HONEY AS A THERAPEUTIC AGENT, AN INSIGHT INTO ITS ANTIMICROBIAL PROPERTIES.

Traditionally, honey has been used as both food and medicine since ancient times worldwide. Due to its nutritious content and sweet flavor, honey has been in great demand worldwide with China being the leading producer. People apply honey on the wound without having any knowledge of its antibacterial properties. Honey has proven to contain some antibacterial properties such as hydrogen peroxide, acidity, low moisture content, pH, etc. Bacteria are ubiquitous and their life has a close association with humans in their diet, food processing, etc. Some bacteria eg Staphylococcus aureus, consist of the normal flora of humans making them partially harmless but some can be harmful and in turn cause infections. Clinically, antibiotics such as tetracycline, penicillin, amoxicillin lincomycin, etc. have been used in the treatment of bacterial infections but some bacteria eg Methicillin Resistant Staphylococcus aureus have shown resistance to some antibiotics. Medical practitioners have opted for the use of honey in treating bacterial infections due to its antibacterial properties. Researches have proven that honey can kill or inhibit almost every bacteria and is very effective in wound treatment as compared to antibiotics. In light of this most medical practitioners prefer the use of honey in treating bacterial infections.


Introduction
Honey is a sweet supersaturated liquid produced by bees such as Apis mellifera, insects from the order Hymenoptera. It has been used all over the world for food and medicinal purposes. The honey composition is complex and variable, and it contains at least 181 different substances (Alvarez-Suarez et al., 2010). Some of the differences in the composition of honey are due to the differences between regions (floral sources) but seasonal differences can also be considered.
According to the World Health Organization (WHO) statistics, up to 80% of the population in some developed countries have used natural products in their primary health care and one example is honey. Natural product used in medical treatment has become a popular approach in modern times. This natural product which includes honey serves as a therapeutic agent in the field of medicine. The antimicrobial properties of honey have been documented in numerous studies (Aurongzeb & Azim, 2011), (Wilczynska, 2010). In recent years, medical authorities reported increased infections and the emergence of strains resistant to certain antibacterial compounds mainly due to the misuse of these substances (Aggad & Guemour, 2014). Honey's potential to assist wound healing has been demonstrated repeatedly (M. D.  has been among the best alternatives with broad-spectrum against bacterial infections. A possible reason behind its activity relies on its ability to generate hydrogen peroxide by the bee-derived enzyme glucose oxidase (Nolan, Harrison, & Cox, 2019). The antibacterial activity of honey has been known since the 19th century. Recently, the potent activity of honey against antibioticresistant bacteria has further increased the interest for the application of honey, but incomplete knowledge of the antibacterial activity is a major obstacle for clinical applicability (Nwankwo, Ezekoye, & Igbokwe, 2014).

Honey Production
The consumption of honey all over the world has increased rapidly especially for diabetic patients.
The annual world honey production is estimated at 1.4 million tonnes (Mamo, 2018). The highest production of honey is in Asia, accounting for about 40% of the world's production (Mutinelli, 2011). Also, China is the largest producer of honey with about 0.3 million tonnes annual production. The production of honey is shared among the best ten honey producing countries which include China, New Zealand, Argentina, Belgium, etc.

Nutritional composition of honey
Honey has been used for millennia in traditional medicine for its potential antibacterial, antiinflammatory, and antioxidant properties (Sforcin, Bankova, & Kuropatnicki, 2017). Dr.
Fessenden said that "honey's many benefits are interrelated, much like the cells of a honeycomb, and at the very least, there are no known medical reasons not to enjoy honey as part of a healthy diet and lifestyle for adults and children over the age of twelve months" (Mamo, 2018). Honey is primarily made up of carbohydrates and water, with several traces of minerals and vitamins.
Niacin, calcium, copper, riboflavin, iron, magnesium, potassium, and zinc can be found in honey.

