Antibiotic Safety Assessment

Abstract

Antibiotics usually have positive risk-benefit ratios, their adverse effects being generally mild and reversible on treatment cessation. However, severe adverse drug reactions (ADR), associated with significant mortality and morbidity have resulted in the withdrawal of several active antibiotics, including new fluoroquinolones. Adverse reactions to antibiotics are often poorly documented. The purpose of this article is to examine current tools for investigating and preventing antibiotic toxicity and to suggest future lines of investigation. Structure/ADR relationships have been investigated with various antibiotics (β-lactams, macrolides, quinolones, etc.) in an attempt to reduce the risk of adverse reactions. Some reactions can be linked to the drug's stereochemical composition. In the case of quinolones for instance, particularly ofloxacin and its derivatives, experimental data show that individual enantiomers have different toxicities. Another major factor that influences the risk of ADRs in a given population is metabolic variability, due to genetic differences in the relevant drug-metabolizing enzymes. Idiosyncratic antibiotic toxicity can be caused by a chemically reactive metabolite. Recent advances in molecular biology, and especially in individual genomic characterization (DNA chip technology, etc.), could in future be useful for identifying patients who are at a special risk of ADR. Finally, certain pharmacokinetic parameters (AUC, Cmax, etc.) can be used to predict adverse effects.

Introduction

There was a time when launching a new antibiotic was a relatively simple undertaking. For example, a few decades ago the aminoglycosides were heralded as miracle drugs giving excellent clinical results, better than anything previously seen; their marked toxicity (including deafness and nephrotoxicity) was initially seen by prescribers as an acceptable risk, and was subsequently avoided by clever dose adjustments. Such a situation is unimaginable today: indeed, if penicillin were to be discovered now, it would no doubt stumble at one or several development hurdles.

Contrary to popular belief, drug development is rarely halted because of animal or human toxicity. A survey of seven British pharmaceutical companies between 1964 and 1985 showed that the main reasons for halting antibiotic development were inefficacy (poor antibacterial activity) and ‘bizarre’ pharmacokinetic behaviour. Animal and human toxicity only halted the development of 11 and 10% of candidate antibiotics, respectively. The figures for drugs other than antimicrobials were 17 and 16%, showing that toxicity observed during the development phase is viewed as less of a problem with antibiotics than with other drugs [1], [2].

In the United States, adverse drug reactions (ADR) cause about 100 000 deaths each year, making them the 4th–6th most frequent cause of death [3], [4]. More and more drugs are being withdrawn from the market because of serious adverse effects (Table 1). This applies to antibiotics too, and particularly to the fluoroquinolones: more than 10 000 different fluoroquinolones have been patented, but only 12 have been approved for clinical use.

In 1992, temafloxacin was withdrawn from the market, 6 months after it had been launched, because of a risk of haemolysis, liver and kidney failure and clotting disorders (the ‘temafloxacin syndrome’). The incidence of this syndrome was very high, at one case per 3500 treatments. Three years later, sparfloxacin saw its indications restricted because of severe phototoxicity. Trovafloxacin, first released onto the market in December 1997, was withdrawn in June 1999 because of the risk of fatal cytolytic hepatitis; this time, however, the risk was low, at about 0.006%. Finally, grepafloxacin, registered in November 1997, was withdrawn by the company in October 1999 because of cases of QT prolongation (seven deaths in Germany); the estimated frequency was below 0.0001% [5], [6].

Thus, several new antibiotics have been withdrawn from the market in recent years because of rare or exceptional but life-threatening adverse effects. The number of patients enrolled in phase I to III clinical trials is far too small to detect such rare adverse effects prior to market release. Between one and five thousand subjects would have to be treated to observe at least one case of a rare adverse effect (frequency between 0.01 and 0.1%), while this number rises to between fifty thousand and half a million when the adverse effect is exceptional (frequency between 0.001 and 0.01%). It is, therefore, impossible to catalogue every potential adverse effect of a new antibiotic before it is released onto the market.

Drug companies must nonetheless precisely assess the risk-benefit ratios of their new candidate antibiotics, at both the individual and population levels, before going ahead with further development. And even when this is done correctly, the road to market remains fraught with pitfalls. In the absence of a clearly demonstrated therapeutic benefit relative to a reference drug, the ‘principle of precaution’ will be applied; if there is an objective risk, even one that is very low, development will be stopped, or the licensing terms will be modified, or the drug will be suspended or even withdrawn.

How then to define and prevent, as far as possible, the risk of poor tolerability? There are at least four approaches to this thorny question.

The first two concern adverse effects linked to the molecular structure of the antibiotic or to its racemic nature.