Adverse effects of fluoroquinolones

Adverse effects of fluoroquinolones
Classification and external resources
ICD-10	Y40.8
ICD-9	E930.8

The adverse effects of fluoroquinolones are the negative and sometimes serious effects that may occur as a result of fluoroquinolone use. The fluoroquinolones are synthetic broad-spectrum antibiotics. In general, the common side-effects are mild to moderate and self-limiting. On occasion, serious adverse effects occur. Some of the serious adverse drug reactions (ADRs) that occur more commonly with fluoroquinolones than with other antibiotic drug classes include central nervous system (CNS) toxicity, phototoxicity, cardiotoxicity, arthropathy, and tendon toxicity.^[1][2] Children and the elderly are at greater risk.^[1][2] ADRs may manifest during, as well as sometimes long after fluoroquinolone therapy has been discontinued.^[3] Events that may occur in acute overdose are rare and include renal failure and seizure.^[4]

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).^[5]

Quinolones and other broad spectrum antibiotics such as fourth generation cephalosporins and clindamycin rank among the highest for risk of causing colonisation with MRSA and C. difficile. Several professional healthcare organizations have recommended limiting the use of fluoroquinolines and/or other broad spectrum antibiotics. The Society for Healthcare Epidemiology of America recommends minimizing the use of fluroquinolones in institutions where MRSA is endemic.^[6] The European Center for Disease Prevention and Control recommends avoiding the use of broad spectrum antibiotics including cephalosporins, clindamycin and fluoroquinolones.^[7] In an Italian study, prior treatment with fluoroquinolones was associated with a higher risk of MRSA infection than prior treatment with non-cephalosporin beta lactam antibiotics. The risk associated was similar to that of broad spectrum cephalosporins.^[8] In 2008, the most widely used fluoroquinolones in the United States included ciprofloxacin, levofloxacin and moxifloxacin.^[9] Many others have been removed from the market, at least in some countries, due to serious ADRs and safety concerns, including gatifloxacin in 2006,^[10] grepafloxacin in 2003,^[11] temafloxacin in 1992,^[12] trovafloxacin and alatrofloxacin.^[13] Other quinolones have had their licensed indications restricted in certain countries due to toxicity issues. These include sparfloxacin in 1995,^[14] norfloxacin in 2008^[15] and moxifloxacin in 2008.^[16]

Only limited research has been conducted into the long-term effects of fluoroquinolones, making epidemiology statistics of the incidence of fluoroquinolone toxicity difficult to ascertain.^[17][18] Therefore, controversy has emerged with large groups of people claiming to be suffering from quinolone toxicity from quinolone derivatives such as quinolone antibiotics and the antiprotozoal quinolone derivative mefloquine (Lariam).^[19][20][21] It has also been found that many of the clinical trials are funded by the manufacturer and conducted by people with ties to the manufacturer, which has the potential to bias the results of trial data. This is true for other antibiotic classes as well, and is unlikely to affect estimates of the relative risk associated with fluoroquinolones compared to other antibiotic classes. The risk of under-reporting of adverse events is offset to some degree by the FDAs requirement for oversight by independent institutional review boards (IRBs). The U.S. Food and Drug Administration (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 during a period in which approximately 10 million doses were prescribed. For comparison, about 30 out of every 10 million Americans die in an automobile accident each day.^[22][23] The controversy over the nature and severity of ADRs, particularly long-lasting ones, concerns the lack of long-term follow-up studies.^[24][25][26]

Contents 1 Background 2 Risk factors and interactions 3 Adverse reactions and toxicities 3.1 Adverse reactions 3.2 Gastrointestinal 3.3 Musculoskeletal System 3.4 CNS effects 3.5 Dermatological effects 3.6 PNS effects 3.7 Cardiac 3.8 Blood disorders 3.9 Blood sugar abnormalities 3.10 Ocular toxicity 3.11 Hearing effects 4 DNA effects 5 Associated fatalities 6 Controversy 7 References 8 External links

Background

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.^[27][28] 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.^[29] The terms fluoroquinolone and quinolone are often used interchangeably, without regard to this distinction.^[30] With the increasing use of this class of antibiotics, even in sometimes benign indications, an increasing number of patients are exposed to the risk of ADRs.^[31]

