Azithromycin: more lethal than chloramphenicol?

Azithromycin: more lethal than chloramphenicol?
Ivan Stratov A,C, Justin Denholm B and Stephen J. Kent A ADepartment of Microbiology and Immunology, University of Melbourne, Melbourne, Vic. 3010, Australia.
BVictorian Infectious Diseases Service, Royal Melbourne Hospital, and Department of Medicine, University of Melbourne, Parkville, Vic. 3010, Australia.
Abstract. Azithromycin is commonly used in sexual health and respiratory medicine, often when the diagnosis is
presumptive. A recent article by Ray et al. reported that 1 out of 20 000 courses of low-dose azithromycin was associated
with (sudden) cardiovascular death (including 1 out of 4000 courses in high-risk cardiovascular patients), ascribing these
deaths to azithromycin itself. Here, we critique the actual study and examine conflicting data from randomised control
trials, animal studies and observational data.
Additional keywords: cardiovascular health, drugs, mortality rate, presumptive diagnosis.
Received 7 August 2012, accepted 18 November 2012, published online 1 March 2013 Introduction
azithromycin, presumably the standard Z-Pak (Pfizer; 500 mg Azithromycin is commonly used in sexual health medicine. The on day 1, then 250 mg on days 2–5; a total of 1.5 g; peak serum Melbourne Sexual Health Centre has dispensed over 24 700 concentration: 0.31–0.41 mg L–1,although results would prescriptions for azithromycin to ambulatory patients since 2004 reasonably apply to chlamydia treatment doses (1 g stat; (including 4069 in 2012), primarily to treat nongonococcal peak serum concentration 0.82–1.07 mg L–1,) used by urethritis, although an azithromycin responsive organism sexual health physicians, as the authors discuss a potential (e.g. Chlamydia trachomatis or Mycoplasma genitalium) is only confirmed in ~30% of such Furthermore, concentrations and the risk of cardiovascular death.,The authors build a narrative around cardiac arrhythmia and clinicians have not assessed, a practice used extensively torsades de pointes (TdP) stating: ‘Our study was prompted internationally and supported by randomised control trials.
by evidence that azithromycin is pro-arrhythmic. . .’ Seven case However, a recent report by Ray et al. indicated oral reports (none of which resulted in death) are cited with disparate azithromycin resulted in 47 additional acute cardiovascular ndings: QT prolongation with no TdP, QT prolongation with (mostly sudden) deaths per million courses.The death rate TdP and TdP without QT In five cases, the (1 out of 21 277 courses) exceeds that ascribed to high-dose oral cumulative dose was 1 g or less, one case occurred at day 7 (total: chloramphenicol (1 out of 21 671),now essentially abandoned 3.5 g azithromycin) and one case was in a foreign language.
because of toxicity. Alarmingly, the death rate amongst high- Issues such as sepsis, concurrent use of proarrhythmic drugs, risk cardiovascular patients was five-fold higher, and estimated hypokalaemia, congenital QT prolongation and underlying at 245 excess cardiovascular deaths per million courses or 1 out cardiomyopathy and dysrhythmia, however, confound the of 4082 patients, with confidence limits stretching to 1 out of 1736 courses. On face value, this should be of great concern to similarities suggestive of plagiarism, partially undermining sexual health physicians. However, we suggest caution be the basis upon which the study was predicated (this issue has exercised interpreting their findings, based on a critique of been brought to the attention of the relevant journal). For the published report, and conflicting evidence arising from example, Matsunaga et al. in described the following multiple randomised control trials, animal data, observational studies and extensive clinical experience. Given the potential ‘Upon presentation, the patients blood impact of the association, we feel it appropriate to detail some of pressure was 126/72 mmHg, heart rate 90 bpm, respiratory rate 26 pm, temperature38.1C, and SpO2 was 93% on room air. He Basis for the study
had left basal crackles but no signs of right The lead author has published numerous articles investigating ventricular failure. Chest X-ray revealed new the relationships between medications and sudden cardiac left basal opacity. White blood cell count was death.The current article studied 5-day courses of oral 16.1/mm3, 93% of which were neutrophils. Arterial blood gas showed pH of 7.49, pCO2 35, category) was not actually associated with prolonged QTc pO2 61, HCO3 26, SaO2 93% on room air.’ intervals (36% v. 31%, P = 0.18). Rather, QTc prolongationwas associated with sepsis, among other things (P = 0.001).
