title: Activity of dalbavancin, alone and in combination with rifampicin, against meticillin-resistant Staphylococcus aureus in a foreign-body infection model.
abstract: The activity of dalbavancin, a representative of the lipoglycopeptide antibiotics, alone and in combination with rifampicin, was investigated against meticillin-resistant Staphylococcus aureus (MRSA) in a foreign-body infection model in guinea pigs. The MIC, MBC and time-kill profile of dalbavancin were determined for MRSA ATCC 43300 in the logarithmic (MBC(log)) and stationary (MBC(stat)) growth phases. The pharmacokinetic profile of dalbavancin was determined in sterile cage fluid in guinea pigs. The activity of intraperitoneal dalbavancin (40, 60 or 80 mg/kg as a single dose), rifampicin (12.5 mg/kg/12 h for 4 days) and their combination was assessed against planktonic and biofilm MRSA. The MIC of dalbavancin was 0.078 mg/L; MBC(log) and MBC(stat) were both >128× MIC. In time-kill studies, bacterial reduction of 3log(10)CFU/mL was achieved after 48 h at ≥32× MIC (logarithmic growth) and at ≥1× MIC (stationary growth). Dalbavancin was neither synergistic nor antagonistic with rifampicin, and prevented the emergence of rifampicin resistance in vitro. The half-life of dalbavancin in cage fluid was 35.8-45.4 h and the concentration remained above the MIC of MRSA during 7 days after a single dose. Dalbavancin reduced planktonic MRSA in cage fluid at high dose (60 mg/kg and 80 mg/kg) but failed to eradicate biofilm MRSA from cages. In combination with rifampicin, dalbavancin at 80 mg/kg cured 36% of infected cages, and emergence of rifampicin resistance was completely prevented. Dalbavancin at 80 mg/kg and in combination with rifampicin eradicated approximately one-third of cage-associated MRSA infections and prevented emergence of rifampicin resistance.
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Baldoni
authors.forename: Ulrika
authors.initials: U
authors.lastname: Furustrand Tafin
authors.forename: Sandrine
authors.initials: S
authors.lastname: Aeppli
authors.forename: Eline
authors.initials: E
authors.lastname: Angevaare
authors.forename: Alessandra
authors.initials: A
authors.lastname: Oliva
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
authors.forename: Werner
authors.initials: W
authors.lastname: Zimmerli
authors.forename: Andrej
authors.initials: A
authors.lastname: Trampuz
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D018441:Biofilms / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D019736:Prostheses and Implants / Q000382:microbiology; D012293:Rifampin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D017334:Teicoplanin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D017334:Teicoplanin; C469289:dalbavancin; D012293:Rifampin
keywords: Dalbavancin; Foreign-body infection; Rifampicin; Staphylococcus aureus