Biofilms in Surgical Site Infections: Recent Advances and Novel Prevention and Eradication Strategies

Introduction

Surgical site infections (SSIs) are common postoperative complications caused by community or hospital-acquired bacteria, as well as other endogenous opportunistic germs, contaminating the surgical wound or implanted medical equipment. Despite various laws and recommendations in place to avoid these infections, SSI rates remain alarmingly high, posing a risk to the healthcare system in terms of morbidity, prolonged hospitalisation, and mortality. Biofilm-forming bacteria are responsible for around 80% of human SSIs, including persistent wound infections.

Biofilm-associated SSIs are exceedingly difficult to treat with standard antibiotics due to the multidrug-resistant bacteria’s tolerance mechanisms, which are typically structured as polymicrobial communities. This review presents and discusses innovative ways for controlling, i.e., preventing and eliminating, biofilms in SSIs, with an emphasis on two appealing approaches: the use of nanotechnology-based composites and natural plant-based products.

An overview of new therapeutic agents and strategic approaches for controlling epidemic multidrug-resistant pathogenic microorganisms, particularly when biofilms are present, is provided, along with other combinatorial approaches as attempts to achieve synergistic effects with conventional antibiotics and restore their efficacy in treating biofilm-mediated SSIs. Some detection and real-time monitoring methods are also addressed in order to improve biofilm management tactics and the diagnosis of human illnesses.

Biofilms in SSIs

Biofilms are defined as complex three-dimensional communities of microorganisms usually found attached to inert or living surfaces and encased within a self-produced protective matrix of extracellular polymeric substances (EPS). The biofilm is essentially composed of water, microbial cells, and EPS, including polysaccharides, proteins, lipids, extracellular enzymes, metal ions, and nucleic acids such as extracellular DNA. Figure 1 illustrates the main constituents of a biofilm.

Biofilm-Forming Bacteria Associated with SSIs

Depending on the procedure performed, some of the most common endogenous microorganisms associated with SSIs are Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus, and Escherichia coli. On the other hand, exogenous sources of microorganisms are usually found in the operating room environment, including air, surgical instruments, materials, and staff members. The most common exogenous microorganisms are staphylococci and streptococci.

Biofilm Recalcitrance to Antimicrobial Treatments

The majority of antimicrobial treatments currently available were generally developed and tested on planktonic bacteria. As a result, these treatments are frequently ineffective against pathogenic biofilms. Antimicrobial tolerance is mediated by several mechanisms, most of which are related to phenotypic alterations and multi-cellularity, rather than the type of genetic adaptation responsible for antibiotic resistance of the cells under planktonic conditions. New strategies for the prevention, removal, and complete eradication of microbial biofilms are urgently required to preclude or treat biofilm-associated infections.

Prevention of SSIs

Since SSIs lead to adverse patient outcomes, including prolonged hospitalization and death, several rules and guidelines must be applied to prevent them. It has been estimated that each patient with an SSI requires at least additional six days of hospitalization, thus doubling hospital care costs. However, approximately 40–60% of SSIs are preventable with the appropriate use of prophylactic antimicrobial agents. Several measures must be performed to guarantee significant reduction of wound infections. These include the following:

  • The patient must be well-prepared and informed about the operation and infection prevention measures
  • It is imperative to ensure that the patient does not have signs of ongoing infections, and if the patient does they need to undergo eradication of the infection before admission
  • Preoperative surgical site skin disinfection and hair removal should be appropriate for the location and type of procedure (clipping is preferred, as shaving causes skin damage and increases the risk of infection)
  • Operating room sterility rules must be followed
  • Peri- and postoperative administration of prophylactic antibiotics and appropriate wound dressings must be guaranteed for the specific procedure

Conventional Treatment and Management of Biofilm-Associated SSIs

In tissue-based infections, surgical debridement is usually performed, which consists of the removal of necrotic (devitalized) or infected skin tissue to promote wound healing. In addition, negative pressure wound therapy (NPWT) is also recommended for patients with an SSI.

On the other hand, device-related infections are caused by the colonization of microorganisms during the implantation processes, constituting a risk to the patient’s wellbeing and compromising the device function. Regarding the antibiotic therapy for the treatment of these It is also important to note that SSIs can be described as biofilm-mediated infections, it is frequently a combina- acute (<30 days) or chronic (>30 days) wound infection therapy of rifampin, a fluoroquinolone, followed by a tions (Figure 3). glycopeptide.

Novel Strategies to Control Biofilm-Associated SSIs

Currently, the survival of biofilm-forming bacteria and the emergence of new resistant bacterial infections pose a serious threat to public health and have created the need for novel antimicrobial and antibiofilm treatment strategies. Some of these strategies that are being presently adopted to treat SSIs associated with biofilm formation are: inhibiting the attachment of the microorganisms to the substratum, using special compounds that interfere with and unsettle the biofilm structure, and disrupting the biofilm at the initial stages.

