10.1016/0002-9343(89)90031-4. PMID 2589393.
- Domagala, Jm (Apr 1994). "Structure-activity and structure-side-effect relationships for the quinolone antibacterials". The Journal of antimicrobial chemotherapy 33 (4): 685–706. doi:10.1093/jac/33.4.685. ISSN 0305-7453. PMID 8056688.
- "products_0_Start" (PDF). Retrieved 2011-03-29.
- Hällgren, J; Tengvall-Linder, M; Persson, M; Wahlgren, Cf (Nov 2003). "Stevens–Johnson syndrome associated with ciprofloxacin: a review of adverse cutaneous events reported in Sweden as associated with this drug". Journal of the American Academy of Dermatology 49 (5 Suppl): S267–9. doi:10.1016/S0190-9622(03)00478-X. ISSN 0190-9622. PMID 14576649.
- "MedWatch - July 2004 Safety-Related Drug Labeling Changes - Detailed". Food and Drug Administration (United States).
- "Safety profile of grepafloxacin compared with other fluoroquinolones". Ralf Stahlmann and Rudolf Schwabe.
- Hedenmalm K, Spigset O (April 1996). "Peripheral sensory disturbances related to treatment with fluoroquinolones". J. Antimicrob. Chemother. 37 (4): 831–7. doi:10.1093/jac/37.4.831. PMID 8722551.
- Aoun M, Jacquy C, Debusscher L, et al. (July 1992). "Peripheral neuropathy associated with fluoroquinolones". Lancet 340 (8811): 127. doi:10.1016/0140-6736(92)90460-K. PMID 1352007.
- Cohen JS (December 2001). "Peripheral neuropathy associated with fluoroquinolones". Annals of Pharmacotherapy 35 (12): 1540–7. doi:10.1345/aph.1Z429. PMID 11793615.
- Falagas ME, Rafailidis PI, Rosmarakis ES (April 2007). "Arrhythmias associated with fluoroquinolone therapy". Int. J. Antimicrob. Agents 29 (4): 374–9. doi:10.1016/j.ijantimicag.2006.11.011. PMID 17241772.
- "UpToDate Inc.". Uptodate.
- [dead link]
- Ball P (February 1989). "Adverse reactions and interactions of fluoroquinolones". Clin Invest Med 12 (1): 28–34. PMID 2646053.
- The antimicrobial drugs By Eric Michael Scholar, William B. Pratt Edition: 2, illustrated Published by Oxford University Press US, 2000 ISBN 0-19-512529-0, ISBN 978-0-19-512529-0 607 pages citing to page 271 and reference , to wit: W. Christ and B. Esch, Adverse reactions to fluoroquinolones in adults and children. Infect Dis Clin Pract 1994;3 (Suppl 3). S168-S176 http://books.google.com/books?id=gACeB8XCnpgC&pg=PA271&lpg=PA271&dq=%22diplopia%22+%22quinolone%22&source=bl&ots=5Mcj9Hc-jm&sig=eZXYD15q5LPQ8EpFtsZgLeDrRMA&hl=en&ei=PTe0SbvYLIGCtwfZvpmtCQ&sa=X&oi=book_result&resnum=9&ct=result
- Poisoning and toxicology handbook By Jerrold B. Leikin, Frank P. Paloucek Edition: 4, illustrated Published by Informa Health Care, 2007 ISBN 1-4200-4479-6, ISBN 978-1-4200-4479-9 Page 503-504 / page 194
- "MedWatch Safety Alerts for Human Medical Products". Fda.gov. 2008-11-06. Retrieved 2011-03-29.
- [dead link]
- Gootz TD, Barrett JF, Sutcliffe JA (January 1990). "Inhibitory effects of quinolone antibacterial agents on eucaryotic topoisomerases and related test systems". Antimicrob. Agents Chemother. 34 (1): 8–12. doi:10.1128/AAC.34.1.8. PMC 171510. PMID 2158274.
- Thomas A, Tocher J, Edwards DI (May 1990). "Electrochemical characteristics of five quinolone drugs and their effect on DNA damage and repair in Escherichia coli". J. Antimicrob. Chemother. 25 (5): 733–44. doi:10.1093/jac/25.5.733. PMID 2165050.
- "Fluoroquinolones and Quinolones". The American Academy of Optometry (British Chapter). Archived from the original on 12 March 2009. Retrieved 29 January 2009.
- Hussy P, Maass G, Tümmler B, Grosse F, Schomburg U (June 1986). "Effect of 4-quinolones and novobiocin on calf thymus DNA polymerase alpha primase complex, topoisomerases I and II, and growth of mammalian lymphoblasts". Antimicrob. Agents Chemother. 29 (6): 1073–8. doi:10.1128/AAC.29.6.1073. PMC 180502. PMID 3015015.
- Forsgren A, Bredberg A, Pardee AB, Schlossman SF, Tedder TF (May 1987). "Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide biosynthesis and cell growth" (PDF). Antimicrob. Agents Chemother. 31 (5): 774–9. doi:10.1128/AAC.31.5.774. PMC 174831. PMID 3606077.
- Yaseen A. Al-Soud; Najim A. Al-Masoudi (2003). "A new class of dihaloquinolones bearing N'-aldehydoglycosylhydrazides, mercapto-1,2,4-triazole, oxadiazoline and a-amino ester precursors: synthesis and antimicrobial activity". J. Braz. Chem. Soc 14 (5): 790. doi:10.1590/S0103-50532003000500014. "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..."
- Elsea SH, Osheroff N, Nitiss JL (July 1992). "Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast". J. Biol. Chem. 267 (19): 13150–3. PMID 1320012.
- Lawrence JW, Darkin-Rattray S, Xie F, Neims AH, Rowe TC (February 1993). "4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210 leukemia cells". J. Cell. Biochem. 51 (2): 165–74. doi:10.1002/jcb.240510208. PMID 8440750.
- Enzmann H, Wiemann C, Ahr HJ, Schlüter G (April 1999). "Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver". Mutat. Res. 425 (2): 213–24. doi:10.1016/S0027-5107(99)00044-5. PMID 10216214.
- Yaseen A. Al-Soud a and Najim A. Al-Masoudi (2003). "A New Class of Dihaloquinolones Bearing N'-Aldehydoglycosylhydrazides, Mercapto-1,2,4-triazole, Oxadiazoline and α-Amino Ester Precursors: Synthesis and Antimicrobial Activity". J. Braz. Chem. Soc 14 (5): 790–796. doi:10.1590/S0103-50532003000500014. "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"
- Suto MJ, Domagala JM, Roland GE, Mailloux GB, Cohen MA (December 1992). "Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity". Journal of Medicinal Chemistry 35 (25): 4745–50. doi:10.1021/jm00103a013. PMID 1469702.
- Kashida Y, Sasaki YF, Ohsawa K, et al. (October 2002). "Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice". Toxicol. Sci. 69 (2): 317–21. doi:10.1093/toxsci/69.2.317. PMID 12377980.
- Verna LK, Holman SA, Lee VC, Hoh J (2000). "UVA-induced oxidative damage in retinal pigment epithelial cells after H2O2 or sparfloxacin exposure". Cell Biol. Toxicol. 16 (5): 303–12. doi:10.1023/A:1026798314217. PMID 11201054.
- Medical Drug Issues on the Open Directory Project
- Certain Antibiotics Spur Widening Reports of Severe Side Effects at PBS NewsHour