Fluoroquinolone Adverse Effects and Drug Interactions

Douglas N. Fish, PharmD

Disclosures

Pharmacotherapy. 2001;21(10s) 

In This Article

Abstract and Introduction

Abstract

Extensive pharmacologic and clinical development of quinolone antimicrobial agents has resulted in improved antimicrobial activity, pharmacokinetic features, toxicity, and drug-drug interaction profiles. Nalidixic acid and other early quinolones had limited use due to poor pharmacokinetics, relatively narrow antimicrobial spectrum of activity, and frequent adverse effects. Beginning with the development of fluoroquinolones, such as norfloxacin and ciprofloxacin, in the 1980s, the agents assumed a greatly expanded clinical role because of their broad antimicrobial spectrum of action, improved pharmacokinetic properties, and more acceptable safety profile. Although the pharmacokinetics and efficacy of the drugs have improved significantly, a major area of continued emphasis is to further reduce the frequency and severity of adverse events and drug-drug interactions. Older agents such as ciprofloxacin and ofloxacin are still extensively prescribed, but the focus of this article is on the newer fluoroquinolones (levofloxacin and other drugs that have been approved or have been under investigation since approximately 1997).

Introduction

Fluoroquinolones are considered to be safe and well tolerated,[1,2,3,4] although there are some notable exceptions, for example, temafloxacin, trova-floxacin, and, more recently, grepafloxacin.[5,6,7,8,9] This is especially true when fluoroquinolones are compared with other commonly prescribed antimicrobials.[3,4] A review of safety results from numerous controlled clinical trials revealed that, overall, the agents are not significantly different from -- and in some cases were superior to -- nonquinolone comparators or placebo in occurrence of adverse events.[10,11] Overall rates of adverse effects and rates of drug discontinuation from premarketing clinical studies of fluoro-quinolones are summarized in Table 1. [2,3,4,6,7,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44]

Fluoroquinolones are generally highly comparable with other classes of antibiotics in terms of overall frequency and severity of adverse effects, although specific adverse effects vary among drug classes. In comparative clinical studies, the overall frequency of adverse effects for various fluoroquinolones was 3-40%. By comparison, these same studies reported adverse event rates of 2-49% for trimethoprim-sulfamethoxazole, 6-35% for penicillins, 12-39% for cephalosporins, 19-23% for doxycycline, and approximately 39% for erythromycin.[10,11]

True rates of adverse effects are often extremely difficult to determine. Comparative clinical studies may report two types of adverse events: treatment-emergent and drug-related. Treatment-emergent adverse effects are reported by study participants during the study. These are frequently quite subjective and are often not related to the study drug(s). Therefore, adverse event rates associated with administration of placebo are often as high as those associated with active agents. Treatment-emergent event rates also reflect adverse effects that are drug related. Although these rates are often much higher than the frequency of true drug-related adverse effects, they are reported because of difficulty determining causality. Drug-related adverse effect rates, when available, are usually much more useful with regard to agents of different classes as well as to those of the same class. Adverse effect rates of fluoroquinolones summarized in Table 1 include those that were reported to be possibly or probably drug related.

Most adverse events caused by fluoroquinolones are comparable, although overall frequency and manifestation of certain adverse effects differ among agents ( Table 2 ).[4,10] Each fluoroquinolone tends to produce a characteristic profile of adverse effects; differences often are explained by structural features and related relationships of the class.[45] The events are typically mild and usually resolve during continued treatment or with discontinuation of therapy, although early discontinuation for an event is unusual. Gastrointestinal effects (e.g., nausea, diarrhea) and central nervous system (CNS) effects (e.g., headache, dizziness) are most common. Toxic effects that are observed only in animal models or that have not been shown to be clinically relevant in humans include chondrotoxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity.[2,3,4,10,11] Concerns regarding bone and joint toxicities in juvenile animal models thus far have precluded approval of fluoroquinolones for treatment of infections in children. However, more recent data indicate that the agents may be safe in this population, and this is being actively explored.

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