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. 2014 Apr;2(2):47–59. doi: 10.1177/2049936114527744

Erythromycin, QTc interval prolongation, and torsade de pointes: Case reports, major risk factors and illness severity

Jules C Hancox ✉, Mehrul Hasnain 1, W Victor R Vieweg 2,*, Michael Gysel 3, Michelle Methot 4, Adrian Baranchuk 5
PMCID: PMC4072045  PMID: 25165555

Abstract

Objectives:

Erythromycin is a macrolide antibiotic that is widely used for various infections of the upper respiratory tract, skin, and soft tissue. Similar to other macrolides (clarithromycin, azithromycin), erythromycin has been linked to QTc interval prolongation and torsade de pointes (TdP) arrhythmia. We sought to identify factors that link to erythromycin-induced/associated QTc interval prolongation and TdP.

Methods and Results:

In a critical evaluation of case reports, we found 29 cases: 22 women and 7 men (age range 18–95 years). With both oral and intravenous erythromycin administration, there was no significant relationship between dose and QTc interval duration in these cases. Notably, all patients had severe illness. Other risk factors included female sex, older age, presence of heart disease, concomitant administration of either other QTc prolonging drugs or agents that were substrates for or inhibitors of CYP3A4. Most patients had at least two risk factors.

Conclusions:

On the basis of case report evaluation, we believe that major risk factors for erythromycin-associated TdP are female sex, heart disease and old age, particularly against a background of severe illness. Coadministration of erythromycin with other drugs that inhibit or are metabolized by CYP3A4 or with QTc prolonging drugs should be avoided in this setting.

Keywords: drug-induced QTc interval prolongation, erythromycin, risk factors, torsade de pointes

Introduction

Erythromycin has been used since the 1950s for various infections of the upper respiratory tract, skin, and soft tissue and as a penicillin substitute in patients allergic to penicillin [Zuckerman, 2004]. However, it was not until 30 years later that clinicians recognized its link to QTc interval prolongation and torsade de pointes (TdP) [McComb et al. 1984; Guelon et al. 1986; Freedman et al. 1987; Ragosta et al. 1989].

Oral erythromycin and sudden cardiac death

Ray and colleagues studied the oral administration of erythromycin and its link to sudden cardiac death (SCD) in a Tennessee Medicaid cohort that comprised 1,249,943 person-years of follow up and 1476 cases of confirmed SCD [Ray et al. 2004]. CYP3A4 inhibitors employed in this study were nitroimidazole antifungal drugs, diltiazem, verapamil, and troleandomycin. Each inhibitor at least doubled the area under the time–concentration curve for a CYP3A4 substrate. To assess possible confounding by indication, amoxicillin (antibiotic with similar indications as erythromycin that does not prolong QTc interval) and previous use of erythromycin were also studied. SCD among patients currently using oral erythromycin was twice as great compared with patients not using any of the study antibiotics. Former use of erythromycin or current use of amoxicillin did not increase the risk of SCD. Among patients coadministered erythromycin and a CYP3A4 inhibitor, there was a fivefold increase in the risk of SCD compared with patients using neither CYP3A4 inhibitors nor study antibiotics. Among patients receiving amoxicillin and CYP3A4 inhibitors or those currently using any of the study medications, there was no increased risk of SCD. Ray and colleagues concluded that the coadministration of erythromycin and strong CYP3A4 inhibitors should be avoided [Ray et al. 2004].

Ray and colleagues commented on both oral and intravenous (IV) erythromycin-related QTc interval prolongation and TdP, but did not identify the risk factors for either of those electrocardiographic (EKG) parameters in their study [Ray et al. 2004]. They noted that IV administration of erythromycin more closely links to drug-induced QTc interval prolongation and TdP than oral administration. Women comprised at least two-thirds of the study cohort and between 16.8% and 26.0% of them were elderly. No attempt was made to judge the severity of patients’ medical illness.

QTc interval prolongation among critically ill patients receiving IV erythromycin lactobionate slowly

Tschida and colleagues noted that rapid IV infusion of erythromycin had recently (as of 1996) been linked to QTc interval prolongation, TdP, and SCD [Tschida et al. 1996]. The authors prospectively studied the relationship between QTc interval prolongation and slow (8.9 ± 3.5 mg/minute, range 3.9–16.7 mg/min) IV infusion of erythromycin lactobionate in 44 critically ill patients receiving IV antibiotics (half receiving erythromycin and the other half ceftazidime, cefuroxime, cefotaxime, ceftriaxone, or ampicillin–sulbactam as controls). Cardiac monitor rhythm strips were taken immediately before and within 15 minutes after completing drug infusion. The authors evaluated only the first set of rhythm strips. No patients demonstrated liver dysfunction but two controls did.

