Adverse effects of fluoroquinolones 1

Adverse effects of fluoroquinolones

Adverse effects offluoroquinolones

Classification and external resources

ICD-10 Y40.8

ICD-9 E930.8 [1]

The fluoroquinolones are synthetic broad-spectrum antibiotics. In general, the common side-effects are mild tomoderate and self-limiting. However, occasional serious adverse effects can occur. A study performed by the UnitedStates Centers for Disease Control (CDC) estimated that adverse events leading to an emergency room visit occur ata rate of 9.2 for every 10,000 fluoroquinolone prescriptions. This rate is greater than that for cephalosporins (6.1 per10,000) and macrolides (5.1 per 10,000), but less than for sulfonamides (18.9 per 10,000), penicillins (13 per10,000), 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 greaterrisk.[][] Tendonopathy may manifest during, as well as sometimes long after fluoroquinolone therapy has beendiscontinued.[] Events that may occur in acute overdose are rare and include renal failure and seizure.[]

Broad spectrum antibiotics including fourth generation cephalosporins, clindamycin, and fluoroquinolones mayfacilitate colonisation with MRSA and C. difficile. Several professional healthcare organizations have recommendedlimiting the use of broad spectrum antibiotics. The Society for Healthcare Epidemiology of America recommendsminimizing the use of fluroquinolones in institutions where MRSA is endemic.[] The European Center for DiseasePrevention 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 wasassociated with a higher risk of MRSA infection than prior treatment with non-cephalosporin beta lactamantibiotics.[] In 2008, the most widely used fluoroquinolones in the United States included ciprofloxacin,levofloxacin and moxifloxacin.[2] Many others have been removed from the market, at least in some countries, due toserious ADRs and safety concerns, including gatifloxacin in 2006,[3] grepafloxacin in 2003,[4] temafloxacin in1992,[5] trovafloxacin and alatrofloxacin.[6] Other quinolones have had their licensed indications restricted in certaincountries due to toxicity issues. These include sparfloxacin in 1995,[7] norfloxacin in 2008[8] and moxifloxacin in2008.[9]

Only limited research has been conducted into the long-term effects of fluoroquinolones, making epidemiologystatistics of the incidence of fluoroquinolone induced tendonopathy difficult to ascertain.[][10] The(FDA) hasinvestigated received case reports for tendon rupture. Based on their analysis of case reports, they have concludedthat fluoroquinolones may cause long-term damage in rare cases. A Swedish study found that fluoroquinolonesoccasionally cause peripheral neuropathy, which in a sizable proportion of cases was long-lasting. The total numberof reported cases, however, was only 37.[][]

BackgroundFluoroquinolones are often effective as antibacterial agents. They are recommended for a number of serious bacterialinfections, and, in some cases of life-threatening infections, they can be life-saving.[11][12] The distinction between aquinolone drug and a fluoroquinolone drug is the addition of the fluorine atom to the basic pharmacophore, resultingin a fluorinated drug.[13] The terms fluoroquinolone and quinolone are often used interchangeably, without regard tothis distinction.

