Although the liver is particularly exposed to drugs and their metabolites, hepatic side-effects of antibiotics are far less frequent than other adverse effects such as gastrointestinal disorders or cutaneous reactions. However, the potential severity of hepatic side-effects for some drugs is stressed. Antibiotic related liver injuries cover most of the clinical and pathological expressions of hepatic dysfunction, including cytotoxic hepatitis (isoniazid), intrahepatic cholestasis (macrolides, penicillins, clavulanic acid), mixed hepatitis (sulphonamides), chronic active hepatitis (nitrofurantoin), or microvesicular steatosis (tetracycline). In most cases, toxicity is idiosyncratic, reactions occurring only in some susceptible individuals. The mechanisms underlying toxicity may be primarily metabolite-dependent (isoniazid), hypersensitivity-mediated (beta-lactams), or result from both processes (sulphonamides, erythromycin derivatives). In some cases, the liver is not the primary target organ for toxicity but appears to mediate the clinical expression of some adverse effects induced by antibiotics. The most significant example of this is hypoprothrombinaemia due to the inhibition of hepatic gamma-carboxylation of vitamin K-dependent clotting factors by sulphydryl group-containing cephalosporins. Inhibition of bilirubin conjugation or transport by rifampicin or fusidic acid may also be viewed as hepatic side-effects of antibiotics. Ascertaining the casual relationship of a given drug to an hepatic adverse effect may prove particularly difficult, because of the potential contribution of host status and concurrent medications. Diagnosis is based mainly on circumstantial evidence, i.e. the temporal relationship between drug administration (or withdrawal) and the time-course of liver dysfunction. Improving morbidity related to drug hepatotoxicity relies on a free flow of information between manufacturers and practitioners in order to optimize detection of potentially serious liver damage, and advances in pharmacogenetics toward a better identification of those at particular risk for developing drug-related liver toxicity.

Cirrhosis encompasses a range of pathophysiological changes that may alter drug disposition. Drugs that are dependent primarily on the liver for their systemic clearance are more likely to be subject to reduced elimination and subsequent accumulation. Drug accumulation may lead to excessive plasma drug concentrations and adverse effects, if the adverse effects of the drug are concentration-dependent. The effects of hepatic insufficiency on the pharmacokinetics of drugs are not consistent or predictable. Furthermore, the influence of hepatic disease on the disposition of various drugs can vary, even though those drugs may share the same apparent metabolic pathway. Problems in forecasting drug kinetic behaviour are further enhanced by the additional impairment of kidney function (frequently encountered in patients with advanced liver disease) and by the unpredictability of the glomerular filtration rate using customary methods in patients with cirrhosis. Accordingly, dosages are generally adapted empirically, with the help of serum drug concentrations, when applicable. However, drugs eliminated predominantly by hepatic metabolism are not among those most commonly inducing adverse drug reactions or causing severe complications in patients with cirrhosis. Electrolyte disturbances and the hepatorenal syndrome produced by furosemide (frusemide)-the disposition of which is not substantially modified in liver disease-appear to be the most frequent adverse drug reactions in patients with liver disease. Furthermore, clinically significant alterations in the action of medications at concentrations generally considered to be in the normal therapeutic range are not uncommon. Tissue responsiveness to the pharmacological action of some drugs may be modified, as evidenced by the increased susceptibility of the brain in patients with cirrhosis to the action of many psychoactive agents. Another example is the greater susceptibility of such patients to the nephrotoxic potential of aminogly-cosides, which should not be used in this patient group. Drugs may also interfere with adaptive physiological processes induced by liver disease. ACE inhibitors and nonsteroidal anti-inflammatory drugs counteract the enhanced activity of the renin-angiotensin system in advanced liver disease, thereby generating a high risk of excessive hypotension or acute renal failure, respectively. These drugs are best avoided in patients with cirrhosis. Finally, there may be pharmacological effects that overlap with some pathophysiological modifications related to the process of liver disease, such as increased portal pressure produced by some calcium antagonists, or hypoprothrombinaemia related to the inhibition of synthesis of vitamin K-dependent clotting factors by some beta-lactam antibacterials (especially moxalactam and cefamandole). Accordingly, the use of these drugs should be avoided in advanced liver disease. It is noteworthy that reduced drug metabolism in patients with liver disease does not seem to have a significant impact on the frequency of he...

Interest in the intestinal absorption mechanisms of drugs has increased because transepithelial passage across the gut does not necessarily follow a passive diffusion process. Amoxycillin, like other amino-beta-lactam antibiotics, has been demonstrated in vitro to use the dipeptide carrier-mediated system in rodent small intestine. In order to assess the in-vivo relevance of these data, we applied the Loo-Riegelman method for a reappraisal of amoxycillin absorption kinetics in healthy human volunteers. The results showed evidence of a saturable carrier-mediated uptake of this antibiotic. With respect to the in-vitro data previously published, the dipeptide carrier system would appear to be the most likely transport mechanism.

In this study, the increased availability of antibiotic guidelines at the time of drug ordering, combined with a periodical reinforcement educational round, was associated with an enhanced physician adherence to these guidelines.