The Bazett formula was used to calculate the QTc interval. Tschida and colleagues [Tschida et al. 1996] did not discuss the limitations of measuring the QTc interval in drug/illness-induced heart rate changes, particularly in the setting of rapid heart rate, a likely finding in critically ill patients [Indik et al. 2006]. For controls, there was no change (p = 0.712) in QTc interval at baseline (423 ± 96 ms, range 300–550 ms) and after infusion (419 ± 96 ms, range 280–610 ms). Among erythromycin patients, these differences reached statistical significance (p = 0.034; baseline 524 ± 105 ms, range 360–810 ms; and after infusion 555 ± 134 ms, range 400–980 ms). That is, erythromycin patients largely maintained QTc interval measurements above the critical threshold of 500 ms, a value associated with TdP [Bednar et al. 2001, 2002; Yap and Camm, 2003]. No patients developed TdP during erythromycin infusion. However, the authors concluded that slow IV infusion of erythromycin lactobionate was associated with significant QTc interval prolongation.

In a prospective study, Haefeli and colleagues sought to determine the incidence of QTc interval prolongation and ventricular arrhythmia (VA) in a consecutive series of seven critically ill patients treated with IV erythromycin in a medical ICU of a university hospital [Haefeli et al. 1992]. Erythromycin was administered over the course of a short infusion and QTc interval was measured before and after antibiotic treatment along with other variables. QTc interval prolongation appeared during 12 of 13 erythromycin infusions in these seven study patients. The magnitude of QTc interval prolongation correlated with erythromycin infusion rate (r = 0.765, p = 0.05). In three study subjects, VAs occurred in close temporal relationship to antibiotic infusion. Two of these three developed ventricular fibrillation shortly after the first and second doses of erythromycin, respectively, and died within 3 hours. The authors concluded that erythromycin-induced QTc interval prolongation appears frequently and correlates with antibiotic infusion rate. They recommended that the slowest possible infusion rate be used and subjects undergo careful cardiac monitoring.

Less critically ill patients receiving erythromycin lactobionate

In a retrospective study of all inpatients receiving IV erythromycin lactobionate over the course of 1 year in a university teaching hospital setting, Oberg and Bauman [Oberg and Bauman, 1995] sought to determine the frequency of QTc interval prolongation (Bazett) and TdP among patients receiving this drug intravenously. A total of 278 patients, all receiving antibiotic treatment for suspected atypical pneumonia (Legionella pneumophila, Mycoplasma pneumoniae), were available and 49 (26 men and 23 women, ages 22–91, 51 ± 18 years) of them had EKGs while receiving and not receiving erythromycin (baseline QTc interval 432 ± 39 ms [range 373–532 ms] and 483 ± 62 ms [range 350–670 ms] while receiving erythromycin). A total of 30 (61.2%) of these 49 subjects had heart disease and QTc interval increase was 15 ± 11% compared with 8.6 ± 10% for the patients without heart disease. QTc interval prolongation was not related to erythromycin dose (mg/kg/day); however, among the nine patients receiving 60 mg/kg/day or greater, increase in QTc interval was greater than 15%. A total of 19 (39%) of the 49 study patients developed QTc interval prolongation ≥500 ms during erythromycin infusion and one of the 278 patients receiving erythromycin lactobionate during the study period of 1 year developed TdP (0.36%). The authors concluded that (1) erythromycin lactobionate treatment commonly induces QTc interval prolongation but rarely links to TdP and (2) heart disease is an important risk factor.

The one patient who developed TdP was a 72-year-old woman with both coronary and valvular heart disease, severe liver dysfunction, and hypertension. She is Case #18 in Table 1 and Online Appendix A.

Table 1.

Risk factors for QTc interval prolongation and torsades de pointes (TdP) by case reports among patients receiving erythromycin (ERM).

