October 2013 1091

Several types of honey are now registered as medicinal honey: Active Manuka, MediHoney (both obtained from the

tea tree bush, leptospermum scoparium, in New Zealand) and Revamil (obtained from proprietary “Revamil source” honey). These are sterilized (by gamma irradiation, so as to not affect antibacterial activity1) to eliminate potentially dangerous microorganisms, and marketed for wound application, claiming various benefits. But are we talking about real benefits for real patients? In this article, I’ll briefly review the evidence we have on the use of honey as a wound treatment.

Laboratory studiesHoney is toxic for many types of bacteria

and fungi. It is effective in concentrations of around 10% and greater, which is important, as after wound application, considerable di-lution might occur. Honey is roughly 4 times more potent than an equivalent sugar solu-tion.2 Its toxicity derives from its acidity and high sugar concentration (80%), as well as the presence of several specific compounds. One main mechanism by which it kills is hy-drogen peroxide (H2O2). But H2O2 is not the only active compound: some honeys (includ-ing manuka) still kill Staphylococcus aureus even if all H2O2 is eliminated.2 Hence, other important chemicals must be present, and the main compounds have now been iden-tified as bee defensin-1 and methylglyoxal. If these two, and H2O2, are removed from honey, and its acidity is neutralized, honey is no more effective in killing bacteria than is sugar water of equivalent concentration.3

Other factors, however, may play a role in the clinical setting. For example, some com-pounds in honey stimulate immune cells to secrete chemicals that promote cell growth and might help wounds heal faster4 (in con-trast to some other wound therapies, honey is not toxic to skin cells5), and honey is able to “quench” toxic superoxide free radical molecules.6

There are substantial differences in the levels of all these compounds between types of honey, and honey processing can affect levels further7, which makes comparisons difficult. Of two types of honey commonly used for medicinal application, manuka and Revamil, the latter contains high con-centrations of H2O2 and bee defensin-1, whereas manuka contains concentrations of methylglyoxal more than 40 times greater than Revamil.8 As might be expected, such differences are also found when instead of unifloral honeys from different plants, wildflower honeys from different regions are compared: for example, honey from the Sahara region of Algeria is much more ef-fective in killing Pseudomonas aeruginosa than is honey from northern Algeria.9 A comparison of 345 samples of New Zealand honey from 26 floral sources showed anti-microbial activity against S. aureus to range 20-fold.2

Interestingly, mixtures of propolis and honey are more effective in killing bacteria (S. aureus and Escherichia coli) than either compound alone.10 Honey from stingless bees has properties similar to that of honey-bees.11

Two properties make honey particularly interesting as a potential treatment for in-fected wounds. First, honey does not induce resistance to its effect as is often the case with antibiotics.12 Second, it is effective against a wide variety of microorganisms. In one study various honeys (including ma-nuka and MediHoney) were active against 12 out of 13 types of bacteria tested.13 In a second, manuka and generic honey were found effective against seven major wound-infecting types of bacteria.14 In volunteers, honey reduced skin colonization with a va-riety of bacteria 100-fold.15 Interestingly, honey is effective against Helicobacter pylori, a common cause of stomach ulcers (this may explain the postulated benefit of honey when used for stomach pain).16 This broad range of targets is quite different from many types of antibiotics, which are often limited in their spectrum, and it is important, as chronic wounds are often colonized by many species of bacteria simultaneously. In addition, in such settings bacteria create a complex “biofilm” that protects the bacteria from both antibiotics and the patient’s im-mune response. Both manuka and Norwe-gian forest honey were shown to effectively penetrate this biofilm and kill complex com-munities of bacteria.17

It may be worth noting that in these and other studies, the commercial “medicinal” honeys only marginally outperform se-lected local ones – if at all. For example, pasture honey is as effective as manuka against 58 strains of S. aureus18, and im-portantly, against methicillin-resistant S.

It’s almost impossible to read a book on beekeeping without finding somewhere the statement that honey has useful antibacterial properties, and that it has been used for medicinal purposes for millennia. It’s not so easy, though, to find out what this actually means. Lots of compounds (let’s say, gasoline) kill bacteria, but that does not mean they have practical, clinical use in that area. Lots of therapies (e.g. bloodletting) have been used for a long time, but are actually without much benefit.

