Please Note: This is a copy of the now removed Adverse Effects of Fluoroquinolones Wikipedia, it was merged with a much more “sanitized” version that downplays the adverse events. There has been a systematic attempt on the Internet to change FQAD from a very serious condition to a more benign version. You may find some of the information slightly outdated but the reference links are invaluable. I am in the process of slowly updating this very extensive article (page). It will take time so you may want to check back often.
The fluoroquinolones are synthetic broad-spectrum antibiotics. In general, the common side-effects are mild to moderate and self-limiting. However, occasional serious adverse effects can occur. A study performed by the United States Centers for Disease Control (CDC) estimated that adverse events leading to an emergency room visit occur at a rate of 9.2 for every 10,000 fluoroquinolone prescriptions. This rate is greater than that for cephalosporins (6.1 per 10,000) and macrolides (5.1 per 10,000), but less than for sulfonamides (18.9 per 10,000), penicillins (13 per 10,000), clindamycin (18.5 per 10,000), and vancomycin (24.1 per 10,000).
Rare serious adverse drug reactions (ADRs) associated with fluoroquinolones include central nervous system (CNS) toxicity, phototoxicity, cardiotoxicity, arthropathy, and tendon toxicity. Children and the elderly are at greater risk.Tendonopathy may manifest during, as well as sometimes long after fluoroquinolone therapy has been discontinued. Events that may occur in acute overdose are rare and include renal failure and seizure. Stopped Here
Broad spectrum antibiotics including fourth generation cephalosporins, clindamycin, and fluoroquinolones may facilitate colonisation with MRSA and C. difficile. Several professional healthcare organizations have recommended limiting the use of broad spectrum antibiotics. The Society for Healthcare Epidemiology of America recommends minimizing the use of fluroquinolones in institutions where MRSA is endemic. The European Center for Disease Prevention and Control recommends avoiding the use of broad spectrum antibiotics including cephalosporins, clindamycin and fluoroquinolones. In an Italian study, prior treatment with cephalosporins or fluoroquinolones was associated with a higher risk of MRSA infection than prior treatment with non-cephalosporin beta lactam antibiotics. In 2008, the most widely used fluoroquinolones in the United States included ciprofloxacin, levofloxacin and moxifloxacin. Many others have been removed from the market, at least in some countries, due to serious ADRs and safety concerns, including gatifloxacin in 2006, grepafloxacin in 2003, temafloxacin in 1992, trovafloxacin and alatrofloxacin. 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.
Only limited research has been conducted into the long-term effects of fluoroquinolones, making epidemiology statistics of the incidence of fluoroquinolone induced tendonopathy difficult to ascertain. The(FDA) has investigated received case reports for tendon rupture. Based on their analysis of case reports, they have concluded that fluoroquinolones may cause long-term damage in rare cases. A Swedish study found that fluoroquinolones occasionally cause peripheral neuropathy, which in a sizable proportion of cases was long-lasting. The total number of reported cases, however, was only 37.
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.
A meta-analysis for fluoroquinolones and skin infections found that fluoroquinolones are associated with more adverse reactions than beta lactams. However the increase was due to a higher rate of mild to moderate nausea and diarrhea. Side effects severe enough to cause withdrawal from the clinical trial occurred at similar rates.
Rarely, fluoroquinolone antibiotics have been associated with serious and detrimental effects on the musculoskeletal system, cardiovascular system, CNS and peripheral nervous system, circulatory system, maxillofacial system, endocrine system, gastrointestinal system, urological system, the liver, the brain, the skin, and the sensory systems; hearing, sight, taste, touch, and smell. Toxic reactions have been reported to occur after a single dose.
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, (although their use is not approved in this age group), 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, muscles, and cartilage. Concurrent use of NSAIDs may induce severe and prolonged seizures including status epilepticus. 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. However, levofloxacin, ofloxacin, ciprofloxacin, and moxifloxacin have all been reported to be associated with liver injuries such as hepatotoxicity, hepatic failure, and delayed and prolonged cholestatic hepatitis.
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.
