The Safety Profile of the Fluoroquinolones

CLINICAL THERAPEUTICS’“/VOL. 22, NO. 7,200O

The Safety Profile of the Fluoroquinolones

Joseph Bertino, Jr., PharmD,’ and Douglas Fish, Pharmti ‘Bassett Healthcare, Cooperstown, New York, and 21Jniversity of Colorado Health Sciences Center, Denver, Colorado

ABSTRACT

Background: Premarketing trials showed the fluoroquinolone agents to have a favor- able 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 re- moval 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.

Key words: fluoroquinolones, safety profile, adverse effects, antibiotics. (Clin Ther. 2000;22:798-8 17)

Accepted for publication May 26, 2000.

Printed in the USA. Reproduction in whole or part is not permitted.

798 0149.2918/00/$19.00

J. BERTINO, JR., AND D. FISH

INTRODUCTION

The quinolone antibiotics act primarily by inhibiting bacterial topoisomerase.’ The first quinolone to be introduced was nalidixic acid, in 1962; the first to receive approval by the US Food and Drug Ad- ministration (FDA) was norfloxacin, in 1984. Compared with more recently introduced fluoroquinolones, the older agents, such as enoxacin, lomefloxacin, and norfloxacin, have been associated with a limited spectrum of activity (encompassing some gram-positive and gram-negative aerobic organisms), lower potency, higher frequency of spontaneous bacterial resistance, lower serum drug concentrations, and shorter half-lives. Their use was es- sentially restricted to treatment of urinary tract infections (UTIs).

The newer fluorinated quinolones, or fluoroquinolones, generally have a broader spectrum of antibacterial activity, encompassing gram-negative and gram-positive aerobic bacteria (enterococci, strepto- cocci, and staphylococci). These agents- levofloxacin, trovafloxacin, sparfloxacin, moxifloxacin, and gatifloxacin-are also active against many Mycobacterium, Chlamydia, Legionella, and Mycoplasma species. They have good activity against most Enterobacteriaceae, facultative anaer- obic bacteria,2 and many bacterial strains that are multiresistant to beta-lactam3 and aminoglycoside antibiotics4 Although the newer agents are less active than ciprofloxacin against Pseudomonas aeruginosa, they are more active against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae. Trovafloxacin also has clinically proven activity against Bacteroides fragilis.5*6

The newer fluoroquinolones have longer elimination half-lives than the older agents, exhibiting high potency, a low incidence of resistance, extensive tissue penetration,‘-s and high oral bioavail- ability. Sparfloxacin, lomefloxacin, enoxacin, norfloxacin, and moxifloxacin are available in oral formulations only, whereas levofloxacin, ofloxacin, ciprofloxacin, trovafloxacin, and gatifloxacin are available in both oral and IV formulations. Of the agents currently available, only levofloxacin and gatifloxacin can be adminis- tered using “switch” therapy, which al- lows conversion from IV to oral therapy without changing the dosage regimen or antibiotic class.

The fluoroquinolones are used pre- dominantly in the treatment of respiratory tract infections, UTIs, sexually transmitted diseaseslo and infections of the skin and soft tissue. Since their introduction in the 1980s >lOO million patients worldwide have received fluorinated quinolone agents.”

Despite a common mechanism of action, individual fluoroquinolones differ significantly in their antimicrobial spec- trums of activity, pharmacokinetic char- acteristics, and safety profiles,‘* primarily as a result of their respective side-chain modifications (Table I). For example, the 8-halogenated derivatives, including sparfloxacin, are most likely to cause phototoxicity, whereas the C7 sub- stituent found in enoxacin is more likely to result in central nervous system (CNS) reactions.‘” Interactions with theophylline are most likely to be seen with agents containing modifications at positions 1, 7, and 8.

As a class, the fluoroquinolones are generally well tolerated and safe. The incidence of adverse events varies significantly

799

CLINICAL THERAPEUTICS”

Table I. Impact of side-chain modifications on side-effect profiles of fluoroquinolones.

Modification Fluoroquinolone Effect

Substituents at position 7 Enoxacin, trovafloxacin CNS effects Modifications at position 8 Sparfloxacin, clinafloxacin Phototoxicity Modifications at position 7 Fleroxacin, enoxacin Interactions with NSAIDs

and piperazines Modifications at positions 1, 7, and 8 Ciprofloxacin, enoxacin Interactions with

theophylline

CNS = central nervous system; NSAIDs = nonsteroidal anti-inflammatory drugs.

Table II. US Food and Drug Administration (FDA) Public Health Advisory on trovafloxacin.2i

The FDA has advised physicians that trovafloxacin should be reserved for use ONLY in the treatment of patients meeting ALL of the following treatment criteria:

Have at least one of the following infections judged by the treating physician to be serious and life- or limb-threatening: nosocomial pneumonia; community-acquired pneumonia; complicated intra-abdominal infections, including postsurgical infections; gynecologic and pelvic infections; or complicated skin and skin-structure infections, including diabetic foot infections.

Receive their initial therapy in an inpatient health care facility.

The treating physician believes that even given the new safety information, the benefit of the product for the patient outweighs the potential risk.

This advisory pertains only to trovafloxacin, and no other fluoroquinolone.

depending on the physicochemical structure of specific agents. The adverse effects associated with fluoroquinolones most commonly include gastrointestinal (GI) disturbances, CNS reactions, and derrnato- logic effects, and are generally mild in severity and reversible on cessation of treatment. There is controversy regarding use of these agents in childreni because of animal data showing arthropathic lesions in juvenile beagle dogs’“*i6 and rats17m20; such lesions have rarely been reported in children, however. Serious adverse events

include phototoxicity associated with sparfloxacin and prolongation of the QTc interval associated with sparfloxacin and grepafloxacin. In addition, as discussed later in the paper, recent reports have found an association between trovafloxacin and liver toxicity that has resulted in significant morbidity and death. This prompted the FDA to issue a Public Health Advisory for trovafloxacin, severely restricting its use (Table II).2’ This advisory pertained only to trovafloxacin and not to any other fluoroquinolone.

800


In June 1992, the fluoroquinolone temafloxacin was removed from the market. Serious adverse events had been reported at a frequency of -1 per 3500 patients treated with temafloxacin and included anaphylaxis, hemolytic anemia, and renal failure, as well as hypoglycemia and severe hemolysis.” These serious side effects became evident only when the agent was used in the general population and hundreds of thousands of patients had taken it. Despite careful analysis of the phase III registration studies, these potential concerns had not been identified. Grepafloxacin was voluntarily removed from the market by its manufacturer in October 1999 as a result of emerging safety concerns regarding severe cardiovascular events.

Known drug interactions with the fluoroquinolones are usually limited in severity and easily managed, either by admin- istering the relevant agents separately or by substituting other appropriate agents. All quinolones have potential interactions with multivalent cation-containing compounds, and some have the potential for drug interactions with theophylline and caffeine. Some fluoroquinolones, including enoxacin and ciprofloxacin, inhibit the hepatic cytochrome P-450 (CYP-450) enzyme system; others, such as ofloxacin and lomefloxacin, have minimal effects on this system, whereas levofloxacin, gatifloxacin, and moxifloxacin have no effects on this system. Drugs that prolong the QTc interval should not be coadmin- istered with sparfloxacin or moxifloxacin.

