ceftriaxone

INTRODUCTION

Ceftriaxone, a third-generation cephalosporin with a broad spectrum of antimicrobial activity, is useful for treating a wide range of infections. The drug is highly bound to protein (85% to 95%) and is eliminated primarily by renal excretion (50%) and hepatic metabolism (40%). Ceftriaxone is less soluble than other cephalosporins, and precipitation has been known to occur, a process resulting in a condition known as “biliary sludge”. This problem is especially of concern in neonates with hyperbilirubinemia, in whom ceftriaxone may cause additional displacement of bilirubin from protein binding sites, which further elevates serum concentrations of unbound bilirubin. Biliary sludging, lithiasis, and nephrolithiasis have occurred in both pediatric and adult patients, and it has been suggested that the mechanism of these phenomena is related to the formation of a precipitant involving ceftriaxone and calcium.

Postmarketing reports by the manufacturer of ceftriaxone (Rocephin; Roche Laboratories, Nutley, New Jersey) identified 5 cases of neonatal death related to ceftriaxone—calcium precipitates. In 4 of these cases, the ceftriaxone and calcium had been administered through the same IV line; in the fifth case, the 2 agents had been administered at different sites and different times (although the exact time difference was not reported). Two of the reports noted that precipitates were identified in the pulmonary and renal vasculature at autopsy. The US Food and Drug Administration (FDA) identified in its own records an additional 4 reports of interactions between ceftriaxone and calcium in children up to 1 year of age. Three of these children died, and an autopsy revealed crystals in the lungs of one of them. The source of the calcium was either calcium gluconate or total parenteral nutrition solution containing calcium. To date, there have been no reports of such intravascular precipitation in patients older than 1 year undergoing concurrent treatment with ceftriaxone and calcium-containing IV solutions.
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In summer 2007, the manufacturer issued letters to health care professionals, advising them of updates in the contraindi­cations, warnings, precautions, adverse reactions, and dosage and administration sections of the product monograph. Subsequently, the FDA and Health Canada issued related warnings about the use of ceftriaxone and calcium-containing IV solutions (in July 2007 and July 2008, respectively). Of greatest relevance to Canadian practitioners, the Health Canada Notice to Hospitals specified that for patients under 10 weeks of age, IV ceftriaxone and calcium-containing IV solutions should not be administered within 5 days of one another. For all other patients, the notice recommended that IV ceftriaxone and calcium-containing IV solutions should not be administered within 48 h of one another. In addition, ceftriaxone and calcium-containing IV solutions, including calcium-containing solutions for continuous infusion, as for parenteral nutrition, should not be mixed or coadministered to any patient, irrespective of age, even through different infusion lines at different sites.

Given an international shortage of cefotaxime (an alterna­tive to ceftriaxone) in 2008, these warnings and recommenda­tions generated substantial discussion in the hospital pharmacy community with respect to their application in clinical practice. The purpose of this study was to assess the opinions and responses of pharmacists and their respective institutions regarding warnings of the calcium-ceftriaxone interaction. generic cialis 20mg