MEDLINE Abstracts: Safety Profile of the Fluoroquinolones
What's the latest in the safety and toxicity of fluoroquinolones? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pharmacotherapy.
Stahlmann R, Lode H
Drugs. 1999; 58:37-42
Reactions of the gastrointestinal tract, the CNS and the skin are the most often observed adverse effects during therapy with fluoroquinolones. At least for some of the newer fluoroquinolones a steep dose-response relationship of adverse effects seems to exist. Pathogenesis of the neurotoxic effects of fluoroquinolones is still unknown. Among the newer drugs, trovafloxacin caused mild CNS reactions such as dizziness and lightheadedness in a considerable proportion of patients. Young females seem to be especially sensitive to this effect, which diminishes during treatment or if taken together with food. Cardiotoxic potentials of sparfloxacin and grepafloxacin are higher than those of other fluoroquinolones, but during therapy no clearcut drug-related serious reactions have been reported, apart from a slight prolongation of the QT interval. However, to avoid risks these drugs should not be prescribed to patients with known prolongation of the QT interval (e.g. patients on antiarrhythmics). Phototoxicity has been described for all quinolones, but derivatives with a halogen atom at position 8 show the highest potential for such reactions. Fleroxacin, sparfloxacin, clinafloxacin and lomefloxacin belong to this group of fluoroquinolones. The phototoxic potential of the other new fluoroquinolones is considerably lower, but extensive exposure to UV light should generally be avoided during therapy with all quinolones. Chondrotoxicity of quinolones, as observed in immature animals, can affect articular cartilage and/or the epiphyseal growth plate, depending on the developmental stage. Pathogenesis of chondrotoxicity can probably be explained by the magnesium-chelating properties of these drugs. As juveniles are especially sensitive, use of these drugs in paediatrics should be restricted to carefully selected indications (such as the use of ciprofloxacin in cystic fibrosis). Another manifestation of the toxic effects of quinolones on connective tissue structures are tendopathies. Tendinitis and tendon ruptures have occurred as late as several months after quinolone treatment. Overall, quinolones are well tolerated drugs. Their specific toxic potentials have to be considered when they are chosen for treatment of bacterial infections.
Lipsky BA, Baker CA
Clin Infect Dis. 1999; 28(2):352-64
For 2 decades fluoroquinolones have been found to be generally well-tolerated and safe. Adverse events may be inherent to the class or influenced by structural modifications. The commonest adverse events are gastrointestinal tract (GI) and central nervous system (CNS) reactions; nephrotoxicity and tendinitis are infrequent, but agents differ greatly in phototoxic potential. Fluoroquinolones are safe in elderly, human immunodeficiency virus-infected, and neutropenic patients, but because of possible effects on articular cartilage, they are not currently recommended for children or pregnant women. Four new agents have recently been licensed. Levofloxacin causes few GI or CNS adverse events and is minimally phototoxic. Sparfloxacin infrequently causes GI or CNS effects but is associated with relatively high rates of phototoxicity and prolongation of the electrocardiographic QTc interval (Q-T interval, corrected for heart rate). Grepafloxacin causes relatively high rates of GI effects, taste perversion, and QTc interval prolongation, but it is minimally phototoxic. Trovafloxacin is associated with a moderate rate of GI effects and a relatively high incidence of dizziness but has low phototoxic potential.
Lode H
Drug Saf. 1999; 21(2):123-35
The new generation fluoroquinolones -- sparfloxacin, levofloxacin, grepafloxacin and trovafloxacin -- have been designed to respond to the clinical need for extended antimicrobial cover in the face of increasing global microbial resistance. Their main focus is in the treatment of respiratory infections, particularly those acquired in the community. CNS adverse effects, such as dizziness and headache, are known to occur relatively commonly with some fluoroquinolones and are not, in general, well tolerated by patients. The structural component of the fluoroquinolone molecule believed to be responsible for improved gram-positive activity is also believed to be implicated in the production of CNS adverse effects, including those arising from drug interactions with theophylline and NSAIDs. Inhibition of brain gamma-aminobutyric acid (GABA) receptor binding appears to be a strong indicator of CNS activity, though N-methyl-D-aspartate receptor binding has also been implicated. In accordance with the results of these predictive studies, clinical trials have found sparfloxacin, levofloxacin and grepafloxacin to be associated with a low incidence of CNS events. Trovafloxacin has been found to be associated with a higher incidence of CNS events (particularly lightheadedness and dizziness) than the other 3 agents. Ongoing and future clinical studies will help to define the usefulness of the predictive models, as well as reveal the full CNS adverse event profile of these and other investigational fluoroquinolones.
