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Manuka Honey Bibliography

Manuka Honey Bibliography

Allen, K. L., Molan P.C. & Reid G.M. (1991). “A survey of the antibacterial activity of some New Zealand honeys.” Journal Of Pharmacy and Pharmacology 43(12), 817-822. Abstract. To assess the variation in antibacterial activity of honey a survey was carried out on 345 samples of unpasteurized honey obtained from commercial apiarists throughout New Zealand. Most of the honeys were considered to be monofloral, from 26 different floral sources. The honeys were tested against Staphylococcus aureus in an agar well diffusion assay, with reference to phenol as a standard. Antibacterial activity was found to range from the equivalent of less than 2% (w/v) phenol to 58% (w/v) phenol, with a median of 13.6 and a standard deviation of 12.5. Neither the age of the honey samples nor whether they had been processed by the apiarist was associated with lower activity. However, the difference between floral sources in the antibacterial activity was very highly significant. Kanuka (Kunzea ericoides (A. Rich.) J. Thompson. Family: Myrtaceae), manuka (Leptospermum scoparium J. R. et G. Forst. Family: Myrtaceae), ling heather (Calluna vulgaris (L.) Hull. Family: Ericaceae) and kamahi (Weinmannia racemosa Linn. f. Family: Cunoniaceae) were shown to be sources likely to give honey with high antibacterial activity. When antibacterial activity was assayed with catalase added to remove hydrogen peroxide, most of the honeys showed no detectable antibacterial activity. Only manuka and vipers bugloss (Echium vulgare L. Family: Boraginaceae) honeys showed this type of activity in a significant proportion of the samples. The high antibacterial activity of manuka honey was in many cases due entirely to this non-peroxide component.

Betts, J.A. & Molan, P.C. (2002) " Results of a pilot trial of manuka honey as a dressing for infected chronic wounds." - a paper presented at the 4th Australian Wound Management Association Conference, Adelaide, Australia.

Bignall J. (2003) "Honey & Heliobacter" The Lancet  342(8875), 858.

Brady N.F., Molan P.C. & Harfoot C.G. (1996) “The Sensitivity of Dermatophytes to the Anti-Microbial Activity of Manuka Honey & Other Honey.” Pharm. Sciences 2(10), 471-473. Abstract. Honey has been reported to have anti-fungal activity and so was tested against clinical isolates of the common dermatophyte species which cause tineas in man. A honey with an average level of hydrogen peroxide and a manuka (Leptospermum scoparium J.R. & G. Forst, Fam. Myrtaceae) honey with an average level of non-peroxide antibacterial activity were used. An agar well diffusion assay was used, the contents of the wells being replaced with freshly prepared honey solutions at 24h intervals over 3-4 days of incubation. The lowest concentrations (% v/v, in steps of 5%) of manuka honey with catalase added to remove hydrogen peroxide, and of the other honey (without catalase) showed that the inhibition of growth around the walls were, repectively Epidermophyton floccosum 25%,10%, Microsporum canis 25%,15%, Microsporum gypseum 55%, 20%, Trichophyton mentagrophytes var. interdigitale 45%, 15%, Trichophyton mentagrophytes var. mentagrophytes 25%,15%, Trichophyton rubrum 20%, 5%, Trichophyton tonsurans 25%, 20%. No inhibitory activity was detected with the other honey at 50% (v/v) with catalase added.  The results of this investigation show that the common dermatophytes are sensitive to the antimicrobial activity of honey, indicating that clinical evaluation of honey in the treatment of tineas is warranted. This would determine whether the hydrogen peroxide or the non-peroxide antifungal agent diffuses better into the skin.

Casey G. & van Rij A. (1997) “Manuka honey & leg ulcers.” New Zealand Med. J. 110(1045), 216.

Chambers J. (2006). “Topical manuka for MRSA-contaminated skin ulcers.” Palliat Med. 20(5), 557.  

Cooper R.A. & Molan P.C. (1999). “The use of honey as an antiseptic in managing Pseudomonas infection.” J. Wound Care 8(4), 161-164. A laboratory study was undertaken to extend existing knowledge about the effectiveness of the antibacterial properties of honey against pseudomonads. To date, sensitivity testing has used non-standardised honeys, which may vary greatly in their antibacterial potency. Pure cultures of Pseudomonas spp, isolated from swabs from 20 infected wounds, were inoculated on the surface of nutrient agar plates containing various concentrations of honey in the medium. Two types of honey were used, a manuka honey and a pasture honey, each selected to have antibacterial activity close to the median for each type. The minimum inhibitory concentration of the manuka honey for the 20 isolates ranged from 5.5-8.7% (v/v) (mean 6.9% (v/v), standard deviation 1.3). The minimum inhibitory concentration of the pasture honey for the 20 isolates ranged from 5.8-9.0% (v/v) (mean 7.1% (v/v), standard deviation 1.0). Honeys with an average level of antibacterial activity could be expected to be effective in preventing the growth of pseudomonads on the surface of a wound even if the honey were diluted more than ten-fold by exudation from the wound.

Cooper R.A. Molan P.C. & Harding K.G. (1999). “Anti-bacterial activity of honey against strains of Staphylococcus aureus from infected wounds.” J. R. Soc. Med. 92(6), 283-285.  Abstract.The antibacterial action of honey in infected wounds does not depend wholly on its high osmolarity. We tested the sensitivity of 58 strains of coagulase-positive Staphylococcus aureus, isolated from infected wounds, to a pasture honey and a manuka honey. There was little variation between the isolates in their sensitivity to honey: minimum inhibitory concentrations were all between 2 and 3% (v/v) for the manuka honey and between 3 and 4% for the pasture honey. Thus, these honeys would prevent growth of S. aureus if diluted by body fluids a further seven-fold to fourteen-fold beyond the point where their osmolarity ceased to be completely inhibitory. The antibacterial action of the pasture honey relied on release of hydrogen peroxide, which in vivo might be reduced by catalase activity in tissues or blood. The action of manuka honey stems partly from a phytochemical component, so this type of honey might be more effective in vivo. Comparative clinical trials with standardized honeys are needed.

Cooper R.A., Molan P.C., Krishnamoorthy L. & Harding K.G. (2001) “Manuka honey used to heal a recalcitrant surgical wound.” Eur J. Clin. Micobiol Infect Dis. 20(10), 758-9.

Cooper R.A. Molan P.C. & Harding K.G. (2002) “The `sensitivity to honey of Gram-positive cocci of clinical significance isolated from wounds.” J. Applied Microbiol 93(5), 857-63. Abstract.AIMS: To determine the sensitivity to honey of Gram-positive cocci of clinical significance in wounds and demonstrate that inhibition is not exclusively due to osmotic effects. METHODS AND RESULTS: Eighteen strains of methicillin-resistant Staphylococcus aureus and seven strains of vancomycin-sensitive enterococci were isolated from infected wounds and 20 strains of vancomycin-resistant enterococci were isolated from hospital environmental surfaces. Using an agar incorporation technique to determine the minimum inhibitory concentration (MIC), their sensitivity to two natural honeys of median levels of antibacterial activity was established and compared with an artificial honey solution. For all of the strains tested, the MIC values against manuka and pasture honey were below 10% (v/v), but concentrations of artificial honey at least three times higher were required to achieve equivalent inhibition in vitro. Comparison of the MIC values of antibiotic-sensitive strains with their respective antibiotic-resistant strains demonstrated no marked differences in their susceptibilities to honey. CONCLUSIONS: The inhibition of bacteria by honey is not exclusively due to osmolarity. For the Gram-positive cocci tested, antibiotic-sensitive and -resistant strains showed similar sensitivity to honey. SIGNIFICANCE AND IMPACT OF THE STUDY: A possible role for honey in the treatment of wounds colonized by antibiotic-resistant bacteria is indicated.

Cooper R.A., Halas E. & Molan P.C. (2002) “The efficacy of honey in inhibiting strains of Pseudomonas aeruginosa from infected burns.” J. Burn Care Rehab. 23(6), 366-370. Abstract. Because there is no ideal therapy for burns infected with Pseudomonas aeruginosa there is sufficient need to investigate the efficiency of alternative antipseudomonal interventions. Honey is an ancient wound remedy for which there is modern evidence of efficacy in the treatment of burn wounds, but limited evidence for the effectiveness of its antibacterial activity against Pseudomonas. We tested the sensitivity of 17 strains of P. aeruginosa isolated from infected burns to two honeys with different types of antibacterial activity, a pasture honey and a manuka honey, both with median levels of activity. All strains showed similar sensitivity to honey with minimum inhibitory concentrations below 10% (vol/vol) both honeys maintained bactericidal activity when diluted more than 10-fold. Honey with proven antibacterial activity has the potential to be an effective treatment option for burns infected or at risk of infection with P. aeruginosa.

Dixon B. (2003) “Bacteria can’t resist honey.” The Lancet Infectious Diseases 3(2), 116. 

English H.K., Pack A.R. & Molan PC. (2004). “The effects of manuka honey on plaque & gingivitis: a pilot study.” J. Int. Acad. Peridontol. 6(2), 63-67. Abstract: Research has shown that manuka honey has superior antimicrobial properties that can be used with success in the treatment of wound healing, peptic ulcers and bacterial gastro-enteritis. Studies have already shown that manuka honey with a high antibacterial activity is likely to be non-cariogenic. The current pilot study investigated whether or not manuka honey with an antibacterial activity rated UMF 15 could be used to reduce dental plaque and clinical levels of gingivitis. A chewable "honey leather" was produced for this trial. Thirty volunteers were randomly allocated to chew or suck either the manuka honey product, or sugarless chewing gum, for 10 minutes, three times a day, after each meal. Plaque and gingival bleeding scores were recorded before and after the 21-day trial period. Analysis of the results indicated that there were statistically highly significant reductions in the mean plaque scores (0.99 reduced to 0.65; p=0.001), and the percentage of bleeding sites (48% reduced to 17%; p=0.001), in the manuka honey group, with no significant changes in the control group. Conclusion: These results suggest that there may be a potential therapeutic role for manuka honey confectionery in the treatment of gingivitis and periodontal disease.

French V.M. Cooper R.A. & Molan P.C. (2005) “The anti-bacterial action of honey against coagulase-negative Staphylococci. “ J. Antimicrob. Biochem. 56(1), 228-231. Abstract. OBJECTIVES: Development of anti-biotic resistant strains of coagulase-negative Staphylococci has complicated the management of infections associated with the use of invasive medical devices, and innovative treatment and prophylactic options are needed. Honey is increasingly being used to treat infected wounds, but little is known about its effectiveness against coagulase-negative Staphylococci.  The aim of this study was to determine the minimum active dilution of two standardised representative honeys for 18 clinical isolates of coagulase-negative Staphylococci. METHODS:  An agar incorporation technique was used to determine the minimum active dilution, with dilution steps of 1% (v/v) [or steps of 5%v/v of a sugar syrup matching the osmotic effects of honey]. The plates were inoculated with 10 microl. spots of cultures of the isolates. RESULTS: The honeys were inhibitory at dilutions down to 3.6 +/- 0.7% (v/v) for the pasture honey, 3.4 +/- 0.5% (v/v) for the manuka honey, and 29.9 +/- 1.9 for the sugar syrup. CONCLUSIONS: Typical honeys are about eight times more potent against coagulase-negative Staphylococci than if bacterial inhibition was due to their osmolarity alone. Therefore, honey applied to the skin at the insertion points of medical devices may have a role in the treatment or prevention of infections by coagulase-negative Staphylococci. 

Gethin G. & Cowman S. (2005) “Case series of use of Manuka honey in leg ulceration.” Int. Wound. J. 2(1), 10-15. Abstract. The historical and current literature reports the successful use of honey to manage a diversity of wound aetiologies. However, only in the last 40 years is research on its mode of action and contribution to wound healing being investigated. The challenge of managing chronic non healing wounds generated interest in researching non standard therapies. The aims of the study were to gain insight into the practical use of Manuka honey in wound management. The objective was to test the feasibility of further rigorous research into the use of honey in the management of chronic wounds. Instrumental case series were used to examine the use of Manuka honey in eight cases of leg ulceration. To collect the necessary data, photographs, acetate tracings, data monitoring and patient comments and observations were used to add greater reliability and validity to the findings. The wounds were dressed weekly with Manuka honey. The results obtained showed three males and five females with ulceration of different aetiologies were studied. A mean initial wound size for all wounds of 5.62 cm(2) was obtained. At the end of four-week treatment period, the mean size was 2.25 cm(2). Odour was eliminated and pain reduced. The conclusions drawn were that the use of Manuka honey was associated with a positive wound-healing outcome in these eight cases. Arterial wounds showed minimal improvement only.

