zithromax and Long-QT-Syndrome

Azithromycin is a macrolide antibiotic. Recent evidence has demonstrated in vitro activity against a wide variety of respiratory tract viruses, including SARS-CoV-2 responsible for the current global pandemic COVID-19. A mechanism of action acting on different phases of the viral cycle is assumed. In addition to its in vitro antiviral properties, some evidence also suggests immunomodulatory and antifibrotic activity. These properties of azithromycin could be useful in the treatment of viral respiratory tract infections such as COVID-19. However, clinical data on the antiviral efficacy of azithromycin in the treatment of respiratory tract infections are inconsistent, both when used as monotherapy and in polypharmacological combination. In addition, cases of azithromycin-induced QT long and malignant arrhythmias are reported. In this short review, we attempt to determine the role of azithromycin in the treatment of viral respiratory tract infections such as COVID-19, therapeutic efficacy, or inefficacy?

Topics: Antiviral Agents; Azithromycin; COVID-19; COVID-19 Drug Treatment; Humans; Long QT Syndrome; SARS-CoV-2

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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 19 (COVID-19), has rapidly spread since December 2019 to become the focus of healthcare systems worldwide. Its highly contagious nature and significant mortality has led to its prioritization as a public health issue. The race to prevent and treat this disease has led to "off-label" prescribing of medications such as hydroxychloroquine, azithromycin, and Kaletra (lopinavir/ritonavir). Currently, there is no robust clinical evidence for the use of these drugs in the treatment of COVID-19, with most, if not all of these medications associated with the potential for QT interval prolongation, torsades de pointes, and resultant drug-induced sudden cardiac death. The aim of this document is to help healthcare providers mitigate the potential deleterious effects of drug-induced QTc prolongation.

Topics: Anti-Bacterial Agents; Antiviral Agents; Azithromycin; COVID-19 Drug Treatment; Drug Combinations; Electrocardiography; Enzyme Inhibitors; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Magnesium; Pandemics; Potassium; Practice Guidelines as Topic; Risk Assessment; Risk Factors; Ritonavir; SARS-CoV-2; Torsades de Pointes

The risk-benefit ratio associated with the use of repurposed drugs to treat severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)-related infectious coronavirus disease 2019 (COVID-19) is complicated because benefits are awaited, not proven. A thorough literature search was conducted to source information on the pharmacological properties of 5 drugs and 1 combination (azithromycin, chloroquine, favipiravir, hydroxychloroquine, remdesivir, and lopinavir/ritonavir) repurposed to treat COVID-19. A risk assessment of drug-induced long QT syndrome (LQTS) associated with COVID-19 repurposed drugs was performed and compared with 23 well-known torsadogenic and 10 low torsadogenic risk compounds. Computer calculations were performed using pharmacokinetic and pharmacodynamic data, including affinity to block the rapid component of the delayed rectifier cardiac potassium current (I

Topics: Antiviral Agents; Azithromycin; COVID-19 Drug Treatment; Drug Repositioning; Humans; Hydroxychloroquine; Long QT Syndrome; Risk Assessment; SARS-CoV-2

Non-clinical studies suggest that chloroquine (CQ) and hydroxychloroquine (HCQ) have antiviral activities. Early clinical reports of successful HCQ-associated reduction in viral load from small studies in COVID-19 patients spurred a large number of national and international clinical trials to test their therapeutic potential. The objective of this review is to summarize the current evidence on the safety and efficacy of these two agents and to provide a perspective on why their repurposing has hitherto failed.. Published studies and rapidly emerging data were reviewed to gather evidence on safety and efficacy of CQ and HCQ in patients with COVID-19 infection or as prophylaxis. The focus is on clinically relevant efficacy endpoints and their adverse effects on QT interval.. At the doses used, the two agents, given alone or with azithromycin (AZM), are not effective in COVID-19 infection. The choice of (typically subtherapeutic) dosing regimens, influenced partly by "QT-phobia," varied widely and seems anecdotal without any pharmacologically reliable supporting clinical evidence. A substantial proportion of patients receiving CQ/HCQ/AZM regimen developed QTc interval prolongation, many with absolute QTc interval exceeding the potential proarrhythmic threshold, but very few developed proarrhythmia.. The strategy to repurpose CQ/HCQ to combat COVID-19 infection is overshadowed by concerns about their QT liability, resulting in choice of potentially subtherapeutic doses. Although the risk of QT-related proarrhythmia is real, it is low and manageable by careful monitoring. Recent discontinuation of HCQ from at least four large studies effectively marks the end of efforts at repurposing of CQ or HCQ for COVID-19 infection. This episode leaves behind important questions on dose selection and risk/benefit balance in repurposing drugs generally.

Topics: Antiviral Agents; Azithromycin; Chloroquine; COVID-19; COVID-19 Drug Treatment; Dose-Response Relationship, Drug; Drug Repositioning; Humans; Hydroxychloroquine; Long QT Syndrome; Treatment Outcome; Viral Load

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

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an enormous challenge to the medical system, especially the lack of safe and effective COVID-19 treatment methods, forcing people to look for drugs that may have therapeutic effects as soon as possible. Some old drugs have shown clinical benefits after a few small clinical trials that attracted great attention. Clinically, however, many drugs, including those currently used in COVID-19, such as chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir, may cause cardiotoxicity by acting on cardiac potassium channels, especially hERG channel through their off-target effects. The blocking of the hERG channel prolongs QT intervals on electrocardiograms; thus, it might induce severe ventricular arrhythmias and even sudden cardiac death. Therefore, while focusing on the efficacy of COVID-19 drugs, the fact that they block hERG channels to cause arrhythmias cannot be ignored. To develop safer and more effective drugs, it is necessary to understand the interactions between drugs and the hERG channel and the molecular mechanism behind this high affinity. In this review, we focus on the biochemical and molecular mechanistic aspects of drug-related blockade of the hERG channel to provide insights into QT prolongation caused by off-label use of related drugs in COVID-19, and hope to weigh the risks and benefits when using these drugs.

Topics: Azithromycin; Chloroquine; COVID-19; COVID-19 Drug Treatment; Drug Combinations; ERG1 Potassium Channel; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Off-Label Use; Ritonavir

Hydroxychloroquine, chloroquine, azithromycin, and lopinavir/ritonavir are drugs that were used for the treatment of coronavirus disease 2019 (COVID-19) during the early pandemic period. It is well-known that these agents can prolong the QTc interval and potentially induce Torsades de Pointes (TdP). We aim to assess the prevalence and risk of QTc prolongation and arrhythmic events in COVID-19 patients treated with these drugs.. We searched electronic databases from inception to September 30, 2020 for studies reporting peak QTc ≥500 ms, peak QTc change ≥60 ms, peak QTc interval, peak change of QTc interval, ventricular arrhythmias, TdP, sudden cardiac death, or atrioventricular block (AVB). All meta-analyses were conducted using a random-effects model.. Forty-seven studies (three case series, 35 cohorts, and nine randomized controlled trials [RCTs]) involving 13 087 patients were included. The pooled prevalence of peak QTc ≥500 ms was 9% (95% confidence interval [95%CI], 3%-18%) and 8% (95%CI, 3%-14%) in patients who received hydroxychloroquine/chloroquine alone or in combination with azithromycin, respectively. Likewise, the use of hydroxychloroquine (risk ratio [RR], 2.68; 95%CI, 1.56-4.60) and hydroxychloroquine + azithromycin (RR, 3.28; 95%CI, 1.16-9.30) was associated with an increased risk of QTc prolongation compared to no treatment. Ventricular arrhythmias, TdP, sudden cardiac death, and AVB were reported in <1% of patients across treatment groups. The only two studies that reported individual data of lopinavir/ritonavir found no cases of QTc prolongation.. COVID-19 patients treated with hydroxychloroquine/chloroquine with or without azithromycin had a relatively high prevalence and risk of QTc prolongation. However, the prevalence of arrhythmic events was very low, probably due to underreporting. The limited information about lopinavir/ritonavir showed that it does not prolong the QTc interval.

Topics: Azithromycin; Chloroquine; COVID-19; COVID-19 Drug Treatment; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Observational Studies as Topic; Ritonavir

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 emergence of the new COVID-19 virus is proving to be a challenge in seeking effective therapies. Since the most severe clinical manifestation of COVID-19 appears to be a severe acute respiratory syndrome, azithromycin has been proposed as a potential treatment. Azithromycin is known to have immunomodulating and antiviral properties. In vitro studies have demonstrated the capacity of azithromycin in reducing production of pro-inflammatory cytokines such as IL-8, IL-6, TNF alpha, reduce oxidative stress, and modulate T-helper functions. At the same time there are multiple clinical evidences of the role of azithromycin in acute respiratory distress syndrome and against Middle East Respiratory syndrome (MERS). Some preliminary evidence has demonstrated controversial results regarding efficacy of azithromycin in combination with hydroxychloroquine in COVID-19. First, a French trial demonstrated 100% virological negativizing of six patients treated with azithromycin plus hydroxychloroquine vs. 57.1% of patients treated with only hydroxychloroquine and 12.5% of the control group (P < 0.05). On the other hand, another case series revealed no efficacy at all on 11 patients treated with the same combination and doses. Furthermore, there are some concerns regarding the association of azithromycin and hydroxychloroquine because of potential QT prolongation. In fact, both drugs have this as a potential side effect and evidence regarding the safe use of this combination is controversial. Despite the necessity to quickly find solutions for COVID-19, extreme caution must be used in evaluating the risk-benefit balance. However, based on preclinical and clinical evidence and some preliminary results in COVID-19, azithromycin could have potential in the fight against this new disease.

