A retrospective multihospital study found that severe adverse events occurred at similarly low rates with ceftriaxone and other IV cephalosporins suggesting there is no evidence to support avoiding ceftriaxone despite recent health department safety alerts.
Ceftriaxone is a third-generation cephalosporin first approved by the FDA in 1982. It is widely used in clinical practice guidelines due to its broad antimicrobial coverage, convenient dosing, favorable pharmacokinetics, and generally mild adverse effect profile.1,2 In the first quarter of 2025, public health alerts emerged from several state health departments, warning of potential serious adverse events temporally associated with ceftriaxone.3,4 The Centers for Disease Control and Prevention (CDC), in collaboration with state and local health departments, initiated an investigation due to reports of serious adverse events following administration of injectable ceftriaxone. These reported events included cardiac arrest and death. Although the reported clusters of events were limited to a few states, several other state health departments also distributed alerts, requesting reports of serious adverse events to assist with the investigation. In response, the authors of this study conducted a retrospective review across a multihospital health care system to better characterize these events and compare their frequency with those associated with other intravenous (IV) cephalosporins.5
The study was designed to align broadly with CDC surveillance criteria, focusing on severe events such as rapid response activations and cardiac arrests occurring shortly after antibiotic administration in non–intensive care unit settings. An electronic health record tool was used to identify events occurring within 4 hours of IV cephalosporin administration between October 2022 and June 2025. The antibiotics included ceftriaxone, cefazolin, cefuroxime, ceftazidime, and cefepime. Although the study window and timing criteria differed slightly from the CDC’s case definition, the same methodology was applied consistently across all groups to allow for comparison. Patient-level data included demographics, allergy history, type of event, timing relative to drug administration, and additional clinical variables such as proton pump inhibitor (PPI) use and corrected QT (QTc) interval in the ceftriaxone group. A total of 211 significant events were identified: 90 in patients who received ceftriaxone and 121 in those who received the 4 other cephalosporins.
Overall, these events were rare relative to the total number of antibiotic administrations. The frequency of adverse events was similar between groups, occurring in 0.047% of ceftriaxone administrations and 0.041% of nonceftriaxone cephalosporin administrations, a difference that was not statistically significant. This suggests that ceftriaxone does not confer a higher overall risk of severe acute events compared with other cephalosporins studied. When examining these events, the authors found that a higher proportion of ceftriaxone-associated cases were classified as cardiac arrests, whereas events in the comparator group were more often rapid response activations. However, this difference did not reach statistical significance. Importantly, only 3 cardiac arrest events were directly attributed to ceftriaxone by treating clinicians, and none in the nonceftriaxone group were attributed to their respective antibiotics.
These cases occurred within 15 minutes of administration and involved patients with multiple comorbid conditions, making it difficult to establish a clear causal relationship. The authors explored several potential mechanisms that might explain these rare but serious events. One consideration is Kounis syndrome, an allergic-mediated acute coronary syndrome that has been reported in association with β-lactam antibiotics, including ceftriaxone.6 This condition typically presents shortly after drug exposure and could plausibly account for the rapid onset of cardiac symptoms observed in some cases. Another hypothesis involves drug interactions, particularly with PPIs. Previous literature has suggested a possible association between ceftriaxone combined with lansoprazole and QTc prolongation, which could increase the risk of arrhythmias.7
However, in this study, patients receiving PPIs were on pantoprazole rather than lansoprazole, and no significant differences in QTc intervals were observed. The study also addressed questions regarding the method of administration, specifically IV push vs intermittent infusion. Although IV push administration has practical advantages, such as faster delivery and reduced resource utilization, concerns have been raised that rapid administration could increase the risk of adverse events. However, there are more data supporting the safety of IV cephalosporins, including ceftriaxone.8 Because of the limited use of intermittent infusions within the study site, the authors were unable to draw meaningful conclusions on this issue. Several limitations of the study should be considered.
As a retrospective analysis, it relies on documentation accuracy and cannot definitively establish causality between ceftriaxone and adverse events. The study population consisted primarily of adult patients, limiting generalizability to pediatric populations. Additionally, the authors used a 4-hour window for event inclusion rather than the 6-hour window specified by the CDC, which may have excluded some relevant cases but was intended to improve the likelihood that included events were drug related. Despite these limitations, the findings provide important context for interpreting recent public health alerts. The overall rate of severe adverse events following ceftriaxone administration was very low and comparable to that of other cephalosporins.
Furthermore, only a small number of events were attributed to ceftriaxone by clinicians, and these occurred in medically complex patients where alternative explanations were plausible. Based on these results, the authors concluded that there is no evidence to support avoiding ceftriaxone in clinical practice. The antimicrobial stewardship team did not recommend changes to current prescribing practices, emphasizing the importance of balancing vigilance for rare adverse events with the need to maintain effective empiric therapy options.
Given the widespread use of ceftriaxone and the absence of definitive causal links to the reported events, abrupt changes in prescribing could have unintended consequences, including suboptimal treatment or increased use of less appropriate antibiotics. Ultimately, this study examined the safety profile of ceftriaxone in the context of the public health alerts and CDC notice, highlighting the challenges faced when responding to safety signals based on limited or preliminary data. Although ongoing surveillance and investigation are not to be discounted, the findings suggest that ceftriaxone remains a safe and appropriate choice in most clinical scenarios. Moving forward, further research is needed to better understand the mechanisms underlying rare acute reactions, identify potential patient-specific risk factors, and determine whether certain administration practices influence risk. This work underscores the importance of careful data interpretation and reinforces that isolated safety alerts, although important, should not automatically drive major changes in clinical practice without supporting evidence. Lastly, it is worth noting that several health departments have since archived the alert or, in some cases, it is no longer accessible online.
The article highlighted is: Paciullo K, Suchindran S, Hojat LS, et al. Real-world evaluation of ceftriaxone-related safety events: a stewardship call to action. Antimicrob Steward Healthc Epidemiol. 2025;6(1):e7. doi:10.1017/ash.2025.10258
DISCLAIMER: Content shared and opinions expressed in this article are solely the author’s and not necessarily those of Option Care Health. Option Care Health does not guarantee the accuracy or reliability of the information provided.
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Contagion Summer 2026 Digital Edition
