Pharmacokinetics of ceftriaxone, gentamicin, meropenem and vancomycin in liver cirrhosis: a systematic review

Patients with liver cirrhosis are prone to develop severe bacterial infections. Pharmacokinetics (PK) of antibiotics in cirrhosis are potentially affected by impaired biotransformation phases 0-3 and consequences of portal hypertension such as portovenous shunting, ascites formation and/or acute kidney injury (AKI). We aimed to elucidate to what extent PK of selected antibiotics and, therefore, dosage recommendations are affected in adults with cirrhosis.

We performed a systematic search in PubMed, Embase, Cochrane and CINAHL on effects of cirrhosis on PK profiles of ceftriaxone, fosfomycin, gentamicin, meropenem, nitrofurantoin, piperacillin/tazobactam and vancomycin in adults. Antibiotics were selected based on the lack of specific dosing recommendations for adults with cirrhosis. We included studies reporting on ≥1 of the following PK parameters: AUC, half-life (t½), CL, volume of distribution (Vd), peak (Cmax) or trough concentrations (Cmin).

We identified 15 studies (ceftriaxone, n = 5; gentamicin, n = 3; meropenem n = 5; vancomycin, n = 2), including 379 patients with cirrhosis, of which two were of high quality. No eligible studies were identified for fosfomycin, nitrofurantoin or piperacillin/tazobactam. Ceftriaxone unbound concentration increased in cirrhosis, but was mitigated by increased renal CL. Gentamicin levels in ascitic fluid were comparable to those in plasma. Meropenem PK parameters were not altered in cirrhosis without AKI, but in the presence of AKI a decrease in CL was observed. In contrast, vancomycin CL decreased in advanced cirrhosis.

Available data in studies of mostly moderate quality suggest that PK of ceftriaxone, meropenem and vancomycin are altered in cirrhosis. More advanced PK studies are needed to provide specific dosing recommendations.