Fluoroquinolone ADRs 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. There have been no studies that have followed up patients long term after completing fluoroquinolone therapy to assess the rate of severe and persisting adverse events. Thus, it is impossible to conclude scientifically what proportion of patients experience fluoroquinolone toxicity and long-term harm. However, a survey of members of an online support group for individuals harmed by fluoroquinolones and reviews of their medical history have been conducted to ascertain the nature of these adverse effects. For some, the side-effects resolve over a period of weeks or months after discontinuation of fluoroquinolones, but, for a number of patients, symptoms can persist for many months or years. For others, symptoms never completely abate and may become permanent in nature. Some of the symptoms can be disabling and very distressing. Whilst people of all ages may experience severe and prolonged adverse drug reactions to the fluoroquinolones, the elderly and especially the young are particularly more susceptible to the toxic effects of fluoroquinolones, and their use in these populations is oftentimes discouraged. Toxic reactions have been reported to occur after a single dose.^[19][32][33]

A meta-analysis of clinical trials for bacterial sinusitus found conflicting findings between blinded (placebo-controlled) and unblinded clinical trials. Blinded trials were associated with higher rates of adverse effects than other antibiotic classes, whereas unblinded clinical trials founded the opposite. However, it was emphasised that the analysis of blinded trials is the most reliable analysis. Lower rates of serious adverse reactions were found for fluoroquinolones. Although individuals having a predisposition to the serious fluoroquinolone adverse effects were excluded from the selection process of the trials for ethical reasons, this is uniformly true in antibiotic clinical trials and is unlikely to affect comparisons between antibiotic classes. Some of the serious adverse effects are rare and only become detectable in post-marketing surveillance, which occurred with gatifloxacin, which was withdrawn from the market due to serious adverse effects on blood glucose. This adverse event was not detected in a clinical trial of gatifloxacin of 290 people, and, thus, bigger trials are needed to detected some of the more rare but serious adverse effects. A further concern was that almost all of the clinical trials were financed and carried out by people paid by the manufacturers. This is true for other classes of antibiotics as well, and is unlikely to bias the comparative safety conclusions for different antibiotic classes. Another 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.^[34]

Risk factors and interactions

Serious adverse reactions can occur in any patient. For example fluoroquinolones induced convulsions can occur in patients with or without a history of convulsions. However, 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.^[35] 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.^{[32][36][37][38][39][40]} 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.^[1] 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.^{[41][42][43][44]} 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.^[45] Fluoroquinolones (and clindamycin) are not recommended as first-line drugs and should be avoided in clinical practice whenever possible due to their high association with Clostridium difficile, a potentially life-threatening super-infection.^[7] Use of quinolones is also highly associated with colonisation with MRSA compared to other antibiotic classes, and avoidance of quinolones is also recommended based on available evidence and clinical guidelines to reduce MRSA infection rates.^[6][8] Shigella toxin expression in EHEC infections has been shown to be upregulated following fluoroquinolone administration.^[46] Fluoroquinolones can have serious and potential fatal reaction when taken with certain other drugs. Some agents decrease theophylline clearance and thus increase toxicity.^[47] Warfarin is also affected by many fluoroquinolones and frequency of INR monitoring needs to be increased in those prescribed both agents.^[48]

Adverse reactions and toxicities

Adverse reactions

The most common adverse effects of the fluoroquinolones involve the gastrointestinal tract, skin, CNS, and PNS. They are for most patients mild and reversible.^[47] 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.^[32] 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.^[49][50][51]

Gastrointestinal

Nausea and vomiting are the most common side-effect of the fluoroquinolones.^[47] The group of side-effects includes nausea, vomiting, abdominal pain, diarrhea, and taste disturbance, which occur in about 2-20% of people taking fluoroquinolones.^[32] This rate is similar to those seen with azithromycin and cefixime.^[47] The highest rates occurred among older agents, which have been discontinued. Newer agents have lower rate of GI side-effects.^[32] Like with all antibiotics, C. difficile diarrhea (CDAd) has been associated with fluoroquinolones.^[32][39] When compared to other antibiotics, however, the risk of CDAD was found to be 2.5 times greater.^[39] Fluoroquinolones are associated with an increased risk of pseudomembranous colitis^{[52][53][54][55]}