Using ciprofloxacin to treat a toxic Escherichia coli infection related to serotype O157:H7 has been shown to increase the amount of Shiga toxin 2 (Stx2), the toxin that causes hemorrhagic colitis and hemolytic-uremic syndrome (HUS), produced by the bacteria. The toxin is produced by the cell due to a virus that infects the E. coli cell, inserts its genome into the host’s chromosome. The gene that codes for Stx2 is located in the late gene region of the viral genome and is not expressed while the cell is in a lysogenic stage. Ciprofloxacin induces the virus to enter the lytic cycle, where it replicates its genome and produces more viral particles. During this period, Stx2 is produced, and, when the cell lyses to release the viral particles, Stx2 is released as well.
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 include ruptures of various tendons (other than just the Achilles) and muscles, as well as damage to the cartilage and ligaments. Fluoroquinolones also have adverse effects on cartilage. 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.
As with any number of other drugs, drug induced fibromyalgia like symptoms are found with the fluoroquinolones. The multiskeletal adverse reactions of the fluoroquinolones may resemble rheumatological disease states, in particular, fibromyalgia, hypothyroidism, or rheumatoid arthritis. There have been numerous reports of fluoroquinolone-induced fibromyalgia. Fluoroquinolone-induced fibromyalgia may be conceptualized as impaired sensory information processing in a neural network, resulting in dysfunctional responses resulting from the CNS and PNS damage outlined above.
One of the most disabling adverse reactions is spontaneous rupture of multiple tendons, which may occur during therapy, as well as up to 6 months after therapy has been discontinued. Although the onset of symptoms typically occurs within 12 weeks, injury was also described within hours to as long as months after the initiation of treatment, and even after discontinuation. Tendon injury was reported to occur as early as two hours after receipt of the first dose of a fluoroquinolone (ciprofloxacin) to as late as 6 months after treatment had been terminated. Tendinitis, arthralgia, myalgia, as well as severe 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. For example:
November 1997 – November 2001—Ciprofloxacin 1,558 events
Bone, Tendon, Muscle and Ligament Damage
- Pain in the Extremity (153)
- Myalgia (148)
- Tendonitis (122)
November 1997 – November 2001—Levofloxacin 2,898 events
Bone, Tendon, Muscle and Ligament Damage
- Arthralgia (368)
- Tendon Disorders (318)
- Tendonitis (232)
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. Within the Netherlands, a large simultaneous increase in non-traumatic tendon ruptures and fluoroquinolone use was observed in the period between 1991 to 1996 following the introduction of the fluoroquinolones. The incidence of spontaneous tendon rupture within the kidney recipient population is even more common. In the renal transplant population, an 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.
It is rare that rhabdomyolysis (muscle death) occurs, sometimes with fatal outcomes. In Japan, the Pharmaceutical Affairs Bureau gave notice to practicing physicians that it had amended the product information to state that rhabdomyolysis may occur with the use of enoxacin, fleroxacin, norfloxacin, sparfloxacin, and tosufloxacin tosilate.
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. Very rare cases of suicidal behavior have been reported to occur, sometimes after a single dose. Drugs that induce suicidal ideation, including antibiotics, are associated with an increased risk of suicide attempts.
Fluoroquinolones can induce a wide range of serious adverse psychiatric effects. These reactions may manifest as extreme anxiety, panic attacks, depression, anhedonia, cognitive dysfunction (or brain fog), depersonalization, paranoia, hallucinations, toxic psychosis, seizures, tremors, taste perversions, abnormal dreams, chronic insomnia, vertigo, delirium, suicidal thoughts, and usually involves all five senses. For some people the symptoms resolve relatively soon after discontinuing the fluoroquinolone; for others, in the case of a neurotoxic effect, symptomatology may persist for months or even years after discontinuation. Fluoroquinolones are associated with a significant number of serious psychiatric events.
In addition, the fluoroquinolones may show depressant activity on the CNS, as was indicated by the depressant syndrome, decreased spontaneous motor activity, and hypothermia found in animal studies. Concomitant use of NSAIDs may increase seizure risk.
A positive correlation exists between the doses of fluoroquinolones and the prolongation (increases) in the caffeine elimination half-life. (In one case a sixfold increase).
Electrolyte imbalances are common with previous reports of fluoroquinolone-induced seizures.
