Time to Abandon Antimicrobial Approaches in Wound Healing: A Paradigm Shift

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.

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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 reported² 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 al⁵ 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 al⁷ found that, as expected, the skin in normal healthy volunteers is rich in biofilm and bacteria. Surprisingly, it was found⁷ 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 al¹⁵ 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. They¹⁵ 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 al¹⁸ 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.

For many years, the normal approach to treating infection has been to kill the microbes with antimicrobial approach using broad-spectrum antibiotics or antiseptics.

For internal body regions (eg, the blood), the body seeks to keep these areas sterile, and an antimicrobial approach will therefore support the efforts of the body. Antibiotics can often resolve a systemic infection in a few days²² and the antimicrobial approach for internal infections has proven highly successful.

On the other hand, external body surfaces are in constant contact with the environment, and the body actively hosts the complex ecosystem of the microbiome such that pathogens (disease-causing microbes) will have difficulty getting a foothold, and no single microbe readily can become dominant and take over control from the immune system. Thus, the body has chosen a fundamentally different approach to protecting its external surfaces compared with its internal areas. In this light, it is relevant to consider the medical value of an antimicrobial treatment approach against infections on external surfaces where the antimicrobial approach would interfere with the microbiome hosted by the body, potentially reducing the ability of the immune system to control healing.

Antimicrobial approaches (eg, antibiotics, antiseptics, honeys, and Dialkylcarbamoyl chloride [DACC]) have been used for the treatment of wounds, ulcers, and burns for many years and their mode-of-action include:

• Antibiotic and antifungal drugs selectively affect or block processes that occur only in bacteria or fungi; they will selectively kill bacteria and fungi without affecting human or animal cells.
• Antiseptics kill bacteria and fungi by chemical action (ie, they are poison to bacteria, fungi, and, often, viruses). They lack the specificity of antibiotics and antifungals, which means they also will kill human and animal cells. 
• Most honeys contain the enzyme glucose oxidase, which generates hydrogen peroxide; this is antimicrobial.
• Manuka honey contains the chemical methylglyoxal, an antimicrobial. Methylglyoxal affects human and animal cells similarly to an antiseptic.
• Dialkylcarbamoyl chloride is a hydrophobic ester that binds bacteria to its surface, if they are sufficiently close. When the layer is removed, the bacteria will be removed as well.

Within the last couple of years, a number of meta-analysis reviews have been conducted of clinical trials available on these approaches, and they have consistently concluded that there is insufficient clinical evidence to support their use in wound healing. Considering that most of these approaches have been in use for decades, this suggests they offer very limited benefits on wound healing. The following are excerpts from some of these analyses:

• “There is no robust evidence on the relative effectiveness of any antiseptic/antibiotic/anti-bacterial preparation evaluated to date for use on SWHSI [surgical wounds healing by secondary intention].”²³
• “The relative effects of systemic and topical antimicrobial treatments on pressure ulcers are not clear. Where differences in wound healing were found, these sometimes favoured the comparator treatment without antimicrobial properties.”²⁴
• “There is currently no robust evidence for differences between wound dressings for any outcome in foot ulcers in people with diabetes (treated in any setting). Practitioners may want to consider the unit cost of dressings, their management properties and patient preference when choosing dressings.”²⁵
• “It was often uncertain whether antiseptics were associated with any difference in healing, infections, or other outcomes [for burns].”²⁶
• “Systemic antibiotic prophylaxis in non-surgical patients was evaluated in three trials (119 participants) and there was no evidence of an effect on rates of burn wound infection.” And “topical silver sulfadiazine is associated with a significant increase in rates of burn wound infection and increased length of hospital stay.”²⁷
• “At present, no evidence is available to support the routine use of systemic antibiotics in promoting healing of venous leg ulcers.” “Current evidence does not support the routine use of honey- or silver-based products.”²⁸
• “Topical antiseptics, including chlorhexidine and povidone-iodine, can have a cytotoxic effect on keratinocytes and may actually impede wound healing as a result. In addition, chlorhexidine in particular can produce both otologic and ocular toxic effects when used on the face.”²⁹
• “Honey dressings do not increase rates of healing significantly in venous leg ulcers when used as an adjuvant to compression. Honey may delay healing in partial- and full-thickness burns in comparison to early excision and grafting.”³⁰
• “There is insufficient evidence to establish whether silver-containing dressings or topical agents promote wound healing or prevent wound infection; some poor quality evidence for silver sulfadiazine (SSD) cream suggests the opposite.”³¹
• “DACC coating was suggested to reduce post-operative infection rates and result in chronic wounds that subjectively looked cleaner and had less bacterial load on microbiological assessments.”³² This was based on a review of 3408 patients; no significant effects on wound healing were reported. 

