bGSK2140944 is a novel bacterial type II topoisomerase inhibitor with in vitro activity against key causative respiratory pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We described the pharmacodynamics of GSK2140944 against MRSA in the neutropenic murine lung infection model. MICs of GSK2140944 were determined by broth microdilution. Plasma and epithelial lining fluid (ELF) pharmacokinetics were evaluated to allow determination of pulmonary distribution. Six MRSA isolates were tested. GSK2140944 doses of 1.56 to 400 mg/kg of body weight every 6 h (q6h) were utilized. Efficacy as the change in log 10 CFU at 24 h compared with 0 h controls and the area under the concentration-time curve for the free, unbound fraction of a drug (fAUC)/MIC required for various efficacy endpoints were determined. GSK2140944 MICs were 0.125 to 0.5 mg/liter against the six MRSA isolates. ELF penetration ratios ranged from 1.1 to 1.4. Observed maximal decreases were 1.1 to 3.1 log 10 CFU in neutropenic mice. The mean fAUC/MIC ratios required for stasis and 1-log-unit decreases were 59.3 ؎ 34.6 and 148.4 ؎ 83.3, respectively. GSK2140944 displayed in vitro and in vivo activity against MRSA. The pharmacodynamic profile of GSK2140944, as determined, supports its further development as a potential treatment option for pulmonary infections, including those caused by MRSA.
While a recent CDC surveillance study reports a decrease in health care-associated invasive methicillin-resistant Staphylococcus aureus (MRSA) infections in the United States from 2005 through 2011 (1), it remains a prevalent pathogen causing hospital-acquired (HAP) and ventilator-associated pneumonia (VAP) (2) and represents a major health threat with significant mortality rates (3, 4). Until lately, most cases of health care-associated pneumonia (HCAP), HAP, and VAP were thought to be caused by the hospital-acquired MRSA (HA-MRSA) strains, but a second variant of MRSA, community-acquired MRSA (CA-MRSA), has emerged in health care settings as a cause of severe pneumonia (2, 4). While the significance of this shift in epidemiology remains unknown (2), CA-MRSA has exhibited more rapid replication (5) and greater efficiency of transfer than HA-MRSA isolates (6). Additionally, virulence factors such as Panton-Valentine leukocidin (PVL), mostly associated with CA-MRSA strains, can cause severe necrotizing pneumonia even in young, otherwise healthy individuals (4).To cope with the emergence of these hard-to-treat multidrugresistant organisms, the development of new classes of antibacterial agents targeting type IIA topoisomerase was prompted in recent years (7). GSK2140944 is one such agent. GSK2140944 is a novel bacterial type II topoisomerase inhibitor with a mode of action distinguished from that of fluoroquinolones currently marketed or under development (8); instead of stabilizing the DNA double-strand breaks like fluoroquinolones, it stabilizes the precleavage topoisomerase-DNA complex prior to DNA cleavage and generates single-strand breaks (7, 9...