Fluoroquinolone Adverse Effects and Drug Interactions

Douglas N. Fish, PharmD

Disclosures

Pharmacotherapy. 2001;21(10s) 

In This Article

Specific Adverse Effects

Gastrointestinal

Gastrointestinal effects do not appear to be related to or affected by structural changes in the fluoroquinolone nucleus.[10,45] They are thought to be caused by a combination of direct gastrointestinal irritation and CNS-mediated effects[45]; thus some may occur when the drugs are administered intravenously. The estimated overall frequency of gastrointestinal effects is 2-20%, and these effects are the most frequently reported adverse effects of fluoroquinolones.[2,3,10,14,17,20,23,24,27,29,38,45,46,47,48] Most common are nausea, anorexia, and dyspepsia; abdominal pain, vomiting, and diarrhea are less frequent but may be more severe.[2,3,10,14,17,20,23,24,27,29,38,45,46,47,48] Clostridium difficile-associated colitis uncom-monly is associated with fluoroquinolones, perhaps because of the agents' minimal effect on gastrointestinal anaerobic flora.[10,14,46,49] There is some concern that newer fluoroquinolones with enhanced anaerobic activity (trovafloxacin, moxifloxacin, gatifloxacin) may be associated with an increased risk of C. difficile-associated colitis, although this cannot be substantiated from data from clinical or surveillance studies.

The degree to which available fluoroquinolones are estimated to cause gastrointestinal adverse effects (rates based on reported clinical studies), ranked from highest to lowest, is as follows: trovafloxacin > sparfloxacin, gatifloxacin, moxifloxacin > ciprofloxacin > norfloxacin > ofloxacin, levofloxacin.[3,4,10,14,17,18,20,21,22,23,27,29,38,50,51,52,53] Most fluoroquinolones are well tolerated, with relatively low gastrointestinal adverse effect rates (~ 3-8%).[4,14,15,23,27,51,54,55,56] In contrast, although grepafloxacin no longer is marketed, it was associated with high rates of these effects, such as nausea (11-16%), vomiting (2-6%), and metallic taste (9-18%).[4,57]

In order of decreasing frequency, nausea, diarrhea, vomiting, and abdominal pain and discomfort occurred in 2-8% of patients receiving ciprofloxacin in clinical trials.[14,53] Approximately 1.5% of patients discontinued the drug for this reason.[14] The overall types and frequency of adverse effects are similar regardless of whether ciprofloxacin is administered orally or intravenously. Ofloxacin is well tolerated after both oral and intravenous administration,[17] although the overall frequency of gastrointestinal adverse effects associated with ofloxacin was somewhat higher than that of levofloxacin (~ 5.2% vs 1.2%) in comparative clinical studies.[15,58,59,60,61] The higher rate for ofloxacin perhaps is associated with the presence of the R-(+) isomer in the drug's racemic mixture. Specific adverse effects were diarrhea, nausea, flatulence, abdominal pain, dyspepsia, taste perversion, and vomiting, each occurring at a frequency of 1% or less.[4,15,20,54] Dose-ranging studies of levofloxacin found no significant dose-related increase in gastrointestinal adverse effects; the frequency did not increase during either oral or intravenous administration, with dosages as high as 1000 mg/day.[58,59,60,61]

Gastrointestinal adverse effects associated with trovafloxacin are nausea (4-8%), vomiting (1-3%), diarrhea (2%), and abdominal pain (1%).[27] Their frequency appears to be slightly lower when the drug is administered intra-venously (as alatrofloxacin) rather than orally.[27] The frequency and severity of nausea and vomiting are dose related, increasing with escalating single oral doses of 30-1000 mg and multiple oral dosages of 100-300 mg/day.[62,63,64] Moxifloxacin-related gastrointestinal adverse effects after oral administration are similar to those with most other fluoroquinolones and are primarily nausea (8%), diarrhea (6%), vomiting (2%), and taste perversion (1%).[38,39] The rates of these events were similar after oral or intravenous administration of gatifloxacin (nausea 8%, diarrhea 4%).[29,30,31,32,33,34,35,36,37]

