Antibacterial action of manuka and medihoney against various strains of
The use of antibiotics to treat bacterial infections have largely been successful. However, the misuse and overuse of these precious drugs have led to the development of bacterial resistance and this seems to have jeopardized their effectiveness. Many antibiotics that hitherto were seen as “miraculous drugs”, have witnessed a low efficacy and this has threatened the life of humanity as never before. The rapid emergence of antibiotic resistance in bacteria is the major cause of this sad development. One such superbug is methicillin-resistant Staphylococcus aureus (MRSA). MRSA is a general problem in most healthcare centers with a reported astronomical incidence of invasive MRSA infections causing death. Honey, a natural product, popular for its antibacterial activity is increasingly being used owing to its reported antibiotic potential against ‘stubborn’ bacteria. This review discusses the fact that though honey is an ancient remedy, it is still relevant and its application in modern medicine for the treatment of chronically infected wounds caused by MRSA should be re-visited. Furthermore, the in vitro antibacterial and antibiofilm activities of medical-grade honey on S. aureus infections and challenges encountered by Researchers in developing honey, into an acceptable medical, therapeutic antibacterial agent for wound care have also been highlighted.
- medical-grade honey
- Staphylococcus aureus
- wound treatment
- antibiotic resistance
MRSA is a major cause of severe healthcare-associated (HA) infections. Although during the last decade, the incidence of HA invasive infections have dropped, accounts of community-associated MRSA (CA-MRSA) infections have soared among the general populace [3, 4, 5, 6, 7]. Globally, MRSA remains one of the most important multidrug-resistant bacteria reported to account for most cSSTIs such as surgical wounds  and is also responsible for the high morbidity and mortality cases due to HA infections. The use of orthodox antibiotics has been the mainstay of treatment for these infections. Though the world’s encounter with antibiotics has been beneficial, several reports have suggested that many antibiotics that used to be seen as “miraculous drugs” have witnessed a low efficacy and this has threatened the life of humanity as never before. The rapid emergence of “superbugs” such as MRSA bacteria that are highly resistant to many classes of antibiotics is the major cause of this sad development. Infections due to MRSA, in comparison with MSSA, are associated with a greater risk of treatment failure, increased patient mortality, and higher costs. Owing to irrational and excessive antibiotic use, the bacterium-
Honey is a sugary thick fluid that has been in use for almost 5500 years back. In the Sumerian tablet, the earliest inscribed information on honey for nutrition and medicinal purposes was found in 2100–2000 B.C. This chapter discusses the fact that though honey is an ancient remedy, its relevance and application in complicated and chronic infected wounds in modern medicine is still relevant and should be re-visited. This piece provides data on the
2. Antibacterial activities of MGH on both MSSA and MRSA
Honey according to Codex Alimentarius, 2001 is “the natural sweet substance produced by honey bees from the nectar of plants or secretions of living parts of plants or excretions of plant-sucking insects on the living parts of plants, which the bees collect, transform by combining with specific substances of their own, deposit, dehydrate, supply and leave in the honeycomb to ripen and mature”. Honey is classified based on many criteria. Based on its nutritional and medicinal applications, two main kinds are known, namely medical and non-medical grades. Fresh honey which has not been exposed to irradiation are referred to as non-medical grade whereas those with radiation exposure are usually called medical grade honey (MGH). Fresh honey can contain bacterial spores, mainly those of bacillus species, and spores of the notorious pathogen Clostridium botulinum, which can cause wound botulism or gangrene. The likely presence of these microorganisms calls for the sterilization of honey through gamma-irradiation to destroy these bacterial spores and other microorganisms. Honey that has passed through this process is referred to as medical-grade honey (MGH) and approved for use in clinical settings. Manuka and medihoney (Comvita, NZ), one of the few honeys that appear to have FDA approval for clinical applications.
The limited knowledge of anti-bacterial compounds in honey and the variability of anti-bacterial activity of other types of honey are however major obstacles to the applicability in clinical use. This section presents information on the antibacterial effects of MGH mentioned earlier and the contribution of individual components in its antimicrobial action. Studies have shown that MGH comprises primarily fructose, glucose, sucrose, water, organic acids, flavonoids, phenolic acids, as well as minor components such as peptides [bee defensin-1 and 2, hemenopectin, apidaecin], enzymes [diastase, invertase, glucose oxidase] amino acids and vitamins [10, 11]. It is important to note that the bioactive components of honey can vary due to the different botanic and geographic origins .
