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Authors: Sumit Gandotra, PharmD and Sandeep Devabhakthuni, PharmD, BCCP
Common extra-cardiac adverse effects of antibiotics are well known, such as Clostridioides difficile infection, allergic reactions, and gastrointestinal intolerance.1 Over the past few years, however, FQs and macrolides have been closely analyzed, and recent data have revealed that these therapeutic classes are associated with a higher risk of cardiovascular (CV) adverse effects (AEs). In light of these data, measures have been taken to restrict their use and educate healthcare providers on associated CV risk (e.g., updates to package labeling) (Figure 1).2-7 Evaluation of their risk-benefit profile is important to ensure safe use when widely prescribed. This blog summarizes recent literature on CV AEs associated with FQs and macrolides and provides recommendations on their use within certain at-risk populations.
Fluroquinolones are the third most commonly prescribed antibiotic class, in part, due to their excellent oral bioavailability and broad-spectrum antibacterial activity.8 They are used for a variety of infections including respiratory, genitourinary, skin and soft tissue (SSTI), and intraabdominal infections (IAIs).9 In recent years, a number of AEs have been reported with these medications that have led to warnings issued by the Food and Drug Administration (FDA) (Figure 1). Some include peripheral neuropathy, tendon rupture, glucose dysregulation (especially in elderly patients and those who take oral hypoglycemic agents), and potential retinal detachment.9-12 Cardiovascular AEs include QTc prolongation, risk for fatal arrhythmias, and aortic aneurysm and dissection.13,14
Fluroquinolone-induced QTc prolongation stems from concentration-dependent blockade of the rapid delayed rectifier potassium channel (IKr), resulting in delayed cardiac repolarization.15,16 Two recent observational studies evaluating risk of serious arrythmias with FQ use reported conflicting results.17,18
Gorelik and colleagues conducted a systematic review and meta-analysis to estimate the risk of CV AEs associated with FQs. Thirteen studies were included, and FQs were associated with an 85% increased relative risk (RR) of arrhythmias (odds ratio [OR], 1.85; 95% confidence interval [CI]: 1.22-2.81) and 71% increased RR for CV mortality (OR, 1.71; 95% CI: 1.39-2.09). Moxifloxacin had the highest risk for arrhthymia and CV mortality. However, this analysis was not designed to explore interaction between CV AEs and comorbidities that may increase CV risk. Other limitations include confounding by indication, lack of information on lifestyle factors influencing CV risk and medication adherence, and significant heterogeneity among trials.19 Based on these reports, FQs should be avoided if an alternative antibiotic can be used in high-risk patients. If FQs are necessary to treat the infection, close monitoring should be considered in those at high risk for arrhythmias (e.g., existing QTc prolongation, bradyarrhythmia, hypokalemia, hypomagnesemia, or use of concomitant medications that are proarrhythmic).
Most recently, a study performed by Etminan and colleagues suggests that the use of FQs may lead to an increased risk of valvular regurgitation (VR).20 This matched nested case-control study used data from the FDA’s adverse reporting system and identified 12,505 patients with reported FQ-related VR and compared it to 125,020 case-control subjects from a random sample of 9 million patients with non-FQ-related VR who received either amoxicillin or azithromycin. Patients with rheumatic fever, strep throat, and infective endocarditis were excluded from the study. There were a total of 102 reported FQ-related VR events, with the highest number of cases attributed to ciprofloxacin (n=44) and levofloxacin (n=52). The adjusted RR of developing VR was significantly higher for current users of FQs (defined as use within the last 30 days) compared to amoxicillin (RR, 2.40; 95% CI: 1.82 to 3.16) and azithromycin (RR, 1.75; 95% CI: 1.34 to 2.29). Remote FQ use (i.e., greater than 30 days) was not associated with increased risk.
The results of this study, among others, indicates that there is a correlation between recent use of oral FQs and development of VR. This may be due to FQs damaging type I and III collagen, which is found in the Achilles tendons, aorta, and aortic valves, as well as reducing collagen production and stimulating the activity of metalloproteinases.20
Similar to FQs, macrolide antibiotics are also used to treat a broad range of infections that include respiratory, genitourinary, SSTI, and IAIs. Despite being well-tolerated, they are commonly associated with increased diarrhea, taste disturbances, and nausea.21 Cardiovascular AEs associated with macrolides include QTc interval prolongation, ventricular arrhythmias (VA), and sudden cardiac death (SCD).21 Large cohort studies have provided conflicting results on the risk of VA and SCD.21-25
Recently, however, a meta-analysis of 33 studies suggested that erythromycin and clarithromycin had a higher risk of myocardial infarction compared to azithromycin (OR 1.58, 95% CI, 1.18-2.11 and OR 1.41, 95% CI, 1.11-1.81, respectively).25 Cheng and colleagues also performed a meta-analysis that included 33 studies (n=20,779,963) in order to assess individual macrolide use and risk of developing VA or SCD. This meta-analysis found a significantly increased risk for developing VA or SCD compared to patients not on macrolide therapy (RR, 2.42; 95% CI: 1.61 to 3.63) or patients taking amoxicillin or penicillin (RR, 1.69; 95% CI: 1.27 to 2.25). Stratified analysis of individual macrolides, including azithromycin, clarithromycin, and erythromyicin, were consistent with the meta-analysis. Overall, risk of CV mortality was increased in patients taking macrolides (RR, 1.31; 95% CI: 1.06 to 1.62).22
While there does appear to be an increased risk of CV AEs with macrolides, the absolute risk of VA or SCD is small, accounting for only 118 cases per 1 million treatment courses. These findings indicate that the CV risk of macrolide use may not be clinically significant and may not require significant changes in prescribing patterns of macrolides in the general population.22 Predisposing comorbid conditions and concomitant medications may influence the AEs reported. These data suggest that macrolides should be used cautiously in patients at high-risk for arrhthymias.
