B-1002. Efficacy of Telavancin in a Murine Model of Acute Suppurative Osteomyelitis Induced by Methicillin-Resistant Staphylococcus aureus
Session: Poster Session: Antistaphylococcal Therapy Testing in Animal Models
Sunday, October 26, 2008: 12:00 AM
Room: Hall C
Background: Acute suppurative osteomyelitis represents an inflammatory reaction to bacterial infection characterized by abscess formation at the diaphyseal end of the bones. Infections with methicillin-resistant S. aureus (MRSA) frequently have severe chronic-progressive course and are particularly difficult to treat. Telavancin (TLV) is an investigational lipoglycopeptide with potent bactericidal activity against Gram-positive organisms, including MRSA. We examined the therapeutic efficacy of TLV, in comparison to vancomycin (VAN), in a murine model of acute suppurative osteomyelitis induced by MRSA. Methods: Acute suppurative osteomyelitis in 4 week old, male ICR mice was induced by intravenous (IV) injection of 1.7×107 CFU of MRSA strain #22048 (clinical isolate from Japan). The animals were randomly assigned to receive at 8 h post-infection and twice a day on the following 3 days a total of 7 doses of TLV 40mg/kg IV, VAN 110mg/kg IV or normal saline IV (control). A fourth group received 3 doses of VAN followed by 4 doses of TLV. Doses were selected to equate clinical AUC exposures. Cohorts of animals (n=6) were sacrificed at 8 h, 48 h and 96 h post-infection and bone marrow samples were collected for bacterial titer determination. Minimum inhibitory concentration (MIC) was determined by the broth microdilution method (CLSI). Results:
Time
post-infection (doses received)
Bacterial Titers in Bone Marrow (Log CFU/g; Mean ± SE)
Control
(n=6)
TLV
(n=6)
VAN
(n=6)
VAN then TLV
(n=6)
8 h (pre-treatment)4.82±0.06n/an/an/a
48 h (3 doses)6.99±0.072.36±0.205.68±0.31a
96h (7 doses)7.49±0.091.15±0.07b5.07±0.461.96±0.15b
MIC (μg/ml)-0.251-
a After 3 doses of VAN;
b P<0.01 vs VAN (Dunnette multiple comparison test);

Conclusions: Systemic antibiotic therapy with TLV was associated with greater reduction in bone marrow bacterial titers when compared to VAN. These preclinical results suggest that that TLV may have utility in the treatment of hematogenous acute suppurative osteomyelitis induced by MRSA.
Katsuyuki Maki1, Kazuo Hatano, PhD2, Shinobu Takeda1, Yoshimi Wakai1 and  K. Hatano,
Astellas Pharma, Inc. Role(s): Employee, Received: Salary., (1)Astellas Pharma Inc., (2)Astellas Pharma Inc., Osaka, Japan