Lode H, Vogel F, Elies W
Clin Ther. 1999; 21(1):61-74
The safety profile of grepafloxacin has been characterized in a number of preclinical and clinical studies. Preclinical investigations have shown that its toxicologic profile is similar to that of other fluoroquinolones, and phase I studies in humans have confirmed these data. A photosensitivity study demonstrated equivalence with ciprofloxacin, and a study in elderly patients taking the highest clinical dose of grepafloxacin indicated that prolongation of the QTc interval by grepafloxacin was less than 2 ms, 15 times less than that observed in a study of erythromycin. In phase II and III clinical investigations conducted in the United States and the United Kingdom, safety data have been gathered from more than 3000 patients with either community-acquired pneumonia or acute bacterial exacerbations of chronic bronchitis. The most common adverse events with grepafloxacin 400 or 600 mg were gastrointestinal, such as nausea, vomiting, and diarrhea. The frequency of these adverse events was similar to that seen with ciprofloxacin. Significantly more patients reported a mild, unpleasant metallic taste with grepafloxacin than with ciprofloxacin, but <1% of patients withdrew from therapy because of this. Headache was observed significantly more often in ciprofloxacin-treated patients than in grepafloxacin-treated patients. Recent postmarketing data confirm the good tolerability and safety profile of grepafloxacin. These data, from a case-report study of more than 9000 patients in Germany, demonstrated that only 2.3% of patients reported adverse events when grepafloxacin was used in routine clinical practice. The most frequently reported events were nausea (0.8%) and gastrointestinal symptoms (0.4%). Dizziness was reported by only 0.3% of patients, and only 4 patients (0.04%) reported photosensitization. Adverse events did not appear to be either dose dependent or related to diagnosis. More than 400,000 patients world-wide have received grepafloxacin treatment. No new safety issues have arisen from the spontaneous-report data and, with the exception of rare reports of an unpleasant taste, the most commonly reported events have been the same as those seen in clinical studies. These data support grepafloxacin as a well-tolerated fluoroquinolone suitable for the treatment of community-acquired respiratory tract infections.
Bertino J, Fish D
Clin Ther. 2000; 22(7):798-817
Background: Premarketing trials showed the fluoroquinolone agents to have a favorable side-effect profile, with treatment-related adverse events comprising gastrointestinal, central nervous system, and dermatologic effects that were generally mild and reversible on cessation of treatment. However, postmarketing surveillance studies have identified severe adverse events, including severe anaphylaxis, QTc-interval prolongation, and potential cardiotoxicity, associated with 3 quinolone agents that either resulted in the removal of the agent from the market (temafloxacin and grepafloxacin) or significantly restricted its use due to substantial mortality and morbidity associated with liver toxicity (trovafloxacin). To date, there have been no such significant adverse events associated with the older fluoroquinolone agents, including ciprofloxacin, ofloxacin, norfloxacin, and levofloxacin. However, there are fewer data from postmarketing surveillance studies on the most recently approved agents, such as moxifloxacin and gatifloxacin, or agents awaiting approval, such as gemifloxacin.
Objective: This paper examines safety data from the premarketing trials and postmarketing surveillance studies of fluoroquinolones available in the United States.
Methods: A MEDLINE search was performed to identify all English-language studies published since 1980 concerning the safety profiles of the fluoroquinolones.
Conclusions: The fluoroquinolone antibacterial agents offer broad-spectrum therapy in patients with a variety of infections. Given similar spectra of activity, the choice between quinolones may be based on differences in efficacy and safety or tolerability profiles. Most drug reactions involving these agents are minor and reversible on discontinuing treatment, but adverse effects can be associated with significant mortality and morbidity, as was seen in the case of trovafloxacin and temafloxacin.
Heyd A, Haverstock D
Clin Ther. 2000; 22(10):1239-50
Background: Ciprofloxacin is a broad-spectrum fluoroquinolone antibiotic used in the treatment of a wide range of mild to moderate gram-positive and gram-negative infections. Although extensive information is available on the safety profile of ciprofloxacin in adults, few published data exist regarding the tolerability and toxicity of this drug in patients aged > or = 65 years.