Central Nervous System

Disturbances of the CNS are the second most commonly reported adverse effects of fluoro-quinolones. Their overall frequency is 1-2%; although, for individual agents it ranges from 0.2-11%.[3,4,14,17,20,23,27,65] Most common symptoms are headache, dizziness, and drowsi-ness; other less common effects are restlessness, insomnia and sleep disorders, agitation, and vision changes. Convulsions and seizures were rarely reported and usually occurred in patients with predisposing factors, such as seizure disorder, head trauma, anoxia, metabolic disturbances, or concomitant therapy with specific interacting drugs (theophylline, nonsteroidal antiinflammatory drugs).[3,4,10,66] The fluoroquinolones are ranked as follows based on the degree to which they are estimated to cause CNS adverse effects (rates based on reported clinical studies): trovafloxacin > norfloxacin, gatifloxacin, moxifloxacin > sparfloxacin > ciprofloxacin > ofloxacin > levofloxacin.[3,4,10,14,17,20,23,27,29,38,50]

Central nervous system disturbances of fluoroquinolones can be broadly divided as those resulting from direct effects and those resulting from drug-drug interactions (pharmacokinetic or pharmacodynamic). Adverse effects may be related to chemical structures of individual drugs.[45] The side chain substituent in the R7 position of the fluoroquinolone nucleus appears to have the greatest influence on the degree of inhibition of g-aminobutyric acid (GABA) binding, which in turn may be related to CNS adverse effects. Such inhibition of GABA receptors is also associated with the neurotoxic effects of b-lactam-type antimicrobials.[65] Bulky substituted side chains at the R7 position appear to lower binding affinity for the GABAA receptor.[45] Although the direct actions of fluoroquinolones in the CNS are thought to be associated with the drugs' ability to inhibit CNS GABAA receptors and their different binding potential to the N-methyl-D-aspartate receptor, correlation between inhibition of GABAA receptors and clinically observed CNS adverse effects is poor. It is likely that penetration of individual agents across the blood-brain barrier plays an important role in determining the relative frequency and severity of CNS toxicity.[45] Although models for predicting the epileptogenic potential of fluoroquinolones reveal differences in the ability of individual drugs to induce seizure activity, these predictions are not well correlated with clinical experience.[4]

Ciprofloxacin is well tolerated, with CNS disturbances occurring in 0.4-1.2% of patients in clinical trials.[14,66,67] The most common disorders were headache (1.2%) and restlessness (1.1%); dizziness, lightheadedness, and insomnia were less frequent (< 1%). Acute hallucinations and psychosis were reported rarely.[66,68,69,70] Seizures also were rare (< 5 cases) and occurred in patients with predisposing conditions and/or potentially interacting drugs (theophylline).[48,66,71]

Like other fluoroquinolones, the most common CNS adverse effects attributed to ofloxacin are headache (~ 4.2%) and insomnia (4.7%).[17,22] Although they were reported to occur at a frequency of up to 14.9%,[25] studies generally found ofloxacin to be well tolerated, with an overall CNS adverse effect rate of 1-5%.[17,22,58,59,60,61,72] The drug was rarely associated with acute psychosis.[19]

Levofloxacin appears to be the best tolerated fluoroquinolone in terms of frequency of CNS adverse effects.[4] The overall frequency of such effects is 0.2-1.1%; the rate with levofloxacin is consistently less than that of ofloxacin and other comparator agents in clinical trials.[15,20,54,58,59,60,61] Most common are mild dizziness, anxiety, fatigue, and headache.[20] They resolve promptly with discontinuation of the drug. It is unknown why levofloxacin and ofloxacin have different CNS adverse effect rates; although, it was speculated that ofloxacin's R-(+) isomer may contribute to the drug's relative side effect profile.

The reported frequency of CNS adverse effects with sparfloxacin is 1.9-4.2%. In clinical studies sparfloxacin was associated with somewhat higher rates of headache but lower rates of dizziness and insomnia, relative to comparator agents.[4,23]

Trovafloxacin is associated with the highest rate of CNS adverse events of fluoroquinolones. The most commonly reported are dizziness (3-11%), lightheadedness (2-4%), and headache (1-5%).[27] They are usually mild, lasting only a few hours after administration of the dose, and often resolve with continued therapy. In clinical studies, approximately 3.5% of patients discontinued trovafloxacin because of these symptoms (dizziness 2.4%, headache 1.1%).[27] Although common to both genders and all age groups, CNS disturbances occurred more frequently in women and patients younger than 45 years, although the reason for this is unknown. The frequency of dizziness and lightheadedness in patients older than 65 years is reported to be 3.1% and 0.6%, respectively.[27] Adverse effects are thought to be related to the drug's relatively high lipophilicity and extensive initial partitioning into the CNS.[28,51,73] Consistent with this theory is the observation that the frequency and severity of light-headedness and headache are dose related, increasing with escalations in single oral doses from 30-1000 mg and with escalations in multiple oral dosages from 100-300 mg/day.[21,51,52] It was recommended that these effects may be minimized by taking the drug with food or at bedtime.[27] Outpatient therapy with trovafloxacin is no longer recommended, owing to rare but severe liver toxicity.[8]