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 fluoroquinolones suppression of the natural microflora of the colon, which creates an environment favorable for C. difficile proliferation. A Clostridium difficile infection is the principal cause of nosocomial, fluoroquinolone-associated diarrhea, and pseudomembranous colitis. C. difficile can be fatal if left untreated.^{[56][57][58][59]}

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.^[60][61][62]

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.^[63] 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.^[64] 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.^[63]

Musculoskeletal System

Joint pain and swelling occurs in approximately 1% of people taking fluoroquinolones and usually remits within days of stopping treatment.^[32] 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.^[3][65] Fluoroquinolones also have adverse effects on cartilage.^[66] The risk of tendon disorders with fluoroquinolone use is 0.1% to 0.4%^[39] or 3 cases per 1000 patient-years of exposure.^[67] These problems usually start 13 days after treatment was started and may possibly persist for a month.^[32] 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.^[17] The achilles is the most common tendon affected.^[39] This risk is greatest in those older than 60, in those taking corticosteroid drugs, and in kidney, heart, and lung transplant recipients.^[68] Because of their possible negative effect on cartilage, they are not recommended for use in pregnant women or children.^[69] The FDA recommends stopping treatment, contacting a physician and resting affected limbs if these adverse events occur.^[32]

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.^[70][71] 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.^[72]

One of the most disabling adverse reactions is spontaneous rupture of multiple tendons, which may occur during therapy, as well as years after therapy has been discontinued.^[73][74] 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)^[75] to as late as 6 months after treatment had been terminated.^[76][77] 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)^[78] 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.^[79] Within the Netherlands,^[80] 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 authors of that study stated that the relative risk of suffering a spontaneous tendon rupture subsequent to fluoroquinolone therapy would be between 1.5 to 10.0 times what occurs in the general public not exposed to fluoroquinolones. The incidence of spontaneous tendon rupture within the kidney recipient population is even more common.^[81] 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.^[82][83] In one study of 149 heart transplant patients,^[84] 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.^{[85][86][86][87][88][89]} 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.^[90]

CNS effects

Any CNS side-effect occurs with an incidence of 1–2 %.^[32] CNS side-effects have been found to occur more frequently with fluoroquinolones. Adverse event reporting for antibiotics found that 12.2% of adverse reaction reports concerning fluoroquinolones involved the CNS versus 3.6% for other antibiotics.^[32] Newer agents to have a lower risk of side-effects have been found.^[47] Seizures are rare, and usually occur when they do in those with an underlying CNS disorder.^[32] However, caution use in patient with epilepsy is still advised.^[32] Very rare cases of suicidal behavior have been reported to occur, sometimes after a single dose.^[91] Drugs that induce suicidal ideation, including antibiotics, are associated with an increased risk of suicide attempts.^[92]

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.^[1][19] Fluoroquinolones are associated with a significant number of serious psychiatric events.^[93]

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.^[94]

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).^[95][96]

Electrolyte imbalances are common with previous reports of fluoroquinolone-induced seizures.^[38]

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),^[97] reduction of brain glucose uptake,^[98] electrolyte imbalances,^[38] neuronal dysfunction^[99] 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.^[1][100]

The fluoroquinolones have been implicated in manifestation of strokes.^[101][102] A study assessing number of strokes in people over 65 found the following rate of strokes per antibiotic prescribed. The number of strokes (per 1,000 person-years) were 9.27 for the fluoroquinolones as compared to 8.58 for trimethoprim-sulfamethoxazole, 7.97 for cephalosporins, 7.49 for tetracyclines, 6.88 for penicillins, 6.64 for macrolides, and 7.29 for subjects with no antibiotic claims.^[103]

Dermatological effects

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).^[49]

Ciprofloxacin-induced toxic epidermal necrolysis was first reported in 1991^[104] with numerous other cases in the following years.^{[105][106][107][108]} Levofloxacin,^{[107][109][110]} Norfloxacin,^[111] Ofloxacin,^[112] and Trovan^[113] 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.^[114] 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.^[115] 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.^[116]

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.^[117] 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.^[118] However, severe rashes are class effects of the fluoroquinolones due to hypersensitivity, regardless of any structural modifications of the drug.