Objectives: The objectives of this retrospective analysis were to compare the safety profile of ciprofloxacin in patients aged > or = 65 years versus patients aged <65 years and to compare the adverse-event profile of ciprofloxacin with that of other comparator antimicrobial agents used in clinical trials.
Methods: We retrospectively reviewed 23 prospective, controlled anti-infective clinical trials in the US Bayer ciprofloxacin database that included patients aged > or = 65 years. These trials comprised the submission file of the original and supplemental New Drug Application for ciprofloxacin. The incidence of treatment-emergent and drug-related adverse events was assessed.
Results: Of the 6863 patients in these 23 clinical trials, 3579 received ciprofloxacin therapy and 3284 received comparator antimicrobial agents. Of the ciprofloxacin-treated patients, 898 (25.1%) were aged > or = 65 years; 887 (27.0%) of the patients who received comparator antimicrobial agents were aged > or = 65 years. Among ciprofloxacin-treated patients, drug-related adverse events were reported more often in those aged <65 years (24.0%) compared with those aged > or = 65 years (17.9%). The incidence of drug-related adverse events in the comparator group was also higher in those aged <65 years (25.1%) than in those aged > or = 65 years (16.8%). Premature discontinuation due to any adverse event was reported in 3.9% (105 of 2681) and 3.7% (33 of 898) of ciprofloxacin-treated patients aged <65 years and > or = 65 years, respectively. Corresponding rates for the comparator antimicrobial group were 3.9% (93 of 2397) and 3.8% (34 of 887), respectively, for patients aged <65 years and > or = 65 years. The most common drug-related adverse events reported for ciprofloxacin-treated patients aged <65 years and > or = 65 years were digestive system-related (18.1% and 11.4%, respectively) and central nervous system-related events (6.6% and 4.9%, respectively).
Conclusions: This retrospective analysis suggests that there is no clinically important difference in the safety profile of ciprofloxacin in patients aged > or = 65 years versus patients aged <65 years.
Lipsky BA, Dorr MB, Magner DJ, et al
Clin Ther. 1999; 21(1):148-59
The safety profile of sparfloxacin, a newer fluoroquinolone antibiotic, was examined through an integrated analysis of safety data from 6 multicenter phase III trials. These consisted of 5 double-masked, randomized, comparative trials of sparfloxacin (a 400-mg oral loading dose followed by 200 mg/d for 10 days) versus standard therapies (erythromycin, cefaclor, ofloxacin, clarithromycin, and ciprofloxacin) and I open-label trial (noncomparative) in patients with: community-acquired pneumonia (2 trials); acute bacterial exacerbations of chronic bronchitis (1 trial); acute maxillary sinusitis (2 trials, one of which was the noncomparative trial); and complicated skin and skin-structure infections (1 trial). Overall, 401 (25.3%) of 1585 patients treated with sparfloxacin and 374 (28.1%) of 1331 receiving a comparator regimen experienced at least 1 adverse event considered to be related to the study medication. Photosensitivity reactions, usually of mild-to-moderate severity, were seen more frequently with sparfloxacin (7.4%) than with comparator agents (0.5%), whereas gastrointestinal reactions (diarrhea, nausea, dyspepsia, abdominal pain, vomiting, and flatulence), insomnia, and taste perversion were more common in patients taking comparator drugs (22.3% vs 12.1%, 4.3% vs 1.5%, and 2.9% vs 1.2%, respectively). Analysis of electrocardiographic findings showed that the mean change from baseline in QT interval corrected for heart rate (QTc) was significantly greater in sparfloxacin-treated patients (10 msec) than in patients given comparator drugs (3 msec), but no associated ventricular arrhythmias were detected. Adverse events led to discontinuation of study medication in 104 (6.6%) patients receiving sparfloxacin and 118 (8.9%) given com parator drugs. Sparfloxacin may be considered an appropriate choice for the treatment of certain community-acquired infections for patients who are not at risk for photosensitivity reactions or adverse events associated with prolongation of the QTc interval.