Lusby P.E. Coombes A. & Wilkinson J.M. (2002) “Honey: a potent agent for wound healing?” J. Wound Ostomy Continence Nurs. 29(6), 273-274. Abstract.  Although honey has been used as a traditional remedy for burns and wounds, the potential for its inclusion in mainstream medical care is not well recognized. Many studies have demonstrated that honey has antibacterial activity in vitro, and a small number of clinical case studies have shown that application of honey to severely infected cutaneous wounds is capable of clearing infection from the wound and improving tissue healing. The physicochemical properties (e.g. osmotic effects and pH) of honey also aid in its antibacterial actions. Research has also indicated that honey may possess anti-inflammatory activity and stimulate immune responses within a wound. The overall effect is to reduce infection and to enhance wound healing in burns, ulcers, and other cutaneous wounds. It is also known that honeys derived from particular floral sources in Australia and New Zealand (Leptospermum have enhanced antibacterial activity, and these honeys have been approved for marketing as therapeutic honeys (Medihoney and Active Manuka honey). This review outlines what is known about the medical properties of honey and indicates the potential for honey to be incorporated into the management of a large number of wound types.

Lusby P.E., Coombes A.L. & Wilkinson J.M. (2005). “Bacterial activity of different honeys against pathogenic bacteria.” Arch. Med. Res. 36(5), 464-467. Abstract. Renewed interest in honey for various therapeutic purposes including treatment of infected wounds has led to the search for new antibacterial honeys. In this study we have assessed the antibacterial activity of three locally produced honeys and compared them to three commercial therapeutic honeys (including Medihoney and manuka honey). METHODS: An agar dilution method was used to assess the activity of honeys against 13 bacteria and one yeast. The honeys were tested at five concentrations ranging from 0.1 to 20%. RESULTS: Twelve of the 13 bacteria were inhibited by all honeys used in this study with only Serratia marcescens and the yeast Candida albicans not inhibited by the honeys. Little or no antibacterial activity was seen at honey concentrations <1%, with minimal inhibition at 5%. No honey was able to produce complete inhibition of bacterial growth. Although Medihoney and manuka had the overall best activity, the locally produced honeys had equivalent inhibitory activity for some, but not all, bacteria. CONCLUSIONS: Honeys other than those commercially available as antibacterial honeys can have equivalent antibacterial activity. These newly identified antibacterial honeys may prove to be a valuable source of future therapeutic honeys.

McGovern D.P., Abbas S.Z., Vivian G. & Dalton H.R. (1999) “Manuka honey against Heliobacter pyroli.” J.R. Soc. Med. 92(8), 439.

McIntosh C.D. & Thomson C.E. (2006) “Honey dressing vs. paraffin tulle gras after toe nail surgery.” J. Wound Care 15(3), 133-136.  Abstract. OBJECTIVE: Anecdotal reports suggest that certain honey dressings have a positive effect on wound healing. However there is  limited empirical evidence supporting its use.  This double-blind randomised controlled trial investigated the effect of a honey dressing on a wound healing following toenail surgery with matrix phenolisation. METHOD: Participants (n=100) were randomly assigned to receive either an active manuka honey dressing (n=52) or paraffin-impregnated tulle gras (n=48). The primary outcome was time (days) taken for complete re-epithelisation of the nail bed. RESULTS: Mean healing times were 40.30 days (SD 18.21) for the honey group and 39.98 days (SD 25.42) for the paraffin tulle gras group. Partial avulsion wounds healed statistically significantly faster (p=0.01) with paraffin tulle gras (19.62 days, SD 9.31) than with the honey dressing (31.76 days, SD 18.8) but no significant difference (p=0.21) was found following total avulsion when comparing honey (45.28 days, SD 18.03) with paraffin tull gras dressings (52.03 days, SD 21.3. CONCLUSION: The results suggest that patients may benefit more from paraffin tulle gras dressings than the honey dressings following partial toenail avulsion. No statistically significant difference was found for healing times after total toenail avulsion., although marginal benefits of the honey dressing on these healing times warrants further investigation.

Moar N.T. (1985) “Pollen analysis of New Zealand hone”. New Zealand J of Agric Res. 28(1), 39-70.

Molan P.C., Allen, K. L., Tan, S. T. & Wilkins, A. L. (1989) "Identification of components responsible for the antibacterial activity of Manuka and Viper's Bugloss honeys" paper presented at the Annual Conference of the New Zealand Institute of Chemistry.

Molan P.C. & Allen K.L. (1996) “The effect of gamma-irradiation on the antibacterial activity of honey.” J. Pharm. Pharmacol. 48(11), 1206-1209. Abstract.There is increasing usage of honey as a dressing on infected wounds, burns and ulcers, but there is some concern that there may be a risk of wound botulism from the clostridial spores sometimes found in honey. It is well-established that the antibacterial activity is heat-labile so would be destroyed if honey were sterilized by autoclaving, but the effect of gamma-irradiation on the antibacterial activity of honey is not known. Therefore an investigation was carried out to assess the effect on the antibacterial activity of honey when the honey was subjected to a commercial sterilization procedure using gamma-irradiation (25 kGy). Two honeys with antibacterial activity due to enzymically-generated hydrogen peroxide and three manuka honeys with non-peroxide antibacterial activity were investigated. The honeys were tested against Staphylococcus aureus in an agar well diffusion assay. There was no significant change found in either type of antibacterial activity resulting from this form of sterilization of honey, even when the radiation was doubled (to 50 kGy). Testing of honey seeded with spores of Clostridium perfringens and C. tetani (10000 and 1000 spores g-1 of honey, respectively) showed that 25 kGy of gamma-irradiation was sufficient to achieve sterility.

Molan P.C. (1999) "The unique properties of manuka honey" Bee Informed (The Journal of the American Apitherapy Society) 6 (1): 5-6.

Natajaran S, Williamson D., Grey J., Harding K.G. & Cooper R.A. (2001) "Healing of an MRSA-colonized, hydroxyurea-induced leg ulcer with honey." J. Dermatol. Treat. 12(1), 33-36. Abstract. BACKGROUND: With the ever increasing emergence of antibiotic-resistant pathogens, in particular methicillin-resistant Staphylococcus aureus (MRSA) in leg ulcers, a means of reducing the bacterial bioburden of such ulcers, other than by the use of either topical or systemic antibiotics, is urgently required. METHODS: We report the case of an immunosuppressed patient who developed a hydroxyurea-induced leg ulcer with subclinical MRSA infection which was subsequently treated with topical application of manuka honey, without cessation of hydroxyurea or cyclosporin. RESULTS: MRSA was eradicated from the ulcer and rapid healing was successfully achieved. CONCLUSION: Honey is recognized to have antibacterial properties, and can also promote effective wound healing. A traditional therapy, therefore, appears to have enormous potential in solving new problems.

Patton T., Barret J., Brennan J. & Moran N. (2005). “Use of a spectrophotometric assay for determination of microbial sensitivity to manuka honey.” J. Microbiol Methods 64(1), 84-95. Abstract. The antimicrobial activity of manuka honey has been well documented (Molan, 1992a,b,c, (1997)) [Molan, P.C. (1992). “The antibacterial activity of honey. 1: the nature of the antibacterial activity.” Bee World 73 (1) 5-28; Molan, P.C. (1992). “The antibacterial activity of honey. 2: variation in the potency of the antibacterial activity.” Bee World  73(2) 59-76; Molan, P.C. (1992). “Medicinal uses for honey.” Beekeepers Quarterly 26; Molan, P.C. (1997). “Finding New Zealand honeys with outstanding antibacterial and antifungal activity.” New Zealand Beekeeper 4(10) 20-26]. The current bioassays for determining this antimicrobial effect employ a well diffusion (Ahn & Stiles, 1990) [Ahn, C. & Stiles, M.E. (1990). “Antibacterial activity of lactic acid bacteria isolated from vacuum-packed meats.” Journal of Applied Bacteriology 69, 302-310], (Weston et al., 1999) [Weston, R.J., Mitchell, K.R., Allen, K.L., 1999. “Antibacterial phenolic components of New Zealand manuka honey.” J. Food Chem. 64, 295-301] or disc diffusion (Taormina et al., 2001) Taormina, P. J., Niemira B.A. & Beuchat L.R. (2001). “Inhibitory activity of honey against food borne pathogens as influenced by the presence of hydrogen peroxide and level of antioxidant power. Int. J. Food Microbiol. 69, 217-225] assay using zones of inhibition as indicators of bacterial susceptibility. The development of a 24-h spectrophotometric assay employing 96-well microtiter plates, that is more sensitive and more amenable to statistical analysis than the assays currently employed, was undertaken. This simple and rapid assay permits extensive kinetic studies even in the presence of low honey concentrations, and is capable of detecting inhibitory levels below those recorded for well or disc diffusion assays. In this paper, we compare the assay to both well and disc diffusion assays. The results we obtained for the spectrophotometric method MIC values show that this method has greater sensitivity than the standard well and disc diffusion assays. In addition, inter- and intra-assay variance for this method was investigated, demonstrating the methods reproducibility and repeatability.

Price S.B. (M.Sc.) Isolation of antibacterial components from manuka honey. (Thesis, 1991).

Russell K.M., Molan P.C. & Wilkins A.L. (1990) “Identification of some antibacterial constituents of New Zealand manuka honey.” J. Agric. Food Chem. 34, 10-13.

Sealey D.F (M.Sc.) Chromatographic investigations of the antibacterial activity in manuka honey. (Thesis 1988)

al Somal N., Coley K.E., Molan P.C. & Hancock B.M. (1994) “Susceptibility of Heliobacter pylori to the anti-bacterial activity of manuka honey.” J.R. Soc. Med. 87(1), 9-12. Abstract. Honey is a traditional remedy for dyspepsia, and is still used for this by some medical practitioners although there is no rational basis for its use. The finding that Helicobacter pylori is probably the causative agent in many cases of dyspepsia has raised the possibility that the therapeutic action of honey may be due to its antibacterial properties. Consequently, the sensitivity of Helicobacter pylori to honey was tested, using isolates from biopsies of gastric ulcers. It was found that all five isolates tested were sensitive to a 20% (v/v) solution of manuka honey in an agar well diffusion assay, but none showed sensitivity to a 40% solution of a honey in which the antibacterial activity was due primarily to its content of hydrogen peroxide. Assessment of the minimum inhibitory concentration by inclusion of manuka honey in the agar showed that all seven isolates tested had visible growth over the incubation period of 72 h. prevented completely by the presence of 5% (v/v) honey.

Snow M.J. & Manley-Harris M. (2004) “On the nature of non-peroxide antibacterial activity in New Zealand manuka honey.” Food Chemistry 84(1), 145-147. Abstract. Some conclusions, which exist in the literature about the nature of non-peroxide antibacterial activity in manuka honey, have been revisited. The stability of non-peroxide antibacterial activity in manuka honey at basic pH was investigated. At pH 11 antibacterial activity was immediately and irreversibly destroyed. This indicates that it is not possible to carry out chromatography of honey solutions at elevated pH with the intent to isolate the active fraction. The effect of 10-fold excess of catalase upon the antibacterial assay was examined. No statistical difference in the outcome was observed between the normal amount of catalase and the 10-fold excess. This indicates that non-peroxide antibacterial activity in manuka honey is not likely to be due to residual hydrogen peroxide.

