title: Efficacy of a novel rifamycin derivative, ABI-0043, against Staphylococcus aureus in an experimental model of foreign-body infection.
abstract: We compared the efficacy of a novel rifamycin derivative, ABI-0043, with that of rifampin, alone and in combination with levofloxacin, against methicillin-susceptible Staphylococcus aureus ATCC 29213 in a guinea pig tissue-cage infection model. The MIC, logarithmic-growth-phase minimal bactericidal concentration, and stationary-growth-phase minimal bactericidal concentration of ABI-0043 were 0.001, 0.008, and 0.25 microg/ml, respectively; the corresponding concentrations of rifampin were 0.016, 0.8, and 3.6 microg/ml, respectively. After a single intraperitoneal dose of 12.5 mg/kg of body weight, the peak concentration in cage fluid was 1.13 micarog/ml of ABI-0043 and 0.98 microg/ml of rifampin. Five days after completion of treatment, levofloxacin administered alone (5 mg/kg/12 h) resulted in bacterial counts in cage fluid that were similar to those for untreated controls (>8.0 log(10) CFU/ml), whereas rifampin and ABI-0043 administered alone (12.5 mg/kg/12 h) decreased the mean titers of bacteria +/- standard deviations to 1.43 +/- 0.28 log(10) and 1.57 +/- 0.53 log(10) CFU/ml, respectively, in cage fluid. In combination with levofloxacin, both rifamycins cleared bacteria from the cage fluid. The cure rates of cage-associated infections with rifampin and ABI-0043 administered alone were 46% and 58%, respectively, and increased to 88% and 92% in combination with levofloxacin. Emergence of rifamycin resistance was observed in 42% of cages after ABI-0043 therapy and in 38% of cages after rifampin therapy; no emergence of resistance occurred with combination treatment with levofloxacin. In conclusion, ABI-0043 had cure rates comparable to that of rifampin. ABI-0043 in combination with a quinolone has the potential for treatment of implant-associated infections caused by susceptible strains of S. aureus, potentially without drug-drug interactions.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Basel, Switzerland.
authors.forename: Andrej
authors.initials: A
authors.lastname: Trampuz
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Murphy
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Widmer
authors.forename: Regine
authors.initials: R
authors.lastname: Landmann
authors.forename: Werner
authors.initials: W
authors.lastname: Zimmerli
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005549:Foreign-Body Reaction / Q000188:drug therapy*; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D064704:Levofloxacin; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D015242:Ofloxacin / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012294:Rifamycins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors
chemical_list: C518212:ABI 0043; D000900:Anti-Bacterial Agents; D012294:Rifamycins; D064704:Levofloxacin; D015242:Ofloxacin; D012293:Rifampin