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Journal of Apicultural Research

ISSN: 0021-8839 (Print) 2078-6913 (Online) Journal homepage: https://www.tandfonline.com/loi/tjar20

Defining the standards for medical grade honey

Renée Hermanns, Cristina Mateescu, Andreas Thrasyvoulou, Chrysoula


Tananaki, Frank A.D.T.G. Wagener & Niels A.J. Cremers

To cite this article: Renée Hermanns, Cristina Mateescu, Andreas Thrasyvoulou, Chrysoula
Tananaki, Frank A.D.T.G. Wagener & Niels A.J. Cremers (2019): Defining the standards for
medical grade honey, Journal of Apicultural Research, DOI: 10.1080/00218839.2019.1693713

To link to this article: https://doi.org/10.1080/00218839.2019.1693713

Published online: 27 Nov 2019.

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https://www.tandfonline.com/action/journalInformation?journalCode=tjar20
Journal of Apicultural Research, 2019
https://doi.org/10.1080/00218839.2019.1693713

REVIEW ARTICLE
Defining the standards for medical grade honey
Renee Hermannsa , Cristina Mateescub , Andreas Thrasyvoulouc , Chrysoula Tananakic , Frank A.D.T.G.
Wagenerd and Niels A.J. Cremersa
a
Triticum Exploitatie BV, Maastricht, the Netherlands; bFood Bioresources National Service for Medicinal, Aromatic Plants and Bee
products, National Institute for Research & Development, Bucharest, Romania; cLaboratory of Apiculture-Sericulture, School of Agriculture
and Forestry, Aristotle University of Thessaloniki, Thessaloniki, Greece; dDepartment of Orthodontics and Craniofacial Biology, Radboud
University Medical Center, Nijmegen, the Netherlands

(Received 19 July 2019; accepted 30 October 2019)

Honey has been used since ancient times for the treatment of wounds. The discovery of antibiotics made its use less
appealing, but the development of antibiotic resistance has again increased the interest in honey for its antibacterial
properties. However, attention must be paid to the quality of the honey used for medical application. Honey may con-
tain toxic compounds when plants in honey harvesting areas are treated with herbicides and pesticides or are polluted
with industrial heavy metals, antibiotics, or exposed to environmental pollution. Moreover, bacterial contamination of
honey with, for example, Clostridium endospores has long been disregarded. Honey directly obtained from the bee-
keeper or from the store may not therefore be suitable and it may even be dangerous for use or for wound healing, as
there is no guarantee that it is safe, or it may not be effective because of inappropriate sterilization methods.
Therefore, there is a need for a clear definition of ‘medical grade honey’ (MGH), to guarantee its safety and efficacy for
therapeutic uses. Due to the current lack of strict guidelines to achieve standardized MGH formulations, this article
poses clear standards and criteria, including those related to the collection, possible contamination, sterilization, produc-
tion, storage, physicochemical, legal and safety issues to which MGH should adhere to distinguish itself from regular
honey. We discuss current honey-based wound care products and whether they adhere to the standards of MGH. The
presented guidelines should result in safe MGH formulations that are effective for wound healing.
Keywords: honey; medical grade honey; definition; standards; safety; wound care