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.^[107] This is also true of other commonly used antibacterial classes, including the penicilins 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.

It is to be noted that, within the clinical studies submitted with the initial submission of NDA 21-158 for Factive (gemifloxacin), a higher-than-expected rate of rash was noted in these clinical studies. During the course of the NDA review of Factive (gemifloxacin), significant questions regarding the safety of gemifloxacin arose.^[119] In spite of the additional risk of the patient's developing toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome as well as Sweet's Syndrome, the FDA approved the drug in 2003 after rejecting the drug in 2001 due to the concerns regarding such ADRs.^[120][121] In 2006, the FDA convened another panel to take yet another look at the safety profile of Factive.^[122][123]

The public record of the FDA meeting in which these rashes were discussed revealed several occasions in which the members of the panel laughed out loud at patients reporting such rashes and ridiculed them even though the risk of rashes associated with Factive are greater than those seen in other fluoroquinolones, especially for women undergoing treatment with Factive.^[124]

PNS effects

Peripheral neuropathy has been rarely reported. Symptoms may include paresthesia (tingling), hypoesthesia (numbness), dysesthesia (pain), and weakness.^[125] Therapy should be discontinued if any neurological symptoms develop in order to prevent the occurrence of a possible irreversible condition.^[125] 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.^[126]

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.^{[22][127][128]}

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

Cardiac

Fluoroquinolones can cause QT prolongation and, thus, predispose a person to Torsades de Pointes.^[4] Some member of the quinolone family are likely to causes an increased QT than others.^[129] 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 very low risk of QT prolongation.^[129]

Blood disorders

Blood abnormalities are believed to occur in less than one percent of patients.^[130] 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.^[12]

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.^[39] Temafloxacin was removed from clinical use in 1992 partially due to several cases of low blood sugar as well.^[131]

Ocular toxicity

• Oral and IV use

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).^[132] Such disturbances may present as blurred and dim vision, disturbed vision, flashing lights, diplopia, floaters,as well as decreased visual acuity and cataracts.^[133] Norfloxacin, ProQuin XR and Ciprofloxacin have also been associated with diplopia.,^{[134][135][136]} as well as Iquix (levofloxacin ophthalmic solution).^[137][138] There are spontaneous reports of cases of double vision (diplopia) becoming permanent, as well as reports of floaters that never resolved in some patients.^[139][140]

Chloroquine is also a member of the quinolone family and has been linked to manifestations of retinal toxicity. In 1958, Cambiaggi first described the classic retinal pigment changes in a patient receiving chloroquine for systemic lupus erythematous (SLE) treatment. In 1959, Hobbs established a definite link between long-term use of chloroquine and subsequent development of retinal pathology. In the United States, despite the variability of the statistics, the incidence of retinopathy increased with both the dose and the duration of treatment. Bernstein estimated an incidence of 10% in unmonitored patients taking 250 mg/d of chloroquine.^[141] It is well known that the older quinolones, such as nalidixic acid, may affect the eye as a potential target organ.^[142] In this connection alteration of the lens or melanin-containing eye tissues (retina, iris, ciliary body) have been reported.

There have also been isolated reports of reversible vision loss and irreversible blindness associated with oral fluoroquinolone therapy.^[143][144] Retinal degeneration has also been observed in animals.^[145][146] These reports, while uncommon, include blindness, temporary blindness, partial blindness, and mydriasis.^[147] While for some patients symptoms resolve relatively soon after discontinuing fluoroquinolone, others reported vision problems that persisted for months or years after discontinuation. In some cases this was permanent.^[139] There have also been three reports of serious macular detachment of the neuro-epithelium involving flumequine.^[148]

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.^[149]