Stephen-Haynes J. (2004) "Evaluation of a honey-impregnated tulle dressing in primary care." Br. J. Community Nurs. June 2004 (Suppl), 21-27. Abstract: Honey has been used for its healing properties for centuries and has been used to dress wounds with favourable results. The emergence of antibiotic resistance and growing interest in "natural" or "complementary" therapies has led to an interest in honey dressings. Much of the research to date has been related to honey's antibacterial properties. However, the healing properties claimed for honey also include stimulating new tissue growth, moist wound healing, fluid handling and promoting epithelialization. Until recently, honey had not been developed as a wound management product and was not a certified pharmaceutical device. Activon Tulle is a sterile, non-adherent dressing impregnated with Leptospermum scoparium honey. The claimed properties of honey dressings would make this a valuable addition to the dressing currently available in the primary care setting. An evaluation was undertaken involving 20 patients with a variety of wounds. A conclusion is drawn that while further research is needed, medical grade honey does appear to be a valuable addition to the wound management formulary.

Tan S.T., Holland P.T., Wilkins A.L., Molan P.C. (1988) “Extractives from New Zealand honeys. White clover, manuka & manuka unifloral honeys.” J. Agric. Food Chem. 36, 453-460. Abstract. Ether extracts were made from aqueous solutions of manuka (Leptospermum scoparium),kanuka (Leptospermumericoides),and clover (Trifolium repens)honeys with use of a continuous liquid/liquid extractor. The components of the extracts were methylated before being separated and identified by gas chromatography and massspectrometry, and alsoby preparative thin-layer chromatography followed by 'H and 13C NMR analyses. A total of 61 different compounds were detected, and 56 of these were

identified. Their concentrations ranged from 0.1 to4000 pg/g. Classes of compounds detected included hydrocarbons (C21-C33) and straight-chain-

monobasic (C8-C23) dibasic, and aromatic acids. The concentration of aromatic acids in manuka and kanuka honeys was much higher than in clover honey. These acids were not present in a chloroform extract of manuka flowers, which contained many terpenes, none of which were present in manuka honey. Compounds reported for the first time in honey include 2-decenedioic, decanedioic, nonanedioic, and octanedioic acids.

Tonks A.J., Cooper R.A., Jones K.P., Blair S., Parton J. & Tonks A. (2003) “Honey stimulates inflammatory cytokine production from monocytes.” Cytokine 21(5), 242-247. Abstract.Clinical observations indicate that honey may initiate or accelerate the healing of chronic wounds and has, therefore, been claimed to have anti-inflammatory properties. The aim of this study was to investigate the effects of honey on the activation state of immunocompetent cells, using the monocytic cell line, MonoMac-6 (MM6), as a model. We investigated the effect of each of the three honeys (manuka, pasture and jelly bush) on the release of important inflammatory cytokines from MM6 cells. These honeys, together with a sugar syrup control (artificial honey), were incubated with MM6 cells at a concentration of 1% (w/v) for 0-24h. Cell culture supernatants were tested using specific ELISA assays for tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta and IL-6. All honeys significantly increased the TNF-alpha, IL-1beta and IL-6 release from MM6 cells (and human monocytes) when compared with untreated and artificial-honey-treated cells (P<0.001). Jelly bush honey significantly induced the maximal release of each cytokine compared with manuka, pasture or artificial honeys (P<0.001).These results suggest that the effect of honey on wound healing may in part be related to the stimulation of inflammatory cytokines from monocytic cells. Such cell types are known to play an important role in healing and tissue repair.

Tonks A.J., Cooper R.A., Price A.J., Molan P.C. & Jones K.P. (2001). “Stimulation of TNF-alpha release in monocytes by honey.” Cytokine 14(4), 240-242. Abstract. Although evidence exists for the antibacterial effects of honey there is limited objective evidence for direct promotion of healing. We investigated the effect of manuka, pasture and an artificial honey on macrophage function. Reactive oxygen intermediate (ROI) production was accessed by luminal enhanced chemoluminescence & tumour necrosis factor (TNF-alpha) release was determined by immunoassay. ROI production was significantly (p<0.001) decreased by pasture honey & manuka honey. TNK-alpha release was significantly enhanced (p<0.001) in unprimed MM6 cells by manuka & pasture honey but was not altered in prime cells. These results could explain the suggested therapeutic properties of honey in promoting wound healing. 

Visser F.R., Allen J.R et al. (1988). “The effect of heat on the volatile flavour fraction from a unifloral honey.”  J Apicultural Res. 27(3), 175-181.

Weston R.J. & Brocklebank R.K. (1999) "The oligosaccharide composition of some New Zealand honeys." Food Chem. 64(1), 33-37. Abstract. The oligosaccharide fraction of samples of manuka (Leptospermum), heather (Calluna), clover (Trifolium) and beech honeydew (Nothofagus) honeys from New Zealand was separated from the monosaccharides and then analysed by high performance anion-exchange chromatography with pulsed amperometric detection (hpaec-pad). Significant oligosaccharide components of manuka honey were isomaltose (or maltulose), kojibiose, turanose (or gentiobiose), nigerose and maltose which was the major component. The composition of clover honey was identical to that of manuka, while heather honey differed from these two only because isomaltose was the major component. Beech honeydew honey was characterised by the complexity of the oligosaccharide composition. The trisaccharides melezitose and panose were the most abundant components. No differences were observed between the oligosaccharide compositions of manuka honeys which did or did not exhibit non-peroxide residual antibacterial activity. Manuka honey was shown to be derived from nectar and not honeydew as has been suggested.

Weston R.J., Mitchell K.R. & Allen K.L (1999) “Anti-bacterial phenolic components of New Zealand manuka honey.” Food Chem 64, 295-301. Abstract. This paper describes several methods for isolation of the antibacterially active phenolic fraction of honey derived from the native New Zealand manuka tree, Leptospermum scoparium (Myrtaceae). This fraction consists of phenolic derivatives of benzoic acids, cinnamic acids and flavonoids, all of which have been identified previously in honeys which do not exhibit non-peroxide residual antibacterial activity. The flavonoids had not previously been identified in manuka honey. Furthermore, the flavonoids were different from those found in the leaves of manuka trees but were the same as those found in European honeys and propolis. While most of these phenolic products possess antibiotic activity, they do not individually or collectively account for the antibacterial activity of ‘active' manuka honey. Essentially all of this activity is associated with the carbohydrate fraction of the honey.

Weston R.J., Brocklebank L.K. & Lu Y. (2000) “Identification & quantitative levels of antibacterial components of some New Zealand honeys.” Food Chem 70(4), 427-435. Abstract.High performance liquid chromatograms of the phenolic fraction of 19 samples of New Zealand manuka honey, some with high levels of non-peroxide antibacterial activity and some with no such activity, were identical, which indicated that phenolic components of this honey are not responsible for the presence or absence of this activity in manuka honey. Similarly, the result showed that geography does not influence the phenolic composition of manuka honey. Antibacterial bee peptides and the antibacterial β-triketone leptospermone were not detected in manuka honey. Methyl syringate constituted approximately 70% w/w of the phenolic fraction of manuka honey and can be regarded as a floral marker for this honey. High performance liquid chromatographic profiles of the phenolic components of manuka, heather, clover and beech honeydew honeys were significantly different and could be used to differentiate honeys if they can be shown to be as consistent as those of manuka honey.

Weston R.J. (2000) “The contribution of catalase & other natural products to the antibacterial activity of honey: a review.” Food Chem 71(2), 235-239.  Abstract. Several natural products are collected or manufactured by bees to construct their hive and produce honey. These include beeswax, flower volatiles, nectar, pollen, propolis and honey itself. Some of the components of these materials possess antibacterial properties and are discussed briefly to ascertain their contribution to the antibacterial activity of honey. New Zealand's manuka honey is known to possess a high level of "non-peroxide" antibacterial activity and research to identify the origin of this activity is briefly reviewed. Finally a hypothesis is advanced to explain the phenomenon of "non-peroxide" antibacterial activity in honey. The author concludes that this activity should be interpreted as residual hydrogen peroxide activity, which is probably due to the absence of plant-derived catalase from honey, an idea first suggested by Dustman in 1971. [Dustman, J. H. (1971). “Über die Katalaseaktivität in Bienenhonig aus der Tracht der Heidekrautgewächse (Ericaceae).” Zeitschrift für Lebensmittel-Untersuchung und Forschung, 145, 292–295].

Wilkins, A. L., Lu, Y. & Molan, P. C. (1993) "Extractable organic substances from New Zealand unifloral manuka (Leptospermum scoparium) honeys." Journal of Apicultural Research 32 (1): 3-9.

D.J. Willix (M.Sc.Tech.) A comparitive study of the antibacterial action spectrum of manuka honey and other honey. (1992) - Thesis.

Willix D.J., Molan P.C. & Harfoot C.G. (1992) “A comparison of the sensitivity of wound-infecting species of bacteria to the anti-bacterial activity of manuka honey & other honeys.” J. Appl. Bacteriol. 73, 388-394. Abstract. Both honey and sugar are used with good effect as dressings for wounds and ulcers. The good control of infection is attributed to the high osmolarity, but honey can have additional antibacterial activity because of its content of hydrogen peroxide and unidentified substances from certain floral sources. Manuka honey is known to have a high level of the latter. Seven major wound-infecting species of bacteria were studied to compare their sensitivity to the non-peroxide antibacterial activity of manuka honey and to a honey in which the antibacterial activity was primarily due to hydrogen peroxide. Honeys with activity in the middle of the normal range were used. A comparison of the median response of the various species of bacteria showed no significant difference between the two types of activity overall, but marked differences between the two types of activity in the rank order of sensitivity of the seven bacterial species. The non-peroxide antibacterial activity of manuka honey at a honey concentration of 1.8% (v/v) completely inhibited the growth of Staphylococcus aureus during incubation for 8 h. The growth of all seven species was completely inhibited by both types of honey at concentrations below 11% (v/v).

Wilkins A.L., Lu Y. & Molan P.C. (1993) “Extractable organic substances from New Zealand unifloral manuka Leptospermum scoparium honeys.” J. Agric. Res. 32, 3-9.

Wilkinson J.M. & Cavanagh H.M.A. (2005). “Antibacterial activity of 13 honeys against Escherichia coli & Pseudomonas aeruginosa.” J. of Medicinal Food 8(1), 100-103. Abstract. In this study the activity of 13 honeys, including 3 commercial antibacterial honeys, against Escherichia coli & Pseudomonas aeruginosa was determined. Antibacterial activity of the honeys was assayed using standard well diffusion methods. All honeys, and an artificial honey, were tested at four concentrations (10%,5%,2.5% & 1% wt/vol) against E. coli & P. aeruginosa, and zones of inhibition were measured. All honeys tested had an inhibitory effect on the growth of E. coli & P. aeruginosa, with one honey still having activity against E. coli and three having activity against P. aeruginosa at 2.5%. No honey was active at 1% concentration. E. coli was more susceptible to inhibition by the honeys used in this study than P. aeruginosa. In this study we have demonstrated that several honeys, in addition to the commercial honeys, can inhibit E. coli & P. aeruginosa and may have potential as therapeutic honeys.

Wood B. et al. (1997) “Manuka Honey: a low cost leg ulcer dressing.” New Zealand Medical J. 110(1040), 107. 

Yao L., Datta N., Francisco A. Tomás-Barberán  F.F., Ferreres M.I. & Singanusong R. (2003). “Flavonoids, phenolic acids and abscisic acid in Australian and New Zealand Leptospermum honeys.” Food Chemistry 81(2),159-168. Abstract. Flavonoids, phenolic acids and abscisic acid of Australian and New Zealand Leptospermum honeys were analyzed by HPLC. Fifteen flavonoids were isolated in Australian jelly bush honey (Leptospermum polygalifolium), with an average content of 2.22 mg/100 g honey. Myricetin (3,5,7,3’,4’,5’-hexahydroxyflavone), luteolin (5,7,3’4’-tetrahydroxyflavone) and tricetin (5,7,3’,4’,5’-pentahydroxyflavone) were the main flavonoids identified. The mean content of total phenolic acids in jelly bush honey was 5.14 mg/100 g honey, with gallic and coumaric acids as the potential phenolic acids. Abscisic acid was quantified as twice the amount (11.6 mg/100 g honey) of the phenolic acids in this honey. The flavonoid profile mainly consisted of  quercetin (3,5,7,3’,4’-pentahydroxyflavone), isorhamnetin (3,5,7,4’-tetrahydroxyflavone 3’-methyl ethyl), chrysin (5,7-dihydroxyflavone), luteolin and an unknown flavanone in New Zealand manuka (Leptospermum scoparium) honey with an average content of total flavonoids of 3.06 mg/100 g honey. The content of total phenolic acids was up to 14.0 mg/100 g honey, with gallic acid as the main component. A substantial quantity (32.8 mg/100 g honey) of abscisic acid was present in manuka honey. These results showed that flavonoids and phenolic acids could be used for authenticating honey floral origins, and abscisic acid may aid in this authentication.

