Dalbavancin and rifampin against methicillin-resistant Staphylococcus aureus in an experimental foreign-body infection
Abstract number: P1024
Baldoni D., John A-K., Aeppli S., Angevaare E., Rajacic Z., Zimmerli W., Trampuz A.
Objectives: Implant-associated infection is a devastating complication caused by biofilms adhering to surface of devices. We investigated the in-vitro susceptibility, pharmacokinetics and treatment efficacy of dalbavancin (DAL), alone and in combination with rifampin (RIF) in a foreign-body MRSA infection model.
Methods: MRSA (ATCC 43300) MIC and MBC was determined by macrodilution method. Time-kill curves were determined in the logarithmic and stationary growth-phase during 48 h. Tween 80 (final concentration 0.002%) was added to all solutions in glass tubes. A guinea pig infection model with subcutaneously implanted Teflon cages was used. DAL concentrations were determined in sterile cages after a single dose of 10, 20 and 40 mg/kg i.p. Cage-associated infection was established by percutaneous injection of MRSA (5×106 CFU/cage). 3 days after infection, i.p. treatment was started (3 animals/treatment regimen): DAL 40 mg/kg single dose, RIF 12.5 mg/kg/12 h × 4 days and their combination. Bacterial titer in cage fluid was determined 5 and 9 days after treatment start. Then were animals sacrificed and cages cultured in TSB for 48 h. Cure rate (%) is the proportion of cage cultures without MRSA. Positive cage cultures were tested for development of RIF resistance.
Results: DAL MIC was 0.06 ug/ml and MBC was >20 ug/ml. Time-kill curve studies showed a reduction of bacterial load >99.9% after 48 h with DAL concentrations 5 mg/mL in logarithmic and 0.157 mg/mL in stationary growth. After single dose of 10, 20 and 40 mg/kg DAL, in cage fluid Cmax was 4.6, 18.2 and 34.9 ug/ml at 1012 h; AUC was 150, 926, 3018 mg/h/ml, respectively. Bacterial counts in cage fluid at start of treatment ranged from 7.07.3 log cfu/ml. Addition of RIF significantly improved the efficacy of DAL on planktonic bacteria in cage fluid during (p = 0.06) and after treatment (p < 0.001) (Figure). The cure rate with DAL alone was 8%, which was improved in combination with RIF to 33% (p < 0.05), which did not differ from the RIF monotherapy, but reduced the frequency of RIF resistant cage cultures from 38% to 25%.
Conclusions: DAL alone reduced 0.51.1 log cfu/ml MRSA in cage fluid and had a cure rate of 8%. DAL combined with RIF reduced >5 log cfu/ml MRSA in cage fluid and achieved a 33% cure rate. The combination DAL plus RIF deserves further studies to determine the optimal dosing for implant-associated MRSA infections are needed.
|Session name:||19th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Helsinki, Finland, 16 - 19 May 2009|
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