• Ophthalmic use

Serious complications are more likely to occur with ophthalmic fluoroquinolone therapy, especially corneal perforation, but also evisceration and enucleation. Corneal perforation occurred most commonly in elderly patients with deep ulcers. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in stromal collagen, leading to a reduction in tectonic strength.^[150][151] An in vitro study assessing the ocular toxicity potential of antibiotics compared a fluoroquinolone against an aminoglycoside antibiotic and found that the fluoroquinolone Ofloxacin was significantly more toxic to stromal human keratocytes.^[152] In regards to ophthalmic use, the relative effects of Ofloxacin on stromal keratocytes had also shown ofloxacin to be more toxic than netilmicin.^[153] Brown et al. stated, again in reference to ophthalmic use, that “serious complications such as corneal perforation, evisceration, or enucleation of the affected eye occurred in 16.7% of patients receiving fluoroquinolone, compared with only 2.4% of patients receiving fortified antibiotic therapy.” The authors of that review estimated those patients taking fluoroquinolones had an 8.9-fold increased risk of serious complications.^[154] Iquix (levofloxacin ophthalmic solution) has also been rarely associated with diplopia.^[138] There have also been a significant number of reports concerning corneal deposits after administration of topical fluoroquinolones.^{[151][155][156][157][158][159]} Gatifloxacin, a fourth-generation fluoroquinolone, can cause intrastromal macroscopic crystalline deposits through a compromised corneal epithelium, similar to what has been described for ciprofloxacin.^[160]

Hearing effects

• Oral and IV use

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.^[161][162] The package inserts for the majority of the fluoroquinolones in use today^[161] all list tinnitus as post marketing events. Specific fluoroquinolones^[163] 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.^[164] There have also been isolated case reports of ototoxicity leading to reversible and irreversible deafness as a result of oral or IV therapy.^[165] There have been spontaneous reports of fluoroquinlone-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.^[166] 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.^[167] 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.^[168] 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.^[169]

DNA effects

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.^{[170][171][172]} 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.^[173] 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.^{[174][175][176][177][178]} Some quinolones have been shown to be capable of causing injury to the chromosome of eukaryotic cells.^[179] 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.^[180][181] 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.^[182]

Associated fatalities

A significant number of fatalities have been associated with this class. Trovan (Trovafloxacin), Raxar (Grepafloxacin), Omniflox (Temafloxacin), and most recently Tequin (Gatifloxacin) have all been removed from clinical use due to such fatalities. Within the latest ADR summaries for Levaquin, Floxin, Cipro, Avelox, and Factive obtained under the freedom of information act from the FDA (December 2008) ^[183] there are 2,661 total death outcomes by case:

• 1038 to be found within the Ciprofloxacin (Cipro) summary,^[184]

• 944 to be found within the Levofloxacin (Levaquin) summary,^[185]

• 337 to be found within the Moxifloxacin (Avelox) summary,^[186]

• 335 to be found within the Floxin (Ofloxacin) summary,^[187]

• 7 to be found within the Gemifloxacin (Factive) summary.^[188]

The FDA notes that reports submitted to the Adverse Event Reporting System have not been and are not verified. The exact wording of the disclaimer found on all ADR summaries provided by the FDA reads as follows:

"Disclaimer: The information contained in these reports has not been scientifically or otherwise verified as to a cause and effect relationship and cannot be used to estimate the incident of adverse drug reactions."^[186]

As such, the information being provided by the FDA cannot be relied upon to estimate the frequency, or the actual number, of fatalities found within this class. The exact number of such fatalities, or frequency of such events, cannot be determined at this time due to the lack of sufficient post-marketing surveillance, and the FDA's current policy of not attempting verification of the reports they receive. It is further complicated by the fact that only a small proportion of adverse reactions tend to be reported to regulatory bodies. Fatalities have also been reported to the FDA with regard to other antibiotics other than those of this class, as well as other drugs currently in clinical use today. These include an estimated 300-500 deaths each year from anaphylactoid reactions to penicillins and cephalosporins.^[189]