Background the medical uses of honey for cleaning and healing of


Prior to modern day non-steroidal anti-inflammatory sores and ulcers (Ali, Fox, & Finlayson, 2013).
drugs (NSAIDs) and antibiotics, small dirty injuries could Nowadays, honey is still part of advanced wound
have been a death sentence because of uncontrolled care. In contrast to historical times, there is currently a
infection. Since antiquity, wounds were treated with the lot of environmental pollution with herbicides, pesti-
same sequence of procedures: washing the wound cides and heavy metals worldwide, as well as plant
(cleansing), covering with plasters (topical therapy) and derivatives like pyrrolizidine alkaloids and their N-
bandaging the wounds (dressings) (Hsieh et al., 2016). oxides that can contaminate honey (Al-Waili, Salom, Al-
Ghamdi, & Ansari, 2012; Connolly, 2017; Cramer &
Many different substances including mud or clay, moldy
Beuerle, 2012). Therefore, it should be noted that
bread, meat, plants, and herbs were applied to wounds
“medicinal” honey and not regular honey must be used
to achieve hemostasis and to form a protective barrier
for wound care purposes. In addition, there is a large
over the wound (Shah, 2011). The ancient Egyptians
variation in the antimicrobial and wound healing activity
would apply honey, Aloe vera, animal fat and lint, as they
of honey, which is due to spatiotemporal variation in
believed closing the wound would protect the patient the origin of the honey. Identification and meeting
from the invasion of evil spirits. It is currently known standardized criteria will help to guarantee both the
that honey serves as a natural antibiotic, whereas the quality and therapeutic potential of medicinal honey.
animal fat functioned as a barrier to pathogens and the For example, it is not advised to obtain honey for med-
lint as an absorbent for wound drainage (Murray, ical purposes directly from the beekeeper or supermar-
Hinkle, & Yun, 2008; Sanchez & Burridge, 2007). ket, as these honeys are not extensively tested and
Nonetheless, the Egyptians must have been aware of there is no guarantee the honey is safe and effective.
honey’s healing properties since it was included in most However, these concerns are often ignored, and this
of the ancient remedies (Eteraf-Oskouei & Najafi, 2013). demands a formal definition of medical grade honey
The Greek physician, Hippocrates (c. 400 BC) described (MGH). Although medical remedies containing honey
Corresponding author: E-mail: niels@mesitran.com

ß 2019 International Bee Research Association


2 R. Hermanns et al.

Figure 1. Flow diagram MGH.

fall under the regulations for drugs or medical devices, elements can also be deposited, causing great variations
there is no regulation governing the standards for pure in the composition depending on the location and type
honey. Therefore, criteria need to be developed and of plant from which the bees collected nectar (Ferreira,
honey must to comply with these criteria before it can Aires, Barreira, & Estevinho, 2009). Furthermore, the
safely be used as MGH. Next, we will discuss the main floral composition from which the honey is produced
characteristics of honey, followed by the necessary cri- determines the type of honey, resulting in countless
teria to turn honey into a medical grade product. sets of honey, depending on their floral or geographical
origin, such as Acacia, Eucalyptus, Clover, Manuka, and
Composition of honey Buckwheat honey. All kinds of honey have different anti-
bacterial and wound healing properties and they vary in
The following definition of honey is given by the Codex
Alimentarius 2001 and the European Honey Directive safety and efficacy. This depends on the composition of
(2001): “Honey is the natural sweet substance produced honey and the environmental origin and it demands a
by honey bees from the nectar of plants or from secre- definition for MGH, declaring the need for
tions of living parts of plants or excretions of plant- MGH standards.
sucking insects on the living parts of plants, that bees
collect and transform by combining it with specific sub-
stances of their own and leave in honeycomb to ripen What is medical grade honey?
and mature (European Honey Directive, 2001). Medical grade honey must fulfill the following criteria:
Each time nectar or honeydew is deposited into the
cell, more amylase and invertase are added by the bees  is organic and free of contaminants and toxic substances,
to convert the watery sucrose nectar. The bees evapor-  is gamma sterilized under standardized conditions and
ate the water by fanning their wings and when the free of dangerous microorganisms,
moisture reaches low levels, they seal the honeycomb  can be safely implemented in medical therapies,
cell with wax. This brings down the water content to  follows strict production and storage standards, and
below 18% from its original 70% and ripens the honey, legal and safety regulations,
yielding the classic thick substance (Langstroth, 1922).  complies to the physicochemical criteria that are impor-
The high sugar-to-water ratio makes honey a supersatu- tant for the use of honey as a wound care product.
rated and highly viscous fluid that readily binds water
molecules, giving honey the ability to generate To achieve the criteria for MGH, standards for
osmotic pressure. honey collection and production need to be tightly fol-
Honey consists of over 200 components including lowed. In Figure 1, a flow diagram is shown summarizing
enzymes, amino acids, carbohydrates, vitamins, and the minimal criteria to which MGH needs to adhere. In
organic acids as well as mineral compounds and other addition to these MGH standards, medical device stand-
derivatives from the environment in which the nectar ards must be followed. These criteria are discussed in
was collected. In this way, heavy metals and other trace the following paragraphs.
Standards for medical grade honey 3

Table 1. Overview regulations honey standards.


