In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

Abstract

cDelafloxacin 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 penicillinsusceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamaseproducing 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. formulations have been developed with promising pharmacokinetic (PK) and efficacy results (1, 2). Delafloxacin has a broad spectrum of activity that includes drug-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae (3-7). Previous clinical studies in patients with acute bacterial skin and skin structure infections (ABSSIs) have demonstrated potency and efficacy, especially with respect to S. aureus (8,9).Pneumonia is one of the most common infectious diseases encountered worldwide and remains a significant cause of morbidity and mortality (10). The major pathogen of community-acquired pneumonia (CAP) continues to be S. pneumoniae despite major advances in vaccination development and administration to at-risk populations. In the hospital setting, S. aureus and Gram-negative bacteria are more commonly encountered and are frequently drug resistant (11).Staphylococcus aureus is particularly challenging due to its inherent pathogenicity and increased prevalence of drug-resistant phenotypes (i.e., methicillin-resistant S. aureus [MRSA]) contributing to serious infections. It is the leading bacterial cause of life-threatening infection due to these attributes (12)(13)(14). For example, in the United States, S. aureus is the most common cause of nosocomial infection and leads to more than 80,000 illnesses and 11,000 deaths yearly (12). Unfortunately, there is a paucity of novel agents to treat MRSA pulmonary infections and even fewer that have oral and i.v. formulation options.The objectives of our experiments were to characterize the in vivo efficacy of delafloxacin using a neutropenic murine lung infection model for three common respiratory tract pathogen groups, including S. aureus, S. pneumoniae, and K. pneumoniae. Specifically, the pharmacokinetic/pharmacodynamic (PK/PD) targets of delafloxacin were examined to provide a framework for

In Vitro Activity of Delafloxacin against Contemporary Bacterial Pathogens from the United States and Europe, 2014

“…Among the S. aureus isolates, 99.5% of MSSA isolates from both U.S. and European study sites were inhibited at the pharmacodynamic breakpoint of ≤0.5 μg/ml (1, 13, 21). European isolates of MRSA, MS-CoNS, and MR-CoNS were slightly more susceptible to delafloxacin than U.S. isolates at an MIC of ≤0.5 μg/ml (for MRSA isolates, 95.3 and 91.2% isolates from Europe and the United States, respectively; for MS-CoNS isolates, 100.0 and 97.6% isolates from Europe and the United States, respectively; and for MR-CoNS isolates, 95.5 and 84.5% isolates from Europe and the United States, respectively) (data not shown).…”

Delafloxacin: design, development and potential place in therapy

“…The results confirm that the pharmacokinetic/pharmacodynamic (PK/PD) parameter that best predicted the therapeutic efficacy was AUC/CMI, and conclude that with the described doses, DLX would a good therapeutic option for the treatment of pneumonia by S. aureus , including the methicillin-resistant S. pneumoniae and the penicillin-resistant K. pneumoniae including the ESBL strains 40. Another study on murine thigh infection model concluded that the pharmacokinetic parameter that best predicts the clinical response is AUC/MIC 41…”

“…The activity against MRSA, and against enterobacterias, makes DLX a reasonable alternative in the treatment of nosocomial pneumonia. In addition, in murine experimental models, DLX showed high penetration in the pulmonary compartment,40 and higher concentrations of free antibiotic in the epithelial lining fluid than in the plasma 53. The loss of C7 in its chemical structure, and with it, the ability to act as zwitterion, facilitates its in vivo activity in acidic mediums.…”

Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

“…However, the magnitude of this PK/PD index associated with 1-log kill of bacterial burden was different in relation to the investigated pathogen. Lepak et al [25] found a median fAUC/ MIC ratio of 7.92 vs. four different strains of S. aureus (one methicillin-susceptible Staphylococcus aureus, (MSSA) and three MRSA); 3.36 vs. four strains of Streptococcus pneumoniae (two penicillin-susceptible and two penicillin-resistant); and 55.2 in four strains of Klebsiella pneumoniae (three of which extended spectrum beta-lactamase, (ESBL)-positive). In contrast, Thabit et al [26] found a median fAUC/MIC of 0.4 vs. two strains of MSSA, 24.7 vs. two strains of MRSA, 31.8 vs. five strains of S. pneumoniae, and 9.6 vs. two strains of K. pneumoniae.…”