CSIRO PUBLISHING

Sexual Health
http://dx.doi.org/10.1071/SH12128

LetterAzithromycin: more lethal than chloramphenicol?
Ivan Stratov A,C, Justin Denholm B and Stephen J. Kent A
A

Department of Microbiology and Immunology, University of Melbourne, Melbourne, Vic. 3010, Australia.
Victorian Infectious Diseases Service, Royal Melbourne Hospital, and Department of Medicine, University of
Melbourne, Parkville, Vic. 3010, Australia.
C
Corresponding author. Email: stratovi@unimelb.edu.au
B

Abstract. Azithromycin is commonly used in sexual health and respiratory medicine, often when the diagnosis ispresumptive. A recent article by Ray et al. reported that 1 out of 20 000 courses of low-dose azithromycin was associatedwith (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 is commonly used in sexual health medicine. The
Melbourne Sexual Health Centre has dispensed over 24 700
prescriptions for azithromycin to ambulatory patients since 2004
(including 4069 in 2012), primarily to treat nongonococcal
urethritis, although an azithromycin responsive organism(e.g. Chlamydia trachomatis or Mycoplasma genitalium) is
only conﬁrmed in ~30% of such patients.1 Furthermore,azithromycin is prescribed for sexual contacts whomclinicians have not assessed, a practice used extensively
internationally and supported by randomised control trials.2
However, a recent report by Ray et al. indicated oralazithromycin resulted in 47 additional acute cardiovascular(mostly sudden) deaths per million courses.3 The death rate
(1 out of 21 277 courses) exceeds that ascribed to high-dose oral
chloramphenicol (1 out of 21 671),4 now essentially abandoned
because of toxicity. Alarmingly, the death rate amongst highrisk cardiovascular patients was ﬁve-fold higher, and estimatedat 245 excess cardiovascular deaths per million courses or 1 outof 4082 patients, with conﬁdence limits stretching to 1 out of
1736 courses. On face value, this should be of great concern tosexual health physicians. However, we suggest caution be
exercised interpreting their ﬁndings, based on a critique ofthe published report, and conﬂicting evidence arising frommultiple randomised control trials, animal data, observational
studies and extensive clinical experience. Given the potential
impact of the association, we feel it appropriate to detail some ofthese issues here.
Basis for the study
The lead author has published numerous articles investigating
the relationships between medications and sudden cardiac
death.5–10 The current article studied 5-day courses of oral
Journal compilation  CSIRO 2013azithromycin, presumably the standard Z-Pak (Pﬁzer; 500 mg
on day 1, then 250 mg on days 2–5; a total of 1.5 g; peak serum
concentration: 0.31–0.41 mg L–111,12), although results would
reasonably apply to chlamydia treatment doses (1 g stat;peak serum concentration 0.82–1.07 mg L–113,14) used bysexual health physicians, as the authors discuss a potential
link between azithromycin serum (rather than tissue)
concentrations and the risk of cardiovascular death.15,16 The
authors build a narrative around cardiac arrhythmia andtorsades de pointes (TdP) stating: ‘Our study was promptedby evidence that azithromycin is pro-arrhythmic. . .’ Seven casereports (none of which resulted in death) are cited with disparateﬁndings: QT prolongation with no TdP, QT prolongation with
TdP and TdP without QT prolongation.17–23 In ﬁve cases, thecumulative dose was 1 g or less, one case occurred at day 7 (total:
3.5 g azithromycin) and one case was in a foreign language.
Issues such as sepsis, concurrent use of proarrhythmic drugs,
hypokalaemia, congenital QT prolongation and underlying
cardiomyopathy and dysrhythmia, however, confound thecases. Two citations21,22 have striking word-for-wordsimilarities suggestive of plagiarism, partially undermining
the basis upon which the study was predicated (this issue has
been brought to the attention of the relevant journal). For
example, Matsunaga et al. in 200321 described the following
clinical picture:‘Upon presentation, the patient’s bloodpressure was 126/72 mmHg, heart rate 90
bpm, respiratory rate 26 pm, temperature
38.1C, and SpO2 was 93% on room air. He
had left basal crackles but no signs of rightventricular failure. Chest X-ray revealed newleft basal opacity. White blood cell count was
16.1/mm3, 93% of which were neutrophils.
www.publish.csiro.au/journals/sh