Both moxifloxacin and gatifloxacin are well tolerated, with low rates of CNS adverse effects. These effects are typically mild, including dizziness (3% both drugs) and headache (moxifloxacin 2%, gatifloxacin 3%).[29,30,31,32,33,34,35,36,37,38,39] Miscellaneous events, such as insomnia, nervousness, anxiety, tremor, and drowsiness, were reported in 1% or fewer of patients receiving oral moxifloxacin.[38] Abnormal dreams, insomnia, tremor, and vertigo occurred in fewer than 3% of patients receiving single or multiple oral or intravenous doses of gatifloxacin.[29]

Dermatologic

Dermatologic adverse effects of fluoroquinolones occur at an overall rate of 0.5-3%. The most notable are phototoxic reactions. These may develop within just a few hours after adminis-tration of the drug and may occur in virtually any patient who has received a sufficient drug dosage and sufficient ultraviolet (UV) exposure. In contrast, photosensitivity reactions are immune mediated and require previous exposure to the offending agent; they usually require more than 1-2 days to develop.[45] Immune-mediated photosensitivity reactions are rare with fluoroquinolones; phototoxic reactions are far more common and appear to be a class effect.[45] Most fluoroquinolones can produce phototoxic reactions given sufficient dosages and tissue concentrations; however, the drugs differ significantly in their phototoxicity potential at clinically relevant dosages and concentrations.[4,11,45]

Phototoxicity reactions may occur on initial exposure to the drug and often develop within just a few hours after exposure to UV light of sufficient intensity or duration.[74] The mechanism appears to be related to photodegradability of individual agents and their ability to induce oxygen free radicals and singlets.[46] It was hypothesized that these reactive oxygen species subsequently attack cellular lipid membranes, which results in lipid peroxidation and subsequent inflammation.[45] The potential of fluoroquinolones to produce significant phototoxicity is dependent on their propensity to generate reactive oxygen species while decomposing through exposure to UVA light. Drugs with the highest reactive potential are those that are halogenated at the 8 position of the quinolone nucleus.[45] The presence of fluorine or chlorine atoms at this position seems to enhance the phototoxicity of these compounds; sparfloxacin and lomefloxacin have fluorine atoms at the 8 position, whereas the investi-gational clinafloxacin has a chlorine atom at the 8 position. A methoxy group at the 8 position appears to remove the phototoxicity risk; that is, gatifloxacin and moxifloxacin.[45,75] The presence of an amino group at the 5 position also appears to enhance phototoxicity potential, as seen with sparfloxacin.[45] In addition to chemical structure, pharmacokinetic variables such as extensive penetration into skin and long half-lives may influence the potential for phototoxicity of individual agents; sparfloxacin has both of these characteristics.[45]

Clinical manifestations of phototoxicity range from mild erythema of sun-exposed areas to severe bullous eruptions. The reaction may be caused by both direct and indirect exposure to sunlight as well as by exposure to UV lamps.[4,45] Fair-skinned persons appear to be at greater risk than dark-skinned individuals.[4] Reactions usually occur within a few days of the start of drug therapy. Although the risk generally diminishes rapidly after discontinuing therapy, reactions may occur up to 3 weeks after discontinuation. This is apparently most likely with drugs with high tissue penetration or long elimination half-lives (sparfloxacin).[45] Avoiding exposure to sources of UV light, wearing protective clothing, and applying topical sun blockers that afford adequate protection against UVA and UVB light may afford protection against phototoxic reactions. Based on the degree to which they are estimated to cause these reactions (rates based on reported drug-related adverse effect rates), available fluoroquinolones are ranked as follows: lomefloxacin > sparfloxacin > ciprofloxacin > norfloxacin, ofloxacin, levofloxacin > trovafloxacin, moxifloxacin, gatifloxacin.[2,4,6,14,17,20,23,24,27,29,38,45,75]

Lomefloxacin caused phototoxicity reactions in 1.7-10% of patients during clinical studies.[12,13,76] Sparfloxacin also was associated with a relatively high frequency of these reactions, ranging from 1-2% in Japan and Europe and from 6.9-9.5% in North America, compared with 0.2-0.9% for comparator agents.[4,24,25,26] Most reactions were mild or moderate, but some were severe. The rates and severity of the reactions occurring during sparfloxacin therapy do not appear to be dose related.[4] Because of the long elimination half-life of sparfloxacin (~ 20 hrs), patients should avoid exposure to sunlight or artificial UV light both during and for 5 days after discontinuing therapy.[23]

