Hydrolysis of cefamandole nafate in dialysis patients

Abstract

The hydrolysis of cefamandole nafate was examined in vivo in five dialysis patients and five subjects with normal renal function. The plasma half-life of cefamandole was prolonged in the patients with renal failure compared with normal subjects (18.3 + 4.5 [standard deviation] versus 10.35 + 1.4 min, P < 0.01). The pharmacokinetics of cefamandole nafate best fit two-compartment, openmodel kinetics. We conclude that patients with severe renal failure are capable of hydrolyzing cefamandole nafate to cefamandole and formate at a rate sufficiently rapid so as not to allow an accumulation of cefamandole nafate. The difference in half-life may be related to urinary excretion of cefamandole nafate in normal individuals.Cefamandole is a new broad-spectrum cephalosporin antibiotic (6). Cefamandole nafate is the O-formyl ester of cefamandole and is the pharmaceutical preparation of choice because of its crystallinity and stability (4). Cefamandole nafate undergoes hydrolysis to free cefamandole and formate in vitro and in vivo (3, 4, 7). Although no difference is seen between cefamandole and cefamandole nafate in routine assay procedures, specially designed studies have demonstrated a potential difference in potency between cefamandole nafate and cefamandole, the latter showing a 5-to 10-fold-higher potency (5). Knowledge of the hydrolysis of cefamandole nafate in vivo may be of clinical importance (5), particularly if cefamandole nafate accumulates due to slow hydrolysis in patients with renal failure. The hydrolysis of cefamandole nafate in patients with diminished renal function has not been described. The present report describes the hydrolysis of the O-formyl ester in five patients with severe chronic renal failure as compared with five subjects with normal renal function.Ten subjects, five with normal renal function and five chronic hemodialysis patients, were studied. The normal subjects ranged in age from 22 to 37 years (mean, 29 years), compared to 43 to 70 years (mean, 61 years) for the dialysis patients. The mean surface area (Dubois method) was 1.84 ± 0.11 (standard deviation) m2 in normal subjects and 1.66 ± 0.24 (standard deviation) m2 in the renal failure group (P > 0.05). The dialysis patients, who were all studied during the intradialytic period, were all oliguric and had endogenous creatinine clearance rates of <2 ml/min. Approval for these studies was obtained from the Indiana University Committee on the Use of Human Subjects in Research.Written informed consent was obtained from all participants.The cefamandole nafate formulation (Eli Lilly & Co.) contained 1.11 g of cefamandole and 68 mg of sodium carbonate in each vial. Vials were diluted with 5% glucose in water and allowed to stand for precisely 15 min before infusion. Upon dilution the initial alkaline pH (ca. 9.0) rapidly falls, with some hydrolysis of the ester to cefamandole and formate (4). Slowing of the hydrolysis occurs as the pH reaches 6 in approximately 5 min, and a very slow hydrolysis takes place thereafter. The 15-min period was chose...

Pharmacokinetics of β-Lactam Antibiotics

“…After intravenous administration of partially hydrolyzed nafate, these investigators followed the degradation of the nafate ester in plasma and detected unchanged cefamandoel nafate in the urine of normal subjects. NIELSEN et al (1979) demonstrated the presence of cefamandole nafate and cefamandole in the plasma of both normal subjects and uremic patients under similar conditions. Although most investigators contend that the two compounds are indistinguishable with regard to antimicrobial potency, TURNER et al (1977) have shown a 5-to lO-fold higher potency of cefamandole for certain organisms.…”

“…Finally, in a study by NIELSEN et al (1979), the disappearance of cefamandole nafate and cefamandole were followed in both normal subjects and dialysis patients while off dialysis. In healthy subjects the half-life of cefamandole nafate in plasma is about 8-12 min while that for dialysis patients is 13-25 min.…”