Case/illness severity/arrhythmia QTc (ms) ERM daily dose/PO/IV Female sex Elderly Heart disease Hepatic/renal failure Hypo- K+ Hypo- Mg++ Bradycardia CYP3A4 substrate/ inhibitor QTc- prolonging drugs Naranjo Scale WHO-UMC Additional risk factors
#1 McComb et al., 1984 / 3+ / Ventricular Tachycardia 603 ms 1000 mg IV Yes Yes Yes None reported No No – None None Probable Probable/Likely Acute medical illness, chronic medical illness
#2 Guelon et al., 1986 / 4+ / TdP ‘Prolonged’ 3000 mg IV Yes No Yes None reported No – – None None Probable Probable/likely Acute medical illness, chronic medical illness
#3 Freedman et al., 1987 / 3+ / TdP, Ventricular Flutter 605 ms 2000 mg PO Yes No Yes None reported No No No None None Probable Probable/likely Acute medical illness
#4 Ragosta et al., 1989 / 3+ / TdP 600 ms 4000 mg IV Yes Yes Yes None reported No – – Disopyramide (substrate) Disopyramide Possible Possible Acute medical illness
#5 Ragosta et al., 1989 / 3+ / TdP 630 ms 2000 mg PO No Yes Yes Acute kidney injury No No – Disopyramide (substrate) Disopyramide Possible Possible Acute medical illness, chronic medical illness
#6 Schoenenberger et al., 1990 / 3+ / TdP 550 ms 3000 mg IV Yes No Yes Potential hepatic disease – elevated LFTs No No – None None Probable Probable/likely Acute medical illness, chronic medical illness
#7 Lindsay, Jr. et al., 1990 / 3+ / TdP 640 ms Unknown IV No No No None reported No No – None Pentamidine Probable Probable/likely Acute medical illness, chronic medical illness
#8 Lindsay, Jr. et al., 1990 / 3+ / TdP ‘Prolonged’ Unknown IV Yes No No Cadaveric kidney transplant with rejection No No No None None Probable Probable/likely Acute medical illness, chronic medical illness
#9 Nattel et al., 1990 / 4+ / TdP 600 ms 4000 mg IV No Yes Yes Renal dysfunction – elevated Cr and BUN No No – Amiodarone (inhibitor) quinidine (substrate) Amiodarone, quinidine (stopped 2 days before ERM) Probable Probable/likely Acute medical illness, chronic medical illness
#10 Haefeli et al., 1992 / 4+ / TdP 562 ms 1000 mg IV No No No Renal dysfunction (kidney graft) – – – None None Possible Possible Acute medical illness, chronic medical illness
#11 Haefeli et al., 1992 / 4+ / Ventricular tachycardia 500 ms 1000 mg IV No Yes No None reported No No – None None Possible Possible Acute medical illness, chronic medical illness
#12 Paris et al., 1994 / 3+ / TdP 531 ms 2000 mg PO Yes No No None reported No No Yes Terfenadine (substrate) Terfenadine Possible Possible Acute medical illness, chronic medical illness
#13 Brandriss et al., 1994 / 4+ / TdP 600 ms 4000 mg IV Yes No Yes None reported No No – None None Probable Probable/Likely Acute medical illness, chronic medical illness
#14 Gitler et al., 1994 / 4+ / TdP 670 ms 3000 mg IV Yes Yes Yes None reported No – – None None Possible Possible Acute medical illness, chronic medical illness
#15 Gitler et al., 1994 / 4+ / TdP 660 ms 1000 mg IV Yes Yes Yes None reported No No No None None Probable Possible Acute medical illness,chronic medical illness
#16 Rezkalla & Pochop, 1994 / 4+ / TdP 517 ms Unknown IV Yes Yes Yes None reported No No – None None Probable Probable/Likely Acute medical illness, chronic medical illness
#17 Biglin et al., 1994 / 4+ / TdP, Ventricular fibrillation 630 ms 1000 mg PO Yes No No None reported No No – Terfenadine (substrate) Terfenadine Possible Possible Acute medical illness
#18 Oberg & Bauman, 1995 / 3+ / TdP 560 ms 4000 mg IV Yes Yes Yes Severe liver disease. No No – None None Probable Probable Acute medical illness, chronic medical illness
#19 Wong & Windle, 1995 / 4+ / TdP 550 ms 1000 mg IV Yes No No None reported Yes – – Fluconazole (inhibitor) Fluconazole Possible Possible Acute medical illness, chronic medical illness
#20 Orban et al., 1995 / 4+ / TdP, Ventricular fibrillation 680 ms 4000 mg IV Yes No Yes Renal transplant with chronic rejection Yes No Yes Cimetidine (inhibitor) None Probable Probable/Likely Acute medical illness,chronic medical illness
#21 Chennareddy et al., 1996 / 3+ / Polymorphic ventricular tachycardia 320 ms 1000 mg IV No No No None reported No No No None None Possible Probable/Likely Acute medical illness,chronic medical illness
#22 Hsieh et al., 1996 / 3+ / TdP 700 ms 1000 mg PO Yes No Yes None reported No No – None Astemizole Possible Possible Acute medical illness
#23 Katapadi et al., 1997 / 3+ / TdP 720 ms 4000 mg IV Yes No Yes None reported – – No None None Probable Probable/likely Acute medical illness
#24 Lin & Quasny, 1997 / 3+ / TdP 631 ms 1500 mg PO No Yes Yes None reported (slightly elevated Cr and BUN) No No No Quinidine (substrate) Quinidine Possible Possible Acute medical illness, chronic medical illness
#25 Vogt & Zollo, 1997 / 3+ / QT prolongation, narrow-complex tachycardia 640 ms 4000 mg PO Yes Yes No Renal insufficiency – – Yes None None Probable Probable/likely Acute medical illness, chronic medical illness
#26 Koh, 2001 / 3+ / TdP 612 ms 1000 mg PO Yes Yes Yes None reported Yes No Yes Carbimazole (minor inhibitor) None Probable Probable/likely Acute medical illness, chronic medical illness
#27 Goldschmidt et al., 2001 / 3+ / QT prolongation 583 ms 2000 mg PO Yes Yes Yes None reported No No Yes Verapamil (inhibitor) None Probable Probable/likely Acute medical illness, chronic medical illness
#28 Kyrmizakis et al., 2002 / 3+ / TdP, Ventricular fibrillation ‘Prolonged’ 2000 mg PO Yes No No None reported No No No Cisapride (substrate) Cisapride Possible Possible Acute medical illness, chronic medical illness
#29 Hinterseer et al., 2006 / 4+ / TdP, Ventricular fibrillation 510 ms 4000 mg IV Yes No Yes None reported No Yes – None None Possible Possible Acute medical illness
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Erythromycin pharmacology