The objective of this review was to in- tegrate data from premarketing trials with those from postmarketing surveillance studies to provide a current overview of the safety profiles of the available fluoroquinolones.

METHODS

A MEDLINE@ search was performed to identify all English-language studies published since 1980 concerning the safety profiles of the fluoroquinolones. More than 200 articles were identified that addressed safety issues, side-effect profiles, and tolerability concerns with the fluoroquinolones, both as an antibacterial class and as individual agents. Because published data on recently approved or investigational agents were often unavailable, 9 abstracts presented at scientific meetings were also referenced. Although such information is usually not as complete as that from published sources, inclusion of these data was judged to be worthwhile to make our review as comprehensive as possible.

CHEMICAL STRUCTURE OF THE FLUOROQUINOLONES

All clinically important fluoroquinolones are synthetic derivatives of nalidixic acid, a 1,8-naphthyridine that was the first mem- ber of the quinolone class. Al1 entail a 4- quinolone nucleus or a modified dual-ring system. 22 Two separate modifications of the original 1,8-naphthyridine nucleus account for the current fluoroquinolone agents: 1 involved a carbon-for-nitrogen substitution at position 8 of the 6-fluoro, 7-piperazinyl quinolone, in addition to other side-chain modifications, which led to the development of ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, and clinafloxacin; the other involved an additional 8-methoxy side chain, which led to the development of moxifloxacin and gatifloxacin. Enoxacin was developed by structural alterations to the naphthyridine core, and trovafloxacin was produced by a 7azabicyclo modification to this core molecule.

801


MECHANISM OF ACTION

Quinolones act by inhibiting the activities of DNA gyrase in gram-negative bacteria, which in turn inhibits replication and tran- scription of bacterial DNA?’ Prevention of DNA synthesis ultimately results in rapid cell death.24 This unique mechanism of action may account for the low rate of cross-resistance with other antimicrobial classes. Quinolones similarly inhibit the in vitro activities of DNA topoisomerase IV, which is believed to be the primary target in gram-positive bacteria.2 Data indicate that mutations in pneumococcal gyrA, parC, and parE genes all contribute to de- creased susceptibility to the newer fluoroquinolones.25

ADVERSE EFFECTS

The most common adverse effects associated with the fluoroquinolones are GI effects such as nausea, vomiting, and diarrhea (- 1%-5%)26,27; skin disturbances (<2.5%)26; and CNS effects, including headaches and dizziness (- 1 %-2%).26928 Less common adverse effects are sleep disturbances, hallucinations, depression, and seizures.26 These adverse effects are generally mild and self-limiting, and sel- dom result in treatment withdrawal.29,“0 Nephrotoxicity has been reported in 2 case studies involving patients receiving coad- ministered cyclosporine and ciprofloxacin.31,“2 Dermatologic effects include rare maculopapular or urticarial eruptions, and more common phototoxic reactions with specific agents. With IV formulations, pain at the injection site has been reported.

Diarrhea and pseudomembranous colitis (PMC) have long been associated with the use of antibiotics.“3,34 Overgrowth of Clostridium diflicile has been identified

as the cause of 10% to 25% of cases of antibiotic-associated diarrhea and almost all cases of antibiotic-associated PMC.“5 Although clindamycin is a well-known cause of antibiotic-induced diarrhea,?6 almost all antibiotics, including fluoroquinolones, may be responsible. Penicillin derivatives”“,“’ have been associated with hemorrhagic colitis. A French retrospec- tive study examined 878 cases of antibiotic-induced PMC within a 6-month pe- riod.38 The antibiotics most frequently associated with PMC included cefixime, amoxicillin-clavulanic acid, amoxicillin, ofloxacin, and trimethoprim-sulfamethoxazole; less frequently associated were cefaclor, cefuroxime axetil, and tetracy- clines. Macrolides were very rarely associated with PMC. Fluoroquinolones were also associated with a very low incidence of PMC.

Fluoroquinolones have been found to in- duce tendon lesions in juvenile rats.‘7.‘9 Electron-microscopic examination has shown hypertrophy, stratification, and an increased number of capillary endothelial cells in juvenile rats, as well as an increased number of fibroblasts and macrophages2’ In the same study, fluoroquinolones were also associated with deposition of collagen in the matrix of the synovial membrane and tendon sheath.

A recent study in immature dogs assessed the biochemical changes occurring in tendons after exposure to fluoroquinolones.39 The dogs were treated for 5 days with oral ciprofloxacin (30 or 200 mg/kg) or placebo. Because previous research had demonstrated quinolone-like defects in joint cartilage owing to magnesium deficiency, an additional group was also fed a magnesium- deficient diet. Tendons were analyzed using antibodies directed against matrix proteins and integrins. Animals treated with cip-

802


rofloxacin and fed the magnesium-deficient diet had statistically significant reductions in all proteins (ie, collagen, fibronectin, elastin, and p, integrin) compared with the control group. The results appeared to sup- port the hypothesis that quinolone-induced toxic effects on connective-tissue structures may be attributable to the magnesium- antagonistic effects of these agents.

The extent of toxic effects varies by the individual fluoroquinolone and the dose. One study found that a single oral dose of 900 mg/kg pefloxacin resulted in more severe lesions in juvenile rats than a comparable dose of levofloxacin.20 Although neither single nor multiple doses of sparfloxacin 600 mg/kg were sufficient to in- duce joint cartilage lesions in juvenile rats, a single dose of 1800 mg/kg was sufficient to cause cartilage lesions in the femoral part of the knee joint. I9 A study comparing 10 fluoroquinolones found that fleroxacin and pefloxacin had the greatest Achilles tendon toxicity in rats, followed by lomefloxacin, levofloxacin, and ofloxacin. I7 Sparfloxacin and enoxacin were minimally toxic, and no Achilles tendon toxicity was seen in rats given norfloxacin or ciprofloxacin. Another study found that grepafloxacin had a low potential for joint toxicity in ratsi

Fluoroquinolone-induced tendinopathy has also been reported in humans.40,4’ Al- though there is some information on this condition in the US literature,42a tendon disorders appear to be far more common in association with fluoroquinolone use in Europe.45 In fact, cutaneous diseases and tendon disorders are among the most frequent adverse drug reactions to fluoroquinolones in France, and tendon disorders are the fifth most common such reaction in the United Kingdom.45 Fluo- roquinolone-associated tendon disorders occur more often in elderly patients43 and

are 2 to 3 times more common in men.43+r Symptoms may occur within 2 to 42 days after starting fluoroquinolone therapy, and up to two thirds of cases resolve within 1 to 2 months after discontinuation of the agent.43 A need for hospitalization, surgi- cal repair, or prolonged periods of dis- ability has been reported.44 Fluoroquino- lone-induced tendinopathy increases the risk of immediate or secondary tendon rupture. 46 Other factors that can increase the risk of tendon inflammation include long-term steroid treatment,42,47 advanced age, and renal failure.38 In addition, studies indicate that fluoroquinolone-induced tendinopathy is more common in tendons under high stress, including the Achilles tendon.42 Therefore, treatment with fluoroquinolones should be discontinued at the first sign of tendon inflammation.

