Evaluation of Telavancin Alone and Combined with Ceftaroline or Rifampin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Biofilm Model

Abstract

ABSTRACT Infections caused by biofilm-producing methicillin-resistant Staphylococcus aureus (MRSA) bacteria are challenging due to increasing antibiotic resistance. Synergistic activities of lipopeptides and lipoglycopeptides with β-lactams have been demonstrated for MRSA, but little is known about biofilm-embedded organisms. Our objective was to evaluate two telavancin (TLV) dosage regimens (7.5 mg/kg of body weight and 10 mg/kg every 24 h [q24h]) alone and in combination with ceftaroline (CPT) (600 mg every 8 h [q8h]) or rifampin (RIF) (450 mg every 12 h [q12h]) against two biofilm-producing MRSA strains (494 and N315). Pharmacokinetic/pharmacodynamic CDC biofilm reactor models with polyurethane coupons were used to evaluate the efficacies of the antibiotic combinations over 72 h. Overall, there were no significant differences observed between the two TLV dosing regimens either alone or in combination with RIF or CPT against these strains. Both TLV dosing regimens and CPT alone demonstrated killing but did not reach bactericidal reduction at 72 h. However, both TLV regimens in combination with RIF demonstrated enhanced activity against both strains, with a rapid decrease in CFU/ml at 4 h that was bactericidal and maintained over the 72-h experiment (−Δ3.75 log 10 CFU/ml from baseline; P < 0.0001). Of interest, no enhanced activity was observed for TLV combined with CPT. No development of resistance was observed in any of the combination models. However, resistance to RIF developed as early as 24 h, with MIC values exceeding 32 mg/liter. Our results show that TLV plus RIF displayed therapeutic improvement against biofilm-producing MRSA. These results suggest that TLV at 7.5 and 10 mg/kg q24h are equally effective in eradicating biofilm-associated MRSA strains in vitro .