Pharmacokinetics

The oral bioavailability of erythromycin is low; however, different ester and salt formulations offer improved oral absorption ranging from 45 to 80%. Both erythromycin estolate and ethylsuccinate are dependent upon hydrolysis to erythromycin base for absorption.

Erythromycin has a large volume of distribution and is lipophilic with extensive penetration in body tissues and fluids, including cardiac tissue [Tschida et al. 1996]. Serum concentrations appear to be lower than tissue concentrations. The time to reach peak serum concentrations after an oral dose ranges from 2 to 4 hours.

Erythromycin is extensively metabolized by the CYP450 enzyme system and is an inhibitor of several isoenzymes. As a result, erythromycin has a potential for increasing serum concentrations of drugs metabolized via this system. The interaction of erythromycin and terfenadine is well documented to cause QTc interval prolongation by both increased serum terfenadine concentrations by CYP450 enzyme inhibition of erythromycin and by erythromycin itself [Paris et al. 1994; Biglin et al. 1994]. The half-life of erythromycin is 2–3 hours. Biliary excretion is responsible for erythromycin elimination and only minute amounts of drug are cleared renally.

Pharmacodynamics

Macrolide antimicrobials, including erythromycin, display time-dependent antibacterial activity. Antimicrobials that are time-dependent require serum drug concentrations above the minimum inhibitory concentration for an extended time period to allow for antimicrobial activity. Erythromycin also displays antimicrobial activity after drug exposure, often termed the post-antibiotic effect [Zhanel et al. 2001].

Erythromycin as a hERG channel inhibitor

Drugs that cause QT interval prolongation and TdP tend to share in common an ability to produce pharmacological inhibition of hERG (human Ether-a-go-go Related Gene) potassium ion channels [Vandenberg et al. 2001; Hancox et al. 2008]. hERG is responsible for the rapid delayed rectifier K+ current, IKr, in cardiac myocytes, which regulates ventricular action potential (AP) repolarization and, thereby, the QT interval duration.

Macrolide antibiotics are well established to inhibit hERG channel current (IhERG) [Volberg et al. 2002; Stanat et al. 2003]. Volberg and colleagues reported IhERG inhibition in a mammalian cell expression system by erythromycin with a half maximal inhibitory concentration (IC50) of 72.2 µM, whilst in the same study its metabolite desmethyl-erythromycin also produced weaker IhERG inhibition (IC50 of 147.1 µM). Some subsequent studies have reported lower IhERG block IC50 values for erythromycin of 38.9 µM [Stanat et al. 2003], 59.3 µM [Duncan et al. 2006], and 21 µM [Wisialowski et al. 2006].

Two studies have reported a marked temperature sensitivity of the inhibitory action of erythromycin against IhERG [Kirsch et al. 2004; Guo et al. 2005]. One of these studies demonstrated an approximately linear increase in IhERG block by the drug over a temperature range between 36℃ and 42℃, whilst also demonstrating markedly temperature-sensitive AP prolongation over a range from 22℃ to 42℃ [Guo et al. 2005]. It is feasible that temperature-sensitivity of IhERG block by erythromycin over a range encompassing physiological temperatures and those relevant to pyrexia may have functional significance [Guo et al. 2005]. Erythromycin has also been reported to have synergic effects with β-estradiol on IhERG [Ando et al. 2011].

In monophasic AP recordings from anesthetized guinea-pigs, erythromycin has been observed to increase both AP duration and alternans [Wisialowski et al. 2006]. The drug has also been shown to increase AP duration in a concentration dependent fashion in rabbit Purkinje fibers and to prolong both QT interval and Tpeak–Tend in a concentration-dependent fashion in an arterial perfused rabbit left ventricular wedge preparation [Lu et al. 2007]. At the highest concentration tested (300 µM), the drug elicited early-after-depolarizations (EADs) in 6 of 7 wedge preparations tested [Lu et al. 2007].