BSexual Health

Arterial blood gas showed pH of 7.49, pCO2 35,
pO2 61, HCO3 26, SaO2 93% on room air.’
Russo et al. in 200622 described their patient with exactly thesame parameters:‘Upon presentation, the patient’s bloodpressure was 126/72 mmHg, heart rate 90
bpm, respiratory rate 26 pm, temperature
38.1C, and SpO2 was 93% at room air. He
presented left basal crackles but no signs ofright ventricular failure. Chest X-ray revealed
new left basal opacity. White blood cell countwas 16.1/mm3, 93% of which were neutrophils.
Arterial blood gas showed pH of 7.49, pCO2 35
mmHg, pO2 61 mmHg, HCO3 26 mmol/L, SaO2
93% at room air.’
To our knowledge, there is only one report of arrhythmic deathassociated with azithromycin (anoxic brain injury after
ventricular tachycardia);24 the patient was hypokalaemic andit was not clear if the patient actually took the prescribedazithromycin.
Randomised control trials
Importantly, Ray et al. do not discuss six randomised placebocontrolled trials in high-risk cardiovascular patients, all showingthat azithromycin reduced mortality (albeit nonsigniﬁcantly,
odds ratio: 0.9125), including sudden death.26–31 The largest(WIZARD) trial,30 utilising azithromycin at a dosage of1800 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
infarction; P < 0.05) and favoured those patients with the highest
ongoing cardiovascular risk: smokers, males and diabetics. The
SPACE trial showed a similar trend.32
Mammalian studies
In at least four mammalian models, TdP could not be inducedby azithromycin,33–36 despite speciﬁc efforts to do so
including supratherapeutic high-dose intravenous infusions,coadministration of chloroquine and use of experimental
atrioventricular block and hypokalaemia. Indeed, Milberg
et al. characterised a mechanism that potentially explains
why azithromycin did not induce TdP even in the presenceof QT prolongation, and further demonstrated thatazithromycin actually suppressed TdP previously provokedby erythromycin.34
Observational cohort data
The issue of drug induced corrected QT (QTc) prolongation
leading to TdP is the subject of anecdotal case reports and longlists of implicated drugs have been compiled from adverse drug
reaction reports, with an ascribed mortality of 4.5%.37 A
prospective 12-month observational study reported that 251
out of 900 patients admitted to advanced cardiac units had
prolonged QTc intervals.38 Interestingly, the use of ‘QTprolonging medication’ (azithromycin was included in that

