The use of honey in modern healthcare stems from its use as a medicine throughout human history. Given the emerging crisis of antimicrobial resistance, it has become imperative to explore other potentially effective alternatives that have probably not been considered before in mainstream practice. According to the World Health Organization (2018), antimicrobial resistance is a major global public health threat, limiting and often negating the prevention and treatment of an ever-increasing range of infections.
The scale of the problem is such that infections caused by antibiotic-resistant bacteria claim at least 50 000 lives each year in Europe and the USA, and 700 000 lives globally. These figures are expected to rise dramatically over the next 30 years (House of Commons Health and Social Care Committee, 2018). Global mortality from antimicrobial resistance is anticipated to reach 10 million per year by 2050. This would be a greater death toll than those from cancer and diabetes combined (Review on Antimicrobial Resistance, 2015). Resistance rates in key infectious bacteria including Escherichia coli, Klebsiella pneumonia, K. oxytoca and Pseudomonas spp have increased over 2012–2016 (Public Health England, 2018). This trend is illustrated in Figure 1 (House of Commons Health and Social Care Committee, 2018).
Given these figures and the fact that only two new antibiotic classes have been introduced in the past 40 years, the consideration of alternatives to conventional treatments either as a true alternative or in combination therapy are taking on a new and pressing urgency. Near the top of the list of alternatives being explored is honey.
Potential use
The decreasing effectiveness of antimicrobials is a significant problem for the clinical management of many conditions, including the treatment of wounds. It is therefore unsurprising that the possibilities of medicinal honey and its products are generating much interest among medical scientists and nursing professionals. The complementary and alternative medicine branch of apitherapy, developed in recent years, offers treatments based on honey and other bee products for many conditions, including infections. Of particular interest is its potential in wound healing and in wound dressing. Table 1 lists some of the ingredients in honey that may contribute to its antimicrobial properties.
| Active constituent/property | Possible mechanism of action |
|---|---|
| High sugar content | Draws moisture out, dehydrating microbes. May also interfere with microbial enzyme activity and weaken the molecular structure of microbial DNA |
| High osmolarity | |
| Acidity (low pH) | Creates a hostile environment for most pathogens to multiply, which limits their ability to colonise |
| Hydrogen peroxide | Antimicrobial |
| Methylglyoxal | Antimicrobial |
| Hygroscopic | Draws out moisture and dehydrates the pathogens |
| Other compounds, eg flavonoids, polyphenols | Contribute to the overall antioxidant properties of honey |
Microorganisms have been associated with the pathophysiology of a range of dermatological disorders. Wound infections, for example, are commonly caused by the Staphylococcus aureus, Pseudomonas aeruginosa and E. coli microorganisms and infection with Staph. aureus is common in atopic dermatitis (McLoone et al, 2016). Other examples include Malassezia yeasts, which have been associated with the skin conditions pityriasis versicolor, seborrheic dermatitis, atopic dermatitis and psoriasis (McLoone et al, 2016). Conventional treatments for some of these conditions are unsatisfactory; for example, corticosteroids can cause skin thinning and ultraviolet radiation therapy has been associated with the development of skin cancer (Gasparro, 2000).
Honey-based products in clinical use
Honey types from different flowering plants vary substantially in their ability to kill bacteria, and this has complicated the literature on honey and sometimes made it difficult to reproduce results (Carter et al, 2016). Nevertheless, in clinical practice today, medical-grade manuka honey is used topically in the management of wound infections.
Products include irradiated honey in gels, ointments and impregnated dressings. Revamil® is a medical-grade honey that has been successful in trials; a 12-week randomised clinical trial comparing it to conventional ear drops in 28 patients with chronically infected mastoiditis concluded that Revamil gel was a safe alternative treatment option for this condition (Henatsch et al, 2015). Revamil is produced in greenhouses in the Netherlands but no further details about how it is manufactured have been disclosed.
Medical-grade honey is also sometimes used after surgery as an adjunct therapy and for treating wound infections (Winter, 2017).
Some medical-grade honeys are listed in Box 1.