Methods

We conducted a critical evaluation (until and including 1 August 2013) of case reports. Initially, we entered the following MeSH terms: ‘erythromycin and qtc prolongation’ and ‘erythromycin and torsade’ into Medline. We searched CredibleMeds (http://www.azcert.org/) for case report of erythromycin, QTc interval prolongation, and TdP. This search was initiated via AZCERT: (“Erythromycin”[MeSH] AND (“Long QT Syndrome”[MeSH] OR “Torsades de Pointes”[MeSH])) OR (((torsade[ti] OR torsadegenic[ti] OR torsades[ti] OR torsadogenesis[ti] OR torsadogenic[ti] OR torsadogenicity[ti]) OR qt[ti]) AND erythromycin[ti]). We searched EMBASE and Cochrane only for case reports. Only human studies were included. We also reviewed reports from our files and reference lists. This process yielded a total of 29 cases as shown in Table 1. (A more detailed case narrative appears in Online Appendix A.) Titles and abstracts were independently reviewed by two investigators (WVRV and AB). Disagreement was resolved by consensus. Assessment of causality was estimated using the ‘Naranjo’ scale for estimating probability of adverse drug reactions [Naranjo et al. 1981] and also the ‘WHO-UMC’ system for standardized case causality assessment (see http://who-umc.org/Graphics/24734.pdf).

Results

We found 29 cases (22 women and 7 men; see Table 1) all of which involved adults (age range 18–95 years; mean 57.5 years [ ± 3.9 standard error of the mean (SEM)], median 59 years, 22 of 29 cases were in individuals older than 40). The reports ranged from 1984 to 2006, with no reports subsequent to 2006 matching our search criteria. Among the 24 cases with both reported erythromycin dose and concurrent QTc interval measurement, we found no statistically significant relationship between erythromycin dose and QTc interval duration in either parametric or non-parametric analyses (Pearson r = 0.219, p = 0.305; Spearman r = 0.108, p = 0.614). These findings did not change when cases were separated into groups according to intravenous and oral administration routes. A total of 15 cases involved IV administration (Pearson r = 0.401, p = 0.138; Spearman r = 0.324, p = 0.239), whilst nine involved oral administration (Pearson r = −0.148, p = 0.704; Spearman r = −0.236, p = 0.552). Major risk factors were female sex (22 cases), heart disease (19 cases) and elderly (13 cases). In 11 cases, patients received other drugs that were either substrates for or inhibitors of CYP3A4, whilst concomitant administration of other QT interval prolonging drug was present in 10 cases. Only seven cases contained evidence of clear renal or hepatic disease/dysfunction. Hypokalemia was found in three cases and hypomagnesemia in 1. Unsurprisingly, given the clinical indications for erythromycin use, all patients had an acute medical illness, whilst 23 of the 29 cases also had a chronic illness (further details are available in the detailed narrative of the case reports in Online Appendix A). We categorized overall severity of illness according to patient management: 1+ representing management as an outpatient; 2+ requiring hospitalization; 3+ requiring admission to ICU and/or careful cardiac monitoring; 4+ requiring some aspect of life support other than cardioversion. A total of 17 cases exhibited illness severity 3+ and the remaining 12 exhibited illness severity 4+. Of the cases for which both QT interval and dose information are available, all possessed at least one risk factor additional to erythromycin treatment and many cases possessed multiple risk factors. One case (#21), reporting polymorphic VT with a QTc interval at the lower end of the normal range (320 ms), exhibited none of the additional tabulated risk factors except for the presence of both acute and chronic illness. Causality assessment according to the Naranjo scale and WHO-UMC criteria led to assessments ranging from possible to probable on the Naranjo scale and from possible to probable/likely on the WHO-UMC scale (see Table 1). It should be noted in respect of causality assessment that: (i) information for Naranjo scale questions 6–9 was seldom present, limiting appropriate application of the scale criteria; (ii) identifying alternate causes, which can lessen the overall score, is open to subjective opinion; and (iii) assessment of ‘certainty’ of adverse effect can benefit from a formal challenge–dechallenge–rechallenge protocol, which may not be possible or desirable to apply systematically in a setting where a potentially life-threatening arrhythmia has occurred. It is notable, however, that appearance of QTc prolongation/TdP was identifiably coincident with intravenous erythromycin administration in some cases (see narratives for cases #6 and #9 in Online Appendix A).