Manuka Honey Related Articles.

Mundo M.A., Padilla-Zakour O.I. & Worobo R.W. (2004) “Growth inhibition of foodborne pathogens & food spoilage organisms by select raw honeys.” Int. J. Food. Microbiol. 97(1), 1-8. 

Therapeutic Manuka Honey: No Longer So Alternative



Medicinal honey research is undergoing a substantial renaissance. From a folklore remedy largely dismissed by mainstream medicine as “alternative”, we now see increased interest by scientists, clinical practitioners and the general public in the therapeutic uses of honey. There are a number of drivers of this interest: first, the rise in antibiotic resistance by many bacterial pathogens has prompted interest in developing and using novel antibacterials; second, an increasing number of reliable studies and case reports have demonstrated that certain honeys are very effective wound treatments; third, therapeutic honey commands a premium price, and the honey industry is actively promoting studies that will allow it to capitalize on this; and finally, the very complex and rather unpredictable nature of honey provides an attractive challenge for laboratory scientists. In this paper we review manuka honey research, from observational studies on its antimicrobial effects through to current experimental and mechanistic work that aims to take honey into mainstream medicine. We outline current gaps and remaining controversies in our knowledge of how honey acts, and suggest new studies that could make honey a no longer “alternative” alternative.

Keywords: manuka honey, antibacterial, Leptospermum, methyl glyoxal, natural product


Honey has been used as a medicine throughout the history of the human race. One of the most common and persistent therapeutic uses of honey has been as a wound dressing, almost certainly due to its antimicrobial properties. With the advent of highly active antibiotics in the 1960s, honey was dismissed as a “worthless but harmless substance” (Soffer, 1976). However, the current and growing crisis of antibiotic resistance has revived interest in the use of honey, both as an effective agent in its own right and as a therapeutic lead to develop new methods of treatment. Honey is usually derived from the nectar of flowers and produced by bees, most commonly the European honey bee Apis mellifera, and is a complex mix of sugars, amino acids, phenolics, and other substances. Honey types derived from different flowering plants vary substantially in their ability to kill bacteria, and this has complicated the literature on honey and made it sometimes difficult to reproduce results across different studies (Allen et al., 1991Irish et al., 2011). The majority of recent studies investigating the mechanism of action of honey have focused on well-characterized, standardized active manuka honey produced by certain Leptospermum species native to New Zealand and Australia, which has been registered as a wound care product with appropriate medical regulatory bodies. Thus, unless otherwise specified, this review will focus on manuka honey.

Chemical Analyses of Active Manuka Honey

Professor Peter Molan of Waikato University, New Zealand, was the first to report the unusual activity of manuka honey and began testing its action against a wide range of different bacterial species in the mid 1980s. However, while it was clear that even low concentrations of manuka honey killed bacterial pathogens, the specific active ingredient responsible for this remained elusive for many years. High sugar and low pH make honey inhibitory to microbial growth, but activity remains when these are diluted to negligible levels. Many different types of honey also produce hydrogen peroxide when glucose oxidase, which is derived from the honey bee, reacts with glucose and water. However, in manuka honey hydrogen peroxide production is relatively low and can be neutralized by catalase, yet activity still remains. The cause of this remaining activity, dubbed “non-peroxide activity” or NPA, was finally revealed in 2008, when two laboratories independently identified methyl glyoxal (MGO) in manuka honey (Adams et al., 2008Mavric et al., 2008). MGO results from the spontaneous dehydration of its precursor dihydroxyacetone (DHA), a naturally occurring phytochemical found in the nectar of flowers of Leptospermum scoparium, Leptospermum polygalifolium, and some related Leptospermum species native to New Zealand and Australia (Adams et al., 2009Williams et al., 2014Norton et al., 2015). MGO can react relatively non-specifically with macromolecules such as DNA, RNA and proteins (Adams et al., 2008Mavric et al., 2008Majtan et al., 2014b), and could theoretically be toxic to mammalian cells (Kalapos, 2008). However, there is no evidence of damage to host cells when manuka honey is either consumed orally or used as a wound dressing; indeed honey appears to stimulate healing and reduce scarring when applied to wounds (Biglari et al., 2013Majtan, 2014Dart et al., 2015). How it exerts this apparently selective toxicity to bacterial cells is not known.

High levels of MGO or hydrogen peroxide usually produce the most active honey, however, the correlation is not always perfect suggesting other components of honey may modulate activity (Molan, 2008Kwakman et al., 2011Chen et al., 2012Lu et al., 2013). Bee defensin-1, an antimicrobial bee-derived peptide is responsible for activity in Revamil honey, an active honey produced from an undisclosed source, but this appears to be structurally modified and inactive in manuka honey (Kwakman et al., 2011Majtan et al., 2012). The level of leptosin, a glycoside found exclusively in Leptospermum honey, correlates with potency and may modulate the antimicrobial activity of manuka honey (Kato et al., 2012). Similarly, various phenolic compounds with potential antimicrobial activity can be present, particularly in darker colored honeys, and although these occur at levels that are unlikely to be inhibitory on their own they may synergize with one another or other components of honey to produce or alter activity (Estevinho et al., 2008Stephens et al., 2010). Phenolics can also act as antioxidants and may be responsible for anti-inflammatory and wound-healing properties of honey (Stephens et al., 2010). It should be noted that not all Leptospermum species produce active honey, and even within L. scoparium and L. polygalifolium honey MGO levels can range from ∼100 to >1200 ppm (Windsor et al., 2012). A survey of Australian honey activity found honey sourced from Leptospermum plants growing around the New South Wales–Queensland border was particularly active, but whether this is due to plant, soil, climate or other factors is not known (Irish et al., 2011).

The Inhibition of Pathogens by Honey

Honey has been tested in vitro on a diverse range of pathogens, particularly those that can colonize the skin, wounds and mucosal membranes, where topical honey treatment is possible. To date, in vitro assays have found manuka honey can effectively inhibit all problematic bacterial pathogens tested (summarized in Table Table11). Of particular interest is that clinical isolates with multiple drug resistance (MDR) phenotypes have no reduction in their sensitivity to honey, indicating a broad spectrum of action that is unlike any known antimicrobial (Willix et al., 1992Blair and Carter, 2005George and Cutting, 2007Tan et al., 2009). In addition, attempts to generate honey-resistant strains in the laboratory have not been successful and there have been no reports of clinical isolate with acquired resistance to honey (Blair et al., 2009Cooper et al., 2010).

Table 1
Bacterial species found to be susceptible to therapeutic manuka honey.

As well as inhibiting planktonic cells, honey can disperse and kill bacteria living in biofilms. Biofilms are communities of cells that are generally enclosed in a self-produced extracellular matrix and found adhering to surfaces, including wounds, teeth, mucosal surfaces, and implanted devices. Microbes resident in biofilms are protected from antimicrobial agents and they can cause persistent, non-resolving infections. Manuka honey disrupts cellular aggregates (Maddocks et al., 2012Roberts et al., 2012) and prevents the formation of biofilms by a wide range of problematic pathogens, including Streptococcus and Staphylococcus species, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Acinetobacter baumannii, and Klebsiella pneumonia (Maddocks et al., 20122013Lu et al., 2014Majtan et al., 2014aHalstead et al., 2016) Importantly, honey can also disrupt established biofilms and kill resident cells, although a higher concentration is required than for planktonic cells (Okhiria et al., 2009Maddocks et al., 2013Lu et al., 2014Majtan et al., 2014a). Very recently, manuka honey was tested on a multispecies biofilm containing Staphylococcus aureus, Streptococcus agalactiae, Pseudomonas aeruginosa, and Enterococcus faecalis and was found to reduce viability of all species but E. faecalis, which could not be eradicated (Sojka et al., 2016). This has clear clinical implications for using honey on wounds containing biofilms, and understanding how the biofilm enables E. faecalis, to survive when it is normally killed by honey is an important and interesting area of future study. MGO appears to be mostly but not fully responsible for the inhibition of biofilms by manuka honey, again highlighting the importance of additional components that modulate activity (Kilty et al., 2011Lu et al., 2014).

The spectrum of activity of honey toward non-bacterial pathogens is yet to be well established. Recent studies examining the antiviral effect of manuka honey have suggested it has potential for treatment of varicella-zoster virus (the cause of chicken pox and shingles) (Shahzad and Cohrs, 2012) and influenza (Watanabe et al., 2014). Fungal pathogens of the skin, including Candida albicans and dermatophyte species are substantially less susceptible than bacteria to manuka honey, but are inhibited by honey with high levels of hydrogen peroxide production (Brady et al., 1996Irish et al., 2006). Manuka and non-manuka honey have been found to reduce the viability of spores of the microsporidian Nosema apis, an important pathogen of bees, but honey could not cure bee infection once this was underway (Malone et al., 2001). There have been very few studies on the use of honey for protozoan or helminth parasites and these have not used honey with well-characterized activity, making it difficult to assess the significance of their findings (Bassam et al., 1997Nilforoushzadeh et al., 2007Sajid and Azim, 2012).

Taking Honey Into Mainstream Medicine: Recent Experimental and Mechanistic Studies Shed Light on How Honey Works

Active manuka honey is widely available as a therapeutic agent and functional food, and most consumers accept it as a holistic, somewhat mysterious product. However, a lack of understanding on how honey kills bacteria and promotes healing limits its acceptance by mainstream medicine where it is still considered “alternative” or “complementary”. The vast majority of research studies on honey to date have been descriptive, however, recent studies are attempting to unravel how honey works and are using mechanistic approaches to determine how it acts at the cellular and the molecular level.

Ultrastructural Studies of Bacterial Cells and Communities Treated by Honey

Honey can profoundly alter the size and shape of bacterial cells, although the extent of this varies in different bacterial species. Using transmission electron microscopy (TEM), S. aureus cultures treated with manuka honey had more cells with completed septa compared to those treated with artificial honey, suggesting cells entered but failed to complete the division stage of the cell cycle, although externally these cells appeared normal by scanning electron microscopy (SEM) (Henriques et al., 2010). More recently, phase-contrast imaging following treatment with a sub-lethal dose of manuka honey found cells of S. aureus and Bacillus subtilis were significantly smaller and were more likely to have condensed DNA than those growing without honey (Lu et al., 2013). It is difficult to directly compare these studies as they used different amounts of honey and treatment times, but overall the results suggest an uncoupling of growth and cell division, which is often seen in response to nutritional and environmental stresses (Silva-Rocha and de Lorenzo, 2010).

Honey treatment has been reported to cause cultures of the Gram negative species E. coli and P. aeruginosato have both abnormally shorter and longer cells (Lu et al., 2013). Interestingly, while P. aeruginosaappears to be less susceptible to inhibition by honey than other species, profound cellular changes were seen using TEM and SEM, including furrows and blebs (protrusions of cellular plasma membranes) on the cell surface and a substantial amount of extracellular debris indicative of cell lysis (Henriques et al., 2011). This was verified in a subsequent study using BacLight live-dead fluorescence staining and confocal microscopy, although this also demonstrated that a relatively large number of live cells remained. These studies used 20% (w/v) honey, which was higher that the MBC for their strain of P. aeruginosa and substantial inhibition and death would be expected. However, atomic force microscopy (AFM) using sub-bactericidal levels still found substantial cell distortion and blebbing in cells treated with MIC (12%) and half MIC (6%) concentrations, along with substantial cell lysis (Roberts et al., 2012). This apparent degeneration of the P. aeruginosa cell was supported by quantitative PCR analysis that showed a 10-fold down-regulation in honey-treated cells of oprF, which encodes an outer-membrane porin that is important for structural stability (Jenkins et al., 2015a).

