Clinical Pharmacokinetics of Newer Antibacterial Agents in Liver Disease

Abstract

Liver disease may produce significant, albeit highly variable, effects on the pharmacokinetic behaviour of antibiotics in serum. Drug disposition may be altered through several pathophysiological mechanisms including reduced hepatobiliary clearance, and modifications in the volume of distribution induced by albumin synthesis deficiency or portal hypertension-related ascites. Antibacterial agents are not affected by potential alteration in hepatic first-pass effects. Only liver cirrhosis-induced effects on serum pharmacokinetics of antibiotics have been extensively studied, unlike those possibly produced by other forms of liver disease. In liver cirrhosis, pharmacokinetic alterations of nearly all beta-lactam or quinolone agents appear not to be marked enough to require dosage adjustment, provided that renal function stays normal. Adaptation in therapeutic schedule, however, is warranted for those drugs that are substantially cleared by the hepatobiliary system, namely mezlocillin, clindamycin, erythromycin, pefloxacin, enoxacin, antituberculous agents or nitroimidazole derivatives. Special caution should also be exercised when using aminoglycosides or vancomycin because of the wide interpatient variability of their pharmacokinetic disposition and their toxic potential. When renal function is impaired and there is an increased volume of distribution due to ascites, as frequently observed in severe liver insufficiency, the elimination half-life of most antibiotics is markedly prolonged, resulting in potential side effects due to drug accumulation. Accordingly, dosage adjustment applies to all drugs. In this regard, it should be remembered that delineating the dosage guidelines for a given antibiotic on the basis of reported pharmacokinetic parameters in patients with liver cirrhosis is awkward and probably of limited value. This pattern is ascribed to large interpatient variability in the active hepatic cell mass, the degree of portal hypertension and the alteration of serum binding capacity. Furthermore, there is no way of predicting accurately the extent of liver insufficiency in an individual patient. Dosage reduction is thus done empirically in most cases. Whenever possible, direct measurements of serum antibiotic concentrations should be the reasonable approach to manage antibiotic therapy in this kind of clinical condition.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

“…Previously it was known that renal drug elimination could be impaired in the hepatorenal syndrome (defined as renal impairment linked solely to liver impairment), but that this syndrome was present only in severe and rapidly advancing liver disease.Pl Evidence was then emerging that renal drug clearance could be impaired in patients with even moderate degrees of liver impairment, and that dosage of renally cleared drugs should be reduced if hepatic function is impaired. [2,8] There was also evidence that the observed serum levels of creatinine may underestimate the decline in renal function.l 90,911…”

How to optimise antimicrobial prescriptions in the Intensive Care Unit: principles of individualised dosing using pharmacokinetics and pharmacodynamics

“…Where hepatic dysfunction is caused by cholestasis or hepatocellular injury, metabolism can significantly decrease leading to accumulation of hepatically cleared antimicrobials [30,31]. A decrease in the hepatic production of albumin can also alter the pharmacokinetics of highly protein-bound antimicrobials (see above) [13,15,16,32].…”

Adaptation des thérapeutiques médicamenteuses en cas d’insuffisance hépatocellulaire

“…Céphalosporines. L'insuffisance hépatocellulaire n'affecte pas la mise à disposition de la plupart des céphalosporines de troisième génération, à l'exception du céfotaxime, de la cefoperazone et du ceftriaxone [46,47], pour lesquels la mesure du résidu sanguin est justifiée en cas d'insuffisance hépatocellulaire en raison d'un risque de surdosage. Pénicillines.…”

“…Trente pourcents de la dose de pénicilline administrée, quelle que soit sa classe, est métabolisée dans le foie. De ce fait, l'insuffisance hépatocellulaire augmente la demi-vie d'élimination des pénicillines de 25 % environ [47]. Quinolones.…”

“…Les concentrations biliaires de quinolones sont trois à quatre fois plus importantes que celles du sang périphérique et 15 % de la dose administrée est excrétée dans les selles. De ce fait, l'insuffisance hépato-cellulaire s'accompagne d'une augmentation de la demi-vie d'élimination [47]. Carbapénèmes.…”