Evaluation of Telavancin Alone and Combined with Ceftaroline or Rifampin against Methicillin-Resistant Staphylococcus aureus (MRSA) in an in vitro Biofilm Model [PublishAheadOfPrint]

Biofilm-producing methicillin-resistant Staphylococcus aureus (MRSA) infections are challenging due to increasing antibiotic resistance. Synergistic activity of lipopeptides and lipoglycopeptides with β-lactams has 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 and 10 mg/kg q 24h)alone and in combination with ceftaroline (CPT) (600 mg q 8 h) or rifampin (RIF) (450 mg q 12h) against two biofilm-producing MRSA (494 and N315). Pharmacokinetic/pharmacodynamic CDC biofilm reactor models with polyurethane coupons were used to evaluate the efficacy of the antibiotic combinations over 72h. 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 or CPT alone demonstrated killing but did not reach bactericidal reduction at 72h. However, both TLV regimens in combination with RIF demonstrated enhanced activity against both strains with a rapid decrease in CFU/ml at 4h that was bactericidal and maintained over the 72h experiment (- 3.75 log10CFU/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 24h with MIC values exceeding 32 mg/L. Our results show that TLV plus RIF displayed therapeutic improvement against biofilm-producing MRSA. These results suggest that the TLV 7.5 and 10mg/kg q24h are equally effective in eradicating biofilm-associated MRSA in vitro.

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