Sunday, 19 February 2017

Antimicrobial Benefits of Manuka Honey

Honey has been used as a medicine throughout the history of the human race. One of the most common and persistent therapeutic uses of honey has been as a wound dressing, almost certainly due to its antimicrobial properties. With the advent of highly active antibiotics in the 1960s, honey was dismissed as a “worthless but harmless substance”.

In traditional medicine, honey has been recognised around the world for its skin healing properties. The ancient Greeks and Egyptians, for example, used topical application of honey to treat skin wounds and burns and Persian traditional medicine documented honey as effective in the treatment of wounds, eczema and inflammation. Micro-organisms have been associated with the pathophysiology of a range of dermatological disorders. Wound infections, for example, are commonly caused by the micro-organisms Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli and infection with S. aureus is common in atopic dermatitis. Other examples are Malassezia yeasts which have been associated with the skin conditions pityriasis versicolor, seborrheic dermatitis, atopic dermatitis and psoriasis. Conventional treatments for some of these conditions are unsatisfactory e.g. corticosteroids which can cause skin thinning and ultraviolet radiation therapy has been associated with the development of skin cancer.

Scientists first reported the ability of honey to kill disease causing microbes in the late 1800s but with the advent of antibiotics in the early 1900s scientific interest in honey waned. Today, with the emergence of antibiotic resistant microbial strains, such as Methicillin resistant Staphylococcus aureus (MRSA); a cause of difficult to treat wound infections and a global health concern, honey has again caught the attention of medical researchers. In clinical practice today, Manuka Honey produced by honey bees (Apis mellifera) collecting nectar from the Manuka tree (Leptospermum scoparium) is used topically in the management of wound infections. Products include: irradiated honey in gels, ointments and impregnated dressings. Revamil honey is another medical grade honey commonly used in clinical practice for wound care. It is produced in greenhouses by manufacturers in the Netherlands but further details about the origin of the honey have not been disclosed.

However, the current and growing crisis of antibiotic resistance has revived interest in the use of honey, both as an effective agent in its own right and as a therapeutic lead to develop new methods of treatment. I have previously written about the growing problem of antimicrobial resistance. You can download the article here: http://www.yaso-shan.co.uk/publishingantimicrobial-resistance/ and http://www.yaso-shan.co.uk/wp-content/uploads/2015/08/Antimicrobial-Resistance-2016.pdf 

Medicinal honey research is undergoing a substantial renaissance. From a folklore remedy largely dismissed by mainstream medicine as “alternative”, we now see increased interest by scientists, clinical practitioners and the general public in the therapeutic uses of honey. There are a number of drivers of this interest: first, the rise in antibiotic resistance by many bacterial pathogens has prompted interest in developing and using novel antibacterials; second, an increasing number of reliable studies and case reports have demonstrated that certain honeys are very effective wound treatments; third, therapeutic honey commands a premium price, and the honey industry is actively promoting studies that will allow it to capitalise on this; and finally, the very complex and rather unpredictable nature of honey provides an attractive challenge for laboratory scientists. Honey is usually derived from the nectar of flowers and produced by bees, most commonly the European honey bee Apis mellifera, and is a complex mix of sugars, amino acids, phenolics, and other substances. Honey types derived from different flowering plants vary substantially in their ability to kill bacteria, and this has complicated the literature on honey and made it sometimes difficult to reproduce results across different studies. 

The majority of recent studies investigating the mechanism of action of honey have focused on well- characterised, standardised, active manuka honey produced by certain Leptospermum species native to New Zealand and Australia, which has been registered as a wound care product with appropriate medical regulatory bodies.

Honey: A realistic antimicrobial for disorders of the skin
Resistance of pathogenic microorganisms to antibiotics is a serious global health concern.  Research investigating the antimicrobial properties of honeys from around the world against skin relevant microbes has previously been evaluated, as illustrated in the table below.



Table 1. Activity of some honeys from around the world against common skin relevant microbes
Type of honeyMRSAStaphylococcus aureusPseudomonas aeruginosaEscherichia coliCandida albicansDermatophytesMalassezia speciesHPV
Manuka honeya+(12)+(11)+(11,12)+(11 and 12)(14 and 15)+(13)ϮϮ
Scottish heather honeyb+(23)+(23)+(23)+(23)ϮϮϮϮ
Portobello honeybϮ+(22)+(22)+(22)ϮϮϮϮ
Tualang honeyc+(11)+(11 and 27)+(11 and 27)+(11 and 27)ϮϮϮϮ
Numbers in brackets are references.
HPV = human papilloma virus; MRSA = methicillin-resistant S. aureus; + = active; − not active or low activity; Ϯ = unknown.



a
New Zealand.
b
Scotland.
c
Malaysia.

Taken from McLoone et al., 2016

A plethora of in vitro studies have revealed that honeys from all over the world have potent microbicidal activity against dermatologically important microbes. Moreover, in vitro studies have shown that honey can reduce microbial pathogenicity as well as reverse antimicrobial resistance. Studies investigating the antimicrobial properties of honey in vivo have been more controversial. It is evident that innovative research is required to exploit the antimicrobial properties of honey for clinical use and to determine the efficacy of honey in the treatment of a range of skin disorders with a microbiological aetiology. 

