zithromax and Arrhythmias--Cardiac

While looking for a solution to treat COVID-19, the massive off-label use of several drugs in COVID-19 has generated concerns in the early phase of the pandemic because of possible arrhythmogenic effects in relation to QTc interval prolongation. Indeed, some of these drugs have been historically associated with QT prolongation and Torsade de Point, a potentially lethal ventricular arrhythmia, and their first-time use on a very large scale has raised several concerns in the scientific community. This work aims to summarize the underlying arrhythmogenic mechanisms related to the use of potentially QT-prolonging drugs used during the pandemic to treat COVID-19.

Topics: Arrhythmias, Cardiac; Azithromycin; COVID-19; COVID-19 Drug Treatment; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; Risk Factors; SARS-CoV-2

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide resulting in significant morbidity and mortality. Arrhythmias are prevalent and reportedly, the second most common complication. Several mechanistic pathways are proposed to explain the pro-arrhythmic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A number of treatment approaches have been trialled, each with its inherent unique challenges. This rapid systematic review aimed to examine the current incidence and available treatment of arrhythmias in COVID-19, as well as barriers to implementation.. Our search of scientific databases identified relevant published studies from 1 January 2000 until 1 June 2020. We also searched Google Scholar for grey literature. We identified 1729 publications of which 1704 were excluded.. The incidence and nature of arrhythmias in the setting of COVID-19 were poorly documented across studies. The cumulative incidence of arrhythmia across studies of hospitalised patients was 6.9%. Drug-induced long QT syndrome secondary to antimalarial and antimicrobial therapy was a significant contributor to arrhythmia formation, with an incidence of 14.15%. Torsades de pointes (TdP) and sudden cardiac death (SCD) were reported. Treatment strategies aim to minimise this through risk stratification and regular monitoring of corrected QT interval (QTc).. Patients with SARS-CoV-2 are at an increased risk of arrhythmias. Drug therapy is pro-arrhythmogenic and may result in TdP and SCD in these patients. Risk assessment and regular QTc monitoring are imperative for safety during the treatment course. Further studies are needed to guide future decision-making.

Topics: Anti-Arrhythmia Agents; Anti-Bacterial Agents; Antimalarials; Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Flutter; Azithromycin; Bradycardia; Cardiac Pacing, Artificial; COVID-19; COVID-19 Drug Treatment; Death, Sudden, Cardiac; Electric Countershock; Hospitalization; Humans; Hydroxychloroquine; Incidence; Long QT Syndrome; SARS-CoV-2; Tachycardia, Ventricular; Torsades de Pointes; Ventricular Fibrillation

Topics: Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Interactions; Heart Rate; Humans; Hydroxychloroquine; Pandemics; Pneumonia, Viral; SARS-CoV-2; Torsades de Pointes

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Humans; Hydroxychloroquine; Monitoring, Physiologic; Pandemics; Patient Selection; Pneumonia, Viral; SARS-CoV-2

COVID-19 infection has shown rapid growth worldwide, and different therapies have been proposed for treatment, in particular, the combination of immune response modulating drugs such as chloroquine and hydroxychloroquine (antimalarials) alone or in combination with azithromycin. Although the clinical evidence supporting their use is scarce, the off label use of these drugs has spread very quickly in face of the progression of the epidemic and the high mortality rate in susceptible populations. However, these medications can pathologically prolong the QT interval and lead to malignant ventricular arrhythmias such that organized guidance on QT evaluation and management strategies are important to reduce morbidity associated with the potential large-scale use.

Topics: Adult; Aged; Antimalarials; Arrhythmias, Cardiac; Azithromycin; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Hydroxychloroquine; Incidence; Long QT Syndrome; Male; Middle Aged; Pandemics; Pneumonia, Viral; Practice Guidelines as Topic; Prognosis; Risk Assessment

The novel coronavirus disease 2019, otherwise known as COVID-19, is a global pandemic with primary respiratory manifestations in those who are symptomatic. It has spread to >187 countries with a rapidly growing number of affected patients. Underlying cardiovascular disease is associated with more severe manifestations of COVID-19 and higher rates of mortality. COVID-19 can have both primary (arrhythmias, myocardial infarction, and myocarditis) and secondary (myocardial injury/biomarker elevation and heart failure) cardiac involvement. In severe cases, profound circulatory failure can result. This review discusses the presentation and management of patients with severe cardiac complications of COVID-19 disease, with an emphasis on a Heart-Lung team approach in patient management. Furthermore, it focuses on the use of and indications for acute mechanical circulatory support in cardiogenic and/or mixed shock.

Topics: Acute Coronary Syndrome; Anti-Bacterial Agents; Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Cardiotonic Agents; Chronic Disease; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Enzyme Inhibitors; Extracorporeal Membrane Oxygenation; Heart Failure; Heart-Assist Devices; Humans; Hydroxychloroquine; Intra-Aortic Balloon Pumping; Myocardial Infarction; Myocarditis; Pandemics; Percutaneous Coronary Intervention; Pneumonia, Viral; SARS-CoV-2; Shock, Cardiogenic; Thromboembolism

Given the speed of viral infection spread, repurposing of existing drugs has been given the highest priority in combating the ongoing COVID-19 pandemic. Only drugs that are already registered or close to registration, and therefore have passed lengthy safety assessments, have a chance to be tested in clinical trials and reach patients quickly enough to help in the current disease outbreak. Here, we have reviewed available evidence and possible ways forward to identify already existing pharmaceuticals displaying modest broad-spectrum antiviral activity which is likely linked to their high accumulation in cells. Several well studied examples indicate that these drugs accumulate in lysosomes, endosomes and biological membranes in general, and thereby interfere with endosomal pathway and intracellular membrane trafficking crucial for viral infection. With the aim to identify other lysosomotropic drugs with possible inherent antiviral activity, we have applied a set of clear physicochemical, pharmacokinetic and molecular criteria on 530 existing drugs. In addition to publicly available data, we have also used our in silico model for the prediction of accumulation in lysosomes and endosomes. By this approach we have identified 36 compounds with possible antiviral effects, also against coronaviruses. For 14 of them evidence of broad-spectrum antiviral activity has already been reported, adding support to the value of this approach. Presented pros and cons, knowledge gaps and methods to identify lysosomotropic antivirals, can help in the evaluation of many drugs currently in clinical trials considered for repurposing to target COVID-19, as well as open doors to finding more potent and safer alternatives.

Topics: Anti-Inflammatory Agents; Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Chemical and Drug Induced Liver Injury; Chloroquine; Computer Simulation; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Evaluation, Preclinical; Drug Repositioning; Endosomes; Humans; Hydrogen-Ion Concentration; Hydroxychloroquine; Intracellular Membranes; Lysosomes; Membrane Lipids; Models, Biological; Pandemics; Phospholipids; Pneumonia, Viral; SARS-CoV-2; Surface-Active Agents; Virus Internalization

Most patients with end-stage renal disease depend on intermittent hemodialysis to maintain levels of serum potassium and other electrolytes within a normal range. However, one of the challenges has been the safety of using a low-potassium dialysate to achieve that goal, given the concern about the effects that rapid and/or large changes in serum potassium concentrations may have on cardiac electrophysiology and arrhythmia. Additionally, in this patient population, there is a high prevalence of structural cardiac changes and ischemic heart disease, making them even more susceptible to acute arrhythmogenic triggers. This concern is highlighted by the knowledge that about two-thirds of all cardiac deaths in dialysis are due to sudden cardiac death and that sudden cardiac death accounts for 25% of the overall death for end-stage renal disease. Developing new approaches and practice standards for potassium removal during dialysis, as well as understanding other modifiable triggers of sudden cardiac death, such as other electrolyte components of the dialysate (magnesium and calcium), rapid ultrafiltration rates, and safety of a number of medications (ie, drugs that prolong the QT interval or use of digoxin), are critical in order to decrease the unacceptably high cardiac mortality experienced by hemodialysis-dependent patients.