Properties of honey relevant to its antibacterial activity
Several factors have been shown to contribute to the antibacterial activity of honey, these are high viscosity, high sugar concentration, and low water content, which helps to provide a protective barrier to prevent infection. Also, the mild acidity and hydrogen peroxide content has obvious antimicrobial effects.
1.3.3. Hydrogen peroxide is a potent antimicrobial agent, produced mainly during glucose oxidation catalyzed by the action of the bee enzyme, glucose oxidase, which is introduced into honey during nectar harvesting by bees (Bizerra, 2012). The rate of production of glucose oxidase and its destruction by catalases determines the hydrogen peroxide concentration in the honey.
According to Bang et al., the production of hydrogen peroxide in some honey samples can increase continuously over time to a point depending on the dilution used (N. A. . It was originally believed that hydrogen peroxide is the only factor responsible for the antibacterial effect of diluted honey, and this antibacterial activity of honey could be completely removed by the addition of catalase (Najla A Albaridi, 2019).
1.3.4. Acidity of honey. According to the National Honey Board, the acidity of honey ranges from a pH of about 3.4 to about 6.1, with an average of 3.9 (Yadata, 2014  . Thus in undiluted honey, acidity is a significant antibacterial factor.
Honey contains several different acids, including about 18 amino acids, many different inorganic acids, as well as aliphatic and aromatic acids. The aromatic acids greatly contribute to the flavor of honey.
1.3.5. Low water activity. Water activity is the partial vapor pressure of water in a substance divided by the standard state partial vapor pressure in water. In the field of food science, the standard state is most often defined as the partial vapor pressure of pure water at the same temperature. Water activity (aw) of honey ranges from 0.562 and 0.62, which means it provides a very low water availability to support the growth of any microorganisms, lower than the range where the growth of bacteria is completely inhibited (aw 0.94-0.99) (Najla A Albaridi, 2019).
Since osmosis normally occurs because of the high sugar content. Undiluted honey can stop the growth of bacteria completely due to the high content of sugar. When there is a high sugar concentration of honey, it exerts osmotic pressure on the bacterial cells which causes water to be transported out of the bacterial cells through osmosis. Cells become dehydrated and unable to grow and proliferate in hypertonic sugar solution. This antibacterial action will be reduced when honey is diluted by body fluids at the site of infection. Staphylococcus aureus has a high tolerance of low water activity therefore the antibacterial activity of honey must be attributed to other factors (Najla A Albaridi, 2019), (Molan, 1992).  in diameter, form grape-like (Greek staphyle) clusters indicative of the ability to divide in more than one plane. Staphylococcus aureus can be commensal bacteria and human pathogen (Shu et al., 2013). About 30% of the human population is colonized by Staphylococcus aureus (Tong, Davis, Eichenberger, Holland, & Fowler, 2015).
aeruginosa contains 12 other members in its family. P. aeruginosa causes infection in the urinary tract, respiratory system, dermis, soft tissue, bacteremia, bone and joint, gastro intestine, and blood, particularly in patients with severe burns, tuberculosis, cancer, and AIDS (Wu, Jin, Bai, & Jin, 2015). Pseudomonas infection can be treated with a combination of an antipseudomonal betalactum (eg, penicillin or cephalosporin) and an aminoglycoside. Carbapenems (eg, imipenem, meropenem) with antipseudomonal quinolones may be used in conjunction with an aminoglycoside.         (Milner, Romagnolo, Connor, & Lee, 2010). It is also proven that the therapeutic potential of honey is always associated with antioxidant capacity against reactive oxygen species (Chua, Rahaman, Adnan, & Eddie Tan, 2013). Oxidative stress results from a lack of balancing chemical reaction between the production of free radicals and the natural protective S. aureus E. coli P. aeruginosa effect of our body resulting in cellular damage and disruption of genetic structure (Kunwar & Priyadarsini, 2011). An antifungal action has been reported for honey against Aspergillus, Penicillium, as well as all the common dermatophytes and Candida albicans. Honey has shown antiviral effects also (Ahmed et al., 2018). According to (Israili, 2014), the topical application of honey on recurrent attacks of herpes lesions concluded that topical honey application was safe and effective in the management of the signs and symptoms of recurrent lesions from labial and genital herpes compared to acyclovir cream. Besides, honey has also been reported to have inhibitory effects on rubella virus activity (Gul, Farooq, Khan, Rehan, & Anees, 2015).  (Abeshu & Geleta, 2016). According to the FDA, Medihoney® dressings are indicated for the management of light to moderately exuding wounds like diabetic foot ulcers, venous or arterial leg ulcers, partial or full-thickness pressure ulcers/sores, first and second partial-thickness burns, and traumatic and surgical wounds (Abeshu & Geleta, 2016).

Wound healing of honey
Subrahmanyam studied a total of 104 cases of superficial burn injury to assess the efficiency of honey as a dressing in comparison with a silver sulfadiazine gauze dressing. In the 52 patients treated with honey, 91 percent of wounds were rendered sterile within 7 days, and 87% healed within 15 days. The study has shown that the healing properties of honey helped burn wounds to heal earlier and with fewer complications than conventional treatment (Subrahmanyam, 1991).

Conclusion
Honey is a sweet organic natural substance produced by honeybees. It has been used as food, medicine, etc. in ancient and modern times. Interest has been developed in the antibacterial activity of honey is due to increasing clinical problems of antibiotic-resistant for example, with methicillinresistant Staphylococcus aureus or Pseudomonas spp. The antimicrobial activity of honey can be attributed to its pH, acidity, low water activity, hydrogen peroxide, etc. Due to the adverse effects of synthetic drugs, researchers have now pay attention to organic natural drugs such as plant-based drugs. The complete elucidation of the mechanisms of activity and synthesis of all components of honey could lead to the generation of optimally antimicrobial synthetic or semisynthetic honey.
Undiluted honey shows a wide broad spectrum of bacterial inhibition than certain conventional antibiotics used to treat bacterial infections.

Recommendation
• We recommend that further studies should be carried out on the antibacterial activity of honey on other bacterial strains.
• We also recommend that further research should be carried out on the use of honey for clinical wound treatment removing the need for antibiotics.
• We recommend that the spectrometry assay technique should be used more to investigate the antimicrobial activity of honey.
• We recommend that studies should be conducted on how the quality of honey can be ascertained