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 contain 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 beekeeper 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, production, 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.

Hospital-acquired infections and treatment-related wound complications constitute a tremendous burden for the health care system, particularly given the serious increase in multidrug resistant pathogens. Imagine that a large part of nosocomial infections can be prevented using a simple treatment. In this respect, honey is used mainly in topical cutaneous wound care because of its potent broad-spectrum antibacterial and wound healing activities. However, therapeutic use outside this scope has been limited. The current review provides an in-depth view of studies using honey outside the conventional wound care indications. Non-conventional routes of honey application include subcutaneous, intra-socket, abdominal, and oral administration in novel indications, such as post colon surgery, mucositis, and tooth extraction. Honey consistently demonstrates beneficial therapeutic activities in these novel applications, orchestrating antimicrobial and prophylactic activity, reducing inflammation and wound dehiscence, and inducing healing, epithelialization, and analgesic activity. Several molecular mechanisms are responsible for these beneficial clinical effects of honey during the course of wound healing. Pro-inflammatory effects of honey, such as induction of iNOS, IL-1β, and COX-2, are mediated by TLR4 signaling. In contrast, honey's anti-inflammatory actions and flavonoids induce anti-inflammatory and antioxidant pathways by inducing NRF2 target genes, including HO-1 and PRDX1. The molecular and biochemical pathways activated by honey during the different phases of wound healing are also discussed in more detail in this review. Variation between different honey origins exists, and therefore standardized medical-grade honey may offer an optimized and safe treatment. Honey is a valuable alternative to conventional antimicrobial and anti-inflammatory therapies that can strongly reduce nosocomial infections.

Biofilms hinder wound healing. Medical-grade honey (MGH) is a promising therapy because of its broad-spectrum antimicrobial activity and the lack of risk for resistance. This study investigated the inhibitory and eradicative activity against multidrug-resistant Pseudomonas aeruginosa biofilms by different established MGH-based wound care formulations. Six different natural wound care products (Medihoney, Revamil, Mebo, Melladerm, L-Mesitran Ointment, and L-Mesitran Soft) were tested in vitro. Most of them contain MGH only, whereas some were supplemented. L-Mesitran Soft demonstrated the most potent antimicrobial activity (6.08-log inhibition and 3.18-log eradication). Other formulations ranged between 0.89-log and 4.80-log inhibition and 0.65-log and 1.66-log eradication. Therefore, the contribution of different ingredients of L-Mesitran Soft was investigated in more detail. The activity of the same batch of raw MGH (1.38-log inhibition and 2.35-log eradication), vitamins C and E (0.95-log inhibition and 0.94-log eradication), and all ingredients except MGH (1.69-log inhibition and 0.75-log eradication) clearly support a synergistic activity of components within the L-Mesitran Soft formulation. Several presented clinical cases illustrate its clinical antimicrobial efficacy against Pseudomonas aeruginosa biofilms. In conclusion, MGH is a potent treatment for Pseudomonas biofilms. L-Mesitran Soft has the strongest antimicrobial activity, which is likely due to the synergistic activity mediated by its supplements.

Candida auris is a pathogenic yeast causing outbreaks in intensive care units with high mortality rates. The treatment of C. auris colonization is challenging due to high resistance rates. A potential alternative antifungal treatment is medical-grade honey. In this study the susceptibility of C. auris and other Candida species to the medical-grade honey-based formulation L-Mesitran^® Soft was investigated. The medical-grade honey formulation reduced the growth of C. auris and other Candida species in a dose-dependent manner. This inhibition was not only due to the honey component, as treatment with an identical concentration of this component only was less effective and even stimulated the growth of C. albicans and C. glabrata, supporting the interpretation that supplements in the medical-grade honey formulation enhanced the antimicrobial activity. Increasing the concentration of the honey component to 40%, as is also present in an undiluted medical-grade honey formulation, lead to a 1- to 4-log inhibition of all Candida species. Unprocessed local honey reduced the growth of nearly all Candida species more strongly than medical-grade honey. C. auris’ susceptibility to the medical-grade honey formulation did not depend on geographic origin or resistance profile, although the multiresistant isolates tended to be more susceptible. Altogether, medical-grade honey formulation has a strong antifungal activity against C. auris and other Candida species. Future studies should demonstrate whether the treatment of open wounds or skin colonized with C. auris is feasible and effective in the clinical setting.

