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Cardiopulmonary Medicine  |   October 2020
QTc Interval Prolongation Associated With Inpatient Azithromycin Therapy for Pneumonia
Author Notes
  • From the Department of Emergency Medicine, Division of Medical Toxicology at Drexel University College of Medicine in Philadelphia, Pennsylvania.  
  • Financial Disclosures: None reported.  
  • Support: None reported.  
  •  *Address correspondence to Maricel Dela Cruz, DO, MPH, 1471 Legend Circle, Vallejo, CA 94591-8694. Email: mdelacruz78@gmail.com
     
Article Information
Cardiovascular Disorders / Pulmonary Disorders
Cardiopulmonary Medicine   |   October 2020
QTc Interval Prolongation Associated With Inpatient Azithromycin Therapy for Pneumonia
The Journal of the American Osteopathic Association Published Online First on October 9, 2020. doi:https://doi.org/10:7556/jaoa.2020.142
The Journal of the American Osteopathic Association Published Online First on October 9, 2020. doi:https://doi.org/10:7556/jaoa.2020.142
Abstract

Context: 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.

Objective: To compare corrected QT (QTc) interval measurements on electrocardiogram (ECG) before and after inpatient azithromycin treatment for pneumonia.

Methods: 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.

Results: 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.

Conclusion: QTc interval increases were observed during inpatient azithromycin therapy for pneumonia, but were not found to be associated with cardiac dysrhythmias during hospitalization.

In 2013, the US Food and Drug Administration issued a warning regarding the use of azithromycin and the risk of fatal dysrhythmias1 after evaluation of a 14-year retrospective study published in 2012 by Ray and colleagues in which Medicaid patients who received a 5-day course of azithromycin were found to have an increased risk of cardiovascular-related death when compared to those who took amoxicillin, ciprofloxacin, or no antibiotics.2 Macrolides, including azithromycin, have the capacity to prolong the corrected QT (QTc) interval on electrocardiogram (ECG) via blockade of the human ether-a-go-go-related gene (hERG) encoded rapidly activating delayed rectifier potassium (IKr) of cardiac cells. Prolongation of the QTc interval may potentially lead to torsades de pointes (TdP).3 
Subsequent to the 2012 study,2 retrospective population-based studies that examined the effects of azithromycin on cardiac outcomes were conducted. A 2013 study conducted in Denmark by Svanstrom et al4 showed no increase in cardiovascular death in patients who had taken azithromycin when compared with those who had taken penicillin V. A 2016 Canadian study by Trac et al5 showed no increase in risk for ventricular arrhythmia in patients who had taken azithromycin when compared with patients who had taken a nonmacrolide antibiotic. Another study6 that evaluated 122 patients with community-acquired pneumonia in Israel showed lengthening of QTc prolongation that was not statistically significant between inpatients treated with azithromycin vs controls treated with nonmacrolide antibiotics. Finally, a study7 evaluating pediatric patients on chronic azithromycin therapy for cystic fibrosis showed no consistent statistically significant prolongation of QTc intervals but did show a statistically significant increase in QTc intervals in an adolescent cohort chronically using azithromycin for cystic fibrosis. Azithromycin is also labeled to treat bronchitis, Chlamydia, and chronic obstructive pulmonary disease, among other conditions; QTc interval prolongation must be taken into consideration for such treatments. 