Topics: Antiviral Agents; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; Drug Therapy, Combination; Humans; Hydroxychloroquine; Immunologic Factors; Long QT Syndrome; Pandemics; Pneumonia, Viral; SARS-CoV-2

Topics: Azithromycin; Betacoronavirus; Biomarkers; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Diagnosis, Differential; Drug Therapy, Combination; Humans; Hydroxychloroquine; Hypoxia; Long QT Syndrome; Myocardial Infarction; Myocarditis; Pandemics; Pericarditis; Pneumonia, Viral; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Tachycardia, Ventricular; Thrombophilia; Ventricular Dysfunction, Left; Ventricular Fibrillation

To evaluate the toxicity of azithromycin in neonates, infants, and children.. A systematic review was performed for relevant studies using Medline (Ovid), PubMed, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, and International Pharmaceutical Abstracts. We calculated the pooled incidence of adverse drug reactions (ADRs) associated with azithromycin based on prospective studies (RCTs and prospective cohort studies) and analyzed the risk difference (RD) of ADRs between azithromycin and placebo or other antibiotics using meta-analysis of RCTs.. We included 133 studies with 4243 ADRs reported in 197,675 neonates, infants, and children who received azithromycin. The safety of azithromycin as MDA in pediatrics was poorly monitored. The main ADRs were diarrhea and vomiting. In prospective non-MDA studies, the most common toxicity was gastrointestinal ADRs (938/1967; 47.7%). The most serious toxicities were cardiac (prolonged QT or irregular heart beat) and idiopathic hypertrophic pyloric stenosis (IHPS). Compared with placebo, azithromycin did not show increased risk ADRs based on RCTs (risk difference - 0.17 to 0.07). The incidence of QT prolonged was higher in the medium-dosage group (10-30 mg/kg/day) than that of low-dosage group (≤ 10 mg/kg/day) (82.0% vs 1.2%).. The safety of azithromycin as MDA needs further evaluation. The most common ADRs are diarrhea and vomiting. The risk of the most serious uncommon ADRs (cardiac-prolonged QT and IHPS) is unknown.

Topics: Age of Onset; Anti-Bacterial Agents; Azithromycin; Child; Diarrhea; Humans; Incidence; Long QT Syndrome; Placebos; Prospective Studies; Pyloric Stenosis, Hypertrophic; Randomized Controlled Trials as Topic; Risk Assessment; Vomiting

Azithromycin and levofloxacin have been shown to be efficacious in treating infections. The adverse drug events associated with azithromycin and levofloxacin were considered rare. However, the US FDA released warnings regarding the possible risk of QT prolongation with azithromycin and levofloxacin.. Case reports/case series, observational studies and clinical trials assessing cardiovascular risks associated with azithromycin and levofloxacin were critically reviewed, including 15 case reports/series, 5 observational studies and 5 clinical trials that investigated the cardiac risks associated azithromycin and levofloxacin.. Results are discordant. Two retrospective studies utilizing large databases demonstrated an increased risk of cardiovascular death with azithromycin, when azithromycin was compared with amoxicillin. Two other retrospective studies found no difference in cardiovascular death associated with azithromycin and other antibiotics. For levofloxacin, the increased risk of cardiovascular death was only found in one retrospective study. Therefore, the risks and benefits of antibacterial therapies should be considered when making prescription decisions. This study should not preclude clinicians from avoiding azithromycin and levofloxacin. If a patient has an indication to receive an antibiotic and if azithromycin or levofloxacin is needed, it may be used, but the potential risks must be understood.

Topics: Anti-Bacterial Agents; Azithromycin; Death; Humans; Levofloxacin; Long QT Syndrome

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

To review the possible association between azithromycin and increased cardiovascular risk.. A literature search of MEDLINE (1946-August 2013) was performed using the search terms macrolide, azithromycin, QT prolongation, cardiovascular, and torsade de pointes. Additional references were identified from a review of literature citations.. All English-language observational studies assessing the association between azithromycin and QT prolongation or cardiovascular risk were evaluated. Case reports describing this potential association were also reviewed.. A total of 6 case reports have shown a possible association between azithromycin and QT prolongation. In 3 of these cases, proarrhythmic events were reported. In a prospective observational study of 47 individuals with low cardiovascular risk, electrocardiograms were compared before and after 5 days of azithromycin treatment. Mild prolongation of the QTc was noted, but it was statistically insignificant compared with baseline. No arrhythmias were observed. A large observational cohort study found a small increase in cardiovascular deaths after azithromycin therapy, primarily among patients with high baseline cardiovascular risk. Conversely, a second cohort study involving a population of young to middle-aged adults failed to find an association.. An emerging body of evidence suggests that azithromycin therapy may prolong the QT interval and, in rare cases, precipitate the potentially fatal arrhythmia torsade de pointes. Patients with additional risk factors for QT prolongation appear to be at highest risk, including women, elderly individuals; those with existing or prior history of cardiovascular disease, QT interval prolongation, hypokalemia, hypomagnesium, or bradycardia; and those using concomitant drugs associated with QT prolongation. For patients without these additional risk factors, azithromycin appears to be relatively safe.

Topics: Anti-Bacterial Agents; Azithromycin; Humans; Long QT Syndrome; Observational Studies as Topic; Risk Factors; Torsades de Pointes

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

Topics: Adult; Aged; Azithromycin; COVID-19; COVID-19 Drug Treatment; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Middle Aged; SARS-CoV-2

This study aimed to characterize adverse drug reactions (ADRs) to hydroxychloroquine in the setting of COVID-19, occurring in Italy in the period March to May 2020. The analysis of the combination therapy with azithromycin or/and lopinavir/ritonavir as well as a comparison with ADRs reported throughout 2019 was performed. ADRs collected by the Italian National Network of Pharmacovigilance were analyzed for their incidence, seriousness, outcome, coadministered drugs, and Medical Dictionary for Regulatory Activities classification. A total of 306 reports were gathered for the quarter of 2020: 54% nonserious and 46% serious, and half of the latter required either the hospitalization or its prolongation. However, most of them were either completely recovered (26%) or in the process of recovery (45%), except for 9 fatal cases. Throughout 2019, 38 reports were collected, 53% nonserious and 47% serious, but no deaths had been reported. Diarrhea, prolonged QT interval, and hypertransaminasemia were the most frequently ADRs reported in 2020, significantly higher than 2019 and specific for COVID-19 subjects treated with hydroxychloroquine. The logistic regression analyses demonstrated that the likelihood of serious ADRs, QT prolongation, and diarrhea significantly increased with hydroxychloroquine dosage. Coadministration of lopinavir/ritonavir and hydroxychloroquine showed a positive correlation with diarrhea and hypertransaminasemia and a negative relationship with the ADR seriousness. The combination therapy with azithromycin was another independent predictor of a serious ADR. Off-label use of hydroxychloroquine for COVID-19, alone or in combination regimens, was associated with increased incidence and/or seriousness of specific ADRs in patients with additional risk factors caused by the infection.

Topics: Azithromycin; COVID-19 Drug Treatment; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Off-Label Use; Pharmacovigilance; Ritonavir

Chloroquine and azithromycin were developed in combination for the preventive treatment of malaria in pregnancy, and more recently were proposed as coronavirus disease 2019 (COVID-19) treatment options. Billions of doses of chloroquine have been administered worldwide over the past 70 years but concerns regarding cardiotoxicity, notably the risk of torsades de pointes (TdP), remain. This investigation aimed to characterize the pharmacokinetics and electrocardiographic effects of chloroquine and azithromycin observed in a large previously conducted healthy volunteer study. Healthy adult volunteers (n = 119) were randomized into 5 arms: placebo, chloroquine alone (600 mg base), or chloroquine with either 500 mg, 1,000 mg, or 1,500 mg of azithromycin all given daily for 3 days. Chloroquine and azithromycin levels, measured using liquid-chromatography tandem mass spectrometry, and electrocardiograph intervals were recorded at frequent intervals. Time-matched changes in the PR, QRS, and heart rate-corrected JT, and QT intervals were calculated and the relationship with plasma concentrations was evaluated using linear and nonlinear mixed-effects modeling. Chloroquine and azithromycin pharmacokinetics were described satisfactorily by two- and three-compartment distribution models, respectively. No drug-drug interaction between chloroquine and azithromycin was observed. Chloroquine resulted in concentration-dependent prolongation of the PR, QRS, JTc and QTc intervals with a minimal additional effect of azithromycin. QRS widening contributed ~ 28% of the observed QT prolongation. Chloroquine causes significant concentration-dependent delays in both ventricular depolarization and repolarization. Co-administration of azithromycin did not significantly increase these effects. The arrhythmogenic risk of TdP associated with chloroquine may have been substantially overestimated in studies which did not separate electrocardiograph QRS and JT prolongation.

Topics: Adult; Antimalarials; Azithromycin; Chloroquine; Coronavirus Infections; COVID-19 Drug Treatment; DNA-Binding Proteins; Electrocardiography; Healthy Volunteers; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Pneumonia, Viral; Torsades de Pointes

Azithromycin is prescribed for atypical antimicrobial cover in severe community-acquired pneumonia. Inappropriate azithromycin administration incurs unnecessary financial costs, exacerbates antimicrobial resistance and risks QTc interval prolongation leading to cardiac arrhythmias. The present study demonstrated that a majority of patients were prescribed azithromycin without having electrocardiograms to assess the QTc interval and without meeting criteria for severe community-acquired pneumonia based on CURB-65 score.

Topics: Anti-Bacterial Agents; Azithromycin; Community-Acquired Infections; Electrocardiography; Humans; Long QT Syndrome; Pneumonia

The treatment of COVID-19 disease remains a dilemma so far because there is no approved therapy for it. This study aimed to evaluate the use of hydroxychloroquine and azithromycin combination in treatment.. This study was carried out to determine the safety and effectiveness of hydroxychloroquine and azithromycin combination in COVID 19 patients.. This study included 90 adult COVID 19 patients. Treatment of all patients followed Egyptian Ministry of Health COVID-19 protocols, receiving a combination of hydroxychloroquine 400mg twice on day 1, then 200 mg twice daily in addition to azithromycin 500mg/day for 5 days. ECG findings, especially the QTc interval, were assessed before and after 5 days from the administration.. All patients showed a statistically significant higher post-treatment QTc readings (433.6 ± 37.2) compared to baseline QTc (402.4 ± 31.3) at p<0.005 with a median QTc prolongation by 26 mSec and IQR (17.8-41.3), but without serious clinical complications. Only 5.6% of patients showed QTc more than 500 mSec and no torsade de points or cardiac arrest. Geriatric patients were at higher risk for QTc prolongation compared to patients aged less than 65 years but without a significant difference as regards the median max QTc difference p˂0.65. The expected therapeutic effectiveness was 82.5% for moderate patients compared to 26% for severe patients (P<0.005).. In a modest safety profile, we support the evidence that HQ/AZ therapy can be used to treat Covid-19 infection with more effectiveness in moderate rather than severe cases, which might be a reflection of the time of administration in the disease course.