Topics: Aged; Arrhythmias, Cardiac; Azithromycin; Bicarbonates; Black or African American; Calcium; Coronary Circulation; Death, Sudden, Cardiac; Drug Interactions; Fatal Outcome; Hemodialysis Solutions; Humans; Hypertension; Hypokalemia; Kidney Failure, Chronic; Long QT Syndrome; Magnesium; Male; Omeprazole; Potassium; Proton Pump Inhibitors; Renal Dialysis; Time Factors; Ultrafiltration

Randomized, controlled trials have demonstrated that chronic therapy with macrolide antibiotics reduces the morbidity of patients with cystic fibrosis, non-cystic fibrosis bronchiectasis, chronic obstructive pulmonary disease, and nontuberculous mycobacterial infections. Lower levels of evidence indicate that chronic macrolides are also effective in treating patients with panbronchiolitis, bronchiolitis obliterans, and rejection after lung transplant. Macrolides are known to cause torsade des pointes and other ventricular arrhythmias, and a recent observational study prompted the FDA to strengthen the Warnings and Precautions section of azithromycin drug labels. This summary describes the electrophysiological effects of macrolides, reviews literature indicating that the large majority of subjects experiencing cardiac arrhythmias from macrolides have coexisting risk factors and that the incidence of arrhythmias in absence of coexisting risk factors is very low, examines recently published studies describing the relative risk of arrhythmias from macrolides, and concludes that this risk has been overestimated and suggests an approach to patient evaluation that should reduce the relative risk and the incidence of arrhythmias to the point that chronic macrolides can be used safely in the majority of subjects for whom they are recommended.

Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cystic Fibrosis; Heart Conduction System; Humans; Macrolides; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Factors

The purpose of this review was to evaluate the literature to assess the incidence and true clinical relevance of recent Food and Drug Administration warnings regarding QT prolongation with azithromycin, given its widespread use, with over 40 million US outpatient prescriptions written in 2011. A literature search of MEDLINE (1946 to May 2013) and International Pharmaceutical Abstracts (1970 to May 2013) was conducted using the terms azithromycin, QT prolongation, torsades de pointes, arrhythmia, and cardiovascular death. A bibliographic search was also performed. Several relevant studies and case reports were identified and reviewed. One cohort study revealed an increased risk of cardiovascular death with azithromycin compared to no antibiotic, especially in those with higher cardiovascular risk. Another cohort study comparing azithromycin, penicillin V, and no antibiotic in a younger Danish population with less cardiac risk found no increased cardiovascular death associated with azithromycin use. The majority of case reports involved ill and/or elderly patients with multiple comorbidities and concomitant medications who were already at a higher risk of cardiovascular events. Although there is evidence that azithromycin may induce QT prolongation and adverse cardiac events, the incidence is fairly limited to patients with high baseline risk, including those with preexisting cardiovascular conditions and concomitant use of other QT-prolonging drugs.

Topics: Age Factors; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cardiovascular Diseases; Electrocardiography; Humans; Risk Factors

Excitation-contraction (E-C) coupling, the interaction of action potential duration (APD) and contractility, plays an essential role in arrhythmogenesis. We aimed to investigate the arrhythmogenic role of E-C coupling in the right ventricular outflow tract (RVOT) in the chloroquine-induced long QT syndrome.. Conventional microelectrodes were used to record electrical and mechanical activity simultaneously under electrical pacing (cycle lengths from 1000-100 ms) in rabbit RVOT tissue preparations before and after chloroquine with and without azithromycin. KB-R7943 (a Na. Sequential infusion of chloroquine and chloroquine plus azithromycin triggered ventricular tachycardia (VT) (33.7%) after rapid pacing compared to baseline (6.7%, p = 0.004). There were greater post-pacing increases of the first occurrence of contractility (ΔContractility) in the VT group (VT vs. non-VT: 521.2 ± 50.5% vs. 306.5 ± 26.8%, p < 0.001). There was no difference in the first occurrence of action potential at 90% repolarization (ΔAPD. ΔContractility (but not ΔAPD) played a crucial role in the genesis of pacing-induced VT in the long QT tissue model, which can be modulated by NCX (but not late sodium current) inhibition or MgSO

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Azithromycin; Long QT Syndrome; Rabbits; Ranolazine; Sodium; Tachycardia, Ventricular

Despite no evidence showing benefits of hydroxychloroquine and chloroquine with or without azithromycin for COVID-19 treatment, these medications have been largely prescribed in Brazil.. To assess outcomes, including in-hospital mortality, electrocardiographic abnormalities, hospital length-of-stay, admission to the intensive care unit, and need for dialysis and mechanical ventilation, in hospitalized COVID-19 patients who received chloroquine or hydroxychloroquine, and to compare outcomes between those patients and their matched controls.. A retrospective multicenter cohort study that included consecutive laboratory-confirmed COVID-19 patients from 37 Brazilian hospitals from March to September 2020. Propensity score was used to select matching controls by age, sex, cardiovascular comorbidities, and in-hospital use of corticosteroid. A p-value <0.05 was considered statistically significant.. From 7,850 COVID-19 patients, 673 (8.6%) received hydroxychloroquine and 67 (0.9%) chloroquine. The median age in the study group was 60 years (46 - 71) and 59.1% were women. During hospitalization, 3.2% of patients presented side effects and 2.2% required therapy discontinuation. Electrocardiographic abnormalities were more prevalent in the chloroquine/hydroxychloroquine group (13.2% vs. 8.2%, p=0.01), and the long corrected QT interval was the main difference (3.6% vs. 0.4%, p<0.001). The median hospital length of stay was longer in the HCQ/CQ + AZT group than in controls (9.0 [5.0, 18.0] vs. 8.0 [4.0, 14.0] days). There was no statistical differences between groups in intensive care unit admission (35.1% vs. 32.0%; p=0.282), invasive mechanical ventilation support (27.0% vs. 22.3%; p=0.074) or mortality (18.9% vs. 18.0%; p=0.682).. COVID-19 patients treated with chloroquine or hydroxychloroquine had a longer hospital length of stay, when compared to matched controls. Intensive care unit admission, invasive mechanical ventilation, dialysis and in-hospital mortality were similar.. Apesar da ausência de evidência mostrando benefícios da hidroxicloroquina e da cloroquina combinadas ou não à azitromicina no tratamento da covid-19, esses medicamentos têm sido amplamente prescritos no Brasil.. Avaliar desfechos, incluindo moralidade hospitalar, alterações eletrocardiográficas, tempo de internação, admissão na unidade de terapia intensiva, e necessidade de diálise e de ventilação mecânica em pacientes hospitalizados com covid-19 que receberam cloroquina ou hidroxicloroquina, e comparar os desfechos entre aqueles pacientes e seus controles pareados.. Estudo multicêntrico retrospectivo do tipo coorte que incluiu pacientes com diagnóstico laboratorial de covid-19 de 37 hospitais no Brasil de março a setembro de 2020. Escore de propensão foi usado para selecionar controles pareados quanto a idade, sexo, comorbidades cardiovasculares, e uso de corticosteroides durante a internação. Um valor de p<0,05 foi considerado estatisticamente significativo.. Dos 7850 pacientes com covid-19, 673 (8,6%) receberam hidroxicloroquina e 67 (0,9%) cloroquina. A idade mediana no grupo de estudo foi 60 (46-71) anos e 59,1% eram mulheres. Durante a internação, 3,2% dos pacientes apresentaram efeitos adversos e 2,2% necessitaram de interromper o tratamento. Alterações eletrocardiográficas foram mais prevalentes no grupo hidroxicloroquina/cloroquina (13,2% vs. 8,2%, p=0,01), e o prolongamento do intervalo QT corrigido foi a principal diferença (3,6% vs. 0,4%, p<0,001). O tempo mediano de internação hospitalar foi maior no grupo usando CQ/HCQ em relação aos controles (9,0 [5,0-18,0] vs. 8,0 [4,0-14,0] dias). Não houve diferenças estatisticamente significativas entre os grupos quanto a admissão na unidade de terapia intensiva (35,1% vs. 32,0%; p=0,282), ventilação mecânica invasiva (27,0% vs. 22,3%; p=0,074) ou mortalidade (18,9% vs. 18,0%; p=0,682).. Pacientes com covid-19 tratados com cloroquina ou hidroxicloroquina apresentaram maior tempo de internação hospitalar, em comparação aos controles. Não houve diferença em relação a admissão em unidade de terapia intensiva, necessidade de ventilação mecânica e mortalidade hospitalar.

