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

Antimicrobial Approaches

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 days[22] 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 review[33] 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 cells[36] 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 al[38] 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 case[41] 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 documented[47] 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 applied[50] 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 antiseptics[51] 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.

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