Topics: Adult; Aged; Azithromycin; COVID-19 Drug Treatment; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; SARS-CoV-2

Topics: Adult; Aged; Aged, 80 and over; Azithromycin; COVID-19; COVID-19 Drug Treatment; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Risk Factors

Combinations of hydroxychloroquine (HCQ) and azithromycin have been promoted as treatments for COVID-19 based on small, uncontrolled clinical trials that have not assessed potential risks. Risks of treatment include QT segment prolongation, Torsades de Pointes (TdP), and death. This comparative pharmacovigilance analysis evaluated the risk of these events.. Data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) (>13 million total reports) were used. Queries extracted reports based on exposures of HCQ/chloroquine (CQ) alone, azithromycin alone, HCQ/CQ + azithromycin, amoxicillin alone, HCQ/CQ + amoxicillin alone. Amoxicillin served as a control. Events of interest included death and TdP/QT prolongation as well as accidents/injuries and depression as control events. Proportional Reporting Ratios (PRR) and 95% confidence intervals (CI) were calculated where a lower limit of the of 95% CI (Lower95CI) value of ≥2.0 is interpreted as a potential safety signal.. Lower95CIs for HCQ/CQ alone showed no potential safety signals for TdP/QT prolongation, death, or any of the control events included. The PRRs and 95% CIs for TdP/QT prolongation was 1.43 (1.29-2.59) with HCQ/CQ use alone and 4.10 (3.80-4.42) for azithromycin alone. For the combined HCQ/CQ + azithromycin group, the PRR and 95% CI was 3.77 (1.80-7.87). For the control of amoxicillin, there were no safety signals when used alone or in combination with HCQ/CQ.. HCQ/CQ use was not associated with a safety signal in this analysis of FAERS data. However, azithromycin used alone was associated with TdP/QT prolongation events and should be used with caution.

Topics: Antiviral Agents; Azithromycin; Chloroquine; COVID-19; COVID-19 Drug Treatment; Drug Interactions; Drug Therapy, Combination; Humans; Hydroxychloroquine; Long QT Syndrome; Pharmacovigilance; Torsades de Pointes; United States

Most of the drugs associations that have been used to treat patients with SARS-CoV-2 infection increase the risk of prolongation of the corrected QT interval (QTc).. To evaluate the effects of an association therapy of hydroxychloroquine (HY) plus ritonavir/darunavir (RD) or azithromycin (AZ) on QTc intervals.. At the beginning of COVID-19 pandemic patients admitted to our hospital were treated with the empiric association of HY/RD; one week later the therapeutic protocol was modified with the combination of HY/AZ. Patients underwent an ECG at baseline, then 3 and 7 days after starting therapy. We prospectively enrolled 113 patients (61 in the HY/RD group-52 in the HY/AZ group).. A significant increase in median QTc was reported after seven days of therapy in both groups: from 438 to 452 ms in HY/RD patients; from 433 to 440 ms in HY/AZ patients (p = 0.001 for both). 23 patients (21.2%) had a QTc > 500 ms at 7 days. The risk of developing a QTc > 500 ms was greater in patients with prolonged baseline QTc values (≥ 440 ms for female and ≥ 460 ms for male patients) (OR 7.10 (95% IC 1.88-26.81); p = 0.004) and in patients with an increase in the QTc > 40 ms 3 days after onset of treatment (OR 30.15 (95% IC 6.96-130.55); p = 0.001). One patient per group suffered a malignant ventricular arrhythmia.. Hydroxychloroquine with both ritonavir/darunavir or azithromycin therapy significantly increased the QTc-interval at 7 days. The risk of developing malignant arrhythmias remained relatively low when these drugs were administered for a limited period of time.

Topics: Aged; Anti-Bacterial Agents; Azithromycin; COVID-19; COVID-19 Drug Treatment; Darunavir; Electrocardiography; Enzyme Inhibitors; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Ritonavir; SARS-CoV-2

Hydroxychloroquine (HCQ) and azithromycin (AZT) have been proposed for COVID-19 treatment. Data available in the literature reported a potential increased risk of fatal arrhythmias under these therapies. The aim of this study was to assess the effects of these drugs on QT interval and outcome in a COVID-19 population.. A total of 112 consecutive COVID-19 patients were included in this analysis and were divided in 3 groups according to the receiving therapeutic regimens: 19 (17%) patients in Group 1 (no treatment), 40 (36%) in Group 2 (HCQ only), 53 (47%) in Group 3 (HCQ/AZT).. A prolonged QTc interval was found in 61% of patients treated with HCQ alone or in combination with AZT, but only 4 (4%) patients showed a QTc > 500 ms. HCQ/AZT combination determined a greater increase of QTc duration compared to the other two strategies (Group 3 452 ± 26.4 vs Group 2 436.3 ± 28.4 vs Group 1 424.4 ± 24.3 ms, respectively; p < 0.001). Multivariate analysis demonstrated that HCQ/AZT combination (OR 9.02, p = 0.001) and older age (OR 1.04, p = 0.031) were independent predictors of QTc prolongation. The risk increased with age (incremental utility analysis p = 0.02). Twenty patients (18%) died, and no cardiac arrest neither arrhythmic fatalities were documented.. The HCQ/AZT combination therapy causes a significantly increase of QT interval compared to HCQ alone. Older patients under such regimen are at higher risk of experiencing QT prolongation. The use of such drugs may be considered as safe relating to arrhythmic risk in the treatment of COVID-19 patients as no arrhythmic fatalities occurred.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Antimalarials; Azithromycin; COVID-19; Drug Therapy, Combination; Electrocardiography; Female; Follow-Up Studies; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Patient Safety; Retrospective Studies

In 2013, the US Food and Drug Administration issued a warning regarding the use of azithromycin and the risk of fatal dysrhythmias after a 14-year retrospective analysis showed increased risk of cardiovascular-related death in patients who had taken a 5-day course of azithromycin compared with those who took amoxicillin, ciprofloxacin, or no antibiotics. At the authors' institution, pneumonia is the most common diagnosis for which azithromycin is used as a treatment for patients who are hospitalized.. To compare corrected QT (QTc) interval measurements on electrocardiogram (ECG) before and after inpatient azithromycin treatment for pneumonia.. The authors retrospectively reviewed the medical records of 642 patients age 18 years and older who were diagnosed with pneumonia and treated with azithromycin at an academic teaching hospital between January 1, 2017 and December 31, 2017. Patients who had an ECG performed both before and after azithromycin treatment were included and divided into 2 groups: those who had 1 dose of azithromycin (Group 1) and those who had 2 doses (Group 2). Patients were excluded if they had a baseline QTc interval on initial ECG greater than or equal to 500 ms, any signs of ischemia or myocardial infarction, any initial dysrhythmia or underlying ECG abnormalities, or absence of pre- and post-ECG results. Outcomes measures included a comparison of QTc intervals on ECG before and after azithromycin, and an analysis of the percentage of patients with a QTc interval measurement greater than 500 ms on ECG after azithromycin treatment. Our primary outcome measurement was the QTc interval measurement on ECG before and after azithromycin in patients treated with azithromycin for community acquired pneumonia. Our secondary outcome measurement was the percentage of patients with a QTc interval measurement of greater than 500 ms on ECG after azithromycin treatment. A Wilcoxon signed-rank test was used to evaluate repeated QTc measures of our primary outcome in Group 1 and Group 2. Our secondary outcome was reported as a percentage of total patients with a QTc interval of greater than 500 ms after azithromycin doses on ECG.. Of 642 patients, 142 had available pre- and post-EGC results available; 100 were included in Group 1 (1 dose) and 42 in Group 2 (2 doses). Mean QTc interval differences after 1 dose of azithromycin exhibited an increase compared to baseline values (424 vs 477 ms). A Wilcoxon signed-rank test indicated a significant QTc prolongation after 1 dose of azithromycin (mean rank, 43.76; Z=-4.921; P<.001). QTc interval differences after 2 doses of azithromycin did not reach statistical significance when compared to baseline values (422 vs 444 ms). A total of 10 patients (10%) in Group 1 and 4 patients (9.5%) in Group 2 had a QTc interval >500 ms after azithromycin. There were no documented dysrhythmias during hospitalization in this study period.. QTc interval increases were observed during inpatient azithromycin therapy for pneumonia, but were not found to be associated with cardiac dysrhythmias during hospitalization.

Topics: Adolescent; Azithromycin; COVID-19; Electrocardiography; Humans; Inpatients; Long QT Syndrome; Pneumonia; Retrospective Studies

The liberal administration of hydroxychloroquine-sulphate (HCQ) to COVID-19 patients has raised concern regarding the risk of QTc prolongation and cardiac arrhythmias, particularly when prescribed with azithromycin. We evaluated the incidence of QTc prolongation among moderately and severely ill COVID-19 patients treated with HCQ and of the existence of concomitant alternative causes.. All COVID-19 patients treated with HCQ (between Mar 1 and Apr 14, 2020) in a tertiary medical centre were included. Clinical characteristics and relevant risk factors were collected from the electronic medical records. Individual patient QTc intervals were determined before and after treatment with HCQ. The primary outcome measure sought was a composite end point comprised of either an increase ≥60 milliseconds (ms) in the QTc interval compared with pre-treatment QTc, and/or a maximal QTc interval >500 ms RESULTS: Ninety patients were included. Median age was 65 years (IQR 55-75) and 57 (63%) were male. Thirty-nine patients (43%) were severely or critically ill. Hypertension and obesity were common (n = 23 each, 26%). QTc prolongation evolved in 14 patients (16%). Age >65 years, congestive heart failure, severity of disease, C-reactive protein level, hypokalaemia and furosemide treatment, were all associated with QTc prolongation. Adjusted analysis showed that QTc prolongation was five times more likely with hypokalaemia [OR 5, (95% CI, 1.3-20)], and three times more likely with furosemide treatment [OR 3 (95% CI, 1.01-13.7)].. In patients treated with HCQ, QTc prolongation was associated with the presence of traditional risk factors such as hypokalaemia and furosemide treatment.