Topics: Aged; Arrhythmias, Cardiac; Azithromycin; Brazil; Chloroquine; Cohort Studies; COVID-19; COVID-19 Drug Treatment; Female; Humans; Hydroxychloroquine; Male; Middle Aged; Retrospective Studies; SARS-CoV-2

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na

Topics: Animals; Antibodies, Monoclonal, Humanized; Arrhythmias, Cardiac; Azithromycin; COVID-19; COVID-19 Drug Treatment; Female; Guinea Pigs; Humans; Hydroxychloroquine; Inflammation; Interleukin-6; Male; SARS-CoV-2

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; COVID-19 Drug Treatment; Drug Therapy, Combination; Humans; Hydroxychloroquine; SARS-CoV-2; Treatment Outcome

Topics: Adverse Drug Reaction Reporting Systems; Anti-Bacterial Agents; Antimalarials; Arrhythmias, Cardiac; Azithromycin; COVID-19 Drug Treatment; Drug Therapy, Combination; Electrocardiography; Humans; Long QT Syndrome; Pharmacovigilance; Torsades de Pointes; United States; United States Food and Drug Administration

Many drugs that have been proposed for treatment of coronavirus disease 2019 (COVID-19) are reported to cause cardiac adverse events, including ventricular arrhythmias. In order to properly weigh risks against potential benefits, particularly when decisions must be made quickly, mathematical modeling of both drug disposition and drug action can be useful for predicting patient response and making informed decisions. Here, we explored the potential effects on cardiac electrophysiology of four drugs proposed to treat COVID-19: lopinavir, ritonavir, chloroquine, and azithromycin, as well as combination therapy involving these drugs. Our study combined simulations of pharmacokinetics (PKs) with quantitative systems pharmacology (QSP) modeling of ventricular myocytes to predict potential cardiac adverse events caused by these treatments. Simulation results predicted that drug combinations can lead to greater cellular action potential prolongation, analogous to QT prolongation, compared with drugs given in isolation. The combination effect can result from both PK and pharmacodynamic drug interactions. Importantly, simulations of different patient groups predicted that women with pre-existing heart disease are especially susceptible to drug-induced arrhythmias, compared with diseased men or healthy individuals of either sex. Statistical analysis of population simulations revealed the molecular factors that make certain women with heart failure especially susceptible to arrhythmias. Overall, the results illustrate how PK and QSP modeling may be combined to more precisely predict cardiac risks of COVID-19 therapies.

Topics: Action Potentials; Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Chloroquine; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; Humans; Lopinavir; Male; Models, Theoretical; Myocytes, Cardiac; Risk Factors; Ritonavir; Therapies, Investigational

Hydroxychloroquine (HCQ) and azithromycin (AZM) are widely used in off-label treatment of novel coronavirus disease (COVID-19). However, cardiac safety of these drugs is still controversial in COVID-19. Therefore, we aimed to evaluate association of HCQ or HCQ + AZM treatment regimens, corrected QT (QTc) interval and malignant ventricular arrhythmias in hospitalized patients.. This is a single-center, retrospective and observational study. All data were extracted from the electronic medical records. The initial and post-treatment mean QTc intervals were calculated and compared in patients with HCQ alone or HCQ + AZM therapy. Associated factors with QTc prolongation, the incidence of ventricular arrhythmia during treatment and in-hospital mortality because of ventricular arrhythmias were evaluated.. Our cohort comprised 101 hospitalized COVID-19 patients (mean age of 49.60 ± 18 years, 54.4% men). HCQ + AZM combination therapy group (n = 56) was more likely to have comorbidities. After 5-days treatment, 19 (18.8%) patients had QTc prolongation, and significant increase in the QTc interval was observed in both two groups (P < .001). However, HCQ + AZM combination group had significantly higher ΔQTc compared to HCQ group (22.5 ± 18.4 vs 7.5 ± 15.3 ms, P < .001). All of 101 patients completed the 5-days treatment without interruption. Also, no malignant ventricular arrhythmia or death secondary to ventricular arrhythmia occurred during the treatment in both groups.. The present study revealed that although HCQ + AZM treatment was independently associated with QTc prolongation, none of patients experienced malignant ventricular arrhythmia or death during treatment. Further prospective studies are needed to determine the exact implications of these drugs on arrhythmias in patients with COVID-19.

Topics: Adult; Aged; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Comorbidity; COVID-19; COVID-19 Drug Treatment; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Retrospective Studies; SARS-CoV-2

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic as declared by World Health Organization (WHO). In the absence of an effective treatment, different drugs with unknown effectiveness, including antimalarial hydroxychloroquine (HCQ), with or without concurrent administration with azithromycin (AZM), have been tested for treating COVID-19 patients with developed pneumonia. However, the efficacy and safety of HCQ and/or AZM have been questioned by recent clinical reports. Direct effects of these drugs on the human heart remain very poorly defined. To better understand the mechanisms of action of HCQ +/- AZM, we employed bioengineered human ventricular cardiac tissue strip (hvCTS) and anisotropic sheet (hvCAS) assays, made with human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCMs), which have been designed for measuring cardiac contractility and electrophysiology, respectively. Our hvCTS experiments showed that AZM induced a dose-dependent negative inotropic effect which could be aggravated by HCQ; electrophysiologically, as revealed by the hvCAS platform, AZM prolonged action potentials and induced spiral wave formations. Collectively, our data were consistent with reported clinical risks of HCQ and AZM on QTc prolongation/ventricular arrhythmias and development of heart failure. In conclusion, our study exposed the risks of HCQ/AZM administration while providing mechanistic insights for their toxicity. Our bioengineered human cardiac tissue constructs therefore provide a useful platform for screening cardiac safety and efficacy when developing therapeutics against COVID-19.

