ADEGUAMENTO DEL DOSAGGIO DEGLI ANTIBIOTICI NELLE TERAPIE RENALI SOSTITUTIVE: USO DI MODELLI IN VITRO QUALE STRUMENTO PREDITTIVO DELLA FARMACOCINETICA

Antimicrobial dosage adjustment for patients with acute or chronic kidney disease undergoing extracorporeal renal replacement therapy is a complex problem frequently under investigated for several drugs. In this setting, the rational approach for appropriate dosage regimen is fundamental, not only to achieve efficacy of pharmacological treatment, but also to avoid toxicity risks. In addition, when an antimicrobial agent is administrated, it has to be taken into account the emergence of resistant pathogen microorganisms. The purpose of this research project was to set up an in vitro models of hemoperfusion (HP) and hemofiltration (HF) techniques in order to investigate antimicrobial removal during extracorporeal circulation. In particular, it focuses on drug adsorption by sorbent or membrane polymers, which is almost unexplored phenomenon reported in literature. The first in vitro model was set up in a direct HP (DHP) mode using a prototype dialysis machine (Bellco, R&D Electronic Division, Mirandola, Italy) with Lixelle S-35 cartridge (Kaneka Corporation, Osaka, Japan). This medical device is a sorbent developed for a selective removal of β2-microglobulin (β2-MG) in dialysis-related amyloidosis (DRA) of chronic kidney disease patients. The aim of the study was to investigate the vancomycin (VAN) and teicoplanin (TEC) adsorption removal by DHP with Lixelle S-35 cartridge. VAN and TEC experiments showed that the cartridge has a high adsorption capacity for both glicopeptides. In the case of TEC, the total mass introduced into the system was adsorbed by Lixelle polymer bed. Considering the high TEC adsorption rate, it was developed and performed an in vitro tool with Lixelle polymer in order to evaluate the possible competitive binding between TEC and β2-MG during adsorption process. Based on these results, TEC and β2-MG did not compete for binding sites of Lixelle polymer. On the contrary, β2-MG seems to enhance the adsorption of TEC. These data suggest that a supplemental dose should be administered in DRA patients when Lixelle S-35 is used for both VAN and TEC. The second in vitro model was configured in DHP as previous system, but it was optimized as close as possible to in vivo conditions. The mock DHP treatments were performed to evaluate gentamicin (GEN) and tobramycin (TOB) adsorption removal by using Bellco prototype dialysis machine with Lixelle S-35 cartridge. XIV GEN was rapidly adsorbed onto polymer bed during experiments without antimicrobial release by the sorbent cartridge. GEN results indicated that a supplemental dose should be taken into account in DRA patients receiving DHP with Lixelle S-35. Conversely, TOB, after its rapid adsorption, was released into the extracorporeal circulation: the redistribution phenomenon occurred. Therapeutic drug monitoring (TDM) should be performed to measure TOB plasma levels before considering an supplemental dose when Lixelle S-35 is used. The antimicrobial adsorption phenomenon could also affect HF treatments and therefore hemofilter membranes. In this direction, it was set up an miniaturized in vitro system with CARPEDIEM dialysis machine (Cardio-Renal Pediatric Dialysis Emergency Machine; Bellco, Mirandola, Italy) using a polysulfone membrane (Medisulfone; Medica, Medolla, Italy). The HF in vitro model was used to study the antimicrobial drug removal of linezolid (LZD) and TOB. LZD HF treatments described a rebound phenomenon of its plasma levels. Indeed, the maximum LZD value adsorbed was observed at the beginning of the experiments, then it was partially released from polysulfone membrane. Although it is still unclear if LZD is completely released from the membrane, the redistribution phenomenon should be considered in patients with acute renal failure (ARF) undergoing continuous HF. The LZD dosage adjustment requires TDM as a tool for defining a potential supplemental dose. On the other side, the TOB adsorption phenomenon can be considered negligible related to the antimicrobial mass removed from the extracorporeal circulation. TOB was primarily cleared by convection during HF experiments. These findings indicate that TOB dose should be adjusted according to the ultrafiltration rate in ARF patients receiving continuous HF. The rationale approaches suggested for antimicrobial dosage the adjustment concern the intimate drug removal of specific extracorporeal techniques investigated by the present research project. In order to prescribe the optimal antimicrobial dosage regimen, clinicians must consider these experimental evidences in a relationship with patient’s pathophysiology which also impacts on pharmacokinetic of drugs.