‘Omics Analyses Assess the Whole-Cell Response to Inhibition by Honey

The ability to assess whole cell outputs has revolutionized the study of drug-pathogen interactions and has particular value for complex natural products like honey where effects on multiple processes are likely. Microarray and proteomic studies of bacteria exposed to honey suggested an induction of stress-related processes and suppression of protein synthesis (Blair et al., 2009Jenkins et al., 2011Packer et al., 2012). While overall this is fairly typical of a response to inhibitory agents, honey produced a unique “signature” of differential expression that included many proteins with hypothetical or unknown functions, suggesting a novel mode of action. Specific genes or proteins found to be down-regulated in ‘omics analyses of S. aureus and E. coli O157/H7 have functions relating to virulence, quorum sensing and biofilm formation (Lee et al., 2011Jenkins et al., 2013), and in P. aeruginosa there was a down-regulation of proteins involved in flagellation (Roberts et al., 2015). These phenotypes are critical for pathogens to establish and produce invasive infection and indicate that as well as inhibiting growth, honey can reduce the pathogenic potential of infecting bacteria.

Although still relatively limited in number and scope, the ‘omics analyses conducted to date suggest a complex cellular response to honey with considerable variation in different bacterial species. Advanced systems biology approaches that allow contextualization of the data, and validation studies using quantitative PCR and gene deletion strains, are now required to unravel this complexity, and these may reveal new approaches for drug therapies aimed at inhibiting bacterial growth (Hudson et al., 2012).

Interactions Between Honey and Conventional Antibiotics

As well as use as a sole agent, there is scope for using honey to augment treatment with conventional antibiotics. This may have particular value when combined with systemic agents that can be delivered to a wound bed via blood circulation while honey is applied topically. Combined treatments can also lower the therapeutic dose of antimicrobial agents and prevent the development of resistance, and in some cases can result in drug synergy, where the combined activity is greater than the sum of the individual activities of each drug partner.

In vitro studies combining therapeutically approved manuka honey with antibiotic agents have found a synergistic effect with oxacillin, tetracycline, imipenem and mupirocin against the growth of an MRSA strain (Jenkins and Cooper, 2012). Furthermore, the presence of a sub-inhibitory concentration of honey in combination with oxacillin restored the MRSA strain to oxacillin susceptibility. The authors found down-regulation of mecR1, which encodes an MRSA-specific penicillin-binding protein (PBP2A) and suggested this as a mechanism of honey synergy. Strong synergistic activity between manuka honey and rifampicin against multiple S. aureus strains, including clinical isolates and MRSA strains, has also been found, and the presence of honey prevented the emergence of rifampicin resistance in vitro (Müller et al., 2013). This is of clinical significance as rifampicin penetrates well into tissues and abscesses and is commonly used to treat superficial staphylococcal infections, but rapidly induces resistance and must therefore be used in combination with another agent. An additional finding from this study was that synergy was not due to MGO, as a synthetic honey spiked with MGO was not synergistic with rifampicin.

Understanding how honey affects the action of antimicrobials with well-characterized modes of action may also further our understanding of how honey affects bacterial pathogens. Liu et al. (2014) extended the analysis of synergy to include additional antibiotics and different S. aureus and MRSA strains. They suggested that an increased susceptibility to clindamycin and gentamicin might result from the combined effect of down-regulated protein synthesis by honey with inhibition of ribosomes by the antibiotics, while synergy with β-lactam antibiotics could be due to increased oxidative stress caused by both partners. As S. aureus and MRSA strains were equally susceptible to the oxacillin-honey combination it appeared that synergy was unlikely to be due to PBP2A down-regulation. In one clinical MRSA isolate, however, there was no increase in sensitivity to clindamycin or gentamicin when honey was present, which is notable as it is the first reported case of a difference in response to honey by MRSA versus S. aureus. Investigating this strain-specific difference using transcriptomic or proteomic analyses would be an interesting avenue for future research (Liu et al., 2014).

Evidence of Efficacy From Animal Studies, Case Reports, and Clinical Trials

Companies that produce and market manuka honey promote high ethical standards and discourage the use of animal models to study infections and wound healing. Manuka honey has, however, been used to treat animals with surgical or accidental wounds, particularly horses, with positive outcomes (Dart et al., 2015Bischofberger et al., 2016). Case reports using honey for non-healing wounds and ulcers have noted significant improvement with resolution of infection where conventional antibiotics had failed (Regulski, 2008Smith et al., 2009). However, despite this and the evidence from numerous in vitro and in vivomodels that honey kills problematic wound pathogens, there is a paucity of robust clinical data for manuka honey. There are various reasons for this, including technical difficulties in performing a double-blind placebo-controlled trial on a distinctive substance like honey, ethical considerations, lack of interest by clinical practitioners and cost-versus-benefit to honey companies, whose focus is on natural products and over-the-counter sales where manuka honey and associated dressings already command a premium price. These may change as antibiotic resistance erodes current treatment options and ongoing research highlighting the potential of honey brings it to the attention of medical practitioners.

Gaps and Emerging Opportunities in the Study of Honey

Great progress has been made recently in our understanding of therapeutic honey, yet its use in clinical medicine remains limited, even when conventional antibiotics are starting to fail. The complexity in honey, which is arguably its greatest strength in killing diverse pathogens and preventing resistance, complicates its study as many factors working together are likely to affect activity. We advocate further mechanistic studies using appropriately registered therapeutic manuka honey, in particular studies that use non-reductionist systems biology approaches, along with detailed chemical and microbiological analyses to elucidate how honey acts at the molecular, cellular and population level, how this can differ in different strains and species of microbial pathogens, and how the host cell responds (Table Table22). Information gained from these studies can then inform therapy and produce the clinical data required to take honey into mainstream medicine; no longer the alternative therapy used only when all else has failed.

Table 2
Studies of manuka honey: findings, gaps, and future studies.

Author Contributions

This review was written by DC, SB, NNC, DB, and PB and was critically reviewed by RS and EH.

Conflict of Interest Statement

DC, PB, and EH report grant and non-financial support in the form of manuka honey from Comvita NZ Limited and Capilano Honey Limited; RS is employed by Comvita NZ Limited, which trades in medical grade manuka honey (Medihoney). The rest of the authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.


ESBL extended spectrum β-lactamase
MBC minimum bactericidal concentration
MGO methyl glyoxal
MIC minimum inhibitory concentration
MRSA methicillin-resistant Staphylococcus aureus
MRSE methicillin-resistant Staphylococcus epidermis
NPA non-peroxide activity
VRE vancomycin-resistant Enterococcus



Funding. NNC receives salary support from the Rural Industries Research and Development Corporation – Honey Bee Program (Grant PRJ-009186).