Hospitalized patients may be more susceptible to adverse events compared with the outpatient population because of comorbidities or other risk factors associated with dysrhythmias.8 Because pneumonia is the most common illness managed with azithromycin for patients who are hospitalized at our institution, we sought to quantify QTc prolongation after azithromycin use in a population of patients diagnosed with community-acquired pneumonia. 
Methods
This research was approved by the Institutional Review Board at Drexel University College of Medicine in Philadelphia, Pennsylvania. We reviewed 642 charts of patients admitted to our teaching hospital between January 1, 2017 and December 31, 2017 who were diagnosed with pneumonia and treated with azithromycin. All patients received an initial dose of 500 mg of intravenous azithromycin, followed with a dosing schedule of 500 mg intravenous azithromycin every 24 hours. 
Inclusion criteria were age 18 years or older, inpatient admission for pneumonia, and a pre- and post azithromycin ECG performed by the primary medical team. 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 the absence of a pre- or post azithromycin ECG available for review in the electronic medical record. A total of 142 eligible patients had retrievable ECGs in their electronic medical records that depicted pre- and post-ECGs performed after 1 dose or 2 doses of azithromycin; included patients were divided into 2 groups based on these doses (Group 1, 1 dose; Group 2, 2 doses). The time between the initial dose of azithromycin and post-dose ECG in this study population was within 6 hours. The second dose of azithromycin in this study population was given 24 hours after the first dose. 
QTc interval measurement was performed by 2 blinded, board-certified emergency medicine physicians (M.D., M.E.) who reviewed ECG lead II and used the Fridericia QTc formula. QT interval was measured according to guidelines determined by the American Heart Association.9 Lead II was used because it is customarily chosen for measurements of QT and because the P, QRS, and T wave vectors are predominantly directed toward this lead.10 The Fridericia formula was chosen because of its lack of over- or underestimation of the QTc interval found with other formulas, such as Bazett's QT interval correction calculator.10 
Our primary outcomes measurement was the QTc interval on ECG before and after azithromycin in patients treated 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; this interval was chosen as a cutoff measurement because in studies performed on patients with congenital long QT syndrome, there was an increased risk of dysrhythmia with a QTc interval greater than 500 ms.8 A Wilcoxon signed-rank test was used to evaluate repeated QTc measures of our primary outcome in both 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 on ECG after azithromycin doses in both Group 1 and Group 2. SPSS statistical software (IBM Inc.) was used to assess statistical significance. 
Results
Of the 642 patient charts reviewed, 142 patients (22.1%) were included in this study: 100 with community-acquired pneumonia who were treated with 1 dose of azithromycin (Group 1) and 42 treated with 2 doses (Group 2) (Table 1). The mean age of patients in Groups 1 and 2 was 58 and 63 years, respectively (standard deviation 15.1 and 14.6 years, respectively). (Table 1). Group 1 consisted of 49 men (49%) and 51 women (51%); Group 2 had 23 men (54.8%) and 19 women (45.2%). (Table 1). 
Table 1.
Patient Demographics
Group 1 (1 dose of azithromycin) Group 2 (2 doses of azithromycin)
Number of patients 100 42
Mean age, years 58 (SD +/- 15.1) 63 (SD +/- 14.6)
Women 51 (51%) 19 (45.2%)
Men 49 (49%) 23 (54.8%)