Finally, in a 2016 review³³ based on published studies as well as clinical guidelines issued by professional organizations, the US Food and Drug Administration concluded: “The available evidence does not appear to demonstrate improved clinical outcomes from the use of antimicrobial dressings over non-antimicrobial dressings for the prevention or treatment of local wound infections or to improve wound healing.”

Several of the reviews mention the cytotoxicity of antiseptics. eTable 1^34-36 shows all antiseptics are toxic to human and animal cells at the concentrations used in wound care. This means all antiseptics, in addition to killing bacteria, also kill cells in the wound, such as newly formed tissue generated to close the wound. The toxic effects are usually seen at concentrations lower than those used clinically. It has, for example, been shown that polyhexamethylene biguanide (PHMB) at a concentration of 0.0002% accumulates internally in cells³⁶ and that PHMB in concentrations of 0.002% to 0.01%, over a period of 3 hours,³⁷ will kill almost all cells. These concentrations are far below the clinical concentrations of 0.1% to 0.5% used in wound care. Furthermore, Yabes et al³⁸ have shown toxicity increases if the cells are exposed to the antiseptics for longer periods of time. Recently, an animal study found 3 commonly used antiseptics (silver, octenidine, and PHMB) inhibited the formation of granulation tissue,^39,40 and a clinical case⁴¹ reported PHMB disrupted the healing process and caused tissue and bone damage. Hence, the cell culture findings are reflected on wounds.

Manuka honey achieves its antimicrobial effects from the chemical methylglyoxal, and it has been shown to be cytotoxic.³⁸ Manuka honey consequently behaves very similar to a traditional antiseptic. Furthermore, research^42-46 has linked methylglyoxal as a causative agent to diabetes, Parkinson’s disease, and Alzheimer’s disease, and methylglyoxal has been documented⁴⁷ to delay wound healing in rats. 

Honeys, other than Manuka honey, normally achieve their antimicrobial properties from the enzymatic generation of hydrogen peroxide.⁴⁸ Hydrogen peroxide is used by the body in a number of physiological functions, including the killing of bacteria by neutrophils,⁴⁹ and the body, consequently, has the necessary enzymes for its degeneration. When the body uses hydrogen peroxide, it is applied locally and short-term, contrasting the way it is used in wound dressings, where it is applied to large areas and normally for longer periods of time. However, hydrogen peroxide increases in toxicity the longer it is applied⁵⁰ and depending upon dose. It will, therefore, cause cytotoxicity when used in wound dressings.

Finally, it is well known that antimicrobial resistance can develop to antibiotics and antifungals. However, data also show similar problems exist for antiseptics⁵¹ and most likely for Manuka honey, too, as it uses chemical action as well. The unrestricted use of antiseptics in situations where they are known not to provide clear clinical benefit should be questioned.

In summary, the use of antimicrobial approaches for the treatment of wound infections has not been supported by clinical data despite the fact that most of these have been used for decades and that substantial clinical experience with them is available. 

Micropore particle technology (MPPT) is a different approach to wound care that does not depend upon antimicrobial action. It (Acapsil [Willingsford Ltd, Southampton, UK]; SertaSil [Willingsford Ltd]; Amicapsil [Willingsford Ltd]; Aprobaxil [Willingsford Ltd]) consists of fine, highly porous particles that absorb wound exudate into a micropore structure (eFigure 2). Here, capillary action pulls the exudate away from the wound surface towards the upper surface of the MPPT layer, where a highly expanded surface area facilitates effective evaporation. The MPPT essentially acts as small micropumps, which, due to their small size, are able to access all crevices in the wound surface. MPPT has not shown any indications of causing cytotoxicity.