I. Stratov et al.

category) was not actually associated with prolonged QTcintervals (36% v. 31%, P = 0.18). Rather, QTc prolongation
was associated with sepsis, among other things (P = 0.001).
Thus, azithromycin may be a surrogate marker for sepsisinduced arrhythmia, rather than the cause. Signiﬁcantly, no
episode of TdP occurred among these 251 high-risk cardiac
patients admitted with prolonged QTc, despite comorbidities
including hypokalaemia, hypomagnesaemia, sepsis and ongoinguse of QT-prolonging drugs. Further, a prospective study of 47
healthy adults taking azithromycin (3 g over 5 days) found no
signiﬁcant increase in the QTc interval.39 At the maximal limitsof these observations, the following theoretical mathematicalprogression could be formulated: (a) 1 in 50 patients onazithromycin get prolonged QTc, (b) 1 in 250 patients withprolonged QTc get TdP and (c) 1 in 20 patients with TdP
progress to sudden death. Hence, it would take at least
250 000 courses of azithromycin to get one sudden death,more than ten-fold above that reported by Ray et al.
Clinical experience
High-dose IV azithromycin is extensively used in monitored
intensive care unit patients with multiple comorbidities where
potentially lethal ventricular arrhythmias (including TdP) should
be more common than in community settings. Considering thatvery few episodes of TdP (perhaps 1 in 20) result in death,37 thedata from Ray et al. suggest that ~1 in 1000 patients prescribedazithromycin would develop TdP, and ~1 in 200 high-risk
cardiovascular patients. It seems likely that this would havebeen observed and reported more widely in routine azithromycin
use in monitored patients.
Critique of the study by Ray et al
Several problems relating to the study design should be
addressed. First, the veracity of death certiﬁcates iscompromised by the 25% error rate acknowledged by theauthors, using a computerised veriﬁcation algorithm
developed and validated in-house.40 The use of International
Classiﬁcation of Diseases 9 (ICD9) codes 798.2 (‘unexplained’
death), 798.8 (‘unattended’ death) and 799.9 (‘unknown’ death)raises doubts over the exact nature of the deaths. Given that there
were only 112 cardiovascular deaths across the three maincohorts (azithromycin 29, amoxicillin 42 and null group 41),
physician review of deaths seems feasible, making the data morerobust and helping to mitigate concerns raised by researchers
about the accuracy of ‘validation’ committees.32,41 Second, it
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
more reliable if the authors had excluded the ~30% of encounters(over 720 000 instances) where clinical data were absent and noantibiotic indication could be assigned, primarily due totelephone prescribing. Exhaustive propensity scoring forunderlying comorbidities cannot adequately compensate forcontemporaneous clinical parameters such as fever,respiratory rate and blood pressure. This is underscored by ahigher rate of respiratory pathology (bronchitis, pneumonia,
respiratory symptoms, chronic obstructive pulmonary diseaseAzithromycin – more lethal than chloramphenicol?

and other respiratory problem) among patients prescribedazithromycin (44.9%) compared with amoxicillin (27.4%),
the clinical import of which is acknowledged by the authors
and substantiated by higher use of b-agonists (themselves
implicated in sudden cardiac death42). With propensity
scoring adjustment, respiratory pathology is calculated at
45.1% versus 44.8%, respectively. However, across suchlarge cohorts, even a small 0.3% difference accounts for over1000 high-risk respiratory patients, where some (or perhapsmost) of the 18 excess deaths (allowing for the 1 : 4 ratio) may
clearly be attributable to the underlying illness rather than theazithromycin itself. Third, one way to evaluate clinically how
well these cohorts were matched at baseline is to observe theearly noncardiovascular mortality, which presumably relates toantibiotic indication and reasonably reﬂects the severity of theillnesses for which the antibiotic was prescribed. Curiously,
during the initial 48 h, no patients in the azithromycin groupsuffered a noncardiovascular death, compared with 11 and 15
for the amoxicillin and no antibiotic groups, respectively; at
72 h, the noncardiovascular deaths were 1, 19 and 28,
respectively. Again, allowing for the 1 : 4 patient ratio, one
would expect at least three or four early azithromycin deaths
to be noncardiovascular in nature. How, then, might the data beclinically explained? It is improbable that the azithromycingroup was actually healthier than the null group at baseline,
as the groups were matched, except for antibiotic indication.
Also, it would be contentious to conclude that azithromycin
is potent enough to reduce noncardiovascular mortality soquickly, although azithromycin potency may explain theremarkably low noncardiovascular mortality seen after day 4of therapy (four azithromycin deaths v. 50 amoxicillin deaths).
Rather, the most plausible explanation for the minimal early
noncardiovascular mortality is that some of the early
cardiovascular deaths were incorrectly assigned. Fourthly, no
allowance is made for compliance, which is a major issue whenassigning adverse drug events in population-based studies.
Under research conditions, compliance with the 5-day
azithromycin z-pak is reported to be 82–93%.43,44 An
estimate of 10% noncompliance would, pro rata, reassign
three (of 29) azithromycin deaths to the null group(41 deaths), an issue that is not relevant to the amoxicillingroup, as the death rate was equal to those who took no
antibiotics. It would be interesting to know what effect a net
shift of six deaths would have on the hazard ratios. Fifthly, we
note in passing that their critical azithromycin mortality
cumulative graph (see ﬁg. 1 of Ray et al.3) appears to beincorrectly plotted – ﬂat-lining at day 5 instead of day 6.
Summary
Good science is about meticulous observation. Retrospective
research predicated on poorly scrutinised references and basedaround patient cohorts for whom antibiotic indications and thecause of death are imprecisely known is hazardous, particularly
when it contradicts prospectively collected data. We suggestthat further study of the association between azithromycin andsudden death is warranted. In the meantime, azithromycin
should be used appropriately to control sexually transmissible
diseases and other infections.