Data indicate that the potential for photo-toxicity of other fluoroquinolones is minimal. It is weak for ciprofloxacin. In a comparative study of ciprofloxacin and grepafloxacin in treatment of bronchitis, the frequency of phototoxicity was 0% for ciprofloxacin.[14,77] In an analysis by the Food and Drug Administration (FDA) of spontaneous adverse drug reaction reports, phototoxicity occurred with 0.1/100,000 prescriptions of ciprofloxacin, compared with 0.4/100,000 prescriptions of ofloxacin and 70/100,000 of lomefloxacin.[78] The frequency of levofloxacin phototoxicity was 0.03% (1/3460) versus 0.36% for comparator agents in nine clinical studies.[18,20,21,22,51,52,53,59] Trovafloxacin's phototoxicity potential is apparently among the lowest of the fluoroquinolones; the reaction occurred in 2 (< 0.03%) of 7069 patients in clinical studies.[4,21]

Moxifloxacin also has little potential for phototoxicity. In vitro and in vivo experimental models compared the drug with ciprofloxacin and sparfloxacin and found that moxifloxacin did not produce phototoxic reactions.[79] Moxifloxacin was evaluated in a double-blind, placebo-controlled and lomefloxacin-controlled study in which healthy volunteers were exposed to light at wavelengths representing UVA, UVB, and visible radiation.[80] The drug produced minimal phototoxic effects, and these were comparable with placebo. No cases of moxifloxacin-related phototoxicity were reported during 20 clinical trials.[81]

In vitro studies found that gatifloxacin did not show generation of singlet oxygen or other reactive oxygen species.[82] In addition, it did not cause breakage of DNA strands under UVA irradiation, effects that were seen with several other fluoroquinolones, such as norfloxacin, enoxacin, ciprofloxacin, and sparfloxacin.[82] In addition to in vitro studies, gatifloxacin did not cause phototoxicity in clinical studies of over 3000 patients.[37] Thus evidence indicates that the agent is associated with minimal to no phototoxicity at clinically relevant dosages.

Other dermatologic adverse reactions caused by fluoroquinolones are rather uncommon. These include rash, pruritus, urticaria, edema, hyperpigmentation, dermatitis, vasculitis, erythema multiforme, eruptions with hemorrhagic bullae, and Henoch-Schönlein purpura.[6,14,20,23,27,67,83,84]

Hepatic

Liver enzyme abnormalities occur in 2-3% of patients who receive fluoroquinolones. Although definitions of hepatic enzyme abnormalities vary among studies, the most common definition in clinical studies was an enzyme level that was 2-3 times greater than the upper limit of normal. Elevations in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase are most commonly reported; elevations in total bilirubin level may also occur.[4,6,10] All such elevations are usually mild and reversible when the drug is discontinued, although discontinuation is rarely necessary.[4] The only marketed fluoro-quinolone with known clinically significant hepatotoxicity is trovafloxacin.

In premarketing studies, trovafloxacin was associated with low rates (< 1%) of elevated liver enzyme levels or hepatic abnormalities.[27] However, long-term therapy (> 28 days) during a clinical study of chronic prostatitis was associated with asymptomatic increases in liver enzyme levels of 3 times or higher than normal values in 9% of 140 patients.[27] Postmarketing surveillance data on trovafloxacin in the United States indicate that liver enzyme abnormalities may occur during shorter durations of therapy (< 28 days). Elevations in levels of hepatic transaminases usually resolved within 2 months of discontinuing therapy.[27] However, post-marketing surveillance also detected nearly 150 cases of clinically symptomatic hepatic injury among approximately 2.5 million patients who had been treated with the drug.[8] These cases included hepatitis and at least 14 cases of acute hepatic failure, as well as symptomatic pancreatitis. Four of these patients required liver transplantation, and five died as a result of liver-related illness.[8] Risk of serious hepatotoxicity appears to be associated with trovafloxacin therapy longer than 2 weeks.[8] Little information is available regarding risk factors, such as previous illnesses or use of other drugs among individuals in whom these toxicities were reported, although serious hepatotoxicity was reported after reexposure to the drug. Although these more severe hepatic and pancreatic abnormalities appear to be very uncommon during trovafloxacin therapy, it is recommended that the drug be restricted to severe, life-threatening indications in hospitalized patients, that therapy be restricted to 14 days, and that liver and pancreatic function tests be monitored or the drug be discontinued in patients who develop symptoms consistent with hepatitis and/or pancreatitis, as clinically indicated.[8,27]