Controversy

Fluoroquinolone toxicity^[190][191] or quinolone toxicity^[192][193] is the long term^[84] or serious physical and mental ADRs that can occur from use of fluoroquinolones. Some support and campaign related groups refer to these adverse events as "fluoroquinolone toxicity syndrome" or to being "floxed". Certain members of these groups (not all) report suffering non-abating injury or long-term medical complications as a direct result of fluoroquinolone therapy. Others fully recovered within weeks, months, or years. The remainder stated their recovery was eventually obtained to a certain degree but with some symptoms remaining.^[19][194] There have been class action lawsuits by individuals alleging their health was damaged by fluoroquinolones; and Public Citizen, a consumer advocacy group, has sued the FDA over this issue.^{[195][196][197][198][199][200][201]} Adverse event reporting in Italy by doctors showed fluoroquinolones among the top-three prescribed drugs for adverse neurological and psychiatric adverse effects. These neuropsychiatric effects included tremor, confusion, anxiety, insomnia, agitation, and, in severe cases, psychosis. Moxifloxacin came out worst among the quinolones for causing CNS toxicity. The central nervous system is an important target for fluoroquinolone-mediated neurotoxicity.^[202]

The Fluoroquinolone Toxicity Research Foundation is one such non-profit organization (as referenced above) that believes that the rate and severity of ADRs to fluoroquinolones have been grossly misrepresented by the manufacturers as well as by the Food and Drug Administration and that the medical community has been intentionally misled regarding these adverse reactions. This organization and some physicians believe that fluoroquinolones should not be used as a first-line antibiotic for any disease state if an equally effective alternative antibiotic exists. The Foundation is an outspoken critic of these drugs, has been collecting research on them for almost a decade, and has stated on their website FQresearch.org since 2001 that they believe that the prescription abuse of fluoroquinolones needs to be urgently curtailed to reduce the incidence of severe ADRs as well as increasing bacterial resistance.^{[203][204][205]} The Fluoroquinolone Toxicity Research Foundation have also been vocal critics of attempts to expand the use of fluoroquinolones in children.^[206]

Public Citizen has also been active in trying to increase awareness of the potential toxicity of fluoroquinolones. Within Public Citizen's publication Worst Pills, Best Pills, a number of fluoroquinolones are listed as "Do Not Use" products.^[207] As a result of the efforts of the Fluoroquinolone Toxicity Research Foundation, Public Citizen and the Attorney General of Illinois, the FDA recommended black box warnings be placed on oral and injectable fluoroquinolones advising consumers of the potentially toxic effects of fluoroquinolones on tendons.^{[23][208][209][210][211][212]}

Musculoskeletal, tendon injury, joint and muscle pain, and a range of CNS symptoms are the most well-known adverse reactions associated with fluoroquinolones. Dr. Jay S. Cohen, M.D., Adjunct Associate Professor of Family and Preventive Medicine, and of Psychiatry, University of California, and Dr. David Flockhart, M.D., Ph.D, Chief of the Division of Clinical Pharmacology, Indiana University School of Medicine, have both expressed serious concerns about the adverse effect profile of fluoroquinolones. Dr. Flockhart believes that up to 30% of people receiving intravenous ciprofloxacin and 10% receiving oral therapy will experience CNS adverse effects that may be mild or moderate; however, in some cases the CNS adverse effects have potential to be very serious. Peripheral effects such as tingling, burning pain, twitching, or spasms are also associated with fluoroquinolone adverse effects. Part of the controversy is that these adverse effects are often not connected with fluoroquinolones by the doctor or the patient. The lack of awareness can be serious as some of the adverse reactions require prompt discontinuation of fluoroquinolones to prevent serious or even permanent toxicity from occurring.^[213][214]

A close chemical cousin of fluoroquinolones, lariam also has a controversial history concerning adverse effects. Lariam is an antimicrobial and a quinolone derivative.^[215] It is used in the treatment of protozoal infections of malaria.^[216]

References

External links

• Adverse effects of fluoroquinolones at the Open Directory Project
• Certain Antibiotics Spur Widening Reports of Severe Side Effects at PBS NewsHour