The CNS ADRs are a combination of the interference with neurotransmissions (gamma-Aminobutyric acid or GABA), inhibiting of the clearance of other drugs (such as caffeine), reduction of brain glucose uptake, electrolyte imbalances, neuronal dysfunction or degeneration and inflammation. The fluoroquinolones are known as GABA inhibitors and as such have the ability to bind to neuroreceptor sites within the brain that appear to play a role in CNS adverse events. In recent years, extensive in vivo and in vitro experiments have been performed, and several mechanisms are thought to be responsible. The involvement of GABA and excitatory amino acid (EAA) neurotransmission as well as the kinetics of fluoroquinolone distribution in brain tissue are thought to be responsible.
Photosensitivity reactions as well as life-threatening cutaneous reactions have been reported with the fluoroquinolone class. Such reactions include Stevens–Johnson syndrome, Sweet’s syndrome, toxic epidermal necrolysis (TEN), and painful and disfiguring rashes. In 2008, Bayer issued a European “Dear Doctor Letter” advising physicians of the risk of potentially life-threatening bullous skin reactions like Stevens-Johnson-Syndrome (SJS) or toxic epidermal necrolysis (TEN) associated with moxifloxacin (Avelox).
Ciprofloxacin-induced toxic epidermal necrolysis was first reported in 1991 with numerous other cases in the following years. Levofloxacin, Norfloxacin, Ofloxacin, and Trovan have also been associated with toxic epidermal necrolysis.
There have been reports of the association between Steven-Johnson’s syndrome and ciprofloxacin, with one case reporting that the syndrome was induced by a single dose of ciprofloxacin. To our knowledge, as of 1997, a total of 6 cases have been reported in the literature documenting an association between oral ciprofloxacin administration and toxic epidermal necrolysis (TEN) or Stevens–Johnson syndrome. A review performed in Sweden (circa 2003) found a total of nine cases. Together with previous data from the literature, these reports support the view that ciprofloxacin, as well as other fluoroquinolones, has the potential to cause fatal or severe adverse cutaneous events.
Photosensitivity reactions reported with the fluoroquinolones mimic those of sunburn, with erythema and edema in the milder forms, and painful blistering with subsequent peeling when severe. A wide spectrum of cutaneous ADRs are reported with fluoroquinolones.
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.
A previous dematologic ADR to a fluoroquinolone can sensitize a patient to more severe adverse reactions (with onset after only a single dose of the subsequent fluoroquinolone), as noted earlier in this presentation. This is also true of other commonly used antibacterial classes, including the penicillins and cephalosporins. Patients having developed any kind of rash to a fluoroquinolone in the past have a potential to develop life-threatening photoallergic reactions when re-challenged with a fluoroquinolone drug later on in life.
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.
Fluoroquinolones have been shown since 1998 to cause irreversible peripheral neuropathy. Typical symptoms involve fasciculations, paresthesia, tinnitus, hyperacusis, and other sensorimotor problems. Symptoms usually occur after a delayed onset, and continue to worsen. Quinolone-induced peripheral neuropathy usually presents as burning pain and numbness, and in some cases this becomes an irreversible condition that disables the patient for life. Most often this is the result of quinolone-induced damage to the peripheral nervous system (as noted above), manifesting as painful burning, cold, stinging, tingling paresthesias, or numbness. This may also result from muscle and tendon damage as well if the pain is of a burning or stabbing nature upon use of the limb affected. The exact manner in which the fluoroquinolones cause such PNS damage remains elusive. Several theories point to direct toxicity or vascular involvement. Peripheral neuropathy has been associated with the fluoroquinolone class since 1988 and has been reported in the leading medical journals for over two decades.
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 significant number 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). There are spontaneous reports of cases of double vision (diplopia) becoming permanent, as well as reports of floaters that never resolved in some patients.
There have also been isolated reports of reversible vision loss and irreversible blindness associated with oral fluoroquinolone therapy. Retinal degeneration has also been observed in animals. These reports, while uncommon, include blindness, temporary blindness, partial blindness, and mydriasis. There have also been three reports of serious macular detachment of the neuro-epithelium involving flumequine.