Discussion

Erythromycin and surrogate markers of TdP

Drug-induced TdP is a comparatively rare, albeit serious, side effect and consequently proxy (surrogate) markers are used to evaluate TdP risk. hERG block is a key preclinical surrogate, though an insufficient predictor of arrhythmia on its own [Hancox et al. 2008; Gintant, 2008]. QTc prolongation is also clearly a marker of arrhythmia rather than arrhythmia per se. The delayed repolarization resulting from pharmacological hERG/IKr inhibition is commonly considered to be linked to TdP through cellular EADs (as an arrhythmia trigger) and exacerbation of transmural dispersion of repolarization (as a substrate for re-entrant arrhythmia). For more in-depth consideration of drug-induced TdP mechanisms the reader is referred to Yap and Camm [Yap and Camm, 2003], Hancox and colleagues [Hancox et al. 2008], and Gintant [Gintant, 2008].

Drug-induced TdP is difficult to predict on an individual basis, but QTc prolongation is most commonly associated with arrhythmia at QTc intervals of >500 ms or more [Bednar et al. 2001; Yap and Camm, 2003]. Of the 29 cases examined here (Table 1), QTc interval data are available for 26: of these, only one case had a QTc interval of <500 ms and 16 cases had QTc intervals of 600 ms or greater. This is in broad agreement with an earlier review of eight cases of TdP with erythromycin found patients had QTc intervals between ∼560 ms and 700 ms [Gitler et al. 1994]. The lack of a clear correlation between erythromycin dose and QTc interval in our analysis is suggestive that, in the setting of patients experiencing erythromycin-induced arrhythmia, drug dose alone is not strongly predictive of outcome.

Erythromycin-induced TdP as a ‘multiple hit’ phenomenon

As drug-induced TdP is an infrequent occurrence, it is most likely to occur when multiple ‘hits’ coincide to precipitate arrhythmia induction [Keating and Sanguinetti, 2001]. In the setting of administration of a hERG/IKr blocking drug, the other ‘hits’ either exacerbate the IKr/hERG-blocking effects of the drug or otherwise diminish ventricular repolarization reserve [Kannankeril and Roden, 2007]. Yap and Camm [Yap and Camm, 2003] have noted the following factors that are likely to increase prolongation of ventricular repolarization or TdP liability: organic heart disease; metabolic (including electrolyte) abnormalities; hepatic impairment; drug related factors (including narrow therapeutic index and effects on cytochrome P450); female sex. In a study of 249 patients who experienced TdP with noncardiac drugs, Zeltser and colleagues identified a number of risk factors of which female sex was the strongest (71% of patients) [Zeltser et al. 2003]. Heart disease was seen in 41% of patients and was particularly prevalent in those with TdP from antibiotics. A total of 39% of patients received coadministration of two or more drugs associated with QTc prolongation. A total of ∼18% of patients had a familial history of long QT syndrome, of prior TdP, or a prolonged QT segment of the ECG in the absence of drugs. Electrolyte abnormalities were also present in a proportion of cases. More than 70% of patients had two or more concurrent risk factors [Zeltser et al. 2003]. In 2002, Shaffer and colleagues examined risk factors in reports of TdP associated with macrolide use, from the FDA’s adverse event reporting system (AERS) [Shaffer et al. 2002]. A total of 53% of the 156 reports examined involved erythromycin (with 36% and 11% involving clarithromycin and azithromycin). Two-thirds of macrolide-only cases involved women and 37% of macrolide only reports involved concomitant cardiac disease [Shaffer et al. 2002]. A 2004 analysis of 25 reports of TdP with erythromycin also highlighted female sex (68% of cases) and presence of underlying cardiovascular disease (16 of 21 reports for which information was available) [Owens, 2004]. A subsequent study of reports of TdP in 78 patients with antibiotics found 66.7% of all patients to be women, also identifying advanced heart disease and concomitant use of other QT-prolonging agents or inhibitors of hepatic drug metabolism to be frequently present [Justo and Zeltser, 2006].

The present case report analysis is in good qualitative agreement with these prior analyses, particularly in respect of prevalence of female sex, which in our analysis accounted for ∼76% (22/29) of cases. Female preponderance of drug-induced TdP is likely linked to well-established sex differences in ventricular repolarization and in the underlying ionic currents [Abi-Gerges et al. 2004; James et al. 2007]. Our analysis in respect of concurrent heart disease (19/29, ∼66%) is also in agreement with, though gives a greater incidence of presence of heart disease than, those reported in some previous analyses [Zeltser et al. 2003; Shaffer et al. 2002], though not others [Owens, 2004]. Impaired hepatic function or concomitant receipt of other drugs that are substrates for or inhibitors of CYP3A4 (∼38% of cases) are significant in that impaired metabolism is likely to lead to increased erythromycin levels, whilst coadministration with other QT prolonging drugs is likely to lead to synergistic effects on hERG/IKr [Hancox et al. 2008]. Class Ia hERG-blocking antiarrhythmic drugs (quinidine/disopyramide) were present in four cases, whilst terfenadine and cisapride, both of which have strongly been associated with hERG block and TdP, were present in three. Pentamidine was present in one case and, whilst this drug does not produce acute IKr/hERG inhibition it impairs hERG trafficking and, thereby, the number of functional IKr channels in the cell membrane [Kuryshev et al. 2005]. One of the longest QTc intervals (case #22; 700 ms) involved coadministration with astemizole, which is one of the most potent hERG blocking drugs thus far identified (IC50 ∼ 1 nM) [Zhou et al. 1999]. Whilst impaired renal function was identified in several cases (Table 1), as renal clearance of erythromycin is small it is unclear whether or not impaired renal function would greatly exacerbate risk.