Antibacterials: nucleic acid inhibitors (J01E, J01M) Antifolates (inhibits purine metabolism, thereby inhibiting DNA and RNA synthesis) DHFR inhibitor 2,4-Diaminopyrimidine (Trimethoprim#, Brodimoprim, Tetroxoprim, Iclaprim†) Sulfonamides (DHPS inhibitor) Short- acting Sulfaisodimidine • Sulfamethizole • Sulfadimidine • Sulfapyridine • Sulfafurazole • Sulfanilamide (Prontosil) • Sulfathiazole • Sulfathiourea Intermediate- acting Sulfamethoxazole • Sulfadiazine# • Sulfamoxole Long- acting Sulfadimethoxine • Sulfalene • Sulfametomidine • Sulfametoxydiazine • Sulfamethoxypyridazine • Sulfaperin • Sulfamerazine • Sulfaphenazole • Sulfamazone Other/ungrouped sulfanilamide (Sulfacetamide, Sulfametrole) Combinations Trimethoprim/sulfamethoxazole# Topoisomerase inhibitors/ quinolones/ (inhibits DNA replication) 1st g. Cinoxacin‡ • Flumequine • Nalidixic acid • Oxolinic acid • Pipemidic acid • Piromidic acid • Rosoxacin Fluoro- quinolones 2nd g. Ciprofloxacin#  • Enoxacin‡ • Fleroxacin‡ • Lomefloxacin • Nadifloxacin • Ofloxacin • Norfloxacin • Pefloxacin • Rufloxacin 3rd g. Balofloxacin • Grepafloxacin‡ • Levofloxacin • Pazufloxacin • Sparfloxacin‡ • Temafloxacin‡ • Tosufloxacin 4th g. Besifloxacin • Clinafloxacin† • Garenoxacin • Gemifloxacin • Moxifloxacin • Gatifloxacin‡ • Sitafloxacin • Trovafloxacin‡/Alatrofloxacin‡ • Prulifloxacin Vet. Danofloxacin • Difloxacin • Enrofloxacin • Ibafloxacin • Marbofloxacin • Orbifloxacin • Pradofloxacin • Sarafloxacin Related (DG) Aminocoumarins: Novobiocin Anaerobic DNA inhibitors Nitro- imidazole derivatives Metronidazole#  • Tinidazole • Ornidazole Nitrofuran derivatives Nitrofurantoin#  • Furazolidone‡  • Nifurtoinol RNA synthesis Rifamycins/ RNA polymerase Rifampicin • Rifabutin • Rifapentine • Rifaximin #WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III M: BAC bact (clas) gr+f/gr+a(t)/gr-p(c)/gr-o drug(J1p, w, n, m, vacc)

Drug reactions (Y40-Y59, E930-E949) Adverse drug reaction/ drug eruption antibiotics: Penicillin drug reaction · Sulfonamide hypersensitivity syndrome · Urticarial erythema multiforme · Adverse effects of fluoroquinolones hormones: Steroid acne · Steroid folliculitis chemotherapy: Chemotherapy-induced acral erythema · Chemotherapy-induced hyperpigmentation · Scleroderma-like reaction to taxanes · Hydroxyurea dermopathy · Exudative hyponychial dermatitis blood: Anticoagulant-induced skin necrosis · Warfarin necrosis · Vitamin K reaction · Texier's disease anticonvulsant: Anticonvulsant hypersensitivity syndrome water-balance/acid-base: Allopurinol hypersensitivity syndrome pulmonary: Leukotriene receptor antagonist-associated Churg–Strauss syndrome vaccine: Eczema vaccinatum other specified agents: Adverse reaction to biologic agents · Adverse reaction to cytokines · Bromoderma · Halogenoderma · Iododerma · Red man syndrome · Methotrexate-induced papular eruption unspecified agent: Acute generalized exanthematous pustulosis · Bullous drug reaction · Drug-induced acne · Drug-induced angioedema · Drug-related gingival hyperplasia · Drug-induced lichenoid reaction · Drug-induced lupus erythematosus · Drug-induced nail changes · Drug-induced pigmentation · Drug-induced pseudolymphoma · Drug-induced urticaria · Fixed drug reaction · Stevens–Johnson syndrome · Injection site reaction · Linear IgA bullous dermatosis · Toxic epidermal necrolysis · HIV disease-related drug reaction · Photosensitive drug reaction · Serum sickness-like reaction