  • Adams C. J., Boult C. H., Deadman B. J., Farr J. M., Grainger M. N. C., Manley-Harris M., et al. (2008). Isolation by HPLC and characterisation of the bioactive fraction of New Zealand manuka (Leptospermum scoparium) honey. Carbohydr. Res. 343 651–659. 10.1016/j.carres.2007.12.011[PubMed] [Cross Ref]
  • Adams C. J., Manley-Harris M., Molan P. C. (2009). The origin of methylglyoxal in New Zealand manuka (Leptospermum scoparium) honey. Carbohydr. Res. 344 1050–1053. 10.1016/j.carres.2009.03.020 [PubMed] [Cross Ref]
  • Al Somal N., Coley K. E., Molan P. C., Hancock B. M. (1994). Susceptibility of Helicobacter pylorito the antibacterial activity of manuka honey. J. R. Soc. Med. 87 9–12. [PMC free article] [PubMed]
  • Allen K., Molan P., Reid G. (1991). A survey of the antibacterial activity of some New Zealand honeys. J. Pharm. Pharmacol. 43 817–822. 10.1111/j.2042-7158.1991.tb03186.x [PubMed][Cross Ref]
  • Allen K. L., Molan P. C. (1997). The sensitivity of mastitis-causing bacteria to the antibacterial activity of honey. N. Z. J. Agric. Res. 40 537–540. 10.1080/00288233.1997.9513276 [Cross Ref]
  • Anthimidou E., Mossialos D. (2012). Antibacterial activity of Greek and Cypriot honeys against Staphylococcus aureus and Pseudomonas aeruginosa in comparison to manuka honey. J. Med. Food16 42–47. 10.1089/jmf.2012.0042 [PubMed] [Cross Ref]
  • Balan P., Mal G., Das S., Singh H. (2016). Synergistic and additive antimicrobial activities of curcumin, manuka honey and whey proteins. J. Food Biochem. 10.1111/jfbc.12249 [Cross Ref]
  • Bassam Z., Zohra B. I., Saada A.-A. (1997). The effects of honey on Leishmania parasites: an in vitro study. Trop. Doctor 27 36–38. [PubMed]
  • Biglari B., Moghaddam A., Santos K., Blaser G., Büchler A., Jansen G., et al. (2013). Multicentre prospective observational study on professional wound care using honey (Medihoney). Int. Wound J.10 252–259. 10.1111/j.1742-481X.2012.00970.x [PubMed] [Cross Ref]
  • Bischofberger A., Dart C., Horadagoda N., Perkins N., Jeffcott L., Little C., et al. (2016). Effect of Manuka honey gel on the transforming growth factor β1 and β3 concentrations, bacterial counts and histomorphology of contaminated full-thickness skin wounds in equine distal limbs. Aust. Vet. J. 9427–34. 10.1111/avj.12405 [PubMed] [Cross Ref]
  • Blair S., Cokcetin N., Harry E., Carter D. (2009). The unusual antibacterial activity of medical-grade Leptospermum honey: antibacterial spectrum, resistance and transcriptome analysis. Eur. J. Clin. Microbiol. Infect. Dis. 28 1199–1208. 10.1007/s10096-009-0763-z [PubMed] [Cross Ref]
  • Blair S. E., Carter D. A. (2005). The potential for honey in the management of wounds and infections. J. Austral. Infect. Control 10 24–31.
  • Brady N., Molan P., Harfoot C. (1996). The sensitivity of dermatophytes to the antimicrobial activity of manuka honey and other honey. Pharm. Pharmacol. Commun. 2 471–473.
  • Carnwath R., Graham E. M., Reynolds K., Pollock P. J. (2014). The antimicrobial activity of honey against common equine wound bacterial isolates. Vet. J. 199 110–114. 10.1016/j.tvjl.2013.07.003[PubMed] [Cross Ref]
  • Chen C., Campbell L., Blair S. E., Carter D. A. (2012). The effect of heat treatment on the antimicrobial properties of honey. Front. Microbiol. 3:265 10.3389/fmicb.2012.00265 [PMC free article] [PubMed] [Cross Ref]
  • Cooper R., Jenkins L., Henriques A., Duggan R., Burton N. (2010). Absence of bacterial resistance to medical-grade manuka honey. Eur. J. Clin. Microbiol. Infect. Dis. 29 1237–1241. 10.1007/s10096-010-0992-1 [PubMed] [Cross Ref]
  • Cooper R. A., Halas E., Molan P. C. (2002a). The efficacy of honey in inhibiting strains of Pseudomonas aeruginosa from infected burns. J. Burn Care Rehabil. 23 366–370. 10.1097/00004630-200211000-00002 [PubMed] [Cross Ref]
  • Cooper R. A., Molan P. C. (1999). The use of honey as an antiseptic in managing Pseudomonasinfection. J. Wound Care 8 161–164. 10.12968/jowc.1999.8.4.25867 [PubMed] [Cross Ref]
  • Cooper R. A., Molan P. C., Harding K. G. (1999). Antibacterial activity of honey against strains of Staphylococcus aureus from infected wounds. J. R. Soc. Med. 92 283–285. [PMC free article][PubMed]
  • Cooper R. A., Molan P. C., Harding K. G. (2002b). The sensitivity to honey of Gram-positive cocci of clinical significance isolated from wounds. J. Appl. Microbiol. 93 857–863. 10.1046/j.1365-2672.2002.01761.x [PubMed] [Cross Ref]
  • Cooper R. A., Wigley P., Burton N. F. (2000). Susceptibility of multiresistant strains of Burkholderia cepacia to honey. Lett. Appl. Microbiol. 31 20–24. 10.1046/j.1472-765x.2000.00756.x [PubMed][Cross Ref]
  • Dart A., Bischofberger A., Dart C., Jeffcott L. (2015). A review of research into second intention equine wound healing using manuka honey: current recommendations and future applications.Equine Vet. Educ. 27 658–664. 10.1111/eve.12379 [Cross Ref]
  • Estevinho L., Pereira A. P., Moreira L., Dias L. G., Pereira E. (2008). Antioxidant and antimicrobial effects of phenolic compounds extracts of Northeast Portugal honey. Food Chem. Toxicol. 46 3774–3779. 10.1016/j.fct.2008.09.062 [PubMed] [Cross Ref]
  • French V. M., Cooper R. A., Molan P. C. (2005). The antibacterial activity of honey against coagulase-negative Staphylococci. J. Antimicrobial Chemother. 56 228–231. 10.1093/jac/dki193[PubMed] [Cross Ref]
  • George N. M., Cutting K. F. (2007). Antibacterial honey (Medihoney): in-vitro activity against clinical isolates of MRSA, VRE, and other multiresistant gram-negative organisms including Pseudomonas aeruginosa. Wounds 19:231[PubMed]
  • Halstead F. D., Webber M. A., Rauf M., Burt R., Dryden M., Oppenheim B. A. (2016). In vitroactivity of an engineered honey, medical-grade honeys, and antimicrobial wound dressings against biofilm-producing clinical bacterial isolates. J. Wound Care 25 93–102. 10.12968/jowc.2016.25.2.93[PubMed] [Cross Ref]
  • Hammond E. N., Donkor E. S. (2013). Antibacterial effect of Manuka honey on Clostridium difficile.BMC Res. 6:188 10.1186/1756-0500-6-188 [PMC free article] [PubMed] [Cross Ref]
  • Henriques A. F., Jenkins R. E., Burton N. F., Cooper R. A. (2010). The intracellular effects of manuka honey on Staphylococcus aureus. Eur. J. Clin. Microbiol. Infect. Dis. 29 45–50. 10.1007/s10096-009-0817-2 [PubMed] [Cross Ref]
  • Henriques A. F., Jenkins R. E., Burton N. F., Cooper R. A. (2011). The effect of manuka honey on the structure of Pseudomonas aeruginosa. Eur. J. Clin. Microbiol. Infect. Dis. 30 167–171. 10.1007/s10096-010-1065-1 [PubMed] [Cross Ref]
  • Hudson N. J., Dalrymple B. P., Reverter A. (2012). Beyond differential expression: the quest for causal mutations and effector molecules. BMC Genomics 13:356 10.1186/1471-2164-13-356 [PMC free article] [PubMed] [Cross Ref]
  • Irish J., Blair S., Carter D. (2011). The antibacterial activity of honey derived from Australian flora.PLoS ONE 6:e18229 10.1371/journal.pone.0018229 [PMC free article] [PubMed] [Cross Ref]
  • Irish J., Carter D. A., Shokohi T., Blair S. E. (2006). Honey has an antifungal effect against Candidaspecies. Med. Mycol. 44 289–291. 10.1080/13693780600931986 [PubMed] [Cross Ref]
  • Jenkins R., Burton N., Cooper R. (2011). Effect of manuka honey on the expression of universal stress protein A in methicillin-resistant Staphylococcus aureus. Int. J. Antimicrob. Agents 37 373–376. 10.1016/j.ijantimicag.2010.11.036 [PubMed] [Cross Ref]
  • Jenkins R., Burton N., Cooper R. (2013). Proteomic and genomic analysis of methicillin-resistant Staphylococcus aureus (MRSA) exposed to manuka honey in vitro demonstrated down-regulation of virulence markers. J. Antimicrobial Chemother. 69 603–615. 10.1093/jac/dkt430 [PMC free article][PubMed] [Cross Ref]
  • Jenkins R., Cooper R. (2012). Improving antibiotic activity against wound pathogens with manuka honey in vitro. PLoS ONE 7:e45600 10.1371/journal.pone.0045600 [PMC free article] [PubMed][Cross Ref]
  • Jenkins R., Roberts A., Brown H. L. (2015a). On the antibacterial effects of manuka honey: mechanistic insights. Res. Rep. Biol. 6 215–224. 10.2147/RRB.S75754 [Cross Ref]
  • Jenkins R., Wootton M., Howe R., Cooper R. (2015b). A demonstration of the susceptibility of clinical isolates obtained from cystic fibrosis patients to manuka honey. Arch. Microbiol. 197 597–601. 10.1007/s00203-015-1091-6 [PMC free article] [PubMed] [Cross Ref]
  • Kalapos M. P. (2008). The tandem of free radicals and methylglyoxal. Chem. Biol. Interact. 171251–271. 10.1016/j.cbi.2007.11.009 [PubMed] [Cross Ref]
  • Kato Y., Umeda N., Maeda A., Matsumoto D., Kitamoto N., Kikuzaki H. (2012). Identification of a novel glycoside, leptosin, as a chemical marker of manuka honey. J. Agric. Food Chem. 60 3418–3423. 10.1021/jf300068w [PubMed] [Cross Ref]
  • Kilty S. J., Duval M., Chan F. T., Ferris W., Slinger R. (2011). Methylglyoxal: (active agent of manuka honey) in vitro activity against bacterial biofilms. Int. Forum Allergy Rhinol. 1 348–350. 10.1002/alr.20073 [PubMed] [Cross Ref]
  • Kronda J. M., Cooper R. A., Maddocks S. E. (2013). Manuka honey inhibits siderophore production in Pseudomonas aeruginosa. J. Appl. Microbiol. 115 86–90. 10.1111/jam.12222 [PubMed][Cross Ref]
  • Kwakman P. H., te Velde A. A., de Boer L., Vandenbroucke-Grauls C. M., Zaat S. A. (2011). Two major medicinal honeys have different mechanisms of bactericidal activity. PLoS ONE 6:e1770910.1371/journal.pone.0017709 [PMC free article] [PubMed] [Cross Ref]
  • Lee J.-H., Park J.-H., Kim J.-A., Neupane G. P., Cho M. H., Lee C.-S., et al. (2011). Low concentrations of honey reduce biofilm formation, quorum sensing, and virulence in Escherichia coliO157: H7. Biofouling 27 1095–1104. 10.1080/08927014.2011.633704 [PubMed] [Cross Ref]
  • Lin S. M., Molan P. C., Cursons R. T. (2011). The controlled in vitro susceptibility of gastrointestinal pathogens to the antibacterial effect of manuka honey. Eur. J. Clin. Microbiol. Infect. Dis. 30 569–574. 10.1007/s10096-010-1121-x [PubMed] [Cross Ref]
  • Liu M., Lu J., Müller P., Turnbull L., Burke C. M., Schlothauer R. C., et al. (2014). Antibiotic-specific differences in the response of Staphylococcus aureus to treatment with antimicrobials combined with manuka honey. Front. Microbiol. 5:779 10.3389/fmicb.2014.00779 [PMC free article] [PubMed] [Cross Ref]
  • Lu J., Carter D. A., Turnbull L., Rosendale D., Hedderley D., Stephens J., et al. (2013). The effect of New Zealand kanuka, manuka and clover honeys on bacterial growth dynamics and cellular morphology varies according to the species. PLoS ONE 8:e55898 10.1371/journal.pone.0055898 [PMC free article] [PubMed] [Cross Ref]
  • Lu J., Turnbull L., Burke C. M., Liu M., Carter D. A., Schlothauer R. C., et al. (2014). Manuka-type honeys can eradicate biofilms produced by Staphylococcus aureus strains with different biofilm-forming abilities. PeerJ 2:e326 10.7717/peerj.326 [PMC free article] [PubMed] [Cross Ref]
  • Maddocks S. E., Jenkins R. E., Rowlands R. S., Purdy K. J., Cooper R. A. (2013). Manuka honey inhibits adhesion and invasion of medically important wound bacteria in vitro. Fut. Microbiol. 81523–1536. 10.2217/fmb.13.126 [PubMed] [Cross Ref]
  • Maddocks S. E., Lopez M. S., Rowlands R. S., Cooper R. A. (2012). Manuka honey inhibits the development of Streptococcus pyogenes biofilms and causes reduced expression of two fibronectin binding proteins. Microbiology 158 781–790. 10.1099/mic.0.053959-0 [PubMed] [Cross Ref]
  • Majtan J. (2014). Honey: an immunomodulator in wound healing. Wound Repair Regenerat. 22 187–192. 10.1111/wrr.12117 [PubMed] [Cross Ref]
  • Majtan J., Bohova J., Horniackova M., Klaudiny J., Majtan V. (2014a). Anti-biofilm effects of honey against wound pathogens Proteus mirabilis and Enterobacter cloacae. Phytother. Res. 28 69–75. 10.1002/ptr.4957 [PubMed] [Cross Ref]
  • Majtan J., Bohova J., Prochazka E., Klaudiny J. (2014b). Methylglyoxal may affect hydrogen peroxide accumulation in manuka honey through the inhibition of glucose oxidase. J. Med. Food 17290–293. 10.1089/jmf.2012.0201 [PMC free article] [PubMed] [Cross Ref]
  • Majtan J., Klaudiny J., Bohova J., Kohutova L., Dzurova M., Sediva M., et al. (2012). Methylglyoxal-induced modifications of significant honeybee proteinous components in manuka honey: possible therapeutic implications. Fitoterapia 83 671–677. 10.1016/j.fitote.2012.02.002[PubMed] [Cross Ref]
  • Majtan J., Majtanova L., Bohova J., Majtan V. (2011). Honeydew honey as a potent antibacterial agent in eradication of multi-drug resistant Stenotrophomonas maltophilia isolates from cancer patients. Phytother. Res. 25 584–587. 10.1002/ptr.3304 [PubMed] [Cross Ref]
  • Malone L. A., Gatehouse H. S., Tregidga E. L. (2001). Effects of time, temperature, and honey on Nosema apis (Microsporidia: Nosematidae), a parasite of the honeybee, Apis mellifera(Hymenoptera: Apidae). J. Invertebrate Pathol. 77 258–268. 10.1006/jipa.2001.5028 [PubMed][Cross Ref]
  • Mavric E., Wittmann S., Barth G., Henle T. (2008). Identification and quantification of methylglyoxal as the dominant antibacterial constituent of Manuka (Leptospermum scoparium) honeys from New Zealand. Mol. Nutrit. Food Res. 52 483–489. 10.1002/mnfr.200700282 [PubMed][Cross Ref]
  • Molan P. M. (2008). An explanation of why the MGO level in manuka honey does not show the antibacterial activity. New Zealand Beekeeper 16 11–13.
  • Mullai V., Menon T. (2007). Bactericidal activity of different types of honey against clinical and environmental isolates of Pseudomonas aeruginosa. J. Alternat. Complement. Med. 13 439–442. 10.1089/acm.2007.6366 [PubMed] [Cross Ref]
  • Müller P., Alber D. G., Turnbull L., Schlothauer R. C., Carter D. A., Whitchurch C. B., et al. (2013). Synergism between Medihoney and rifampicin against methicillin-resistant Staphylococcus aureus(MRSA). PLoS ONE 8:e57679 10.1371/journal.pone.0057679 [PMC free article] [PubMed][Cross Ref]
  • Mundo M. A., Padilla-Zakour O. I., Worobo R. W. (2004). Growth inhibition of foodborne pathogens and food spoilage organisms by select raw honeys. Int. J. Food Microbiol. 97 1–8. 10.1016/j.ijfoodmicro.2004.03.025 [PubMed] [Cross Ref]
  • Nilforoushzadeh M. A., Jaffary F., Moradi S., Derakhshan R., Haftbaradaran E. (2007). Effect of topical honey application along with intralesional injection of glucantime in the treatment of cutaneous leishmaniasis. BMC Complement Altern. Med. 7:1 10.1186/1472-6882-7-1 [PMC free article] [PubMed] [Cross Ref]
  • Norton A. M., McKenzie L. N., Brooks P. R., Pappalardo L. J. (2015). Quantitation of dihydroxyacetone in Australian Leptospermum nectar via High-Performance Liquid Chromatography. J. Agric. Food Chem. 63 6513–6517. 10.1021/acs.jafc.5b01930 [PubMed][Cross Ref]
  • Okhiria O., Henriques A., Burton N., Peters A., Cooper R. (2009). Honey modulates biofilms of Pseudomonas aeruginosa in a time and dose dependent manner. J. ApiProduct. ApiMedical Sci. 1 6–10. 10.3896/IBRA. [Cross Ref]
  • Osato M. S., Reddy S. G., Graham D. Y. (1999). Osmotic effect of honey on growth and viability of Helicobacter pylori. Dig. Dis. Sci. 44 462–464. 10.1023/A:1026676517213 [PubMed] [Cross Ref]
  • Packer J. M., Irish J., Herbert B. R., Hill C., Padula M., Blair S. E., et al. (2012). Specific non-peroxide antibacterial effect of manuka honey on the Staphylococcus aureus proteome. Int. J. Antimicrob. Agents 40 43–50. 10.1016/j.ijantimicag.2012.03.012 [PubMed] [Cross Ref]
  • Regulski M. (2008). A novel wound care dressing for chronic leg ulcerations. Podiatry Manag. 27235–246.
  • Roberts A. E., Maddocks S. E., Cooper R. A. (2012). Manuka honey is bactericidal against Pseudomonas aeruginosa and results in differential expression of oprF and algD. Microbiology 1583005–3013. 10.1099/mic.0.062794-0 [PubMed] [Cross Ref]
  • Roberts A. E. L., Maddocks S. E., Cooper R. A. (2015). Manuka honey reduces the motility of Pseudomonas aeruginosa by suppression of flagella-associated genes. J. Antimicrob. Chemother. 70716–725. 10.1093/jac/dku448 [PubMed] [Cross Ref]
  • Sajid M., Azim M. K. (2012). Characterization of the nematicidal activity of natural honey. J. Agric. Food Chem. 60 7428–7434. 10.1021/jf301653n [PubMed] [Cross Ref]
  • Shahzad A., Cohrs R. J. (2012). In vitro antiviral activity of honey against varicella zoster virus (VZV): a translational medicine study for potential remedy for shingles. Transl. Biomed. 3:2[PMC free article] [PubMed]
  • Sherlock O., Dolan A., Athman R., Power A., Gethin G., Cowman S., et al. (2010). Comparison of the antimicrobial activity of Ulmo honey from Chile and Manuka honey against methicillin-resistant Staphylococcus aureusEscherichia coli and Pseudomonas aeruginosa. BMC Complement Altern. Med. 10:47 10.1186/1472-6882-10-47 [PMC free article] [PubMed] [Cross Ref]
  • Silva-Rocha R., de Lorenzo V. (2010). Noise and robustness in prokaryotic regulatory networks.Annu. Rev. Microbiol. 64 257–275. 10.1146/annurev.micro.091208.073229 [PubMed] [Cross Ref]
  • Smith T., Hanft J. R., Legel K. (2009). Topical Leptospermum honey in recalcitrant venous leg wounds: a preliminary case series. Adv. Skin Wound Care 22 68–71. 10.1097/01.ASW.0000345283.05532.9a [PubMed] [Cross Ref]
  • Soffer A. (1976). Chihuahuas and laetrile, chelation therapy, and honey from Boulder, Colorado [editorial]. Arch. Intern. Med. 136 865–866. 10.1001/archinte.136.8.865 [PubMed] [Cross Ref]
  • Sojka M., Valachova I., Bucekova M., Majtan J. (2016). Antibiofilm efficacy of honey and bee-derived defensin-1 on multi-species wound biofilm. J. Med. Microbiol. 10.1099/jmm.0.000227 [Epub ahead of print]. [PubMed] [Cross Ref]
  • Stephens J. M., Schlothauer R. C., Morris B. D., Yang D., Fearnley L., Greenwood D. R., et al. (2010). Phenolic compounds and methylglyoxal in some New Zealand manuka and kanuka honeys.Food Chem. 120 78–86. 10.1016/j.foodchem.2009.09.074 [Cross Ref]
  • Tan H. T., Rahman R. A., Gan S. H., Halim A. S., Hassan S. A., Sulaiman S. A., et al. (2009). The antibacterial properties of Malaysian tualang honey against wound and enteric microorganisms in comparison to manuka honey. BMC Complement Altern. Med. 9:34 10.1186/1472-6882-9-34 [PMC free article] [PubMed] [Cross Ref]
  • Watanabe K., Rahmasari R., Matsunaga A., Haruyama T., Kobayashi N. (2014). Anti-influenza viral effects of honey in vitro: potent high activity of manuka honey. Arch. Med. Res. 45 359–365. 10.1016/j.arcmed.2014.05.006 [PubMed] [Cross Ref]
  • Wilkinson J. M., Cavanagh H. M. A. (2005). Antibacterial activity of 13 honeys against Escherichia coli and Pseudomonas aeruginosa. J. Med. Food 8 100–103. 10.1089/jmf.2005.8.100 [PubMed][Cross Ref]
  • Williams S., King J., Revell M., Manley-Harris M., Balks M., Janusch F., et al. (2014). Regional, annual, and individual variations in the dihydroxyacetone content of the nectar of manuka (Leptospermum scoparium) in New Zealand. J. Agric. Food Chem. 62 10332–10340. 10.1021/jf5045958 [PubMed] [Cross Ref]
  • Willix D. J., Molan P. C., Harfoot C. G. (1992). A comparison of the sensitivity of wound-infecting species of bacteria to the antibacterial activity of manuka honey and other honey. J. Appl. Bacteriol.73 388–394. 10.1111/j.1365-2672.1992.tb04993.x [PubMed] [Cross Ref]
  • Windsor S., Pappalardo M., Brooks P., Williams S., Manley-Harris M. (2012). A convenient new analysis of dihydroxyacetone and methylglyoxal applied to Australian Leptospermum honeys. J. Pharmacogn. Phytother. 4 6–11.

