Use of pharmacodynamic indices to predict efficacy of combination therapy in vivo

Although combination therapy with antimicrobial agents is often used, no av ailable method explains or predicts the efficacies of these combinations sa tisfactorily. Since the efficacies of antimicrobial agents can be described by pharmacodynamic indices (PDIs), such as area under the concentration-ti me curve (AUC), peak level, and the time that the concentration is above th e MIC (time > MIC), it was hypothesized that the same PDIs would be valid i n explaining efficacy during combination therapy. Twenty-four-hour efficacy data (numbers of CFU) for Pseudomonas aeruginosa in a neutropenic mouse th igh model were determined for various combination regimens: ticarcillin-tob ramycin (n = 41 different regimens), ceftazidime-netilmicin (n = 60), cipro floxacin-ceftazidime (n = 59), netilmicin-ciprofloxacin (It = 38) and for e ach of these agents given singly. Multiple regression analysis was used to determine the importance of various PDIs (time > MIC, time > 0.25 x the MIG , time > 4x the MIC, peak level, AUG, AUC/MIC, and their logarithmically tr ansformed values) during monotherapy and combination therapy, The PDIs that best explained the efficacies of single-agent regimens were time > 0.25x t he MIC for beta-lactams and log AUC/MIC for ciprofloxacin and the aminoglyc osides. For the combination regimens, regression analysis showed that effic acy could best be explained by the combination of the two PDIs that each be st explained the response for the respective agents given singly. ri regres sion model for the efficacy of combination therapy was developed by use of a linear combination of the regression models of the PDI with the highest R -2 for each agent given singly. The model values for the single-agent thera pies were then used in that equation, and the predicted values that were ob tained were compared with the experimental values. The responses of the com bination regimens could best be predicted by the sum of the responses of th e single-agent regimens as functions of their respective PDIs (e.g., time>0 .25 x the MIC for ticarcillin and log AUC/MIC for tobramycin), The relation ship between the predicted response and the observed response for the combi nation regimens may be useful for determination of the presence of synergis m, We conclude that the PDIs for the individual drugs used in this study ar e class dependent and predictive of outcome not only when the drugs are giv en as single agents but also when they are given in combination. When given in combination, there appears to be a degree of synergism independent of t he dosing regimen applied.