Adverse effects of fluoroquinolones 2

A meta-analysis for fluoroquinolones and skin infections found that fluoroquinolones are associated with moreadverse reactions than beta lactams. However the increase was due to a higher rate of mild to moderate nausea anddiarrhea. 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 musculoskeletalsystem, 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 interactionsCertain patient groups are at increased risk of fluoroquinolone ADRs. A 1998 retrospective survey of the use of thefluoroquinolones in the pediatric population showed that the fluoroquinolones were oftentimes prescribed inchildren, (although their use is not approved in this age group), and that numerous serious side effects had beenrecorded.[14] Fluoroquinolones are not recommended in patient groups that are predisposed to adverse events (forexample, because of diabetes, G6PD deficiency, renal impairment, myasthenia gravis, previous psychiatric, seizuredisorder, 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 extravigilance for adverse reactions. There is also an increased risk of adverse events in the elderly, including tendonruptures and seizures. Use in children or pregnant or breast-feeding women is not recommended and should beavoided. In the UK, the prescribing indications for fluoroquinolones for children is severely restricted. Only inhalantanthrax and pseudomonal infections in cystic fibrosis infections are licensed indications in the UK due to ongoingsafety concerns. At the first sign of psychiatric, neurological, peripheral neuropathy, tendonitis, or hypersensitivityreactions, fluoroquinolones should be discontinued. Quinolones are contraindicated in patients having had previousquinolone-related tendinopathy. Dose, length of time, and number of exposures to fluoroquinolones, as well ascombination with corticosteroids, NSAIDs, or theophylline, increase the risk adverse reactions. Concurrent use ofcorticosteroids increases the risk of multiskeletal injury, manifesting as chronic tendonitis or spontaneous ruptures oftendons, muscles, and cartilage. Concurrent use of NSAIDs may induce severe and prolonged seizures includingstatus epilepticus.[][15][16][][][17] Most cases of fluoroquinolone-precipitated seizures occur in the elderly or thosewith severe cerebral arteriosclerosis, epilepsy, brain tumour, anoxia, and alcohol dependence, as well as those takingtheophylline or the NSAIDs.[] Those who are benzodiazepine-dependent or in benzodiazepine withdrawal have ahigher rate of adverse severe CNS effects possibly due to fluoroquinolones' displacement of benzodiazepines fromtheir receptor site or pre-existing GABA underactivity due to withdrawal, thus leading to an increased sensitivity tofluoroquinolone toxicity.[18][19][20][21] Articaine may worsen certain symptoms in an individual with fluoroquinolonetoxicity. 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 dentalprocedures involving patients having had adverse reactions to the fluoroquinolones.[22] Broad spectrum antibacterialsincluding cephalosporins, Fluoroquinolones (and clindamycin) have been associated with Clostridium difficile, apotentially life-threatening super-infection.[] Use of quinolones is also highly associated with colonisation withMRSA compared to some other antibiotic classes.[][] Shigella toxin expression in EHEC infections has been shownto be upregulated following fluoroquinolone administration.[23] Fluoroquinolones can have serious and potential fatalreaction when taken with certain other drugs. Some agents decrease theophylline clearance and thus increasetoxicity.[] Warfarin is affected by many many drugs including fluoroquinolones and frequency of INR monitoringneeds to be increased in those prescribed both agents.[24]

Adverse effects of fluoroquinolones 3

Adverse reactions and toxicities

Adverse reactionsThe 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), hemolyticuremic syndrome (temafloxacin), and eosinophilic pneumonitis are thought to be specific to individual agents and assuch not considered to be a class effect.[] However, levofloxacin, ofloxacin, ciprofloxacin, and moxifloxacin have allbeen reported to be associated with liver injuries such as hepatotoxicity, hepatic failure, and delayed and prolongedcholestatic hepatitis.[][25][26]

Mechanism of toxicityThe mechanisms of the toxicity of fluoroquinolones has been attributed to their interactions with different receptorcomplexes such as blockade of the GABAa receptor complex within the central nervous system, leading toexcitotoxic type effects[] and oxidative stress.[]

GastrointestinalNausea and vomiting are the most common side-effect of the fluoroquinolones.[] The group of side-effects includesnausea, vomiting, abdominal pain, diarrhea, and taste disturbance, which occur in about 2-20% of people takingfluoroquinolones.[] This rate is similar to those seen with azithromycin and cefixime.[] The highest rates occurredamong 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 areassociated with an increased risk of pseudomembranous colitis[27][28][29][30]

The spectrum of this disease ranges from asymptomatic carrier state to life-threatening pseudomembranous colitisand toxic megacolon. Pathogenesis of pseudomembranous colitis results from the suppression of the naturalmicroflora of the colon by broad spectrum antibiotics, which creates an environment favorable for C. difficileproliferation. A Clostridium difficile infection is the principal cause of nosocomial, antibiotic-associated diarrhea,and pseudomembranous colitis. C. difficile can be fatal if left untreated.[31][32][33][34]

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 carefuluse, especially in acute hospitals, has been suggested.[35][36][37]

Using ciprofloxacin to treat a toxic Escherichia coli infection related to serotype O157:H7 has been shown toincrease the amount of Shiga toxin 2 (Stx2), the toxin that causes hemorrhagic colitis and hemolytic-uremicsyndrome (HUS), produced by the bacteria.[] The toxin is produced by the cell due to a virus that infects the E. colicell, inserts its genome into the host's chromosome. The gene that codes for Stx2 is located in the late gene region ofthe viral genome and is not expressed while the cell is in a lysogenic stage.[38] Ciprofloxacin induces the virus toenter the lytic cycle, where it replicates its genome and produces more viral particles. During this period, Stx2 isproduced, and, when the cell lyses to release the viral particles, Stx2 is released as well.[]

