Open Access Research BMJ Open: first published as 10.1136/bmjopen-2013-002857 on 11 July 2013. Downloaded from Comparing two types of macrolide antibiotics for the purpose of assessing population-based drug interactions Jamie L Fleet,1 Salimah Z Shariff,1,2 David G Bailey,3 Sonja Gandhi,1,4 David N Juurlink,2,5,6 Danielle M Nash,1,2 Muhammad Mamdani,2,6,7 Tara Gomes,2 Amit M Patel,1 Amit X Garg1,2,4 To cite: Fleet JL, Shariff SZ, ABSTRACT et al ARTICLE SUMMARY Bailey DG, . Comparing Objective: Clarithromycin strongly inhibits enzyme two types of macrolide cytochrome P450 3A4, preventing the metabolism of antibiotics for the purpose of Article focus some other drugs, while azithromycin is a weak assessing population-based ▪ This study describes the differences in adverse drug interactions. BMJ Open inhibitor. Accordingly, blood concentrations of other outcomes when either clarithromycin or azithro- 2013;3:e002857. drugs increase with clarithromycin coprescription mycin is prescribed in the absence of interacting doi:10.1136/bmjopen-2013- leading to adverse events. These macrolide antibiotics drugs. 002857 also differ on other properties that may impact ▪ Knowledge of the underlying differences between outcomes. In this study, we compared outcomes in these two drugs is important for the interpret- ▸ Prepublication history and two groups of macrolide antibiotic users in the ation of population-based drug–drug interaction additional material for this absence of potentially interacting drugs. studies. paper is available online. To Design: Population-based retrospective cohort study. view these files please visit Setting: Ontario, Canada, from 2003 to 2010. Key messages ▪ There were no significant differences between the journal online Patients: Patients (mean 74 years) prescribed (http://dx.doi.org/10.1136/ clarithromycin and azithromycin on 12 hospital- clarithromycin (n=52 251) or azithromycin (referent bmjopen-2013-002857). isation outcomes; however, clarithromycin was group, n=46 618). associated with a slightly higher risk of all-cause Main outcomes: The primary outcomes were Received 8 March 2013 mortality. hospital admission within 30 days of a new antibiotic http://bmjopen.bmj.com/ Revised 24 May 2013 ▪ Since there is no difference between clarithromy- Accepted 14 June 2013 prescription with any of the 12 conditions examined cin and azithromycin in hospitalisation outcomes separately (acute kidney injury, acute myocardial in the absence of interacting drugs, the use of infarction, neuroimaging (proxy for delirium), azithromycin as a reference group is appropriate This final article is available hypotension, syncope, hyperkalaemia, hyponatraemia, in drug–drug interaction studies. for use under the terms of hyperglycaemia, arrhythmia, ischaemic stroke, the Creative Commons ▪ Most outcomes from drug–drug interaction gastrointestinal bleeding and sepsis). The secondary Attribution Non-Commercial studies can be attributed to the interaction rather outcome was mortality. 3.0 Licence; see than the underlying differences in these macro- http://bmjopen.bmj.com Results: The baseline characteristics of the two lide antibiotics. on September 30, 2021 by guest. Protected copyright. groups, including patient demographics, comorbid conditions, infection type and prescribing physician Strengths and limitations of this study specialty, were nearly identical. The median daily dose ▪ This is the first population-based study to was 1000 mg for clarithromycin and 300 mg for compare outcomes between clarithromycin and azithromycin and the median duration of dispensing azithromycin while excluding interacting drugs. antibiotics was 10 and 5 days, respectively. There was ▪ Our large sample size allowed greater precision no difference between the groups in the risk of around the estimates reported and is representa- hospitalisation for any condition studied (relative risk tive of the province of Ontario as a whole. ranged from 0.67 to 1.23). Compared with ▪ Further studies examining differences in all-cause azithromycin, clarithromycin was associated with a mortality between the two antibiotics as well as slightly higher risk of all-cause mortality (0.46% vs non-macrolide antibiotics are warranted. 