Time to Abandon Antimicrobial Approaches in Wound Healing

A Paradigm Shift

Jeanette Sams-Dodd, BSc, BScVet; Frank Sams-Dodd, PhD, Dr.med

Disclosures

Wounds. 2018;30(11):345-352. 

In This Article

Abstract and Introduction

Abstract

Antimicrobial approaches (eg, antibiotics and antiseptics) have been used for decades in the treatment of infected wounds, ulcers, and burns. However, an increasing number of meta-analyses have raised questions regarding the therapeutic value of these approaches. Newer findings show that the body actively hosts an ecosystem of bacteria, fungi, viruses, and mites on its outer surfaces, known as the microbiome, as part of its defense against pathogens. Antimicrobials would disrupt this system and thereby work against the strategy the body has chosen. Recently, a new technology, micropore particle technology (MPPT), has been identified; it is not an antimicrobial but instead acts as a passive immunotherapy that disrupts the weaponry bacteria and fungi use to inhibit the immune system, allowing the immune system to recover. Clinical findings show MPPT removes wound infections 60% quicker than antibiotics and antiseptics and promotes the healing of chronic wounds that have not responded to antimicrobials. These effects are achieved without antimicrobial action and, considering the limited therapeutic benefits of antibiotics and antiseptics for wound infections, it is valid to question the use of antimicrobial approaches in wound care and the dogma that a reduction in microbial burden will lead to a reduction in infection. Instead, it may be time to consider a paradigm shift in wound healing away from antimicrobials and towards therapies that support the immune system and the microbiome. This review covers the increasing evidence that infections on external surfaces have to be treated fundamentally differently to internal infections.

Introduction

Bacteria, fungi, and biofilm normally are associated with disease states, but an increasing body of data clearly proves that the skin in its normal, healthy state is inhabited by a rich variation of microorganisms, including bacteria, fungi, viruses, and mites.[1] It has been reported[2] that more than 1000 species of bacteria live on the human body. This mini-ecosystem, which extends deep into the subepidermal layers,[3] is called the microbiome, and data indicate that the immune system controls the composition of the microbiome and that this composition is individual, age, hormonal state, food, and location dependent.[1,4] Pellegatta et al[5] showed the microbiome and the immune system interact, with the immune system learning from the microbiome. From a biological perspective, this seems logical as the body would have to utilize enormous resources if it had to keep the body surfaces sterile. Evolutionarily, it would be much more advantageous to adapt the body to the presence of microorganisms on external surfaces and to use them for its own protection. This contrasts with the situation inside the body, where it is possible to maintain a sterile environment.[6]

Microorganisms must attach themselves to the body surface, and a recent study by Ring et al[7] found that, as expected, the skin in normal healthy volunteers is rich in biofilm and bacteria. Surprisingly, it was found[7] that patients with hidradenitis suppurativa, a chronic inflammatory skin disease, lack biofilm and have a low presence of skin bacteria, indicating that the disease state was the absence of a healthy microbiome embedded in biofilm. Therefore, these findings support the hypothesis that the presence of biofilm and a rich microbiome is required for healthy skin.

The generation of a wound suddenly creates an area filled with moisture, warmth, and nutrients, where the balance of the microbiome is completely disturbed or absent; this area creates opportunities for colonization by new microorganisms or for expansion by existing microorganisms. Studies have found bacterial species that form part of the healthy skin microbiome can become pathogenic if they are given the opportunity to dominate, such as Staphylococcus epidermidis,[8] but also that the same bacterium in a different context can assist the body in reducing strains that have achieved a dominant position, eg, S epidermidis can inhibit biofilm formation by S aureus.[9] This suggests if one or a few bacterial species become dominant, an infection or critical colonization is likely to develop and may interfere with healing. The immune system will seek to avoid this from happening, but bacteria secrete toxins and degrading enzymes to inhibit the functions of immune cells[10–13] and secrete biofilm to create a fortress around them that the immune cells cannot penetrate.[14] The defense systems of bacteria and fungi will, in this way, seek to inhibit the immune system, and they will instead try to become dominant to control the environment.

Loesche et al[15] found chronic diabetic foot ulcers with a fluctuating microbiome had a higher probability of healing compared with those with a less varied and less fluctuating microbiome, and if the microbiome stalled (ie, stopped changing), the wound would remain nonhealing. Presumably, a fluctuating microbiome can reduce the probability of a specific organism assuming control and will make it easier for the immune system to control the environment. They[15] also reported the use of antibiotics destabilized the microbiome but did not appear to alter the overall diversity or relative abundance of specific species (ie, the microbiome did not shift to a new state) and it did not lead to healing. The same group also discovered that the fungal microbiome was more predictive of healing than the bacterial microbiome for chronic wounds.[16] To achieve healing, the goal seems to be for the wound to reach a balance consisting of a diverse population of bacteria and fungi coexisting in the skin but controlled by the immune system. Newer findings indicate the existence of a dedicated "skin immune system," emphasizing the importance of controlling and maintaining this external barrier.[17]

To determine the impact of the microbiome on the wound healing process, Canesso et al[18] compared wound healing in germ-free (GF; ie, sterile) mice with normal mice and, in parallel, monitored the immune response to determine what this would be without any interference from bacteria and fungi (eFigure 1). The GF mice demonstrated significantly faster wound closure compared with normal mice, indicating that under normal conditions the early invasion of the wound by bacteria and fungi has a negative effect on the healing process. The immune response in the GF mice demonstrated a lower proportion of neutrophils and an earlier and higher proportion of macrophages and mast cells compared with normal mice. Neutrophils usually are the first immune cells to reach a wound, where they produce antimicrobial substances and proteases that help kill and degrade potential pathogens as well as phagocytize them, and they furthermore clean the wound of dead or dying tissue. High levels of neutrophils have been associated with reduced healing, although it is not known whether it is the neutrophils themselves or the problem they are seeking to solve that is interfering with healing. Macrophages, on the other hand, are required for healing and they normally appear later in the wound healing process compared with neutrophils.[19–21] These findings also indicate that under normal conditions (without an actual infection), the presence of microorganisms has a negative influence on wound healing and that the immune system responds to this presence by early increased levels of neutrophils followed by a later increase in macrophages, presumably when the wound is ready to move to the next phase in the healing process. In contrast, if these microorganisms are absent, the neutrophil response is reduced, and a more rapid shift to the next phase (an increase in macrophages) is seen, which likely will translate into the faster healing observed.

eFigure 1.

The influence of commensal microbiome on tissue repair of excisional skin wounds was evaluated in germ-free (GF) Swiss mice. (A) The macroscopic wound closure rate was accelerated in GF mice; and the wounds of GF mice presented a significant (B) decrease in neutrophil accumulation and (C) an increase in macrophage infiltration into wounds.
From Figures 1B, 3A, and 3B of Canesso et al.18 Reprinted with permission; copyright 2014. The American Association of Immunologists, Inc.

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