As shown in eTable 2, MPPT lacks in vitro antimicrobial action. One gram of MPPT was added to 100 mL tryptone soya broth (TSB) and 5 mL of the mixture was pipetted into each of 8 MPPT Petri dishes, 5 mL of pure TSB was pipetted into each of 8 control Petri dishes, and 0.1 mL of suspension of each bacterial strain to be evaluated (~1 x 10³ CFU/mL) was added to 2 Petri dishes of each group. Molten tryptone agar was added to each Petri dish, mixed, and allowed to settle. The strains evaluated were Pseudomonas aeruginosa, S aureus, Bacillus subtilis, and Candida albicans. The plates were incubated for 4 days at 30°C, after which the number of colonies were counted. The number of organisms recovered in the MPPT group was similar to the control, demonstrating MPPT does not have any antimicrobial effects on bacteria or fungi. 

In collaboration with Dr. M. Alhede from the Biofilm Test Facility, University Hospital of Copenhagen (Copenhagen, Denmark), the effects of MPPT on biofilm were evaluated.^52,53 Three separate cultures, each with 4 replicates, were established of P aeruginosa. The surface of the biofilm was exposed directly to the air. One culture was the control, a second had 3 mm of MPPT applied onto the surface of the culture at 0 hours, and a third culture had 3 mm of MPPT applied at 24 hours.⁵³ All cultures were analyzed at 48 hours, which corresponds to a mature biofilm culture. The samples were rinsed and 1 culture from each dish was photographed and the thickness of the cultures was determined by confocal laser scanning microscopy.⁵³

As shown in eFigure 3, MPPT disrupted the surface of the cultures, but it did not inhibit the ability of the bacteria to produce biofilm, which can be seen by the increased thickness of the cultures. In a separate experiment, MPPT was applied at 32 hours and washed off at 48 hours, and, at 72 hours, the cultures were sectioned and dyed to image any dead cells; the procedure was selected to resemble the clinical use of MPPT. The MPPT group did not show any signs of increased numbers of dead bacteria.

Micropore particle technology has been evaluated in a randomized, comparative clinical study with 266 patients.⁵⁴ The effects of MPPT on the healing of critically colonized to locally infected wounds, diabetic foot and venous leg ulcers, and burns were compared with a topical antibiotic (gentamicin in a polydimethylsiloxane absorbent powder) and to an antiseptic (iodine/dimethyl sulfoxide [DMSO] combination, where DMSO improves iodine tissue penetration). Bilyayeva et al⁵⁴ found MPPT, relative to the antibiotic and the antiseptic, reduced the time to reaching a wound free of necrosis, pus, and infection by 60% and initiated 50% faster onset of granulation and epithelialization; the effects were independent of wound type. In addition, MPPT reduced hospitalization days by 41% for acute wounds, 31% for diabetic foot ulcers, and 19% for venous leg ulcers relative to the antibiotic and by 44%, 51%, and 36%, respectively, relative to the antiseptic. These effects appeared to correlate with the degree of underlying disease processes.

In addition, MPPT has been evaluated at Bristol University Hospital⁵⁵ on 9 dehisced surgical wounds and 1 category 4 pressure ulcer. Most of the wounds displayed > 40% slough and signs of local infection. The MPPT was applied once daily for 2 to 5 days, and this was sufficient to reach a clean, actively healing wound and facilitate a rapid build-up of granulation tissue. All wounds continued towards full closure much faster than normal. No adverse events were reported.Standard of care normally would have consisted of, on average and assuming no complications developed, 1 week with UrgoClean (URGO Medical, Paris, France) followed by 2 or more weeks with negative pressure wound therapy to reach a stage where exudate level and critical colonization were under control and the wound had initiated healing (ie, the stage reached in 2-5 days with MPPT). 

At University Hospitals Birmingham, MPPT was evaluated in 3 cases of stable, inactive, chronic pyoderma gangrenosum (PG) ulcers.⁵⁶ The patients were on immunosuppressants (mycophenolate mofetil), antibiotics (doxycycline), and corticosteroids (dermovate). Micropore particle technology was applied to the ulcers once daily for 5 days. In all patients, increased granulation, reduced slough, and controlled exudate were seen, and the ulcers continued to improve 2 to 3 months after the last application (latest observation). In 1 patient, the dose of immunosuppressant was reduced.

