Nephrotoxicity cephalosporins

Cephalosporin Nephrotoxicity Role of Proximal Tubular Secretion... 

Tune BM, Kuo CH, Hook JB, Hsu CY, Fravert D. Effects of piperonyl butoxide on cephalosporin nephrotoxicity in the rabbit. An effect on cephaloridine transport. J Pharmacol Exp Ther 1983 224(3) 520-524. 

Tune BM, Browning MC, Hsu CY, Fravert D. Prevention of cephalosporin nephrotoxicity by other cephalosporins and by penicillins without significant inhibition of renal cortical uptake. J Infect Dis 1982 145(2) 174-180. 

The cellular mechanism of direct cephalosporin-induced nephrotoxicity may include several possible actions of the cephalosporins. Nephrotoxic cephalosporins are known to induce lipid peroxidation and cellular membrane damage, acylate cellular proteins, and/or interfere with mitochondrial respiration. Mitochondrial respiration appears to be inhibited due to acylation of mitochondrial transporters for metabolic substrates, thereby depriving mitochondria of the necessary intermediates to utilize oxygen. Ultimately, the formation of adenosine triphosphate (ATP), needed to supply cellular energy, also declines to inhibit energy-dependent cellular functions. 

Generally, nephrotoxicity is not a problem. Some cephalosporins, especially those with the 3-methylthiotetrazole side chain, such as moxalactam (48), show a tendency to promote bleeding. This appears to be due to a reduction in the synthesis of prothrombin and can be a problem especially in elderly patients, patients with renal insufficiency, or patients suffering from malnutrition (219). The same side chain seems to promote a disulfiramlike reaction in patients consuming alcohol following a cephalosporin dose (80,219). 

Other adverse reactions that may be seen with administration of the cephalosporins are headache, dizziness, nephrotoxicity (damage to the kidneys by a toxic substance), malaise, heartburn, and fever. Intramuscular (IM) administration often results in pain, tenderness, and inflammation at the injection site Intravenous (IV) administration has resulted in thrombophlebitis and phlebitis. 

The older adult is more susceptible to the nephrotoxic effects of the cephalosporins particularly if renal function is already diminished because of age or disease. If renal impairment is present, a lower dosage and monitoring of blood creatinine levels are indicated. Bood creatinine levels greater than 4 mg/dL indicate serious renal impairment. In elderly patients with decreased renal function, a dosage adjustment may be necessary. 

Administration of the aminoglycosides with the cephalosporins may increase the risks of nephrotoxicity. When the aminoglycosides are administered with loop diuretics there is an increased risk of ototoxicity (irreversible hearing loss). There is an increased risk of neuromuscular blockage (paralysis of the respiratory muscles) if the aminoglycosides are given shortly after general anesthetics (neuromuscular junction blockers). 

Renal function impairment Cephalosporins may be nephrotoxic use with caution in the presence of markedly impaired renal function (Ccr less than 50 mL/min/1.73 m ). Hepatic function impairment Cefoperazone is extensively excreted in bile. Serum half-life increases 2-fold to 4-fold in patients with hepatic disease or biliary obstruction. 

Cefditoren (Spectrac ) [Antibiotic/Cephalosporin-3rd Generation] Uses Acute exacCTbations of chronic bronchitis, pharyngitis, tonsillitis skin Infxns Action 3rd-gen cqjhalosporin -I- ceU wall S5mth Dose Adults Feds >12 y Skin 200 mg PO bid X 10 d Chronic bronchitis, pharyngitis, tonsillitis 400 mg PO bid X 10 d avoid antacids w/in 2 h take w/ meals X in renal impair Caution [B, ] Renal/hqiatic impair Contra C halosporin/PCN allergy, milk protein, or carnitine deficiency Disp Tabs SE HA, N/V/D, cohtis, nephrotox. 

Uses Infxns of the resp tract, skin, bone, urinary tract Action 3rd-gen cephalosporin -1- cell wall synth Dose Adults. 400 mg PO daily-bid Peds. 8-20 mg/kg/d PO daily—bid -1- in renal impair Caution [B, +] Contra Cephalosporin allergy Disp Susp SE N/V/D, flatulence, abd pain Interactions t Nqjhrotox W/ aminoglycosides, loop diuretics t effects W/ nifedipine, probenecid EMS t Risk of nephrotox w/ loop diuretics monitor for signs of electrolyte disturbances and hypovolemia d/t D monitor pt for super Infxn OD May cause N/V/D, Szs, muscles spasms symptomatic and supportive... 

The severity of aminoglycoside nephrotoxicity is additive with that of vancomycin, polymixin, gallium, furosemide, enflurane, cisplatin, and cephalosporins. Aminoglycoside nephrotoxicity is synergistic with that of amphotericin B and cyclosporine. 

Cephalosporins Ethacrynic acid, furosemide, gentamycin Increased nephrotoxicity. 

Table 3.5 Accumulation of Cephalosporins in the Kidney and Relation to Nephrotoxicity...

Figure 7.34 The structures of the two cephalosporin antibiotics. Cephaloridine is nephrotoxic, cephalothin is not.

However, the nephrotoxicity involves more than this accumulation, as other cephalosporins such as cephalexin, which is not nephrotoxic, also accumulate and reach similar concentrations, although these are not sustained. Cephaloglycin is another nephrotoxic drug of the same class this drug accumulates initially, but is also not sustained. So, clearly, other factors are also important. 

Damage to the mitochondria and the intracellular respiratory processes. Damage to this organelle has been detected soon after exposure to the nephrotoxic cephalosporins along with reduced mitochondrial respiration (Fig. 7.35). 

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