Anaphylaxis and Cardiac Arrest Induced by Initial Intravenous Ceftriaxone: A Case Report

Introduction

Ceftriaxone, a third-generation cephalosporin antibiotic, exhibits broad-spectrum activity against both gram-positive and gram-negative pathogens [1]. Its favorable pharmacokinetic profile – characterized by prolonged half-life, extensive tissue penetration, and compatibility with once-daily administration – has established its clinical utility in managing severe infections such as pneumonia, meningitis, and sepsis [1,2]. Nonetheless, ceftriaxone therapy is not devoid of risks, with reported adverse effects spanning gastrointestinal disturbances, immune-mediated hemolytic anemia, biliary pseudolithiasis, and, albeit rarely, life-threatening anaphylaxis [2–6]. Notably, severe hypersensitivity reactions, including anaphylaxis and cardiopulmonary arrest, have been reported even following initial exposure in patients with no previous history of drug allergy [7,8]. Although such events are uncommon, they highlight the potential for unpredictable and serious allergic responses associated with ceftriaxone administration. This report describes a case of immediate cardiac arrest following the first ceftriaxone infusion in a patient with no known drug allergies. Successful resuscitation followed prompt cardiopulmonary intervention. Shortly after initiation of the ceftriaxone infusion, the patient experienced cardiovascular collapse, cardiac arrest, bilateral pulmonary wheezing, and generalized urticaria. Acute myocardial infarction, arrhythmia, and other potential etiologies were systematically excluded. In accordance with diagnostic criteria for anaphylaxis established by the World Allergy Organization (WAO) [9] and the Brighton Collaboration case definition [10], this episode was classified as a severe drug-induced allergic reaction, fulfilling Level 1 diagnostic certainty. The reaction had a sudden and fulminant onset that was independent of dosage, consistent with a type I (IgE-mediated) hypersensitivity reaction and a type B adverse drug event. This case highlights the risk of anaphylaxis even with initial ceftriaxone exposure and emphasizes the need for clinician vigilance when administering this antibiotic, even to low-risk patients. This report aims to improve the pharmacovigilance and safety of patients using ceftriaxone.

Case Report

On 10 February 2024, at 10: 30, a 61-year-old woman with a history of cured secondary pulmonary tuberculosis presented to the emergency room due to a 3-day history of cough and dizziness. She had been taking cefuroxime and aminophylline orally during this period. She had no other chronic comorbidities or known drug allergies. Although she had prior exposure to multiple cephalosporins, there was no documented history of ceftriaxone administration.

On physical examination, her vital signs were: pulse 88 beats/min (regular), blood pressure 140/76 mmHg, respiratory rate 20 breaths/min, oxygen saturation 95% on room air, and temperature 36.8°C. Cardiac and pulmonary auscultations were unremarkable. An initial electrocardiogram (ECG) revealed a mildly elevated sinus rhythm without other abnormalities.

Laboratory investigations in the emergency room showed a white blood cell count of 10.3 k/uL (reference range: 4.0–10.0 k/uL); hemoglobin, 11.7 g/dL (reference range: 11.0–15.0 g/dL); platelets, 307 k/uL (reference range: 100–300 k/uL); creatinine, 0.5 mg/dL (reference range: 0.5–1.1 mg/dL); C-reactive protein, 1.7 mg/dL (reference range: <0.8 mg/dL); troponin I, <0.01 ng/mL (reference range: <0.04 ng/mL); and NT-proBNP, 122.95 pg/mL (reference range: <125 pg/mL). Chest CT demonstrated post-tuberculous changes with new consolidation in the right lower lobe.

At 13: 02, intravenous ceftriaxone was initiated for treatment of pneumonia. Within 30 seconds of administration, the patient developed acute severe cough, dyspnea, irritability, and cyanosis. The ceftriaxone infusion was immediately discontinued and replaced with 0.9% saline. She was promptly transferred to the resuscitation unit of the emergency department at 13: 04. Continuous electrocardiographic monitoring of heart rate, blood pressure, and oxygen saturation was initiated, and high-flow oxygen was administered via facemask.

At 13: 05, she developed profound hypotension (blood pressure 68/60 mmHg), rapidly followed by loss of consciousness, absence of carotid artery pulsation, and cardiac arrest characterized by asystole on electrocardiographic monitoring. ACLS measures, including chest compressions, bag-mask ventilation, intravenous adrenaline (1 mg), and dexamethasone (10 mg), were promptly initiated. Return of spontaneous circulation (ROSC) was achieved after 2 minutes. The patient regained partial consciousness within minutes, displaying marked tachycardia, hypoxemia, and widespread wheezing, which improved following continued high-flow oxygen and intravenous methylprednisolone. Subsequently, she developed a transient, generalized urticarial rash, which resolved spontaneously. She was then transferred to the ICU for further observation and management. Levofloxacin was administered as an alternative antibiotic for pneumonia.