Sexual HealthC

Conﬂicts of interest
None declared.
Acknowledgements
We thank Ms C Forrester and Dr G Flaker for helpful contributions.

References
1 Bradshaw CS, Tabrizi SN, Read TR, Garland SM, Hopkins CA, Moss
LM, et al. Etiologies of nongonococcal urethritis: bacteria, viruses,
and the association with orogenital exposure. J Infect Dis 2006; 193:
336–45. doi:10.1086/499434
2 Cameron ST. Patient-delivered partner therapy for chlamydia: arealistic public health measure in the UK. BJOG 2009; 116: 345–6.
doi:10.1111/j.1471-0528.2008.01971.x
3 Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin
and the risk of cardiovascular death. N Engl J Med 2012; 366:
1881–90. doi:10.1056/NEJMoa1003833
4 Wallerstein RO, Condit PK, Kasper CK, Brown JW, Morrison FR.
Statewide study of chloramphenicol therapy and fatal aplastic anemia.
JAMA 1969; 208: 2045–50. doi:10.1001/jama.1969.03160110017004
5 Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, et al.
Risk of acute myocardial infarction and sudden cardiac death inpatients treated with cyclo-oxygenase 2 selective and non-selective
non-steroidal anti-inﬂammatory drugs: nested case–control study.
Lancet 2005; 365: 475–81.
6 Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast
PG, et al. ADHD medications and risk of serious cardiovascular eventsin young and middle-aged adults. JAMA 2011; 306: 2673–83.
doi:10.1001/jama.2011.1830
7 Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypicalantipsychotic drugs and the risk of sudden cardiac death. N Engl J
Med 2009; 360: 225–35. doi:10.1056/NEJMoa0806994
8 Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic
antidepressants and the risk of sudden cardiac death. Clin
Pharmacol Ther 2004; 75: 234–41. doi:10.1016/j.clpt.2003.09.019
9 Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT.
Antipsychotics and the risk of sudden cardiac death. Arch Gen
Psychiatry 2001; 58: 1161–7. doi:10.1001/archpsyc.58.12.1161
10 Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM.
Oral erythromycin and the risk of sudden death from cardiac causes. N
Engl J Med 2004; 351: 1089–96. doi:10.1056/NEJMoa040582
11 Pﬁzerlabs. Zithromax product information. New York: Pﬁzer Inc.;
2012.
12 Wildfeuer A, Laufen H, Leitold M, Zimmermann T. Comparison of
the pharmacokinetics of three-day and ﬁve-day regimens ofazithromycin in plasma and urine. J Antimicrob Chemother 1993;
31: 51–6.
13 Bergan T, Jorgensen NP, Olszewski W, Zhang Y. Azithromycin
pharmacokinetics and penetration to lymph. Scand J Infect Dis
Suppl 1992; 83: 15–21.
14 Höfﬂer D, Koeppe P, Paeske B. Pharmacokinetics of azithromycin innormal and impaired renal function. Infection 1995; 23: 356–61.
doi:10.1007/BF01713565
15 Schoenenberger RA, Haefeli WE, Weiss P, Ritz RF. Association of
intravenous erythromycin and potentially fatal ventricular tachycardia
with Q-T prolongation (torsades de pointes). BMJ 1990; 300: 1375–6.
doi:10.1136/bmj.300.6736.1375
16 Simkó J, Csilek A, Karaszi J, Lorincz I. Proarrhythmic potential of
antimicrobial agents. Infection 2008; 36: 194–206. doi:10.1007/
s15010-007-7211-8
17 Arellano-Rodrigo E, Garcia A, Mont L, Roque M. Torsade de pointes
and cardiorespiratory arrest induced by azithromycin in a patient withcongenital long QT syndrome. Med Clin (Barc) 2001; 117: 118–9.

