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1 Assistant Professor Department of Medical Microbiology Faculty of Medicine
University of Manitoba Clinical Pharmacist—Infectious Diseases
Pharmaceutical Services Health Sciences Centre Winnipeg Room MS-189 820
Sherbrook Street Winnipeg, Manitoba R3A 1R9, Canada fax 204/787-3195
agin{at}hsc.mb.ca
2 Pharmacy Resident Winnipeg Regional Health Authority Winnipeg, Manitoba,
Canada
3 Clinical Practice Lead—Infectious Diseases Pharmacy Department
Calgary Health Region Calgary, Alberta, Canada
Published Online, January 29, 2008. www.theannals.com, DOI 10.1345/aph.1K410a
Ceftriaxone-associated biliary sludging/lithiasis or nephrolithiasis has been documented in both pediatric and adult patients. In vitro and animal models studying the physiochemical basis for the sludge/lithiasis have suggested that when the solubility product of the ceftriaxone-calcium salt is exceeded, precipitation may occur, although this is not always predictable.2,3
To date, the deaths attributed to a ceftriaxone-calcium interaction have occurred in neonates or newborns. The cases submitted to the FDA from the manufacturer may refer to those cases documented in France. The Commission Nationale de Pharmacovigilance in France documented severe reactions in 1996 (4 cases) and 2002 (1 case).4,5 Four neonatal deaths were recorded, with 3 patients receiving ceftriaxone and calcium simultaneously through the same intravenous line. Precipitates were observed in the intravenous line or pulmonary or renal tissue. In the 2002 fatal case, ceftriaxone and calcium were administered at different times and sites. The FDA subsequently identified 4 additional cases (3 fatal), with crystals found in the lung of 1 patient.6 Recently, ceftriaxone and calcium infusion coadministration resulted in 2 separate episodes of hemodynamic and respiratory instability in a premature neonate.6 Possible risk factors for precipitation of ceftriaxone-calcium salts in the neonate include low blood volume (80 mL/kg), prolonged half-life of ceftriaxone, and the need for calcium infusion in the premature neonate.4,5 To date there are no reports of similar ceftriaxone-calcium interactions in adults.7
The manufacturer and the FDA have recommended that ceftriaxone be avoided in neonates 28 days of age or younger. In addition, solutions containing ceftriaxone and calcium should not be coadministered within 48 hours of each other (based on 5 ceftriaxone half-lives), regardless of patient age.8 In contrast, it was recommended in France that ceftriaxone be avoided in premature infants up to a corrected age of 41 weeks or in newborns up to 28 days old with hyperbilirubinemia and/or those receiving intravenous calcium infusions.4,5 It was also ecommended that ceftriaxone and calcium solutions not be infused through the same intravenous line or at the same time.
Given the available data, there is certainly evidence for extreme concern in using ceftriaxone in neonates, although the incidence of calcium-ceftriaxone adverse effects is unknown. However, the extension to adults is perplexing, considering differences in blood volume, pharmacokinetics, and experience. Although we believe that we should err on the side of patient safety, the extension of the calcium-ceftriaxone warning to adults has placed many clinicians at a difficult juncture given the lack of adult data. This discordance has generated discussion among our colleagues regarding solubility product calculations, effectiveness of postmarketing surveillance, and ability to detect adverse events in the presence of an underlying disease state. Before wholesale abandonment of ceftriaxone occurs, we suggest that further research be conducted and complete details of case reports and clinical study data be made available to assess the ceftriaxone-calcium interaction in all populations and the implications of a universal versus population-specific warning. "Why now?" indeed!
References
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