Interactions Between Antiepileptic and Antibiotic Drugs: A Systematic Review and Meta-Analysis with Dosing Implications

Abstract

Introduction: Qualitative studies on drug-drug interactions (DDIs) between anticonvulsants and antibiotics report pharmacokinetic changes that may increase the clinical risks in terms of adverse drug reactions (ADRs) and efficacy. However, no studies have provided a systematic and quantitative analysis of anticonvulsant-antibiotic pharmacokinetic DDIs. To provide such indications, we systematically and critically reviewed the literature on anticonvulsant-antibiotic DDIs in terms of quantitative pharmacokinetic changes and related ADRs. We also investigated less-known interactions for the possible occurrence of clinically relevant events.

Methods: We conducted a systematic review of all reports of DDIs between anticonvulsants and antibiotics assessing pharmacokinetic parameters published until 9 June 2017.

Results: We were able to meta-analyse the effect of macrolides on carbamazepine area under the concentration-time curve from time zero to infinity [AUC_∞] (+ 34.5 µg/mL*h, p = 0.005, n = 38), clearance (- 2.88 mL/min, p < 0.001, n = 46) and trough plasma concentration [Ct] (+ 8.0 µg/mL, p = 0.002, n = 23), and of carbapenems on valproic acid Ct (- 42.9 µg/mL, p < 0.001, n = 262). Pharmacokinetic parameters with other DDIs were insufficiently reported to allow a statistical analysis.

Conclusions: Therapeutic drug monitoring in patients receiving long-term antiepileptic therapies may help, in specific conditions, to improve safety while preserving efficacy. Such a procedure would also increase scientific information on how pharmacokinetic variations are associated with ADR occurrence, and possibly epileptological outcomes for those DDIs for which available information is suggestive of a relevant effect but is not yet sufficient to draw conclusions.