Ball P, Mandell L, Niki Y, et al
Drug Saf. 1999; 21(5):407-21
The most common adverse effects of the fluoroquinolones involve the gastrointestinal tract, skin and CNS, and are mainly mild and reversible. Of the gastrointestinal events, nausea and vomiting are the most common. Mild hepatic reactions are a class effect, usually presenting as mild transaminase level increases without clinical symptoms. However, postmarketing surveillance has revealed significant hepatotoxicity with trovafloxacin. It is not currently known whether the severe reactions to trovafloxacin are specific to that agent or simply represent an extreme of an emerging class effect. The enormous worldwide usage of, and extensive published adverse effect data on the other fluoroquinolones and naphthyridones suggests the former. In perspective, rare but serious hepatotoxicity has been reported with other fluoroquinolones and the overall incidence of trovafloxacin hepatotoxicity is not dissimilar to that reported with flucloxacillin and amoxicillin-clavulanic acid. CNS reactions vary in severity and include dizziness, convulsions (notably with lomefloxacin) and psychoses. Fluoroquinolones differ in their pro-convulsive activity, relating to their differing potential as gamma-aminobutyric acid antagonists and binding to the N-methyl-D-aspartate receptor. The basis for the increased seizure potential following the coadministration of nonsteroidal anti-inflammatory drugs with certain fluoroquinolones is not fully understood. Fluoroquinolone phototoxicity, caused by the generation of toxic free oxygen species under exposure to UVA radiation, is significantly more common with 8-halogenated compounds. Certain patient groups, e.g. patients with cystic fibrosis, are predisposed to this adverse effect. Murine photocarcinogenicity has been demonstrated with lomefloxacin, but no such effects have been reported in humans. Prolongation of the QTc interval is also a class effect, although cardiac arrhythmias have only been linked with sparfloxacin. Among the newer fluoroquinolones, clinically significant cardiac events are rare or absent but possible interactions in patients receiving other drugs capable of causi ng QT prolongation should be anticipated. Tendinitis and rupture, usually of the Achilles tendon, are rare, class-effects of fluoroquinolones, most frequently reported with pefloxacin. Predisposing factors include aging, corticosteroid use, renal disease, haemodialysis and transplantation. Use of fluoroquinolones in paediatric patients remains contentious. However, accruing human data suggest that restrictions on paediatric use imposed because of fluoroquinolone-induced cartilage damage in juvenile animals, may soon be relaxed. Data from over 1700 children in the UK failed to disclose arthropathy and extensive paediatric use of norfloxacin in Japan and ciprofloxacin in developing countries has been free of articular effects.
What's the latest in the safety and toxicity of fluoroquinolones? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pharmacotherapy.
Stahlmann R, Lode H
Drugs. 1999; 58:37-42
Reactions of the gastrointestinal tract, the CNS and the skin are the most often observed adverse effects during therapy with fluoroquinolones. At least for some of the newer fluoroquinolones a steep dose-response relationship of adverse effects seems to exist. Pathogenesis of the neurotoxic effects of fluoroquinolones is still unknown. Among the newer drugs, trovafloxacin caused mild CNS reactions such as dizziness and lightheadedness in a considerable proportion of patients. Young females seem to be especially sensitive to this effect, which diminishes during treatment or if taken together with food. Cardiotoxic potentials of sparfloxacin and grepafloxacin are higher than those of other fluoroquinolones, but during therapy no clearcut drug-related serious reactions have been reported, apart from a slight prolongation of the QT interval. However, to avoid risks these drugs should not be prescribed to patients with known prolongation of the QT interval (e.g. patients on antiarrhythmics). Phototoxicity has been described for all quinolones, but derivatives with a halogen atom at position 8 show the highest potential for such reactions. Fleroxacin, sparfloxacin, clinafloxacin and lomefloxacin belong to this group of fluoroquinolones. The phototoxic potential of the other new fluoroquinolones is considerably lower, but extensive exposure to UV light should generally be avoided during therapy with all quinolones. Chondrotoxicity of quinolones, as observed in immature animals, can affect articular cartilage and/or the epiphyseal growth plate, depending on the developmental stage. Pathogenesis of chondrotoxicity can probably be explained by the magnesium-chelating properties of these drugs. As juveniles are especially sensitive, use of these drugs in paediatrics should be restricted to carefully selected indications (such as the use of ciprofloxacin in cystic fibrosis). Another manifestation of the toxic effects of quinolones on connective tissue structures are tendopathies. Tendinitis and tendon ruptures have occurred as late as several months after quinolone treatment. Overall, quinolones are well tolerated drugs. Their specific toxic potentials have to be considered when they are chosen for treatment of bacterial infections.