Although liver function abnormalities were reported to occur in 0.3-1.9% of patients taking ciprofloxacin during clinical trials, spontaneous adverse drug reaction reports indicate that serious abnormalities in liver enzyme levels occurred in only 144 (< 0.01%) of approximately 8 million patients worldwide who had received the drug through 1993. Serious hepatic toxicities were rare and included hepatitis, hepatic necrosis, and hepatic insufficiency or failure.[2,4] Two cases of cholestatic jaundice were associated with the agent.[85,86]

In clinical trials, levofloxacin was associated with elevations in liver enzyme levels 2-3 times greater than the upper limit of normal in 0.3% or fewer patients; rates were similarly low for ofloxacin.[17,20] Severe hepatic toxicities are rarely reported for norfloxacin and ofloxacin.[87,88,89] Elevated liver enzyme levels occurred in fewer than 1% of gatifloxacin-treated patients in premarketing clinical trials; these abnormalities were apparently asymptomatic, and levels returned to normal after drug discontinuation.[29,30] Liver function abnormalities during moxifloxacin therapy is uncommon, occurring in approximately 1.2% of patients versus 1.5% for comparators.[82]

Urinary Tract

Nephrotoxic effects of the fluoroquinolones are uncommon, although rare cases of hematuria, interstitial nephritis, and acute renal failure were reported.[3,10,45,53,90] The reported frequency of serum creatinine elevations during fluoroquinolone therapy is 0.2-1.3%, and the frequency of azotemia is similarly low.[6,10,14,17,20,23,27] According to a review of safety data related to long-term (> 30 days) therapy with ciprofloxacin, urogenital adverse effects occurred in 4 (1.2%) of 339 patients, but the review did not specify their nature.[16] The analysis did state that neither interstitial nephritis nor crystalluria was reported; it appears that the risks of such toxicities are not increased with long-term ciprofloxacin therapy. Nearly all cases of acute renal failure after ciprofloxacin administration occurred in patients older than 50 years, and the onset of renal dysfunction was typically within 3-7 days of the start of therapy.[4,90] The disorder usually resolved promptly with discontinuation of the drug, and renal function returned to normal within several weeks, with no long-term consequences.[6,10,90] No similar cases of acute renal failure have been reported with other fluoroquinolones except for temafloxacin. With that drug, acute renal failure occurred in association with severe hemolytic anemia and/or the presence of disseminated intravascular coagulation; the disorder did not occur in the absence of other morbidities consistent with the so-called "temafloxacin syndrome."[5]

Crystalluria was seen in animals receiving fluoroquinolones. Precipitation of the drugs in urine is explained by decreased solubility of fluoroquinolones at physiologic or alkaline pH, owing to their zwitterionic chemical nature; changes in molecular structure that improve water solubility also reduce the potential for crystalluria and possibly other adverse effects involving the urinary tract.[45,75] However, crystalluria appears to occur only rarely in the normally acidic urine of humans.[45,75] Although crystalluria caused obstructive uropathy in animals, it is not clear whether it is associated with renal toxicities in humans.[10,45,48,75] Accordingly, unlike older sulfonamide agents, patients do not have to take a fluoroquinolone with large amounts of water.

Ocular

Nalidixic acid and pefloxacin were associated with ocular damage when given to animals in high dosages. Manifestations included cataracts, multiple punctate lenticular opacities, retinal morphologic changes, and altered visual acuity.[78] Whether these effects were actually related to fluoroquinolone exposure is unknown, and no such toxicities were reported with drugs of this class in dosages administered to humans.[14,17,20,23,27,78]

Musculoskeletal

Arthropathy. Fluoroquinolone-induced arthropathy is reported to occur in approximately 1% of all patients exposed to these agents.[91] The most common manifestations were joint pain, stiffness, and swelling of weight-bearing joints, particularly knees. Symptom onset is usually within the first few days of therapy and is most common in patients younger than 30 years. Joint manifestations usually resolve within days to weeks after discontinuing the drug. Arthropathy was observed in animal studies, particularly in juvenile dogs, and was characterized by damage to chondrocytes, fissures in the extracellular matrix, and loss of collagens and glycosamino-glycans from immature articular cartilage. Possible mechanisms for this articular damage include inhibition of synthesis of collagens and glycosaminoglycans, fluoroquinolone-induced oxidative injury to chondrocytes, inhibition of chondrocyte DNA synthesis, chondrocyte mitochondrial dysfunction, and chelation of magnesium ions by fluoroquinolones that results in changed function of chondrocyte surface integrin receptors.[92] The risk of arthropathy appears to be a class effect that is not altered by structural changes of the drug; virtually all fluoroquinolones reportedly cause arthropathy at some dosage.[45]

