Tolerability of Fluoroquinolone Antibiotics Past, Present and Future

Abstract

New fluoroquinolones have been in clinical use for 10 years and have an excellent record of safety and tolerance. The main elements of their adverse reaction profile were predictable from human experience with precursor naphthyridines and quinolones, and from toxicological studies in animals. Thus gastrointestinal reactions (1 to 5%), skin disturbances (less than 2.5%) and central nervous system (CNS) effects (usually around 1 to 2%) were anticipated. Individual group members exhibit particular properties in relation to their chemical structures, for example the phototoxicity associated with 8-halogenation of the nucleus and found to be a particular problem with lomefloxacin and sparfloxacin. Other members, for example ofloxacin, are linked to a higher than usual incidence of CNS reactions and psychological disturbance. However, despite increasing usage, none of the present group have been implicated in joint damage in children, which had been a major concern following reports of this effect in juvenile animals in chronic toxicity studies. Furthermore, intravenous formulations appear to have no associated increase in toxicity. Crystalluria with associated renal damage, originally thought likely to limit intravenous dosage, has not proved to be a problem in humans. Clinically significant interactions may occur but, as with those involving various NSAIDs and potentially leading to convulsions, they have been defined and are thus avoidable. Postmarketing surveillance studies and prescription event monitoring have largely confirmed the limited adverse reaction profile defined during clinical trials. However, some unexpected reactions have appeared after launch, most notably the episodes of haemolysis, renal failure and hypoglycaemia which led to the withdrawal of temafloxacin. These effects have not been observed with other fluoroquinolones. However, severe tendinitis appears to be a group effect, albeit rare, and anaphylactoid reactions have been reported with several of the fluoroquinolone group, often in AIDS patients. The new fluoroquinolones are essentially a well tolerated group of antibacterials, the benefits of which clearly outweigh their disadvantages in a wide range of indications. Clinical efficacy has been a larger determinant of which members have succeeded in the marketplace than potential toxicity. However, the lesser potential for adverse effects of some of the class, e.g. norfloxacin, ofloxacin and ciprofloxacin, has undoubtedly led to their more widespread use. For others, e.g. enoxacin, limited clinical utility and a perception of increased toxicity have resulted in sidelining. There remains the potential for development of safer and yet more active fluoroquinolones via chemical manipulation both of the nucleus and the side chain substituents.

Quinolones: structure-activity relationships and future predictions

“…Despite the transient unpleasant consequences of these effects, no specific structure has yet been identified as their main cause and thus no quinolone has yet been designed which is free of gastrointestinal effects. Adverse dermatological symptoms, such as skin rash or pnuitis, occur in 0.5-3% of patients [7], and may be consequences of histamine release, as has been suggested for BMY 40062 [8]. An animal model developed to ascertain the effect of alkylation of the piperazinyl at position 8 showed this alkylation to be beneficial, [5] and it appears that such an animal model may be of value in examining future quinolones.…”

“…An animal model developed to ascertain the effect of alkylation of the piperazinyl at position 8 showed this alkylation to be beneficial, [5] and it appears that such an animal model may be of value in examining future quinolones. Effects within the central nervous system (CNS) are generally some of the more frequent adverse consequences of quinolone therapy [7]. It is convenient to categorise the quinolones into those that act directly on the CNS receptors, and those that exert an effect when given with other agents.…”

Efficacy and safety of levofloxacin in the context of other contemporary fluoroquinolones: a review

“…55,56 Comparisons between agents also may be influenced by the period of investigation, with agents assessed in the period before intensive examination of ADRs having significantly lower rates than those assessed afterward. For example, ciprofloxacin (PO and IV) ADR rates derived from ∼1985 to 1995 were ∼5% to 7%, 57 and levofloxacin, Ͻ3% in Japanese patients and Յ9.9% in North Americans. 56,58 These findings contrast with those of PO moxifloxacin (25% in US and German trials) and gatifloxacin (29% in US trials), which were investigated in the late 1990s.…”

“…Spontaneous reports of drug toxicity in the postmarketing phase are often incomplete; occur against a poorly defined, chronologically asynchronous denominator population; and involve considerable observer error 57,78 in relation to the compound, severity of response, requirement for corrective or therapeutic action, and contribution of comorbidity and concomitant therapy. Nonetheless, interesting comparisons can be made in terms of the rate of spontaneous reports during the immediate postlaunch period (4 and 15 months after launch).…”

Reacciones adversas neurológicas asociadas a ciprofloxacino

“…Las reacciones adversas sobre el SNC pueden aparecer en cualquier momento del tratamiento 1 -1 0 . La incidencia parece ser algo mayor con la administración oral que con la intravenosa 5 .…”