Musculoskeletal SystemJoint 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.[][39] Fluoroquinolones also have adverse effects on cartilage.[40] The risk of tendon disorders with fluoroquinolone use is 0.1% to 0.4%[] or 3 cases per 1000 patient-years of exposure.[41]

These problems usually start 13 days after treatment was started and may possibly persist for a month.[] Risk of

Adverse effects of fluoroquinolones 4

tendon rupture is even less with only 38 of 46,000 people treated with fluoroquinolone suffering a rupture of theachilles. 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 lungtransplant recipients.[42] Because of their possible negative effect on cartilage, they are not recommended for use inpregnant women or children.[] The FDA recommends stopping treatment, contacting a physician and resting affectedlimbs 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, inparticular, fibromyalgia, hypothyroidism, or rheumatoid arthritis. There have been numerous reports offluoroquinolone-induced fibromyalgia.[43][44] Fluoroquinolone-induced fibromyalgia may be conceptualized asimpaired sensory information processing in a neural network, resulting in dysfunctional responses resulting from theCNS and PNS damage outlined above.[45]

One of the most disabling adverse reactions is spontaneous rupture of multiple tendons, which may occur duringtherapy, as well as up to 6 months after therapy has been discontinued.[46][47] Although the onset of symptomstypically occurs within 12 weeks, injury was also described within hours to as long as months after the initiation oftreatment, and even after discontinuation. Tendon injury was reported to occur as early as two hours after receipt ofthe first dose of a fluoroquinolone (ciprofloxacin)[48] to as late as 6 months after treatment had beenterminated.[49][50] Tendinitis, arthralgia, myalgia, as well as severe joint, muscle, and tendon pain, are found to bethe top-three adverse reactions reported to the FDA via the Adverse Event Reporting System (AERS)[51] for all thedrugs within this class. For example:November 1997 – November 2001—Ciprofloxacin 1,558 eventsBone, Tendon, Muscle and Ligament Damage

•• Pain in the Extremity (153)•• Myalgia (148)•• Tendonitis (122)November 1997 – November 2001—Levofloxacin 2,898 eventsBone, 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.[52]

Within the Netherlands,[53] a large simultaneous increase in non-traumatic tendon ruptures and fluoroquinolone usewas observed in the period between 1991 to 1996 following the introduction of the fluoroquinolones. The incidenceof spontaneous tendon rupture within the kidney recipient population is even more common.[54] In the renaltransplant population, an incidence of 12.2%–15.6% is reported, compared with 0.6%–3.6% for transplant recipientsnot receiving fluoroquinolones.[55][56] In one study of 149 heart transplant patients,[] fourteen (9.5%) patientsdeveloped Achilles tendinopathy, which in three patients (2.25%) progressed to tendon rupture.It is rare that rhabdomyolysis (muscle death) occurs, sometimes with fatal outcomes.[57][][][58][59][60] In Japan, thePharmaceutical Affairs Bureau gave notice to practicing physicians that it had amended the product information tostate that rhabdomyolysis may occur with the use of enoxacin, fleroxacin, norfloxacin, sparfloxacin, and tosufloxacintosilate.[61]

Adverse effects of fluoroquinolones 5

CNS effectsAny 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.[] Neweragents to have a lower risk of side-effects have been found.[] Seizures are rare, and usually occur when they do inthose with an underlying CNS disorder.[] However, caution use in patient with epilepsy is still advised.[] Very rarecases of suicidal behavior have been reported to occur, sometimes after a single dose.[62] Drugs that induce suicidalideation, including antibiotics, are associated with an increased risk of suicide attempts.[63]

Fluoroquinolones can induce a wide range of serious adverse psychiatric effects. These reactions may manifest asextreme 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 resolverelatively 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 witha significant number of serious psychiatric events.[64]

In addition, the fluoroquinolones may show depressant activity on the CNS, as was indicated by the depressantsyndrome, decreased spontaneous motor activity, and hypothermia found in animal studies. Concomitant use ofNSAIDs may increase seizure risk.[65]