Topics: Aged; Azithromycin; COVID-19 Drug Treatment; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; SARS-CoV-2

Topics: Aged; Anti-Bacterial Agents; Antimalarials; Azithromycin; COVID-19; COVID-19 Drug Treatment; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; SARS-CoV-2

The aim of this study was to describe the QTc prolongation and related adverse cardiac events during the administration of hydroxychloroquine (HCQ) and its combinations for the treatment of coronavirus disease 2019 (COVID-19). Hospitalized patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who received HCQ and had initial and follow-up electrocardiograms performed between March 10 and May 30, 2020 were included. Critical QTc prolongation was detected in 12% of the patients. On multivariate analysis, diabetes mellitus (odds ratio 5.8, 95% confidence interval 1.11-30.32, p = 0.037) and the use of oseltamivir (odds ratio 5.3, 95% confidence interval 1.02-28, p = 0.047) were found to be associated with critical QTc prolongation.

Topics: Adult; Aged; Aged, 80 and over; Azithromycin; COVID-19 Drug Treatment; Electrocardiography; Female; Humans; Hydroxychloroquine; Influenza, Human; Long QT Syndrome; Male; Middle Aged; Oseltamivir; SARS-CoV-2

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

Chronic Azithromycin (AZM) is a common treatment for lung infection. Among adults at risk of cardiac events, AZM use has been associated with cardiovascular harm. We assessed cardiovascular safety of AZM among children with CF, as a secondary analysis of a placebo-controlled, clinical trial, in which study drug was taken thrice-weekly for a planned 18 months. Safety assessments using electrocardiogram (ECG) occurred at study enrollment, and then after 3 weeks and 18 months of participation. Among 221 study participants with a median of 18 months follow-up, increased corrected QT interval (QTc) of ≥30 msec was rare, at 3.4 occurrences per 100 person-years; and incidence of QTc prolongation was no higher in the AZM arm than the placebo arm (1.8 versus 5.4 per 100 person-years). No persons experienced QTc intervals above 500 msec. Long-term chronic AZM use was not associated with increased QT prolongation.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Double-Blind Method; Female; Humans; Long QT Syndrome; Male; Multicenter Studies as Topic; Pseudomonas Infections; Randomized Controlled Trials as Topic; Respiratory Tract Infections

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

Topics: Anti-Bacterial Agents; Antimalarials; Antiviral Agents; Azithromycin; Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Interactions; Drug Repositioning; Drug Synergism; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; Monitoring, Physiologic; Patient Safety; RNA, Viral; SARS-CoV-2; Treatment Outcome

Topics: Anti-Bacterial Agents; Antimalarials; Antiviral Agents; Azithromycin; Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Interactions; Drug Repositioning; Drug Synergism; Electrocardiography; Humans; Hydroxychloroquine; Hyperkalemia; Hypokalemia; Long QT Syndrome; SARS-CoV-2

Topics: Anti-Bacterial Agents; Antimalarials; Antiviral Agents; Azithromycin; Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Interactions; Drug Repositioning; Drug Synergism; Electrocardiography; Humans; Hydroxychloroquine; Hyperkalemia; Hypokalemia; Long QT Syndrome; Magnesium; Patient Safety; RNA, Viral; SARS-CoV-2; Treatment Outcome

This study aimed to characterize corrected QT (QTc) prolongation in a cohort of hospitalized patients with coronavirus disease-2019 (COVID-19) who were treated with hydroxychloroquine and azithromycin (HCQ/AZM).. HCQ/AZM is being widely used to treat COVID-19 despite the known risk of QT interval prolongation and the unknown risk of arrhythmogenesis in this population.. A retrospective cohort of COVID-19 hospitalized patients treated with HCQ/AZM was reviewed. The QTc interval was calculated before drug administration and for the first 5 days following initiation. The primary endpoint was the magnitude of QTc prolongation, and factors associated with QTc prolongation. Secondary endpoints were incidences of sustained ventricular tachycardia or ventricular fibrillation and all-cause mortality.. Among 415 patients who received concomitant HCQ/AZM, the mean QTc increased from 443 ± 25 ms to a maximum of 473 ± 40 ms (87 [21%] patients had a QTc ≥500 ms). Factors associated with QTc prolongation ≥500 ms were age (p < 0.001), body mass index <30 kg/m. An increase in QTc was seen in hospitalized patients with COVID-19 treated with HCQ/AZM. Several clinical factors were associated with greater QTc prolongation. Changes in QTc were not associated with increased risk of death.

Topics: Age Factors; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; Body Mass Index; Comorbidity; COVID-19; COVID-19 Drug Treatment; Creatinine; Drug Therapy, Combination; Electrocardiography; Enzyme Inhibitors; Female; Heart Failure; Hospitalization; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Mortality; Proportional Hazards Models; Risk Factors; SARS-CoV-2; Troponin I

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

Coronavirus disease-2019 (COVID-19) causes severe illness and multi-organ dysfunction. An abnormal electrocardiogram is associated with poor outcome, and QT prolongation during the illness has been linked to pharmacological effects. This study sought to investigate the effects of the COVID-19 illness on the corrected QT interval (QTc).. For 293 consecutive patients admitted to our hospital via the emergency department for COVID-19 between 01/03/20 -18/05/20, demographic data, laboratory findings, admission electrocardiograph and clinical observations were compared in those who survived and those who died within 6 weeks. Hospital records were reviewed for prior electrocardiograms for comparison with those recorded on presentation with COVID-19.. Patients who died were older than survivors (82 vs 69.8 years, p < 0.001), more likely to have cancer (22.3% vs 13.1%, p = 0.034), dementia (25.6% vs 10.7%, p = 0.034) and ischemic heart disease (27.8% vs 10.7%, p < 0.001). Deceased patients exhibited higher levels of C-reactive protein (244.6 mg/L vs 146.5 mg/L, p < 0.01), troponin (1982.4 ng/L vs 413.4 ng/L, p = 0.017), with a significantly longer QTc interval (461.1 ms vs 449.3 ms, p = 0.007). Pre-COVID electrocardiograms were located for 172 patients; the QTc recorded on presentation with COVID-19 was longer than the prior measurement in both groups, but was more prolonged in the deceased group (448.4 ms vs 472.9 ms, pre-COVID vs COVID, p < 0.01). Multivariate Cox-regression analysis revealed age, C-reactive protein and prolonged QTc of >455 ms (males) and >465 ms (females) (p = 0.028, HR 1.49 [1.04-2.13]), as predictors of mortality. QTc prolongation beyond these dichotomy limits was associated with increased mortality risk (p = 0.0027, HR 1.78 [1.2-2.6]).. QTc prolongation occurs in COVID-19 illness and is associated with poor outcome.

Topics: Azithromycin; COVID-19; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Prognosis; SARS-CoV-2

Critical illness, a marked inflammatory response, and viruses such as SARS-CoV-2 may prolong corrected QT interval (QTc).. To evaluate baseline QTc interval on 12-lead electrocardiograms (ECGs) and ensuing changes among patients with and without COVID-19.. This cohort study included 3050 patients aged 18 years and older who underwent SARS-CoV-2 testing and had ECGs at Columbia University Irving Medical Center from March 1 through May 1, 2020. Patients were analyzed by treatment group over 5 days, as follows: hydroxychloroquine with azithromycin, hydroxychloroquine alone, azithromycin alone, and neither hydroxychloroquine nor azithromycin. ECGs were manually analyzed by electrophysiologists masked to COVID-19 status. Multivariable modeling evaluated clinical associations with QTc prolongation from baseline.. COVID-19, hydroxychloroquine, azithromycin.. Mean QTc prolongation, percentage of patients with QTc of 500 milliseconds or greater.. A total of 965 patients had more than 2 ECGs and were included in the study, with 561 (58.1%) men, 198 (26.2%) Black patients, and 191 (19.8%) aged 80 years and older. There were 733 patients (76.0%) with COVID-19 and 232 patients (24.0%) without COVID-19. COVID-19 infection was associated with significant mean QTc prolongation from baseline by both 5-day and 2-day multivariable models (5-day, patients with COVID-19: 20.81 [95% CI, 15.29 to 26.33] milliseconds; P < .001; patients without COVID-19: -2.01 [95% CI, -17.31 to 21.32] milliseconds; P = .93; 2-day, patients with COVID-19: 17.40 [95% CI, 12.65 to 22.16] milliseconds; P < .001; patients without COVID-19: 0.11 [95% CI, -12.60 to 12.81] milliseconds; P = .99). COVID-19 infection was independently associated with a modeled mean 27.32 (95% CI, 4.63-43.21) millisecond increase in QTc at 5 days compared with COVID-19-negative status (mean QTc, with COVID-19: 450.45 [95% CI, 441.6 to 459.3] milliseconds; without COVID-19: 423.13 [95% CI, 403.25 to 443.01] milliseconds; P = .01). More patients with COVID-19 not receiving hydroxychloroquine and azithromycin had QTc of 500 milliseconds or greater compared with patients without COVID-19 (34 of 136 [25.0%] vs 17 of 158 [10.8%], P = .002). Multivariable analysis revealed that age 80 years and older compared with those younger than 50 years (mean difference in QTc, 11.91 [SE, 4.69; 95% CI, 2.73 to 21.09]; P = .01), severe chronic kidney disease compared with no chronic kidney disease (mean difference in QTc, 12.20 [SE, 5.26; 95% CI, 1.89 to 22.51; P = .02]), elevated high-sensitivity troponin levels (mean difference in QTc, 5.05 [SE, 1.19; 95% CI, 2.72 to 7.38]; P < .001), and elevated lactate dehydrogenase levels (mean difference in QTc, 5.31 [SE, 2.68; 95% CI, 0.06 to 10.57]; P = .04) were associated with QTc prolongation. Torsades de pointes occurred in 1 patient (0.1%) with COVID-19.. In this cohort study, COVID-19 infection was independently associated with significant mean QTc prolongation at days 5 and 2 of hospitalization compared with day 0. More patients with COVID-19 had QTc of 500 milliseconds or greater compared with patients without COVID-19.