EU USA
Food standards CAC CAC
Regulated by CODEX STAN 12-1981, revised CODEX STAN 12-1981, revised
CODEX 2001 CODEX 2001
Organic standards EC regulations 834 and 889 USDA Organic Seal
Directive 2001/110/EC
Directive 2014/63/EU
Regulated by The Council of the European Union and The NOP, and EPA (Environmental
local inspection bodies, which follows Protection Agency)
DIN EN ISO/IEC 17025
Detection limits for residues of toxic heavy European Food Safety Authority FDA - Code of Federal Regulations, Title
metals and drugs Regulation EC 1881/2006, which 21, Part 556 and 530.
Regulated by follows the limits in 396/2005, 470/ Section 2107(a)(6) of the Organic Food
2009 and 37/2010 Production Act of 1990

Organic origin respecting what they produce. For example, the hives
Honey is a complex yet delicate substance, whose com- used must be made of natural materials and positioned
position is dependent on its environmental origin and it within a radius of 3 km from areas mainly planted with
is further influenced by different collection and produc- organic crops or wild plants. The hives can only be pro-
tion modalities. One way to conform to production tected by organic products (wax, propolis, plant oils,
standards and to ensure a safe and effective product is etc.), and sufficient honey and pollen must be left for
through avoiding pollutants by restricting the colony’s the winter, or if the bees do not have reserves, organic
foraging area, which can extend up to 10 km, to geo- food products must be given. These specifications must
graphic areas that are far from polluted environments be followed for over one year before the beekeepers
(Hagler, Mueller, Teuber, Machtley, & Van Deynze, can use the word ‘organic’ on the labels of their prod-
2011; Pasquet et al., 2008). The same applies to anti- ucts (Association for Organic Agriculture, 2005).
biotic treatment of the bee colony since, in the long To confirm the honey was collected in an organic
run, trace amounts can contribute to the global burden environment, specific testing in a qualified laboratory is
of antibiotic resistance. To produce MGH, raw honey necessary to guarantee that the MGH is free of pollu-
should at least meet organic food standards and be free tants, using specific set limits and accredited protocols
and ISO certifications according to DIN EN ISO/IEC
of detectable amounts of pollutants and it should pref-
17025. Honey must be free of detectable levels of her-
erably be certified as organic.
bicides, pesticides, antibiotics (full range of sulfonamides,
A worldwide collection of standards, guidelines, and
trimethoprim, streptomycin, and tetracyclines), and
codes of practice has been collated by the Revised
heavy metals that are toxic even at low levels (arsenic,
Codex Alimentarius Commission (CAC) to create
lead, and cadmium). The levels of iron and zinc must
harmonized international food standards. This and other
not exceed the maximum levels set for comparable
regulatory protocols and agencies can be found in
foodstuffs and must lie within the range of the naturally
Table 1.
occurring range for honey (Bogdanov, 2006; MAFF,
The CAC is a joint intergovernmental body of the
1995). The examined parameters of the honey must
Food and Agriculture Organization of the United Nations
correspond to the limit of quantification and the legal
(FAO) and the World Health Organization (WHO) with
regulations according to EC 1881/2006, 396/2005, 470/
188 Member Countries. Their Codex Alimentarius, or
2009, and 37/2010.
“Food Code” describes the standard for honey in
CODEX STAN 12-1981(Commission, 1981).
In addition to these international food standards, Sterilization
organic standards have been made stricter by demand- The collection of honey in an organic environment is
ing additional requirements to comply with the stand- not enough to ensure the absence of all potential pollu-
ards of organic farming and promote ecological balance tants. Many different bacteria, yeasts and moulds can be
and conserve biodiversity. Beekeepers can obtain present in honey (Olaitan, Adeleke, & Ola, 2007).
organic certification when they follow such regulations. Microorganisms may influence the quality and safety of
For example, Europe has defined the criteria that need the honey (Snowdon & Cliver, 1996). Clostridium botu-
to be fulfilled to obtain European organic certification in linum is a bacterium ubiquitous to products from
EC regulations 834/2007 and 889/2008. This certifica- nature. The endospores of this microorganism have
tion is monitored at every stage by local inspection been revealed to different degrees in honey from over
bodies. Organic production is a comprehensive system the world, ranging from 5% to 64% (Grenda et al.,
of agricultural management and food production and it 2018; Nakano, Okabe, Hashimoto, & Sakaguchi, 1990).
involves caring for the wellbeing of the bees and While harmless when confronted by healthy persons
4 R. Hermanns et al.

