title: Pharmacodynamic and pharmacokinetic profiling of delafloxacin in a murine lung model against community-acquired respiratory tract pathogens.
abstract: Increasing antimicrobial resistance in community-acquired pneumonia (CAP) pathogens has contributed to infection-related morbidity and mortality. Delafloxacin is a novel fluoroquinolone with broad-spectrum activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to define the pharmacodynamic profile of delafloxacin against CAP pathogens using a neutropenic murine lung infection model. Five S. pneumoniae, 2 methicillin-susceptible S. aureus (MSSA), 2 MRSA and 2 Klebsiella pneumoniae isolates were studied. Delafloxacin doses varied from 0.5 mg/kg/day to 640 mg/kg/day and were given as once-daily to every 3 h regimens over the 24-h treatment period. Efficacy was measured as the change in log10CFU at 24 h compared with 0-h controls. Plasma and bronchopulmonary pharmacokinetic studies were conducted. Delafloxacin demonstrated potent in vitro and in vivo activity. Delafloxacin demonstrated high penetration into the lung compartment, as epithelial lining fluid concentrations were substantially higher than free drug in plasma. The ratio of the area under the free drug concentration-time curve to the minimum inhibitory concentration of the infecting organism (fAUC/MIC) was the parameter that best correlated with the efficacy of the drug, and the magnitude required to achieve 1 log10CFU reduction was 31.8, 24.7, 0.4 and 9.6 for S. pneumoniae, MRSA, MSSA and K. pneumoniae, respectively. The observed in vivo efficacy of delafloxacin was supported by the high pulmonary disposition of the compound. The results derived from this pre-clinical lung model support the continued investigation of delafloxacin for the treatment of community-acquired lower respiratory tract infections.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA; Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Abrar K
authors.initials: AK
authors.lastname: Thabit
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA; Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA. Electronic address: david.nicolau@hhchealth.org.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D058491:Bacterial Load; D015169:Colony Count, Microbial; D017714:Community-Acquired Infections / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000302:isolation & purification; D008168:Lung / Q000737:chemistry / Q000382:microbiology; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D010949:Plasma / Q000737:chemistry; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000302:isolation & purification; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C477891:delafloxacin
keywords: Delafloxacin; Klebsiella pneumoniae; MRSA; MSSA; Pneumonia; Streptococcus pneumoniae