A positive correlation exists between the doses of fluoroquinolones and the prolongation (increases) in the caffeineelimination half-life. (In one case a sixfold increase).[66][67]

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 orGABA), inhibiting of the clearance of other drugs (such as caffeine),[68] reduction of brain glucose uptake,[69]

electrolyte imbalances,[] neuronal dysfunction[70] or degeneration and inflammation. The fluoroquinolones areknown as GABA inhibitors and as such have the ability to bind to neuroreceptor sites within the brain that appear toplay 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 beresponsible.[][71]

Dermatological effectsPhotosensitivity reactions as well as life-threatening cutaneous reactions have been reported with thefluoroquinolone class. Such reactions include Stevens–Johnson syndrome, Sweet's syndrome, toxic epidermalnecrolysis (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[72] with numerous other cases in thefollowing years.[73][74][][75] Levofloxacin,[][76][77] Norfloxacin,[78] Ofloxacin,[79] and Trovan[80] have also beenassociated with toxic epidermal necrolysis.There have been reports of the association between Steven-Johnson's syndrome and ciprofloxacin, with one casereporting that the syndrome was induced by a single dose of ciprofloxacin.[81] To our knowledge, as of 1997, a totalof 6 cases have been reported in the literature documenting an association between oral ciprofloxacin administrationand toxic epidermal necrolysis (TEN) or Stevens–Johnson syndrome.[82] A review performed in Sweden (circa2003) found a total of nine cases. Together with previous data from the literature, these reports support the view thatciprofloxacin, as well as other fluoroquinolones, has the potential to cause fatal or severe adverse cutaneousevents.[83]

Adverse effects of fluoroquinolones 6

Photosensitivity reactions reported with the fluoroquinolones mimic those of sunburn, with erythema and edema inthe milder forms, and painful blistering with subsequent peeling when severe. A wide spectrum of cutaneous ADRsare reported with fluoroquinolones.The phototoxic potentials of fluoroquinolones are influenced not only by the substituent at position 8 (Halogenationat position C8) but also by those at position 1. Drugs such as Lomefloxacin and Sparfloxcacin, with a C8-fluorinesubstituent, and Clinafloxacin, with a C8-chlorine substituent, exhibit a greater incidence of phototoxic reactionsthan drugs without this substituent.[84] Clinafloxacin was subsequently removed from clinical use due to severephototoxicity reactions and in June 1995 The Medicines Agency restricted the use of Sparfloxacin due to the largenumber of reports of phototoxicity associated with its use.[85]

A previous dematologic ADR to a fluoroquinolone can sensitize a patient to more severe adverse reactions (withonset after only a single dose of the subsequent fluoroquinolone), as noted earlier in this presentation.[] This is alsotrue of other commonly used antibacterial classes, including the penicillins and cephalosporins. Patients havingdeveloped any kind of rash to a fluoroquinolone in the past have a potential to develop life-threatening photoallergicreactions when re-challenged with a fluoroquinolone drug later on in life.

PNS effectsPeripheral neuropathy has been rarely reported. Symptoms may include paresthesia (tingling), hypoesthesia(numbness), dysesthesia (pain), and weakness.[] Therapy should be discontinued if any neurological symptomsdevelop in order to prevent the occurrence of a possible irreversible condition.[] Rare cases of sensory impairmentinvolving taste or smell have been reported with a number of fluoroquinolones and may last for up to severalmonths.[86]

Fluoroquinolones have been shown since 1998 to cause irreversible peripheral neuropathy. Typical symptomsinvolve fasciculations, paresthesia, tinnitus, hyperacusis, and other sensorimotor problems. Symptoms usually occurafter a delayed onset, and continue to worsen. Quinolone-induced peripheral neuropathy usually presents as burningpain and numbness, and in some cases this becomes an irreversible condition that disables the patient for life. Mostoften this is the result of quinolone-induced damage to the peripheral nervous system (as noted above), manifestingas painful burning, cold, stinging, tingling paresthesias, or numbness. This may also result from muscle and tendondamage as well if the pain is of a burning or stabbing nature upon use of the limb affected. The exact manner inwhich the fluoroquinolones cause such PNS damage remains elusive. Several theories point to direct toxicity orvascular involvement. Peripheral neuropathy has been associated with the fluoroquinolone class since 1988 and hasbeen reported in the leading medical journals for over two decades.[][87][88]

In 2004, the FDA added warnings to the package inserts about the possibility of irreversiblefluoroquinolone-innduced peripheral neuropathy.