The severe quinolone-induced arthropathy previously observed in animalsi5~t7*t9 has not been clearly documented in ado- lescents or adults exposed to these agents. Although arthralgia with or without effu- sion has been documented, it occurs at a relatively low rate (11.5%)48-50 and re- solves completely once drug therapy is discontinued, with no evidence of serious or long-term sequelae. Although none of the currently available fluoroquinolones are approved for use in children, their use in this population appears to be justilied46 on the basis of risk-benefit considerations under compelling clinical circumstances (eg, cystic fibrosis patients with multidrug- resistant gram-negative infection).

Animal research has also examined the impact of fluoroquinolones on fracture healing. As noted above, quinolones have demonstrated chondrotoxicity in developing articular cartilage in juvenile mam- ma1s.15,17,19 In a process similar to that in developing articular cartilage, fracture re-

803


pair involves cartilage callus formation, followed by differentiation into cancel- lous bone. A study in Wistar rats” compared the mechanical strength of experimental fracture calluses after treatment with ciprofloxacin, trovafloxacin, and no treatment. The mechanical strength of fractures was statistically significantly lower among the rats treated with either antibiotic agent (P < 0.05), with no statistically significant difference between the 2 agents.

These musculoskeletal effects have led to contraindication of the routine use of fluoroquinolones in children, whose skel- etal growth is incomplete, as well as in pregnant and lactating women. However, a recent consensus report from the Inter- national Society of Chemotherapy concluded that “critical and cautious use of fluoroquinolones” in selected patients is justifiable by “experimental and clinical data when alternative safe therapy is not available.“52 Although there are a few class effects, there are also significant differences between the safety and tolerability profiles of specific fluoroquinolone agents, often related to the physicochemical structure of the drug.26 It is not possible to predict the extent to which serious side effects and toxicities will occur

in a population without involving many thousands of patients; this was particularly apparent in the case of temafloxacin and perhaps trovafloxacin. To date, the safety profiles of ofloxacin, ciprofloxa- tin, sparfloxacin, grepafloxacin, and levofloxacin have been studied most exten- sively (Table III).

Ciprojloxacin

GI disturbances are the most common adverse effects associated with ciprofloxacin.53 A review of the manufacturer’s US ciprofloxacin database found nausea to be the most commonly reported adverse event in premarketing clinical trials ( 10.0%).54 In clinical trials, disorders of the digestive system were the most common adverse events (4.9%) with nearly 9500 oral treatment courses through 1988.55 Similarly, GI disturbance (particularly nausea and diarrhea) is a common effect (3.0%) of IV ciprofloxacin therapy.5” Skin and CNS reactions are also common.

Until recently, ciprofloxacin was not recommended for use in children or pregnant women, as it has been shown to cause articular damage in juvenile animals.26 However, data from >1500 pediatric patients treated with ciprofloxacin for infec-

Table III. Incidence of the most common drug-related adverse events occurring with the newer fluoroquinolones, based on package inserts.

Event (%) Ciprofloxacin Levofloxacin Sparfloxacin Trovafloxacin Lomefloxacin

Nausea 5.2 1.2 4.3 8.0 3.7 Diarrhea 2.3 1.2 4.6 2.0 I .4 Taste perversion 0.02 0.2 1.4 - <I.0 Headache I.2 0.1 4.2 5.0 3.2 Dizziness <I.0 0.3 2.0 11.0 2.3 Phototoxicity 0.4 <o. I 7.9 <0.03 2.4

804


tions related to cystic fibrosis have shown a safety profile in children and adoles- cents comparable to that in adult patients.57 Thirty-six of 1113 patients (3.2%) with cystic fibrosis experienced reversible arthralgia. Gl and CNS reactions were the most common adverse events, occurring in 5% to 15% of patients. Additional worldwide data involving nearly 1800 children (2030 courses of treatment) identified arthralgia in 1.5% of treatment courses, with 60.0% of these cases in children with cystic fibrosis.50 The majority of these events (86.2%) were of mild (9/29) to moderate (16129) severity, and 25.0% resolved spontaneously.

In a review of 146 clinical trials of oral ciprofloxacin, 55 3.3% of treated patients exhibited CNS symptoms, including dizziness, headache, tremor, and restlessness. Even at a high dosage of 400 mg every 8 hours, seizures were rarely reported (<I%).

There have been ~7 documented cases of anaphylactoid reactions to ciprofloxa- tin in HIV-infected patients, as well as 3 cases of life-threatening hypersensitivity reactions (2 in HIV-infected patients).58 Use of ciprofloxacin in HIV-infected patients may increase the risk for hypersensitivity or anaphylactoid reactions, but this is not yet proved.

Ojloxacin

Gl disturbances are the most common adverse events associated with use of ofloxacin, including nausea (3.0%), diarrhea (l.O%), and abdominal discomfort (1 .0%-3.0%).59 Common CNS complaints include headache (1 .O%), dizziness (1 .O%), and restlessness (3.0%). Dizziness and sleep disturbances may be problematic, particularly at higher dosages.60 Hallucina- tions and psychotic reactions have been re-

ported (sO.~%).~~ In a study that compared three 4-quinolone antibiotics with azithromycin and cefixime,62 the most common adverse events with ofloxacin during the week following initiation of treatment included nausea/vomiting (4.9/1000 patients), headache/migraine ( 1.5/ 1000 patients), and malaise/lassitude (1.411000 patients).

Norfloxacin

In a review of worldwide clinical trials of norfloxacin in the treatment of UTI, the overall incidence of adverse events was 2.3%.63 However, in another study,@ 12 of 50 patients (24.0%) experienced adverse reactions, particularly nausea, dizziness, and headache. Similarly, another trial found that Gl disturbance constituted the majority of adverse effects associated with the use of norfloxacin.65

Sparfloxacin

Sparfloxacin has been associated with infrequent Gl or CNS effects but relatively high rates of phototoxicity and prolongation of the QTc interva1.67,68 Pho- totoxicity is one of the most common adverse effects associated with sparfloxacin, occurring in -8.0% of patients.67 A comparative trial of sparfloxacin versus ofloxacin involving 900 women diag- nosed with community-acquired acute uncomplicated UT1 found phototoxicity to be more frequent in the women receiving sparfloxacin compared with ofloxacin (6.9% vs 0.5%).59 Women in both treatment groups reported Gl effects and headache; women receiving ofloxacin reported more insomnia (3.7%) than women in the sparfloxacin group (1 .O%).

805

CLINICAL THERAPEUTICS’

In a double-blind study comparing sparfloxacin once daily versus ofloxacin twice daily in the treatment of acute exacerbations of chronic bronchitis,69 adverse-effect profiles were significantly different between the 2 agents. Approximately 8.0% of patients receiving sparfloxacin experienced phototoxic reactions, and 15.0% of patients taking ofloxacin reported insomnia.

Two double-blind, randomized clinical studies70x71 compared oral sparfloxacin regimens with either cefaclor or erythromycin in the management of community- acquired pneumonia. Diarrhea was common with all 3 agents; as in other studies, -8.0% of patients taking sparfloxacin experienced photosensitivity. This phototoxicity may occur with indirect exposure to sunlight or despite sunscreen use; thus, patients taking sparf’loxacin are advised to avoid sunlight during therapy and for 5 days after and to cover themselves completely when sun avoidance is not possible. Similar phototoxicity effects have been seen with clinafloxacin.72

A recent integrated analysi&* examined safety data from 6 multicenter phase III trials involving 1585 patients treated with spaffloxacin and 133 1 receiving a comparator antibiotic. Phototoxicity was far more frequent with sparfloxacin (7.4% vs 0.5%; P < 0.001). GI reactions were the most common adverse events associated with sparfloxacin (22.3%) versus comparator (I 2.1%; P = 0.002), including diarrhea, nausea, dyspepsia, abdominal pain, vomiting, and flatulence. The mean change from baseline in the QTc interval was significantly greater in sparfloxacin- treated patients than comparator patients (10 vs 3 milliseconds; P = 0.062).