Abbreviations: SD, standard deviation.

Table 1.
Patient Demographics
Group 1 (1 dose of azithromycin) Group 2 (2 doses of azithromycin)
Number of patients 100 42
Mean age, years 58 (SD +/- 15.1) 63 (SD +/- 14.6)
Women 51 (51%) 19 (45.2%)
Men 49 (49%) 23 (54.8%)

Abbreviations: SD, standard deviation.

×
The mean QTc interval was found to be longer after 1 dose of azithromycin than at pre azithromycin baseline (477 ms vs 422 ms; post azithromcyin; range, 308-489 ms vs 375-589 ms, respectively) (Table 2). The average QTc interval after 2 doses was also longer than baseline (444 ms vs 422 ms; range, 369-594 vs 336-496, respectively) (Table 2). A Wilcoxon signed-rank test indicated a significant QTc prolongation after 1 dose of azithromycin (mean rank, 43.76; Z=−4.921; P<.001), but no statistically significant QTc prolongation after 2 doses of azithromycin (P=.08). A total of 10 patients (10%) in Group 1 and 4 patients (9.5%) in Group 2 had a QTc interval greater than 500 ms. Although QTc interval increased after inpatient azithromycin therapy for pneumonia, relatively few patients had a QTc interval greater than 500 ms in both Groups 1 and 2 (10% and 9.5%, respectively). There were no cases of TdP or other dysrhythmias reported. 
Table 2.
QTc Interval Findings
Group 1 (1 dose of azithromycin) Group 2 (2 doses of azithromycin)
Pre-dose Post-dose Pre-dose Post-dose
Mean QTc, ms 424 447 422 444
QTc range, ms 308-489 375-589 336-496 369-594
Post electrocardiogram QTc >500 ms 10 (10%) 4 (9.5%)
Table 2.
QTc Interval Findings
Group 1 (1 dose of azithromycin) Group 2 (2 doses of azithromycin)
Pre-dose Post-dose Pre-dose Post-dose
Mean QTc, ms 424 447 422 444
QTc range, ms 308-489 375-589 336-496 369-594
Post electrocardiogram QTc >500 ms 10 (10%) 4 (9.5%)
×
Discussion
A number of medications have been associated with QT interval prolongation, including macrolide antibiotics.11 Other factors may be associated with ECG abnormalities unrelated to azithromycin use, including age, electrolytes, other prescribed medications, and comorbidities such as stroke and metabolic disease.12,13 Although the literature reveals a relative increase in risk for dysrhythmia in patients with congenital and genetically related prolonged QT syndrome when the QT interval is greater than 500 ms, the actual association between QT interval measurement and risk for dysrhythmia, as well as TdP, is still unknown.13 The risk would be difficult to study because the incidence of TdP is rare; therefore, a QT interval greater than 500 ms currently serves as a surrogate marker when determining the risk of dysrhythmia and TdP.14 
Implications of this study include effects of antibiotic azithromycin in the wake of the recent coronavirus epidemic. Azithromycin may be used for its antiinflammatory effects in the treatment of coronavirus disease 2019 (COVID-19). Physicians must be cognizant of their use of multiple QTc-prolonging drugs and other drug-drug interactions. For example, the combined use of hydroxychloroquine in the treatment of COVID-19 and the use of azithromycin for secondary bacterial pneumonia may lead to QTc prolongation and the risk of TdP or other harmful dysrhythmias. A study by Mercuro et al15 found that patients diagnosed with COVID-19 and treated with both hydroxychloroquine and azithromycin vs hydroxychloroquine alone had an increased risk of QTc prolongation.15 
With the management of pneumonia and the potential use of any antibiotic or medication, it is important to for osteopathic physicians to evaluate the patient as a whole, taking into account inherent risk factors. Age, gender, comorbidities, drug-to-drug interactions, as well as use of over-the-counter, herbal, supplemental, and nonprescribed medications must be considered. With azithromycin use, it is important to counsel patients specifically on all options and the risk factors of any other alternative medications. Osteopathic treatment can be used in combination with antibiotic therapy, if antibiotic therapy is deemed necessary, and future studies could be performed to determine whether osteopathic manipulation may have any effect on ECG and QTc findings in patients diagnosed with pneumonia and treated with azithromycin. 
The observational retrospective study performed by Ray et al,2 which led the US Food and Drug Administration to issue a distinct warning on the use of azithromycin and risk of cardiovascular death,1 is worth taking into account when prescribing this antibiotic; however, if the benefit of this medication outweighs its risk, it should be considered as a viable antibiotic for use with the appropriate population.16 The findings in the present study most closely emulate the results found by Goldstein et al,6 which showed that inpatients treated for community-acquired pneumonia with azithromycin vs controls treated with non-macrolide antibiotics for experienced prolongation of the QTc interval that was not found to be statistically significant.6 
Limitations