Topics: Aged, 80 and over; Anti-Infective Agents; Azithromycin; COVID-19; COVID-19 Drug Treatment; COVID-19 Testing; Drug Therapy, Combination; Electrocardiography; Female; Hospitalization; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; New York; Outcome and Process Assessment, Health Care; Risk Factors; SARS-CoV-2; Time Factors

Coronavirus disease of 2019 (COVID-19) has rapidly become a worldwide pandemic. Many clinical trials have been initiated to fight the disease. Among those, hydroxychloroquine and azithromycin had initially been suggested to improve clinical outcomes. Despite any demonstrated beneficial effects, they are still in use in some countries but have been reported to prolong the QT interval and induce life-threatening arrhythmia. Since a significant proportion of the world population may be treated with such COVID-19 therapies, evaluation of the arrhythmogenic risk of any candidate drug is needed.. Using the O'Hara-Rudy computer model of human ventricular wedge, we evaluate the arrhythmogenic potential of clinical factors that can further alter repolarization in COVID-19 patients in addition to hydroxychloroquine (HCQ) and azithromycin (AZM) such as tachycardia, hypokalaemia, and subclinical to mild long QT syndrome. Hydroxychloroquine and AZM drugs have little impact on QT duration and do not induce any substrate prone to arrhythmia in COVID-19 patients with normal cardiac repolarization reserve. Nevertheless, in every tested condition in which this reserve is reduced, the model predicts larger electrocardiogram impairments, as with dofetilide. In subclinical conditions, the model suggests that mexiletine limits the deleterious effects of AZM and HCQ.. By studying the HCQ and AZM co-administration case, we show that the easy-to-use O'Hara-Rudy model can be applied to assess the QT-prolongation potential of off-label drugs, beyond HCQ and AZM, in different conditions representative of COVID-19 patients and to evaluate the potential impact of additional drug used to limit the arrhythmogenic risk.

Topics: Azithromycin; COVID-19 Drug Treatment; Death, Sudden, Cardiac; Humans; Hydroxychloroquine; Long QT Syndrome; SARS-CoV-2

Topics: Aged; Azithromycin; COVID-19; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; SARS-CoV-2

QTc prolongation is an adverse effect of COVID-19 therapies. The use of a handheld device in this scenario has not been addressed.. To evaluate the feasibility of QTc monitoring with a smart device in COVID-19 patients receiving QTc-interfering therapies.. Prospective study of consecutive COVID-19 patients treated with hydroxychloroquine ± azithromycin ± lopinavir-ritonavir. ECG monitoring was performed with 12-lead ECG or with KardiaMobile-6L. Both registries were also sequentially obtained in a cohort of healthy patients. We evaluated differences in QTc in COVID-19 patients between three different monitoring strategies: 12-lead ECG at baseline and follow-up (A), 12-lead ECG at baseline and follow-up with the smart device (B), and fully monitored with handheld 6-lead ECG (group C). Time needed to obtain an ECG registry was also documented.. One hundred and eighty-two COVID-19 patients were included (A: 119(65.4%); B: 50(27.5%); C: 13(7.1%). QTc peak during hospitalization did significantly increase in all groups. No differences were observed between the three monitoring strategies in QTc prolongation (p = 0.864). In the control group, all but one ECG registry with the smart device allowed QTc measurement and mean QTc did not differ between both techniques (p = 0.612), displaying a moderate reliability (ICC 0.56 [0.19-0.76]). Time of ECG registry was significantly longer for the 12-lead ECG than for handheld device in both cohorts (p < 0.001).. QTc monitoring with KardiaMobile-6L in COVID-19 patients was feasible. Time of ECG registration was significantly lower with the smart device, which may offer an important advantage for prevention of virus dissemination among healthcare providers.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Antiviral Agents; Azithromycin; COVID-19 Drug Treatment; Drug Combinations; Electrocardiography; Enzyme Inhibitors; Feasibility Studies; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Male; Middle Aged; Point-of-Care Systems; Prospective Studies; Reproducibility of Results; Ritonavir; SARS-CoV-2

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

Topics: Anti-Bacterial Agents; Antirheumatic Agents; Antiviral Agents; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19 Drug Treatment; Drug Interactions; Drug Repositioning; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; SARS-CoV-2; Torsades de Pointes

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: Anti-Infective Agents; Azithromycin; Betacoronavirus; Contraindications, Drug; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Pneumonia, Viral; SARS-CoV-2; Torsades de Pointes

Topics: Azithromycin; Chloroquine; Coronavirus Infections; COVID-19; Drug Therapy, Combination; Humans; Hydroxychloroquine; Long QT Syndrome; Mental Disorders; Pandemics; Pneumonia, Viral; Risk Factors

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

There is no known effective therapy for patients with coronavirus disease 2019 (COVID-19). Initial reports suggesting the potential benefit of hydroxychloroquine/azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns about the potential risk of QT interval prolongation and induction of torsade de pointes (TdP).. The purpose of this study was to assess the change in corrected QT (QTc) interval and arrhythmic events in patients with COVID-19 treated with HY/AZ.. This is a retrospective study of 251 patients from 2 centers who were diagnosed with COVID-19 and treated with HY/AZ. We reviewed electrocardiographic tracings from baseline and until 3 days after the completion of therapy to determine the progression of QTc interval and the incidence of arrhythmia and mortality.. The QTc interval prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc interval prolongation to >500 ms, a known marker of high risk of TdP, had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc interval of patients exhibiting extreme QTc interval prolongation was normal.. The combination of HY/AZ significantly prolongs the QTc interval in patients with COVID-19. This prolongation may be responsible for life-threatening arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in light of its unproven efficacy. Strict QTc interval monitoring should be performed if the regimen is given.

Topics: Aged; Anti-Bacterial Agents; Antimalarials; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Female; Humans; Hydroxychloroquine; Incidence; Long QT Syndrome; Male; Middle Aged; Pandemics; Pneumonia, Viral; Retrospective Studies; SARS-CoV-2; Torsades de Pointes

Hydroxychloroquine and azithromycin combination therapy is often prescribed for coronavirus disease 2019 (COVID-19). Electrocardiographic (ECG) monitoring is warranted because both medications cause corrected QT-interval (QTc) prolongation. Whether QTc duration significantly varies during the day, potentially requiring multiple ECGs, remains to be established.. We performed 12‑lead ECGs and 12‑lead 24-h Holter ECG monitoring in all patients aged <80 years admitted to our medical unit for COVID-19, in oral therapy with hydroxychloroquine (200 mg, twice daily) and azithromycin (500 mg, once daily) for at least 3 days. A group of healthy individuals matched for age and sex served as control.. Out of 126 patients, 22 (median age 64, 82% men) met the inclusion criteria. ECG after therapy showed longer QTc-interval than before therapy (450 vs 426 ms, p = .02). Four patients had a QTc ≥ 480 ms: they showed higher values of aspartate aminotransferase (52 vs 30 U/L, p = .03) and alanine aminotransferase (108 vs 33 U/L, p < .01) compared with those with QTc < 480 ms. At 24-h Holter ECG monitoring, 1 COVID-19 patient and no control had ≥1 run of non-sustained ventricular tachycardia (p = .4). No patients showed "R on T" premature ventricular beats. Analysis of 24-h QTc dynamics revealed that COVID-19 patients had higher QTc values than controls, with no significant hourly variability.. Therapy with hydroxychloroquine and azithromycin prolongs QTc interval in patients with COVID-19, particularly in those with high levels of transaminases. Because QTc duration remains stable during the 24 h, multiple daily ECG are not recommendable.

Topics: Antiviral Agents; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; Death, Sudden, Cardiac; Drug Monitoring; Electrocardiography; Female; Hospitalization; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Outcome and Process Assessment, Health Care; Pandemics; Pneumonia, Viral; SARS-CoV-2

Topics: Adrenergic beta-Agonists; Aged; Anti-Infective Agents; Azithromycin; Betacoronavirus; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Testing; Electrocardiography; Humans; Hydroxychloroquine; Isoproterenol; Long QT Syndrome; Male; Myocarditis; Pandemics; Pneumonia, Viral; SARS-CoV-2; Treatment Outcome; Troponin I

Background Despite a lack of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected coronavirus disease 2019 (COVID-19). Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation. Methods and Results We analyzed a case series of COVID-19-positive/suspected patients admitted between February 1, 2020, and April 4, 2020, who were treated with azithromycin, hydroxychloroquine, or a combination of both drugs. We evaluated baseline and postmedication QT interval (corrected QT interval [QTc]; Bazett) using 12-lead ECGs. Critical QTc prolongation was defined as follows: (1) maximum QTc ≥500 ms (if QRS <120 ms) or QTc ≥550 ms (if QRS ≥120 ms) and (2) QTc increase of ≥60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Of 490 COVID-19-positive/suspected patients, 314 (64%) received either/both drugs and 98 (73 COVID-19 positive and 25 suspected) met study criteria (age, 62±17 years; 61% men). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448±29 ms and increased to 459±36 ms (

Topics: Anti-Bacterial Agents; Antimalarials; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Pandemics; Pneumonia, Viral; Prognosis; Risk Factors; SARS-CoV-2

Topics: Azithromycin; COVID-19; Humans; Hydroxychloroquine; Incidence; Long QT Syndrome; Pandemics; Patients; SARS-CoV-2; Torsades de Pointes

Topics: Anti-Infective Agents; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Dimensional Measurement Accuracy; Drug Monitoring; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Outcome Assessment, Health Care; Pandemics; Pneumonia, Viral; SARS-CoV-2; Torsades de Pointes

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-Bacterial Agents; Antimalarials; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Pneumonia, Viral; SARS-CoV-2; Torsades de Pointes; Treatment Outcome

