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Adverse effects of fluoroquinolones

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This is an old revision of this page, as edited by 98.155.21.76 (talk) at 14:12, 4 January 2014 (→Risk factors and interactions: did not see reference to "severe and prolonged" seizures or status epilepticus in any of the cited refs. Removed an international patent application incorrectly cited as a World Health Organization publication). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Adverse effects of fluoroquinolones

In general, fluoroquinolones are well tolerated, with most side effects being mild to moderate.[1] On occasion, serious adverse effects occur.[2]Common side effects include gastrointestinal effects such as nausea, vomiting and diarrhea, as well as headache and insomnia.

The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes.[3][4][5][6] A U.S. Centers for Disease Control study found patients treated with fluoroquinolones experienced adverse events severe enough to lead to an emergency department visit more frequently than those treated with cephalosporins or macrolides, but less frequently than those treated with penicillins, clindamycin, sulfonamides, or vancomycin.[7]

Post-marketing surveillance has revealed a variety of relatively rare but serious adverse effects that are associated with all members of the fluoroquinolone antibacterial class. Among these, tendon problems and exacerbation of the symptoms of the neurological disorder myasthenia gravis are the subject of "black box" warnings in the United States. The most severe form of tendonopathy associated with fluoroquinolone administration is tendon rupture, which in the great majority of cases involves the Achilles tendon. Younger people typically experience good recovery, but permanent disability is possible, and is more likely in older patients.[8] The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin is has been estimated at 17 per 100,000 treatments.[9][10] Risk is substantially elevated in the elderly and in those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture.[11] Tendon damage may manifest during, as well as up to a year after fluoroquinolone therapy has been completed.[12]

FQs prolong the QT interval by blocking voltage-gated potassium channels.[13] Prolongation of the QT interval can lead to torsades de pointes, a life threatening arrhythmia, but this appears relatively uncommon in part because the most widely prescribed fluoroquinolones (ciprofloxacin and levofloxacin) only minimally prolong the QT interval.[14]

Clostridium difficile associated diarrhea may occur in connection with the use of any antibacterial drug, especially those with a broad spectrum of activity such as clindamycin, cephalosporins, and fluoroquinolones. Fluoroquinoline treatment is associated with risk that is simlar to[15] or less [16][17] than that associated with broad spectrum cephalosporins.

Studies examining nervous system effects have estimated that neurotoxicity occurs in approximately 1% to 4.4% of patients taking FQs, with serious adverse effects occurring less than 0.5% of the time.[14] The most important of these may be peripheral neuropathy, which can be permanent.[18] Other nervous system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis[19] Other rare and serious adverse events have been observed with varying degrees of evidence for causation.[20][21][22][23]

Events that may occur in acute overdose are rare, and include renal failure and seizure.[24] Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.[1][25][26]

Other quinolones have had their licensed indications restricted in certain countries due to toxicity issues. These include sparfloxacin in 1995,[27] norfloxacin in 2008[28] and moxifloxacin in 2008.[29]


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.[30][31] 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.[32] The terms fluoroquinolone and quinolone are often used interchangeably, without regard to this distinction.

Risk factors and interactions

Certain patient groups are at increased risk of fluoroquinolone ADRs. A 1998 retrospective survey of the use of the fluoroquinolones in the pediatric population showed that the fluoroquinolones were oftentimes prescribed in children, and that numerous serious side effects had been recorded.[33] Fluoroquinolones are not recommended in patient groups that are predisposed to adverse events (for example, because of diabetes, G6PD deficiency, renal impairment, myasthenia gravis, previous psychiatric, seizure disorder, or children (under 18)). An alternative antibiotic class should be used wherever possible in such patients, and,if used, special caution is advised; for example, possible dosage reduction may be required as well as extra vigilance for adverse reactions. There is also an increased risk of adverse events in the elderly, including tendon ruptures and seizures. Use in children or pregnant or breast-feeding women is not recommended and should be avoided. In the UK, the prescribing indications for fluoroquinolones for children is severely restricted. Only inhalant anthrax and pseudomonal infections in cystic fibrosis infections are licensed indications in the UK due to ongoing safety concerns. At the first sign of psychiatric, neurological, peripheral neuropathy, tendonitis, or hypersensitivity reactions, fluoroquinolones should be discontinued. Quinolones are contraindicated in patients having had previous quinolone-related tendinopathy. Dose, length of time, and number of exposures to fluoroquinolones, as well as combination with corticosteroids, NSAIDs, or theophylline, increase the risk adverse reactions. Concurrent use of corticosteroids increases the risk of multiskeletal injury, manifesting as chronic tendonitis or spontaneous ruptures of tendons, and cartilage. Concurrent use of NSAIDs may in rare cases induce seizures.[34][35][36][37][22][38] 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.[2] 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.[39][40][41][42] 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.[43] Broad spectrum antibacterials including cephalosporins, Fluoroquinolones (and clindamycin) have been associated with Clostridium difficile, a potentially life-threatening super-infection.[44] Use of quinolones is also highly associated with colonisation with MRSA compared to some other antibiotic classes.[45][46] Shigella toxin expression in EHEC infections has been shown to be upregulated following fluoroquinolone administration.[47] Fluoroquinolones can have serious and potential fatal reaction when taken with certain other drugs. Some agents decrease theophylline clearance and thus increase toxicity.[48] Warfarin is affected by many many drugs including fluoroquinolones and frequency of INR monitoring needs to be increased in those prescribed both agents.[49]

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.[48] 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.[34] 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.[50][51][52]

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[2] and oxidative stress.[53]

