Can amoxicillin-clavulanate (Augmentin) cause tachycardia or any other cardiac adverse effects?

Comment by InpharmD Researcher

There is a lack of data directly investigating the risk of cardiotoxicity with amoxicillin-clavulanate (Augmentin®). It appears that a study in 2004 had first established use of amoxicillin as a control antibiotic to compare with other agents, as amoxicillin is not known to increase risk of sudden death from cardiac causes. Amoxicillin, however, is associated with Kounis syndrome, a rare type of acute coronary syndrome caused by allergic reaction; Kounis syndrome typically presents as coronary spasms (Type I), acute myocardial infarction (Type II), or stent thrombosis (Type III). Kounis syndrome may also present as tachycardia, ventricular dysfunction, or atrioventricular block, based on descriptions from case reports.

Background

A series of studies were conducted to investigate the cardiotoxicity of certain antibiotics. However, these studies were notable in that amoxicillin was used as the control group for treatment of similar infections to azithromycin and macrolides. The first study to utilize amoxicillin as a control was from 2004 by Ray et al., where it is stated by the authors that amoxicillin is not known to increase the risk of sudden death from cardiac causes. Because of this, it seems that subsequent studies based their designs on this notion, comparing investigational antibiotics with amoxicillin as the control agent to determine risk of cardiotoxicity. These studies have observed incidences of cardiovascular death or complications associated with amoxicillin use. However, comparisons with other antibiotics show either similar or lower rates. It remains uncertain whether amoxicillin poses a true risk or if any observed risks are confounded by concurrent use of medications that prolong the QT interval. [1], [2], [3], [4], [5]

Kounis syndrome is an acute coronary syndrome caused by allergic reaction, and as such is more common in patients with a history of allergies, hypertension, smoking, diabetes, and hyperlipidemia. There are three types of Kounis syndrome described. Type I is coronary spasms in patients with normal or near-normal coronary arteries but without predisposing factors for coronary artery disease; the allergy results in coronary spasms, with or without elevation of markers of myocardial injury. Type II is in patients with pre-existing atherosclerotic disease, acute allergy causing plaque erosion or rupture, presenting as acute myocardial infarction. Type III is characterized by allergic manifestations and stent thrombosis after coronary drug stent implantation. Based on case reports (N= 33), the most common symptoms in patients with amoxicillin-induced Kounis syndrome were allergic rash/pruritus/erythema (75.8%), chest pain (63.6%), hypotension (36.3%), neurological reactions (altered consciousness, dizziness) (30.3%), and gastrointestinal adverse events (30.3%). Electrocardiography showed elevated ST in most patients (81.2%). An additional hallmark was elevated troponin-I, which was seen in 21/24 (87.5%) of patients tested. Treatment of amoxicillin-induced Kounis syndrome was medication discontinuation in 100% of cases, followed by steroids (66.7%), antihistamines (66%), antiplatelet therapy (42.4%), anticoagulation (30.3%), nitrates (24.2%), and/or epinephrine (18.2%). Of the 33 case reports, 8 (24.2%) patients underwent percutaneous coronary intervention. [6]

The pathophysiology of Kounis syndrome is not fully understood, but it is known to be caused by an allergic reaction or exposure to specific antigens. The main inflammatory cells that are involved in the development of Kounis syndrome are mast cells that interact with macrophages and T-cells. Mast cell infiltration into plaque erosion or rupture areas is a common pathway in allergic and non-allergic coronary events. This can lead to peripheral vasodilatation, hypotension, coronary spasm, coronary atherosclerosis erosion, rupture of plaque-like plaques, or thrombosis in coronary stents. [6]

References:

[1] Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-1890. doi:10.1056/NEJMoa1003833
[2] Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351(11):1089-1096. doi:10.1056/NEJMoa040582
[3] Patel H, Calip GS, DiDomenico RJ, Schumock GT, Suda KJ, Lee TA. Comparison of Cardiac Events Associated With Azithromycin vs Amoxicillin. JAMA Netw Open. 2020;3(9):e2016864. Published 2020 Sep 1. doi:10.1001/jamanetworkopen.2020.16864
[4] Trac MH, McArthur E, Jandoc R, et al. Macrolide antibiotics and the risk of ventricular arrhythmia in older adults. CMAJ. 2016;188(7):E120-E129. doi:10.1503/cmaj.150901
[5] Trifirò G, de Ridder M, Sultana J, et al. Use of azithromycin and risk of ventricular arrhythmia. CMAJ. 2017;189(15):E560-E568. doi:10.1503/cmaj.160355
[6] Wang C, Zhou Y, Fang W, Li Z, Zhao S. Clinical features, diagnosis and management of amoxicillin-induced Kounis syndrome. Front Pharmacol. 2022;13:998239. Published 2022 Oct 31. doi:10.3389/fphar.2022.998239
Relevant Prescribing Information

The prescribing label for Augmentin® does not mention adverse events related to tachycardia or cardiac events. The listed serious events are related to hypersensitivity reactions, hepatic dysfunction, Clostridioides difficile infection, etc. Effect on heart rate or blood pressure is also not listed within the label. [7]

References:

[7] AUGMENTIN (amoxicillin and clavulanate potassium for suspension). Prescribing information. Allegis Holdings, LLC; 2023.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Can amoxicillin-clavulanate (Augmentin) cause tachycardia or any other cardiac adverse effects?

Please see Table 1 for your response.

 

Allergic acute coronary syndrome: Amoxicillin/clavulanic acid intake

Design

 Case report

Case presentation

A 78-year-old Caucasian woman with a medical history of hypertension, atrial fibrillation, and obstructive sleep apnea and obesity syndrome presented to the emergency department after a sudden loss of consciousness with absence of prodromal symptoms or traumatic brain injury. She reported recent chest pain and a history of shortness of breath and dyspnea. Two months prior, she had reported shortness of breath and dyspnea and recently had a productive cough. She was treated with oral amoxicillin-clavulanate 875-125 mg BID x8 days and clarithromycin 500 mg daily x5 days for that presumed infection. 

In the current case (antibiotic day 8), the patient was unresponsive with a Glasgow Coma Scale score of 3 and breathing associated with cardiorespiratory arrest. She was given atropine and epinephrine out-of-hospital, which led to recovery of peripheral function and consciousness. An ECG revealed atrial fibrillation and ST elevation. Blood tests showed elevated levels of cardiac troponin-I, but no sign of elevated inflammatory markers. The providers suspected Koudis syndrome.

During hospitalization, she underwent a chest CT scan that revealed cardiomegaly and fibrous atheromatous plaques in her neck vessels. Coronary angiography showed 70-90% narrowing in the circumflex artery. She was prescribed aspirin 100 mg daily and bisoprolol 5 mg daily. She was discharged after 5 days, and further tests showed normal heart function.

Post-discharge allergy tests confirmed a reaction suggestive of Kounis syndrome, a reaction of allergic reaction coupled with acute coronary syndrome. Upon resolution of this report, the patient was well-controlled with anti-ischemic therapy up to 1 year after the incident.

Study Author Conclusions

This case report describes a patient with type I Kounis syndrome induced by amoxicillin-clavulanate since she previously had normal coronary arteries. 

It is important to recognize and treat Kounis syndrome in patients with exposure to a documented allergen which
requires the thoughtful use of several common drugs. The primary focus of treatment should be directed towards the
allergic insult and removal of the offending allergens.

One proposed mechanism of Kounis syndrome secondary to amoxicillin use is due to the presence of mast cells in heart tissue. Differentiating primary myocardial damage secondary to mast cell activation from the damage caused by global
myocardial hypoperfusion can be challenging. Both may present as tachycardia, ventricular dysfunction, and
atrioventricular block.

 

References:

Filipa Ribeiro Lucas, João Gigante, Steve Harakeh, Pedro Vieira. Allergic acute coronary syndrome: Amoxicillin/clavulanic acid intake. World J Adv Res Rev. 2021;11(2):064-068. doi:10.30574/wjarr.2021.11.2.0369