Fluoroquinolones displayed the potential to be cytotoxic to human corneal keratocytes and endothelial cells, depending on drug concentration and duration of exposure. The potential for cytotoxicity may differ among fluoroquinolones.
Hearing loss appears to be a very rare event, while fluoroquinolone-induced tinnitus appears to be far more common. Both oral use and IV use of the fluoroquinolones have been reported to cause hearing loss, decreased hearing acuity, hypoacusis, and tinnitus. The package inserts for the majority of the fluoroquinolones in use today all list tinnitus as post marketing events. Specific fluoroquinolones list the loss of hearing as reported events. Within the AERS maintained by the FDA, hearing loss, tinnitus, decreased hearing acuity, and hypoacusis have all been reported with the fluoroquinolone class. There have also been isolated case reports of ototoxicity leading to reversible and irreversible deafness as a result of oral or IV therapy. There have been spontaneous reports of fluoroquinlone-induced tinnitus being permanent, together with loss of hearing in the higher frequencies.
There have been studies showing some in vitro ototoxicity potential in fluoroquinolones. Within a 1992 animal study involving Long Evan rats, nalidixic acid showed partial loss of the outer hair cells of the organ of Corti in the cochlea, suggesting that nalidixic acid has slight ototoxicity.The package insert for Ofloxacin otic solution list the loss of hearing as reported events. There has also been a case report associating the use of Ciprofloxacin ear drops and seizures. Nevertheless, the fluoroquinolone eardrop solutions are believed to be non-ototoxic and are preferred over the known ototoxic aminoglycoside antibiotics, in the topical treatment of ear infections.
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.
- ^ Shehab N, Patel PR, Srinivasan A, Budnitz DS (September 2008). “Emergency Department Visits for Antibiotic-Associated Adverse Events” (PDF). Clin. Infect. Dis. 47 (6): 735–43. doi:10.1086/591126. PMID 18694344.
- ^ a b c d e f De Sarro A, De Sarro G (March 2001). “Adverse reactions to fluoroquinolones. an overview on mechanistic aspects”. Curr. Med. Chem. 8 (4): 371–84. PMID 11172695.
- ^ a b 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.
- ^ a b 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.
- ^ a b 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.
- ^ a b 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.
- ^ a b 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.
- ^ a b 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.
- ^ Carroll DN, Carroll DG (May 2008). “Interactions between warfarin and three commonly prescribed fluoroquinolones”. Ann Pharmacother 42 (5): 680–5. doi:10.1345/aph.1K605. PMID 18413687.
- ^ Schmid, Randolph E. (May 1, 2006). “Drug Company Taking Tequin Off Market”. Associated Press. Retrieved 2006-05-01.
- ^ Food and Drug Administration; DEPARTMENT OF HEALTH AND HUMAN SERVICES (9 July 2007). “Otsuka Pharmaceutical Co., Ltd. Withdrawal of Approval of a New Drug Application; Correction” (PDF). Federal Register (USA: US Government Printing Office) 72 (130).
- ^ a b 
- ^ “Trovafloxacin and alatrofloxacin: suspended: Spain”. WHO Pharmaceuticals Newsletter (World Health Organisation) 07 (8). 1999.
- ^ “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”.
- ^ a b 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.
- ^ van der Linden PD, van Puijenbroek EP, Feenstra J, et al. (June 2001). “Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998”. Arthritis Rheum. 45 (3): 235–9. doi:10.1002/1529-0131(200106)45:3<235::AID-ART254>3.0.CO;2-7. PMID 11409663.
- ^ a b 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.
- ^ “FDA orders ‘black box’ label on some antibiotics”. CNN. 8 July 2008. Archived from the original on 10 July 2008. Retrieved 2008-07-08.
- ^ 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 Chemistry6: 49–56.
- ^ Karageorgopoulos, DE.; Giannopoulou, KP.; Grammatikos, AP.; Dimopoulos, G.; Falagas, ME. (Mar 2008). “Fluoroquinolones compared with β-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials”. CMAJ 178 (7): 845–54. doi:10.1503/cmaj.071157. PMC 2267830. PMID 18362380.
- ^ a b c d e f g h i j k l m 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.