and persons with an intact immune system, these bac- 2008). Therefore, ozone treatment is inferior to gamma
teria can cause a life-threatening condition in immuno- irradiation. Regardless of market trends, honey-based
compromised individuals. In infants under the age of medical preparations should always be sterilized without
1 year, honey is the primary cause of botulism since risking the decay of honey’s bioactive components to
their intestinal immune system is still underdeveloped, provide augmentation of the wound healing trajectory
making them vulnerable to pathogen proliferation after and the best possible protection for immunocomprom-
ingestion, resulting in the release of the dangerous tox- ised patients.
ins (Abdulla et al., 2012; Hoarau et al., 2012; Joseph, Although bacteria are killed by sterilization, endotox-
Khoo, & Lee, 2017; Lopez-Laso et al., 2014; Sobel, ins can be released into the honey as a result, such as
2005; WHO, 2018b). LPS, subsequently causing an inflammatory pyrogenic
Hence, the MGH end product must be sterile and response. The amount of released toxins correlates
any bacterial endospores of Clostridium botulinum, with the number of endospores and therefore it is
Clostridium tetani and other unwanted microorganisms important during the selection of honey that the honey
must be eliminated to remove the risk of botulism and contains a low number of microorganisms. We propose
other morbidities. To disclose safe use and consump- establishing strict microbiological criteria for bacteria at
tion, gamma irradiation is the standard procedure for a maximal limit of 10 CFU/g honey and a maximum limit
sterilizing all medical devices and food products (Chou, for fungi and moulds of 10 CFU/g honey should also
Skornicki, & Cohen, 2018). While different methods of be maintained.
sterilization can be applied to kill bacteria effectively,
almost all of these procedures also inactivate the Clinical implementation
enzymes and components that grant honey its anti-
The term ‘medical grade honey’ has been generally
microbial and pro-healing activity. For this reason,
adopted by the scientific and medical community. Even
honey bought in a grocery store often loses its wound
so, some studies that have included honey other than
care stimulating characteristics, as this honey is most commercially available MGH products lack the descrip-
likely to be heat sterilized. Gamma irradiation, on the tion of using a sterilized and standardized MGH.
other hand, achieves product sterilization while preserv- Unclear terminology can raise confusion and for this
ing honey’s pro-healing and antibacterial efficacy (Gupta should be scrutinized. For example, if a case were to
& Reybroeck, 2014; Molan, 1992; Molan & Allen, 1996; refer to ‘medicated honey’ as the culprit of botulism in
Postmes, van den Bogaard, & Hazen, 1993). According an infant (Joseph et al., 2017). However, it remains
to ISO 11137, specific regulations and protocols for unclear whether the applied product was a standardized
sterilization must be followed when applying gamma MGH or if therapeutic agents were added to regular
irradiation; the level of irradiation should not be too honey which was then applied. Since botulism occurred,
low, as endospores may survive, or too high to prevent it can be safe to say that the honey was, in fact, neither
alteration of honey’s beneficial properties (Postmes, van medical grade nor properly processed, yet the author’s
den Bogaard, & Hazen, 1995). use of terminology does not help in distinguishing
Next to gamma irradiation, the only other proven the error.
sterilization technique that maintains honey’s bioactivity Once the honey is irradiated, it is suitable for med-
is ozonation. By bubbling ozone gas through liquids in ical application and could be called medical grade honey
an ozone-resistant container, bacterial residues and (MGH), providing the honey still presents bio-activity
endospores are effectively neutralized (Vestergard, (Molan & Allen, 1996; Postmes et al., 1995).
1994). In the food and meat industry, ozonated water is The levels of bioactivity differ among the vast variety
often used to wash fruit and vegetables to remove fer- of available honey, and it has been reported that the
tilizers, mycotoxins, Clostridium perfringens, E. coli, and antibacterial activity of different honey sources can vary
Salmonella (Castillo, Mckenzie, Lucia, & Acuff, 2003; a 100-fold (Lusby, Coombes, & Wilkinson, 2005; Mandal
Crowe, Bushway, Bushway, Davis-Dentici, & Hazen, & Mandal, 2011). Thus, many monofloral kinds of honey
2007; Crowe, Bushway, Bushway, & Hazen, 2006; Kim, from trees and plants such as lime, acacia, elm, thyme,
Yousef, & Dave, 1999; Novak & Yuan, 2004; Young, buckwheat, and manuka and polyfloral wildflower or
Zhu, & Zhou, 2006). Currently, the method of ozone jungle honey have been the subject of studies in the
sterilization of honey and honey-based wound care fields of wound healing, oncology, and immunology. The
preparations is patented under WO 2008/049578. This mechanisms by which honey conveys its antioxidant and
is reflected in the market as all other MGH prepara- anti-inflammatory action are well-documented and they
tions are sterilized by gamma irradiation. However, have been found to be related to its phenolic compo-
according to the patent, microorganisms are not com- nents which are found in high levels in monofloral
pletely eliminated by this method, but only reduced in honey, such as manuka and buckwheat, as well as poly-
number from, on average, 250-1000 colony-forming floral jungle honeys like tualang honey (Ahmed &
units (CFU) per g in raw, unheated biological honey to Othman, 2013; Alvarez-Suarez, Gonzalez- Paramas,
100 CFU/g or less after ozone treatment (Vandeputte, Santos-Buelga, & Battino, 2010; Alvarez-Suarez, Tulipani,
Standards for medical grade honey 5