Topics: Anti-Bacterial Agents; Antimalarials; Arrhythmias, Cardiac; Azithromycin; Chloroquine; COVID-19 Drug Treatment; Drug-Related Side Effects and Adverse Reactions; Humans; Myocardial Contraction; Myocytes, Cardiac; Pluripotent Stem Cells; Tissue Engineering; Ventricular Function

QTc interval monitoring, for the prevention of drug-induced arrhythmias is necessary, especially in the context of coronavirus disease 2019 (COVID-19). For the provision of widespread use, surrogates for 12‑lead ECG QTc assessment may be useful. This prospective observational study compared QTc duration assessed by artificial intelligence (AI-QTc) (Cardiologs®, Paris, France) on smartwatch single‑lead electrocardiograms (SW-ECGs) with those measured on 12‑lead ECGs, in patients with early stage COVID-19 treated with a hydroxychloroquine-azithromycin regimen.. Consecutive patients with COVID-19 who needed hydroxychloroquine-azithromycin therapy, received a smartwatch (Withings Move ECG®, Withings, France). At baseline, day-6 and day-10, a 12‑lead ECG was recorded, and a SW-ECG was transmitted thereafter. Throughout the drug regimen, a SW-ECG was transmitted every morning at rest. Agreement between manual QTc measurement on a 12‑lead ECG and AI-QTc on the corresponding SW-ECG was assessed by the Bland-Altman method.. 85 patients (30 men, mean age 38.3 ± 12.2 years) were included in the study. Fair agreement between manual and AI-QTc values was observed, particularly at day-10, where the delay between the 12‑lead ECG and the SW-ECG was the shortest (-2.6 ± 64.7 min): 407 ± 26 ms on the 12‑lead ECG vs 407 ± 22 ms on SW-ECG, bias -1 ms, limits of agreement -46 ms to +45 ms; the difference between the two measures was <50 ms in 98.2% of patients.. In real-world epidemic conditions, AI-QTc duration measured by SW-ECG is in fair agreement with manual measurements on 12‑lead ECGs. Following further validation, AI-assisted SW-ECGs may be suitable for QTc interval monitoring.. ClinicalTrial.govNCT04371744.

Topics: Adult; Arrhythmias, Cardiac; Artificial Intelligence; Azithromycin; COVID-19 Drug Treatment; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Pandemics

Topics: Angiotensin-Converting Enzyme 2; Anti-Bacterial Agents; Antimalarials; Arrhythmias, Cardiac; Azithromycin; Cardiovascular Diseases; Chloroquine; Comorbidity; COVID-19; COVID-19 Drug Treatment; Drug Interactions; Humans; Hydroxychloroquine; Long QT Syndrome; Myocytes, Cardiac; Receptors, Coronavirus; SARS-CoV-2; Torsades de Pointes

Hydroxychloroquine with or without azithromycin was one of the common therapies at the beginning of the COVID-19 pandemic. They can prolong QT interval, cause torsade de pointes, and lead to sudden cardiac death. We aimed to assess QT interval prolongation and its risk factors in patients who received hydroxychloroquine with or without azithromycin.. This study was a retrospective cohort study. One hundred seventy-two confirmed COVID-19 patients were included in this study, hospitalized at Babol University of Medical Sciences hospitals between. 83.1% of patients received hydroxychloroquine plus azithromycin vs. 16.9% of patients who received only hydroxychloroquine. The mean age of patients was 59.2 ± 15.4.The mean of posttreatment QTc interval in the monotherapy group was shorter than the mean of posttreatment QTc interval in the combination therapy group, but it had no significant statistical difference (462.5 ± 43.1 milliseconds vs. 464.3 ± 59.1 milliseconds;. Hospitalized patients treated by hydroxychloroquine with or without azithromycin had no significant difference in prolongation of QT interval and outcome. The numbers of patients with prolonged QT intervals in this study emphasize careful cardiac monitoring during therapy, especially in high-risk patients.

Topics: Adult; Aged; Arrhythmias, Cardiac; Azithromycin; COVID-19 Drug Treatment; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Retrospective Studies; SARS-CoV-2

Only a handful of US Food and Drug Administration (FDA) Emergency Use Authorizations exist for drug and biologic therapeutics that treat severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. Potential therapeutics include repurposed drugs, some with cardiac liabilities. We report on a chronic preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with repurposed hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock phase I safety clinical trial. The MPS contained human heart muscle derived from induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements, such as QT interval (action potential duration) and drug-biomarker pairing. Chronic exposure (10 days) of heart muscle to HCQ alone elicited early afterdepolarizations and increased QT interval past 5 days. AZM alone elicited an increase in QT interval from day 7 onward, and arrhythmias were observed at days 8 and 10. Monotherapy results mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4-8. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Biomarkers, most of them measurable in patients' serum, were identified for negative effects of monotherapy or polytherapy on tissue contractile function, morphology, and antioxidant protection. The cardiac MPS correctly predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe coronavirus disease 2019 (COVID-19) therapeutics.

Topics: Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; Clinical Trials as Topic; COVID-19 Drug Treatment; Drug Therapy, Combination; Humans; Hydroxychloroquine; Long QT Syndrome; SARS-CoV-2

Topics: Ambulatory Care; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; COVID-19 Drug Treatment; Enzyme Inhibitors; Humans; Hydroxychloroquine; Patient Selection; Randomized Controlled Trials as Topic; Risk Assessment; SARS-CoV-2; Telemedicine; United States; United States Department of Veterans Affairs; Veterans

The aim of the current study was to evaluate the index of Cardiac Electrophysiological Balance (iCEB) in hospitalized COVID-19 patients receiving Hydroxychloroquine / azithromycin (HCQ / AZ) combination therapy to determine the susceptibility to ventricular arrhythmia among these patients.. Sixty-seven COVID-19 patients admitted to the ward were included in the study. Electrocardiograms (ECGs) were obtained from all patients before the initiation of treatment and on treatment day 5. QT/QRS (iCEB) and QTc/QRS (iCEBc) ratios were calculated.. QRS, QT and QTc intervals were significantly prolonged on day 5 measurements compared to pre-treatment period (p <0.05). Overall, mean iCEB was 3.6±0.4 before treatment and 3.8±0.4 on day 5 in the study population (p <0.001). Considering the iCEBc values, a significant increase was observed in patients receiving HCQ/AZ treatment compared to pre-treatment period (4.1±0.5 vs 4.4±0.6; p <0.001).. To the best of our knowledge, this was the first study to investigate iCEB and iCEBc parameters in patients with COVID-19 on HCQ/AZ therapy. In this study, we demonstrated significantly increased iCEB and iCEBc values following HCQ/AZ treatment in COVID-19 patients. iCEB and iCEBc may serve as a noninvasive, simple, and novel biomarker for detecting increased pro-arrhythmia risk in COVID-19 patients (Tab. 3, Fig. 3, Ref. 36).