ABJ_Oct_2013.indb 1091 9/6/2013 11:56:54 AM

American Bee Journal1092

aureus (MRSA) and vancomycin-resistant enterococci19 (as their names suggest, both these bacteria are largely resistant to current antibiotics, and are major human disease agents). Chilean Ulmo tree (Eucryphia cor-difolia) honey has substantially greater po-tency than manuka honey against MRSA.20

Clinical studiesSo what does all of this mean in real life?

Clinically, most interest in honey treatments has focused on wound healing. Particularly leg wounds in patients with blood vessel problems (so-called “venous ulcers”) can be very difficult to heal, and they frequently be-come infected. Bacteria in these wounds are often resistant to antibiotics, and the result is a chronic, non-healing ulcer. No proven therapy exists. Burns are another important type of wound, and again, little evidence is available about optimal treatments. Can honey be helpful in this settings? A review in 2009 found positive findings of honey use reported in 17 randomized trials (compared with standard care) that enrolled a total of almost 2000 patients.21 Here, we’ll briefly look at the major studies.

Chronic woundsThe best study done in this area was

published in 2008 in the British Journal of Surgery: the Honey as Adjuvant Leg Ulcer Therapy (HALT) trial.22 This well-performed study compared manuka honey dressings with standard care in 368 patients with chronic leg ulcers, using as the pri-mary outcome the percent of ulcers that had healed completely after 12 weeks. The in-vestigators found no difference between the treatments in this measure (55.6% healed if honey-treated, 49.7% otherwise; these

numbers are statistically equivalent; see Fig. 1). Similarly, time to healing, change in ulcer size, infection rates, and quality of life were not different. More side effects were seen in the honey group (in particular, more pain), and cost of the honey treatment was probably greater. Thus, disappointingly, the authors had to conclude that “honey-impregnated dressings did not significantly improve venous ulcer healing.” 22

Does this mean that honey is without ben-efit in this area? Not necessarily, although the HALT trial carries much weight be-cause of its size and strong design. Another, smaller trial (108 patients) found decreased wound size, more healing at 12 weeks (44% vs. 33%) and less infection with manuka dressings.23 Specifically, MRSA was elimi-nated from 70% of ulcers (but the number of MRSA-infected patients was extremely small).24 A very small (36 patients) study from Turkey showed that, after 5 weeks, use of honey dressings was associated with approximately 4 times the rate of healing of the control group.25 On the other hand, no benefit of honey was seen in 50 patients in a study from Nigeria26, and, similarly, a study of 105 patients comparing manuka with conventional wound care showed no statis-tical differences.27

It is very common in research for small, poorly designed studies to show benefits that are not confirmed by subsequent large-scale, well-designed multi-center trials. Hence, on the weight of the current evidence, our con-clusion must be that it seems doubtful that honey dressings speed healing of chronic ul-cers as compared with standard therapy (but then again, there’s little evidence to show that “standard therapy” is effective either). Still, other aspects of honey treatment might

make it useful: for example, it tends to im-prove wound odor in chronic wounds.28

Burns and other acute woundsWhat about acute wounds? A number

of studies have compared honey treatment with standard management for burns, most of them performed by one investigator in India. These data were reviewed in 200129 and 2009.21 All trials were of limited qual-ity (because of study design). All but one reported benefits of honey, particularly a shorter time to healing. More infected wounds became sterile after one week when honey was used: 85% vs 30%, but after three weeks healing rates were high for all patients. Unfortunately, the weaknesses of these studies make it very difficult to draw any definitive conclusions.

Honey has also been used on postop-erative wounds. After abdominal surgery, honey treatment (in 26 patients, compared with 24 control treatments) led to faster eradication of bacterial infection (6 days vs. 15 days), shorter antibiotic use, faster com-plete wound healing (10 days vs. 22 days) and a shorter hospital stay (9 days vs. 20 days; see Fig. 2).30 Honey-treated wounds healed faster and length of hospital stay was reduced in children after abscess surgery.31

Taken together, the studies on honey use for acute wounds, although limited in qual-ity, seems overall to be supportive of its use.