et al., 2010; Khalil, Alam, Moniruzzaman, Sulaiman, & of 5-hydroxymethyl furfuraldehyde (HMF), which
Gan, 2011; Moniruzzaman, Amrah Sulaiman, & Gan, increases following overheating, storage in poor condi-
2017; Pasini, Gardini, Marcazzan, & Caboni, 2013; tions or as honey ages. In Directive 110/2001, the
Porcza, Simms, & Chopra, 2016; Sergiel, Pohl, & European Union describes the maximum value for HMF,
Biesaga, 2014; van den Berg et al., 2008). Hence, which in general should not exceed 40 mg/kg.
research has been conducted on tualang honey, to Exceptions for this are Baker’s honey and honey of
account for its immune function and anti-tumor activity tropical origin, for which the HMF value should not
(Fukuda et al., 2011). Aside from their phenolic con- exceed 80 mg/kg; however, these honey types may be
tents, animal studies and in vitro assays revealed less appropriate for the use in wound care products.
increased efficacy in wound healing of acacia and buck-
wheat honey, in contrast to manuka, as demonstrated
Physicochemical criteria and antibacterial
by the activation of keratinocyte re-epithelialization
properties of honey as a wound care product
(Abd Ghafar, Ker-Woon, Hui, Mohd Yusof, & Wan
Ngah, 2016; Ker-Woon, Abd Ghafar, Kien Hui, & Mohd Honey contains more than 200 different compounds, of
Yusof, 2014; Moniruzzaman et al., 2017; Ranzato, which the greater part are sugars, predominantly fruc-
Martinotti, & Burlando, 2013; Sergiel et al., 2014). tose and glucose, as well as enzymes, minerals, vitamins,
and solid particles derived from the honey collection
such as pollen, and phenolic compounds, which give rise
Making honey ‘medical grade’ - production and to honey’s anti-inflammatory capacities (Ahmed &
storage regulations & safety Othman, 2013; Alvarez-Suarez, Gonzalez- Paramas,
Honey for consumption must comply with several Food et al., 2010, Alvarez-Suarez, Tulipani, et al., 2010; van
Standards, such as the Global Standard for Food Safety, den Berg et al., 2008). Furthermore, honey contains dif-
and the International Food Standard (IFS) certifications. ferent volatile substances such as ketones, esters, alde-
However, higher quality standards are needed for honey hydes, hydrocarbons, alcohols and sulfur compounds
in medical use, and additional guidelines and restrictions that are deposited in honey following collection from
can further guarantee its safety for medical purposes, different floral sources, the transformation from plant
such as the Organic Certification and country-dependent compounds or production by bees or during honey
certifications (for example, the British BRC, French FCD, processing and storage (Kruzık, Gregrova, Rajchl, &
Dutch EKO, and Italian ANCC, ANCD and  ızkova, 2017). Research shows how these volatile
C
Federdistribuzione), that follow stricter protocols components directly influence the flavor of honey and