Prolongation of the QTc interval is another serious concern associated with the use of spaffloxacin. 67,73 Results from phase

I and III studies consistently indicate that the increase in QTc interval is moderate (mean, 3.0%). 74 Increased plasma concentrations of sparfloxacin in patients with renal insufficiency do not appear to augment the drug’s effects on the QTc interval or the risk of adverse events75; all reported adverse cardiovascular events have occurred in patients with an underlying cardiac condition. Patients are warned to avoid concomitant use of drugs known to produce QTc-interval prolongation, including amiodarone, disopyramide, terfenadine, quinidine, procainamide, sotalol, erythromycin, cisapride, metoclopramide, and bepridil.67

Levofloxacin

Levofloxacin has been associated with low levels of GI upset, including nausea and diarrhea.7M’ Levofloxacin is the left optical isomer of ofloxacin and is assoc- ated with few CNS effects such as headache and dizzinesss2 Unlike sparfloxacin, phototoxicity is not a concern with levofloxacin.x3s4 GI effects such as nausea and diarrhea are the most common side effects associated with this agent and are usually mild. A number of studies of levofloxacin have shown a rate of adverse events between 2.0% and 9.9%,x5 with an overall incidence of adverse effects during clinical trials of 6.2%.76

In a study comparing the safety and efficacy of levofloxacin with those of ceftriaxone/cefuroxime axetil in the treatment of 590 patients with community-acquired pneumonia,77 5.8% of patients receiving levofloxacin reported adverse reactions, compared with 9.5% of patients receiving ceftriaxone/cefuroxime axetil. Complaints in both treatment groups were predomi- nantly of GI upset or CNS symptoms. Two

806


comparative studies of the safety and efficacy of levofloxacin versus cefaclor79 and cefuroxime axetils6 in the treatment of acute bacterial exacerbations of chronic bronchitis found GI-related symptoms to be the most commonly reported complaint. Overall rates of adverse effects were 7.0% for levofloxacin versus cefaclor (4.9%) and 9.9% for levofloxacin versus cefuroxime axetil (7.9%). Nausea was the most common complaint in patients receiving levofloxacin, and diarrhea was more common in patients receiving cefaclor.

A multicenter, randomized, open-label study involving 615 patients with acute maxillary sinusitis found the incidence of GI events to be lower in levofloxacin- treated patients than in patients receiving amoxicillin/clavulanate.87 The investiga- tors concluded that once-daily levofloxacin was as effective as and better tolerated than amoxicillin/clavulanate 3 times a day.

In a study comparing levofloxacin with ciprofloxacin and lomefloxacin in the treatment of acute pyelonephritis,78 levofloxacin-treated patients had the lowest rates of reported adverse events (2.0% compared with 8.0% and 5.0%, respec- tively). A similar study found oral levofloxacin to be comparable in tolerability (4.0% vs 3.0%) to oral ciprofloxacin in the treatment of complicated UTLs8 Stud- ies comparing levofloxacin with ciprofloxacin in the management of uncomplicated skin and skin-structure infections obtained similar results.80,89

Grepafloxacin

As stated earlier, grepafloxacin was withdrawn from the worldwide market in 1999 as a result of emerging concerns about its cardiovascular safety. Specifical-

ly, these concerns involved QTc-interval prolongation. Two confirmed cases and 1 unconfirmed case of torsades de pointes were reported. Although these cardiovascular events were rare, the manufacturer (Glaxo Wellcome, Greenford, Middlesex, UK) was “no longer convinced that the benefits of Raxar (grepafloxacin) out- weigh the potential risk to patients given the availability of alternative antibiotics.“90

Lomejloxacin

CNS reactions are among the most common adverse effects associated with lomefloxacin use. The incidence of dizziness, tremors, and seizures is higher with lome- tloxacin than with ciprofloxacin, ofloxacin, or norfloxacin; in fact, the rate of reported seizures is -45 per million prescriptions of lomefloxacin, compared with 10 per million prescriptions with the other 3 agentsT6 The increased rate of seizures has been associated with drug interactions, often between the fluoroquinolone and theophylline or nonsteroidal anti-inflammatory drugs (NSAIDs). m Although animal studies indicate that any combination of NSAIDs and fluoroquinolones can be epileptogenic, the most potent combination appears to be fenbufen and either lomefloxacin or enoxacin,61 with the least potent combinations involving levofloxacin, sparfloxacin,26 or newer agents such as gatifloxacin and moxifloxacin. Phototoxic reactions are another concern associated with the use of lomefloxacin. An increased incidence of phototoxic reactions has resulted in the circulation of warning letters from the manufacturer (Unimed Pharmaceuti- cals, Inc, Buffalo Grove, Illinois) to pre- scribers in the United States and other countries. According to an analysis of spon-

807

CLINICAL THERAPEUTICS’

taneous reports to the FDA,60 lomefloxacin- induced phototoxicity occurred in 70 patients per 100,000 prescriptions, compared with ~0.1 patient per 100,000 prescriptions of ciprofloxacin and 0.4 patient per 100,000 prescriptions of ofloxacin.

A multicenter, randomized, open-label trial involving 42 1 patients9’ compared the efficacy and safety of lomefloxacin 400 mg once daily for 3 days with those of norfloxacin 800 mg twice daily for 10 days in the treatment of recurrent uncomplicated lower UT1 in women. The most commonly reported adverse effects with lomefloxacin included vaginal infections, dermatologic disorders, and GI complaints.

TrovajZoxacin

Trovafloxacin is a fluoroquinolone with enhanced in vitro activity against gram- positive and gram-negative organisms, atypical pathogens, and anaerobes. Its pharmacokinetic profile facilitates once- daily oral or IV (alatrofloxacin) dosing.92 Until recently, trovafloxacin had been considered of relatively comparable safety and tolerability to other fluoroquinolones. It had been associated only with a moderate rate of GI effects, a relatively high incidence of first-dose dizziness or light- headedness in young women,93 headache, and a low potential for phototoxicity.

Trovafloxacin has been well tolerated in double-blind, randomized, multicenter trials involving >I700 patients. Nausea, headache, and dizziness were the most common treatment-related adverse events, in addition to pruritus and injection-site reactions. No serious quinolone toxicity (phototoxicity, cardiovascular toxicity, hemolytic anemia) or drug interactions were reported, and there was no mortality related to trovafloxacin administration.

Before its approval in 1997, premarketing clinical trials in 7000 patients found no cases of hepatic failure or death of a possible hepatic etiology associated with the use of trovafloxacin. It has been esti- mated that >2,500,000 patients have received trovafloxacin since its approval for marketing in 1998, since which time 150 cases of clinically symptomatic liver toxicity have been reported in patients receiving the drug, including ~14 cases of acute liver failure. Four patients required liver transplants, and an additional 5 died of liver-related illness. Although these events were extremely rare (occurring in 0.006% of patients), the rate was significantly higher than would be expected to occur idiopathically in the general population. Use of trovafloxacin for >14 days appeared to substantially increase the risk of acute liver failure; however, trovafloxacin- related liver failure appeared to be unpre- dictable, and liver failure had been reported with even short-term exposure (2 days). It is difficult to manage such a risk by liver function monitoring. As a result of these postmarketing reports of rare but severe liver injuries leading to transplants and deaths, the FDA issued a Public Health Advisory to physicians in early June 1999 concerning the risks of liver toxicity associated with the use of trovafloxacin.2’

The advisory suggests that physicians reserve trovafloxacin for the treatment of patients meeting specific criteria (Table II).

