Treating biofilm infections on implanted medical devices is formidable, even with extensive antibiotic therapy. The aim of this study was to investigate whether ultrasound (US)-targeted microbubble (MB) destruction (UTMD) could enhance vancomycin activity against Staphylococcus epidermidis RP62A biofilms. Twelve-hour biofilms were treated with vancomycin combined with UTMD. The vancomycin and MB (SonoVue) were used at concentrations of 100 g/ml and 30% (vol/vol), respectively, in studies in vitro. After US exposure (0.08 MHz, 1.0 W/cm 2 , 50% duty cycle, and 10-min duration), the biofilms were cultured at 37°C for another 12 h. The results showed that many micropores were found in biofilms treated with vancomycin combined with UTMD. Biofilm densities (A 570 values) and the viable counts of S. epidermidis recovered from the biofilm were significantly decreased compared with those of any other groups. Furthermore, the highest percentage of dead cells was found, using confocal laser scanning microscopy, in the biofilm treated with vancomycin combined with UTMD. The viable counts of bacteria in biofilms in an in vivo rabbit model also confirmed the enhanced effect of vancomycin combined with UTMD. UTMD may have great potential for improving antibiotic activity against biofilm infections.Bacteria that adhere to implanted medical devices, such as vascular catheters, prosthetic joints, and artificial heart valves, can cause persistent infections because bacteria sequestered in biofilms show increased tolerance of normal antibiotic therapies (6). The mechanism of this resistance is very complicated. Current hypotheses on the subject include the heterogeneity of biofilm-encased bacteria and the failure of an antibiotic to penetrate the full depth of the biofilm (10). So far, the most effective treatment against biofilm infections is to remove the implant, treat the patient with antibiotics at safe levels, and later insert a new implant, which is a costly and difficult procedure (6, 7). Therefore, it is necessary to explore more effective methods of dealing with infections caused by biofilms on implanted devices.Studies have shown that low-frequency ultrasound (US) combined with antibiotics can significantly enhance the bactericidal activity of antibiotics in both planktonic and biofilm forms (2, 4, 12). The mechanism may be that US increases cell membrane permeability (27), enhances microconvection from ultrasonic heating, and stimulates active or passive uptake of the antibiotics, as US can give rise to high-pressure, high-shear stress, or cavitation, causing cell membrane and biofilm disruption (23, 31).Recently, microbubble (MB)-based US contrast agents have been used widely in clinical sonography. MB agents can provide nuclei for inertial cavitation and lower the threshold for US-induced cavitation. Destruction of MBs by US increases the membrane permeability of cells by shear stress, rising temperature, and activation of reactive oxygen species. Therefore, such MBs have also evolved as tools to deliver drugs or gene...

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Treating staphylococcal biofilm-associated infections is challenging. Based on the findings that compound 2 targeting the HK domain of Staphylococcus epidermidis YycG has bactericidal and antibiofilm activities against staphylococci, six newly synthesized derivatives were evaluated for their antibacterial activities. The six derivatives of compound 2 inhibited autophosphorylation of recombinant YycG′ and the IC50 values ranged from 24.2 to 71.2 μM. The derivatives displayed bactericidal activity against planktonic S. epidermidis or Staphylococcus aureus strains in the MIC range of 1.5–3.1 μM. All the derivatives had antibiofilm activities against the 6- and 24-h biofilms of S. epidermidis. Compared to the prototype compound 2, they had less cytotoxicity for Vero cells and less hemolytic activity for human erythrocytes. The derivatives showed antibacterial activities against clinical methicillin-resistant staphylococcal isolates. The structural modification of YycG inhibitors will assist the discovery of novel agents to eliminate biofilm infections and multidrug-resistant staphylococcal infections.Electronic supplementary materialThe online version of this article (doi:10.1007/s00253-014-5685-8) contains supplementary material, which is available to authorized users.