In a preclinical rat wound model,⁵⁷ the effects of MPPT on wound healing and the immune response were measured. An aseptic abscess was induced by injecting an alkaline solution into the skin under local anesthesia. After the abscess had formed, it was opened surgically, then the animals were divided into 3 groups: MPPT, topical antibiotic (gentamicin in a polydimethylsiloxane absorbent powder), and untreated control. The products were applied once daily until reaching a clean wound (ie, free from necrosis, pus, and fibrinogenous thickenings). The group receiving MPPT reached the clean-wound stage 60% faster than the other groups, and the wounds closed significantly faster (the same degree of effect as reported in the comparative clinical study⁵⁴). The study⁵⁷ was performed in young, still growing animals and only rats in the MPPT group gained weight during the study, whereas the other groups demonstrated impeded growth. Retarded growth is a very important indicator of an organism being exposed to severe stressors, and the weight gain in the MPPT group indicates that MPPT reduced the impact of the stress associated with the wound on the organism.

The speed of invasion of microorganisms into the wound was measured, and it was identical for the MPPT and the control groups, whereas the topical antibiotic had a significantly slower rate of invasion.⁵⁷ This demonstrates that MPPT does not inhibit normal wound colonization, which is consistent with its lack of antimicrobial effects and that an antibiotic, as expected, will delay invasion. 

Swabs of the wounds were taken at regular intervals during the first 48 hours and analyzed for the presence of immune cells. It was found (eFigure 4⁵⁷) that the topical antibiotic and the control groups both almost exclusively showed a presence of neutrophils throughout the measurement period, whereas the MPPT group had a faster and significantly stronger invasion of immune cells with a lower proportion of neutrophils and higher proportions and earlier presence of monocytes (precursor of macrophages) and lymphocytes.⁵⁷ Similar to macrophages (monocytes), lymphocytes are essential to healing. Comparing these findings (eFigure 4⁵⁷) to the study in GF mice (eFigure 1¹⁸), the distribution and temporal pattern of immune cells in the MPPT group is very similar to the pattern seen in the faster healing GF mice (ie, a reduced proportion of neutrophils and an earlier presence and higher proportion of immune cells associated with the second phase of the immune response). This indicates that the application of MPPT results in a wound environment more closely resembling a GF state, in which the impact of the presence of microorganisms on the wound and on the immune response is reduced. 

Clinical findings^54-56 and veterinary use of MPPT for wound care have consistently shown MPPT will remove critical colonization and local infections from wounds and support healing. Micropore particle technology lacks antimicrobial action and uses only physical actions for the removal of wound exudate, but it is a powder that is in direct, close contact with the wound surface. Here, the micropumping action will effectively remove any wound exudate, and this action will simultaneously remove the toxins and degrading enzymes secreted by bacteria and fungi into the wound exudate to inhibit the immune system. The removal of these toxins and enzymes will enable the immune system to recover and regain its ability to control the composition of the microbiome, such as selectively killing unwanted microorganisms. Also, as aforementioned, MPPT will create holes by suction in biofilm, which consists of 90% to 95% water, and this will furthermore enable the immune cells to enter the biofilm and reach microorganisms hiding within. Together, these effects of MPPT essentially would disrupt the 2 primary defense systems of bacteria and fungi; thus, it would act as a passive immunotherapy that returns the control of the microbiome and the healing process to the immune system. It can, thereby unhindered, remove unwanted microorganisms to reach the composition or balance of microorganisms in the microbiome the body seeks. These actions would be consistent with the immune responses seen in the preclinical study⁵⁷ as well as with the observation in PG that a persistent change is seen in the wound environment. Finally, this mode of action also has the advantage that it will not be limited by or contribute to antimicrobial resistance, because it is based solely on physical action. 

Guest et al⁵⁸ reported that 48% of the wounds falling within the responsibility of a Clinical Commissioning Group in the United Kingdom (a group responsible for primary care in a certain geographic region) are chronic wounds. This is a very high proportion and raises the question of whether this can be attributed to the treatment approaches used in wound care, which predominantly would be antimicrobial approaches.⁵⁹ If this is the case, it is possible that the use of a nonantimicrobial approach could improve the outcome for these wounds. 