Hydroxychloroquine, chloroquine, and azithromycin have been used for treatment of COVID-19, but may cause QT prolongation. Minority populations are disproportionately impacted by COVID-19. This study evaluates the risk of QT prolongation and subsequent outcomes after administration of these medications in largely underrepresented minority COVID-19 patients.. We conducted an observational study on hospitalized COVID-19 patients in the Montefiore Health System (Bronx, NY). We examined electrocardiograms (ECG) pre/post-medication initiation to evaluate QTc, HR, QRS duration, and presence of other arrhythmias.. One hundred five patients (mean age 67 years; 44.8% F) were analyzed. The median time from the first dose of any treatment to post-medication ECG was 2 days (IQR: 1-3). QTc in men increased from baseline (440 vs 455 ms, p < 0.001), as well as in women (438 vs 463 ms, p < 0.001). The proportion of patients with QT prolongation increased significantly (14.3% vs 34.3%, p < 0.001) even when adjusted for electrolyte abnormalities. The number of patients whose QTc > 500 ms was significantly increased after treatment (16.2% vs. 4.8%, p < 0.01). Patients with either QTc > 500 ms or an increase of 60 ms had a higher frequency of death (47.6% vs. 22.6%, p = 0.02) with an odds ratio of 3.1 (95% CI: 1.1-8.7). Adjusting for race/ethnicity yielded no significant associations.. Hydroxychloroquine, chloroquine, and/or azithromycin were associated with QTc prolongation but did not result in fatal arrhythmias. Our findings suggest that any harm is unlikely to outweigh potential benefits of treatment. Careful risk-benefit analyses for individual patients should guide the use of these medications. Randomized control trials are necessary to evaluate their efficacies.

Topics: Age Distribution; Aged; Aged, 80 and over; Antimalarials; Azithromycin; Chloroquine; Coronavirus Infections; COVID-19; Electrocardiography; Female; Follow-Up Studies; Hospitalization; Humans; Hydroxychloroquine; Incidence; Long QT Syndrome; Male; Middle Aged; Pandemics; Pneumonia, Viral; Risk Assessment; Sex Distribution; Urban Population

Hydroxychloroquine alone or in combination with azithromycin has been increasingly used for patients with coronavirus disease 2019, in both children and adults. Drugs are generally well tolerated in clinical practice; however, both can cause corrected QT prolongation. We aimed to report our experience of QT interval evaluation associated with the use of hydroxychloroquine with concurrent azithromycin among children testing positive for coronavirus disease 2019.. Our single-centre; retrospective, study evaluated children with coronavirus disease 2019 disease admitted to the Pediatric Department at Sancaktepe Training and Research Hospital Istanbul, Turkey from 10 March, 2020 to 10 April, 2020. The data including demographics, clinical symptoms, co-morbid diseases, laboratory, radiological findings as well as electrocardiographs of the patients were obtained from our records. Electrocardiograms were evaluated before, one day after and at the termination of the treatment.. 21 patients aged 9 to 18 years were evaluated. The median age was 170 months (range 112-214), 51.1% of them were girls and 48.9% were boys. Their laboratory results did not reveal any abnormalities. None of them needed intensive care. We did not detect QT prolongation during or at the termination of the treatment.. We did not detect QT prolongation during or at the termination of the treatment in our patients due to the fact that they were not severely affected by the disease. Patients were treated in our inpatient clinic and none of them required intensive care. Laboratory results were also insignificant. Furthermore, they did not need other medications.

Topics: Adolescent; Anti-Infective Agents; Azithromycin; Child; Coronavirus Infections; COVID-19; Electrocardiography; Female; Hospitalization; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Outcome and Process Assessment, Health Care; Pandemics; Pneumonia, Viral; Retrospective Studies; Turkey

This longitudinal, prospective cohort study aimed to assess risk of QTc interval prolongation and its predicting factors in subjects treated with combinations containing hydroxychloroquine (HCQ) for COVID-19. Moderate-to-severe QTc prolongation during therapy was defined as a QTc interval >470 ms in men or >480 ms in women. Patients were treated under strict cardiac supervision. A total of 105 adults were included [56% male; median (IQR) age 69 (57-79) years]. All patients received therapy with HCQ in combination with azithromycin (AZM), and 95 (90%) also with lopinavir/ritonavir (LPV/r). Concomitant medications classified as having risk of developing torsades de pointes (TdP) were simultaneously used in 81 patients (77%). Moderate-to-severe QTc prolongation was observed in 14 patients (13%), mostly at Days 3-5 from baseline, with 6 (6%) developing severe prolongation (>500 ms). There was no evidence of TdP arrhythmia or TdP-associated death. Adding LPV/r to HCQ+AZM did not significantly prolong the QTc interval. Multivariable Cox regression revealed that comedications with known risk of TdP (HR = 11.28, 95% CI 1.08-117.41), higher neutrophil-to-lymphocyte (NLR) ratio (HR = 1.10, 95% CI 1.03-1.18 per unit increase) and higher serum hs-cardiac troponin I (HR = 4.09, 95% CI 1.36-12.2 per unit increase) were major contributors to moderate-to-severe QTc prolongation. In this closely screened and monitored cohort, no complications derived from QTc prolongation were observed during pharmacological therapy containing HCQ for COVID-19. Evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically higher NLR, are conditions requiring careful QTc interval monitoring.

Topics: Aged; Anti-Infective Agents; Azithromycin; Betacoronavirus; Biomarkers; Coronavirus Infections; COVID-19; Disease Progression; Drug Combinations; Female; Humans; Hydroxychloroquine; Intensive Care Units; Long QT Syndrome; Lopinavir; Lymphocytes; Male; Middle Aged; Neutrophils; Pandemics; Pneumonia, Viral; Prognosis; Proportional Hazards Models; Retrospective Studies; Ritonavir; SARS-CoV-2; Treatment Outcome; Troponin I

Topics: Azithromycin; COVID-19; Humans; Hydroxychloroquine; Incidence; Long QT Syndrome; 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

Administration of hydroxychloroquine with or without azithromycin for the treatment of coronavirus disease 2019 (COVID-19)-associated pneumonia carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias.. To characterize the risk and degree of QT prolongation in patients with COVID-19 in association with their use of hydroxychloroquine with or without concomitant azithromycin.. This was a cohort study performed at an academic tertiary care center in Boston, Massachusetts, of patients hospitalized with at least 1 positive COVID-19 nasopharyngeal polymerase chain reaction test result and clinical findings consistent with pneumonia who received at least 1 day of hydroxychloroquine from March 1, 2020, through April 7, 2020.. Change in QT interval after receiving hydroxychloroquine with or without azithromycin; occurrence of other potential adverse drug events.. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin; 44 (48.9%) were female, and the mean (SD) body mass index was 31.5 (6.6). Hypertension (in 48 patients [53.3%]) and diabetes mellitus (in 26 patients [28.9%]) were the most common comorbid conditions. The overall median (interquartile range) baseline QTc was 455 (430-474) milliseconds (hydroxychloroquine, 473 [454-487] milliseconds vs hydroxychloroquine and azithromycin, 442 [427-461] milliseconds; P < .001). Those receiving concomitant azithromycin had a greater median (interquartile range) change in QT interval (23 [10-40] milliseconds) compared with those receiving hydroxychloroquine alone (5.5 [-15.5 to 34.25] milliseconds; P = .03). Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (8%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. The likelihood of prolonged QTc was greater in those who received concomitant loop diuretics (adjusted odds ratio, 3.38 [95% CI, 1.03-11.08]) or had a baseline QTc of 450 milliseconds or more (adjusted odds ratio, 7.11 [95% CI, 1.75-28.87]). Ten patients had hydroxychloroquine discontinued early because of potential adverse drug events, including intractable nausea, hypoglycemia, and 1 case of torsades de pointes.. In this cohort study, patients who received hydroxychloroquine for the treatment of pneumonia associated with COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc. Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage.

Topics: Aged; Anti-Bacterial Agents; Antimalarials; Azithromycin; Betacoronavirus; Cohort Studies; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Therapy, Combination; Female; Hospitalization; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Pandemics; Pneumonia, Viral; Risk Assessment; SARS-CoV-2

Topics: Aged; Anti-Bacterial Agents; Antimalarials; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Critical Care; Drug Therapy, Combination; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Pandemics; Pneumonia, Viral; Retrospective Studies; SARS-CoV-2

In late 2019, a new coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-was discovered in Wuhan, China, and the World Health Organization later declared coronavirus disease 2019 (COVID-19) a pandemic. Numerous drugs have been repurposed and investigated for therapeutic effectiveness in the disease, including those from "Solidarity," an international clinical trial (azithromycin, chloroquine, hydroxychloroquine, the fixed combination lopinavir/ritonavir, and remdesivir).. Our objective was to evaluate adverse drug reaction (ADR) reporting for drugs when used in the treatment of COVID-19 compared with use for other indications, specifically focussing on sex differences.. We extracted reports on COVID-19-specific treatments from the global ADR database, VigiBase, using an algorithm developed to identify reports that listed COVID-19 as the indication. The Solidarity trial drugs were included, as were any drugs reported ≥ 100 times. We performed a descriptive comparison of reports for the same drugs used in non-COVID-19 indications. The data lock point date was 7 June 2020.. In total, 2573 reports were identified for drugs used in the treatment of COVID-19. In order of frequency, the most reported ADRs were electrocardiogram QT-prolonged, diarrhoea, nausea, hepatitis, and vomiting in males and diarrhoea, electrocardiogram QT-prolonged, nausea, vomiting, and upper abdominal pain in females. Other hepatic and kidney-related events were included in the top ten ADRs in males, whereas no hepatic or renal terms were reported for females. COVID-19-related reporting patterns differed from non-pandemic reporting for these drugs.. Review of a global database of suspected ADR reports revealed sex differences in the reporting patterns for drugs used in the treatment of COVID-19. Patterns of ADR sex differences need further elucidation.