Patients receiving trovafloxacin under the circumstances cited in the advisory would probably be treated initially with IV formulations and switched to the oral drug once their condition was clinically stable. Use of oral trovafloxacin is not warranted for less serious infections. Further, therapy with trovafloxacin should not exceed 14 days, and it should be discontinued earlier

808


if the patient experiences any clinical signs or symptoms of liver dysfunction, such as fatigue, anorexia, jaundice, or icterus; severe stomach pain with nausea or vomiting; or dark urine. It should be emphasized that the FDA Public Health Advisory*’ was for trovafloxacin only, and does not apply to the other currently available fluoroquinolone agents.

Moxijloxacin

To date, studies of moxifloxacin have found a low propensity for phototoxicity or CNS excitatory effects, with GI disturbances the most common adverse effects.95 Moxifloxacin has been found to produce minor and insignificant electrocardiographic changes. It was associated with a mean prolongation of the QTc interval of 6 milliseconds in -800 patients undergo- ing paired electrocardiographic evaluation during clinical studies.96 Although these changes were observed in patients without any cardiac history who had not received any concomitant agents causing QTc- interval prolongation, no clinically significant cardiac events were associated with moxifloxacin use. A summary of moxifloxacin safety in >8000 patients97 reported that mean QTc-interval prolonga- tions of 4 milliseconds were reported in patients receiving moxifloxacin, compared with 2 milliseconds in patients receiving clarithromycin; no clinical events were associated with these changes.

However, in October 1999, the FDA Anti-Infective Drugs Advisory Committee convened an advisory panel on moxifloxacin. In the course of this meeting, data were presented regarding the QTc-interval prolonging effects of moxifloxacin. Results from phase III trials demonstrated that -2.5% of patients receiving this agent had

QTc-interval prolongation of s60 milliseconds. As a result of the advisory panel’s recommendation, the product labeling now contains the following warning: “Moxiflox- acin has been shown to prolong the QT interval of the electrocardiogram in some patients. The drug should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hy- pokalemia, and patients receiving class IA (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic agents, due to the lack of clinical experience with the drug in these patient populations.“”

Gatifloxacin

The most common side effects occurring during therapeutic trials of gatifloxacin were nausea (S.O%), vaginitis (6.0%), diarrhea (4.0%), headache (3.0%), and dizziness (3.0%).98 Phototoxicity was not observed at the recommended doses. Volunteer studies showed no abnormal QTc-interval prolongation, 98 although the principal investigator in the present study (J.B.) recommends that gatifloxacin be avoided in patients receiving selected antiarrhythmic agents (quinidine, procainamide, amiodarone, or sotalol) and be used with caution in patients receiving other drugs that may prolong the QTc interval (eg, cisapride, erythromycin, tricyclic antidepressants, antipsychotics). Seizures were not reported in clinical trials.

DRUG INTERACTIONS

All fluoroquinolone agents interact with multivalent cation-containing products, such as aluminum- or magnesium-containing antacids, and products containing calcium, iron, or zinc.67~76~98-‘00 Concomi- tant use of these products results in a significant reduction in the oral bioavailabil-

809


ity of the quinolone. Patients can avoid this complication by taking the multivalent cation-containing products 2 to 4 hours after the antibiotic.

Concomitant use of fluoroquinolones and NSAIDs is also a concern because of reports of possible seizures. Seizures have been reported when enoxacin was used concomitantly with fenbufen, an NSAID.60 The mechanism of this potential interaction appears to be potentiation by the NSAID of the fluoroquinolone’s competi- tive inhibition of y-aminobutyric acid re- ceptors. Although the interaction between fenbufen and both enoxacin and ciprofloxacin has been observed to produce convulsions in rats,‘01,‘02 a study in humans failed to find any evidence of a significant interaction between ciprofloxacin and fenbufen.‘O” No additional case reports of an NSAID-fluoroquinolone interaction have appeared in the literature. Based on the evidence to date, it does not appear that any interaction between NSAIDs and fluoroquinolones, particularly the newer agents, will be clinically significant.‘02,‘WJ0s

Another important drug interaction involves specific fluoroquinolones and concomitant theophylline or other methyl- xanthines such as caffeine. Fluoroquinolone- induced inhibition of the hepatic CYP-450 enzyme system significantly reduces the metabolism of xanthines.‘(K’08 This effect is particularly pronounced with ciprofloxa- tin, which can raise serum theophylline concentrations by 1308%.‘09 Use of ciprofloxacin with theophylline requires reduction of the theophylline dose and monitoring of serum drug concentrations. Ofloxacin and lomefloxacin have only minimal effects on the CYP-450 enzyme system.‘1° In addition, interactions between theophylline and trovafloxacin (8.4% increased theophylline concentrations),“’ sparfloxacin (4.3%

increase),“* and levofloxacin (2.0%-l 1 .O% increase)‘13 are not clinically significant and do not require adjustment of the theophylline dosage. To date, studies of moxi- floxacin95 and gatifloxacin”4 have found no clinically significant interaction with theophylline.

Synergistic nephrotoxicity has been reported with concomitant use of ciprofloxacin and cyclosporine, resulting in pronounced but clinically acceptable serum creatinine levels (1.2-1.9 mg/dL).“g”* This has not been observed with other fluoroquinolones. Clinicians need to be aware of the possibility of interactions between fluoroquinolones, warfarin, and digoxin. Patients receiving fluoroquinolones and either warfarin or digoxin should be closely monitored for signs of enhanced pharmacologic effect or toxicity.“3v”5 As previously mentioned, fluoroquinolones that prolong the QTc interval (including sparfloxacin, moxifloxacin, and possibly gatifloxacin) should not be combined with drugs known to produce QTc-interval prolongation.67,73

DISCUSSION AND 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.

The economic impact of adverse events is another important consideration. Among hospitalized patients, antibacterial adverse

810


events account for nearly 25% of adverse drug reactions.116 In 1 study,lr7 an adverse event in a hospitalized patient was generally associated with an excess 1.9 days in length of stay, at an extra cost of $2262.

The adverse-effect potential of individual fluoroquinolone agents may need to be considered by institutions when deciding which anti-infective agents to include in their formularies. In today’s medicolegal environment, the decision as to which agents to use may rest on demonstrated long-term, worldwide safety profiles. The fact that significant safety issues with cer- tain of the agents did not arise until postmarketing surveillance studies suggests that until further data are available, it may be preferable to use other agents with comparable efficacy and known safety profiles.

ACKNOWLEDGMENT

This paper was supported by an unre- stricted educational grant from Ortho- McNeil Pharmaceutical, Raritan, New Jersey.

Address correspondence to: Joseph Bertino, Jr., PharmD, Bassett Healthcare, Clinical Pharmacology Research Center, 1 Atwell Road, Cooperstown, NY 13326.