Micropore particle technology has been used on a number of infected wounds and ulcers that had not responded to a wide range of antimicrobial approaches and a few of these previously unpublished cases are briefly summarized below; MPPT was able to rapidly advance the healing of these wounds in these cases.

Case 1: chronic pressure ulcer
A 74-year-old paraplegic man had developed a category 3 or 4 pressure ulcer on the buttock. Hydrogel, Manuka honey, and Flaminal Forte (Flen Health, Senningerberg, Luxembourg), all in combination with DURAFIBER (Smith & Nephew, London, UK) packing, were used daily over a 9-week period, but no signs of healing were noted. The wound remained nonhealing and slowly deteriorating (ie, expanding). After having developed the ulcer, the patient at one point developed septicemia, which most likely originated from the ulcer. At 9 weeks, the ulcer had an external opening of 2 cm x 1.5 cm, but was deep with 2 sinuses (3 cm and 2.5 cm deep) and undermining (1 cm along the left half of the opening). Micropore particle technology was applied once daily for 3 consecutive days into the ulcer (ie, into the sinuses and covering all surfaces of the undermining). It immediately initiated healing, and from day 0 to day 6, there was > 90% reduction in the volume of the wound; the wound continued towards closure. 

Case 2: chronic diabetic foot ulcer
An 80-year-old woman with type 2 diabetes had a 3-year-old diabetic foot ulcer covering the entire plantar heel with a surface area of about 30 cm². A wide range of approaches had been attempted to facilitate healing without success. The ulcer was associated with considerable pain in the leg but not in the wound itself, which was without sensation due to diabetic neuropathy. The wound was washed with water and dried, MPPT was applied, and the foot was enclosed in a full cast to offload the heel. The following day, the wound had changed from a dark-red, very dull, lifeless appearance to a red color, normal of healing tissue; clear signs of granulation and epithelialization were present, and the pain level had reduced. This rapid reduction in pain level continued the following 2 days, and on the third day after first application, the pain was gone. This alone led to a huge increase in the patient’s state of mind. Four weeks after first application, the ulcer had decreased 55% in surface area, and at 16 weeks after first application, the wound had closed by 85%. Due to the necessity of the full cast, daily application was only achieved the first 3 days, thereafter it was applied twice weekly throughout the treatment period. 

Case 3: venous stasis ulcer
A 51-year-old man had developed a venous stasis ulcer of about 7 cm x 4 cm on the foot in the malleolus area. For the first 4 weeks, the ulcer had been managed with plain absorbent dressings without antimicrobials, and the severe pain had been just manageable with co-codamol (30 mg codeine/500 mg paracetamol) every 6 hours; this necessitated the daily use of laxatives. However, an infection developed. The ulcer was dressed with Manuka honey underneath full compression. The pain was reported to be excruciating and not controllable with the permitted maximum daily dose of co-codamol. As the ulcer had not improved after 2 weeks, treatment was changed to an iodine dressing under full compression. The pain level would increase even further, and this forced the removal of the dressing after 3 days (4 days prior to the planned dressing change). The ulcer was left for 6 days dressed with plain absorbent occlusive dressings. The pain reduced to the level of excruciating. As the infection and the pain were still uncontrolled, PHMB dressings under light compression were applied for 10 days, during which time the pain remained unchanged. After 10 days with PHMB, the infection and the pain were still not under control and MPPT was tried. The MPPT was applied on days 0 and 1. Twenty-four hours after first application, the infection had cleared and the pain reduced by half, this measure was based on the need of pain killers being halved. Within the subsequent 24 hours, the pain reduced again to the level that only 1 dose of pain relief was needed in the morning instead of 4 daily doses. Over the next days, the pain continued to reduce steadily, and 3 weeks after the first MPPT application, the patient did not need pain killers. As the infection was gone after the second application, the wound started healing with no further need of treatment. The wound was left with a permeable contact layer dressing, kept in place by stockinette. It was checked, and the described dressing changed after 3 days, then 5, then 7. After that, dressing changes were performed every other week, which then was extended to every 3 weeks. On day 90, the patient was discharged by his physician because they did not consider their supervision necessary. The wound was 2 mm x 3 mm, noninfected, and causing no pain. The ulcer closed fully.