Topics: Arrhythmias, Cardiac; Azithromycin; COVID-19; Electrocardiography; Humans; Long QT Syndrome; SARS-CoV-2

To measure the prevalence of cardiac risk factors among patients prescribed azithromycin before and after the United States Food and Drug Administration (FDA) issued a warning on May 17, 2012, on the risk of potentially fatal heart rhythms associated with the drug.. Retrospective cohort study using administrative claims data.. Truven Health Analytics MarketScan database.. A total of 12,971,078 unique patients with 23,749,652 azithromycin prescriptions dispensed between January 2009 and June 2015 were included. Patients had to be continuously enrolled in a health plan for at least 365 days (baseline) before the date of azithromycin dispensing (index date). Cohorts were assigned based on the index dates of the azithromycin prescriptions, either before (January 1, 2009-May 1, 2012) or after (June 1, 2012-June 30, 2015) the FDA warning was issued.. A cardiac risk factor included either a cardiac condition (heart failure or dysrhythmias) or concurrent use of drugs that prolong the QT interval. The unit of analysis was each prescription of azithromycin. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of cardiac risk factors. Mean age of the patients was 40.1 ± 21.3 years old, with 60.8% females. Prior to the FDA warning, 11,596,022 (48.8%) azithromycin prescriptions were identified, and 12,153,630 (51.2%) were identified after the warning. The prevalence of a preexisting cardiac condition was 7.3% versus 7.9% (p<0.0001) before and after the FDA warning, respectively. Concurrent use of a QT-interval-prolonging drug was 23.3% versus 24.2% (p<0.0001) before and after the FDA warning, respectively. After controlling for confounders, the odds of having a cardiac risk factor after the FDA warning were significantly lower (odds ratio 0.938, 95% CI 0.936-0.940) compared with before the FDA warning.. Despite the 2012 FDA warning, a nontrivial number of azithromycin prescriptions was prescribed concurrently in patients with preexisting a cardiac condition (1 of 12 azithromycin prescriptions) and in those using a QT-interval-prolonging drug (1 of 5 azithromycin prescriptions). After adjusting for confounders, the odds of cardiac risk factors being present in patients prescribed azithromycin were modestly lower after the warning; however, the prevalence remained essentially unchanged before and after the FDA warning was issued.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cohort Studies; Female; Humans; Male; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; United States; United States Food and Drug Administration; Young Adult

The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Canada; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Pneumonia, Viral; Risk Management; Ritonavir; SARS-CoV-2

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; Drug Monitoring; Electrocardiography; Female; Humans; Hydroxychloroquine; Inpatients; Intersectoral Collaboration; Male; Middle Aged; Pandemics; Pneumonia, Viral; Risk Adjustment; SARS-CoV-2; Telemedicine; Treatment Outcome; United States

The novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is responsible for the global coronavirus disease 2019 pandemic. Small studies have shown a potential benefit of chloroquine/hydroxychloroquine±azithromycin for the treatment of coronavirus disease 2019. Use of these medications alone, or in combination, can lead to a prolongation of the QT interval, possibly increasing the risk of Torsade de pointes and sudden cardiac death.. Hospitalized patients treated with chloroquine/hydroxychloroquine±azithromycin from March 1 to the 23 at 3 hospitals within the Northwell Health system were included in this prospective, observational study. Serial assessments of the QT interval were performed. The primary outcome was QT prolongation resulting in Torsade de pointes. Secondary outcomes included QT prolongation, the need to prematurely discontinue any of the medications due to QT prolongation, and arrhythmogenic death.. Two hundred one patients were treated for coronavirus disease 2019 with chloroquine/hydroxychloroquine. Ten patients (5.0%) received chloroquine, 191 (95.0%) received hydroxychloroquine, and 119 (59.2%) also received azithromycin. The primary outcome of torsade de pointes was not observed in the entire population. Baseline corrected QT interval intervals did not differ between patients treated with chloroquine/hydroxychloroquine (monotherapy group) versus those treated with combination group (chloroquine/hydroxychloroquine and azithromycin; 440.6±24.9 versus 439.9±24.7 ms,. In the largest reported cohort of coronavirus disease 2019 patients to date treated with chloroquine/hydroxychloroquine±azithromycin, no instances of Torsade de pointes, or arrhythmogenic death were reported. Although use of these medications resulted in QT prolongation, clinicians seldomly needed to discontinue therapy. Further study of the need for QT interval monitoring is needed before final recommendations can be made.

Topics: Anti-Bacterial Agents; Antimalarials; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Chloroquine; Coronavirus Infections; COVID-19; Drug Therapy, Combination; Electrocardiography; Follow-Up Studies; Humans; Hydroxychloroquine; Incidence; Pandemics; Pneumonia, Viral; Prospective Studies; Risk Factors; SARS-CoV-2; United States

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; Chloroquine; Coronavirus Infections; COVID-19; Dehydration; Drug Interactions; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Pneumonia, Viral; Risk Assessment; Water-Electrolyte Imbalance

Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events.. To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19.. Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020.. Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither.. Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation).. Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings.. Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.

Topics: Adolescent; Adult; Aged; Anti-Infective Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Therapy, Combination; Female; Heart Arrest; Hospital Mortality; Hospitalization; Humans; Hydroxychloroquine; Logistic Models; Male; Middle Aged; New York; Pandemics; Pneumonia, Viral; Proportional Hazards Models; Retrospective Studies; SARS-CoV-2; Young Adult

Topics: Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; Electrocardiography; Humans; Hydroxychloroquine; Oxygen; Pandemics; Pneumonia, Viral; SARS-CoV-2; Torsades de Pointes; Viral Load

The pandemic caused by the SARS-COV-2 or COVID-19 virus has been a global challenge given its high rate of transmission and lack of effective therapy or vaccine. This scenario has led to the use of various drugs that have demonstrated a potential effect against the virus in vitro. However, time has not been enough to properly evaluate their clinical effectiveness. The use of chloroquine/hydroxychloroquine, azithromycin and antiviral treatment and has been proposed by various groups, supported by in-vitro studies and limited patient series, without the adequate scientific rigor that precedes drug prescription. Although it may represent the only hope for many patients, it is important to know the main adverse effects associated with the use of these drugs and to better select patients who may benefit from them.. La pandemia por el virus SARS-COV-2 causante de la enfermedad COVID-19 representa un reto mundial dada su alta tasa de transmisión y ausencia de una terapia efectiva o vacuna. Este escenario ha propiciado el uso de diversos fármacos que in vitro han demostrado un potencial efecto contra el virus. Sin embargo, el tiempo no ha sido suficiente para evaluar su efectividad clínica con el adecuado rigor científico que precede a la prescripción de medicamentos. El uso de cloroquina/hidroxicloroquina, azitromicina y esquemas antivirales ha sido propuesto por diversos grupos, apoyado por series de pacientes limitada en número. Si bien puede representar la única esperanza para muchos enfermos, es importante conocer los principales efectos adversos asociados al uso de estas drogas y seleccionar mejor a los pacientes que puedan beneficiarse de ellas. El riesgo de arritmias ventriculares incrementa tanto por el uso de fármacos como por la gravedad de la propia enfermedad viral.

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Humans; Hydroxychloroquine; Pandemics; Pneumonia, Viral

There is limited data regarding the electrophysiological abnormalities and arrhythmias in children with COVID-19, including those associated with treatment using potentially proarrhythmic hydroxychloroquine (HCQ) and azithromycin (AZN).. To describe the electrophysiologic findings and arrhythmias associated with pediatric COVID-19 and its treatment.. A single-center retrospective chart review was undertaken and included all patients with (1) symptoms of COVID-19 and (2) PCR-positive nasopharyngeal swabs for SARS-CoV-2 who were placed on continuous telemetry for the duration of their hospitalization during March through May, 2020.. Thirty-six patients were included in the study. Significant arrhythmias were found in 6 (nonsustained ventricular tachycardia in 5 and sustained atrial tachycardia in 1). All were self-resolving and half prompted prophylactic antiarrhythmic therapy. Patients with significant arrhythmias were likely to have noncardiac comorbidities (4/6), but these were not more common than in patients without arrhythmias (20/30, P = 1). The use of HCQ was associated with statistically significant QTc prolongation (413 ± 19 ms vs 425 ± 16 ms, P =.005). QTc was not statistically different in patients with and without arrhythmias (425 ± 15 ms vs 425 ± 15 ms, P = 1).. In pediatric patients with PCR-positive active COVID-19 infection, significant arrhythmias are infrequent, but are more common than expected in a general pediatric population. Comorbidities are not more common in patients with arrhythmias than in patients without arrhythmias. COVID-19 treatment using HCQ is associated with QTc prolongation but was not associated with arrhythmias in pediatric patients.