Lipsky BA, Baker CA
Clin Infect Dis. 1999; 28(2):352-64
For 2 decades fluoroquinolones have been found to be generally well-tolerated and safe. Adverse events may be inherent to the class or influenced by structural modifications. The commonest adverse events are gastrointestinal tract (GI) and central nervous system (CNS) reactions; nephrotoxicity and tendinitis are infrequent, but agents differ greatly in phototoxic potential. Fluoroquinolones are safe in elderly, human immunodeficiency virus-infected, and neutropenic patients, but because of possible effects on articular cartilage, they are not currently recommended for children or pregnant women. Four new agents have recently been licensed. Levofloxacin causes few GI or CNS adverse events and is minimally phototoxic. Sparfloxacin infrequently causes GI or CNS effects but is associated with relatively high rates of phototoxicity and prolongation of the electrocardiographic QTc interval (Q-T interval, corrected for heart rate). Grepafloxacin causes relatively high rates of GI effects, taste perversion, and QTc interval prolongation, but it is minimally phototoxic. Trovafloxacin is associated with a moderate rate of GI effects and a relatively high incidence of dizziness but has low phototoxic potential.
Lode H
Drug Saf. 1999; 21(2):123-35
The new generation fluoroquinolones -- sparfloxacin, levofloxacin, grepafloxacin and trovafloxacin -- have been designed to respond to the clinical need for extended antimicrobial cover in the face of increasing global microbial resistance. Their main focus is in the treatment of respiratory infections, particularly those acquired in the community. CNS adverse effects, such as dizziness and headache, are known to occur relatively commonly with some fluoroquinolones and are not, in general, well tolerated by patients. The structural component of the fluoroquinolone molecule believed to be responsible for improved gram-positive activity is also believed to be implicated in the production of CNS adverse effects, including those arising from drug interactions with theophylline and NSAIDs. Inhibition of brain gamma-aminobutyric acid (GABA) receptor binding appears to be a strong indicator of CNS activity, though N-methyl-D-aspartate receptor binding has also been implicated. In accordance with the results of these predictive studies, clinical trials have found sparfloxacin, levofloxacin and grepafloxacin to be associated with a low incidence of CNS events. Trovafloxacin has been found to be associated with a higher incidence of CNS events (particularly lightheadedness and dizziness) than the other 3 agents. Ongoing and future clinical studies will help to define the usefulness of the predictive models, as well as reveal the full CNS adverse event profile of these and other investigational fluoroquinolones.
Lode H, Vogel F, Elies W
Clin Ther. 1999; 21(1):61-74
The safety profile of grepafloxacin has been characterized in a number of preclinical and clinical studies. Preclinical investigations have shown that its toxicologic profile is similar to that of other fluoroquinolones, and phase I studies in humans have confirmed these data. A photosensitivity study demonstrated equivalence with ciprofloxacin, and a study in elderly patients taking the highest clinical dose of grepafloxacin indicated that prolongation of the QTc interval by grepafloxacin was less than 2 ms, 15 times less than that observed in a study of erythromycin. In phase II and III clinical investigations conducted in the United States and the United Kingdom, safety data have been gathered from more than 3000 patients with either community-acquired pneumonia or acute bacterial exacerbations of chronic bronchitis. The most common adverse events with grepafloxacin 400 or 600 mg were gastrointestinal, such as nausea, vomiting, and diarrhea. The frequency of these adverse events was similar to that seen with ciprofloxacin. Significantly more patients reported a mild, unpleasant metallic taste with grepafloxacin than with ciprofloxacin, but <1% of patients withdrew from therapy because of this. Headache was observed significantly more often in ciprofloxacin-treated patients than in grepafloxacin-treated patients. Recent postmarketing data confirm the good tolerability and safety profile of grepafloxacin. These data, from a case-report study of more than 9000 patients in Germany, demonstrated that only 2.3% of patients reported adverse events when grepafloxacin was used in routine clinical practice. The most frequently reported events were nausea (0.8%) and gastrointestinal symptoms (0.4%). Dizziness was reported by only 0.3% of patients, and only 4 patients (0.04%) reported photosensitization. Adverse events did not appear to be either dose dependent or related to diagnosis. More than 400,000 patients world-wide have received grepafloxacin treatment. No new safety issues have arisen from the spontaneous-report data and, with the exception of rare reports of an unpleasant taste, the most commonly reported events have been the same as those seen in clinical studies. These data support grepafloxacin as a well-tolerated fluoroquinolone suitable for the treatment of community-acquired respiratory tract infections.