For example, to help control the rate of SSIs, new antiadhesive surfaces with altered physical, chemical, and topographical properties that prevent microbial adhesion and thereby biofilm formation have been tested on several medical devices. Figure 4 details the antimicrobial and more importantly antibiofilm agents and strategic approaches that are currently being explored in several studies to help control biofilm-associated SSIs.

Nanotechnology-Based Strategies

Nanotechnology-based approaches, specifically functionalized NPs, have recently been investigated to be used against bacterial biofilm-mediated SSIs due to their strong bactericidal and antibiofilm properties. The study focused on assessing the efficacy of these NPs as natural drug carriers and coating agents on surgical sutures against 10 different reference microorganisms associated with biofilm formation in SSIs. For the study, a mixture of TIAB alongside Aloe vera extract and hyaluronic acid was applied on three commercially available and commonly used braided surgical sutures and exposed to different microorganisms (S. aureus, Enterococcus faecalis, and E. coli).

The results presented in this work confirmed that surgical sutures coated with Ag+–TiO2 NPs have the potential to interfere with the microbial QS system, thereby affecting biofilms’ adhesion and formation post-surgery, which decreases the chance of developing an SSI. The results regarding the in vivo wound healing assay confirmed that this PCBDA@AgNPs-CG dressing not only effectively inhibited biofilm formation of E. coli, the S. aureus reference strain, and methicillin-resistant S. aureus (MRSA) isolates but also reduced inflammation and promoted wound healing.

Plant-Based Strategies

Nevertheless, medicinal and aromatic plants per se constitute a large part of natural flora and are considered an important resource in various fields, especially in the pharmaceutical, flavor and fragrance, perfumery, and cosmetic industries. In this sense and considering their unique role in the self-defense mechanisms of plants against pathogenic microorganisms, phytochemicals have emerged as a promising alternative to current antimicrobial agents.

In addition, phytochemicals can be effective against multidrug-resistant bacteria, including S. aureus, E. coli, and K. pneumoniae, in both planktonic and biofilm forms. Moreover, phytochemicals can inhibit the QS mechanism primarily by blocking intercellular communication inducers, thereby suppressing signal transduction; play a significant role in inhibiting bacterial adhesions and suppression of genes involved in biofilm formation, and have the potential to interfere with the biofilm’s access to nutrients essentially required for adhesion and bacterial growth.

Implementation of Detection and Real-Time Monitoring Systems to Improve Biofilm Control Strategies

It is still necessary to develop accurate diagnostic tools for the detection and monitoring of bacterial infections. Machine learning systems can be an asset to determine bacterial concentrations in biofilms. More importantly, these deep learning models based on artificial intelligence can be trained to detect polymicrobial biofilms with 90% accuracy in contrast to 50% when compared to human experts, thus offering an accurate alternative to the commonly used and time-consuming biochemical methods. This approach alongside other important improvements of ultrasound contrast agents, such as encapsulated gas micro and nanobubbles, constitutes an advantage for monitoring the formation and growth of biofilms in real-time, as well as establishing the difference between infectious and healthy tissues.

Nevertheless, other studies in the literature also indicate that the use of ultrasound-assisted therapies can be efficient not only to detect early and mature biofilms, but also, to some extent, to help combat these microbial communities. However, several other approaches that were not referred to in the course of this review, especially ones based on synthetic biology, deserve to be mentioned as these hold substantial promise for controlling biofilms by improving and expanding existing biological tools.

Conclusion

Biofilms pose serious challenges to the global healthcare community as they are responsible for many difficult-to-treat infections, including SSIs, caused by pathogenic multidrug-resistant and biofilm-forming bacteria. Since biofilms are particularly problematic due to their inherited tolerance to host immune defenses, antimicrobials, and other stresses, some of the presently available conventional antibiotics are unable to completely treat infections, triggering the development of resistant bacteria. In recent years, many researchers have focused their attention on the development of new, safe, environmentally conscious, and efficient antibiofilm strategies as alternatives to conventional approaches. It was confirmed that these approaches constitute highly promising resistance-modifying antibiofilm agents and potent adjuvants that enhance the activity of conventional antibiotics through synergistic effects obtained in different combinations.

Although various antibiofilm strategies have been developed, it is still necessary to carry out additional studies to overcome issues associated with the lack of mechanistic and biological understanding of compound activity/biofilm interactions.

Source:  Hrynyshyn A, Simões M, Borges A. Biofilms in Surgical Site Infections: Recent Advances and Novel Prevention and Eradication Strategies. Antibiotics (Basel). 2022;11(1):69. Published 2022 Jan 7. doi:10.3390/antibiotics11010069