A methodology based on multiple criteria decision analysis for combining antibiotics in empirical therapy

The current situation of critical progression in resistance to more effective antibiotics has forced the reuse of old highly toxic antibiotics and, for several reasons, the extension of the indications of combined antibiotic therapy as alternative options to broad spectrum empirical mono-therapy. A key aspect for selecting an appropriate and adequate antimicrobial therapy is that prescription must be based on local epidemiology and knowledge since many aspects, such as prevalence of microorganisms and effectiveness of antimicrobials, change from hospitals, or even areas and services within a single hospital. Therefore, the selection of combinations of antibiotics requires the application of a methodology that provides objectivity, completeness and reproducibility to the analysis of the detailed microbiological, epidemiological, pharmacological information on which to base a rational and reasoned choice.

We proposed a methodology for decision making that uses a multiple criteria decision analysis (MCDA) to support the clinician in the selection of an efficient combined empiric therapy. The MCDA includes a multi-objective constrained optimization model whose criteria are the maximum efficacy of therapy, maximum activity, the minimum activity overlapping, the minimum use of restricted antibiotics, the minimum toxicity of antibiotics and the activity against the most prevalent and virulent bacteria. The decision process can be defined in 4 steps: (1) selection of clinical situation of interest, (2) definition of local optimization criteria, (3) definition of constraints for reducing combinations, (4) manual sorting of solutions according to patient's clinical conditions, and (5) selection of a combination.

In order to show the application of the methodology to a clinical case, we carried out experiments with antibiotic susceptibility tests in blood samples taken during a five years period at a university hospital. The validation of the results consists of a manual review of the combinations and experiments carried out by an expert physician that has explained the most relevant solutions proposed according to current clinical knowledge and their use.

We show that with the decision process proposed, the physician is able to select the best combined therapy according to different criteria such as maximum efficacy, activity and minimum toxicity. A method for the recommendation of combined antibiotic therapy developed on the basis of a multi-objective optimization model may assist the physicians in the search for alternatives to the use of broad-spectrum antibiotics or restricted antibiotics for empirical therapy. The decision proposed can be easily reproduced for any local epidemiology and any different clinical settings.