Adverse Reactions to Fluoroquinolones. An Overview on Mechanistic Aspects

This review focuses on the most recent research findings on adverse reactions caused by quinolone antibiotics. Reactions of the gastrointestinal tract, the central nervous system (CNS) and the skin are the most often observed adverse effects. Occasionally major events such as phototoxicity, cardiotoxicity, arthropathy and tendinitis occurr, leading to significant tolerability problems. Over the years, several structure-activity and side-effect relationships have been developed, in an effort to improve overall antimicrobial efficacy while reducing undesiderable side-effects. In this article we review the toxicity of fluoroquinolones, including the newer derivatives such levofloxacin, sparfloxacin, graepafloxacin and the 7-azabicyclo derivatives, trovafloxacin and moxifloxacin. A special attention is given to new data on mechanistic aspects, particularly those regarding CNS effects. In recent years extensive in vivo and in vitro experiments have been performed in an attempt to explain the neurotoxic effects of quinolones sometimes observed under therapeutic conditions. However, the molecular target or receptor for such effects is still not exactly known. Several mechanisms are thought to be responsible. The involvement of γ-aminobutyric acid (GABA) and excitatory aminoacid (EAA) neurotransmission and the kinetics of quinolones distribution in brain tissue are discussed. In addition, quinolones may interact with other drugs – theophylline and nonsteroidal antinflammatory drugs (NSAIDs) – in producing CNS effects This article provides information about the different mechanisms responsible of quinolones interaction with NSAIDs, methylxanthines, warfarin and antiacids. INTRODUCTION whereas the converse is true for amino or aminomethylpyrrolidinyl agents. Overall, new quinolone-3carboxylic acids having a fluorine or chlorine at position C-8 are more prevalent than their 8-H or 1,8-naphthyridine counterparts [33,109]. Quinolones comprise a relatively large, growing and most interesting group of antibiotics which have made a major impact on the field of antimicrobial chemotherapy, particularly in the past few years. Despite some rather unpromising features of the early compounds, persistent efforts have been made over the years to produce congeners with superior antimicrobial properties, and these received considerable stimulus from the discovery that introducing fluorine into the molecule had beneficial effects [33,57]. The mechanism of action of quinolones is through the inhibition of bacterial gyrase, an enzyme involved in DNA replication, recombination and repair [64]. By interfering with gyrase, quinolones arrest bacterial cell growth. The affinity of quinolones to metal ions seems to be an important prerequisite of their antibacterial activity: probably, quinolones bind to the DNA-gyrase-complex via a magnesium ion [74]. Quinolones consist of a bicyclic ring structure (Fig. 1) in which there is a substitution at position N-1, with various moieties. All the current agents have a carboxyl group at position 3, a keto group at position 4, a fluorine atom at position 6, and a piperazinyl group or a methylpiperazinyl group at the C-7 position. Differences in the moiety present at N-1 position or at C-7 position markedly influence both microbiological and pharmacokinetic properties [107]. Compared to the early quinolones, with their poor pharmacokinetic profile and limited in vitro antimicrobial activity, the new fluorinated quinolones have much broader spectra of antibacterial activity and better pharmacokinetic profiles. In fact, they attain concentrations in most tissues and body fluids that are at least equivalent to the minimal inhibiting concentration (MIC) designated as the breakpoint for bacterial susceptibility. Thus, they have a much greater therapeutic potential than their forerunners. Generally, the 7-piperazinylated compounds have better Gram-negative than Gram-positive antimicrobial potency, Though over 10,000 chemical entities have been patented, only a very limited number of them has been approved for human use. Many have been shown to have an *Address correspondence to this author at the Istituto di Farmacologia, Facoltà di Medicina e Chirurgia, Torre Biologica, Policlinico Universitario, Via Consolare Valeria, 98125 Messina, ITALIA. Tel: 39-90-2213649; Fax: 39-90-2213300; Email: [email protected] 0929-8673/01 $28.00+.00 © 2001 Bentham Science Publishers Ltd. 372 Current Medicinal Chemistry, 2001, Vol. 8, No. 4 De Sarro and De Sarro