(Postmes et al., 1993). Beyond these pre-manufacturing how they can be used to determine its botanical source
parameters focusing on the honey, a standardized prepar- (Bicchi, Belliardo, & Frattini, 1983; Bouseta, Scheirman,
ation of MGH also extends to the handling, production, & Collin, 1996; Graddon, Morrison, & Smith, 1979;
and storage of MGH. Improper manufacture and storage Radovic et al., 2001). Thus, depending on the location
conditions, such as exposure to heat or light, can affect where honey is collected, the regional environment and
the physicochemical properties, and subsequently, result plant origin determine the exact composition, consist-
in reduced or loss of antimicrobial and wound healing ency, color, flavor, and aroma (European Honey
properties (Mandal & Mandal, 2011). It is therefore Directive, 2001).
important to follow the production and storage guide- Before being sold on the market, MGH needs to
lines strictly, in accordance with good manufacturing meet several composition criteria to guarantee the qual-
practice principles. MGH falls within the scope for med- ity of the honey as described by the European Union
ical devices, more specifically, Class 2 b medical devices (Directive 110/2001) and as listed in Table 2, below
and the EN ISO 13485 certification is therefore manda- (European Honey Directive, 2001).
tory and needs to be confirmed by specifically notified When brought into contact with water, honey’s
bodies. To comply with the EU legislation of the supersaturated nature employs an effect of osmosis.
European Medicine Agency (EMA) and the American Furthermore, the conversion of large amounts of sugar
Food and Drug Administration (FDA), it is important to into gluconic acid lends honey a lowset pH ranging
strictly follow their guidelines for obtaining the CE and between 3.2 and 4.5 which is enough to inhibit the pro-
FDA quality certification marks MDD 93/42/EEC and liferation of bacteria that usually thrive in more alkaline
21CFR820, respectively. In addition, the requirements of conditions such as are often seen in chronic wounds
EN ISO14971 provide manufacturers with a framework (Allen, Molan, & Reid, 1991; Pridal AMZaLU, 2002).
for risk analysis, evaluation, control, and management, Leveen et al. (1973) showed that topical acidification
and they specify a procedure for review and monitoring improves healing through the increased release of oxy-
during production and post-production (International gen from hemoglobin into the wound environment,
Organization for Standardization, 2007). which can be exploited by the regenerating tissues
Several physicochemical factors can be examined to (Leveen et al., 1973). During the formation of gluconic
check for the decay of the product during production, acid, the antiseptic hydrogen peroxide is produced as a
storage and handling, e.g., measuring the concentration by-product (Kleppe, 1966). Next to peroxide-dependent
6 R. Hermanns et al.