Russo et al. in described their patient with exactly the Thus, azithromycin may be a surrogate marker for sepsis- induced arrhythmia, rather than the cause. Significantly, no ‘Upon presentation, the patients blood episode of TdP occurred among these 251 high-risk cardiac pressure was 126/72 mmHg, heart rate 90 patients admitted with prolonged QTc, despite comorbidities bpm, respiratory rate 26 pm, temperature including hypokalaemia, hypomagnesaemia, sepsis and ongoing 38.1C, and SpO2 was 93% at room air. He use of QT-prolonging drugs. Further, a prospective study of 47 presented left basal crackles but no signs of healthy adults taking azithromycin (3 g over 5 days) found no right ventricular failure. Chest X-ray revealed significant increase in the QTc At the maximal limits new left basal opacity. White blood cell count of these observations, the following theoretical mathematical was 16.1/mm3, 93% of which were neutrophils. progression could be formulated: (a) 1 in 50 patients on Arterial blood gas showed pH of 7.49, pCO2 35 azithromycin get prolonged QTc, (b) 1 in 250 patients with mmHg, pO2 61 mmHg, HCO3 26 mmol/L, SaO2 prolonged QTc get TdP and (c) 1 in 20 patients with TdP progress to sudden death. Hence, it would take at least250 000 courses of azithromycin to get one sudden death, To our knowledge, there is only one report of arrhythmic death more than ten-fold above that reported by Ray et al.
associated with azithromycin (anoxic brain injury afterventricular tachycardia);the patient was hypokalaemic and Clinical experience
it was not clear if the patient actually took the prescribedazithromycin.
High-dose IV azithromycin is extensively used in monitoredintensive care unit patients with multiple comorbidities where Randomised control trials
potentially lethal ventricular arrhythmias (including TdP) shouldbe more common than in community settings. Considering that Importantly, Ray et al. do not discuss six randomised placebo- very few episodes of TdP (perhaps 1 in 20) result in the controlled trials in high-risk cardiovascular patients, all showing data from Ray et al. suggest that ~1 in 1000 patients prescribed that azithromycin reduced mortality (albeit nonsignificantly, azithromycin would develop TdP, and ~1 in 200 high-risk odds ratio: including sudden death.The largest cardiovascular patients. It seems likely that this would have (WIZARD) utilising azithromycin at a dosage of been observed and reported more widely in routine azithromycin 1800 mg over 3 days, followed by 600 mg azithromycin weekly for 11 weeks, indicated the benefit was greatest early(a 30% reduction in mortality and recurrent acute myocardial Critique of the study by Ray et al
infarction; P < 0.05) and favoured those patients with the highestongoing cardiovascular risk: smokers, males and diabetics. The Several problems relating to the study design should be compromised by the 25% error rate acknowledged by theauthors, Mammalian studies
developed and validated in-house.The use of International In at least four mammalian models, TdP could not be induced Classification of Diseases 9 (ICD9) codes 798.2 (‘unexplained’ by azithromycin,–despite specific efforts to do so death), 798.8 (‘unattended’ death) and 799.9 (‘unknown’ death) including supratherapeutic high-dose intravenous infusions, raises doubts over the exact nature of the deaths. Given that there coadministration of chloroquine and use of experimental were only 112 cardiovascular deaths across the three main atrioventricular block and hypokalaemia. Indeed, Milberg cohorts (azithromycin 29, amoxicillin 42 and null group 41), et al. characterised a mechanism that potentially explains physician review of deaths seems feasible, making the data more why azithromycin did not induce TdP even in the presence robust and helping to mitigate concerns raised by researchers about the accuracy of ‘validation’ committees.,Second, it azithromycin actually suppressed TdP previously provoked seems unavoidable (given the large size of the cohorts) to assign ‘presumptive’ diagnoses, for which antibiotics were prescribedbased on (1) a predetermined algorithm of ‘likely’ diagnoses and(2) recent Medicaid encounters. However, the data would be Observational cohort data
more reliable if the authors had excluded the ~30% of encounters The issue of drug induced corrected QT (QTc) prolongation (over 720 000 instances) where clinical data were absent and no leading to TdP is the subject of anecdotal case reports and long antibiotic indication could be assigned, primarily due to lists of implicated drugs have been compiled from adverse drug telephone prescribing. Exhaustive propensity scoring for reaction reports, with an ascribed mortality of A underlying comorbidities cannot adequately compensate for prospective 12-month observational study reported that 251 out of 900 patients admitted to advanced cardiac units had respiratory rate and blood pressure. This is underscored by a prolonged QTc Interestingly, the use of ‘QT- higher rate of respiratory pathology (bronchitis, pneumonia, prolonging medication’ (azithromycin was included in that respiratory symptoms, chronic obstructive pulmonary disease Azithromycin – more lethal than chloramphenicol? and other respiratory problem) among patients prescribed Conflicts of interest
azithromycin (44.9%) compared with amoxicillin (27.4%), the clinical import of which is acknowledged by the authorsand substantiated by higher use of b-agonists (themselves Acknowledgements
implicated in sudden cardiac With propensityscoring adjustment, respiratory pathology is calculated at We thank Ms C Forrester and Dr G Flaker for helpful contributions.
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