CardiacFluoroquinolones can cause QT prolongation and, thus, predispose a person to Torsades de Pointes which issometimes 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 QTprolongation.[]

Blood disordersBlood abnormalities are believed to occur in less than one percent of patients.[] However, Temafloxacin wasremoved from clinical use in 1992 due to its side-effects of hemolytic anemia (destruction of red blood cells) andother blood cell abnormalities; kidney dysfunction requiring renal dialysis (in 50% of patients affected); and severeliver dysfunction.[5]

Adverse effects of fluoroquinolones 7

Blood sugar abnormalitiesChanges in blood sugar levels may occur with fluoroquinolones. Risks for this complication includes diabetes, oldage, renal failure, and sepsis. Gatifloxacin was removed from the market in the US and Canada partly due to itsnegative effects on blood sugar.[] Temafloxacin was removed from clinical use in 1992 partially due to several casesof low blood sugar as well.[89]

Ocular toxicity•• Oral and IV useOral 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 colordistortion and diplopia (double vision).[90] Such disturbances may present as blurred and dim vision, disturbedvision, flashing lights, diplopia, floaters,as well as decreased visual acuity and cataracts.[91] Norfloxacin, ProQuinXR and Ciprofloxacin have also been associated with diplopia.,[92][93][94] as well as Iquix (levofloxacin ophthalmicsolution).[95][96] There are spontaneous reports of cases of double vision (diplopia) becoming permanent, as well asreports of floaters that never resolved in some patients.[97]

There have also been isolated reports of reversible vision loss and irreversible blindness associated with oralfluoroquinolone therapy.[98][99] Retinal degeneration has also been observed in animals.[100] These reports, whileuncommon, include blindness, temporary blindness, partial blindness, and mydriasis.[101] There have also been threereports of serious macular detachment of the neuro-epithelium involving flumequine.[102]

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 amongfluoroquinolones.[103]

Hearing effects•• Oral and IV useHearing 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.[104][105] The package inserts for the majority of the fluoroquinolones in use today[104] alllist tinnitus as post marketing events. Specific fluoroquinolones[106] list the loss of hearing as reported events. Withinthe AERS maintained by the FDA, hearing loss, tinnitus, decreased hearing acuity, and hypoacusis have all beenreported with the fluoroquinolone class.[107] There have also been isolated case reports of ototoxicity leading toreversible and irreversible deafness as a result of oral or IV therapy.[108] There have been spontaneous reports offluoroquinlone-induced tinnitus being permanent, together with loss of hearing in the higher frequencies.•• Otic use (ear drops)There have been studies showing some in vitro ototoxicity potential in fluoroquinolones.[109] Within a 1992 animalstudy involving Long Evan rats, nalidixic acid showed partial loss of the outer hair cells of the organ of Corti in thecochlea, suggesting that nalidixic acid has slight ototoxicity.[110] The package insert for Ofloxacin otic solution listthe loss of hearing as reported events. There has also been a case report associating the use of Ciprofloxacin eardrops and seizures.[111] Nevertheless, the fluoroquinolone eardrop solutions are believed to be non-ototoxic and arepreferred over the known ototoxic aminoglycoside antibiotics, in the topical treatment of ear infections.[112]

Adverse effects of fluoroquinolones 8

DNA effectsThe fluoroquinolones exert their therapeutic effects by interfering with bacterial DNA replication by inhibiting anenzyme complex called DNA gyrase. Research has indicated that fluoroquinolones at therapeutically used doseshave little effect on enzymes involved in DNA replication in mammalian cells including human cells; however, notall subtypes of eucaryotic topoisomerases have been routinely studied in clinical studies.[113][114][115] In vitro studiesin human fibroblast cells have shown that nalidixic acid can impair repair type DNA synthesis at a relatively lowdosage (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.[116] Fluoroquinolones increase the uptake of deoxyuridine,uridine, and thymidine into the DNA of human lymphocytes and decrease pyrimidine production. A reduction inleucine occurs. With some quinolones, these effects appear to occur at therapeutic dose levels. Quinolones alsoappear 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 thatwould be seen in clinical practice.[117][118][119][120][121] Some quinolones have been shown to be capable of causinginjury to the chromosome of eukaryotic cells.[122] As such, some fluoroquinolones may cause injury to thechromosome of eukaryotic cells. There is some debate in the medical literature as to whether these DNA effects areto be considered one of the mechanisms of action concerning some of the severe ADRs and toxicities experienced bysome patients following fluoroquinolone therapy. It has been speculated that the effects of fluoroquinolones onhuman eukaryotic topoisomerases have potential to cause cytotoxicity. Fluoroquinolones may have the potential tocause clastogenicity and the induction of micronuclei.[123][124] Retinal pigment epithelial cells are critical to thefunctioning of the eye and are involved in many eye diseases. In one study, DNA damage to RPE cells was observedwith Sparfloxacin.[125]