Mode of action
The complex nature of honey's antimicrobial activity means that the potency of various types of honey can vary more than 100-fold (Molan and Cooper, 2000). Many factors affect this difference, including geography, season collected, botanical source, harvesting, processing and storage conditions. The mechanism of action of honey is predominantly attributed to two major ingredients: hydrogen peroxide and methylglyoxal.
Hydrogen peroxide destroys bacterial cell walls and cell membranes, induces ribosomal lesions and ruptures bacterial DNA; methylglyoxal reacts with DNA, RNA and protein synthesis and therefore disrupts bacterial function. Conveniently, honey does not affect mammalian cells but does the opposite by promoting healing (Carter et al, 2016). Honeys with high levels of methylglyoxal and/or hydrogen peroxide (they do not always occur together) are usually the most potent but the correlation is not perfect, which implies that other compounds in honey may modulate antimicrobial activity. No studies to explore potential synergistic activity of the various compounds have been conducted.
Other possible mechanisms of action may relate to infections caused by viruses, fungi, protozoa or helminths (parasitic worms such as tapeworm). These are summarised in Table 2.
| Mode of action | Comment |
|---|---|
| Disrupts cell division | Uncoupling of growth and cell division, which reduces survival and the potential to cause disease. Randomised controlled trials are needed to make direct comparisons. Studies so far have used different imaging methods, and varying amounts of honey and treatment times, making direct comparisons of honey with non-honey treatments unreliable |
| Cells become significantly smaller | |
| DNA becomes condensed | |
| Cells abnormally shorter or longer | Morphological or structural abnormality, leading to malfunction and lack of colonisation that limits ability to cause disease |
| Profound cellular changes such as protrusions, furrows or blebs on the cell surface | |
| Increased extracellular debris | Indication of cell lysis and thus cell death |
| Stimulation of monocytes (immature precursors to macrophages) | Promotes non-specific immunity by stimulating the secretion of tumour necrosis factor-alpha, a cell signalling protein or cytokine known to induce the mechanism of wound repair |
| Reduces the release of reactive oxygen intermediates | Limits tissue damage by activated macrophages during wound healing |
| Production of a cytotoxic antimicrobial peptide | Production of bee defensin-1, which increases the permeability of bacterial cell membranes, thus causing cell lysis and cell death. Coincides with the inhibition of DNA, RNA and protein synthesis in bacterial infections |
| Production of antioxidants | Polyphenols and flavonoids may protect host cells from the damaging effects of free radicals that can be produced by infections |
| Peroxide activity | Prevents bacterial growth and kills bacteria |
| Methylglyoxal activity |
Evidence of efficacy
The majority of recent studies investigating honey's mechanism of action have focused on well-characterised, standardised active manuka honey produced from certain Leptospermum species that are native to New Zealand and Australia, which has been registered as a wound care product by medical regulatory bodies.
A biofilm is a thin layer of microorganisms that sticks to the skin or wound area and establishes stubborn communities of microorganisms that can become tolerant to antibiotics or other agents. Manuka honey has been shown to disrupt cellular aggregates and prevent the formation of biofilms by a wide range of problematic pathogens, including Streptococcus and Staphylococcus species, P. aeruginosa, E. coli, Proteus mirabilis, Enterobacter cloacae, Acinetobacter baumannii and K. pneumoniae (Maddocks et al, 2012; 2013; Lu et al, 2014; Majtan et al, 2014; Halstead et al, 2016). Honey has also been shown to disrupt established biofilms and kill resident cells (Okhiria et al, 2009; Maddocks et al, 2013; Lu et al, 2014; Majtan et al, 2014).
Recently, manuka honey was shown to reduce the viability of Staph. aureus, Streptococcus agalactiae, P. aeruginosa, and Enterococcus faecalis species when tested on a biofilm containing all these species. Only E. faecalis could not be eradicated (Sojka et al, 2016). An understanding of how the biofilm enables E. faecalis to survive when it is normally killed by honey is an important and interesting area for future study (Carter et al, 2016).
