Clinical Relevance of Drug–Drug Interactions With Antibiotics as Listed in a National Medication Formulary: Results From Two Large Population‐Based Case‐Control Studies in Patients Aged 65–100 Years Using Linked English Primary Care and Hospital Data

This study evaluated drug–drug interactions (DDIs) between antibiotic and nonantibiotic drugs listed with warnings of severe outcomes in the British National Formulary based on adverse drug reaction (ADR) detectable with routine International Classification of Diseases, Tenth Revision coding. Data sources were Clinical Practice Research Databank GOLD and Aurum anonymized electronic health records from English general practices linked to hospital admission records. In propensity‐matched case‐control study, outcomes were ADR or emergency admissions. Analyzed were 121,546 ADR‐related admission cases matched to 638,238 controls. For most antibiotics, adjusted odds ratios (aORs) for ADR‐related hospital admission were large (aOR for trimethoprim 4.13; 95% confidence interval (CI), 3.97–4.30). Of the 51 DDIs evaluated for ADR‐related admissions, 38 DDIs (74.5%) had statistically increased aORs of concomitant exposure compared with nonexposure (mean aOR 3.96; range 1.59–11.42); for the 89 DDIs for emergency hospital admission, the results were 75 (84.3%) and mean aOR 2.40; range 1.43–4.17. Changing reference group to single antibiotic exposure reduced aORs for concomitant exposure by 76.5% and 83.0%, respectively. Medicines listed to cause nephrotoxicity substantially increased risks that were related to number of medicines (aOR was 2.55 (95% CI, 2.46–2.64) for current use of 1 and 10.44 (95% CI, 7.36–14.81) for 3 or more medicines). In conclusion, no evidence of substantial risk was found for multiple DDIs with antibiotics despite warnings of severe outcomes in a national formulary and flagging in electronic health record software. It is proposed that the evidence base for inclusion of DDIs in national formularies be strengthened and made publicly accessible and indiscriminate flagging, which compounds alert fatigue, be reduced.