Diabetic ulcers are at risk of becoming chronic and infected, as diabetics have hampered vascular structures, limiting oxygen and nutrient supply. These wounds can lead to pain, malodor, functional problems, and amputation. The current rise in antibiotic resistance demands for complementary therapies. Medical-grade honey (MGH) forms an attractive option because of its antimicrobial and pro-healing properties. We aim to show the beneficial effects of MGH in infected diabetic ulcers. We present six patients with infected diabetic ulcers, of which some were at risk of (further) amputation. Previous treatments with antibiotics, silver and alginate dressings, surgical closure, and maggot therapy were ineffective; therefore, the treatment was switched to the application of MGH. MGH therapy typically reduced the malodor in a couple of days and controlled infection within 2–3 weeks. MGH also enhanced wound healing by promoting granulation tissue formation, angiogenesis, and re-epithelialization, by decreasing inflammatory and oxidative stress and providing nutrients. Together, wound healing was enhanced, and the patient’s quality of life improved. MGH is safe and cost-effective for treating complicated diabetic wounds with (antibiotic-resistant) infections and at risk of amputation. MGH forms a promising alternative or complementary therapy to replace antibiotics for treating locally infected wounds.

Monocytes are dominant cells present within the inflamed synovium during osteoarthritis (OA). In mice, two functionally distinct monocyte subsets are described: pro-inflammatory Ly6Chigh and patrolling Ly6Clow monocytes. Alarmins S100A8/A9 locally released by the synovium during inflammatory OA for prolonged periods may be dominant proteins involved in stimulating recruitment of Ly6Chigh monocytes from the circulation to the joint. Our objective was to investigate the role of S100A8/A9 in the mobilization of Ly6Chigh and Ly6Clow monocytic populations to the inflamed joint in collagenase-induced OA (CiOA). S100A8 was injected intra-articularly to investigate monocyte influx. CiOA was induced by injection of collagenase into knee joints of wild-type C57BL/6 (WT), and S100a9-/- mice. Mice were sacrificed together with age-matched saline-injected control mice (n = 6/group), and expression of monocyte markers, pro-inflammatory cytokines, and chemokines was determined in the synovium using ELISA and RT-qPCR. Cells were isolated from the bone marrow (BM), spleen, blood, and synovium and monocytes were identified using FACS. S100A8/A9 was highly expressed during CiOA. Intra-articular injection of S100A8 leads to elevated expression of monocyte markers and the monocyte-attracting chemokines CCL2 and CX3CL1 in the synovium. At day 7 (d7) after CiOA induction in WT mice, numbers of Ly6Chigh, but not Ly6Clow monocytes, were strongly increased (7.6-fold) in the synovium compared to saline-injected controls. This coincided with strong upregulation of CCL2, which preferentially attracts Ly6Chigh monocytes. In contrast, S100a9-/- mice showed a significant increase in Ly6Clow monocytes (twofold) within the synovium at CiOA d7, whereas the number of Ly6Chigh monocytes remained unaffected. In agreement with this finding, the Ly6Clow mobilization marker CX3CL1 was significantly higher within the synovium of S100a9-/- mice. Next, we studied the effect of S100A8/A9 on release of Ly6Chigh monocytes from the BM into the circulation. A 14% decrease in myeloid cells was found in WT BM at CiOA d7. No decrease in myeloid cells in S100a9-/- BM was found, suggesting that S100A8/A9 promotes the release of myeloid populations from the BM. Induction of OA locally leads to strongly elevated S100A8/A9 expression and an elevated influx of Ly6Chigh monocytes from the BM to the synovium.