REFERENCES

1. Von Rosenstiel N, Adam D. Quinolone antibacterials. An update of their pharmacology and therapeutic use. Drugs. 1994;47:872-901.

2. Blondeau JM. Expanded activity and util- ity of the new fluoroquinolones: A review. Clin Thu. 1999;21:340; discussion l-2.

3. Cunha BA. The fluoroquinolones for urinary tract infections: A review. Adv Thu. 1994;11:277-296.

4. Jones RN, Low DE, Pfaller MA. Epi- demiologic trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: The role of streptogramins and other newer compounds. Diagn Microbial Infect Dis. 1999;33:101-112.

5. Cunha BA. Quinolones: Clinical use and formulary considerations. Adv Ther. 1998; 15277-287.

6. Ernst ME, Ernst EJ, Klepser E. Levo- floxacin and trovaffoxacin: The next generation of fluoroquinolones? Am J Health Syst Pharm. 1997;54:2569-2584.

7. Stratton C. Fluoroquinolone antibiotics: Properties of the class and individual agents. Clin Ther. 1992;14:348-375.

8. Guay DR. The role of the fluoroquinolones. Pharmacotherapy. 1992; 12:7 1 S-85s.

9. Fong IW. The role of fluoroquinolones in the management of skin, soft tissue, and bone infections. Clin Invest Med. 1989; 12:4U9.

10. Hendershot EF. Fluoroquinolones. Infect Dis Clin North Am. 1995;9:7 15-730.

I I. Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs. 1993; 45(Suppl 3):59-64.

12. Just PM. Overview of the fluoroquinolone antibiotics. Pharmacotherapy. 1993; 13:4S- 17s.

13. Domagala JM. Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother. 1994;33:685-706.

14. Green SD. Indications and restrictions of fluoroquinolone use in children. Br J Hosp Med. 1996;56:420-423.

811


15. Takizawa T, Hashimoto K, Minami T, et al. The comparative arthropathy of fluoroquinolones in dogs. Hum Exp Toxicol. 1999;18:392-399.

16. Burkhardt JE, Hill MA, Lamar CH, et al. Effects of difloxacin on the metabolism of glycosaminoglycans and collagen in or- gan cultures of articular cartilage. Fun- dam Appl Toxicol. 1993;20:257-263.

17. Kashida Y, Kato M. Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: Comparison of toxicities of IO fluoroquinolones and effects of anti- inflammatory compounds. Antimicroh Agents Chemother. 1997;41:2389-2393.

18. Takizawa T, Hasimoto K, Itoh N, et al. A comparative study of the repeat dose toxicity of grepafloxacin and a number of other fluoroquinolones in rats. Hum Exp Toxicol. 1999; 18:3845.

19. Stahlmann R, Zippel U, Forster C, et al. Chondrotoxicity and toxicokinetics of sparfloxacin in juvenile rats. Antimicrob Agents Chemother. 1998;42: 1470-1475.

20. Kashida Y, Kato M. Toxic effects of quinolone antibacterial agents on the musculoskeletal system in juvenile rats. Toxi- co1 Pathol. 1997;25:635-643.

21. US Food and Drug Administration Web site. Public Health Advisory. Trovan (trovafloxacin/alatrofloxacin mesylate). June 9, 1999. Available at: http:l/www. fda.gov/cder/news/trovan.

22. Physicians’ Desk Reference@. 54th ed. Montvale, NJ: Medical Economics; 2000.

23. Wiedemann B, Heisig P. Mechanisms of quinolone resistance. Infection. 1994;22 (Suppl 2):S73-S79.

24. Paton JH, Reeves DS. Fluoroquinolone antibiotics. Microbiology, pharmacokinet-

its and clinical use. Drugs. 1988;36: 193-228.

25. Jorgensen JH, Weigel LM, Ferraro MJ, et al. Activities of newer fluoroquinolones against Streptococcus pneumoniae clinical isolates including those with mutations in the gyrA, parC. and parE loci. Antimicrob Agents Chemother. 1999;43:329-334.

26. Ball P, Tillotson G. Tolerability of fluoroquinolone antibiotics. Past, present and future. Drug Sqf. 1995; 13:343-358.

27. Wolfson JS, Hooper DC. Overview of fluoroquinolone safety. Am J Med. 1991;9 1: 153S-161s.

28. Janknegt R. Fluoroquinolones. Adverse reactions during clinical trials and postmarketing surveillance. Pharm Week& Sci. 1989;11:124-127.

29. Ball P. Adverse reactions and interactions of fluoroquinolones. Clin Invest Med. 1989; 12:28-34.

30. Halkin H. Adverse effects of the fluoroquinolones. Rev Infect Dis. 1988;(Suppl l):S258-S261.

31. Elston RA, Taylor J. Possible interaction of ciprofloxacin and cyclosporin A. J An- timicrob Chemother. 1988;2 1:674480.

32. Avent CK, Krinsky D, Kirklin JK, et al. Synergistic nephrotoxicity due to ciprofloxacin and cyclosporin A. Am J Med. 1988;85:452-453.

33. Vogel LC. Antibiotic-induced diarrhea. Orthop Nurs. 1995;14:38-41.

34. Jacobs NF Jr. Antibiotic-induced diarrhea and pseudomembranous colitis. Postgrad Med. 1994;95:111-114,117-120.

35. Bartlett JG. Clostridium dificile: History of its role as an enteric pathogen and the

812


36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

current state of knowledge about the or- ganism. Clin Infect Dis. 1994; 18(Suppl 4):S265-S272.

Tedesco FJ. Clindamycin-associated colitis. Review of the clinical spectrum of 47 cases. Am J Dig Dis. 1978;21:2632.

Gould PC, Khawaja FI, Rosenthal WS. Antibiotic-associated hemorrhagic colitis. Am J Gastroenterol. 1982;77:491-493.

Carbon C, Richard A, Bons B. Pseudomem- branous colitis caused by antibiotic therapy. Results of a survey of the patient material from the praxis of 900 gastroenterologists [in French]. Therapie. 1994;49:325-331.

Stahlmann R, Kuchner S, Shakibaei M, et al. Chondrotoxicity of ciprofloxacin in immature beagle dogs: Immunohistochem- istry, electron microscopy and drug plasma concentrations. Arch Toxicol. 2000;73:564-572.

Movin T, Gad A, Guntner P, et al. Pathol- ogy of the Achilles tendon in association with ciprofloxacin treatment. Foot Ankle ht. 1997;18:297-299.

McGarvey WC, Singh D, Trevino SG. Par- tial Achilles tendon ruptures associated with fluoroquinolone antibiotics: A case report and literature review. Foot Ankle Int. 1996; 17:496498.

Harrell RM. Fluoroquinolone-induced tendinopathy: What do we know? South Med J. 1999;92:622425.

Pierfitte C, Gillet P, Royer RJ. More on fluoroquinolone antibiotics and tendon rupture. N Engl J Med. 1995;332: 193. Letter.

Szarfman A, Chen M, Blum MD. More on fluoroquinolone antibiotics and tendon rupture. N Engl J Med. 1995;332: 193. Letter.

Royer RJ. Adverse drug reactions with fluoroquinolones. Therapie. 1996;51:414-416.

46.

47.

48.

49.

50.

51

52.

53.

54.

Hayem G, Carbon C. A reappraisal of quinolone tolerability. The experience of their musculoskeletal adverse effects. Drug SajI 1995;13:338-342.