Topics: Anti-Infective Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Child; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Testing; Electrocardiography; Female; Humans; Hydroxychloroquine; Incidence; Long QT Syndrome; Male; New York City; Outcome and Process Assessment, Health Care; Pandemics; Pneumonia, Viral; Retrospective Studies; Risk Factors; SARS-CoV-2

Topics: Anti-Infective Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; COVID-19 Testing; Drug-Related Side Effects and Adverse Reactions; Hospitalization; Humans; Hydroxychloroquine; Italy; Outcome Assessment, Health Care; Pandemics; Pneumonia, Viral; SARS-CoV-2; Time-to-Treatment

Among candidate drugs to treat coronavirus disease 2019 (COVID-19), the combination of hydroxychloroquine (HCQ) and azithromycin (AZ) has received intense worldwide attention. Even as the efficacy of this combination is under evaluation, clinicians have begun to use it largely. As these medications are known to prolong the QT interval, we analyzed serial electrocardiograms recorded in patients hospitalized for COVID-19 pneumonia and treated with HCQ + AZ. Fifty consecutive patients received the combination of HCQ (600 mg/d for 10 days) and AZ (500 mg/d on day 1 and 250 mg/d from day 2 to day 5). Twelve-lead electrocardiograms were recorded before treatment, at day 3, at day 5, and at discharge. The median age of patients was 68 years (interquartile range, 53-81 years); 28 (56%) were men. The main comorbidities were hypertension (36%; n=18) and diabetes (16%; n=8). The mean corrected QT (QTc) interval was 408 ms at baseline and increased up to 437 ms at day 3 and to 456 ms at day 5. Thirty-eight patients (76%) presented short-term modifications of the QTc duration (>30 ms). Treatment discontinuation was decided in 6 patients (12%), leading to QTc normalization in 5 of them. No deaths and no cardiac arrhythmic events were observed in this cohort. Our report confirms that a short duration treatment with HCQ + AZ modifies the QTc interval. The treatment had to be discontinued for QTc modifications in 12% of patients. Nevertheless, in inpatients hospitalized for COVID-19, we did not observe any clinically relevant consequences of these transitory modifications. In conclusion, when patients are treated with HCQ + AZ, cardiac monitoring should be regularly performed and hospital settings allow monitoring under in safe conditions.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; Drug Administration Schedule; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hydroxychloroquine; Male; Middle Aged; Pandemics; Pneumonia, Viral; SARS-CoV-2; Treatment Outcome

Topics: Arrhythmias, Cardiac; Azithromycin; COVID-19; Humans; Hydroxychloroquine; Pandemics; Pharmacogenetics; SARS-CoV-2

Conflicting evidence exists on the association between azithromycin use and cardiac events.. To compare the odds of cardiac events among new users of azithromycin relative to new users of amoxicillin using real-world data.. This retrospective cohort study used data from Truven Health Analytics MarketScan database from January 1, 2009, to June 30, 2015. Patients receiving either amoxicillin or azithromycin and enrolled in a health care plan 365 days before (baseline period) the dispensing date (index date) were included in the study. Patients were matched 1:1 on high-dimensional propensity scores. Data were analyzed from October 1, 2018, to December 31, 2019.. New use of azithromycin compared with new use of amoxicillin.. The primary outcome consisted of cardiac events, including syncope, palpitations, ventricular arrhythmias, cardiac arrest, or death as a primary diagnosis for hospitalization at 5, 10, and 30 days from the index date. Logistic regression models were used to estimate odds ratios (ORs) with 95% CIs.. After matching, the final cohort included 2 141 285 episodes of each index therapy (N = 4 282 570) (mean [SD] age of patients, 35.7 [22.3] years; 52.6% female). Within 5 days after therapy initiation, 1474 cardiac events (0.03%) occurred (708 in the amoxicillin cohort and 766 in the azithromycin cohort). The 2 most frequent events were syncope (1032 [70.0%]) and palpitations (331 [22.5%]). The odds of cardiac events with azithromycin compared with amoxicillin were not significantly higher at 5 days (OR, 1.08; 95% CI, 0.98-1.20), 10 days (OR, 1.05; 95% CI, 0.97-1.15), and 30 days (OR, 0.98; 95% CI, 0.92-1.04). Among patients receiving any concurrent QT-prolonging drug, the odds of cardiac events with azithromycin were 1.40 (95% CI, 1.04-1.87) greater compared with amoxicillin. Among patients 65 years or older and those with a history of cardiovascular disease and other risk factors, no increased risk of cardiac events with azithromycin was noted.. This study found no association of cardiac events with azithromycin compared with amoxicillin except among patients using other QT-prolonging drugs concurrently. Although azithromycin is a safe therapy, clinicians should carefully consider its use among patients concurrently using other QT-prolonging drugs.

Topics: Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; Cohort Studies; Drug Interactions; Drug Therapy, Combination; Female; Heart Arrest; Humans; Logistic Models; Long QT Syndrome; Male; Middle Aged; Mortality; Odds Ratio; Retrospective Studies; Risk Factors; Syncope; Tachycardia, Ventricular

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; Cell Differentiation; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Embryonic Stem Cells; Humans; Mice; Myocytes, Cardiac; Pandemics; Pneumonia, Viral

Previous studies have suggested an increased risk of cardiac events with azithromycin, but the predictors of such events are unknown. We sought to develop and validate two prediction models to identify such predictors. We used data from Truven Marketscan Database (01/2009 to 06/2015). Using a split-sample approach, we developed two prediction models, which included baseline demographics, clinical conditions (Model 1), concurrent use of any drug (Model 1) and therapeutic class (Model 2) with a risk of QT-prolongation (CQT-Rx). Patients enrolled in a health plan for 365 days before and five days after dispensing of azithromycin (episodes). Cardiac events included syncope, palpitations, ventricular arrhythmias, cardiac arrest as a primary diagnosis for hospitalization including death. For each model, a backward elimination of predictors using logistic regression was applied to identify predictors in 100 random samples of the training cohort. Predictors prevalent in >50% of the models were included in the final model. A score for the Assessment of Cardiac Risk with Azithromycin (ACRA) was generated using the training cohort then tested in the validation cohort. A cohort of 20,134,659 episodes with 0.03% cardiac events were included. Over 60% included females with mean age of 40.1±21.3 years. Age, sex, history of syncope, cardiac dysrhythmias, non-specific chest pain, and presence of a CQT-Rx were included as predictors for Model-1 (c-statistic = 0.68). For Model-2 (c-statistic = 0.64), predictors included age, sex, anti-arrhythmic agents, anti-emetics, antidepressants, loop diuretics, and ACE inhibitors. ACRA score is available online (bit.ly/ACRA_2020). The ACRA score may help identify patients who are at higher risk of cardiac events following treatment with azithromycin. Providers should assess the risk-benefit of using azithromycin and consider alternative antibiotics among high-risk patients.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cardiovascular Diseases; Databases, Factual; Female; Heart Arrest; Humans; Logistic Models; Male; Middle Aged; Models, Theoretical; Risk Factors; Young Adult