At least 10 cases of arthropathy occurred in children and adolescents receiving fluoroquinolones; 7 of these cases involved pefloxacin, which is not available in the U.S.[92] Clinical features were joint swelling or pain in one or more joints and usually included the knees. Most patients recovered completely over a few days to several months, with no radiographic evidence of bone or joint changes. Only one patient had evidence of significant joint damage, specifically, damage to the right hip and both knees.[93] This 17-year-old boy had received pefloxacin for more than 2 months before onset of symptoms; however, he had several underlying factors that may have contributed to joint damage. In addition, pefloxacin was continued for an additional 4 weeks after the appearance of symptoms.[92] A review of these 10 cases concluded that chondrotoxicity can occur in children and adolescents who receive fluoroquinolones but that it is uncommon, usually relatively mild, and reversible with discontinuation of the drug. These cases illustrate features likely to be found in other cases of fluoroquinolone-induced chondrotoxicity.

In contrast to these 10 cases, no evidence of arthropathy or chondrotoxicity was found in 31 other reports of more than 7000 children and adolescents who received various fluoroquinolones.[92] Although arthralgia with or without clinical signs of arthritis occurred in up to 14% of children with cystic fibrosis who were treated with pefloxacin, a larger database of 1795 children who received ciprofloxacin indicated that arthralgia occurred in only 1.5% of over 2000 courses of treatment.[92,94,95] In these patients, joint manifestations were reversible after discontinuation of the drug, and no evidence of arthropathy was documented.

Several studies attempted to document bone or cartilage toxicities among children exposed to fluoroquinolones.[96,97,98,99] In these studies, children received the drugs for 11-93 days, some for up to 600 days. Assessments were performed by clinical evaluation, magnetic resonance imaging, and/or histopathology after follow-up ranging from less than 6 months to 12 years. No evidence of fluoroquinolone-induced effects was found.

In summary, the severe fluoroquinolone-induced arthropathy observed in animals is not clearly documented to occur in adults and adolescents exposed to the drugs. Although arthralgia with or without effusions was reported, it occurred at a relatively low rate (< 1.5%) and completely resolved after discontinuation of drug therapy, with no evidence of long-term or serious sequelae. Although no available fluoroquinolone is FDA approved for children, therapy with the drugs in this population appears to be justified on the basis of risk versus benefit considerations in compelling clinical circumstances (e.g., patients with cystic fibrosis with multidrug-resistant gram-negative infection).

Tendinitis and Tendon Rupture. More recent concerns regarding musculoskeletal adverse effects of fluoroquinolones involve the possibility of tendinitis and tendon rupture. Tendon disorders most often involved the Achilles tendon, although the shoulder joint and hand also were affected; these disorders may occur either unilaterally or bilaterally.[4,100,101]

The relative risk of Achilles tendon rupture was 4-fold higher among individuals receiving a fluoroquinolone than in those not receiving the drugs.[102] However, the overall frequency of this effect appears to be quite low. Postmarketing surveillance data for sparfloxacin indicate that tendinitis and tendon rupture occurred in approximately 1/1430 and 1/200,000 patients, respectively.[4] These patients were usually older than 50 years (range 25-84 yrs) and often received concomitant corticosteroid therapy; patients who are both older than 60 years and receiving corticosteroids may be at up to 14-fold greater risk of Achilles tendon rupture during fluoroquinolone therapy compared with individuals of all ages who are not receiving the antimicrobials.[100,101,102] Men appear to be more commonly affected than women.[100,101] Symptoms may occur within 2-42 days after starting therapy and usually resolve within 1-2 months after discontinuation of the drug. Need for hospitalization, surgical repair, and prolonged periods of disability have been reported.[101]

Five fluoroquinolones -- norfloxacin, ciprofloxacin, enoxacin, ofloxacin, and sparfloxacin -- are reported to cause either tendinitis or tendon rupture. Levofloxacin caused tendinitis but not rupture.[4,102] Although not observed in clinical trials, patients receiving moxifloxacin or gatifloxacin are assumed to be at risk for tendon disorders because these disorders are considered to be a class effect.[29,38] It is recommended that patients experiencing tendon pain or inflammation during fluoroquinolone therapy discontinue the drug and refrain from exercise until they can be adequately assessed for tendinitis.[100,101,102,103]