The patient recovered fully and was discharged after 3 days. At the 1-month follow-up, she remained well, with no cardiac or neurological complications.

Discussion

This case report demonstrates that initial intravenous ceftriaxone can induce severe anaphylactic reactions and cardiac arrest, even in patients without a history of drug allergy. It underscores the importance of vigilant monitoring and preparedness for immediate resuscitation during antibiotic administration. These observations can inform clinical practice by reminding clinicians to consider the possibility of rare, life-threatening reactions to commonly used antibiotics.

Our patient had dyspnea, shock, and subsequent cardiopulmonary arrest within 30 seconds after ceftriaxone injection. The abnormal performance of the anaphylactic reaction was clearly correlated with the time of injection of ceftriaxone, and no other intravenous drug was administered prior to the onset of anaphylaxis. Potential alternative etiologies, including vasovagal syncope, acute airway obstruction, acute myocardial infarction, arrhythmia, pulmonary embolism, and septic shock, were systematically excluded based on the patient’s initial hemodynamic stability, full consciousness, and absence of symptoms such as chest pain, palpitations, dyspnea, nausea, or excessive sputum production. Furthermore, ECG findings, serum myocardial enzyme levels, and serum D-dimer levels were within normal ranges prior to intravenous administration of ceftriaxone. The causal relationship between ceftriaxone administration and the subsequent anaphylactic reaction was systematically evaluated through the Naranjo Adverse Drug Reaction Probability Scale [11], demonstrating a score of 7 (Table 1), which corresponds to a ‘probable’ drug-related association. This severe adverse event was further confirmed to meet the Level 1 (highest) diagnostic certainty criteria for anaphylaxis according to the standardized case definitions jointly established by the WAO [9] and Brighton Collaboration [10]. Consequently, a definitive diagnosis of ceftriaxone-induced cardiopulmonary arrest secondary to anaphylaxis was established based on these comprehensive assessments.

According to the Coombs and Gell classification of the pathomechanisms underlying allergic reactions [12,13], 4 types are distinguished: IgE-mediated immediate-type reactions (type I), the very rare cytotoxic (type II) and immune complex-mediated reactions (type III), and the more common delayed-type hypersensitivity reactions mediated by T lymphocytes (type IV). In the present case, the rapid onset of symptoms following ceftriaxone administration suggests a type I (IgE-mediated) hypersensitivity reaction. Although the clinical presentation was consistent with anaphylaxis, we did not perform laboratory tests (such as serum tryptase or specific IgE assays) to definitively confirm the underlying immune mechanism due to limitations in hospital laboratory capabilities. Therefore, our conclusion is based on the temporal relationship, clinical features, and known pharmacology of ceftriaxone. Within the classical pharmacological framework [14], this case is classified as a severe type B adverse drug event. In contrast to the more common type A reactions, which are dose-dependent, predictable, and directly related to the drug’s pharmacological properties, type B adverse events are rare, unpredictable, and frequently mediated by immunological mechanisms. Such events can result in life-threatening consequences, presenting substantial challenges in clinical practice.

Anaphylaxis following the administration of cephalosporins is rare, with reported incidence rates ranging from approximately 0.0001% to 0.1% among exposed patients [15]. The incidence of ceftriaxone-associated anaphylaxis has been estimated at approximately 0.0093% [16]. Progression to cardiopulmonary arrest after ceftriaxone administration is even rarer; a systematic search of electronic medical databases identified only 5 documented English-language case reports of ceftriaxone-induced cardiopulmonary arrest [5,8,17–19]. Saritas et al (2012) [8] and Abodunrin et al (2015) [5] documented cases of ceftriaxone-induced cardiac arrest in a 55-year-old man and a 66-year-old woman, respectively. Both patients recovered rapidly, one following CPR and the other through spontaneous resolution. Similarly, Aboul-Fotouh et al (2018) [17] reported successful resuscitation in a 44-year-old man who developed bradycardia, bronchospasm, and hypotension prior to arrest following a single ceftriaxone injection for surgical prophylaxis. In contrast, reports by Ul Mustafa et al (2019) [18] and Riezzo et al (2021) [19] described cases in which ceftriaxone-induced cardiac arrest did not respond to intervention, ultimately resulting in patient death. The cases reported in the literature share several characteristics with our own. Notably, in all instances, the patients had no prior cephalosporin allergy history, were first-time ceftriaxone recipients, and the reactions occurred unpredictably. Additionally, the onset of cardiac arrest was sudden and occurred shortly after ceftriaxone administration, providing the healthcare team with minimal time to respond effectively. This situation poses significant challenges to the emergency response capabilities of healthcare staff.

