Trimethoprim and sudden death in patients over 65 years with urinary tract infection

Date of ISAC Approval: 
29/07/2016
Lay Summary: 
A previous study found that older patients given a combination antibiotic containing trimethoprim had a higher risk of sudden death than those who received a different class of antibiotic. However, this result may be due to the second antibiotic in the combination drug (sulfamethoxazole) rather than the trimethoprim, or may be because the combination antibiotic was used for patients with more severe infections than the antibiotics it was compared with. We will investigate this by looking at the association between treatment with trimethoprim and sudden death. To check whether any difference we see in the amount of sudden death in those on trimethoprim compared to other antibiotics is due to infection severity, we will investigate the association between trimethoprim and sudden death in patients treated for the same type of infection (urinary tract infection). It has been suggested that if trimethoprim does cause sudden death, this is because it also causes high potassium levels or sudden decrease in kidney function. Therefore we will also investigate the association between the type of antibiotic treatment and these other outcomes. The results will help in forming guidelines for treatment of infections in people who are at high risk of these outcomes.
Technical Summary: 
We aim to investigate the association between trimethoprim and sudden death. We will identify a cohort of all patients over 65 during the period April 1997 to September 2015. To test whether trimethoprim is associated with sudden death, we will use logistic regression, adjusting for potential confounders, to estimate the odds ratio of sudden death following antibiotic prescription for trimethoprim compared to amoxicillin, nitrofurantoin, ciprofloxacin, or cefalexin. To limit confounding by antibiotic indication we will restrict the analysis to patients with antibiotic prescription for urinary tract infection. We will also examine whether diabetes mellitus, and ACEI/ARB or potassium-sparing diuretic therapy, modify the effect of trimethoprim on sudden death. We will investigate acute kidney injury and hyperkalaemia (proposed as causal mechanisms for sudden death in this context) as secondary outcomes. We will examine the robustness of our results through sensitivity analyses. In a further analysis we will use propensity scores to ensure exposure groups are comparable.
Health Outcomes to be Measured: 
Death within 14 days of antibiotic exposure Hospitalisation for acute kidney injury (AKI) Hyperkalaemia
Collaborators: 

Dr Laurie Tomlinson - Chief Investigator - London School of Hygiene & Tropical Medicine (LSHTM)
Adrian Root - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Clemence Leyrat - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Dr Dorothea Nitsch - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Elizabeth Crellin - Corresponding Applicant - CPRD
Elizabeth Williamson - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Ian Douglas - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Kate (Kathryn) Mansfield - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Professor Liam Smeeth - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Pascal Frey - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Pascal Frey - Researcher - London School of Hygiene & Tropical Medicine (LSHTM)
Timo Smieszek - Collaborator - NOAA - National Oceanic and Atmospheric Administration
Timo Smieszek - Researcher - NOAA - National Oceanic and Atmospheric Administration

Linkages: 
HES Admitted;ONS;Patient IMD;Practice IMD (Standard)