One limitation of this study was the low percentage of ECGs in the electronic medical record available for review. Not all patients treated with azithromycin for the diagnosis of pneumonia and admitted to this teaching hospital had an ECG performed both before and after their first or second dose of azithromycin and thus could not be included in the study. This decreased our study population size. A statistically significant difference between mean QTc before azithromycin dosing compared to mean QTc after 2 doses of azithromycin may not have been appreciated secondary to the small sample size in this group. The 2 groups studied here were created secondary to the available ECG data on admitted patients. 
There were no documented dysrhythmias during the patient hospitalizations evaluated during this study period, but it is possible that some were missed and unrecorded outside of hospitalization. Also, dysrhythmias might have been missed while patients were hospitalized but not placed on a continuous cardiac monitor; thus, dysrhythmias are not documented in this retrospective analysis of patient charts. 
Conclusions
The results of our study, like others, showed that QTc intervals increased during inpatient azithromycin therapy for community-acquired pneumonia but not to a level of statistical significance. While further study is needed and previous warnings are worth considering when prescribing azithromycin, our results suggest that it remains a viable option in an appropriate patient population when benefits outweigh risks. 
Author Contributions
Dr Dela Cruz provided substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; Drs Ershad and Mustafa drafted the article or revised it critically for important intellectual content; all authors gave final approval of the version of the article to be published; and all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
References
Food and Drug Administration. FDA drug safety communication: azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms. Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm341822.htm. Accessed September 1, 2018.
Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. . 2012;366(20):1881-1890. doi: 10.1056/NEJMoa1003833 [CrossRef] [PubMed]
Li M, Ramos LG. Drug-induced QT prolongation and torsades de pointes. P T. . 2017; 42(7):473-477. [PubMed]
Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. . 2013;368(18):1704-1712. doi: 10.1056/NEJMoa1300799 [CrossRef] [PubMed]
Trac MH, McArthur E, Jandoc R, et al. Macrolide antibiotics and the risk of ventricular arrhythmia in older adults. CMAJ. . 2016. 188(7):E120-E129. doi: 10.1503/cmaj.150901 [CrossRef] [PubMed]
Goldstein LH, Gabin A, Fawaz A, et al. Azithromycin is not associated with QT prolongation in hospitalized patients with community-acquired pneumonia. Pharmacoepidemiol Drug Saf. . 2015;24(10):1042-1048. doi: 10.1002/pds.3842 [CrossRef] [PubMed]
Lenehan PJ, Schramm CM, Collins MS. An evaluation strategy for potential QTc prolongation with chronic azithromycin therapy in cystic fibrosis. J Cyst Fibros. . 2016;15(2):192-195. doi: 10.1016/j.jcf.2015.11.012 [CrossRef] [PubMed]
Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol. . 2010;55(9):934-947. doi: 10.1016/j.jacc.2010.01.001 [CrossRef] [PubMed]
Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation. . 2009;119(10):e241-e250. doi: 10.1161/CIRCULATIONAHA.108.191096 [CrossRef] [PubMed]
Postema PG,Wilde AAM. The measurement of the QT interval. Curr Cardiol Rev. . 2014;10(3):287-294. doi: 10.2174/1573403x10666140514103612 [CrossRef] [PubMed]
Jr Owens RC. QT prolongation with antimicrobial agents: understanding the significance. Drugs. . 2004;64(10):1091-1124. doi: 10.2165/00003495-200464100-00005 [CrossRef] [PubMed]
Pasquier M, Pantet O, Hugli O, et al. Prevalence and determinants of QT interval prolongation in medical inpatients. Intern Med J. . 2012;42(8):933-940. doi: 10.1111/j.1445-5994.2011.02447.x [CrossRef] [PubMed]
Rezus C, Moga VD, Ouatu A, Floria M. QT interval variations and mortality risk: is there any relationship? Anatol J Cardiol. . 2015;15(3):255-258. doi: 10.5152/akd.2015.5875 [CrossRef] [PubMed]
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Table 1.
Patient Demographics
Group 1 (1 dose of azithromycin) Group 2 (2 doses of azithromycin)
Number of patients 100 42
Mean age, years 58 (SD +/- 15.1) 63 (SD +/- 14.6)
Women 51 (51%) 19 (45.2%)
Men 49 (49%) 23 (54.8%)

Abbreviations: SD, standard deviation.

Table 1.
Patient Demographics
Group 1 (1 dose of azithromycin) Group 2 (2 doses of azithromycin)
Number of patients 100 42
Mean age, years 58 (SD +/- 15.1) 63 (SD +/- 14.6)
Women 51 (51%) 19 (45.2%)
Men 49 (49%) 23 (54.8%)

Abbreviations: SD, standard deviation.

×
Table 2.
QTc Interval Findings
Group 1 (1 dose of azithromycin) Group 2 (2 doses of azithromycin)
Pre-dose Post-dose Pre-dose Post-dose
Mean QTc, ms 424 447 422 444
QTc range, ms 308-489 375-589 336-496 369-594
Post electrocardiogram QTc >500 ms 10 (10%) 4 (9.5%)
Table 2.
QTc Interval Findings
Group 1 (1 dose of azithromycin) Group 2 (2 doses of azithromycin)
Pre-dose Post-dose Pre-dose Post-dose
Mean QTc, ms 424 447 422 444
QTc range, ms 308-489 375-589 336-496 369-594
Post electrocardiogram QTc >500 ms 10 (10%) 4 (9.5%)
×