sitafloxacin and Staphylococcal-Infections

Sitafloxacin is a new quinolone active against multi-resistant Gram-positive pathogens. An open study was conducted in patients with serious systemic infections with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococcus (VRE). Patients with MRSA were recruited if treatment with glycopeptides had failed. Of 11 patients with MRSA infection, four were cured, six failed treatment and one was indeterminate. Of nine patients with VRE infection (one patient had both pathogens), five were cured and four failed. Fifteen adverse events in 12 patients were potentially related to the study drug. Sitafloxacin was effective in VRE and some recalcitrant MRSA infections.

Topics: Adolescent; Adult; Aged; Anti-Infective Agents; Enterococcus; Fluoroquinolones; Gram-Positive Bacterial Infections; Humans; Methicillin Resistance; Middle Aged; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve "target-and-release" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Methicillin; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Mice; Osseointegration; Osteomyelitis; Staphylococcal Infections; Vancomycin

Topics: Animals; Anti-Bacterial Agents; Diphosphonates; Disease Models, Animal; Fluoroquinolones; Methicillin-Resistant Staphylococcus aureus; Mice; Osteomyelitis; Staphylococcal Infections; Staphylococcus aureus; Tissue Distribution; Vancomycin

Antibiotic activity can differ depending on whether the bacterial target is extracellular or intracellular. To determine extracellular and intracellular activities of sitafloxacin (STX) against Staphylococcus aureus in comparison with levofloxacin (LVX) and moxifloxacin (MXF) in vivo and in vitro, three S. aureus strains (ATCC25923, 29213, 43300) were evaluated. MIC, MBC and mutant prevention concentration (MPC) of the test quinolone for S. aureus were determined by microdilution in broth, and intracellular activity was determined in RAW264.7 cells after phagocytosis of bacteria. Cellular quinolone accumulation was determined by HPLC. The time- and concentration-kill relationships were examined in vitro (in broth and in RAW264.7 cells, respectively) and in vivo by use of a mouse peritonitis model. The results showed that the activity of STX in broth cultures, including the MIC, MBC, MPC and the time- and concentration-kill relationships, were greater for STX than those for LVX and MXF. In particular, STX exhibited the strongest activity against intramacrophage S. aureus. The intracellular effects could be ranked in the following order as the mean change in the log10 number of cfu ml(-1) (log10 cfu ml(-1)) between treated and untreated mice: STX>LVX>MXF. It also showed that the dominant factor of intracellular activity in vivo was the frequency of doses. There was a poor correlation between the intracellular accumulation of the three different quinolones and the actual intracellular effect. The results of the intracellular and extracellular time- and concentration-kill relationships indicated that STX has the potential to display useful activity against extracellular and intracellular S. aureus.

Topics: Animals; Anti-Bacterial Agents; Aza Compounds; Cell Line; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Space; Fluoroquinolones; Intracellular Space; Levofloxacin; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Moxifloxacin; Ofloxacin; Peritonitis; Quinolines; Staphylococcal Infections; Staphylococcus aureus; Time Factors