# Novel Approaches to Combat Medical Device-Associated BioFilms
## 3 Novel Approaches to Combat Medical Device-Associated Biofilms
### Bacteriophage Therapy  
Bacteriophages (or phages) are viruses that can infect and replicate in bacterial cells. They are widely found in soil and water bodies and play an important role in microbial physiology. Bacteriophages have strict host specificity, reside in susceptible host bacteria, and can lyse bacteria, so they are sometimes used as adjuvant therapy for local infections. However, because of the emergence of bacterial infections for which antibiotics and surgery are not sufficient for eradication, bacteriophage therapy has attracted attention, and it has become a possible choice for the treatment of refractory bacterial infections (Figure 1). A recent study conducted by [PERSON]'s group showed that phages can lyse bacterial cells in vitro, even inside biofilms. In particular, the antibiofilm properties of some phages have been observed, such as the ability to kill persistent cells and degrade the extracellular matrix. These properties may be due to the depolymerase activity of the virus-encoded enzyme, which degrades the extracellular polysaccharide of the matrix, allowing phages or antibiotics to reach the bacteria and kill them [253]. Phage lysins have also been effectively used to remove bacterial biofilms. For example, in vitro, the phage lysin LysGH15 can efficiently prevent the biofilm formation of staphylococcal species. LysGH15 also showed notable disruption of 24-h and 72-h biofilms formed by _S. aureus_ and coagulase-negative species [254]. The ability of LysGH15 to inhibit biofilm formation is most likely attributable to its rapid bactericidal activity prior to biofilm formation. At higher doses, LysGH15 can also destroy biofilms because it can dissolve the bacteria in the biofilm, thereby destroying the integrity of the biofilm instead of destroying the biofilm matrix [254]. Similarly, the effectiveness of phages against biofilms was demonstrated in vivo. In the established murine model of prosthetic joint infection, the combination of PlysS2 (a bacteriophage-derived lysin) (2.5 mg/kg, Intraperitoneal, q24 hr) with vancomycin (110 mg/kg, Subcutaneous, q12 hr) can significantly reduce the bacterial load in periprosthetic tissues and on implant surfaces [255]. In a recent case reported by [PERSON] et al., bacteriophages cured urinary tract infections that were recurrent despite previous treatment with effective antibiotics and the replacement of ureteral stents. After two weeks of lytic phage therapy, the presence of the KPC producer _K. pneumoniae_ was no longer found in the urine and ureteral stent of the patient, and no microbial colonization was observed during the following two consecutive years [256]. However, due to host specificity, phage tolerance, and the complexity of the mature biofilm structure, phages have difficulty completely removing biofilms. Moreover, personalized phage cocktail (mixed phages) therapy has been developed. These phages work together to expand the scope of action to increase the potential of phage therapy. A study of phage cocktails composed of five phages against orthopedic implant biofilm infections caused by _S. aureus_ showed that viable bacterial numbers within biofilms on titanium surfaces were significantly reduced in vitro [257]. In another case reported by [PERSON] et al., a cocktail of bacteriophages (5 \(\times\) 10\({}^{8}\) pfu/mL, 50 mL bladder irrigation and kidney irrigation, q48 hr) was selected for activity against all 21 heterogeneous _K. pneumoniae_ strains to eradicate multifocal colonization, combined with piperacillin/tazobactam treatment. Finally, the patient recovered, with an obviously improved bladder [258]. Bacteriophages are species specific against bacterial infections. Antibiotics can easily cause dysregulation or resistance in the bacterial population. Bacteria are less likely to develop tolerance to bacteriophages. Therefore, bacteriophage therapy has good prospects alone or in combination with antibiotics in the treatment of biofilm infections.