0.37%, relative risk 1.25, 95% CI 1.03 to 1.52). Conclusions: Clarithromycin can be used to assess drug interactions in population-based studies with INTRODUCTION azithromycin serving as a control group. However, any Certain medication combinations can lead to For numbered affiliations see differences in mortality observed between the two end of article. altered pharmacokinetics that result in a antibiotic groups in the setting of other drug use may higher systemic concentration of the drugs be partially attributable to factors beyond the inhibition and accompanying greater risk of toxicity.1 Correspondence to of drug metabolising enzymes and transporters, as the The commonly used macrolide antibiotic clari- Dr Amit Garg; difference for this outcome was significant. [email protected] thromycin can inhibit the drug metabolising Fleet JL, Shariff SZ, Bailey DG, et al. BMJ Open 2013;3:e002857. doi:10.1136/bmjopen-2013-002857 1 Using macrolide antibiotics to assess drug interactions BMJ Open: first published as 10.1136/bmjopen-2013-002857 on 11 July 2013. Downloaded from enzyme cytochrome P450 3A4 (CYP3A4), as well as the databases, which are available for evaluation at the Organic Anion Transporting Polypeptide transporters 1B1 Institute for Clinical Evaluative Sciences in Ontario, (OATP1B1) and OATP1B3.2 These transporters and Canada. We conducted a population-based retrospective enzyme are present in the liver and small intestine, and cohort study using these large linked healthcare data- about half of all the medications used today are affected bases. We focused on adults over the age of 65 years, by their processes.3 These include many types of statins, given their risk of drug toxicity and the availability of – antiepileptics and antipsychotics.4 6 Interestingly, another prescription data. We conducted this study according to macrolide antibiotic, azithromycin, is prescribed for a prespecified protocol that was approved by the similar indications and in comparable patients as clarithro- research ethics board at Sunnybrook Health Sciences mycin, but unlike clarithromycin, it is only a very weak Centre (Toronto, Canada). The reporting of this study – inhibitor of this enzyme and transporters.7 9 Thus, there is followed guidelines for observational studies (detailed in a growing interest in conducting population-based studies online supplementary appendix A).17 examining two groups of individuals newly prescribed either clarithromycin or azithromycin, where all patients Data sources are also chronically using another drug, such as a statin, We ascertained drug use, covariate information and which may interact with clarithromycin.10 The outcomes outcome data using records from five administrative of the two groups can then be compared (with the azithro- databases. Outpatient prescription drug information mycin users acting as a control group) to assess the including the dispensing date, quantity of pills and outcomes attributable to the clarithromycin–statin number of days supplied is accurately recorded in the interaction.10 Ontario Drug Benefit Plan database, with an error rate However, as per the prescribing references, the two less than 1%.18 Detailed diagnosis and procedural infor- macrolide antibiotics do differ on the total daily dose mation on all inpatient hospitalisations in Ontario are and the recommended duration of therapy to treat recorded in the Canadian Institute for Health infection which may influence compliance, as a dose Information Discharge Abstract Database. Up to 25 would be more likely to be missed if taken over a longer unique diagnosis codes (ie, codes for acute kidney period of time.11 12 It is possible that these, and other injury or hyperkalaemia) can be assigned at discharge to properties of macrolide antibiotics, also impact patient each hospital stay. The Ontario Health Insurance Plan outcomes. We wanted to be assured that outcomes database contains all health claims for inpatient and out- observed in population-based drug interaction studies of patient fee-for-service physician services. The Ontario clarithromycin compared with azithromycin are most Registered Persons Database contains demographic and likely attributable to the drug interaction being studied vital statistics information on all Ontario residents who http://bmjopen.bmj.com/ rather than other inherent differences between the two have ever been issued a health card. We have previously – macrolide antibiotics.10 13 15 For example, we recently used these four databases to research adverse drug – published a study assessing statin and macrolide drug events, health outcomes and health services.19 21 The interactions, and noted that older patients coprescribed databases were complete for all variables used in this clarithromycin were more likely to be hospitalised with study. We also used the Ontario Registrar General acute kidney injury in the subsequent 30 days compared Database to assess the cause of death for patients who with older patients coprescribed azithromycin.10 died during follow-up. Observing an increase in the risk of acute kidney injury Codes used to assess comorbidities in the 5 years prior on September 30, 2021 by guest. Protected copyright. with clarithromycin versus azithromycin in the presence to the receipt of the relevant prescription