In the past four decades, there have been various studies regarding honey and its components and how it drives the anti-bacteria character. Several studies have shown that no “stubborn” or resistant bacteria can be isolated after subjecting isolates of MRSA obtained from wound to various concentrations of MGH or MGH-based dressings [13, 14, 15, 16]. This is reported to be as a result of the fact that these types of honey contain various antibacterial constituents and conditions such as low pH, high sugar content, methylglyoxyl (MGO), hydrogen peroxide, antimicrobial peptides (bee defensin-1) and other active substances [10, 17, 18]. It is of interest to note that MGO has been identified as one of the principal antimicrobic ingredient of most MGHs [19, 20]. Cooper and colleagues in 2010, demonstrated that some honeys also contain an antimicrobial peptide (bee defensin-1), which contributes substantially to bactericidal activity .
The antimicrobial qualities are critical in dermatologic applications, owing to the presence of active constituents, like MGO and antimicrobial peptides. MGH-based dressings are appropriate for the dressing of wounds and burns and have also been included in treatment therapy against diseases such as diaper dermatitis, dandruff, pityriasis, and psoriasis. It also exerts emollient, humectant, soothing, and hair conditioning effects, keeps the skin juvenile and retards wrinkle formation, regulates pH, and prevents pathogen infections . Studies have also shown that Community-associated methicillin-resistant
|Type of Honey||MIC||Test method||Reference|
|Manuka||34 𝜇g||O4–277-35671||Broth microdilution|||
|Manuka||8.0 w/v %||NCTC83253||Microdilution assay|||
|8.0 w/v %||RPAH181,2|
|8.0 w/v %||MW21,2|
|Medihoney||4.2 w/v %||MRSA2||Agar dilution method|||
|4.1 w/v %||Non-MRSA Clinical isolate1|
|4.2 w/v %||Resistant to all antibiotics4|
|4.4 w/v %||sensitive to all antibiotics5|
|Medihoney||8.0 w/v %||NCT83253||Microdilution assay|||
|8.0 w/v %||RPAH181,2|
|8.0 w/v %||MW21,2|
|Manuka||3.0 v/v||MRSA1||Broth dilution method|||
|Manuka||12.5 v/v||MRSA ATCC 433003||Broth dilution method|||
|12.5 v/v||MRSA 07912|
|12.5 v/v||MRSA 289652|
|12.5 v/v||MRSA 013222|
|12.5 v/v||MRSA 07452|
|Medihoney||4.0 v/v||BORSA mecA neg1||Broth dilution method|||
|4.0 v/v||Multiresistant mecA neg1|
|Manuka||60000 mg/ml||EMRA-15 NCTC 131422||E-test strip|||
|60000 mg/ml||Broth dilution|
|60000 mg/ml||Checker board|
|60000 mg/ml||Time kill curve|
Non-MRSA Clinical isolate1; MRSA2; Non–MRSA Lab strain3; Resistant to all antibiotics4; Isolates sensitive to all antibiotics5.
MIC- Minimum Inhibitory Concentration; ZI- Zone of Inhibition; R- Resistant.
3. Combinatorial effect of MGH and antibiotics on
One of the ways to curb the upsurge in antimicrobial resistance is to introduce novel approaches to combat these pathogens. Merging antimicrobial drugs with other agents such as honey that counteract and obstruct the antibiotic resistant mechanisms expressed by these pathogens is a novel strategy. The natural product, honey, is gaining acceptance as an alternative antimicrobial agent. Medical grade honey offers a favorable alternative for topical use, as a single or a multi-component agent in combination with other antibiotics . One of the approaches to fight antimicrobial resistance is combination drug therapy . This upturns efficacy and enhances the value of existing antimicrobials in the dearth of new antibiotics discovery and development. There are instances where, combining antimicrobial agents have made drug action synergistic. This has the benefits of lessening both the treatment costs and the risk of possible side effects owing to the reduced concentrations of both agents used . This phenomenon is especially vital for chronic wounds where antibiotic therapy is usually applied for long-term. Moreover, combining antibiotics and other drug agents is reported to exhibit different, modes of action and as such reduces the risk of resistance arising during treatment.