Cases 4 and 5: biofilm in a pressure ulcer and in a venous stasis ulcer
eFigures 5 and 6 show 2 wounds – the first in a horse and latter in a person with venous stasis. Both wounds had a pale, lifeless appearance and had been stagnant for several months despite a number of attempts to promote healing. Twenty-four hours after MPPT application, the surface appearance changed completely, and the wounds started to progress towards healing (additional applications were required to reach closure). 

While these effects need to be formally evaluated, they are consistent with the notion that MPPT enables the immune system to rapidly regain control of the wound environment.

In a comprehensive analysis of the burden of wound care in the United Kingdom, Guest et al⁶⁰ found that 2.2 million wounds require extended treatment annually, placing a financial burden of £5.3 billion in direct cost on the health care system. These numbers highlight the significance of wounds in health care, but more worrying is the fact that the study found 39% of the wounds were unhealed during the observation period of 1 year and a subsequent study by the same group⁵⁷ reported 48% of the wounds managed in primary care are chronic. These statistics strongly signal that wound healing represents a substantial unmet medical need in terms of treatment options. Several reviews^23-33 have reached the conclusion that most of the existing approaches to wound care are ineffective and some may even interfere with healing. The limitations of these treatment options can explain the large proportion of chronic wounds seen and also the substantial costs associated with wound care, such as the average cost of a wound in the United Kingdom being £2410. 

Newer research^1-5 has found that the body actively supports a microbiome on its external surfaces and that it uses these microorganisms as part of its defense against pathogens in the environment. An antimicrobial approach necessarily will interfere with this environment and this may explain why antimicrobial approaches that have proven so effective for internal infections have minimal efficacy against skin and wound infections as they work in disagreement with the immune system.

Micropore particle technology is not antimicrobial, but instead acts as a passive immunotherapy, which by physical action disrupts the defense systems of bacteria and fungi. This results in 60% quicker removal of wound infections compared with antibiotics and antiseptics across many wound types. Furthermore, it has been able to initiate the healing of a number of nonhealing wounds that had failed to respond to existing approaches. These effects of MPPT clearly demonstrate the removal of wound infections does not require antimicrobial actions, but the data also suggest supporting the existing microbiome and the immune system will lead to substantially improved clinical outcomes compared with those achieved by an antimicrobial approach.

As of now, MPPT is the only therapy available that relies on this type of mode of action, but it demonstrates that it is feasible to remove infections without antimicrobial action and points to the possibility of pursuing completely new principles for the treatment of infection on external surfaces that harbor a microbiome. The data obtained with MPPT furthermore question the value of antimicrobial approaches and whether their routine use should be continued given that a number of meta-analysis studies^23-32 have not shown they provide clear medical benefits, given the high number of wounds that are nonhealing and that they contribute to the creation of antimicrobial resistance. The strong focus on antimicrobial approaches primarily stems from antibiotics and their highly successful use in the treatment of internal infections. This has led to the assumption in wound care that a reduction in microbial load equals a reduction in wound infection, but this assumption is not supported by clinical data. Therefore, as the body employs fundamentally different strategies for its protection against pathogens on external surfaces, it might be worth considering whether the treatment focus should follow a similar distinction. After all, the body might have its reasons as it has been dealing with this problem on an evolutionary timescale. Consequently, it may be time to propose a paradigm shift in the treatment of wounds away from antimicrobial approaches and towards approaches that support the immune system and the microbiome. 

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

Affiliation: Willingsford Ltd, Southampton, Hampshire, United Kingdom

Correspondence: Frank Sams-Dodd, PhD, Dr.med, Willingsford Ltd, NFEC, Rushington Business Park, Chapel Lane, Totton, Southampton, Hampshire SO40 9LA United Kingdom; fsd@willingsford.com

Disclosure: Mrs. Sams-Dodd and Dr. Sams-Dodd are paid employees of Willingsford Ltd (Southampton, Hampshire, United Kingdom).