- ^ Bertino J, Fish D (July 2000). “The safety profile of the fluoroquinolones”. Clin Ther 22 (7): 798–817; discussion 797. doi:10.1016/S0149-2918(00)80053-3. PMID 10945507.
- ^ 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.
- ^ 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.
- ^ a b c Kushner JM, Peckman HJ, Snyder CR (October 2001). “Seizures associated with fluoroquinolones”. Ann Pharmacother 35 (10): 1194–8. doi:10.1345/aph.10359. PMID 11675843.
- ^ a b c d e f Mehlhorn AJ, Brown DA (November 2007). “Safety concerns with fluoroquinolones”. Ann Pharmacother 41 (11): 1859–66. doi:10.1345/aph.1K347. PMID 17911203.
- ^ “(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. 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.
- ^ “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.
- ^ a b c d e 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.
- ^ a b 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.
- ^ 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 (2011 Sep). “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. 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”. Ann Pharmacother 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.
- ^ a b Gamage, Shantini D.; et al., JE; Chalk, CL; Weiss, AA (June 2003). “Nonpathogenic Escherichia coli Can Contribute to the Production of Shiga Toxin”. Infection and Immunity 71 (6): 3107–3115. doi:10.1128/IAI.71.6.3107-3155.2003. PMC 155771. PMID 12761088
- ^ Wagner, P.L.; et al., MN; Zhang, X; Acheson, DW; Waldor, MK; Friedman, DI (2001). “Role for a Phage Promoter in Shiga Toxin 2 Expression from a Pathogenic Escherichia coli Strain”. Journal of Bacteriology 183 (6): 3081–2085. doi:10.1128/JB.183.6.2081-2085.2001. PMC 95105. PMID 11222608
- ^ 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.
- ^ Bertin P, Gillet P, Treves R, Netter P (1998). “[Do some drugs have adverse effects on cartilage?]”. Therapie (in French) 53 (1): 17–20. PMID 9773095.
- ^ “UpToDate Inc.”.
- ^ “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.
- ^ di Fazano CS, Bertin P (October 2001). “The pharmacological management of drug-induced rheumatic disorders”. Expert Opin Pharmacother 2 (10): 1623–31. doi:10.1517/146565126.96.36.1993. PMID 11825305.
- ^ Vergne P, Bertin P, Bonnet C, Scotto C, Trèves R (October 2000). “Drug-induced rheumatic disorders: incidence, prevention and management”. Drug Saf 23 (4): 279–93. doi:10.2165/00002018-200023040-00002. PMID 11051216.
- ^ Wahle M, Krause A, Pierer M, Hantzschel H, Baerwald CG (June 2002). “Immunopathogenesis of rheumatic diseases in the context of neuroendocrine interactions”. Ann. N. Y. Acad. Sci. 966: 355–64. doi:10.1111/j.1749-6632.2002.tb04235.x. PMID 12114292.
- ^ 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.
- ^ Jagose JT, McGregor DR, Nind GR, Bailey RR (December 1996). “Achilles tendon rupture due to ciprofloxacin”. N. Z. Med. J. 109 (1035): 471–2. PMID 9006634.
- ^ 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.
- ^ van der Linden PD, Nab HW, Simonian S, Stricker BH, Leufkens HG, Herings RM (June 2001). “Fluoroquinolone use and the change in incidence of tendon ruptures in the Netherlands”. Pharm World Sci 23 (3): 89–92. doi:10.1023/A:1011254030271. PMID 11468881.
- ^ 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.
- ^ 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.
- ^ Nakamae H, Hino M, Yamane T, Ohta K, Aoyama Y, Kumura T, Sannomiya Y, Tatsumi N. (September 2000). A Case of Rhabdomyolysis due to Levofloxacin 20 (3). pp. 203–205.
- ^ a b Baril L, Maisonobe T, Jasson-Molinier M, Haroche J, Bricaire F, Caumes E (December 1999). “Acute rhabdomyolysis during treatment with ofloxacin-a case report”. Clin. Infect. Dis. 29 (6): 1598–9. doi:10.1086/313551. PMID 10585836.
- ^ Petitjeans F, Nadaud J, Perez JP, et al. (December 2003). “A case of rhabdomyolysis with fatal outcome after a treatment with levofloxacin”. Eur. J. Clin. Pharmacol. 59 (10): 779–80. doi:10.1007/s00228-003-0688-x. PMID 14576967.
