There is a need for systematic studies specifically designed to assess the efficacy of rationally optimized combination dosage regimens versus monotherapy in the treatment of CR GNB. From our perspective, it is critical to leverage latest in vitro and animal infection models to rationally optimize combination dosage regimens and consider the infection site specific PK profiles of each antibiotic before evaluating optimized combinations in patients. This translational process can be excellently supported by mechanism-based modeling. Future studies should address the following questions for each specific CR GNB species: Is rationally optimized combination therapy superior to monotherapy? If so, is it superior even when combining a non-susceptible drug? Which combination schemes may be more suitable for each pathogen and site of infection? Is high-dose initial combination therapy beneficial? What is the optimal duration of therapy and should therapy be de-escalated after, for example, 2 or 3 days?
Indeed, it is unlikely that these questions will be answered in the next five years. Nonetheless, it can be expected that a clearer definition on the role of combining drugs against CR GNB, particularly against CR Enterobacteriaceae, will be obtained during this period. Meanwhile, it seems that combination therapy will continue to be the standard of care in the treatment of severe infections by CR GNB. This approach and further studies assessing it should always take into account the PK/PD principles for optimizing the use of cornerstone agents (specifically polymyxins) as well as adjuvant antibiotics in combination treatments to maximize bacterial killing and minimize further emergence of resistance.
Expert Rev Anti Infect Ther. 2013;11(12):1333-1353. © 2013 Expert Reviews Ltd.