Bertino J, Fish D
Clin Ther. 2000; 22(7):798-817
Background: Premarketing trials showed the fluoroquinolone agents to have a favorable side-effect profile, with treatment-related adverse events comprising gastrointestinal, central nervous system, and dermatologic effects that were generally mild and reversible on cessation of treatment. However, postmarketing surveillance studies have identified severe adverse events, including severe anaphylaxis, QTc-interval prolongation, and potential cardiotoxicity, associated with 3 quinolone agents that either resulted in the removal of the agent from the market (temafloxacin and grepafloxacin) or significantly restricted its use due to substantial mortality and morbidity associated with liver toxicity (trovafloxacin). To date, there have been no such significant adverse events associated with the older fluoroquinolone agents, including ciprofloxacin, ofloxacin, norfloxacin, and levofloxacin. However, there are fewer data from postmarketing surveillance studies on the most recently approved agents, such as moxifloxacin and gatifloxacin, or agents awaiting approval, such as gemifloxacin.
Objective: This paper examines safety data from the premarketing trials and postmarketing surveillance studies of fluoroquinolones available in the United States.
Methods: A MEDLINE search was performed to identify all English-language studies published since 1980 concerning the safety profiles of the fluoroquinolones.
Conclusions: The fluoroquinolone antibacterial agents offer broad-spectrum therapy in patients with a variety of infections. Given similar spectra of activity, the choice between quinolones may be based on differences in efficacy and safety or tolerability profiles. Most drug reactions involving these agents are minor and reversible on discontinuing treatment, but adverse effects can be associated with significant mortality and morbidity, as was seen in the case of trovafloxacin and temafloxacin.
Heyd A, Haverstock D
Clin Ther. 2000; 22(10):1239-50
Background: Ciprofloxacin is a broad-spectrum fluoroquinolone antibiotic used in the treatment of a wide range of mild to moderate gram-positive and gram-negative infections. Although extensive information is available on the safety profile of ciprofloxacin in adults, few published data exist regarding the tolerability and toxicity of this drug in patients aged > or = 65 years.
Objectives: The objectives of this retrospective analysis were to compare the safety profile of ciprofloxacin in patients aged > or = 65 years versus patients aged <65 years and to compare the adverse-event profile of ciprofloxacin with that of other comparator antimicrobial agents used in clinical trials.
Methods: We retrospectively reviewed 23 prospective, controlled anti-infective clinical trials in the US Bayer ciprofloxacin database that included patients aged > or = 65 years. These trials comprised the submission file of the original and supplemental New Drug Application for ciprofloxacin. The incidence of treatment-emergent and drug-related adverse events was assessed.
Results: Of the 6863 patients in these 23 clinical trials, 3579 received ciprofloxacin therapy and 3284 received comparator antimicrobial agents. Of the ciprofloxacin-treated patients, 898 (25.1%) were aged > or = 65 years; 887 (27.0%) of the patients who received comparator antimicrobial agents were aged > or = 65 years. Among ciprofloxacin-treated patients, drug-related adverse events were reported more often in those aged <65 years (24.0%) compared with those aged > or = 65 years (17.9%). The incidence of drug-related adverse events in the comparator group was also higher in those aged <65 years (25.1%) than in those aged > or = 65 years (16.8%). Premature discontinuation due to any adverse event was reported in 3.9% (105 of 2681) and 3.7% (33 of 898) of ciprofloxacin-treated patients aged <65 years and > or = 65 years, respectively. Corresponding rates for the comparator antimicrobial group were 3.9% (93 of 2397) and 3.8% (34 of 887), respectively, for patients aged <65 years and > or = 65 years. The most common drug-related adverse events reported for ciprofloxacin-treated patients aged <65 years and > or = 65 years were digestive system-related (18.1% and 11.4%, respectively) and central nervous system-related events (6.6% and 4.9%, respectively).
Conclusions: This retrospective analysis suggests that there is no clinically important difference in the safety profile of ciprofloxacin in patients aged > or = 65 years versus patients aged <65 years.