- ^ Hsiao SH, Chang CM, Tsao CJ, Lee YY, Hsu MY, Wu TJ (January 2005). “Acute rhabdomyolysis associated with ofloxacin/levofloxacin therapy”. Ann Pharmacother 39 (1): 146–9. doi:10.1345/aph.1E285. PMID 15562138.
- ^ Nea Zealand Government (26 June 2003). “Adverse Reaction Reporting and IMMP”. New Zealand: Medsafe. Retrieved 30 January 2009.
- ^ (JPNARD) Information on Adverse Reactions to Drugs, No.128, , Oct 1994
- ^ “Tavanic SPC”. Sanofi-aventis.
- ^ Robertson, HT.; Allison, DB.; Wright, James M. (2009). “Drugs Associated with More Suicidal Ideations Are also Associated with More Suicide Attempts”. In Wright, James M. PLoS ONE 4 (10): e7312. doi:10.1371/journal.pone.0007312. PMC 2749439. PMID 19798416.
- ^ Cohen JS (December 2001). “Peripheral Neuropathy Associated with Fluoroquinolones” (PDF). Ann Pharmacother 35 (12): 1540–7. doi:10.1345/aph.1Z429. PMID 11793615.
- ^ Doussau de Bazignan A, Thiessard F, Miremont-Salamé G, Conri C, Haramburu F (June 2006). “[Psychiatric adverse effects of fluoroquinolone: review of cases from the French pharmacologic surveillance database]”. Rev Med Interne (in French) 27 (6): 448–52. doi:10.1016/j.revmed.2006.02.003. PMID 16580096.
- ^ Rollof J, Vinge E (September 1993). “Neurologic adverse effects during concomitant treatment with ciprofloxacin, NSAIDS, and chloroquine: possible drug interaction”. Ann Pharmacother 27 (9): 1058–9. PMID 8219437.
- ^ 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.
- ^ Harder S, Staib AH, Beer C, Papenburg A, Stille W, Shah PM (1988). “4-quinolones inhibit biotransformation of caffeine”. Eur. J. Clin. Pharmacol. 35 (6): 651–6. doi:10.1007/BF00637602. PMID 2853056.
- ^ Ge DT, Law PY, Kong SK, Ho YY (January 2009). “Disturbance of cellular glucose transport by two prevalently used fluoroquinolone antibiotics ciprofloxacin and levofloxacin involves glucose transporter type 1”. Toxicol. Lett. 184 (2): 81–4. doi:10.1016/j.toxlet.2008.10.017. PMID 19022360.
- ^ Roos K (August 2006). “Inflammatory diseases and infection”. Curr. Opin. Neurol. 19 (4): 339–40. doi:10.1097/01.wco.0000236611.28721.5d. PMID 16914970.
- ^ Dodd PR, Davies LP, Watson WE, et al. (May 1989). “Neurochemical studies on quinolone antibiotics: effects on glutamate, GABA and adenosine systems in mammalian CNS”. Pharmacol. Toxicol. 64 (5): 404–11. doi:10.1111/j.1600-0773.1989.tb00676.x. PMID 2771865.
- ^ Tham TC, Allen G, Hayes D, McGrady B, Riddell JG (August 1991). “Possible association between toxic epidermal necrolysis and ciprofloxacin”. Lancet 338 (8765): 522. doi:10.1016/0140-6736(91)90602-L. PMID 1678488.
- ^ Urbina, F; Barrios, M; Sudy, E (Apr 2006). “Photolocalized purpura during ciprofloxacin therapy”. Photodermatology, photoimmunology & photomedicine 22 (2): 111–2. doi:10.1111/j.1600-0781.2006.00210.x. ISSN 0905-4383. PMID 16606417.
- ^ Rodríguez-Morales, A; Llamazares, Aa; Benito, Rp; Cócera, Cm (Apr 2001). “Fixed drug eruption from quinolones with a positive lesional patch test to ciprofloxacin”. Contact dermatitis 44 (4): 255. doi:10.1034/j.1600-0536.2001.440409-10.x. ISSN 0105-1873. PMID 11336009.
