Due to a lack of effective antibiotics, Acinetobacter baumannii is one of the six most dangerous bacterial ?superbugs? that cause one of the world?s three most serious human health threats. Exacerbating this is a dramatic decline in the number of new antibiotics effective against A. baumannii, which can cause serious bloodstream, respiratory tract, wound, and other infections with very high morbidity and up to 80% mortality. Carbapenem (a member of the ?-lactam class of antibiotics)-resistant (CR) A. baumannii infections cost the U.S. health-care system $389 million per year. As A. baumannii isolates resistant to most or all antibiotics in monotherapy are rapidly increasing in the United States and worldwide, monotherapy is clearly no longer viable. With clinicians therefore being forced to use empiric, non-optimized combinations that may fail and lead to even more resistance, the development of novel dosing strategies that use antibiotics in efficacious combinations is critical. This project will yield promising combination dosing schemes to combat multidrug- resistant (MDR) and pandrug-resistant (PDR) A. baumannii. Our preliminary data show that combining a carbapenem with an aminoglycoside antibiotic is highly effective against MDR A. baumannii. To rationally optimize therapies, this project will provide the first systematic data on the binding of ?-lactam antibiotics to their bacterial target receptors in A. baumannii (Aim 1, stage 1). This will identify the optimal sets of bacterial target receptors that should be bound and inactivated by ?-lactam antibiotics and will greatly improve optimal ?-lactam therapies. In stage 2 of Aim 1, in vitro infection models will assess bacterial killing and resistance prevention for innovative two- and three-drug combination dosing strategies against MDR and PDR A. baumannii. These in vitro models can simulate antibiotic concentration-time profiles that mirror those in patients. Combination regimens to be tested include simultaneous and sequential dosing with normal and short-course aminoglycoside therapy. The ability of novel broad-spectrum ?-lactamase inhibitors to significantly enhance the activity of ?-lactam antibiotics in A. baumannii will be assessed.
In Aim 2, the kinetics of target receptor binding by ?-lactams will be evaluated, and transcriptomic and genomic approaches applied to elucidate the mechanistic basis for resistance prevention, using bacterial samples from Aim 1. Next, in Aim 3, data on target receptor binding, drug concentrations, bacterial killing, resistance prevention, and resistance mechanisms will be used to develop new mechanism-based models. Applying these models will rationally optimize two- and three-drug combination dosing strategies that better target MDR and PDR A. baumannii.
In Aim 4, these regimens will be validated prospectively via dynamic in vitro and murine pneumonia models with an intact or compromised immune system. This project holds excellent promise for developing efficacious and robust combination dosing strategies against MDR and PDR A. baumannii for testing in future clinical trials.
Acinetobacter baumannii is a Gram-negative superbug that costs the U.S. health-care system $389 million per year, and the number of serious infections caused by A. baumannii isolates resistant to most or all available antibiotics in monotherapy is rapidly rising. As highlighted by the Executive Office of the President and the World Health Organization, we are facing a serious global health crisis due to a lack of effective antibiotics that is arguably more severe for A. baumannii than for any other superbug. This project will provide novel insights into the mechanisms of antibiotic action, synergy, and resistance prevention, and develop efficacious antibiotic combination dosing strategies against resistant A. baumannii for testing in future clinical trials.