BACKGROUND Azithromycin is a commonly prescribed antibiotic due to several advantages, including the broad range of indications, spectrum of activity, favorable drug interaction profile, and convenience of dosing. Although azithromycin carries a black-box warning for QTc prolongation and ventricular arrhythmias, these are considered rare adverse effects. CASE REPORT We present the case of a 37-year-old woman who received azithromycin (500 mg) for follicular tonsillitis and was admitted for worsening of symptoms. On the same day of admission to a secondary hospital, she became unresponsive and had cardiac arrest, for which cardiopulmonary resuscitation (CPR) was performed for 26 min. As per the input from the secondary hospital, she had multiple ventricular tachycardia (VT) and ventricular fibrillation, and needed to be transferred to a tertiary care hospital for further management. Veno-arterial extracorporeal membrane oxygenation (ECMO) support was inserted to support her hemodynamics, and serial ECGs showed significant QT interval prolongation up to 600 msec. The QT prolongation resolved over 10 days and she was successfully weaned-off ECMO. CONCLUSIONS Although azithromycin has a relatively safe profile, it is also associated with life-threatening cardiac arrhythmias that may require surgical intervention to stabilize the patient hemodynamically.

Topics: Adult; Arrhythmias, Cardiac; Azithromycin; Cardiopulmonary Resuscitation; Extracorporeal Membrane Oxygenation; Female; Heart Arrest; Humans

Chloroquine (CQ) and hydroxychloroquine (HCQ) were among the first drugs repurposed for the treatment of SARS-CoV-2 infection. A few in vitro studies confirmed that both drugs exhibited dose dependent anti-SARS-CoV-2 activities. These observations and the encouraging results from early poorly conducted observational studies created a major hype about the therapeutic potential of these drugs in the treatment of COVID-19 disease. This was further catalyzed by media and political influences leading to a widespread use of these agents. Subsequent randomized trials revealed lack of efficacy of these agents in improving the outcomes of COVID-19 or in preventing infection in post-exposure prophylaxis studies. Nevertheless, many ongoing trials continue to actively recruit tens of thousands of patients to receive HCQ worldwide. In this perspective, we address the possible mechanisms behind the lack of efficacy and the increased risk of cardiac toxicity of HCQ in COVID-19 disease. For the lack of efficacy, we discuss the fundamental differences of treatment initiation between in vitro and in vivo studies, the pitfalls of the pharmacological calculations of effective blood drug concentrations and related dosing regimens, and the possible negative effect of HCQ on the antiviral type-I interferon response. Although it has been repeatedly claimed that HCQ has a longstanding safety track record for many decades in use, we present counterarguments for this contention due to disease-drug and drug-drug interactions. We discuss the molecular mechanisms and the cumulative epidemiological evidence of HCQ cardiac toxicity.

Topics: Animals; Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Bradycardia; COVID-19 Drug Treatment; Death, Sudden, Cardiac; Drug Interactions; Heart; Heart Failure; Humans; Hydroxychloroquine; Interferon Type I; Mice; Observational Studies as Topic; Randomized Controlled Trials as Topic; Risk; SARS-CoV-2

Topics: Arrhythmias, Cardiac; Azithromycin; Humans; Precision Medicine; Syndrome

There are conflicting findings from observational studies of the arrhythrogenic potential of azithromycin. Our aim was to quantify the association between azithromycin use and the risk of ventricular arrhythmia.. We conducted a nested case-control study within a cohort of new antibiotic users identified from a network of 7 population-based health care databases in Denmark, Germany, Italy, the Netherlands and the United Kingdom for the period 1997-2010. Up to 100 controls per case were selected and matched by age, sex and database. Recency of antibiotic use and type of drug (azithromycin was the exposure of interest) at the index date (occurrence of ventricular arrhythmia) were identified. We estimated the odds of ventricular arrhythmia associated with current azithromycin use relative to current amoxicillin use or nonuse of antibiotics (≥ 365 d without antibiotic exposure) using conditional logistic regression, adjusting for confounders.. We identified 14 040 688 new antibiotic users who met the inclusion criteria. Ventricular arrhythmia developed in 12 874, of whom 30 were current azithromycin users. The mean age of the cases and controls was 63 years, and two-thirds were male. In the pooled data analyses across databases, azithromycin use was associated with an increased risk of ventricular arrhythmia relative to nonuse of antibiotics (adjusted odds ratio [OR] 1.97, 95% confidence interval [CI] 1.35-2.86). This increased risk disappeared when current amoxicillin use was the comparator (adjusted OR 0.90, 95% CI 0.48-1.71). Database-specific estimates and meta-analysis confirmed results from the pooled data analysis.. Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication.

Topics: Aged; Aged, 80 and over; Amoxicillin; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Case-Control Studies; Female; Humans; Male; Middle Aged; Risk Factors

Many respiratory tract infections are treated with macrolide antibiotics. Regulatory agencies warn that these antibiotics increase the risk of ventricular arrhythmia. We examined the 30-day risk of ventricular arrhythmia and all-cause mortality associated with macrolide antibiotics relative to nonmacrolide antibiotics.. We conducted a population-based retrospective cohort study involving older adults (age > 65 yr) with a new prescription for an oral macrolide antibiotic (azithromycin, clarithromycin or erythromycin) in Ontario from 2002 to 2013. Our primary outcome was a hospital encounter with ventricular arrhythmia within 30 days after a new prescription. Our secondary outcome was 30-day all-cause mortality. We matched patients 1:1 using propensity scores to patients prescribed nonmacrolide antibiotics (amoxicillin, cefuroxime or levofloxacin). We used conditional logistic regression to measure the association between macrolide exposure and outcomes, and repeated the analysis in 4 subgroups defined by the presence or absence of chronic kidney disease, congestive heart failure, coronary artery disease and concurrent use of a drug known to prolong the QT interval.. Compared with nonmacrolide antibiotics, macrolide antibiotics were not associated with a higher risk of ventricular arrhythmia (0.03% v. 0.03%; relative risk [RR] 1.06, 95% confidence interval [CI] 0.83-1.36) and were associated with a lower risk of all-cause mortality (0.62% v. 0.76%; RR 0.82, 95% CI 0.78-0.86). These associations were similar in all subgroups.. Among older adults, macrolide antibiotics were not associated with a higher 30-day risk of ventricular arrhythmia than nonmacrolide antibiotics. These findings suggest that current warnings from the US Food and Drug Administration may be overstated.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Clarithromycin; Cohort Studies; Erythromycin; Female; Humans; Logistic Models; Macrolides; Male; Ontario; Propensity Score; Retrospective Studies; Risk Assessment; Risk Factors

Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Heart Conduction System; Humans; Macrolides

Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Clarithromycin; Coronary Artery Disease; Coronary Disease; Death, Sudden, Cardiac; Erythromycin; Humans; Macrolides; Plaque, Atherosclerotic; Risk Factors; Torsades de Pointes

Topics: Adult; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Humans; Macrolides