A role for illness severity?

A striking feature of the cases examined here is that all patients had serious illness (illness severity 3+ or 4+; Table 1 and Online Appendix A). This raises a question as to whether or not illness severity may be a factor in the development of erythromycin-linked acquired long QT syndrome? The recent ‘QT in Practice’ (QTIP) study examined the incidence of QTc interval prolongation in the critical care setting and found episodes of QTc prolongation to >500 ms of 15 minutes or more in 252 of 1039 patients studied (24%) [Pickham et al. 2012]. More women than men developed QT prolongation and significant predictors were female sex, administration of QT-prolonging drugs, cerebrovascular incident, hypertension, thyroid disease, diabetes, renal disease, hepatic disease, electrolyte and creatinine abnormalities. Patients with QT prolongation were ‘overrepresented in hospital deaths’ which was ‘attributable to greater illness severity and existing comorbidities’ [Pickham et al. 2012]. An independent study has recently considered factors influencing mortality in patients in an ICU setting receiving antibiotic therapy for severe bacterial infection [Suefke et al. 2012]. When illness severity and antibiotic effect was comparable, survival of women was significantly linked to use of QTc-prolonging drugs, age, and lower body weight. Women with at least two of these factors fared less well than men. The results raise for consideration the issue as to whether or not in such settings QTc-prolonging antibiotics should be replaced in elderly women of low (lean) bodyweight [Suefke et al. 2012]. Whilst these recent studies do not prove a causal link between illness severity and QTc prolongation/TdP, they are suggestive of an association between illness severity and a poorer outcome, which in the setting of erythromycin therapy may exacerbate the drug’s QT-prolonging effect. The mechanism(s) underlying such an association remain to be established, although it is tempting to speculate that increased hERG-block and AP prolongation by erythromycin reported at pyrexic temperatures [Guo et al. 2005] could be one contributing factor.

Limitations and strengths of approach

Multiple regression analysis is frequently used to evaluate the effects of more than one independent variable on a dependent variable. However, the assumption is that neither the independent variables nor the dependent variable undergo change in the course of analysis. In the ICU, independent and dependent characterization may change from moment to moment. We believe that risk factors associated with drug-induced QTc interval prolongation and TdP may change dynamically and interact in a nonlinear fashion [Vieweg et al. 2012, 2013a, 2013b; Kogut et al. 2013; Hancox et al. 2013]. We therefore suspect that nonlinear dynamics may best describe the interaction of drug-linked QTc interval prolongation and attendant risk factors to produce TdP. At present, we do not have a mathematical approximation of this linkage and must struggle with the clinical setting and risk factors identified from case reports to best understand the potentially fatal cardiac arrhythmia TdP [Vieweg et al. 2012, 2013a, 2013b; Kogut et al. 2013; Hancox et al. 2013]. The use of case reports is, however, subject to some limitations. First, plasma drug concentrations at time of TdP are not universally available making attractive an analysis based on administered drug dose. Nonetheless, it must be acknowledged that overall drug dose is not necessarily equivalent to subsequent plasma concentration. In this regard, a recent review of antibiotic-induced arrhythmias has highlighted that oral administration of recommended doses of erythromycin is unlikely to lead to drug levels sufficient to produce significant IKr/hERG blockade, but that rapid IV administration can produce high plasma levels [Abo-Salem et al. 2014] which, by extension, would be anticipated to produce a greater effect on IKr/hERG and thereby repolarization and QTc interval [Abo-Salem et al. 2014]. Second, due to the fact that fatalities are not always reported, the evaluation of case reports may be subject to the selection bias inherent in publication of case reports. Third, case reporting can be inconsistent between studies and so, as highlighted recently [Selvaraj et al. 2013], the utility of case reports for identifying adverse events would be improved through the use of standardized checklists for reporting, which would include a variety of information incorporating consideration of dechallenge/rechallenge (or their absence) and laboratory results including serum drug levels (for further discussion see Selvaraj and colleagues [Selvaraj et al. 2013]). Fourth, because drug-induced TdP is a relatively rare event the number of case reports for given drugs is limited and so the results of case study analysis must only be extrapolated to populations with caution. Thus, large group as well as case studies are required in order to gain an overall picture of QTc prolongation with particular drugs. Whilst large cohort analysis and ‘thorough QT’ studies on healthy volunteers can yield useful information on frequency and extent of QTc prolongation with particular drugs, they are insufficient on their own as they necessarily focus on an arrhythmia surrogate rather than TdP itself. In this regard, case studies provide important information.