Cardiovascular

Administration of fluoroquinolones, most notably sparfloxacin and grepafloxacin, was associated with prolongation of the electro-cardiograph (ECG)-derived corrected QT (QTc) interval.[23,57,104] Effects of the drugs on myocardial tissue are apparently related to the human ether-a-go-go gene (HERG), which encodes the rapidly activating delayed-rectifier potassium channel (IKr) in the heart. Fluoroquinolone-induced inhibition of HERG/IKr can induce prolongation of the QTc interval and, in turn, potentially lead to ventricular arrhythmias and sudden cardiac death. Studies of HERG-inhibiting effects of various fluoroquinolones showed that all drugs evaluated produce dose-dependent HERG blockade, although with markedly differing potencies.[105] The HERG-inhibiting activity of grepafloxacin and sparfloxacin occurs at clinically achievable plasma concentrations and may be associated, at least in part, with QTc interval prolongation. Gatifloxacin and ciprofloxacin had negligible effects on HERG at 30 µM, a concentration approximately 3- to 4-fold greater than the mean maximum concentration for these drugs in humans; the effects of moxifloxacin were slightly greater.[105]

Most clinical data related to prolongation of the QTc interval are derived from ECGs per-formed during clinical trials and from post-marketing surveillance studies. Approximately 1-3% of patients receiving sparfloxacin during clinical studies developed a QTc interval prolongation of 500 msec or greater, which is considered to be potentially clinically significant.[4,18,104] These ECG changes also appeared to be dose related; prolongations increased progressively from 9 msec to 26 msec over QTc baseline levels as dosages increased from 100 mg/day to 400 mg/day.[104] However, the relative changes in QTc interval among patients experiencing this drug-related effect appear to be less than those associated with erythromycin.[104]

Serious adverse cardiovascular events were reported in seven patients receiving sparfloxacin; three cases of reversible ventricular tachycardia and one each of syncope, sinus tachycardia, asystole resulting in death, and sudden death. However, all of the patients had severe preexisting cardiovascular disease, and this event rate was not significantly different from that in patients receiving comparator antimicrobials.[104] At least one episode of torsades de pointes is considered to be probably related to sparfloxacin.[23] Although limited data are available for grepafloxacin, this agent was withdrawn from the U.S. market because of reports of at least seven serious cardiac events, including torsades de pointes.[9] Detailed patient information, including evidence of QTc prolongation, is unavailable.

Levofloxacin has apparently minimal effects on the QTc interval and was associated with a mean change of only 4.6 msec among 37 patients undergoing paired ECG. Cases of QTc prolongation and torsades de pointes were described,[106,107] but considering the large numbers of patients who have been treated with levofloxacin, these appear to be very rare. At least one case occurred in an individual receiving the antiarrhythmic amiodarone, known also to cause such adverse events.[107]

Ciprofloxacin and trovafloxacin (including alatrofloxacin) have not been associated with significant prolongation of QTc interval during drug administration.[14,27] Prolongation of the QTc interval (averaging ~ 2 msec) was reported with gatifloxacin; however, this was considered to be clinically insignificant, and the drug appears to have minimal effects on the QTc.[29,30,108]

Moxifloxacin produces minor and insignificant ECG changes. It was associated with mean prolongation of the QTc interval of 6 msec in approximately 800 patients undergoing paired ECG during clinical studies.[38] Although the changes occurred in patients who had no history of cardiac disease and who did not receive concomitant agents that caused QTc interval prolongation, no clinically significant cardiac events were associated with moxifloxacin. Pooled data from additional clinical studies indicate that the drug was taken by at least 228 patients who received concomitant agents known to cause QTc interval prolongation; no evidence of excessive cardiovascular adverse events was found.[109] Data derived from clinical studies indicate that mean changes in QTc interval ranged from 1-7 msec during moxifloxacin therapy and was not associated with adverse cardiovascular events.[39,109] A report summarizing moxifloxacin safety data in 1.2 million patients described a single case of torsades de pointes; this occurred in an 83-year-old woman with significant hypokalemia and underlying cardiovascular disease who was receiving concomitant therapy with antiarrhythmic agents.[39] Thus, moxifloxacin appears to be associated with minimal risk of cardiac toxicity.