Gastrointestinal

Nausea and vomiting are the most common side-effect of the fluoroquinolones.[48] The group of side-effects includes nausea, vomiting, abdominal pain, diarrhea, and taste disturbance, which occur in about 2-20% of people taking fluoroquinolones.[34] This rate is similar to those seen with azithromycin and cefixime.[48] The highest rates occurred among older agents, which have been discontinued. Newer agents have lower rate of GI side-effects.[34] C. difficile-associated diarrhea (CDAD) has been associated with all antibiotics.[34][22] When compared to other antibiotics, however, the risk of CDAD was found to be 2.5 times greater with fluoroquinolones.[22][54] Fluoroquinolones are associated with an increased risk of pseudomembranous colitis[55][56][57][58]

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.[59][60][61][62]

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.[63][64][65]

Musculoskeletal System

Joint pain and swelling occurs in approximately 1% of people taking fluoroquinolones and usually remits within days of stopping treatment.[34] A rare but serious adverse reaction with fluoroquinolones involves spontaneous tendon ruptures. Such injury to the patient potentially include ruptures the Achilles or other tendons.[12][66] The risk of tendon disorders with fluoroquinolone use is 0.1% to 0.4%[22] 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.[34] 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.[68] The achilles is the most common tendon affected.[22] This risk is greatest in those older than 60, in those taking corticosteroid drugs, and in kidney, heart, and lung transplant recipients.[69] [70] Because of their possible negative effect on cartilage, they are not recommended for use in pregnant women or children.[71] The FDA recommends stopping treatment, contacting a physician and resting affected limbs if these adverse events occur.[34] Achjilles tendon rupture has been observed up to a year post-treatment.[72][73] [74][75] Tendinitis, arthralgia, myalgia, as well as joint, muscle, and tendon pain, are found to be the top-three adverse reactions reported to the FDA via the Adverse Event Reporting System (AERS)[76] for all the drugs within this class.

The odds ratios (ORs) of suffering a spontaneous rupture of the achilles tendon are 4.3, for current exposure 2.4, recent exposure and 1.4 for past exposure to a fluoroquinolone drug, respectively, compared with non-exposure.[77] The incidence of spontaneous tendon rupture within the kidney recipient population is even more common.[78] In the renal transplant population, a tendonopathy incidence of 12.2%–15.6% is reported, compared with 0.6%–3.6% for transplant recipients not receiving fluoroquinolones.[79][80] In one study of 149 heart transplant patients,[81] fourteen (9.5%) patients developed Achilles tendinopathy, which in three patients (2.25%) progressed to tendon rupture.

CNS effects

Any CNS side-effect occurs with an incidence of 1–2%.[34] Adverse event reporting for antibiotics found that 12.2% of adverse reaction reports concerning fluoroquinolones involved the CNS versus 3.6% for other antibiotics.[34] Newer agents to have a lower risk of side-effects have been found.[48] Seizures are rare, and usually occur when they do in those with an underlying CNS disorder.[34] However, caution use in patient with epilepsy is still advised.[34] Very rare cases of suicidal behavior have been reported to occur, sometimes after a single dose.[82] Drugs that induce suicidal ideation, including antibiotics, are associated with an increased risk of suicide attempts.[83]

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.

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.[84]

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).[85][86]

Electrolyte imbalances are common with previous reports of fluoroquinolone-induced seizures.[37]

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),[87] reduction of brain glucose uptake,[88] electrolyte imbalances,[37] neuronal dysfunction[89] 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.[2][90]

Dermatological effects

Photosensitivity reactions have been reported with the fluoroquinolone class. The phototoxic potentials of fluoroquinolones are influenced not only by the substituent at position 8 (Halogenation at position C8) but also by those at position 1. Drugs such as Lomefloxacin and Sparfloxcacin, with a C8-fluorine substituent, and Clinafloxacin, with a C8-chlorine substituent, exhibit a greater incidence of phototoxic reactions than drugs without this substituent.[91] 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.[92]

Extremely rare cases of cutaneous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. One review estimated the incidence of fluoroquinolone-associated Stevens-Johnson syndrome at less than 0.5 cases per million patients treated. [93]

PNS effects

Peripheral neuropathy has been rarely reported. Symptoms may include paresthesia (tingling), hypoesthesia (numbness), dysesthesia (pain), and weakness.[94] Therapy should be discontinued if any neurological symptoms develop in order to prevent the occurrence of a possible irreversible condition.[94] 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.[95][96][97][98]

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 which is sometimes fatal.[24] Some members of the quinolone family are more likely to causes an increased QT than others.[99] 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.[99]

Blood disorders

Blood abnormalities are believed to occur in less than one percent of patients.[100] 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.[101]

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.[22] Temafloxacin was removed from clinical use in 1992 partially due to several cases of low blood sugar as well.[102]

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).[103] Such disturbances may present as blurred and dim vision, disturbed vision, flashing lights, diplopia, floaters,as well as decreased visual acuity and cataracts.[104] Norfloxacin, ProQuin XR and Ciprofloxacin have also been associated with diplopia.,[105][106][107] as well as Iquix (levofloxacin ophthalmic solution).[108][109] There are spontaneous reports of cases of double vision (diplopia) becoming permanent, as well as reports of floaters that never resolved in some patients.[110]

There have also been isolated reports of reversible vision loss and irreversible blindness associated with oral fluoroquinolone therapy.[111][112] Retinal degeneration has also been observed in animals.[113] These reports, while uncommon, include blindness, temporary blindness, partial blindness, and mydriasis.[114] There have also been three reports of serious macular detachment of the neuro-epithelium involving flumequine.[115]

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.[116]

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.[117][118][119] 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.[120] 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.[121][122][123][124][125] Some quinolones have been shown to be capable of causing injury to the chromosome of eukaryotic cells.[126] 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.[127][128] 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.[129]

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