Comparison with clarithromycin and azithromycin

Whilst the present study is limited to the evaluation of 29 case reports with erythromycin, there is good concordance between its findings and the results of recent analyses of case reports with other macrolide agents (azithromycin and clarithromycin) that we have conducted [Hancox et al. 2013; Vieweg et al. 2013a; Gysel et al. 2013]. For both azithromycin and clarithromycin there was no significant correlation between administered drug dose and QTc interval of the cases examined, whilst female sex, old age and heart disease were identified as major risk factors [Hancox et al. 2013; Vieweg et al. 2013a]. The present evaluation of erythromycin complements well these recent studies, whilst further identifying illness severity as a factor in the case of erythromycin. A question arises as to whether any of these drugs may be associated with a lower risk than the others of arrhythmia. The limited number of available case reports that we have evaluated (29 in the present study, 12 for azithromycin [Hancox et al. 2013], and 21 for clarithromycin [Vieweg et al. 2013]) and broad similarity in identified risk factors for the different drugs make us reluctant to speculate in this regard. Azithromycin has received a great deal of interest recently, however, following a high-profile study that showed a small but significantly increased risk of cardiovascular deaths during 5 days of azithromycin therapy [Ray et al. 2012]. A recent data-mining study of the FDA AERS over the 8-year period from 2004 to 2011 [Raschi et al. 2013] has reported more cases of TdP and QT interval abnormalities with azithromycin than for either clarithromycin or erythromycin. When VA and SCD were also taken into account, clarithromycin had a higher number of reports than azithromycin, with erythromycin having fewer reports than either other drug during this period [Raschi et al. 2013]. Moreover, whilst erythromycin showed disproportionality with respect to TdP/QT abnormalities, azithromycin and clarithryomycin showed disproportionality both with respect to TdP/QT abnormalities and for VA/SCD [Raschi et al. 2013]. Notably, in this AERS analysis many cases of TdP/QT abnormalities with azithromycin occurred in middle-aged rather than elderly individuals, supporting the notion that azithromycin is not necessarily a safer macrolide option in generally healthy patients [Raschi et al. 2013]. On the other hand, a separate analysis of a national Danish cohort of 18–64 years of age failed to find an increased risk of death from cardiovascular causes with azithromycin use [Svanström et al. 2013]. In considering the risk with azithromycin, Giudicessi and Ackerman [Giudicessi and Ackerman, 2013] have noted that the exposure (prescription) rates differ between drugs with that for azithromycin being higher; they also noted limitations with the AERS that complicate reliable comparison between the different macrolides. They concluded with respect to azithromycin-related risk for cardiovascular events that ‘for most otherwise-healthy patients the absolute risk is miniscule’ [Giudicessi and Ackerman, 2013]. Moreover, in a recent independent analysis of azithromycin, Howard has concluded that in the absence of complications or additional risk factors (including female sex, old age, existing cardiovascular disease, and other known risk factors for QTc prolongation), azithromycin is relatively safe, although suggesting that in cases of serious infection in a hospital setting, a baseline ECG should be obtained and electrolytes kept within the normal range [Howard, 2013].

Conclusion

Erythromycin is an effective and widely used antibiotic and QT interval prolongation and cardiac arrhythmia is a rare side effect. Our analysis of the available case report literature suggests that cases of marked QTc prolongation and TdP in adults receiving the drug occur predominantly, although not exclusively, in middle-aged and older adults. Major identified risk factors are female sex, old age, and presence of heart disease. Other risks include concomitant administration of drugs that impair erythromycin metabolism or that are associated with QTc prolongation in their own right. Coadministration of erythromycin with such agents should be avoided. In all cases examined here, patients were severely ill. It is therefore reasonable to suggest that erythromycin should be administered with great caution to severely ill patients with concomitant risk factors for QTc prolongation, particularly elderly females and those with heart disease. For severely ill patients in a hospital setting, it would certainly be advisable to take a baseline ECG prior to considering administration of erythromycin, to correct any modifiable risk factors such as electrolyte abnormalities and to repeat ECG monitoring during erythromycin administration, should it be given. The administration of alternative antibiotics free of QTc prolonging effects may be worth considering for severely ill individuals.

Acknowledgment

All authors acknowledge the inspiration provided by W Victor Vieweg, who instigated this paper and passed away whilst it was in preparation.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. JCH acknowledges support of his hERG pharmacology research by the British Heart Foundation and Heart Research UK.

Conflict of interest statement

The authors have no conflicts of interest to declare.

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