- ^ a b c Christie, Mj; Wong, K; Ting, Rh; Tam, Py; Sikaneta, Tg (May 2005). “Generalized seizure and toxic epidermal necrolysis following levofloxacin exposure”. The Annals of pharmacotherapy 39 (5): 953–5. doi:10.1345/aph.1E587. ISSN 1060-0280. PMID 15827068.
- ^ Moshfeghi, M; Mandler, Hd (Dec 1993). “Ciprofloxacin-induced toxic epidermal necrolysis”. The Annals of pharmacotherapy 27 (12): 1467–9. ISSN 1060-0280. PMID 8305780.
- ^ Digwood-Lettieri S, Reilly KJ, Haith LR, et al. (June 2002). “Levofloxacin-induced toxic epidermal necrolysis in an elderly patient”. Pharmacotherapy 22 (6): 789–93. doi:10.1592/phco.22.9.789.34074. PMID 12066972.
- ^ Digwood-Lettieri, S; Reilly, Kj; Haith, Lr, Jr; Patton, Ml; Guilday, Rj; Cawley, Mj; Ackerman, Bh (Jun 2002). “Levofloxacin-induced toxic epidermal necrolysis in an elderly patient”. Pharmacotherapy 22 (6): 789–93. doi:10.1592/phco.22.9.789.34074. ISSN 0277-0008. PMID 12066972.
- ^ Sahin, Mt; Ozturkcan, S; Inanir, I; Filiz, Ee (Apr 2005). “Norfloxacin-induced toxic epidermal necrolysis”. The Annals of pharmacotherapy 39 (4): 768–70. doi:10.1345/aph.1E530. ISSN 1060-0280. PMID 15713789.
- ^ Melde, Sl (Nov 2001). “Ofloxacin: a probable cause of toxic epidermal necrolysis”. The Annals of pharmacotherapy 35 (11): 1388–90. doi:10.1345/aph.1Z433. ISSN 1060-0280. PMID 11724089.
- ^ Matthews MR, Caruso DM, Phillips BJ, Csontos LG (October 1999). “Fulminant toxic epidermal necrolysis induced by trovafloxacin”. Arch. Intern. Med.159 (18): 2225. doi:10.1001/archinte.159.18.2225. PMID 10527301.
- ^ Gohel DR, Oza JJ (August 1994). “Steven-Johnson’s syndrome following single dose of ciprofloxacin”. J Assoc Physicians India 42 (8): 665. PMID 7868575.
- ^ Livasy, Ca; Kaplan, Am (1997). “Ciprofloxacin-induced toxic epidermal necrolysis: a case report”. Dermatology (Basel, Switzerland) 195 (2): 173–5. doi:10.1159/000245726. ISSN 1018-8665. PMID 9310730.
- ^ 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.
- ^ 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.
- ^ a b “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.
- ^ 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”. Ann Pharmacother 35 (12): 1540–7. doi:10.1345/aph.1Z429. PMID 11793615.
- ^ a b 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.
- ^ http://www.fda.gov/ohrms/dockets/ac/98/briefingbook/1998-3454B1_03_WL49.pdf
- ^ 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.
- ^ 
- ^ http://vistakonpharmaceutical.com/pdf/iquix_pi.pdf
- ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21571_iquix_lbl.pdf
- ^ Fraunfelder, Fw; Fraunfelder, Ft (Jul 2009). “Diplopia and Fluoroquinolones”. Ophthalmology 116 (9): 1814–7. doi:10.1016/j.ophtha.2009.06.027. ISSN 0161-6420. PMID 19643481.
- ^ Vrabec TR, Sergott RC, Jaeger EA, Savino PJ, Bosley TM (June 1990). “Reversible visual loss in a patient receiving high-dose ciprofloxacin hydrochloride (Cipro)”. Ophthalmology 97 (6): 707–10. PMID 2374675.
- ^ “Case Presentation – Moxifloxacin (Avelox)”. written at Canada (PDF). Canadian Adverse Drug Reaction Newsletter. October 2002. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v12n4-eng.pdf. Retrieved on 30 January 2009.
