Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention

Abstract

The nephrotoxic beta-lactam antibiotics cause acute proximal tubular necrosis. Significant renal toxicity, which has been rare with the penicillins and uncommon with the cephalosporins, is a greater risk with the penems. Mechanisms of injury include: (1) transport into the tubular cell, mainly through the antiluminal organic anion secretory carrier; (2) acylation of target proteins, causing respiratory toxicity by inactivation of mitochondrial anionic substrate carriers; and (3) lipid peroxidation. The most nephrotoxic beta-lactams available for study are cephaloridine, cephaloglycin, and imipenem; panipenem, which is comparably nephrotoxic, is currently available only in Japan. Cephaloridine has several unique properties, probably all caused by its pyridinium side-group: (1) its secretory transport into the tubular cell is followed by minimal cell to luminal fluid movement, resulting in extreme intracellular sequestration; (2) it is the only beta-lactam shown to cause significant oxidative injury; (3) it has a limited ability to attack the mitochondrial carriers for pyruvate and the short-chain fatty anions. Cephaloglycin and imipenem undergo less intracellular trapping than cephaloridine, but have sufficient tubular cell uptake, reactivity, and generalized toxicity to mitochondrial substrate carriers to be severely nephrotoxic. Cephaloridine and cephaloglycin are no longer used clinically. Imipenem and panipenem are marketed in combination with nephroprotective renal transport inhibitors. Strategies for avoiding renal toxicity with new cephalosporins and penems are discussed.

The Activity of Proximal Tubule Enzymes in the Urine of Cephalexin-Treated Patients

“…However, investigations performed during the last decade clearly demonstrated that cephalexin can provoke in some patients acute tubular necrosis, primarily acute tubulointerstitial nephritis (3)(4)(5). Tubular necrosis results from changes in the cell membranes of proximal tubules leading to disturbances in organic ion transport across the cell membranes (6-8) due to the antibiotic binding to protein carriers of organic ions, acylation of target proteins involved in the transport and lipid peroxidation (9).…”

Antimicrobial Renal Injury in a Pediatric Intensive Care Unit: β-Lactams vs. Vancomycin

“…β-lactam antimicrobials are also thought to be nephrotoxic in some capacity [19][20][21][22]. Most of the investigations to date have evaluated the incidence or association with renal injury in patients that received a β-lactam in conjunction with another class of antimicrobial, most commonly being an aminoglycoside.…”

“…The mechanism of renal injury associated with β-lactams is thought to be a result of acute proximal tubular necrosis [19]. Most investigations regarding β-lactam renal injury in the adult and pediatric literature have evaluated the incidence of renal injury of β-lactam therapy in conjunction with an aminoglycoside [20][21][22].…”

Toxicity of β-Lactam Antibiotics: Pathophysiology, Molecular Biology and Possible Recovery Strategies

“…The other mechanism is acylation of target proteins, which cause respiratory arrest by inactivation of mitochondrial anionic substrate carriers in cells. The other nephrotoxic side efects occur via lipid peroxidation of renal cortex [11,82]. For critically ill patients, it is very dangerous to use antibiotics such as tazobactam with piperacillin because of the toxic efect on renal tubule [83].…”

“…β-lactam antibiotics are neurotoxic, nephrotoxic, genotoxic and some are reproductive toxic. The nephrotoxic efects of β-lactams lead to proximal tubular necrosis [11]. Some are toxic to reproductive system; tazobactam/piperacillin has a toxic efect on reproductive systems and also developmental toxicity reported that tazobactam has an inluence on maternal toxicity [12].…”