Previous studies have demonstrated increased cardiovascular mortality related to azithromycin and levofloxacin. Risks associated with alternative drugs in the same class, including clarithromycin and moxifloxacin, were unknown. We used the Taiwan National Health Insurance Database to perform a nationwide, population-based study comparing the risks of ventricular arrhythmia and cardiovascular death among patients using these antibiotics.. Between January 2001 and November 2011, a total of 10 684 100 patients were prescribed oral azithromycin, clarithromycin, moxifloxacin, levofloxacin, ciprofloxacin, or amoxicillin-clavulanate at outpatient visits. A logistic regression model adjusted for propensity score was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for adverse cardiac outcomes occurring within 7 days after the initiation of antibiotic treatment.. Compared with amoxicillin-clavulanate treatment, the use of azithromycin and moxifloxacin was associated with significant increases in the risks of ventricular arrhythmia and cardiovascular death. The adjusted ORs for ventricular arrhythmia were 4.32 (95% CI, 2.95-6.33) for azithromycin, 3.30 (95% CI, 2.07-5.25) for moxifloxacin, and 1.41 (95% CI, .91-2.18) for levofloxacin. For cardiovascular death, the adjusted ORs for azithromycin, moxifloxacin, and levofloxacin were 2.62 (95% CI, 1.69-4.06), 2.31 (95% CI, 1.39-3.84), and 1.77 (95% CI, 1.22-2.59), respectively. No association was noted between clarithromycin or ciprofloxacin and adverse cardiac outcomes.. Healthcare professionals should consider the small but significant increased risk of ventricular arrhythmia and cardiovascular death when prescribing azithromycin and moxifloxacin. Additional research is needed to determine whether the increased risk of mortality is caused by the drugs or related to the severity of infection or the pathogens themselves.

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; beta-Lactamase Inhibitors; Cardiovascular Diseases; Ciprofloxacin; Clarithromycin; Comorbidity; Female; Fluoroquinolones; Humans; Levofloxacin; Logistic Models; Male; Moxifloxacin; Risk; Taiwan

Topics: American Heart Association; Anti-Bacterial Agents; Antibiotic Prophylaxis; Arrhythmias, Cardiac; Azithromycin; Heart Defects, Congenital; Humans; Risk Factors; Time Factors; United States; United States Food and Drug Administration

Azithromycin is a commonly prescribed macrolide antibiotic for the management of community-acquired pneumonia in the outpatient setting. Recent data have led to a growing concern of abnormal changes in cardiac electrophysiology and arrhythmias associated with its use. As azithromycin continues to be prescribed, clinicians should be aware of the new safety data and how it may affect concomitant medications or comorbid conditions in a patient. This article utilizes a case-based approach to assess azithromycin use and the risk of QT-prolongation and cardiac arrhythmias.

Topics: Aged; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Community-Acquired Infections; Humans; Long QT Syndrome; Male; Pneumonia, Bacterial; Risk

Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Bacterial Infections; Death, Sudden, Cardiac; Heart Rate; Humans

Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Drug Labeling; Humans; Long QT Syndrome; United States; United States Food and Drug Administration

Although several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death.. We studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score-matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions).. During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.. During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.).

Topics: Adult; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cardiovascular Diseases; Cohort Studies; Death, Sudden, Cardiac; Female; Humans; Incidence; Male; Medicaid; Middle Aged; Retrospective Studies; Risk; United States

Prolongation of the electrocardiogram QT interval by some, but not all drugs, has been associated with increased incidence of sudden cardiac death. Current preclinical regulatory assays cannot discriminate the arrhythmia liability of these drugs. Consequently, many new medications that prolong the QT interval are not developed despite their potential therapeutic benefit. Alternans (action potential duration alternations) is a measure of cardiac instability in humans and animals associated with the onset of ventricular fibrillation. Due to potential arrhythmia risk from observed QT prolongation, alternans was assessed in the anesthetized guinea pig after azithromycin or chloroquine alone and after combination treatment at clinically relevant concentrations proposed for the management of malaria. Chloroquine alone, but not azithromycin, caused a profound increase in action potential duration but with only minimal effects on alternans (approximately 10 ms). Azithromycin alone and in combination with chloroquine showed no increase in alternans beyond vehicle baseline responses indicating no additional arrhythmia liability.

Topics: Action Potentials; Anesthesia; Animals; Antimalarials; Arrhythmias, Cardiac; Azithromycin; Blood Pressure; Chloroquine; Dose-Response Relationship, Drug; Guinea Pigs; Heart; Heart Rate; Male

9-month-old infant was inadvertently administered azithromycin 50 mg/kg, taken from floor stock, instead of the prescribed ceftriaxone. Shortly thereafter, she became unresponsive and pulseless. The initial heart rhythm observed when cardiopulmonary resuscitation was started was a widecomplex bradycardia, with a prolonged rate-corrected QT interval and complete heart block. The baby was resuscitated with epinephrine and atropine, but she suffered severe anoxic encephalopathy. Torsade de pointes and QT-interval prolongation have been reported after administration of macrolide antibiotics, including azithromycin, both intravenously and orally. This has occurred especially in the context of coadministered drugs that inhibit the cytochrome P450 (CYP) 3A4 isoenzyme, such as ketoconazole and astemizole. However, bradycardia with complete heart block has not, to our knowledge, been reported specifically with intravenous administration of azithromycin alone, either with therapeutic doses or overdose. Clinicians should be alerted about the potential of azithromycin to cause life-threatening bradycardia, and pharmacy systems should be implemented to ensure special care in the safe administration of this drug, especially when dispensed from a point-of-care source.

Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cardiopulmonary Resuscitation; Electroencephalography; Epinephrine; Female; Hemodynamics; Humans; Infant; Medical Errors

The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not been shown to cause torsades de pointes arrhythmias (TdP). Azithromycin is a macrolide antibiotic that has rarely been associated, clinically, with cases of proarrhythmia. As there is a lack of clinical data available, the cardiac safety of these drugs was assessed in a TdP-susceptible animal model by evaluating their repolarization and proarrhythmia effects.. In transfected HEK cells, the IC(50)s for I (hERG) were 45+/-6 and 856+/-259 microg ml(-1) for moxifloxacin and azithromycin, respectively. Intravenous administration of 2 and 8 mg kg(-1) moxifloxacin (total peak-plasma concentrations 4.6+/-1.5 and 22.9+/-6.8 microg ml(-1)) prolonged the QT(c) in 6 anaesthetized dogs with chronic AV block by 7+/-3 and 21+/-19%, respectively. Similar intravenous doses of azithromycin (total peak-plasma concentrations 5.4+/-1.3 and 20.8+/-4.9 microg ml(-1)) had no electrophysiological effects in the same dogs. The reference compound, dofetilide (25 microg kg(-1) i.v.) caused QT(c) prolongation (29+/-15%) and TdP in all dogs. Beat-to-beat variability of repolarization (BVR), quantified as short-term variability of the left ventricular monophasic action potential duration, was only increased after dofetilide (1.8+/-0.7 to 3.8+/-1.5 ms; P<0.05).. As neither moxifloxacin nor azithromycin caused TdP or an increase in the BVR, we conclude that both drugs can be used safely in clinical situations.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Anti-Bacterial Agents; Arrhythmias, Cardiac; Aza Compounds; Azithromycin; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Electroencephalography; Electrophysiology; Fluoroquinolones; Heart Block; Heart Rate; Long QT Syndrome; Moxifloxacin; Phenethylamines; Quinolines; Sulfonamides; Torsades de Pointes

Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Electrocardiography; Humans; Male; Middle Aged

Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.

Topics: Animals; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Blood Pressure; Clarithromycin; Electrocardiography; Erythromycin; Heart; Heart Rate; In Vitro Techniques; Long QT Syndrome; Male; Rabbits; Time Factors; Torsades de Pointes

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms. ml/microg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

Topics: Algorithms; Animals; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Body Temperature; Clarithromycin; Electrocardiography; Heart Rate; Infusions, Intravenous; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Roxithromycin