Articles from Frontiers in Microbiology are provided here courtesy of Frontiers Media SA

Manuka Essential Oil Monograph.

(Leptospermum scoparium J.R. & G. Forster).

Botany & Natural Habitat.

Manuka (Leptospermum scoparium J.R. & G. Forster) (Allan 1961) is the most abundant shrub/small tree found in New Zealand, & the only endemic Leptospermum spp. native to New Zealand (Thompson 1989, Porter 2004) out of some seventy-nine known Leptospermum spp. It is an invasive, bushy, usually conical-shaped shrub or tree, which typically grows to 4m., but can reach 6-8m., with stems  measuring from 10 -12cm. in diameter (Ward 2000). The branches of the shrub are covered in string bark, which, on breaking, reveals a hard reddish-coloured, or sometimes whitish, wood. The shrub is covered all year in small lanceolate shaped spiky-ended leaves, and flowers periodically especially May-June, having individual white or sometimes pink hermaphroditic (therefore insect-pollinated) flowers, about 10-12mm. across. The plant shows considerable morphological variation in from, habitat, leaf size & shape, flower & leaf colouration, foliage density etc. (Porter 2004). The branches and leaves are covered in silky white hairs, which release essential oil when rubbed.  The shrub is prone to attack by the scale insect Eriococcus orariensis, eradicating it in some areas (Anon 1956).

The manuka shrub is found in scrub-forest all over New Zealand, including the Stewart & Chatham Islands, & in Tasmania, as well as in Australia, growing at elevations ranging from sea level to 1000m. It has also been reported as an alien species on several islands in Hawaii. Manuka is capable of growing in a variety of acidic and low nutrient soils, from sand dunes to mountainous areas. Ward (2000) points out that manuka shrubs are often confused with the larger & faster growing kanuka plants [Kunzea ericoides (A. Rich) J. Thompson, and the author further provides a number of morphological indicators to distinguish the two species.

The word ‘manuka’ comes from the Maori term meaning nervousness or anxiety, and is famously associated with Captain Cook, who’s men who made a refreshing tea from manuka leaves, which has to be brewed for a longer period to release the flavour than for conventional tea from Camellia sinensis (although many consider it superior). The plant parts are used in traditional Maori remedies (Brooker et al. 1987; Riley 1994).  The leaves exude a sweet manna which is composed of d-mannitol (Cambie & Seelye 1959) – there is a debate as to the cause of this exudation, whether it be natural or as a result of insect damage (Booker et al. 1991).

Essential oil of Manuka.

As with many species of the Myrtaceae, the essential oil of manuka occurs in schizogenous cavities (oil sacs) on the (underside) leaf surfaces and the seed capsules, and is obtained in practice by the steam distillation of the wild harvested terminal leaves and branches. Perry et al. (1997) reports the yield of essential oil as ranging from 0.14% to 0.80% dry weight of vegetation. The volatile oil is extremely variable in composition according to vegetation source (see chemotypes listed below), and variation of certain components has been reported from to maturity, and from natural variability within plants sourced at a single location. The ‘normal’ oil presented commercially has been described as an amber coloured liquid; the odour is fresh but rather unpleasant-bitter, clove-terpene like/bitter-herbaceous, resinous, with a hint of fruitiness. The dry-out on a perfumers strip is ambery, slightly scented, and soapy (Burfield 2000). Joulain (1996) previously commented that “the intense characteristic odour of this type of product (referring to tea tree oil from Melaleuca alternifolia) is often a handicap for wider uses, such as bodycare products. The problem also exists, albeit to a lesser extent, for the essential oil of Leptospermum scoparium (manuka) …” However the buying public has become familiar & accepting of the earthy aromatic odour of tea tree oil over the years, and these remarks may not now apply.

Earlier studies on Manuka oil chemistry.

Although analytical work on Manuka oil has been carried out for nearly 100 years initially with the identification of leptospermol (Penfold 1921, Gardner 1924; Gardner 1924a) – later to be renamed leptospermone (Short 1926), only in the last few years has the chemistry associated with the high variability of the oil started to become clear.. Flynn et al. (1979) identified several mono-& sequiterpenoids in manuka oil by GC-MS & IR spectroscopy. Häberlein & Tschiersch (1994) identified several isoflavones and triterpenoids in a dichloromethane extract of manuka vegetation. The b-triketones exhibit keto-enol tautomerism: one of the possible -enol forms of leptospermone is illustrated below:


Douglas et al. (2001) investigated oils from the foliage of 132 samples from 44 collecting sites on the North Island of New Zealand, and distinguished 5 chemotypes: mono-terpene-rich, sesquiterpene-rich, triketone-enriched, mono-sesquiterpene type and methyl cinnamate types. Previously an unpublished survey carried out by the New Zealand Institute for Crop & Food Research Limited, studied prepared essential oils from manuka leaves gathered from various locations on the S. Island, revealing the presence of four separate chemotypes: monoterpene rich; sesquiterpene rich; enhanced triketones in sesquiterpene rich oils and mixed oils with a balance of monoterpenes and sesquiterpenes (Ward 2000).  Later Douglas et al. (2004) conducted a survey analyzing oils from 261 manuka plants across 87 sites in New Zealand and identified 11 chemotypes: a-pinene, sesquiterpene-rich with high myrcene, sesquiterpene-rich with elevated (β-)-caryophyllene and (α-)-humulene; sesquiterpene-rich with an unidentified sesquiterpene hydrocarbon; high geranyl acetate; sesquiterpene-rich with high a-ylangene + a-copaene and elevated triketones; sesquiterpene-rich with no distinctive components; sesquiterpene-rich with high trans-methyl cinnamate; high linalol; and sesquiterpene-rich with elevated elemene and selinene.


Monoterpenes are generally below 3% in Manuka oils, although a high a-pinene chemotypes were identified in the North of the N. Island by Douglas et al. (2004). Other monoterpenes hydrocarbons such as myrcene, and oxygenated monoterpenes such as 1,8-cineole & linalool are also common. The presence of a cluster of a high geranyl acetate.(to 48.6%) chemoptype towards the South of the N. Island, was also  identified by Douglas et al. (2004


Low levels of esters are found in manuka oils, but the ocuurence of a trans-methyl cinnamate chemotype (at up to 30% methyl cinnamate) was reported by Douglas et al. (2004) in several S. Island samples.


