Novel Approach to Characterization of Combined Pharmacodynamic Effects of Antimicrobial Agents

Abstract

There is considerable need for new modeling approaches in the study of combined antimicrobial effects. Current methods based on the Loewe additivity and Bliss independence models are associated with implicit assumptions about the interacting system. To circumvent these limitations, we propose an alternative approach to the quantification of pharmacodynamic drug interaction (PDI). Pilot time-kill studies were performed with 10 8 CFU of Pseudomonas aeruginosa/ml at baseline with meropenem or tobramycin alone. The studies were repeated with 25 concentration combinations of meropenem (0 to 64 mg/liter) and tobramycin (0 to 32 mg/liter) in a five-by-five array. The data were modeled with a three-dimensional response surface using effect summation as the basis of null interaction. The interaction index (Ii) is defined as the ratio of the volumes under the planes (VUP) of the observed and expected surfaces: VUP observed /VUP expected . Synergy and antagonism are defined as Ii values of <1 and >1, respectively. In all combinations, an enhanced killing effect was seen compared to that of either drug at the same concentration. The most significant synergism was observed between 1 and 5 mg/liter of meropenem and between 1 and 4 mg/liter of tobramycin; seven out of nine combinations had a >2-log drop compared to the more potent agent. The Ii was found to be 0.76 (95% confidence interval, 0.65 to 0.91) for the concentration ranges of the agents. The results corroborate previous data indicating that meropenem is synergistic with an aminoglycoside when used in combination against P. aeruginosa. Our parametric approach to quantifying PDI appears robust and warrants further investigations.The ability to describe combined drug effects objectively is one of the major challenges in anti-infective pharmacology and is of paramount importance in the study of combination therapy. The pharmacodynamic drug interaction (PDI) of antimicrobials is typically described by qualitative terms, such as synergy, additivity (indifference), or antagonism. It is increasingly recognized that these standard approaches lack the sensitivity to capture various kinds of important information, such as the variability of the interacting system, extent of interaction, and emergence of resistance. Consequently, it is difficult to compare different combinations in a rational and robust manner.When attempting to evaluate pharmacodynamic interaction (synergism and antagonism), one typically constructs an expected null interaction model, which predicts the effect of multiple drugs in the absence of interaction. Without a physically and theoretically founded null interaction model, it would be difficult to make any reasonable evaluations of the combined action of multiple pharmacological agents. Two main metrics which are widely adopted exist for pharmacodynamic interactions, each presenting a consistent and well-supported perspective on the expected effect of noninteracting agents. They are the Loewe additivity and Bliss independence models. Each of these methodol...

Optimization of Meropenem Minimum Concentration/MIC Ratio To Suppress In Vitro Resistance of Pseudomonas aeruginosa

“…2F. This combination has previously been shown to be synergistic when the two drugs are used concurrently (30).…”

“…We previously found that meropenem and tobramycin exhibited synergistic killing when they were used in combination (30). Therefore, we examined the feasibility of adding an aminoglycoside to lower the meropenem pharmacodynamic threshold necessary to suppress resistance.…”

Quantitative Assessment of Combination Antimicrobial Therapy against Multidrug-Resistant Acinetobacter baumannii

“…Previous attempts to quantify arbitrary agent interactions are unsatisfactory as they are associated with multiple implicit assumptions of the interacting system; they have been reviewed in detail previously (5,25). Briefly, the fractional inhibitory concentration index (the most widely used method for the in vitro interaction of antimicrobial agents) is based on Loewe additivity, in which linear concentration-effect relationships are implicitly mandated for all agents in a combination.…”

“…Specific concentrations for each agent used (including a placebo control) were as determined in the previous section. The total bacterial burden at 24 h (in triplicate) was determined by quantitative culture as described above, and the data were mathematically modeled using a three-dimensional response surface as described previously (25). Briefly, effect summation was used as the definition of additivity (null interaction) (5), as follows:…”

In Vitro Activity of MK-7655, a Novel β-Lactamase Inhibitor, in Combination with Imipenem against Carbapenem-Resistant Gram-Negative Bacteria

“…The concentration ranges examined were constrained to those clinically achievable in human serum (up to 40 mg/liter for both imipenem [5,12] and MK-7655 [unpublished data on file]); specific concentrations used were based on the best-fit parameter estimates and optimal sampling for the most precise characterization of bacterial killing. The total bacterial burden at 24 h (in triplicate) was mathematically modeled using a three-dimensional response surface as described in detail elsewhere (Mathematica 5.2; Wolfram Research, Inc., Champaign, IL) (18). Volumes under the plane (VUP) of the observed (VUP observed ) and expected (VUP expected ) surfaces were computed by interpolation and double integration, respectively.…”