Topics: Abdominal Pain; Adenosine Monophosphate; Alanine; Antibodies, Monoclonal, Humanized; Antiviral Agents; Azithromycin; Chemical and Drug Induced Liver Injury; Chloroquine; COVID-19 Drug Treatment; Databases, Pharmaceutical; Diarrhea; Drug Combinations; Drug Eruptions; Drug Repositioning; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Male; Nausea; Oseltamivir; Ritonavir; Sex Distribution; Sex Factors; Vomiting

COVID-2019 pandemic is affecting people worldwide in the absence of an effective treatment strategy. Several suggestive therapeutic options through drug repurposing are recommended, but a complete consensus is not reached. A combination of Hydroxychloroquine (HCQ) and Azithromycin (AZM) has been widely tried and discussed but its administration has also led to potential adversities in patients. Studies are suggesting that most prominent adverse event with HCQ and AZM combination is QT interval prolongation. We studied interaction of HCQ with AZM and subsequent effect of this drug combination on QT interval prolongation. We performed system biological investigation of HCQ and AZM targets and screened important targets and pathways possibly involved in QT interval prolongation. The best core hub protein drug targets involved in QT interval prolongation were identified as HSP90AA1 exclusively associated with HCQ, while AKT1 exclusively associated with AZM on the basis of node degree value. It was found that PI3K/Akt, VEGF, ERBB2 pathways must be given consideration for understanding the role of HCQ and AZM in QT interval prolongation. Conclusion: Computational methods have certain limitations based on source database coverage and prediction algorithms and therefore this data needs experimental correlation to draw final conclusion, but current findings screen targets for QT interval prolongation associated with HCQ and AZM. These proteins and pathways may provide ways to reduce this major risk associated with this combination.

Topics: Azithromycin; COVID-19; COVID-19 Drug Treatment; Drug Combinations; HSP90 Heat-Shock Proteins; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Protein Interaction Maps; Proto-Oncogene Proteins c-akt; SARS-CoV-2; Signal Transduction

Combination of hydroxychloroquine and azithromycin for the treatment of coronavirus disease 2019 (COVID-19) carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias..  To characterize the ventricular repolarization indexes which are associated with malignant ventricular arrhythmias in patients treated with hydroxychloroquine and concomitant azithromycin for COVID-19.. A total of 81 patients who had hydroxychloroquine and azithromycin combination therapy because of possible or  reverse-transcription polymertase chain reaction (RT-PCR) confirmed diagnosis of COVID-19 were included in the study. Baseline and control electrocardiograms (before and after treatment) were analyzed retrospectively. Tp-e interval, Tp-e/QT and Tp-e/QTc ratios, which are ventricular repolarization indexes, were calculated.. While there was no significant increase in QTc interval in patients receiving combination therapy, there was a significant increase in ventricular repolarization indexes.. The increase in ventricular replarization indexes is associated with the risk of arrhythmia. In patients using QTc prolonging medication for COVID-19 treatment, QTc monitoring alone may not be sufficient to follow-up for arrhythmia. Even if there is no prolongation in QTc, an increase in ventricular repolarization indexes may be seen (Tab. 5, Ref. 37).

Topics: Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Therapy, Combination; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Pneumonia, Viral; Retrospective Studies; SARS-CoV-2

To assess and identify the risk of prolonged QT about hydroxychloroquine (HQ) and azithromycin (AZ) used in the treatment of patients with COVID-19.. Cohort study.. Kartal Dr. Lütfi Kırdar City Hospital, İstanbul, Turkey, from March to May 2020.. One hundred and forty-four patients with the diagnosis of COVID-19, confirmed by Rt-PCR (reverse transcription-polymerase chain reaction), were restrospectively reviewed. Patients who were hospitalised, received HQ or HQ plus AZ treatment, had a baseline electrocardiogram (ECG), and had at least one ECG after treatment were included in the study. Patients with missing data were excluded.. Fifty-one (35.4%) patients were given hydroxychloroquine monoterapy (HQ), 93 (64.6%) were given hydroxychloroquine plus azithromycin (HA), and 70 (48.6%) were women. Pre-treatment mean QTc measurements were calculated as 410.61 ± 29.44 milliseconds (ms) for HQ group and 412.02 ± 25.37 ms for HA group, while the mean values of post-treatment QTc measurements were calculated as 432.31 ± 33.97 ms for HQ group and 432.03 ± 27.0 ms for the HA group. Post-treatment QTc measurements of both HA group and HQ group were prolonged compared to pre-treatment measurements. Ventricular arrhythmia was not observed in any patient.. For COVID-19, no globally accepted definite treatment has yet been found. Both of hydroxychloroquine monotherapy and hydroxychloroquine plus azithromycin treatment regimens cause QTc measurement to increase at a statistically significant level. We concluded that this increase in QTc did not cause ventricular arrhythmia. Key Words: COVID-19, QTc interval, Hydroxychloroquine, Azithromycin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antimalarials; Azithromycin; COVID-19; COVID-19 Drug Treatment; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electrocardiography; Female; Follow-Up Studies; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Pandemics; Prognosis; Retrospective Studies; SARS-CoV-2; Young Adult

SARS-CoV-2 is a rapidly evolving pandemic causing great morbimortality. Medical therapy with hydroxicloroquine, azitromycin and protease inhibitors is being empirically used, with reported data of QTc interval prolongation. Our aim is to assess QT interval behaviour in a not critically ill and not monitored cohort of patients. We evaluated admitted and ambulatory patients with COVID-19 patients with 12 lead electrocardiogram at 48 h after treatment initiation. Other clinical and analytical variables were collected. Statistical analysis was performed to assess the magnitude of the QT interval prolongation under treatment and to identify clinical, analytical and electrocardiographic risk markers of QT prolongation independent predictors. We included 219 patients (mean age of 63.6 ± 17.4 years, 48.9% were women and 16.4% were outpatients. The median baseline QTc was 416 ms (IQR 404-433), and after treatment QTc was prolonged to 423 ms (405-438) (P < 0.001), with an average increase of 1.8%. Most of the patients presented a normal QTc under treatment, with only 31 cases (14.1%) showing a QTc interval > 460 ms, and just one case with QTc > 500 ms. Advanced age, longer QTc basal at the basal ECG and lower potassium levels were independent predictors of QTc interval prolongation. Ambulatory and not critically ill patients with COVID-19 treated with hydroxychloroquine, azithromycin and/or antiretrovirals develop a significant, but not relevant, QT interval prolongation.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antimalarials; Antiviral Agents; Azithromycin; COVID-19 Drug Treatment; Critical Illness; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Male; Middle Aged; Potassium; Protease Inhibitors; Risk Factors; SARS-CoV-2; Ventricular Fibrillation; Young Adult

Oral azithromycin (AZM) has been shown to reduce airway inflammation and disrupt biofilm formation. However, chronic AZM therapy may result in QT interval (QTc) prolongation.. The goals of this study were twofold: (i) to characterize the risk of QTc prolongation in adult patients with cystic fibrosis (CF) receiving AZM and other potential QTc-prolonging agents, and (ii) to describe and capture the number of potential QTc-prolonging agents patients with CF are prescribed.. A retrospective study was conducted over a 3-year period in an adult CF center. QTc values were recorded from electrocardiograms. Univariate and multivariate analyses were conducted. Standard QTc prolongation definitions (males ≥ 450 msec, females ≥ 470 msec) were used.. A total of 89 adult CF patient's records were reviewed. Sixty-eight patients received chronic AZM therapy. Two male patients had prolonged QTc, but only 1 received chronic AZM therapy. The median QTc interval between patients receiving and not receiving AZM was not significantly different (405 [interquartile range, IQR: 388-425] vs 394 [IQR: 384-413] msec, respectively, p=0.14). Also, the QTc interval for patients taking chronic AZM 500 mg Monday/Wednesday/Friday or 250 mg daily was not significantly different (401 [IQR: 383-419] vs 409 [IQR: 394-427] msec, respectively, p=0.48). When stratified by the number of QTc-prolonging medications (AZM vs no AZM), there was no significant difference in median QTc values between patients receiving zero to ≥ 5 QTc-prolonging medications.. An association between chronic AZM therapy and longer QTc intervals or significant QTc prolongation was not shown.

Topics: Adult; Azithromycin; California; Cystic Fibrosis; Female; Humans; Long QT Syndrome; Male; Retrospective Studies

Azithromycin exposure has been reported to increase the risk of QT prolongation and cardiovascular death. However, findings on the association between azithromycin and cardiovascular death are controversial, and azithromycin is still used in actual practice. Additionally, quantitative assessments of risk have not been performed, including the risk of QT prolongation when patients are exposed to azithromycin in a real-world clinical setting. Therefore, in this study, we aimed to evaluate the risk of exposure to azithromycin on QT prolongation in a real-world clinical setting using a 21-year medical history database of a tertiary medical institution.. We analyzed the electrocardiogram results and relevant electronic health records of 402,607 subjects in a tertiary teaching hospital in Korea from 1996 to 2015. To evaluate the risk of QT prolongation of azithromycin, we conducted a case-control analysis using amoxicillin for comparison. Multiple logistic regression analysis was performed to correct for age, sex, accompanying drugs, and disease.. The odds ratio (OR) for QT prolongation (QTc>450 ms in male and >460 ms in female) on azithromycin exposure was 1.40 (95% confidence interval [CI], 1.23-1.59), and the OR for severe QT prolongation (QTc>500 ms) was 1.43 (95% CI, 1.13-1.82). On the other hand, the ORs on exposure to amoxicillin were 1.06 (95% CI, 0.97-1.15) and 0.88 (95% CI, 0.70-1.09). In a subgroup analysis, the risk of QT prolongation in patients aged between 60 and 80 years was significantly higher when they are exposed to azithromycin.. The risk of QT prolongation was increased when patients, particularly the elderly aged 60-79 years, were exposed to azithromycin. Therefore, clinicians should pay exercise caution using azithromycin or consider using other antibiotics, such as amoxicillin, instead of azithromycin.