Additionally, other in vitro studies have shown that honeys from all over the world, not just manuka, have potent antimicrobial activity against dermatologically important microbes (Table 3). Moreover, honey can reduce microbial pathogenicity as well as reverse antimicrobial resistance (McLoone et al, 2016).
| Type of honey MRSA | Staphylococcus | aureus | Pseudomonas aeruginosa | Escherichia coli Candida | albicans | Malassezia species | HPV |
|---|---|---|---|---|---|---|---|
| Manuka honeya | + | + | + | + | - | ‡ | ‡ |
| Scottish heather honeyb | + | + | + | + | ‡ | ‡ | ‡ |
| Portobello honeyb | ‡ | + | + | + | ‡ | ‡ | ‡ |
| Tualang honeyc | + | + | + | + | ‡ | ‡ | ‡ |
Sources:
New Zealand: Brady et al, 1996, Tan et al, 2009; Sherlock et al, 2010;
Scotland: Carnwath et al, 2014, using Scottish heather honey; Schneider et al, 2013, using Portobello honey;
Malaysia: Tan et al, 2009
HPV = human papilloma virus;
+ = active;
- not active or low activity;
‡ = unknown
In contrast, however, in vivo studies have proven to be more controversial.
A brief report published in 2001 by Cooper et al described how treatment of a Staph. aureus-infected, recalcitrant surgical wound in a 38-year-old woman using manuka honey-impregnated dressings and oral co-amoxiclav resulted in significant healing of the wound and bacterial clearance 7 days after treatment was started. The wound was 3 years old and had failed to respond to conventional wound treatments and antibiotics during the 3-year period before the honey/antibiotic combination therapy was started.
In another report published in 2001, an MRSA-infected leg ulcer of an immunosuppressed patient was treated with a topical application of manuka honey; the MRSA was eradicated and the wound healed (Natarajan et al. 2001). Chambers (2006) reported bacterial clearance in three cases of MRSA-infected leg ulcers following treatment with topical manuka honey.
Visavadia et al (2008) reported that, because of clinical experience, manuka honey was made a first-line treatment for infected wounds at the maxillofacial unit at the Royal Surrey County Hospital in Guildford, UK (McLoone et al, 2016). However, this decision was based on two cases of early infections even though honey-impregnated dressings had been used in the wound care clinic on the ward for more than a year.
Honey also appears to help heal partial thickness burns more quickly than conventional treatment and infected postoperative wounds more quickly than antiseptics and gauze (Jull et al, 2015).
However, larger clinical studies have produced mixed 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 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 eliminated infection in 50% of wounds. (McLoone et al, 2016).
In 2008, Jull et al conducted a randomised clinical trial with 368 participants, and found no significant differences in occurrence of infection between venous leg ulcers treated with dressings impregnated with manuka honey and those given usual care. A more recent Cochrane review by Jull et al (2015) concluded that it is difficult to draw overall conclusions regarding the effects of honey as a topical treatment for wounds because of the heterogeneous nature of the patient populations and comparators studied. Beyond these comparisons, any evidence of differences in the effects of honey and comparators is of low or very low quality so does not form a robust basis for decision-making.
Another clinical study showed no significant difference, in terms of the development of 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 (McLoone et al, 2016). The implications of these findings on clinical practice are that personalised treatments could be tailored to those who respond favourably to honey compared with conventional antimicrobials routinely used in primary healthcare.
Findings and conclusions from other studies are summarised in Table 4, as well as areas for further research (Carter et al, 2016).
