Pharmacodynamic Issues in Antibiotic Combinations

For over decades, antibiotics have been used in various combinations to treat infections. From a clinical perspective a number of studies have shown that combination treatments can significantly reduce mortality in certain subsets of patients including those who are both bacteremic and severely ill. However, there is significant controversy over their current role and definitions of appropriate applications of antibiotic combinations, particularly as it to relates to pharmacodynamics and measurements of effect. The emerging health care crisis surrounding multidrug-resistant bacteria and the lack of novel antibiotics highlight the importance of optimizing these combinations. The fundamental principles of effective combination regimens are increased bactericidal activity with decreased potential for resistance selection upon treatment and to minimize exposure-associated toxicity. Furthermore, quantification of two drug’s combined effect is of major importance when weighing the benefits and disadvantages of their use compared to monotherapy. Qualitative terms like synergy, additivity, or antagonism all help to categorize the nature of the interaction between two antibiotics. There has been much debate as to which definitions of drug interactions are most appropriate but the two main metrics used to help qualify the nature of the combination (or interactions between any two drugs) are Loewe additivity and Bliss independence. Overall, despite the apparent benefits of combination therapy, pharmacodynamic concerns exist about these regimens including: definitions of synergy, indifference, and antagonism; duration of studies; bacterial inoculum; model systems utilized; and a number of other issues exist. The primary objective of the chapter is to review the state of the art pharmacodynamic issues regarding antibiotic combinations.