The investigation identified 31 cases across 27 healthcare facilities in 18 states between September 2024 and August 2025. Twelve patients died and 19 received successful CPR. Median age was 67, with an interquartile range of 60 to 81. Twenty-three of the cases involved anaphylaxis-type presentations, and in 65 percent of those there was no skin or mucosal involvement — no hives, no rash, no swelling of the lips or face.
Why anaphylaxis without rash is harder to act on
Speed of recognition drives whether epinephrine is given in time, and anaphylaxis without rash is harder to flag quickly both for the person receiving the shot and the staff monitoring them. Most of the facilities involved in the ceftriaxone anaphylaxis cases were outpatient settings, not hospitals. Sixty-five percent of the 27 facilities were outpatient, and the drug was most often given for respiratory infections, which accounted for 42 percent of the indications in the series.
Ceftriaxone is routinely administered in primary care offices, urgent care centers, and emergency departments, where observation practice after an injection varies widely and no universal required waiting period exists. Hospitals typically have resuscitation equipment immediately at hand. A small outpatient clinic administering a shot may not routinely observe a patient afterward, the way some allergy treatments require.
How the CDC review started
The investigation began in December 2024 after an Alabama county coroner reported two unexpected deaths immediately following ceftriaxone injections at two separate primary care clinics within a single week. The Alabama Department of Public Health then received a report of a third death in a hospitalized patient plus two nonfatal events. In February 2025 the CDC issued a national call for reports of any otherwise unexplained death or successful CPR within six hours of a ceftriaxone injection outside intensive care.
The case definition captured 31 patients across 18 states. The cases spanned September 2024 through August 2025, and the median age of 67 reflects a population that overlaps heavily with the people most likely to receive the drug for respiratory infections in outpatient settings.
Cardiac patients and prior exposure
Twenty-one of the 31 patients had received ceftriaxone previously without incident, undercutting the common assumption that a first dose carries the highest risk and later doses are safer. Cardiac patients were the most consistent shared feature in the dataset: 24 of 31 patients had cardiac comorbidities, and antihypertensive use was documented in 19 of 28 patients with medication information available.
Beta-blockers were the most commonly reported medication in that group, a class of blood pressure drug that can blunt the body’s response to epinephrine and make anaphylaxis harder to reverse. The combination of older cardiac patients on blood pressure medication and outpatient administration without a fixed observation window is the pattern the investigation surfaces, though the authors did not establish why these particular patients reacted.
What product testing did and did not find
The investigators were direct about what they did not find. FDA product testing turned up no evidence of tampering, adulteration, endotoxin, or purity and potency problems. Analyses of Medicare claims and a national adverse drug event surveillance system showed stable trends across 2016 through 2019 and 2020 through 2024. The authors wrote that product testing and trend analyses “did not identify evidence of a new safety issue,” and that the initial Alabama deaths may represent a chance clustering of known severe reactions.
An accompanying editorial commentary in the same journal, titled A Signal Without an Answer and written by Santiago Alvarez-Arango, MD, PhD, of the University of Texas Southwestern Medical Center in Dallas, and Elizabeth J. Phillips, MD, of Vanderbilt University Medical Center, frames the episode around the limits of what a public health investigation can resolve. The work documented a clinical pattern — anaphylaxis without rash, in older cardiac patients, in outpatient clinics — but did not establish whether the cardiac and antihypertensive pattern reflects true added risk or the underlying age of the population.
What Happens Next
Ceftriaxone is given to a large number of patients every year, and 31 severe cases across a full year of national reporting is a very small number against that denominator, with national surveillance data showing no increase over nearly a decade. No new federal guidance has been issued, and clinicians have not been told to change prescribing. The authors called for continued vigilance and for reporting of serious adverse events to the FDA’s MedWatch program. For cardiac patients in the highest-risk group described in the dataset — older adults on blood pressure medication — the practical step after a ceftriaxone injection in an outpatient clinic is to ask whether the office wants an observation period, report any symptom immediately, and call 911 for difficulty breathing, throat tightness, dizziness, or collapse. The open questions for the field are whether observation periods after outpatient injections should change, whether the cardiac and antihypertensive pattern is a true risk marker, and why prior doses offered no protection in these cases. The investigation does not answer them, but it reframes how clinicians should read a ceftriaxone anaphylaxis reaction that does not look like one.
— Aisha Mensah, health desk, AXO News