Anaphylactic shock and cardiac arrest occurred on first exposure to ceftriaxone in this case, probably due to cross-reactivity between cephalosporins. β-Lactam antibiotics, including penicillins, cephalosporins, carbapenems, and monobactams, are characterized by a shared β-lactam ring structure, yet they exhibit variations in their peripheral ring systems and side chains, notably the R1 side chain [20]. Cross-reactivity among these agents is partially attributed to the common β-lactam core; however, it is predominantly influenced by similarities in the R1 side chain, particularly between cephalosporins and penicillins [20]. Immunologic cross-recognition occurs when compounds possess identical or closely related R1 side chains, increasing the likelihood of allergic reactions [21]. The risk of cross-reactivity is significantly elevated among β-lactam antibiotics with identical or similar R1 groups, whereas those with distinct side chains demonstrate a markedly reduced risk [20, 21]. For example, the rate of cross-reactivity between penicillins and cephalosporins is generally about 2% to 5% [13,15], and immunologically mediated reactions between cephalosporins occur in 1% to 3% of patients, even in the absence of a penicillin allergy history [21]. However, when specific agents share identical R1 side chains, such as amoxicillin and cefadroxil, the cross-reactivity rate can exceed 30% [15]. Aminopenicillins (ampicillin and amoxicillin), which possess very similar aminobenzyl R1 side chains, display nearly 100% intra-class cross-reactivity [13]. Cephalosporins with identical methoxyimino-containing R1 groups (eg, cefuroxime, cefotaxime, and ceftriaxone) have an intra-class cross-reactivity of approximately 43.8%, while aminocephalosporins (those with amino-phenylacetamido groups) have a rate of 15.4% [15,22]. In our study, prior exposure to cefotaxime in this patient may have induced the production of IgE antibodies directed against the shared methoxyimino-containing R1 side chain. This immunological sensitization can subsequently precipitate severe allergic reactions upon initial administration of ceftriaxone.

Anaphylaxis is a critical medical emergency characterized by rapid onset and potentially life-threatening consequences, necessitating immediate recognition and intervention. Guidelines from the Australian and New Zealand College of Anaesthetists stress the importance of early diagnosis based on detailed drug allergy histories and clinical signs, which can encompass cutaneous, respiratory, and cardiovascular symptoms [23].However, a patient’s drug allergy history may be unreliable, as cross-reactivity can occur among cephalosporins, and cephalosporins skin testing lacks predictive value for allergic reactions [16]. In such circumstances, the identification of an allergic reaction often relies on the sequence of medication administration and the symptoms presented. When anaphylaxis is suspected, immediate treatment with intramuscular epinephrine is imperative, with recommended dosages of 0.5 mg (0.5 mL of a 1: 1000 solution) for adults and 0.01 mg/kg (not exceeding 0.3 mg) for children [24]. In life-threatening situations such as cardiac arrest, intravenous epinephrine is recommended. While adjunctive medications like glucocorticoids and antihistamines can provide supportive care – glucocorticoids reducing inflammation and antihistamines alleviating itching and hives – they should never replace epinephrine as the primary treatment [23,24]. Fluid resuscitation is another critical component of effective anaphylaxis management, especially as increased vascular permeability can lead to hypovolemia and exacerbated hemodynamic instability. Administering intravenous fluids, typically crystalloid solutions, is essential to maintain organ perfusion, with repeated boluses of 20 mL/kg considered for patients in shock [24]. Furthermore, continuous monitoring of a patient’s vital signs is essential because anaphylaxis can result in a biphasic reaction in which symptoms can reappear after initial resolution [25]. Therefore, it is recommended that patients be observed for an extended period of time, ranging from several hours to days, following the administration of epinephrine. If cardiac arrest occurs, it is imperative to initiate the chain of survival and implement ACLS measures without delay. This proactive approach is crucial to improving patient outcomes in these critical scenarios [23,24].

This case report has several limitations. First, due to hospital resource constraints, serum histamine levels were not assessed during either hospitalization or follow-up, which limited our ability to further elucidate the pathophysiologic mechanisms underlying the allergic reaction. Second, serum sIgE testing was not conducted following disease onset or during the follow-up period to assess persistent immunologic activity. Finally, the patient did not undergo skin testing in the Department of Immunology and Allergy during follow-up, which prevented further characterization of her allergic profile. These limitations, primarily attributable to resource and patient compliance constraints, should be considered when interpreting the findings. Nevertheless, given the classic clinical manifestations observed in this case, these limitations do not preclude the diagnosis or management of ceftriaxone-induced anaphylaxis in the patient.

Conclusions

Initial intravenous administration of ceftriaxone can trigger rare but serious anaphylactic reactions, including cardiopulmonary arrest, even in patients without a history of drug allergy. The present report shows the importance of vigilant monitoring during intravenous administration of ceftriaxone, with prompt recognition and immediate emergency intervention being critical for patient survival.