Product classes to combat wound infections

How infections are treated

The normal approach to treating infection is to kill the microbes using broad-spectrum antibiotics and antiseptics. For internal body regions, e.g. the blood, these approaches will be optimal because they will support the body’s efforts to keep these areas sterile, e.g. antibiotics can often resolve a systemic infection in a few days.

However, external body surfaces are in constant contact with the environment and this makes it impossible to keep them sterile. Instead the body has chosen a different strategy and instead actively hosts a complex microbiome - i.e. an ecosystem of bacteria, fungi, viruses and mites – such that the pathogens, i.e. the dangerous microbes, cannot get a foothold and such that no single microbe can become dominant and suddenly take over control. Over 1000 species of bacteria have been identified on the human skin and studies have found that the diversity of the microbiome is often reduced in skin disease. This indicates that the optimal way to treat infections of external body surfaces is by supporting the re-establishment of the proper microbiome.

How to compare products?

The main parameters for comparing products are whether they are:

  • antimicrobial, i.e. kills bacteria and fungi.
  • cytotoxic, i.e. has toxic effects on the body’s own cells.
  • balancing the microbiome, i.e. returning control of the wound to the immune system.
  • able to remove wound infection and promote healing in patients.
 

Antimicrobial

Cytotoxic to human and animal cells

Balances the microbiome

Days to non-infected wound (mean±SD)*

Antibiotics

+

-

-

7.0 ± 1.2
Antiseptics

+

+

-

8.0 ± 1.1
MPPT

-

-

+

3.0 ± 0.9

Comparison of antibiotics, antiseptics and MPPT. *Data from Bilyayeva et al. (2017). The number of days to reach a non-infected wound, i.e. free of necrosis, pus and fibrinogenous thickenings, were recorded for MPPT (n=88), a topical antibiotic (gentamicin) (n=90) and an antiseptic (iodine combined with DMSO) (n=88).

The table above summarises the results from the clinical study, which compared the three main product groups and it was found that:

  • Antibiotics remove wound infections and start the healing significantly quicker than antiseptics. This correlate well with the finding that antiseptics are toxic to the body.
  • MPPT, which does not kill cells but instead balances the microbiome, removes infection and starts the healing 60% quicker than antibiotics and antiseptics.

Below the traditional product classes to resolve wound infections are described in detail with respect to their mode-of-action, cytotoxicity and effects on wound healing. They include:

  • Antibiotics and antifungals
  • Antiseptics
  • Honey and Manuka honey

 

Antibiotic and antifungal drugs

These drugs have been developed to selective affect or block processes that only occur in bacteria or fungi, e.g. preventing normal cell wall synthesis. Antibiotic and antifungal drugs will therefore selective kill bacteria and fungi without affecting the cells in our body or that of animals. However, they will affect all the bacteria or fungi that have that specific process and as the majority of these drugs have been developed to be “broad-spectrum”, i.e. affecting a wide range of types of bacteria and fungi, this means that they will kill most of the bacteria and fungi that they come in contact with. In relation to the microbiome, this will mean that they affect its composition significantly.

Antibiotics and antifungals have huge benefits in the treatment of infections, but they also have some disadvantages:

  • microbes can develop resistance to the drugs.
  • antibiotics have difficulty penetrating biofilm.
  • some individuals become sensitive to certain drug classes, e.g. penicillin.
  • prolonged use can cause side-effects, e.g. kidney damage.

 

Antiseptics

Antiseptics kill bacteria and fungi by chemical action. In contrast to antibiotics and antifungals, which affect specific physiological processes that only occur in bacteria or fung (pharmacological action), the antiseptics lack this specificity and therefore then to affec any living cells. This means that they also have effects on the body's own cells and this is often seen at the same or almost the same concentrations at which they kill microbes. Consequently, cell culture and animal studies often report toxic effects of antiseptics and clinical studies tend to show mixed effects of antiseptics as they both help to fight an infection, but at the same time inhibit the generation of new cells to heal the wound.

Antisepcits include compounds such as: PHMB, iodine (iodine, povodine, cadexomer), silver and chlorhexidine.

PHMB

PHMB (Poly(hexamethylene) biguanide hydrochloride with INCI name Polyaminopropyl Biguanide) was originally developed as a disinfecant, e.g. for swimming pools, but due to its strong antimicrobial actions its use was widened to wound care as well as in cosmetics. However, due to toxicity the maximal concentration in cosmetics was recently reduced from 0.3% to 0.1%.

PHMB is used in a number of wound care products, but its clinical effects have always been limited (Bellingeri et al. 2016; Norman et al, 2016 and 2017; Dumville et al. 2017). Recently, new data have emerged on PHMB.