Table 2. Criteria to guarantee the quality of the honey.


Component General requirement Exceptions
Fructose and glucose content blossom honey: 60 g/100 g
honeydew honey: 45 g/100 g
Sucrose content 5 g/100 g false acacia, alfalfa, firewood Banksia,
French honeysuckle, red gum,
leatherwood, citrus spp.: 10 g/100 g
lavender, borage: 15 g/100 g
Moisture content 18% Calluna, erica (23%)
Water-insoluble content 0.1 g/100 g pressed honey: 0.5 g/100 g
Electrical conductivity blossom honey: 0.8 mS/cm honeydew strawberry tree, bell heather, eucalyptus,
honey: 0.8 mS/cm lime tree, tea tree, ling heather,
manuka or jelly bush.
Free acid 50 milli-equivalents acid/1000 g
Diastase activity 8 (Schade scale) Honey with natural low enzyme content
(e.g., citrus honey) and HMF content
15 mg/kg: 3 (Schade scale)
HMF 40 mg/kg Fresh and unheated honey: 15 mg/kg
Honeys of tropical origin: 80 mg/kg

activity, manuka honey exerts antimicrobial activity in a However, this may also be influenced by the dilution of
“non-peroxide dependent” manner by the dehydration the honey, as it has been demonstrated that 30-50%
of dihydroxyacetone (DHA) to methylglyoxal when dilutions of honey yields the highest hydrogen peroxide
honey is produced from nectar (Adams, Manley-Harris, concentrations (Bang, Buntting, & Molan, 2003). In add-
& Molan, 2009). The amount of methylglyoxal depends ition, since the antimicrobial properties of honey rest
on its precursor molecule. That is present in the plants on multiple mechanisms, other factors should also be
and increases as the reaction continues as honey is taken into account making it more complex. Another
stored. The presence of methylglyoxal reduces the per- option would be that the antimicrobial activity of each
oxide-dependent activity of honey as methylglyoxal has honey batch needs to be tested against common micro-
been found to inhibit glucose oxidase thus lowering the organisms and must be effective at a certain dilution.
concentration of H2O2 (Majtan, Bohova, Prochazka, & For the biological activity on wound healing, other fac-
Klaudiny, 2013). tors may be more important, such as the amount of
While manuka honey is being sold as a therapeutic phenols, the anti-oxidative and anti-inflammatory action
agent worldwide, current studies show other monoflo- and its effects on cell proliferation, differentiation
ral, and polyfloral kinds of honey perform equally well, and migration.
if not better than manuka honey against a wide spec-
trum of the pathogens often encountered in wounds MGH in wound care
(Grego et al., 2016; Lusby et al., 2005; Majtan et al., In times of rising antibiotic resistance, health care can
2013; Sherlock et al., 2010). When compared to benefit from novel antimicrobial agents that have limited
manuka honey, Grego et al. present the increased bac- risk to develop resistance (WHO, 2018a). Since the
teriostatic and bactericidal activity of honeydew, chest- antimicrobial effects of honey are based on multiple
nut, and polyfloral honey against Gram-positive bacteria physicochemical properties and different constituents,
and E. coli ESBL (Grego et al., 2016). Similarly, Kus et al. there is a limited risk of the development of antimicro-
have described the higher antibacterial activity of buck- bial resistance against honey formulations and that
wheat, cornflower, thyme, and tansy phacelia honey explains the resurgence of this ancient remedy in health
when compared to manuka honey (Kus, Szweda, care (Maddocks & Jenkins, 2013). Generally, it is stated
Jerkovic, & Tuberoso, 2016). that the variety in antibacterial activity among different
Early scientific research of manuka honey may have kinds of honey is a result of the different concentrations
hyped the use of this specific honey type for honey- of hydrogen peroxide or methylglyoxal, the concentra-
based wound dressings, but the growing number of new tion of honey used and the type of bacteria involved
studies using other honey types – including studies pro- (Mandal & Mandal, 2011). Hence, a greater concentra-
viding comparison data on manuka – should be sufficient tion of honey should result in a more versatile antibac-
to stimulate the diversification of MGH-based wound terial agent (Badawy, Shafii, Tharwat, & Kamal, 2004).
healing products. Variation in antimicrobial activity may exist between
Criteria for the biological activity should be estab- honey types, but it may also differ between bacterial
lished to guarantee its efficacy during wound healing. isolates as bacteria differ in susceptibility towards the
For example, to assure the antimicrobial activity, a min- different killing mechanisms of honey (Alvarez-Suarez,
imum amount of methylglyoxal or hydrogen peroxide Gasparrini, Forbes-Hernandez, Mazzoni, & Giampieri,
needs to be present in manuka or other types of honey. 2014; Boateng & Diunase, 2015; Kwakman, Te Velde,
Standards for medical grade honey 7

