A Beneficial Interaction between Imipenem and Piperacillin Possibly through Their Renal Excretory Process

Abstract

NotesAntibiotics are often coadministered to patients with severe infectious diseases. We previously investigated the actual situation of parenteral antibiotics use at the Hokkaido Prefectural Hospital Haboro and found that a combination therapy of imipenem (IPM) and piperacillin (PIPC) was often undertaken for the treatment of serious infections such as sepsis. In most cases, this treatment was shifted from PIPC monotherapy to combination therapy of IPM and PIPC with clinical deterioration, in spite of the fact that the antimicrobial spectrum widely overlapped in these two b-lactam antibiotics. The combination therapy of an appropriate b-lactam antibiotic and an aminoglycoside or a fluoroquinolone is generally recommended for sepsis. 1) On the other hand, a recent review has suggested that the combination therapy of an aminoglycoside and a b-lactam antibiotic is discouraged for sepsis and, in fact, increases the risk of nephrotoxicity.2) Supporting this, our investigation showed that the combination therapy of an aminoglycoside and IPM or PIPC was much less common compared with the combination therapy of IPM and PIPC at the hospital. Moreover, the physicians empirically realized the outcomes of the concomitant use of IPM with PIPC for severe sepsis although they did not know the exact reason. As antibiotics are often expensive, a combination therapy has to be chosen to surpass monotherapy on the basis of potential advantages such as synergism and prevention of developed resistance. However, little information has been available to date on the benefit of the combination therapy of IPM and PIPC.It is well known that a variety of b-lactam antibiotics are excreted into urine via the organic anion transporters (OATs) located on the basolateral membranes of proximal tubules. 3)Furthermore, it has been reported that PIPC is capable of inhibiting renal transport of several b-lactam antibiotics possibly mediated by OATs. 4,5) However, it has been implied that IPM might be a substrate of a renal OAT.6) Thus, a likely benefit of combination therapy of IPM and PIPC over IPM or PIPC monotherapy is that PIPC interferes with the renal transport of IPM via an OAT, retards the renal clearance of IPM, and maintains the high blood concentration of IPM. Moreover, as IPM is one of the most nephrotoxic b-lactam antibiotics, 7) it is also likely that the combination therapy of IPM and PIPC is beneficial in reducing this nephrotoxicity. However, there have been no reports demonstrating that IPM and PIPC mutually interfere with their renal transport via an OAT. In order to clarify the clinical benefit of the combination therapy of IPM and PIPC, the pharmacokinetic interactions between these two b-lactam antibiotics were investigated in this study by measuring their uptake by rat renal cortical slices and by determining blood concentrations after intravenous infusion to rabbits. In Vitro Uptake by Rat Renal Cortical Slices In this study the animal experiments were performed in accordance with the Guidelines for the Care and Use of Labor...

Protective effect of morin on the imipenem-induced nephrotoxicity in rabbits

“…Those results appeared to be comparable to some of previous reports (Hirouchi et al, 1994;Saitoh et al, 2006). Saitoh et al (2006) have demonstrated that the combination therapy of imipenem and piperacillin was beneficial for the treatment of serious infectious diseases through a mechanism by which piperacillin interfered with an OAT-mediated imipenem transport across the renal basolateral membrane. Hirouchi et al (1994) also have reported that betamipron reduced the nephrotoxicity of carbapenems through inhibiting the active transport of carbapenems in the renal cortex.…”

Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial

“…Time–clearance slope modelling identified competitive inhibition of renal tubular secretion as the most likely explanation. Piperacillin-induced reduction of imipenem clearance19 and of tazobactam clearance has also been found,20 and a high correlation between creatinin clearance and piperacillin clearance has been documented,21 and thus, it is plausible that piperacillin specifically causes nephrotoxicity.…”

Inhibition of flucloxacillin tubular renal secretion by piperacillin

“…Piperacillin inhibits the renal clearance of cefazolin and the renal and nonrenal clearance of cefoperazone in rabbits [16], as well as the total clearance of moxalactam [17]. Concomitant administration of piperacillin increased plasma concentrations of imipenem in rabbits [41]. In addition to the interactions with other β‐lactams, azlocillin reduces the renal and nonrenal clearance of ciprofloxacin [24].…”

“…Probenecid decreased the renal clearance of piperacillin [12] and flucloxacillin AUC [53]. From studies in rats and rabbits it was concluded that piperacillin inhibits renal clearance of imipenem by inhibition of its OAT‐mediated transport [41]. The interaction involves inhibition of transporters, but it is not possible to identify these transporter(s) by a PK study in humans.…”