| Study | Findings to date | Gaps and controversies | Suggested future studies |
|---|---|---|---|
| Chemical analyses |
|
The constituents that modulate antibacterial activity, produce synergy between honey and antibiotics, and promote wound healing have not been identified | Fractionation, purification and testing of constituents alone and in various combinations |
| Pathogen inhibition | Manuka honey: |
Few studies on non-bacterial pathogens and mixed-species biofilms | Test honey on pathogenic fungi, parasites, and viruses; analyse biofilms produced by consortia of bacteria and yeasts |
| Omics and systems biology | Treatment with manuka honey results in a unique signature of differential gene expression with downregulation of stress response and virulence-related genes | Analyses restricted to differential gene expression; only single time points explored; only performed in Escherichia coli and Staphylococcus aureus; very little validation | Contextualise using advanced systems biology tools; assess dynamics of cell response; validate using quantitative polymerase chain reaction testing and gene deletion/overexpression strains |
| Ultrastructure | Vastly different morphological alterations in different bacterial species; it is suggested Staph. aureus fails to complete cell cycle; Pseudomonas aeruginosa has extensive cell degeneration and lysis | Few species and strains analysed to date | Extend to additional strains and species, including mixed-species biofilms and wound biopsies |
| Drug interactions |
|
Only Staph. aureus and MRSA tested to date; there are substantial differences between strains; substance(s) causing synergy unknown | Extend to additional strains and species; test honey fractions to determine compound(s) responsible for synergy; determine strain-specific differences in response using omics approaches |
| In vivo use and clinical trials | Case studies and the use of therapeutic manuka honey on wounded animals shows honey can clear infections and promote wound healing | Robust clinical trials have not been undertaken | Use data obtained previously to inform treatment and devise clinical trials |
Honey's potential as a therapeutic agent begs the question as to why clinical trials are not being conducted on the benefits of honey, particularly on honeys thought to have medicinal properties. This is restricted by a number of limitations to randomised controlled trials (RCTs), the three most important of which are:
Using honey in clinical practice
In light of the growing problems with antimicrobial resistance and the lack of new drugs on the immediate horizon, there is scope to consider using honey alongside conventional treatments in combination therapy. This may augment treatment, especially if a two-pronged approach is adopted, ie, honey is used topically (externally) while conventional drugs are administered systemically (internally). This means lower doses of therapeutic drugs can then be used, which will also prevent the development of drug resistance, which is limiting treatment in some infections. In vitro studies have shown that this synergistic action is more effective than when honey and antibiotics are used as individual treatments. For instance, medical-grade honey combined with the antibiotic oxacillin (Jenkins and Cooper, 2012a) and later tetracycline, imipenem, mupirocin, colistin and rifampicin has been shown to work synergistically against the growth of a strain of MRSA (Jenkins and Cooper, 2012b), suggesting a potential of honey as a useful adjunct.
An in vitro study also demonstrated strong synergistic activity between manuka honey and rifampicin against multiple Staph. aureus strains, including clinical isolates of MRSA. Moreover, the presence of honey has prevented the emergence of resistance to rifampicin (Müller et al, 2013). Further research into a combination of honeys and their synergistic effect has demonstrated that natural honeys possess in vitro activity against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains (Nishio et al, 2016). This could lead to the development of broad spectrum antimicrobials that have the potential to prevent the emergence of resistant pathogenic strains.
Use of honey for diabetic wounds and ulcers
Diabetic wounds are notoriously difficult to treat because they are slow to heal. Honey can be an effective choice because it provides comparatively rapid wound healing (Alam et al, 2014). It also seems to work better for more sensitive skin as it is less of an irritant. Box 2 lists some of the general guidelines that nurses and other healthcare practitioners could follow, particularly when wounds prove unresponsive to conventional treatments and are stubborn to heal.
On a note of caution, honey is not free from adverse effects. Some patients have reported a stinging sensation upon application (Oluwatosin et al, 2000). Manuka honey has a pronounced methylglyoxal content compared with other honeys; while this has antimicrobial properties, it is an important precursor to other molecules that play a role in the formation of diabetic wounds and could, paradoxically, delay wound healing (Majtan, 2011). Further research, especially RCTs, is needed to elucidate the true clinical usefulness of manuka honey in diabetic wound management.
Prophylactic use of honey
Literature on the prophylactic use of topical honey as an antimicrobial is sparse so no conclusions can be drawn on the benefits of this.
However, honey is a beneficial food product (it contains vitamins, minerals, proteins and antoxidants in the form of phenolic acids and flavonoids, and is low in fat and cholesterol) but, because of its high sugar content, is not advocated for patients with diabetes. Supplements such as propolis and royal jelly (both made by bees) are better favoured, based on initial studies comparing these products to honey (Pasupuleti et al, 2017). Propolis has been reported to have various health benefits related to gastrointestinal disorders, allergies, and gynaecological, oral and dermatological problems, and royal jelly is known for its protective effects regarding reproductive health, neurodegenerative disorders, wound healing and ageing (Pasupuleti et al, 2017).