D

Sexual HealthI. Stratov et al.

18 Huang BH, Wu CH, Hsia CP, Yin Chen C. Azithromycin-induced
torsade de pointes. Pacing Clin Electrophysiol 2007; 30: 1579–82.
doi:10.1111/j.1540-8159.2007.00912.x
19 Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD.
Azithromycin as a cause of QT-interval prolongation and torsadede pointes in the absence of other known precipitating factors. J
Interv Card Electrophysiol 2007; 18: 243–6. doi:10.1007/s10840007-9124-y
20 Kim MH, Berkowitz C, Trohman RG. Polymorphic ventriculartachycardia with a normal QT interval following azithromycin.
Pacing Clin Electrophysiol 2005; 28: 1221–2. doi:10.1111/j.15408159.2005.50146.x
21 Matsunaga N, Oki Y, Prigollini A. A case of QT-interval prolongation
precipitated by azithromycin. N Z Med J 2003; 116: U666.
22 Russo V, Puzio G, Siniscalchi N. Azithromycin-induced QT
prolongation in elderly patient. Acta Biomed 2006; 77: 30–2.
23 Samarendra P, Kumari S, Evans SJ, Sacchi TJ, Navarro V. QTprolongation associated with azithromycin/amiodarone combination.
Pacing Clin Electrophysiol 2001; 24: 1572–4. doi:10.1046/j.14609592.2001.01572.x
24 Del Rosario ME, Weachter R, Flaker GC. Drug-induced QT
prolongation and sudden death. Mo Med 2010; 107: 53–8.
25 Baker WL, Couch KA. Azithromycin for the secondary prevention ofcoronary artery disease: a meta-analysis. Am J Health Syst Pharm
2007; 64: 830–6. doi:10.2146/ajhp060539
26 Cercek B, Shah PK, Noc M, Zahger D, Zeymer U, Matetzky S, et al.
Effect of short-term treatment with azithromycin on recurrent
ischaemic events in patients with acute coronary syndrome in the
Azithromycin in Acute Coronary Syndrome (AZACS) trial: arandomised controlled trial. Lancet 2003; 361: 809–13.
doi:10.1016/S0140-6736(03)12706-7
27 Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB,
Cohen JD, et al. Azithromycin for the secondary prevention ofcoronary events. N Engl J Med 2005; 352: 1637–45. doi:10.1056/
NEJMoa043526
28 Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm
AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular
events, and azithromycin in male survivors of myocardial
infarction. Circulation 1997; 96: 404–7. doi:10.1161/01.CIR.96.2.
404
29 Muhlestein JB, Anderson JL, Carlquist JF, Salunkhe K, Horne BD,
Pearson RR, et al. Randomized secondary prevention trial ofazithromycin in patients with coronary artery disease: primaryclinical results of the ACADEMIC study. Circulation 2000; 102:
1755–60. doi:10.1161/01.CIR.102.15.1755
30 O’Connor CM, Dunne MW, Pfeffer MA, Muhlestein JB, Yao L,
Gupta S, et al. Azithromycin for the secondary prevention ofcoronary heart disease events: the WIZARD study: a randomized
controlled trial. JAMA 2003; 290: 1459–66. doi:10.1001/jama.290.11.
1459
31 Stone AF, Mendall MA, Kaski JC, Edger TM, Risley P, Poloniecki J,
et al. Effect of treatment for Chlamydia pneumoniae and Helicobacter
pylori on markers of inﬂammation and cardiac events in patientswith acute coronary syndromes: South Thames Trial of Antibiotics in
Myocardial Infarction and Unstable Angina (STAMINA). Circulation
2002; 106: 1219–23. doi:10.1161/01.CIR.0000027820.66786.CF