Yabes et al. (2017), as shown above, found concentration and time-dependent cytotoxic effects of PHMB on keratinocyte, fibroblast and osteoblast survival in culture. For example at a concentration of 0.1% PHMB, which usually is used in wound care products, and exposure for 24 hours only 5-9% of these cells survived. The data are expressed as a percentage of the control group, which was saline.

Furthermore, Carroll & Ingram (2017) have reported in a porcine model of wound healing that PHMB completely inhibited the formation of granulation tissue. The study was made to evaluate the use of fluids to be infused into a NPWT (negative pressure wound therapy) setup as a number of studies have shown that the use of saline is beneficial. The idea was to evaluate an antimicrobial component, but instead of it helping the healing, it completely inhibited the generation of new tissue in the wound.

Recently, these findings have been extended to patients. A patient with a complicated, slow-healing wound (see case story) developed a strong adverse reaction to 0.1% PHMB, which included the appearence of gas production, possible damage to exposed bone and wound regression with damage to granulation tissue, fascia and epithelialising wound edges.

Together, these in vitro, in vivo and clinical findings clearly demonstrate that PHMB exerts toxic effects on the tissue and damages the wound.

Honey and Manuka Honey

Honey has been used for centuries in wound care, but detailed analysis has also found that all honeys are not the same. Honey has a number of actions, including the removal of wound exudate by osmosis but the main focus has been on its antimicrobial effects. Honey contains high amounts of sugar and it has, therefore, been necessary for the bees to find ways to limit bacterial growth.

Most honeys contain the enzyme glucose oxidase. This generates hydrogen peroxide, which is antimicrobial, i.e. kills bacteria and fungi. In relation to wound healing, hydrogen peroxide has the advantage that It exists naturally in the body, which means that the enzymes to degrade it will be available. However, it will damage the microbiome, because it is antimicrobial, i.e. kills bacteria and fungi broadly and high levels for longer periods are toxic to cells of the body(Tatnall et al. 1991).

  • Manuka Honey, in contrast, obtains its antimicrobial effects from the chemical methylglyoxal (Mavric et al. 2008), which originates from the flowers visited by the bees.
  • The concentration of methylglyoxal in Manuka honeys is up to 100-fold higher than in conventional honeys (Majtan 2011). Methylglyoxal is a potent protein-glycating agent and an important precursor of advanced glycation end products (AGEs), i.e. it damages proteins and produces toxic compounds.
  • Methylglyoxal and AGEs play a role in the pathogenesis of impaired diabetic wound healing and can modify the structure and function of target molecules. Berlanga et al. (2005) showed that methylglyoxal, when given orally to rats, causes microvascular damage and other diabetes-like complications, which are linked to delayed wound healing.
  • Yabes et al. (2017) showed that Manuka honey is toxic to cells involved in wound healing (kertinocytes, fibroblasts and osteoblasts). The data are shown above.
  • De Simone et al. (2017) demonstrated that methylglyoxal is a potent neurotoxin, i.e. it kills nerve cells and Retamal et al. (2016), using primary cultures of human fibroblasts, found that soluble methylglyoxal is highly cytotoxic and induces cell death through apoptosis.
  • Liu et al. (2017) found a higher incidence of Parkinson’s Disease in diabetics and diabetics have high level of methlyglyoxal as a result of type 2 diabetes and Xiu et al. (2017) found that methylglyoxal caused increased dopamine release.
  • Angeloni et al. (2014) reported that methylglyoxal is strictly correlated with an increase of oxidative stress in Alzheimer’s disease and that many studies show that methylglyoxal and methylglyoxal-derived AGEs play a key role in the etiopathogenesis of Alzheimer's disease.
  • There is a lack of studies demonstrating clear wound healing effects of Manuka honey (Jull et al. 2015; Carter et al. 2016).
  • It is well known that bees can collect honey from certain flowers and that this can result in toxic to lethal honey (Islam et al. 2014).

In conclusion, the use of any type of honey will damage the wound microbiome and disrupt the actions of the immune system toward regaining control over the wound. With respect to Manuka honey it has repeatedly been shown to kill the cells involved in wound healing and a strong body of data indicate that it induces a state comparable to diabetes, which will result in delayed wound healing.