Topics: Amoxicillin; Azithromycin; Electrocardiography; Female; Humans; Logistic Models; Long QT Syndrome; Male; Middle Aged; Odds Ratio; Risk Assessment; Risk Factors

Topics: Anti-Bacterial Agents; Azithromycin; Child; Fatal Outcome; Female; Humans; Long QT Syndrome; Medical Order Entry Systems; Medication Errors; Otitis Media; Sinusitis

Azithromycin is used in the inpatient setting for a variety of conditions. In 2013, the US Food and Drug Administration released a warning regarding risk for corrected QT (QTc) prolongation and subsequent arrhythmias. Knowledge of inpatient prescribing patterns of QTc prolonging medications with respect to patient risk factors for adverse cardiovascular events can help recognize safe use in light of these new warnings.. To assess inpatient prescribing patterns, risk factors for QTc prolongation, and relationship between drug-drug interactions and cardiac monitoring in patients receiving azithromycin.. Retrospective cohort study.. One hundred inpatients ≥ 19 years of age were randomly selected from 1610 patient encounters between October 2012 and April 2013 who were administered at least 1 dose of azithromycin.. Length of stay, reason for use, therapy duration, and concomitant medications were recorded. Telemetry charges and baseline electrocardiogram (ECG) prior to administration were assessed.. Seventy-nine percent of azithromycin use was empiric. Sixty-five percent of patients received a baseline ECG prior to prescribing azithromycin, of which 60% had borderline or abnormal QTc prolongation. Seventy-six percent of patients were prescribed 2 or more QTc prolonging medications, of which there were more abnormal ECGs at baseline (P = 0.03) despite having telemetry ordered less than half of the time.. In a cohort of hospitalized patients, azithromycin was prescribed despite risk factors for QTc prolongation and administration of interacting medications. Selection of azithromycin by providers appears to be independent from these risk factors, and education and vigilance to drug-drug interactions may be useful in limiting cardiac events with prescribing azithromycin.

Topics: Academic Medical Centers; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; Brugada Syndrome; Cardiac Conduction System Disease; Drug Interactions; Electrocardiography; Female; Humans; Inappropriate Prescribing; Long QT Syndrome; Male; Middle Aged; Monitoring, Physiologic; Retrospective Studies; Risk Factors; Telemetry; United States

Long-term daily azithromycin therapy reduces the frequency of exacerbations in chronic obstructive pulmonary disease (COPD) in a randomized controlled clinical trial setting. Concerns exist regarding arrhythmic and auditory toxicities from chronic use in the real-world setting. We hypothesized that risk factors for adverse drug reactions to azithromycin would be more frequent than previously reported, that certain specific subgroups would have different frequencies of these risk factors and that the whispered voice test would be a useful test with which to test for hearing deficits.. Following ethical approval, 47 consecutive hospital-based patients with a mean age 69 years ± 8.2, and with physician-diagnosed COPD (mean FEV. In total, 38 patients (80.9 %) had at least one risk factor or contraindication to azithromycin treatment. 19 patients (40.4 % of total) had subjective hearing impairment. 17 (36.1 %) had prolonged QTc intervals. 4 patients (8.51 %) had contraindicating co-morbidities. Those on long-term oxygen therapy were significantly more likely to have at least one risk factors or contraindications to azithromycin (p = 0.0025).. In a COPD population who would otherwise potentially be candidates for long-term daily azithromycin therapy, over 80 % had risk factors for complications from long-term daily azithromycin. Preventative treatment with long-term daily azithromycin may be appropriate for fewer COPD patients than previously thought, especially in those on long-term oxygen therapy.

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Contraindications; Female; Hearing Disorders; Heart Failure; Humans; Long QT Syndrome; Male; Middle Aged; Oxygen; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Risk Factors; Treatment Outcome

Chronic azithromycin therapy is recommended for CF patients with persistent Pseudomonas aeruginosa colonization. Other macrolide antibiotics have been reported to cause QT prolongation, but cardiac effects of azithromycin have not been studied in pediatric populations. We analyzed changes in QTc interval after starting chronic azithromycin in a pediatric CF population. Adolescent males showed increased QTc intervals after initiation of therapy. Given the possible effects of azithromycin on the QTc interval, particularly in patients predisposed to cardiac events, we suggest that the QTc interval of CF patients should be monitored throughout the course of chronic azithromycin.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Electrocardiography; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Long QT Syndrome; Male; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Young Adult

Topics: Anti-Bacterial Agents; Azithromycin; Cardiovascular Physiological Phenomena; Child; Chronic Disease; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Electrophysiologic Techniques, Cardiac; Female; Humans; Long QT Syndrome; Male; Respiratory Tract Diseases; Spain; Treatment Outcome

Azithromycin has been reported to increase the risk of death from cardiovascular causes among patients with high baseline risk. Since the information is still limited to bridge the gap between electrophysiological properties of azithromycin in vitro and cardiac death in patients, we initially assessed its electropharmacological effects in doses of 3 and 30 mg/kg, i.v., with the halothane-anesthetized dogs (n = 4). The low dose provided 5.2 times higher than the therapeutic concentration, whereas the high dose attained 17.0 times higher. The high dose delayed the ventricular repolarization in a reverse use-dependent manner, reflecting blockade of the rapid component of delayed rectifier K(+) current, and the potency was relatively weak; namely, maximum change in QTc was +20 ms (+5.6%). The high dose also induced the negative inotropic effect possibly through Ca(2+) channel-independent pathway. In order to clarify proarrhythmic risk, 30 mg/kg, i.v., of azithromycin was examined with the chronic atrioventricular block dogs (n = 4). Azithromycin neither induced torsade de pointes nor affected beat-to-beat variability of repolarization. Thus, azithromycin can be considered to lack proarrhythmic potential, but caution has to be paid on its use for patients with left ventricular dysfunction.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Dogs; Female; Heart Ventricles; Long QT Syndrome; Male; Myocardial Contraction; Time Factors; Torsades de Pointes

Topics: Anti-Bacterial Agents; Azithromycin; Death, Sudden, Cardiac; Female; Humans; Long QT Syndrome; Middle Aged; Mitral Valve Prolapse; NAV1.5 Voltage-Gated Sodium Channel; Out-of-Hospital Cardiac Arrest

Large data-based studies have reported excess cardiovascular mortality in high-risk patients treated with azithromycin, but whether or not azithromycin causes QT prolongation remains controversial. The purpose of this study was to examine the association of azithromycin treatment on QT prolongation in a cohort of patients hospitalized with community-acquired pneumonia (CAP) METHODS: One-hundred twenty-two hospitalized patients with CAP were enrolled in the study. We compared the baseline QTc, with daily post antibiotic QTc. Other risk factors for QT prolongation such as medication or electrolyte abnormalities were recorded.. Ninety (73.8%) patients were treated with azithromycin (usually in combination with ceftriaxone), and 32 (26.2%) patients with other antibiotics (ampicillin-clavulanate, chloramphenicol, doxcycline, or ceftriaxone); 72.1% (88) of the cohort experienced QT lengthening; 72.7% with QT lengthening had a normal baseline QTc. Azithromycin was not associated with the post-antibiotic QTc. Wide (pathological) post-antibiotic QTc was associated with the pneumonia score. Every 10-point increase in the pneumonia score raised the risk for a pathological post antibiotic QTc by 1.249 (95%CI: 1.050-1.486). Analysis of patients with non-pathological baseline QTc revealed that pathological post-antibiotic QTc was only associated with previous stroke and not with the type of antibiotic.. Azithromycin treatment was not associated with QT prolongation in patients with severe CAP. Nonetheless, in a large majority of hospitalized CAP patients, QT prolongation and pathological QTc develop regardless of the antibiotic used, especially in patients with previous stroke or a higher pneumonia score.

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Community-Acquired Infections; Female; Hospitalization; Humans; Long QT Syndrome; Male; Pharmacoepidemiology; Pneumonia, Bacterial; Prospective Studies

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: Aged; Anti-Bacterial Agents; Azithromycin; Female; Humans; Long QT Syndrome; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Retrospective Studies; Time Factors

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

Topics: Anti-Bacterial Agents; Azithromycin; Cardiovascular Diseases; Humans; Long QT Syndrome; Risk

During treatment with azithromycin, a 55 year-old woman developed a newly prolonged QT interval and torsade de pointes in the absence of known risk factors. Female gender and acute renal failure may be considerations in patients treated with azithromycin.

Topics: Anti-Bacterial Agents; Azithromycin; Bradycardia; Female; Humans; Long QT Syndrome; Middle Aged; Pacemaker, Artificial; Torsades de Pointes

Topics: Anti-Bacterial Agents; Azithromycin; Humans; Long QT Syndrome; Torsades de Pointes

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

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

Prolongation of the corrected Q-T (Q-Tc) interval is associated with a risk of severe and even life-threatening arrythmias. It may occur as an adverse effect of various pharmacological agents including macrolides. We opted to study the influence of the azalide antibiotic azithromycin on the duration of Q-Tc interval as data on this subject are limited.. A prospective study was performed on 47 patients, 31 females and 16 males, aged 19-77 (median 52) years, treated with azithromycin (total dosage 3 g, divided over 5 days) for typical solitary erythema migrans. The patients were previously healthy and were not receiving any other medication. In all of them ECGs were performed before as well as 7 and 14 days after initiation of the azithromycin therapy. Thus, a total of 141 ECG tracings were analyzed. Q-T intervals were measured manually in a blinded manner and corrected for heart rate according to Bazzet's formula: Q-Tc = measured Q-T (ms)/square root of R-R (s).. Comparison of the Q-Tc intervals before, 7 days, and 14 days after the initiation of azithromycin treatment revealed a mild, but not significant prolongation (median values 406, 412.5 and 419 ms with ranges of 339-488, 352-510, and 346-505 ms, respectively). Q-Tc intervals exceeding the upper normal value of 440 ms were found in the same proportion of patients prior to as after institution of treatment. None of the ECG tracings showed significant arrhythmias.. In previously healthy persons, a modest statistically insignificant prolongation of the Q-Tc interval without clinical consequences was observed after completion of a course of 3 g of azithromycin administered over a period of 5 days for solitary erythema migrans.

Topics: Adult; Aged; Anti-Bacterial Agents; Azithromycin; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Erythema Chronicum Migrans; Female; Humans; Long QT Syndrome; Male; Middle Aged; Prospective Studies; Risk

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Electrocardiography; Female; Heart Arrest; Humans; Long QT Syndrome; Torsades de Pointes