The prevalence of diabetes mellitus (DM) strongly increased over the last few decades [1
]. In 2000, the prevalence was estimated to be 171 million, while this number increased to 451 million in 2017 [1
]. The latter number already exceeds the predictions from 2004, in which 336 million people were predicted to be affected by 2030 [2
]. Recent estimations predict a prevalence of 693 million by 2045 [1
]. The comorbidities accompanying DM are serious life-threatening health problems that contribute to higher healthcare costs, reduced quality of life for the patient, and higher mortality rates [3
]. A common complication is diabetic foot ulcers (DFU), with one-quarter of all diabetics developing one or more DFUs during their life. The definition of a diabetic foot is an “infection, ulceration, or destruction of tissues of the foot associated with neuropathy and/or peripheral artery disease in the lower extremity of a person with (a history of) diabetes mellitus” [4
]. DFUs can lead to pain, malodor, functional problems, and eventually amputation when not receiving good care. Especially in diabetics, these ulcers are at risk of becoming chronic and getting infected, as they have hampered vascular structures, limiting oxygen and nutrient supply and transport of leucocytes that are needed to promote wound repair. In addition, DM patients often suffer from neuropathy, which means they cannot feel pain and notice the wounds properly, subsequently resulting in inadequate wound care and exacerbation of the injury. DFUs precede 84% of all diabetes-related lower-leg amputations as they are often contaminated with persistent infections [5
]. Forceful drug marketing, competence of medical personnel, and patient compliance are factors contributing to the rise in antimicrobial resistance. The current surge in antibiotic resistance worsens the global outcome of pathogen persistence in infected wounds. Novel therapies working independently of resistance profiles are invaluable. Fortunately, medical-grade honey (MGH) formulations may form a promising complementary therapy that can become more popular in the healthcare sector.
Honey is used for wound healing since ancient times because of its broad-spectrum antimicrobial and wound-healing activities [6
]. Antibiotics replaced the use of honey, but the development of antibiotic resistance returned its use [7
]. To assure the safety and efficacy of honey for clinical application, strict guidelines are followed to introduce MGH [8
]. MGH must be free of any form of contamination, such as herbicides, pesticides, heavy metals, and dormant endospores. MGH must be collected in organic regions and gamma-sterilized, in addition to following strict quality, processing, and storage standards and regulations, in order to ensure the safety of the honey [8
]. MGH has multiple physicochemical properties that result in antimicrobial and healing activities.
MGH consists of more than 200 different constituents, of which water (17–18%) and carbohydrates (about 80%), such as glucose, fructose, and sucrose, encompass the relative majority. The sugar-rich composition has a hygroscopic activity, attracting fluid from the surrounding environment. This process also leads to dehydration of present microorganisms, making them vulnerable. The acidic pH of MGH makes it even harder for bacteria to persist. The release of the known antimicrobial hydrogen peroxide subsequently kills almost all microorganisms, including those resistant to antibiotics. Hydrogen peroxide is formed by the enzyme glucose oxidase, which the bees add to the honey, and it catalyzes glucose in the presence of water and oxygen into gluconic acid and hydrogen peroxide (C6
O + O2
→ gluconic oxidase→ C6
). Moreover, other molecules present in MGH also have a direct antimicrobial effect, such as phenolic compounds, flavonoids, methylglyoxal, and Bee defencin-1 [6
]. Since the antimicrobial activity of MGH is based on multiple mechanisms, microorganisms are not capable of developing resistance toward MGH [10
]. Interestingly, smart honey formulations have added supplements such as vitamins C and E to further enhance the antimicrobial activity of raw honey [11
]. MGH decreases the bacterial load, while it additionally prevents the invasion of new pathogens by forming a physical barrier when applied to the wound. Together, MGH offers a potent alternative for antibiotics for the treatment of locally infected wounds.
In addition to antimicrobial activity, MGH possesses strong healing activity [7
]. MGH enhances healing by providing a moist and more regenerative wound environment, being anti-inflammatory and anti-oxidative, and by stimulating autolytic debridement, angiogenesis, and re-epithelialization [7
]. Moreover, quality of life is improved by reducing pain, minimizing scar formation, and deodorizing wounds [7
Despite all these beneficial effects, the use of MGH is reserved and often limited to later lines of therapy, because clinicians unfortunately tend to stick to conventional treatments such as povidone iodine and antibiotics. Therefore, we aim to raise awareness for MGH as an alternative antimicrobial chemotherapeutic by presenting a case series of infected diabetic ulcers treated with MGH. Most cases were ineffectively treated previously with other therapies, including antibiotics. The use of MGH as an earlier line of treatment can enhance healing and prevent exacerbation of the injuries and potential subsequent amputations. This case series demonstrates the efficacy of MGH against antibiotic-resistant infections and the ease of application that will favor patient and healthcare.
Diabetic patients with advanced wounds, such as presented in this case series, typically do not take good care of themselves and have bad hygiene. In addition, they have different comorbidities, such as obesity, hampered blood flow, atherosclerosis, neuropathy, and a bad nutritional diet, which attenuate the wound healing, making them even more prone to developing infections. Due to these comorbidities, these patients do not sense the pain at the beginning of a wound. When stayed unnoticed, wounds will worsen and get infected, especially with a lack of hygiene, such as walking in dirty bathrooms on bare feet and inadequate or no cleaning and wound care. Regular pedicure visits may prevent the development of wounds. However, when wounds are present, MGH may be a potent treatment strategy that should be considered more often as first-line therapy.