References[1] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=E930. 8[5] (http:/ / www. fda. gov/ bbs/ topics/ NEWS/ NEW00279. html)[51][51] Summaries received from the FDA under the Freedom of Information Act. Accessed November of 2001[61][61] (JPNARD) Information on Adverse Reactions to Drugs, No.128, , Oct 1994[89] http:/ / www. fda. gov/ ohrms/ dockets/ ac/ 98/ briefingbook/ 1998-3454B1_03_WL49. pdf[91] 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 [160], to wit: W. Christ and B. Esch, Adversereactions 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

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Adverse effects of fluoroquinolones 9

Levofloxacin (Levaquin) package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2008/021721s020_020635s57_020634s52_lbl. pdfNorfloxacin (Noroxin) package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2008/019384s052lbl. pdfProquin XR package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2008/ 021744s008lbl. pdfSparfloxacin (Zagam) package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2003/020677s006lbl. pdfCinoxacin (Cinobac) package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2002/ 18067s29lbl.pdfEquin (Solage) package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2007/ 020922s003lbl. pdfOfloxacin otic package insert:[106] Ciprofloxacin (Cipro) package insert:http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2008/

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Ofloxacin otic package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2003/20799slr012_floxin_lbl. pdfNorfloxacin (Noroxin) package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2008/019384s052lbl. pdfProquin XR package insert: http:/ / www. accessdata. fda. gov/ drugsatfda_docs/ label/ 2008/ 021744s008lbl. pdf[107] 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)

[108] ^ "Ciprofloxacin: suspected association with deafness and reduced hearing" (PDF). Canadian Adverse Reaction Newsletter (HealthCanada) 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.

[110][110] 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.

[112] ^ Coats H (April 2008). "Ear drops and ototoxicity". Australian Prescriber 31 (2): 40–1. http:/ / www. australianprescriber. com/ magazine/31/ 2/ 40/ 1/

External links• Adverse effects of fluoroquinolones (http:/ / www. dmoz. org/ Society/ Issues/ Health/ Drugs/ Medical/ ) at the

Open Directory Project• Certain Antibiotics Spur Widening Reports of Severe Side Effects (http:/ / www. pbs. org/ newshour/ bb/ health/

jan-june11/ antibiotics_06-16. html) at PBS NewsHour

Article Sources and Contributors 10

Article Sources and ContributorsAdverse effects of fluoroquinolones  Source: http://en.wikipedia.org/w/index.php?oldid=558855199  Contributors: 4meter4, A Bertheim, AManWithNoPlan, Acdx, Alfred Bertheim, Allens,Angiotensinogen, Arcadian, Ariel., BD2412, Budageek, Cabazap, Chowbok, CopperKettle, Corruptcopper, Da5id1, Davidtfull, Dbcipro, Dcirovic, Doctorfluffy, Dougher, Download,Drphilharmonic, Eastlaw, EoGuy, Fiftytwo thirty, Flopster2, Ground Zero, Hal peridol, Hwang.joshua, J04n, JamesLockson, Jmh649, Jon123nyc, LeadSongDog, Lightning23x, LilHelpa, Lmatt,MagmaManiac, Mandarax, Marianna Fink, Marinersfan08, Mashford, MikeJamie, MrADHD, Nima1024, RDBrown, Rhadamante, Rich Farmbrough, Rjwilmsi, Scientiae Defensor, Scray, Serrin,ShelfSkewed, Shisha-Tom, Smodtactical, Sreejiraj, Tim1357, Ultra Venia, Whosasking, Δ, 31 anonymous edits

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