Zabraniecki L, Negrier I, Vergne P, et al. Fluoroquinolone induced tendinopathy: Report of 6 cases. J Rheumatol. 1996; 23:5 16-520.

Burkhardt JE, Waterspiel JN, Schaad UB. Quinolone arthropathy in animals versus children. Clin infect Dis. 1997;25: 1196 1204.

Chysky V, Kapila K, Hullman R, et al. Safety of ciprofloxacin in children: World- wide clinical experience based on compassionate use. Emphasis on joint evaluation. Infection. 199 1;4:289-296.

Hampel B, Hullmann R, Schmidt H. Cip- rofloxacin in pediatrics: Worldwide clinical experience based on compassionate use-safety report. Pediatr Infect Dis J. 1997;16:127-129.

Prpa B, Rouse M, Piper KE, et al. The effect of ciprofloxacin or trovahoxacin on experimental fracture healing. In: Program and abstracts of the 39th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, California. Abstract 1766.

Schaad UB, abdus Salam M, Aujard Y, et al. Use of fluoroquinolones in pediatrics: Consensus reports of an International So- ciety of Chemotherapy commission. Pedi- atr Infect Dis J. 1995;14:1-9.

Segev S, Yaniv I, Haverstock D, Reinhart H. Safety of long-term ciprofloxacin: Data analysis of controlled clinical trials and review. Clin Infect Dis. 1999;28:299-308.

Pryka R, Kowasksy S, Haverstock D. Ef- ficacy and tolerability of twice-daily cip-

813

55.

56.

57.

58.

59.

60.

61.

62.

63.

rofloxacin 750 mg in the treatment of patients with acute exacerbations of chronic bronchitis and pneumonia. Clin Ther. 1998;20: 141-155.

Schacht P, Arcieri G, Hullman R. Safety of oral ciprofloxacin. An update based on clinical trial results. Am J Med. 1989;87: 98S-102s.

Arcieri GM, Becker N, Esposito B, et al. Safety of intravenous ciprofloxacin. A review. Am J Med. 1989;87:92S-97s.

Kubin R. Safety and efficacy of ciprofloxacin in paediatric patients-review. Infection. 1993;2 1:4 1342 I.

Deamer RL, Prichard JG, Luman GJ. Hy- persensitivity and anaphylactoid reactions to ciprofloxacin. Arm Pharmacother. 1992; 26: 1081-1084.

Henry D, Ellison W, Sullivan J, et al. Treatments of community-acquired acute uncomplicated urinary tract infection with sparfloxacin versus ofloxacin. The Sparfloxacin Multi-Center UUTI Study Group. Antimicrob Agents Chemother. 1998;42:2262-2266.

Beringer PM, Wong-Beringer A, Rho JP Economic aspects of antibacterial adverse effects. Pharmacoeconomics. 1998; 13: 35-49.

Christ W. Central nervous system toxicity of quinolones: Human and animal find- ings. J Antimicrob Chemother. 1990;26 (Suppl B):219-225.

Wilton LV, Pearce CL, Mann RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J Clin Pharmacol. 1996;41:277-284.

Miano L, Goldoni S, Tubaro A, et al. Re- view of norfloxacin in lower urinary tract

64.

65.

66.

67.

68.

69.

70.


infections. Eur Ural. 1990;17(Suppl I): 13-18.

Seidmon EJ, Krisch EB, Truant AL, et al. Treatment of recurrent urinary tract infections with norfloxacin versus trimethoprim-sulfamethoxazole. Urology. I990;35: 187-193.

Jonsson M, Englund G, Norgard K. Nor- floxacin vs pivmecillinam in the treatment of uncomplicated lower urinary tract infections in hospitalized elderly patients. Stand J Infect Dis. 1990;22:339-344.

Martin SJ, Meyer JM, Chuck SK, et al. Levofloxacin and sparfloxacin: New quinolone antibiotics. Ann Pharmacother. 1998;32:320-336.

Sparfloxacin [package insert]. Col- legeville, Pa: Rhone-Poulenc Rorer Phar- maceuticals Inc; 1997.

Lipsky BA, Dorr MB, Magner DJ, Talbot GH. Safety profile of sparfloxacin, a new fluoroquinolone antibiotic. C/in Ther. 1999;21:148-159.

DeAbate CA, for the SPAR Multicenter ABECB Study Group. Treatment of acute bacterial exacerbations of chronic bronchitis (ABECB) with spartloxacin (SPAR) and ofloxacin (OFL). In: Program and abstracts of the 36th Interscience Confer- ence on Antimicrobial Agents and Chemo- therapy; September 15-18, 1996; New Orleans, La. Abstract LM9.

Donowitz G, for the SPAR Multicenter CAP Study Group. Treatment of community acquired pneumonia (CAP) with sparfloxacin (SPAR) and cefaclor (CEF). In: Program and abstracts of the 36th In- terscience Conference on Antimicrobial Agents and Chemotherapy; September 15-18, 1996; New Orleans, La. Abstract LMlO.

814


71.

72.

73.

74.

75.

76.

77.

78.

Bensch G, for the SPAR Multicenter CAP Study Group. Treatment of community acquired pneumonia (CAP) with sparfloxacin (SPAR) and erythromycin (ERY). In: Pro- gram and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 1.5-18, 1996; New Orleans, La. Abstract LM12.

Stahlmann R, Lode H. Toxicity of quinolones. Drugs. 1999;58(Suppl 2): 37-42.

Morganroth J, Talbot GH, Dorr MB, et al. Effect of single ascending, supratherapeu- tic doses of sparlloxacin on cardiac repo- larization (QTc interval). Clin Ther. 1999;21:818-828.

Jaillon P, Morganroth J, Brumpt I, Talbot G. Overview of electrocardiographic and cardiovascular safety data from sparfloxacin. Sparfloxacin Safety Group. JAn- timicrob Chemother. 1996;37(Suppl A): 161-167.

Dorr MB, Johnson RD, Jensen B, et al. Pharmacokinetics of sparfloxacin in patients with renal impairment. Clin ‘fher. 1999;21:1202-1215.

Levofloxacin [package insert]. Raritan, NJ: Ortho Pharmaceutical Corp; 1996.

File TM, Segreti J, Dunbar L, et al. A multi-center randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in the treatment of adults with community-acquired pneumonia. Antimicrob Agents Chem- other. 1997;41:1965-1972.

Richard GA, Klimberg IN, Fowler C, CalleryD’Amico S. A combined analysis of two studies comparing levofloxacin with two other fluoroquinolones for the

79.

80.

81.

82.

83.

84.

85.

86.

treatment of acute pyelonephritis. In: Pro- gram and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 15-l 8, 1996; New Orleans, La. Abstract LM3.

Habib MP, Gentry LO, Rodriguez-Gomez G, et al. Multi-center, randomized study comparing efficacy and safety of oral levofloxacin and cefaclor in treatment of acute bacterial exacerbation of chronic bronchitis. Infect Dis Clin Pruct. 1998;7:101-109.

Nicodemo AC, Robledo JA, Jasovich A, Neto W. A multicenter, double-blind, randomized study comparing the efficacy and safety of oral levofloxacin versus ciprofloxacin in the treatment of uncomplicated skin and skin structure infections. Int / Clin Pratt. 1998;52:69-74.