Honey is a natural product substance applied in different forms such as gels for topical management of infected chronic wounds . MGH-based dressings have been licensed by some national health authorities and are available to health professionals in many countries. Honey has a multifaceted substance  with well-known, broad-spectrum antibacterial activity against a various microorganism, including those that are commonly associated with chronic wounds such as
|Type of Honey||Antibiotics||FICI||Test method||Reference|
|Manuka||NCTC83253||0.445||Agar diffusion test|||
|Medihoney||Rifampicin||NCTC83253||0.445||Agar diffusion test|||
|Manuka||Oxacillin||EMRSA-15 NCTC 131422||0.001||Etest strip|||
|Time kill curve|
The fractional inhibitory concentration index (FICI) range of 0.5 to 4.0 is usually used to define additivity results in most combination studies. The fractional inhibitory concentration index (FICI) is calculated as the sum of the minimum inhibitory concentration (MIC) of each compound divided by the MIC of one compound used alone. Synergy and antagonism are defined by FICI ≤ 0.5 and FICI > 4 respectively, while FICI > 0.5 or 4 ≤ is considered indifferent.
It is clear that MGH combining with gentamicin or clindamycin recorded the highest FICI compared with other antibiotics used as shown on Table 2.
Non-MRSA Clinical isolate1; MRSA2; Non–MRSA Lab strain3.
4. Mechanisms of action of honey on
Understanding how MGH impacts the action of orthodox antibiotics and their mode on action may broaden our knowledge of how honey affects these pathogens. It is important to state that much evidence would be displayed using data on manuka honey because much research has been undertaken on it since sterile preparations of it is available commercially. According to a publication by Majtan, in 2014 there is no evidence of damage to host cells, when MGH is either consumed orally or used as a wound dressing. Honey appears to stimulate healing and reduce scarring when applied to wounds .
The antibacterial property of honey has been linked to some mechanisms. The high osmolarity of honey as a result of its high sugar content inhibits microbial growth ; the sugar molecules within the honey hold onto the water molecules, thereby denying the bacteria enough water to support their growth. However, this effect gets lessened as the honey becomes more diluted by wound exudates.
There is another mechanism that lies in the fact that its antimicrobial properties are retained, even when the honey is diluted by wound exudate. This is partly due to the presence of hydrogen peroxide, which is slowly released as a result of the action of glucose oxidase present in the honey. The latter gets diluted by the exudate and in the process becomes activated .
Biofilms are generally populations of cells typically covered in a self-produced extracellular matrix and usually clinging on surfaces such as teeth, implanted devices and wounds. Generally, these microbes in biofilms are safeguarded from antimicrobial agents which can lead to stubborn infections. MGH is reported to disrupt cellular aggregates and averts the formation of biofilms formed by many pathogens, including
5. Proof of efficacy from animal and case studies, and hurdles so far encountered
MGH has been used on animals with accidental or surgical wounds, such as rhinos, Horses, etc., with positive outcomes [42, 43]. Case reports using MGH for non-healing wounds and ulcers have recorded substantial improvement where conventional antibiotics had failed [44, 45, 46, 47, 48].
In the intervention studies, the treatment of non-healing wounds with MGH-based dressings resulted in a higher number of completely healed wounds and a faster rate of wound size reduction. Also, it was observed that wound odor was neutralized with the provision of topical protection, and a reduction in wound pain intensity.
There is evidence from case studies of MGH-based dressing used to treat wounds that have failed with treatment with orthodox antibiotics. Though MGH has shown potent antibacterial actions in the past three decades and has high potential for use to treat chronic wounds caused by
Meanwhile there are challenges that cannot be overlooked. There are countless reasons for this, including technical challenges in performing a double-blind placebo-controlled trial on a distinctive substance like honey. The issue of ethical considerations and lack of interest by clinical practitioners are other worries that affect patronage. Additionally, the use of honey ointment has been portrayed as messy as it leaves behind a sticky residue . There are also apprehensions with the application of honey to vertical wounds in ambulatory patients. The newer honey-dressings have resolved such issues and there appears to be good ease of use, retention and removal and patient comfort with MGH- impregnated tulle.
There has been a collective effort to find or develop novel agents with antimicrobial activity in order to increase the collection of drugs against methicillin-resistant
Conflict of interest
The authors declare no conflict of interest.
We are grateful to Professor Michael D. Wilson for continuous support.
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