The sesquiterpenes found in mauka oils include those components with cubebene/copaene, elemene, gurjunene/aromadendrene, farnescene/caryophyllene, selinene, calamenene & cadinene types of skeletons (Porter & Wilkins 1998)

Melching et al. (1997) succeeding in isolating & identifying the labile sesquiterpene (-)-(!R,7S,10R)-cadina-3,5-diene, zonarene & (+)-d-amorphene which constitute 5-10% of Manex oil (the trade name of Manuka oil from Te Araroa, East Cape  as marketed by Tairawhiti Pharmaceuticals Ltd.). .


Of the N. Island oils, the triketone-enriched East Cape chemotype is rich in the b-triketones flavesone, leptospermone & iso-leptospermone, & has a much lower discernable odour, especially if the oil is fractionated to enhance the concentration of these components.  Analytically, the presence of the b-triketones distinguishes manuka oil from Kanuka oil from Kunzea ericoides.

The presence of 3 further minor ketonic compounds in Manuka oil illustrated below was established by Melching (1997) and was confirmed by Porter & Wilkins (1998):

One of these compounds, 2-(1-oxobutyl)-4,4,6,6-tetramethylcyclohexan-1,3,5-trione has previously been named grandiflorone after it was found as a substituent of the Australian essential oil of L.  flavescens (Brooker et al. 1963; Hellyer 1968; Brophy et al. 1996).

The East Cape Chemotype of Manuka Oil.

Essential oils prepared from manuka vegetation in the N. Island were found to contain from 0.1 to 33.3% (average 5.8%) of the triketones flavescone, isoleptospermone, and leptosepermone (Douglas et al 2001). Later, Douglas et al. (2004) identified b-triketone levels of >20% with only a slight seasonal variation, from surveying 36 plants in the East Cape area, although triketone levels of up to 20% were also found in the Marlborough Sounds area of the S. Island. High triketone plants with triketone levels of >20% only have a limited distribution within the East Cape area, and commercial exploitation of this chemotype is dependent on maximizing foliage production.& regrowth (Douglas et al. 2004)..

Porter (Porter 2004) further comments that under agricultural pressure, wild stands of Manuka are being cleared and that therapeutic lines of the East Cape variety may be lost, although trial plantations have been established. High levels of these compounds are aided by companies involved in East Cape oil production (e.g. Tairawhiti Pharmaceuticals which distills foliage from Te Araroa, East Cape) by prolonging distillation times (4-6 hours), and/or by high-vacuum fractionation of the oil, making oil production a more expensive exercise than, for say, tea-tree oil from Melaleuca alternifolia. Careful analytical monitoring of production batches has to be maintained to ensure product consistency due to the variability of the essential oil from the East Cape vegetation sources.  A high β-triketone containing fraction of East Cape manuka oil is commercially available  containing over 96% β-triketone ocontent.:





                 57.7% to 67.0%


                 13.0% to 23.0%


                 13.0% to 23.0%

Table 1.  Constituents of high β-triketone fraction of manuka oil.

The biosynthetic pathway for the formation of these b-triketones is unknown at present, and Brophy et al. (1999) did not find any b-triketones in Australian L. scoparium samples. Further, Perry et al. (1997) proposes that New Zealand oils from L. scoparium are a different chemotype to the corresponding Australian oils, and that the New Zealand plants are morphologically different from Tasmanian L. scoparium specimens. Further, Porter & Wilkins (1998) advise that kanuka oil is characterized by high levels of a-pinene (>50%) whereas monoterpenes are typically present at low levels (<3%) in many manuka oils The presence of higher levels of b-triketones has been advised as offering a high level of anti-microbial activity against Gm-positive organisms such as Staphylococcus, Enterococcus & Streptococcus spp., and certain dermatophytic fungi (see below).


The flavonoids in a petroleum extract of the aerial parts of manuka, separated on silica gel were characterized by Mayer (1990) who confirmed the identity of seven compounds, four of which were already noted in the literature, and found that a triterpene diol previously identified as betulinol was in fact a mixture of uvaol & betulinol. The new flavonoids were 5-methoxy-7-hydroxy-6,8-dimethylflavone, 5-hydroxy-6-methyl-7-methoxyflavone & 5,7-dimethoxy-6-methylflavone, Further investigations were conducted by Tscheirsch et al. (1992) and Haberlein & Tschiersch (1993) who discovered a further flavanoid, 5,7-dimethoxy-6-methylflavone.


Tannins in Leptospermum scoparium were investigated by Cain (1963).

Triterpene Acids.

Triterpene acids in Leptospermum scoparium were investigated by Corbett & McDowell (1958).

Anti-microbial properties of Manuka oil.

General Remarks.

The manuka oil chemotype, the manuka oil composition and the microbiological testing method employed are some of the major factors with respect to reported anti-microbial activity of manuka oil. Intimate contact between essential oil molecules and micro-organisms, is notoriously difficult to achieve in aqueous media because of the hydrophobicity of essential oils. Various microbiological techniques employed to assess the anti-microbiological activity of manuka oils have included the inhibitory zone technique (Perry et al. 1997), the agar well technique (Lis-Balchin et al. 1996), the broth dilution method (Christolph et al. 2000; Harkenthal et al. 1999) and the broth susceptibility method (Carson & Riley 1994) amongst others. However, various considerations point to test method dependency. For example the effect of any surfactant employed may have a direct bearing on the results. Thus van Zyl et al. (2000) on testing 20 nature identical essential oil constituents remark that in their findings “the relative inactivity of citronellal, (+)-αβ-thujone, p-cymene and 1,8-cineol has been associated with low water solubility & hydrogen bonding capacity, thus limiting their entry into Gm-ive organisms that possess sufficient hydrophobic pathways in the outer membrane (quoting Griffin et al. 1999). Elsewhere Burt (2004) remarks that Gm –ive bacteria are less susceptible to the action of essential oils due to the presence of an lipopolysaccharide coving to the outer membrane to their cell wall which restricts the diffusion of lipophilic compounds. 

The anti-microbial properties of mixtures of a high β-triketone fraction of manuka oil with other essential oils have also been investigated e.g. with niaouli or Australian tea tree oil by Christolph et al. (2001). In the latter study good activity was noted against Staphylococcus aureus and Moraxella catarrhalis, with total kill times determined at 240 mins. for both types of admixture, which was superior to that for myrtol, the proprietary product for the treatment of acute and chronic bronchitis and sinusitis. Combinations of manuka and tea tree, calendula and tea extracts & essential oils were tested for potential use as an oral mouthwash against the periodontal pathogens Actinobacillus actinomycetemcomitans, Tanerella forsythensis (Lauten et al. 2005) but the results did not reach statistical significance.

Combinations of the β-trietone fraction of manuka oil and antibiotics have also been investigated against a number of pathogenic organisms (Kim 1999). 

Comparative anti-microbiological activity testing.

Christolph et al. (2000) found that Lema oil® came`second in kill time performance in a series of oils tested against Staphylococcus aureus (Australian tea-tree oil, cajuput oil, niaouli oil, Lema oil, kanuka oil, manuka & the beta-triketone isolate of manuka oil),  where a 2% concentration of oil a complete 6.8 log10 reduction of cell numbers in suspensions within 60 min.

Harkenthal et al.  (1999) found that manuka oil had a higher kill activity against Gm +ive bacteria than tea tree oil, with a MIC value of around 0.12%. The authours also found that both manuka and tea tree had a good activity against anti-biotic resistant strains of Staphylococcus aureus, but only a poor activity against Pseudomonas aeruginosa.

Takarada et al (2004) investigated a number of essential oils including manuka oil, tea tree oil, eucalyptus oil, lavandula oil, and rosmarinus oil against a number of oral pathogens, Porphyromonasgingivalis, Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, Streptococcus mutans, and Streptococcus sobrinus, finding that that, among the essential oils tested, manuka oil and tea tree oil in particular had strong antibacterial activity against periodontopathic and cariogenic bacteria.

Filoche et al. (2005) tried a number of essential oils including manuka oil, Listerine Coolmint, and menthol & thymol, alone and in combination with chlorhexidine gluconate, against biofilm & planktonic cultures of Streptococcus mutans & Lactobacillus plantarum. Manuka oil showed some activity but less than cinnamon oil.

Virucidal Properties.

Reichking et al.(2005) established the virucial activity of beta-triketone rich manuka oil fractions against the Herpes Simplex organisms HSV-1 & HSV-in vitro on RC-37 cells (monkey kidney cells) using a plaque reduction assay.Pretreatment of the viruses with manuka oil for 1 h prior to cell infection showed that significant inhibition could be achieved for both HSV-1 & HSV-2 strains.

Dermatophytic organisms. 

Action of manuka oil against the dermatophyte Trichophyton mentagrophytes was investigated by Lis-Balchin et al (1996). Tea tree oil was found to have no action but the manuka oil was effective against this organism in this study.

Ethnic Uses of Manuka.

Manuka was renowned for its use as a tea substitute by sailors visiting Aotearoa, hence the name “tea-tree” was born, although manuka is of course, quite different from tea-tree.

The bark/leaves/sap/seed capsules of manuka have been used for beverages or medicinal preparations (Best 1905; Brooker et al. 1981). Decoctions of leaves used for aromatic teas for treating fevers & for treating colds, as an emetic, purgative & diuretic; oil infusion of leaves used against chronic sores (Porter 2004). Carr (Carr 2004) conveniently presents the ethnic uses of manuka plant parts in tabulated form, based on the above noted published information by Brooker et al. (1981).


A yellow-green dye is obtained from manuka flowers & a greenish-black dye from the flowers, branches & leaves (Grae 1974).  Daniels (1997) throws some light on the use of tannin-rich manuka vegetation which is boiled with the leaves of Phormiun tenax and plunged into mud to make a traditional black dye for bark-cloth & baskets by Maori weavers.

Other properties & applications  of Manuka oil.

Spasmolytic effect.

Lis-Balchin & Heart (1998) & Lis-Balchin et. al. (2000) studying the effects of tea tree, manuka & kanuka oils on guinea-pig ileum, skeletal muscle (chick biventer muscle and the rat phrenic nerve diaphragm) and also rat uterus in vitro, noted a spasmolytic effect in smooth muscle for manuka oil, but it is unclear which precise chemotype of manuka oil was tested. Lis- Balchin & Hary considerd a post-synaptic mechanism involving cAMP was implicated in the spasmolytic effect.  The authors also warned against the use of all three oils during childbirth based on the in vitro observations on the effects of the essential oils on rat uterus, where they caused a decrease in the force of the spontaneous contractions.

Anti-oxidant effect.

Lis-Balchin et. al. (2000) noted anti-oxidant effects for manuka oil.  Anti-oxidant & free radical quenching abilities of various manuka honeys have been investigated (Henriques et al. 2006).

Effects against proteases.

Carr (1998) reported that Manuka can be effective against cysteine proteases implicated in muscle wasting diseases, such as muscular dystrophy, viral replication, tumour invasion etc., building on previous enzyme inhibitory properties shown by manuka (Carr 1991).  

Cosmetic uses.

Beta-triketone fractions of manuka oil have been incorporated, with other active ingredients, as components of an anti-dandruff shampoo, based on the alleged fungiostatic properties of the manuka fractions towards Malassezia (:lipophilic yeast) species which proliferate in the scalp sebum.

Manuka is used in fragrances for toiletries in New Zealand's domestic­ market. 

Insecticidal uses.

Leptospermone has previously been shown to have anti-helmintic properties, and to have some synergistic insecticidal properties. A patent has been filed concerning the use of manuka oil against arthropods (Watanabe Keisuke & Sugano Masayo 2003).

References – see Manuka Biblio.

Extra References in Manuka Biblio above:

Allan, H. H. (1961). Flora of New Zealand, Vol. 1. Wellington: DSIR.

Best E. (1905) Polynesian Society Journal 13, 213.

Antimicrobial activity of honey in periodontal disease: a systematic review