North DS, Fish DN, Redington JJ. Lev- ofloxacin, a second-generation fluoroquinolone. Pharmacotherapy. 1998; 18: 915-935.

Davis R, Bryson HM. Levofloxacin. A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs. 1994;47:677-700.

Wagai N, Yoshida M, Takayama S. Pho- totoxic potential of the new quinolone antibacterial agent levofloxacin in mice. Arzneimittel-Forsch Drug Res. 1992;42: 404-405.

Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: A review focusing on newer agents. Clin Infect Dis. 1999;28: 352-364.

Wimer SM, Schoonover L, Garrison MW. Levofloxacin: A therapeutic review. Clin Ther. 1998;20: 1049-1070.

DeAbate CA, Russell M, McElvaine P, et al. Safety and efficacy of oral levofloxacin

815


87.

88.

89.

90.

91.

92.

93.

94.

95.

versus cefuroxime axetil in acute bacterial exacerbation of chronic bronchitis. Respir Care. 1997;42:206-2 13.

96. Moxifloxacin [package insert]. West Haven, Conn: Bayer Corporation; 2000.

Adelglass J, DeAbate CA, McElvaine P, Fowler CL. Comparison of levofloxacin qd and amoxicillin-clavulanate tid for the treatment of acute bacterial sinusitis. Clin Infect Dis. 1996;23:913. Abstract 290.

97.

98.

99.

100.

101.

Springklee M. Safety and tolerability profile of moxifloxacin (MXF). In: Proceed- ings of the Ninth European Congress on Chemotherapy, Microbiology and Infec- tious Diseases; May 2 l-24, 1999; Berlin, Germany. Abstract PO208.

Richard GA, Childs S, Fowler C, et al. A comparison of levofloxacin and ciprofloxacin for the treatment of complicated urinary tract infections. Clin Infect Dis. 1996;23:913. Abstract 293.

Gatifloxacin [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2000.

Nichols RL, Smith JW, Gentry LO, et al. Multicenter, randomized study comparing levofloxacin and ciprofloxacin for uncomplicated skin and skin structure infections. South Med .I. 1997;90: I 193-l 200.

Ciprofloxacin [package insert]. West Haven, Conn: Bayer Corporation; 1997.

Trovafloxacin [package insert]. New York: Roerig, Division of Pfizer Inc; 1998.

Glaxo Wellcome voluntarily withdraws Raxar (grepafloxacin). October 27, 1999. Available at: http:/lwww.glaxowellcome. co.uk/news/press-release/mn_PR941029 794.html.

Kamei C, Sugimoto Y, Ohishi H, et al. Epileptogenic activity induced by combined treatment with antiinflammatory drugs and enoxacin and its inhibition by a calcium antagonist, nicardipine. Meth- ods Find Exp Clin Pharrnacol. 1996; 18: 579-588.

Guibert J, Herman H, Capron MH. Treat- ment of uncomplicated recurrent cystitis in women: Lomefloxacin versus nortloxacin. Contracept Fertil Sex. 1997;25:79-84.

Williams DJ, Hopkins S. Safety and tolerability of intravenous-to-oral treatment and single-dose intravenous or oral pro- phylaxis with trovafloxacin. Am J Surg. 1998;176(Suppl):74S-79s.

102. Shintani S, Kusunoki A, Hosoki E, Ya- mashita S. Drug interaction of OPC- 17116, a new quinolone antibacterial agent, with nonsteroidal antiinflammatory drugs in experimental animals. In: Pro- gram and abstracts of the 3 I st Interscience Conference on Antimicrobial Agents and Chemotherapy; September 29-October 2, 1991; Chicago, III. Abstract 1479.

Garey KW, Amsden GW. Trovafloxacin: An overview. Pharmacotherapy. 1999; l9:21-34.

Alghasham AA, Nahata MC. Trovaflox- acin: A new fluoroquinolone. Ann Phartna- cother. 1999;33:48%60.

103. Kamali F, Ashton CH, Marsh VR, Cox J. Assessment of the effects of combination therapy with ciprofloxacin and fenbufen on the central nervous systems of healthy volunteers by quantitative electroen- cephalogmphy. Antimicrob Agents Chemo- ther. 1998;42:1256-1258.

Balfour JA, Wiseman LR. Moxifloxacin. 104. Akahane K, Kato M, Takayama S. Drugs. 1999;57:363-373. Involvement of inhibitory and excitatory

816


105.

106.

107.

108.

109.

110.

111.

neurotransmitters in levofloxacin- and ciprofloxacin-induced convulsions in mice. Antimicrob Agents Chemother. 1993;37: 1764-1770.

Nozaki M, Kohnok K, Tsurumi K. No convulsion was observed in mice: Concomitant use of DU6859a and nonsteroidal anti-inflammatory drugs. In: Program and abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy; October 17-20, 1993; New Orleans, La. Abstract 1003.

Wijnands WJA, Vree TB, van Hetwaarden CLA. The influence of quinolone derivatives on theophylline clearance. Br J Clin Pharmacol. 1986;22:677-683.

Davey PG. Overview of drug interactions with the quinolones. J Antimicrob Chemo- ther. 1988;22(Suppl C):97-107.

Rodvold KA, Piscitelli SC. New oral macrolide and fluoroquinolone antibiotics: An overview of pharmacokinetics, interactions, and safety. Clin Infect Dis. 1993; 17(Suppl l):Sl92-S199.

Davis R, Markham A, Balfour JA. Ciprofloxacin: An updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs. 1996;51:1019-1074.

Marchbanks CR. Drug-drug interactions with fluoroquinolones. Pharmacotherapy. 1993;13:238-283.

Dickens GR, Vincent J, Wermeling D. Phase I pilot study of the effects of trovatloxacin

112.

113.

114.

115.

116.

117.

(CP-99,219) on the pharmacokinetics of theophylline in healthy men. J Clin Pharmacof. 1997;37:248252.

Takagi K, Hasegawa T, Kuzuya T, et al. Effect of a new quinolone, sparfloxacin, on the pharmacokinetics of theophylline in asthmatic patients. Antimicrob Agents Chemother. 1991;35:1137-1141.

Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharm- acokinet. 1997;32: 101-I 19.

Manita S, Toriumi C, Kusajima H, Momo K. The influence of gatifloxacin (AM- 1155) on pharmacokinetics and metabolism of theophylline in rats and humans. In: Program and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 24-27, 1998; San Diego, Ca. Abstract A-16a.

Jolson HM, Tanner LA, Green L, Grasela TH Jr. Adverse reaction reporting of interaction between warfarin and fluoroquinolones. Arch Intern Med. 1991;15 1: 1003-1004.

Classen DC, Pestotnik SI, Evans RS, et al. Computerized surveillance of adverse drug events in hospital patients. JAMA. 1991;266:2847-2851.

Classen DC, Pestotnik SL, Evans RS, et al. Adverse drug events in hospitalized patients: Excess length of stay, extra costs, and attributable mortality. JAMA. 1997;277:301-306.

817

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具

http://www.xuebalib.com/cloud/

http://www.xuebalib.com/

http://www.xuebalib.com/cloud/


http://www.xuebalib.com/vip.html

http://www.xuebalib.com/db.php

http://www.xuebalib.com/zixun/2014-08-15/44.html


The Safety Profile of the Fluoroquinolones

Documents

Transcript of The Safety Profile of the Fluoroquinolones