Classification of medicinal honey
Given that medical-grade honey is often applied as impregnated wound dressings, it is classified by the European Medicines Agency as a medical device so regulations on its use are the same as those for all medical devices in conventional medicine.
The National Institute for Health and Care Excellence (NICE) issues guidelines on the use of dressings that bear the European Conformity (CE) mark and regulatory approval as sterile medical devices for external use on wounds. These are discussed within the general guidance on wound dressings and wound management: KTT14 was last updated February 2018 and ESMPB2 March 2016 (NICE, 2016; 2018). This is useful for nurses who provide frontline care in wound management.
However, the administration of medical-grade honey internally as a drug has not been approved, probably because of limitations regarding clinical trials as stated above. In any event, no honey-based product for internal use or medicinal drug has been formulated.
Future treatment options to tackle resistance
Honey is one of many strategies being employed to combat the increasing problem of antimicrobial resistance. It is encouraging to note a number of other potential and future treatment options in antimicrobials. These are highlighted in Table 5 (Shan, 2016).
| New treatment option | Comments |
|---|---|
| Teixobactin | A newly discovered antibiotic in a screen of uncultured bacteria: it inhibits bacterial cell wall synthesis, suggesting promising strategies for developing antibiotics that are likely to delay or avoid any development of resistance |
| Bacteriophage therapy | Bacteriophages (commonly referred to as phages) are viruses that infect bacteria but not humans. Bacteriophage therapy is not new; it has been widely used in Russia and parts of eastern Europe for nearly a century, even though it is only now being considered in the West. Some notable limitations include the fact that many phage strains are needed to cover the many sources of infection, phages are quickly cleared from the bloodstream and much of the early Russian work on phages was of a low standard |
| New drugs in clinical trials | In 2010, the Infectious Diseases Society of America established a global initiative to develop 10 new antibiotics by 2020. Since then, six new antibiotics have been approved by the Food and Drug Administration for a range of infections in primary and secondary care. A promising new agent is combined meropenem/vaborbactam (Carbavanc; Medicines Co); this is going through phase 3 trials and showing effectiveness against the most resilient carbapenem-resistant Enterobactericaceae |
| Policy and incentives for drug development | In 2012, then US President Barack Obama signed the Generating Antibiotics Incentives Now (GAIN) Act into law to help address the significant cost burden of bringing new drugs to the market. The act offers a 5-year extension on patent life for new antibacterial agents that are designated as qualified infectious disease products (QIDPs), thereby increasing their value |
| Revisiting older antimicrobials | Extending the clinical utility of existing agents or those that have fallen out of favour could optimise the pharmacodynamics/effectiveness of older antimicrobials, as well as lead to novel dosing regimens and new combination therapies to combat the most resistant pathogens |
| Natural alternatives | Nutrition and herbal medicines have formed the backbone of addressing infections in a natural way. Herbal medicines can contain effective antimicrobial agents; some modern drugs are refined or modified versions of their active constituents. More recently, the evaluation of the antibacterial activity of peppermint oil and different extracts of Mentha piperita mint against some Gram-positive and Gram-negative bacterial strains indicate strong antibacterial and antioxidant activities. However, additional investigations need to be performed to confirm the safety of these concentrations (minimum inhibition concentration) for human consumption (Singh et al, 2015) |
Conclusion
In vitro studies demonstrate that honey has powerful antimicrobial activity against dermatologically relevant microbes. These findings are promising, given that the problem of antimicrobial drug resistance is considered a global crisis and the WHO (2018) has acknowledged the possibility of a post-antibiotic era in which common infections could kill.
More encouraging are the in vitro findings that honey can reverse antimicrobial resistance and reduce microbial pathogenicity. 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. The research potential for honey remains significant, especially for clinical practice and against a range of other skin disorders where microbes are implicated.
Countless varieties of honey are produced worldwide, and some may have superior antimicrobial activities that are yet to be discovered.