Because of experience with older fluoro-quinolones (grepafloxacin) and relative lack of experience with newer ones, the FDA recom-mends that package insert warnings for all new fluoroquinolones (including gatifloxacin and moxifloxacin) contain a statement suggesting that the risk of arrhythmias may be reduced by avoiding their use or administering them with caution in patients with known underlying cardiac conditions, those with known QTc interval prolongation or history of significant cardiac arrhythmias, those with uncorrected hypokalemia, and those receiving concomitant therapy with agents known to increase the QTc interval or to cause bradycardia (metoclopramide, cisapride, erythromycin, classes Ia and III antiarrhythmics, and tricyclic antidepressants).[23,29,57,104] The FDA also has requested that all manufacturers of fluoroquinolones document the effects of their products on QTc prolongation.

Other cardiovascular adverse effects associated with fluoroquinolones include hypotension or hypertension, tachycardia, syncope, migraine headaches, edema, and chest pain.[14,17,20,23,27,29,38] Most of these are rare or are of uncertain causal relationship to fluoroquinolones.

Hematologic

Hematologic abnormalities such as anemia, methemoglobinemia, leukopenia, granulo-cytopenia, increased or decreased prothrombin time, and increased or decreased platelet counts were associated with fluoroquinolones.[14,17,20,23,27,29,38,81,110] They were reported uncommonly (~ < 0.3-1%), and a causal relationship was not definitely established in most cases. With the exception of temafloxacin, hemolytic anemia is rarely associated with the agents.

Immunologic

Hypersensitivity reactions to fluoroquinolones occurred in 0.6-1.4% of patients in clinical studies.[3] Skin manifestations such as erythema, pruritus, urticaria, and rash may be caused by either an allergic reaction or through release of histamine. Histamine release and hypotension were noted during rapid intravenous infusion of fluoroquinolones,[4] and cutaneous erythema, itching, and a burning sensation were seen during intravenous administration of ciprofloxacin.[111] A serum sickness-type reaction also occurred during ciprofloxacin therapy, and fatal hypersensitivity vasculitis was associated with both ciprofloxacin and ofloxacin.[112,113]

Anaphylactic reactions to fluoroquinolones are rare, with a frequency of 0.46-1.2 cases/100,000.[4,46,48] Such reactions occurred from 5-60 minutes after drug administration. History of serious hypersensitivity to one fluoroquinolone should prompt extreme caution in administration of other fluoroquinolones.[6,46]

The so-called temafloxacin syndrome consists of hemolytic anemia with renal dysfunction, hepatic dysfunction, and/or coagulopathy. It was well described in at least 95 patients and occurred at an estimated frequency of 1/3500 patients treated with the agent.[5,6] This frequency caused temafloxacin to be voluntarily withdrawn from the worldwide market in 1992, only 4 months after FDA approval. Although the pathophysiologic mechanism responsible for the syndrome is not conclusively determined, it is postulated that the toxicities might have an immunologic basis.[5] The syndrome did not appear to be dose related and occurred in only small numbers of patients. It occurred after the first dose of temafloxacin in 18 patients who had previously received fluoroquinolones other than temafloxacin, suggesting sensitization after exposure to drugs of the class. In addition, the onset of hemolysis usually occurred more than 5 days after beginning temafloxacin, a time interval consistent with that required to mount a primary immune response in drug-induced immune hemolytic anemia.

The chemical nucleus of the fluoroquinolones closely resembles that of quinine and quinidine, drugs that are known to cause immune-mediated hemolytic anemia and thrombocytopenia.[5] It was also originally speculated that the temafloxacin syndrome was caused by extensive hepatic metabolism that resulted in liberation of free fluorine atoms from the trifluorinated drug molecule, with subsequent toxicities.[4,5] Initially, there was concern over the fact that trovafloxacin shares a close structural resemblance to temafloxacin -- they are both trifluorinated quinolones -- and it might cause similar adverse effects.[4,52]

An increased risk of adverse effects was seen in studies of fleroxacin, a third trifluorinated quinolone; 84% of patients receiving fleroxacin experienced adverse events, primarily of the CNS and gastrointestinal tract. However, a temafloxacin-like syndrome has not been reported during treatment with either fleroxacin or trovafloxacin, and if the basis for the syndrome is indeed immune mediated, the syndrome would be unlikely to occur with trovafloxacin any more than with other agents that share the fluoroquinolone nucleus. However, an immune-mediated mechanism of trovafloxacin-induced hepatotoxicity has not been ruled out.

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