Evaluation of High-Dose Daptomycin Versus Vancomycin Alone or Combined with Clarithromycin or Rifampin Against Staphylococcus aureus and S. epidermidis in a Novel In Vitro PK/PD Model of Bacterial Biofilm

Abstract

IntroductionMedical device infections are associated with significant morbidity and mortality. These difficult-to-treat infections often result in antibiotic failure and resistance. Combination therapy is often required, however, the most optimal combination is unknown. We evaluated the in vitro activity of daptomycin (DAP) or vancomycin (VAN) alone and in combination with rifampin (RIF) or clarithromycin (CLA) against strains of Staphylococcus aureus and S. epidermidis grown in biofilm on 3 prosthetic device materials.MethodsOne methicillin-resistant S. aureus (MRSA R5266), one heteroresistant vancomycin-intermediate S. aureus (hVISA R3640), and one methicillin-resistant S. epidermidis (MRSE R461) strain was evaluated in a CDC biofilm reactor with titanium, Teflon®, and steel coupons. Regimens simulated included DAP 10 mg/kg/day, and VAN 1 g q12h alone or in combination with RIF 600 mg q24h or CLA 250 mg q12h. Additional regimens including DAP 12 mg/kg/day or VAN ± RIF 450 mg q12h were evaluated against the hVISA strain.ResultsDAP + RIF or VAN + RIF demonstrated enhanced activity against R3640 in embedded biofilm (EB) cells in all materials versus DAP or VAN alone (P ≤ 0.040). Only DAP + RIF demonstrated sustained bactericidal activity (≥3.80 log10 CFU/cm2 reduction from baseline) against EB and planktonic cells of R5266 and EB cells of R461 in all 3 materials. Of interest, CLA did not appear to enhance DAP or VAN killing activities, and the addition of RIF prevented the emergence of resistance to DAP or VAN in all organisms.ConclusionUsing an in vitro bacterial biofilm model containing three common prosthetic device materials, DAP + RIF and VAN + RIF were the most effective regimens. DAP + RIF displayed the greatest activity and represents a promising combination to evaluate for treatment of biofilm-associated staphylococcal infections.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0055-5) contains supplementary material, which is available to authorized users.

Rifamycin Derivatives Are Effective Against Staphylococcal Biofilms In Vitro and Elutable From PMMA

“…The ability of rifampin to readily diffuse and its activity independent of bacterial growth make it an ideal treatment for biofilms. Although this is not the first report documenting activity of rifampin against biofilms, our study confirms and extends these observations to other rifamycin derivatives, including rifabutin, rifapentine, and rifaximin, which to our knowledge have not been previously evaluated for activity against staphylococcal biofilms [24,47,52]. Studies demonstrating the role of biofilms in orthopaedic infections highlight that rifamycin class agents may be an effective antimicrobial agent for the clinical management of infection.…”

Bacteriophage Lysin CF-301, a Potent Antistaphylococcal Biofilm Agent

“…Aggressive antibiotic therapies can reduce biofilms and control dispersed planktonic bacteria; however, eradication is difficult because of the high antibiotic concentrations that must be sustained (50,(52)(53)(54). To avoid the limitations of antibiotics, a promising new strategy was proposed based on the emerging understanding of bacteriophage lysins as antibiofilm agents (32,43).…”

Dalbavancin Alone and in Combination with Ceftaroline against Four Different Phenotypes of Staphylococcus aureus in a Simulated Pharmacodynamic/Pharmacokinetic Model

“…The free antibiotic concentrations for model experiments were determined from the estimated protein binding of 93% for DAL, 50% for VAN, and 20% CPT (46)(47)(48)(49). Table 3 depicts a summary of targeted half-lives and peak concentrations for each antibiotic (14,46,(50)(51)(52)(53).…”