Other applicationsThe use of honey has been studied in a

number of other clinical settings. Honey dressings on so-called central venous cath-eters in the intensive care unit have been studied, in an effort to reduce blood stream infections. Unfortunately, no benefit was seen.32 A trial of 101 patients on renal di-alysis showed honey to be as effective as standard treatment in preventing bacterial growth on dialysis catheters.33

Pressure ulcers in patients with spinal cord injury are common. A series of 20 patients treated with MediHoney showed rapid elimination of infection and complete wound healing after 4 weeks in 90% of pa-tients.34 This finding should be followed up with a study comparing honey treatment against a control group. Good results have been reported using honey for treatment of wounds after cancer surgery in children.35

ConclusionsSo what can we conclude from this in-

formation? The laboratory studies strongly suggest potentially beneficial antimicrobial effects of honey when applied in clinically feasible concentrations. In agreement, the available clinical data indicate that honey may be as effective as standard treatments on chronic wounds, and may outperform standard treatment in acute wounds. This suggests that in resource-poor settings, where “standard treatment” maybe too ex-pensive or hard to come by, honey could be very useful indeed. In our setting, it might not be worth the trouble using it on chronic wounds, but it should be considered for (in-

Figure 1: Percent of patients with chronic venous leg ulcers in which complete wound healing was obtained after 12 weeks in the Honey as Adjuvant Leg Ulcer Therapy (HALT) trial. 187 patients were randomized to honey, and 181 to usual care. Honey treatment consisted of a calcium alginate dressing impregnated with manuka dressing. There was no benefit of using the honey dressings.22

ABJ_Oct_2013.indb 1092 9/6/2013 11:56:55 AM

October 2013 1093

fected) acute wounds (and some high-qual-ity studies in that area would be of value).

The use of honey for treating antibiotic-resistant bacteria seems to have support from both the laboratory work and preliminary clinical studies. Considering the disease burden caused by MRSA, even a limited benefit of honey would be very worthwhile in this setting, and more research would be welcome.

In summary, honey does have clear anti-biotic properties in the laboratory, and these translate, at least for a subset of patients, to the clinical setting. There is real benefit for some patients.

About the AuthorProf. Marcel Durieux says “I’m a back-

yard beekeeper in Charlottesville, VA, who happens to do medical research for a living (I’m professor of anesthesiology at the Uni-versity of Virginia). I also happen to have an interest in alternative approaches to wound healing because of work I do in Africa. This article brought all of this together!”

References1. Molan PC, Allen KL. The effect of

gamma-irradiation on the antibacterial activity of honey. J Pharm Pharmacol. 1996;48(11):1206-1209.

2. Allen KL, Molan PC, Reid GM. A sur-vey of the antibacterial activity of some New Zealand honeys. J Pharm Pharma-col. 1991;43(12):817-822.

3. Kwakman PH, te Velde AA, de Boer L, Speijer D, Vandenbroucke-Grauls CM, Zaat SA. How honey kills bacteria. FASEB J. 2010;24(7):2576-2582.

4. Tonks AJ, Dudley E, Porter NG, et al. A 5.8-kDa component of manuka honey stimulates immune cells via TLR4. J Leu-koc Biol. 2007;82(5):1147-1155.

5. Du Toit DF, Page BJ. An in vitro evaluation of the cell toxicity of honey and silver dressings. J Wound Care. 2009;18(9):383-389.

6. Henriques A, Jackson S, Cooper R, Burton N. Free radical production and quenching in honeys with wound heal-ing potential. J Antimicrob Chemother. 2006;58(4):773-777.

7. Chen C, Campbell LT, Blair SE, Carter DA. The effect of standard heat and filtra-tion processing procedures on antimicro-bial activity and hydrogen peroxide levels in honey. Front Microbiol. 2012;3:265.

8. Kwakman PH, Te Velde AA, de Boer L, Vandenbroucke-Grauls CM, Zaat SA. Two major medicinal honeys have different mechanisms of bactericidal ac-tivity. PLoS One. 2011;6(3):e17709.