Lipsky BA, Dorr MB, Magner DJ, et al
Clin Ther. 1999; 21(1):148-59
The safety profile of sparfloxacin, a newer fluoroquinolone antibiotic, was examined through an integrated analysis of safety data from 6 multicenter phase III trials. These consisted of 5 double-masked, randomized, comparative trials of sparfloxacin (a 400-mg oral loading dose followed by 200 mg/d for 10 days) versus standard therapies (erythromycin, cefaclor, ofloxacin, clarithromycin, and ciprofloxacin) and I open-label trial (noncomparative) in patients with: community-acquired pneumonia (2 trials); acute bacterial exacerbations of chronic bronchitis (1 trial); acute maxillary sinusitis (2 trials, one of which was the noncomparative trial); and complicated skin and skin-structure infections (1 trial). Overall, 401 (25.3%) of 1585 patients treated with sparfloxacin and 374 (28.1%) of 1331 receiving a comparator regimen experienced at least 1 adverse event considered to be related to the study medication. Photosensitivity reactions, usually of mild-to-moderate severity, were seen more frequently with sparfloxacin (7.4%) than with comparator agents (0.5%), whereas gastrointestinal reactions (diarrhea, nausea, dyspepsia, abdominal pain, vomiting, and flatulence), insomnia, and taste perversion were more common in patients taking comparator drugs (22.3% vs 12.1%, 4.3% vs 1.5%, and 2.9% vs 1.2%, respectively). Analysis of electrocardiographic findings showed that the mean change from baseline in QT interval corrected for heart rate (QTc) was significantly greater in sparfloxacin-treated patients (10 msec) than in patients given comparator drugs (3 msec), but no associated ventricular arrhythmias were detected. Adverse events led to discontinuation of study medication in 104 (6.6%) patients receiving sparfloxacin and 118 (8.9%) given com parator drugs. Sparfloxacin may be considered an appropriate choice for the treatment of certain community-acquired infections for patients who are not at risk for photosensitivity reactions or adverse events associated with prolongation of the QTc interval.
Ball P, Mandell L, Niki Y, et al
Drug Saf. 1999; 21(5):407-21
The most common adverse effects of the fluoroquinolones involve the gastrointestinal tract, skin and CNS, and are mainly mild and reversible. Of the gastrointestinal events, nausea and vomiting are the most common. Mild hepatic reactions are a class effect, usually presenting as mild transaminase level increases without clinical symptoms. However, postmarketing surveillance has revealed significant hepatotoxicity with trovafloxacin. It is not currently known whether the severe reactions to trovafloxacin are specific to that agent or simply represent an extreme of an emerging class effect. The enormous worldwide usage of, and extensive published adverse effect data on the other fluoroquinolones and naphthyridones suggests the former. In perspective, rare but serious hepatotoxicity has been reported with other fluoroquinolones and the overall incidence of trovafloxacin hepatotoxicity is not dissimilar to that reported with flucloxacillin and amoxicillin-clavulanic acid. CNS reactions vary in severity and include dizziness, convulsions (notably with lomefloxacin) and psychoses. Fluoroquinolones differ in their pro-convulsive activity, relating to their differing potential as gamma-aminobutyric acid antagonists and binding to the N-methyl-D-aspartate receptor. The basis for the increased seizure potential following the coadministration of nonsteroidal anti-inflammatory drugs with certain fluoroquinolones is not fully understood. Fluoroquinolone phototoxicity, caused by the generation of toxic free oxygen species under exposure to UVA radiation, is significantly more common with 8-halogenated compounds. Certain patient groups, e.g. patients with cystic fibrosis, are predisposed to this adverse effect. Murine photocarcinogenicity has been demonstrated with lomefloxacin, but no such effects have been reported in humans. Prolongation of the QTc interval is also a class effect, although cardiac arrhythmias have only been linked with sparfloxacin. Among the newer fluoroquinolones, clinically significant cardiac events are rare or absent but possible interactions in patients receiving other drugs capable of causi ng QT prolongation should be anticipated. Tendinitis and rupture, usually of the Achilles tendon, are rare, class-effects of fluoroquinolones, most frequently reported with pefloxacin. Predisposing factors include aging, corticosteroid use, renal disease, haemodialysis and transplantation. Use of fluoroquinolones in paediatric patients remains contentious. However, accruing human data suggest that restrictions on paediatric use imposed because of fluoroquinolone-induced cartilage damage in juvenile animals, may soon be relaxed. Data from over 1700 children in the UK failed to disclose arthropathy and extensive paediatric use of norfloxacin in Japan and ciprofloxacin in developing countries has been free of articular effects.
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