- ^ Gelatt KN, van der Woerdt A, Ketring KL, et al. (June 2001). “Enrofloxacin-associated retinal degeneration in cats”. Vet Ophthalmol 4 (2): 99–106. doi:10.1046/j.1463-5224.2001.00182.x. PMID 11422990.
- ^ Shimoda K, Okawara S, Kato M (September 2001). “Phototoxic retinal degeneration and toxicokinetics of sitafloxacin, a quinolone antibacterial agent, in mice”. Arch. Toxicol. 75 (7): 395–9. doi:10.1007/s002040100263. PMID 11693179.
- ^ Sirbat D, Saudax E, Hurault de Ligny B, Hachet E, Raspiller A (1983). “[Serous macular detachment of the neuro-epithelium and flumequine]”. J Fr Ophtalmol (in French) 6 (10): 829–36. PMID 6672059.
- ^ Bezwada P, Clark LA, Schneider S (February 2008). “Intrinsic cytotoxic effects of fluoroquinolones on human corneal keratocytes and endothelial cells”. Curr Med Res Opin 24 (2): 419–24. doi:10.1185/030079908X261005. PMID 18157922.
- ^ a b Moxifloxacin (Avelox) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021085s039,021277s033lbl.pdf Ciprofloxacin (Cipro) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf Ofloxacin (Floxin) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019735s059lbl.pdf Levofloxacin (Levaquin) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021721s020_020635s57_020634s52_lbl.pdf Norfloxacin (Noroxin) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019384s052lbl.pdf Proquin XR package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021744s008lbl.pdf Sparfloxacin (Zagam) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/020677s006lbl.pdf Cinoxacin (Cinobac) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18067s29lbl.pdf Equin (Solage) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020922s003lbl.pdf Ofloxacin otic package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019735s059lbl.pdf
- ^ Paul J, Brown NM (July 1995). “Tinnitus and ciprofloxacin”. BMJ 311 (6999): 232. PMC 2550285. PMID 7627041.
- ^ Ciprofloxacin (Cipro) package insert:http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdfOfloxacin otic package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20799slr012_floxin_lbl.pdf Norfloxacin (Noroxin) package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019384s052lbl.pdf Proquin XR package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021744s008lbl.pdf
- ^ http://www.fdable.com/basic_query/aers/7e829e140dd289c9dec44e9541ca7846 (ciprofloxacin) http://www.fdable.com/basic_query/aers/cf0caad8d6cdfcab19e88d5f0bec72a0 (moxifloxacin) http://www.fdable.com/basic_query/aers/4d2af494063504d3bf8c9559180915cc (ofloxacin) http://www.fdable.com/basic_query/aers/5fc512f95c82788f16456a4a4853dfcd (levofloxacin) http://www.fdable.com/basic_query/aers/97cfd7d5bcdeabe2bbaf89d4d2c7a3da (norfloxacin) http://www.fdable.com/basic_query/aers/714e096436dd911b78b410cb28b1a07e (cinoxacin)
- ^ ^ “Ciprofloxacin: suspected association with deafness and reduced hearing” (PDF). Canadian Adverse Reaction Newsletter (Health Canada) 14 (1). January 2004. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v14n1-eng.pdf. Retrieved on 18 February 2009.
- ^ Russell PT, Church CA, Jinn TH, Kim DJ, John EO, Jung TT (January 2001). “Effects of common topical otic preparations on the morphology of isolated cochlear outer hair cells”. Acta Otolaryngol. 121 (2): 135–9. doi:10.1080/000164801300043208. PMID 11349764.
- ^ Ophthalmotoxicity and ototoxicity of the new quinolone antibacterial agent levofloxacin in Long Evans rats. Nomura M, Yamada M, Yamamura H, Kajimura T, Takayama S. Drug Safety Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
- ^ Orr, Cf; Rowe, Db (Apr 2003). “Eardrop attacks: seizures triggered by ciprofloxacin eardrops”. The Medical journal of Australia 178 (7): 343. ISSN 0025-729X. PMID 12670280.
- ^ ^ Coats H (April 2008). “Ear drops and ototoxicity”. Australian Prescriber 31 (2): 40–1. http://www.australianprescriber.com/magazine/31/2/40/1/
- ^ 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”. J. Med. Chem. 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