Table 3. Overview of MGH-based formulations currently available on the wound care market.
Sterilization
Product name Manufacturer Honey type MGH % method Certification Supplements
Medihoney Derma Sciences Manuka 80% Gamma irradiation FDA & CE
Activon Advancis Manuka 100% Gamma irradiation FDA & CE
Manuka Fill Links Medical Manuka 100% Gamma irradiation FDA & CE
Products Inc.
Mesitran Triticum Organic honey 40 and 48% Gamma irradiation FDA & CE Vitamin C, vitamin
E, zinc oxide,
essential oils
Revamil Bfactory Polyfloral 100% Gamma irradiation CE
Health
Products
Surgihoney Matoke Any honey 100% Gamma irradiation CE
Holdings
Limited
Vivamel Tosama Chestnut 100% Gamma irradiation CE
Principelle IF Principelle Dark buckwheat n/a Gamma irradiation CE Minerals, trace
elements,
and oxides
Melladerm Plus SanoMed Polyfloral 45% Ozonation CE Vitamin C, vitamin
Manufacturing E,
glucose oxidase

de Boer, Vandenbroucke-Grauls, & Zaat, 2011). Many and wet weather as experienced during autumn and
studies have compared the antimicrobial activity of winter brings other challenges and reduces crop quality
manuka honey with other natural honey, and it is evi- (Ministry for Primary Industries, 2018). The increased
dent that manuka honey is not superior. In contrast, demand in manuka together with the decreased avail-
the antibacterial properties of the diverse honey types ability will probably further inflate its price.
produced worldwide have been reported to be similar While all presented products have received the
or superior compared to manuka honey and they may Conformite Europeenne (CE) mark, only four of them
have distinct advantages over manuka honey are FDA approved. Acquisition of the FDA approval is a
(Anthimidou & Mossialos, 2013; Mandal & Mandal, 2011; costly procedure yet it proves its worth by informing
Stagos et al., 2018). Despite these findings, many of the the general public that the benefits of the product out-
products available worldwide are based on 80% to weigh the known risks for the intended use.
100% manuka honey solutions (Table 3). Some of the described MGH products have add-
There are a number of things that stand out when itional ingredients, such as lanolin, polyethylene or poly-
looking at Table 3. propylene glycol, added to their formulation. These
Most of the products that are approved by the FDA ingredients may help with the application of the MGH,
use manuka honey. As discussed before, this popularity as there are difficulties described with pure honey prod-
probably proceeds from early honey research focusing ucts, that are hard to apply and can drip from the
on manuka honey. Other honey types have been wounds in warm environments.
described to be similar, or more biologically active, than To assure the best possible MGH-based wound care
manuka, which supports the use of other kinds of products, the honey should adhere to organic standards
honey. Due to its popularity, the price of manuka has (CAS 8028- 66-8) and be present in an amount of 30 -
risen sharply in recent decades and it will probably 50% w/w or at least 20- 60% w/w to guarantee efficacy
increase further in the near future as demand continues as a wound healing product. Furthermore, the compos-
to outpace increases in supply (Spence, 2018). The ition preferably includes substances that improve the
honey yield in 2016 per hive in New Zealand dropped applicability of the honey, such as hypoallergenic lanolin
36% from 29.1 kg/hive to 18.7 kg/hive. Despite an (CAS 8006-54-0) and one or more components chosen
increase of 16% in beehives in 2017, the production of from the group of PEG (CAS 57-55-6), PEG 4000 (CAS
manuka honey dropped by a further 4% (Ministry for 25322-68-3). Moreover, supplementation with additional
Primary Industries, 2018). These decreases in honey ingredients that enhance the antimicrobial and pro-
production are mainly attributed to poor weather: dry healing activity should be considered, such as ascorbic
and hot summers, windy weather, and increased risk of acid (CAS 50-81-7), Vitamin A, Vitamin D, Vitamin E,
fires (Ministry for Primary Industries, 2018). Instead of and Omega 3.
collecting honey, bees have switched to collecting water All the products listed in Table 3 are sterilized with
for cooling, which costs a lot of energy for the bees gamma irradiation, except for one using ozonation.
and affects their health (Brugman, 2014; Ministry for Although both sterilization methods may maintain hon-
Primary Industries, 2018). In contrast, extremely cool ey’s bioactivity, gamma irradiation can be considered as
8 R. Hermanns et al.

the golden standard, especially since ozonation only Chrysoula Tananaki http://orcid.org/0000-0002-0056-483X
reduces the number of microorganisms and does not Frank A.D.T.G. Wagener http://orcid.org/0000-0003-
4837-1559
completely eliminate them (Vandeputte, 2008).
Niels A.J. Cremers http://orcid.org/0000-0003-4042-8987
Since the products shown in Table 3 have all been
tested and at least CE certified, these products are all
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