Antimicrobial properties of Manuka honey against skin relevant microbes: in vitro studies
The most widely researched honey, to date, is Manuka honey from New Zealand. Studies have shown that Manuka honey has antimicrobial activity in vitro against the most common wound-infecting microorganisms, including MRSA, S. aureus, P. aeruginosa, and E. coli. Manuka honey can also inhibit the growth of Streptococcus pyogenes, a cause of cellulitis, impetigo, and necrotising fasciitis, and the dermatophyte Trichophyton mentagrophyte, a cause of ringworm.

Indeed, Manuka honey has been shown to inhibit the growth of a range of dermatophytes, including Epidermophyton floccosum, Microsporum canis, Microsporum gypseum, Trichophyton rubrum, and Trichophyton tonsurans, indicating that honey may be a therapeutic in the treatment of dermatophytosis (tinea infections). Studies have reported that Candida albicans (cause of thrush and general dysbiosis) is more resistant to Manuka honey than many other microbial species. Manuka honey has also been shown to have antiviral activity in vitro against Varicella zoster virus, suggesting that honey may be a therapeutic for viral skin rashes. The antiviral properties of honey against other skin relevant viruses such as human papilloma virus may be worth investigating.

As the antimicrobial activity of honey varies not only between different types of honey but also between batches of the same type of honey, Manuka honey is often ascribed a unique Manuka factor (UMF). The UMF is a measure of the strength of the antibacterial activity of the honey against S. aureus and is calculated based on the concentration of a phenol solution that gives a similar zone of growth inhibition, in a radial diffusion assay, to the honey being tested. A criticism of the UMF classification is that it is a measure of  activity against S. aureus only and not against other relevant microbes.

Antimicrobial properties of honey: in vivo human studies
The majority of studies to date have demonstrated the antimicrobial activity of honey against a range of microbial strains including clinical isolates, using in vitro antimicrobial assays. Fewer studies have demonstrated the antimicrobial activity of honey in vivo; studies carried out so far have mainly investigated the antimicrobial activity of honey in relation to wound infections. In the first decade of the 21st century, several case studies involving wound patients produced optimistic findings. A brief report published in 2001 by Cooper et al., described how treatment of a S. aureus-infected, recalcitrant surgical wound in a 38-year-old female with Manuka honey-impregnated dressings and oral coamoxiclav resulted in significant healing of the wound and bacterial clearance 7 days after commencing the treatment. The wound was 3 years old, and had failed to respond to other conventional wound treatments and antibiotics during the 3-year period prior to commencing the honey/antibiotic combination therapy. 

In another report published in 2001, Natarajan et al., treated an MRSA-infected leg ulcer of an immunosuppressed patient with topical application of Manuka honey; consequently, MRSA was eradicated and the wound successfully healed. Another scientific study (Chamber, 2006) reported that bacterial clearance in three cases of MRSA-infected leg ulcers following treatment with topical Manuka honey, while Visavadia et al., in 2008 reported that Manuka honey, based on clinical experience, was now one of their first-line treatments for infected wounds at the Maxillofacial Unit at the Royal Surrey County Hospital, Guildford, Surrey.

However, larger clinical studies have produced more controversial findings. Gethin and Cowman (2008) recruited 108 patients with venous leg ulcers and treated them with either Manuka honey or hydrogel. In their study, Manuka honey successfully eliminated MRSA from 70% of MRSA-infected wounds; in comparison, hydrogel eradicated MRSA from only 16% of infected wounds. For P. aeruginosa-infected wounds, Manuka honey cleared infection in just 33% of wounds, whereas hydrogel cleared infection in 50% of wounds. In 2008, Jull et al., conducted results from a randomised clinical trial of 368 participants, and reported that were no significant difference in occurrence of infection in venous leg ulcers treated with either Manuka honey impregnated dressings or usual care. Another clinical study showed no significant difference, in terms of development of peritoneal dialysis-related infections when patients undergoing peritoneal dialysis were treated with either Medihoney antibacterial wound gel (containing honey from Leptospermum species) or the topical antibiotic mupirocin applied to catheter exit sites.

CONCLUSIONS
It can be concluded from in vitro studies that honey has powerful antimicrobial activity against dermatologically relevant microbes. These findings are particularly promising in current times when the problem of antimicrobial drug resistance is considered a global crisis and the World Health Organization (2014) has acknowledged the possibility of a postantibiotic era in which common infections can kill. Even more exciting are the in vitro findings that honey can reverse antimicrobial resistance and reduce microbial pathogenicity. Despite these optimistic findings in vitro, the use of honey in clinical practice today as an antimicrobial agent does not appear to have yet reached its full potential. Innovative research that can maximally exploit the antimicrobial properties of this natural substance  and overcome obstacles associated with in vivo use may, in the future, lead to the production of an antimicrobial agent that is highly valued in clinical practice.

Interestingly, no honey-resistant microbial strains have emerged to date, and this may be unlikely because of the multifactorial nature of the antimicrobial properties of honey. As honeys from diverse floral origins have been shown to have antimicrobial activity against a range of skin relevant microbes, research should continue to investigate the efficacy of honey in the treatment of other types of skin disorders where microbes have been implicated in the pathophysiology of the disease. There are countless varieties of honeys being produced worldwide, and some may have superior antimicrobial activities that are yet to be discovered.

References
  1. McLoone P, et al., Honey: A realistic antimicrobial for disorders of the skin, Journal of Microbiology, Immunology and Infection (2015), http://dx.doi.org/10.1016/j.jmii.2015.01.009
  2. Carter, D.A. et al., Therapeutic Manuka Honey: No Longer So Alternative. Frontiers in microbiology 2016; 7: 569. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837971/