The association of CV AEs with macrolides and FQs remain controversial. However, recent data suggests that judicious use and prudent monitoring are needed for these medications for patients at high risk of CV events (Table 1). Use of FQs and macrolides should be avoided in patients with high risk for arrhythmias unless there are no alternative antibiotics (Figure 2). Patients at high risk for arrhythmias include those with existing QTc prolongation, history of TdP, congenital long QT syndrome, hypokalemia, hypomagnesemia, bradyarrhythmias, and those on concomitant medications known to cause QTc prolongation. If there are no alternatives, FQs can be used in these high-risk patients with close monitoring and risk reduction strategies such as repletion of electrolytes and temporarily discontinuing other medications that can produce QTc prolongation. Due to recent data linking FQ use with VR and aortic rupture, this medication class should be avoided in patients with existing aortic or mitral regurgitation or aortic dissection or aneurysm unless no alternatives are available (Figure 2).
Sumit Gandotra, PharmD
At the time of this writing, Sumit Gandotra was a postgraduate year 1 (PGY1) pharmacy practice resident at ChristianaCare in Newark, DE. He obtained his Doctor of Pharmacy from University of Maryland School of Pharmacy. Follow him on Twitter @sgandotraPharmD.
Sandeep Devabhakthuni, PharmD, BCCP
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- Levofloxacin tablet, film coated [package insert]. Roorkee-247661, India. Jubilant Generics Limited. April 2019.
- Moxifloxacin hydrochloride tablet, film coated [package insert]. GuangDong Province, P.R. China. Sunshine Lake Pharma Co., Ltd. July 2018.
- Ciprofloxacin tablet, film coated [package insert]. Dayton, NJ. Aurobindo Pharma LLC. May 2012.
- Azithromycin monohydrate tablet, film coated [package insert]. GuangDong Province, P.R. China. Sunshine Lake Pharma Co., Ltd. December 2018.
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- Erythromycin capsule, delayed release pellets [package insert]. Greenville, NC. Mayne Pharma. March 2019.
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- Etminan M, Brophy JM, Samii A. Oral fluoroquinolone use and risk of peripheral neuropathy: A pharmacoepidemiologic study. Neurology. 2014;83:1261–
- Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015;5:e010077.
- Chui CSL, Wong ICK, Wong LYL, Chan EW. Association between oral fluoroquinolone use and the development of retinal detachment: a systematic review and meta-analysis of observational studies. J Antimicrob Chemother. 2014;70:971–
- Porta L, Lee M-TG, Hsu W-T, Hsu T-C, Tsai T-Y, Lee C-C. Fluoroquinolone use and serious arrhythmias: a nationwide case-crossover study. Resuscitation. 2019;139:262–
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- Inghammar M, Svanstrom H, Melbye M, Pasternak B, Hviid A. Oral fluoroquinolone use and serious arrhythmia: bi-national cohort study. BMJ. 2016;352:1-8.
- Gorelik E, Masarwa R, Perlman A, et al. Fluoroquinolones and CV risk: a systematic review, meta-analysis and network meta-analysis. Drug Safety. 2019;42:529-538.
- Etminan M, Sodhi M, Ganjizadeh-Zavareh S, et al. Oral fluoroquinolones and risk of mitral and aortic regurgitation. J Am Coll Cardiol. 2019;74(11):1444-1450.
- Hansen MP, Scott AM, McCullough A, et al. Adverse events in people taking macrolide antibiotics versus placebo for any indication. Cochrane Database Syst Rev. 2019; 1:CD011825.
- Cheng YJ, Nie XY, Chen XM, et al. The role of macrolide antibiotics in increasing CV risk. JACC. 2015;66(20):2173-84.
- Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;35:1089-1096.
- Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of CV death. N Engl J Med. 2012;366:1881-1890.
- Gorelik E, Masarwa R, Perlman A, Rotshild V, Muszkat M, Matok I. Systematic review, meta-analysis, and network meta-analysis of the CV safety of macrolides. Antimicrob Agents Chemother. 2018;62:e00438-18.
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