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Pharmacodynamics and Antibacterial Resistance 479and pharmacodynamic interactions observed with one representative strain(P. aeruginosa GB2) are shown in Figure 4. Data from this study demonstrated thatresistance emerged rapidly during treatment of all strains with either levofloxacinor imipenem alone. As predicted, imipenem-selected resistance was associated withthe decreased expression of oprD, whereas levofloxacin was found to select for avariety of mutant phenotypes, some of which were associated with the overexpressionof multidrug efflux pumps. In contrast to the emergence of resistance andfailure of each drug alone, the levofloxacin-imipenem combination rapidly eradicatedall three P. aeruginosa from the IVPM and prevented the emergence ofresistance. Furthermore, the combination was effective in preventing the emergenceof resistance associated with overexpression of the MexEF-OprN efflux pump, aphenotype that is characterized by loss of susceptibility to both fluoroquinolonesand imipenem. Although imipenem is not a substrate of the MexEF-OprN effluxpump, overexpression of MexEF-OprN is associated with a decrease in expressionof the outer membrane porin OprD and loss of susceptibility to imipenem (91, 92).Subsequent studies have extended these initial observations and demonstrated thatthe combination of levofloxacin-imipenem can effectively eradicate P. aeruginosathat has already lost susceptibility to one or both drugs in the combination, andprevent the emergence of higher levels of resistance (93).Our studies with the combinations of cefepime-aztreonam and levofloxacinimipenemdemonstrate the importance of pharmacodynamic research in theevaluation of potential antibacterial combinations for preventing the emergence ofresistance. Neither of these combinations exhibited true synergistic interactionswith regard to their bacterial killing dynamics and therefore would not have beenidentified as effective combinations in routine susceptibility or synergy assays.However, the use of pharmacodynamic methods provided insight into the potentialof these combinations to prevent the emergence of resistance during therapy, aproblem that is a primary concern for the treatment of P. aeruginosa.CONCLUDING REMARKSAntibacterial resistance is an inevitable consequence of the use and overuse ofantibiotics in the environment and its inevitability is heightened by suboptimalpharmacodynamics. The emergence of multidrug resistance among prominentgram-positive and gram-negative pathogens presents serious therapeutic problems.As the development of stronger or novel antimicrobial agents decline, we may befaced with the feared “postantibiotic era.” Already clinicians are facing the dilemmaof treating bacteria, which are resistant to virtually all antibacterial agents. Now isthe time for scientists to begin searching for ways to prevent or slow the emergenceof resistance in the environment. One approach is to control the use of antibiotics inthe environment and rotate antibiotics before resistance becomes a problem. Thistheory is referred to as antibiotic cycling (94). A further step, which can be taken isto scientifically optimize antimicrobial therapy such that the evolution of mutationalresistance is slowed. This requires dosing antibiotics such that peak concentrationsat the site of infection exceed the MICs of the parent and any resistantsubpopulations that might be present. A final approach is to identify combinationsof antibacterial agents that can prevent, or slow, the emergence of resistance duringtherapy. Through the combination of judicious antimicrobial use and pharmacodynamicallybased optimization of dosing strategies, the evolution of antibioticresistance can be curved and the “postantibiotic era” need not become a reality.