References

Bellingeri A, Falciani F, Traspedini P, Moscatelli A, Russo A, Tino G, Chiari P, Peghetti A. Effect of a wound cleansing solution on wound bed preparation and inflammation in chronic wounds: a single-blind RCT. J Wound Care 2016;25(3):160, 162-6, 168. https://www.ncbi.nlm.nih.gov/pubmed/26947697

Berlanga et al. Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds. Clin Sci (Lond). 2005 Jul;109(1):83-95. https://www.ncbi.nlm.nih.gov/pubmed/15755259

Carroll, AC and Ingram, S. Comparison of Topical Wound Solutions for Negative Pressure Wound Therapy with Instillation: Effect on Granulation in an Excisional Non-Infected Acute Porcine Wound Model. Symposium on Advanced Wound Care, October 20-22, 2017, Las Vegas, NV. http://www.acelity.com/cs/Satellite?blobcol=urldata&blobkey=id&blobtable=MungoBlobs&blobwhere=1440448146017&ssbinary=true

Carter DA, Blair SE, Cokcetin NN, Bouzo D, Brooks P, Schothauer R, Harry EJ. Therapeutic Manuka Honey: No Longer So Alternative. Front Microbiol. 2016;7:569. https://www.ncbi.nlm.nih.gov/pubmed/27148246

De Simone U, Caloni F, Gribaldo L, Coccini T. Human Co-culture Model of Neurons and Astrocytes to Test Acute Cytotoxicity of Neurotoxic Compounds. Int J Toxicol. 2017;36(6):463-477. https://www.ncbi.nlm.nih.gov/pubmed/29153031

Dumville JC, Lipsky BA, Hoey C, Cruciani M, Fiscon M, Xia J. Topical antimicrobial agents for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. 2017;6:CD011038. https://www.ncbi.nlm.nih.gov/pubmed/28613416

Liu S (2017) Potential role of methylglyoxal in inducing Parkinson’s disease. Thesis: https://rucore.libraries.rutgers.edu/rutgers-lib/52228/

Islam MN, Khalil MI, Islam MA, Gan SH. Toxic compounds in honey. J Appl Toxicol. 2014 Jul;34(7):733-42. doi: 10.1002/jat.2952. https://www.ncbi.nlm.nih.gov/pubmed/24214851

Jull AB, Cullum N, Dumville JC, Westby MJ, Deshpande S, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev 2015;(3):CD005083. https://www.ncbi.nlm.nih.gov/pubmed/25742878

Majtan J. Methylglyoxal-a potential risk factor of manuka honey in healing of diabetic ulcers. Evid Based Complement Alternat Med. 2011;2011:295494. doi: 10.1093/ecam/neq013. Epub 2010 Oct 14. https://www.hindawi.com/journals/ecam/2011/295494/

Mavric E, Wittmann S, Barth G, Henle T. (2008) Identification and quantification of methylglyoxal as the dominant antibacterial constituent of Manuka (Leptospermum scoparium) honeys from New Zealand. Mol Nutr Food Res. 2008 Apr;52(4):483-9. doi: 10.1002/mnfr.200700282. https://www.ncbi.nlm.nih.gov/pubmed/18210383

Norman G, Dumville JC, Moore ZE, Tanner J, Christie J, Goto S. Antibiotics and antiseptics for pressure ulcers. Cochrane Database Syst Rev. 2016;4:CD011586. https://www.ncbi.nlm.nih.gov/pubmed/27040598

Norman G, Christie J, Liu Z, Westby MJ, Jefferies JM, Hudson T, Edwards J, Mohapatra DP, Hassan IA, Dumville JC. Antiseptics for burns. Cochrane Database Syst Rev 2017;7:CD011821. https://www.ncbi.nlm.nih.gov/pubmed/28700086

Retamal IN, Hernández R, González-Rivas C, Cáceres M, Arancibia R, Romero A, Martínez C, Tobar N, Martínez J, Smith PC. Methylglyoxal and methylglyoxal-modified collagen as inducers of cellular injury in gingival connective tissue cells. J Periodontal Res. 2016;51(6):812-821. https://www.ncbi.nlm.nih.gov/pubmed/26847600

Tatnall FM, Leigh IM, Gibson JR. Assay of antiseptic agents in cell culture: conditions affecting cytotoxicity. J Hosp Infect. 1991 Apr;17(4):287-96. https://www.ncbi.nlm.nih.gov/pubmed/1677654

Yabes JM, White BK, Murray CK, Sanchez CJ, Mende K, Beckius ML, Zera WC, Wenke JC, Akers KS. In Vitro activity of Manuka Honey and polyhexamethylene biguanide on filamentous fungi and toxicity to human cell lines. Med Mycol. 2017;55(3):334-343. https://www.ncbi.nlm.nih.gov/pubmed/27601610

Xie et al. Methylglyoxal increases dopamine level and leads to oxidative stress in SH-SY5Y cells. Acta Biochim Biophys Sin (Shanghai). 2014 Nov;46(11):950-6. doi: 10.1093/abbs/gmu094. Epub 2014 Oct 1. https://www.ncbi.nlm.nih.gov/pubmed/25274329