9. Boukraa L, Niar A. Sahara honey shows higher potency against Pseudomonas ae-ruginosa compared to north algerian types of honey. J Med Food. 2007;10(4):712-714.

10. Al-Waili N, Al-Ghamdi A, Ansari MJ, Al-Attal Y, Salom K. Synergistic effects of honey and propolis toward drug multi-resistant Staphylococcus aureus, Esche-richia coli and Candida albicans isolates in single and polymicrobial cultures. Int J Med Sci. 2012;9(9):793-800.

11. Boorn KL, Khor YY, Sweetman E, Tan F, Heard TA, Hammer KA. Anti-microbial activity of honey from the sting-less bee Trigona carbonaria determined

by agar diffusion, agar dilution, broth mi-crodilution and time-kill methodology. J Appl Microbiol. 2010;108(5):1534-1543.

12. Blair SE, Cokcetin NN, Harry EJ, Carter DA. The unusual antibacterial activity of medical-grade leptospermum honey: Antibacterial spectrum, resistance and transcriptome analysis. Eur J Clin Microbiol Infect Dis. 2009;28(10):1199-1208.

13. Lusby PE, Coombes AL, Wilkinson JM. Bactericidal activity of different honeys against pathogenic bacteria. Arch Med Res. 2005;36(5):464-467.

14. Willix DJ, Molan PC, Harfoot CG. A comparison of the sensitivity of wound-infecting species of bacteria to the an-tibacterial activity of manuka honey and other honey. J Appl Bacteriol. 1992;73(5):388-394.

15. Kwakman PH, Van den Akker JP, Guclu A, et al. Medical-grade honey kills antibiotic-resistant bacteria in vitro and eradicates skin colonization. Clin Infect Dis. 2008;46(11):1677-1682.

16. al Somal N, Coley KE, Molan PC, Hancock BM. Susceptibility of Heli-cobacter pylori to the antibacterial ac-tivity of manuka honey. J R Soc Med. 1994;87(1):9-12.

17. Merckoll P, Jonassen TO, Vad ME, Jeansson SL, Melby KK. Bacteria, bio-film and honey: A study of the effects of honey on ‘planktonic’ and biofilm-em-bedded chronic wound bacteria. Scand J Infect Dis. 2009;41(5):341-347.

18. Cooper RA, Molan PC, Harding KG. Antibacterial activity of honey against strains of Staphylococcus aureus from infected wounds. J R Soc Med. 1999;92(6):283-285.

19. Cooper RA, Molan PC, Harding KG. The sensitivity to honey of gram-positive cocci of clinical significance isolated from wounds. J Appl Microbiol. 2002;93(5):857-863.

20. Sherlock O, Dolan A, Athman R, et al. Comparison of the antimicrobial ac-tivity of ulmo honey from chile and ma-nuka honey against methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. BMC Complement Altern Med. 2010;10:47-6882-10-47.

21. Molan PC. The evidence supporting the use of honey as a wound dressing. Int J Low Extrem Wounds. 2006;5(1):40-54.

22. Jull A, Walker N, Parag V, Molan P, Rodgers A, Honey as Adjuvant Leg Ulcer Therapy trial collaborators. Ran-domized clinical trial of honey-impreg-nated dressings for venous leg ulcers. Br J Surg. 2008;95(2):175-182.

23. Gethin G, Cowman S. Manuka honey vs. hydrogel--a prospective, open label, multicentre, randomised controlled trial to compare desloughing efficacy and healing outcomes in venous ulcers. J Clin Nurs. 2009;18(3):466-474.

24. Gethin G, Cowman S. Bacteriologi-cal changes in sloughy venous leg ulcers treated with manuka honey or hydrogel:

Figure 2: Data from a trial of patients with infected wounds after caesarean sections or hysterectomies (removal of the womb), who were either treated with honey dressings or standard treatment. The honey treatment group (26 patients) received 12-hourly application of crude honey; the standard treat-ment group (24 patients) received local antiseptics, such as 70% ethanol and povidone iodine. “Sterilization” indicates the time to eradication of the bacterial infection. 30

ABJ_Oct_2013.indb 1093 9/6/2013 11:56:56 AM