As presented in the current case series, whereas the previous therapies proved ineffective in treating DFUs, the application of MGH effectively enhanced wound repair. Within days, the malodor of the wounds neutralized, and inflammation and infection were controlled after a couple of weeks, including those with antibiotic-resistant bacteria. MGH holds multiple antimicrobial mechanisms that are very effective in resolving infections and, therefore, must be considered as a complementary treatment for antibiotics, especially since no resistance will be developed toward MGH. In addition to the antimicrobial activity, MGH also enhances wound healing. Here, MGH clearly enhanced autolytic debridement, leading to quick elimination of slough and the appearance of healthy granulation tissue within the following weeks. Due to the underlying pathologies, healing time ranged from 1.5–8 months.
Chronic wounds may be arrested in an inflammatory phase due to an ongoing infection or chronic inflammatory or oxidative stress in the wound bed. MGH can create a switch in the micro-environment of the wound by eradicating the bacterial load and changing the wound physiology due to its anti-inflammatory and anti-oxidative activities. Moreover, MGH accommodates a moist wound environment, has a low pH, and modulates oxygen levels, osmotic pressure, and proteinase activities that can cause non-healing wounds to suddenly start healing.
Edema, such as experienced in cases 1 and 6, can increase pressure on the wound, and it often leads to pain and a decreased quality of life for the patients. Infected wounds typically produce a lot of exudate, being presented as wet wounds. MGH consists of about 80% sugars (glucose, fructose, and sucrose), and these have a hygroscopic activity, attracting fluid from their environment. In wounds, this helps to draw out lymph fluid and clean the wound, stimulates autolytic debridement to remove necrotic tissue and slough, and decreases edema, as demonstrated in cases 1 and 2. The osmotic activity of MGH can result in elevated production of exudate, which may sometimes be noticed during wound dressing changes, especially at the beginning of MGH therapy when the MGH switches the wound environment.
Venous insufficiency will limit the transport of leucocytes and nutrition to the wound site, which is necessary to fight infections and promote healing. MGH will replace the task of leucocytes via its antimicrobial activity, and it can serve as an important nutrient source that is needed for proliferation and migration of epithelial cells during the re-epithelialization process [19
The efficacy and the safety of MGH for the treatment of DFUs were often investigated. Observational studies demonstrated that MGH can be used safely [21
]. Makhdoom et al. observed excellent results with natural honey in 14 diabetic wounds, and the disability of these patients was minimized by decreasing the rate of leg or foot amputations [22
]. A larger study in 172 diabetic patients also showed that the use of honey significantly reduced the amputation rate and improved wound healing in chronic diabetic foot ulcers [23
]. Moghazy et al. found that commercial clover honey is a clinical and cost-effective dressing for diabetic wounds in developing countries [24
]. In the systematic review and meta-analysis of Wang et al., MGH treatment shortened the wound debridement time, wound healing time, and bacterial clearance time and increased the wound healing rate and bacterial clearance rate during the first 1–2 weeks of use [25
]. Many different MGH formulations exist, andm since honey is a natural product, there is a difference in antimicrobial and healing activities.
A direct in vitro comparison study of L-Mesitran Soft and Medihoney against multiple (antibiotic-resistant) strains of staphylococci and Pseudomonas
spp. pathogens showed that L-Mesitran had a more robust antimicrobial activity, despite containing half the concentration of honey [11
]. This may have been caused by the difference in the type of honey, as there can be a 100-fold difference in antimicrobial activity between honey types [26
]; alternatively, it may have been caused by the supplements added to L-Mesitran Soft [11
]. Other studies demonstrated that L-Mesitran Soft has a stronger antimicrobial activity than its raw honey, which supports that the supplements added to the formulation, such as vitamins C and E, enhance the antimicrobial activity [11
The quality of life of patients with DFUs is negatively affected. The malodor is unpleasant and may limit people who want to visit; additionally, the wound may heavily exudate that may stain clothes and require extra care, or these wounds with or without edema may be excruciating. MGH will attenuate all these problems and improve the quality of life for patients suffering from (infected) DFUs. MGH offers an alternative nutrient source for the bacteria, which switch from catabolizing smelling tissue debris and proteins to the odorless consumption of glucose, which subsequently rapidly decreases malodor. The high sugar content of MGH attracts lymph fluid and wound exudate out of the tissue into the wound dressing. This process, together with the anti-inflammatory activity of MGH, will subsequently reduce edema and pain. Diabetic patients with advanced wounds typically do not take good care of themselves and have bad hygiene. In addition, they have different comorbidities, such as obesity, hampered blood flow, atherosclerosis, neuropathy, and a bad nutritional diet, which attenuate the wound healing, making them even more prone to developing infections. These patients do not sense the pain of a beginning wound because of their neuropathy and do not adequately clean their wounds. Regular pedicure visits may prevent the development of wounds. However, when wounds are present, MGH may be a potent treatment strategy. In line with previous conclusions, we agree that MGH with its antimicrobial activity, via decreasing wound healing time and amputations and, thus costs, is a cost-effective treatment for the treatment of DFUs [22
]. To illustrate, hospitalization costs for DFU patients needing an amputation range from United States dollars (USD) $
12,851 to USD $
]. By reducing the number of chronic wounds, not only will the wound care and societal costs decrease, but the quality of life for the patients will also be substantially improved [27
In this case series, the products were easy to apply and provided excellent patient comfort. MGH prevents the adherence of newly formed granulation tissue into the wound dressing and does not re-open the tissue after removal; therefore, dressings can be replaced without pain. The high sugar content of the honey did not influence the blood glucose levels of the patients.