Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for 
the treatment of bacterial pneumonia. The goal of the study was to determine the 
pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection 
model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella 
pneumoniae Four isolates of each species were utilized for in vivo studies: for 
S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; 
S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates; 
K. pneumoniae, one wild-type and three extended-spectrum 
beta-lactamase-producing isolates. MICs were determined using CLSI methods. A 
neutropenic murine lung infection model was utilized for all treatment studies, 
and drug dosing was by the subcutaneous route. Single-dose plasma 
pharmacokinetics was determined in the mouse model after administration of 2.5, 
10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of 
delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to 
infected mice. Treatment outcome was measured by determining organism burden in 
the lung (CFU counts) at the end of each experiment (24 h). The Hill equation 
for maximum effect (Emax) was used to model the dose-response data. The 
magnitude of the PK/PD index, the area under the concentration-time curve over 
24 h in the steady state divided by the MIC (AUC/MIC), associated with net 
stasis and 1-log kill endpoints was determined in the lung model for all 
isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges 
include the following: for maximum concentration of drug in serum (Cmax), 2 to 
70.7 mg/liter; AUC from 0 h to infinity (AUC0-∞), 2.8 to 152 mg · h/liter; 
half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10 
CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10 
CFU/lung over the study period. There was a relatively steep dose-response 
relationship observed with escalating doses of delafloxacin. Maximal organism 
reductions ranged from 2 log10 to more than 4 log10 The median free-drug AUC/MIC 
magnitude associated with net stasis for each species group was 1.45, 0.56, and 
40.3 for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. AUC/MIC 
targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin 
demonstrated in vitro and in vivo potency against a diverse group of pathogens, 
including those with phenotypic drug resistance to other classes. These results 
have potential relevance for clinical dose selection and evaluation of 
susceptibility breakpoints for delafloxacin for the treatment of lower 
respiratory tract infections involving these pathogens.