With its broad spectrum of activity against a number of key organisms, its safety profile, and its availability on the market for over 20 years, ceftriaxone has become an important antimicrobial that is prescribed and administered regularly by many clinicians. In view of the vast clinical experience with this agent and the fact that no cases of an intravascular interaction between ceftriaxone and calcium have been documented in adults, the warnings from Health Canada and the manufacturer about avoiding the concurrent use of ceftriaxone and calcium-containing IV solutions has caused considerable concern among Canadian health care professionals. This concern was compounded by the fact that a reasonable alternative to ceftriaxone, cefotaxime, was unavailable at the time of the Health Canada Notice to Hospitals.
The survey described here assessed the views of pharmacy practitioners at institutions across the country. The results indicate that the warnings from the manufacturer and from Health Canada were of importance to hospital pharmacy practitioners. Almost all participants had an opinion about the warnings, with the vast majority being at least somewhat concerned. It was striking that half of the survey participants did not agree with a strict interpretation of the recommended 48-h window for calcium avoidance.
In Canada, ceftriaxone is not routinely used for neonates, as the availability of safer agents allows use of ceftriaxone to be minimized in this population. Thus, the section of the Health Canada Notice to Hospitals recommending avoidance of concurrent administration of ceftriaxone and calcium-containing solutions within 5 days of each other in patients less than 10 weeks of age is of minimal relevance. The second part of the notice, which recommends that ceftriaxone be avoided for 48 h in patients from all other age groups who are receiving calcium-containing IV solutions, has proven much more disconcerting. It is likely that few would disagree with this recommendation as it pertains to coadministration of these agents through the same IV line or admixture bag; however, coadministration through separate IV lines and/or infusion sites and/or at different times within the 48-h window is a different matter.
Two main factors may have contributed to the disagreement and concern among pharmacy practitioners: the frequency of this combination of medications and the age of patients with documented interactions, as described in more detail below.
First, coadministration of ceftriaxone and calcium-containing IV solutions within a 48-h period is relatively frequent. Ceftriaxone is commonly prescribed for adults and has a wide range of indications, including infections of the lower respiratory tract, upper respiratory tract, urinary tract, skin and skin structures, bones and joints, pelvis, and central nervous system, as well as intra-abdominal infections.9
Utilization of this drug for hospital inpatients has been quantified as 63 days of therapy per 1000 patient-days, which is less than that of cefazolin (94 days) and levofloxacin (75 days) but more than that of vancomycin (53 days) and piperacillin–tazobactam (43 days).10
In a Toronto intensive care unit, ceftriaxone was the third most commonly prescribed antibiotic in the year 2000.11
Furthermore, calcium-containing IV fluids, such as total parenteral nutrition solutions and lactated Ringer’s solution, are ubiquitous in the hospital setting and are often administered by continuous IV infusion. For many institutions, adherence to the 48-h avoidance window would be impractical and problematic and in theory might adversely affect patient care.
Second, the intravascular interactions documented to date have been limited to patients up to 1 year of age, who may be at risk because of the anatomic structure of their pulmonary vasculature, low volume of circulating blood, and prolonged half-life of the medication.7,12,13
Puzovic and Hardy14
mathematically demonstrated the stark differences between neonates and adults in weight-based dosing of ceftriaxone and calcium, with neonates potentially receiving 2 to 5 times the adult dose of ceftriaxone and 10 to 20 times the adult dose of calcium, with associated increases in the risk of precipitation. Notably, no difference in all-cause mortality was observed in a recent retrospective comparison of 465 patients who received concomitant ceftriaxone and calcium-containing IV solutions (i.e., within 48 h of each other) with 805 patients who received only ceftriaxone.15
Close to 90% of the patients in that study were adults.15
Subsequently, much discussion has focused on the appropriateness of extrapolating the risk of precipitation from the neonatal to the adult population.7,12–14
In the study reported here, almost 70% of respondents’ institutions had changed their policies with respect to administration of ceftriaxone in response to the warnings. Conversely, only 14.7% of respondents indicated that their institutions considered the coadministration of ceftriaxone and calcium-containing IV solutions to be an absolute contraindication. This may indicate that the impact of the Health Canada Notice to Hospitals on actual practice has been limited.
The limitations of this study should be considered in the interpretation of the results. The survey tool has not been validated and was intended for exploratory analysis. For the sake of timeliness, the questions were developed and the survey conducted within a relatively short period of time. The survey was intentionally brief to ensure the highest possible response rate, but this brevity came at the cost of not fully exploring the reasoning behind respondents’ opinions. The sample size was relatively small, and the possibility of selection bias is inherent to the method used to solicit participation. We did not receive confirmation from all PSNs that participation in the survey had been solicited. Unfortunately, it was not possible to accurately determine the survey response rate, because individual respondents might have belonged to more than one PSN, and information about such overlap was not available. Limiting participation in the survey to practitioners belonging to one or more of the CSHP PSNs may have led to selection of a subset of practitioners who were most strongly affected by this issue. Also, the survey responses were from individual pharmacists, not institutions, which limited the ability to fully assess institutional responses to the warnings. The survey was conducted in English only, which may have limited responses from Quebec.
Despite strongly worded warnings issued by the manufacturer and Health Canada, only a small percentage of institutions represented by participants in this survey had changed their ceftriaxone administration polices to comprehensively reflect the warnings. Furthermore, the study results signify that the warnings are impractical and may not reflect the true risk among adults. Until more evidence for adults is available, a more reasonable warning might be that, in situations in which the benefit outweighs the risk, ceftriaxone may be used for patients receiving calcium-containing IV solutions, but only on a case-by-case basis, with careful clinical assessment performed each time the drug is administered.