32 Vainas T, Stassen FR, Schurink GW, Tordoir JH, Welten RJ, van den
Akker LH, et al. Secondary prevention of atherosclerosis throughchlamydia pneumoniae eradication (SPACE trial): a randomised
clinical trial in patients with peripheral arterial disease. Eur J Vasc
Endovasc Surg 2005; 29: 403–11.
33 Ohtani H, Taninaka C, Hanada E, Kotaki H, Sato H, Sawada Y, et al.
Comparative pharmacodynamic analysis of Q-T interval prolongationinduced by the macrolides clarithromycin, roxithromycin, andazithromycin in rats. Antimicrob Agents Chemother 2000; 44:
2630–7. doi:10.1128/AAC.44.10.2630-2637.2000
34 Milberg P, Eckardt L, Bruns HJ, Biertz J, Ramtin S, Reinsch N, et al.
Divergent proarrhythmic potential of macrolide antibiotics despite
similar QT prolongation: fast phase 3 repolarization prevents early
afterdepolarizations and torsade de pointes. J Pharmacol Exp Ther
2002; 303: 218–25. doi:10.1124/jpet.102.037911
35 Thomsen MB, Beekman JD, Attevelt NJ, Takahara A, Sugiyama A,
Chiba K, et al. No proarrhythmic properties of the antibiotics
moxiﬂoxacin or azithromycin in anaesthetized dogs with chronicAV block. Br J Pharmacol 2006; 149: 1039–48. doi:10.1038/
sj.bjp.0706900
36 Fossa AA, Wisialowski T, Duncan JN, Deng S, Dunne M.
Azithromycin/chloroquine combination does not increase cardiac
instability despite an increase in monophasic action potential
duration in the anesthetized guinea pig. Am J Trop Med Hyg 2007;
77: 929–38.
37 Darpo B. Spectrum of drugs prolonging QT interval and the incidenceof torsades de pointes. Eur Heart J Suppl 2001; 3: K70–80.
doi:10.1016/S1520-765X(01)90009-4
38 Tisdale JE, Wroblewski HA, Overholser BR, Kingery JR, Trujillo TN,
Kovacs RJ. Prevalence of QT interval prolongation in patients
admitted to cardiac care units and frequency of subsequentadministration of QT interval-prolonging drugs: a prospective,
observational study in a large urban academic medical center in the
US. Drug Saf 2012; 35: 459–70. doi:10.2165/11598160-00000000000000
39 Strle F, Maraspin V. Is azithromycin treatment associated withprolongation of the Q-Tc interval? Wien Klin Wochenschr 2002;
114: 396–9.
40 Chung CP, Murray KT, Stein CM, Hall K, Ray WA. A computer casedeﬁnition for sudden cardiac death. Pharmacoepidemiol Drug Saf
2010; 19: 563–72. doi:10.1002/pds.1888
41 Gottlieb SS. Dead is dead – artiﬁcial deﬁnitions are no substitute.
Lancet 1997; 349: 662–3. doi:10.1016/S0140-6736(97)22010-6
42 Cazzola M, Santus P, D’Adda A, Pizzolato S, Di Marco F, Centanni S.
Acute effects of higher than standard doses of salbutamol andipratropium on tiotropium-induced bronchodilation in patients withstable COPD. Pulm Pharmacol Ther 2009; 22: 177–82. doi:10.1016/
j.pupt.2008.10.010
43 Devasia RA, Jones TF, Collier B, Schaffner W. Compliance withazithromycin versus erythromycin in the setting of a pertussis
outbreak. Am J Med Sci 2009; 337: 176–8. doi:10.1097/MAJ.
0b013e318184e72f
44 Martinez SM, Kemper CA, Haiduven D, Cody SH, Deresinski SC.
Azithromycin prophylaxis during a hospitalwide outbreak of a
pertussis-like illness. Infect Control Hosp Epidemiol 2001; 22:
781–3. doi:10.1086/501863

www.publish.csiro.au/journals/sh