Abstract Cooper, R. (2008) Using honey to inhibit wound pathogens.
Nursing Times; 104: 3, 46–49.
This article reviews the laboratory and clinical evidence that relates to the antimicrobial properties of honey. Observations show it is a broad spectrum antimicrobial agent with efficacy against bacteria, fungi, protozoa and viruses. It is also capable of eliminating malodours from wounds, eradicating antibiotic-resistant strains of bacteria from wounds and acting as an effective prophylactic agent at the exit sites of medical devices.
Author Rose Cooper, PhD, PGCE, BSc, is reader in Microbiology, University of Wales Institute, Cardiff.
Honey is a sweet product made by bees from the nectar of flowering plants or from the exudate (honeydew) of plants. Long regarded as a valuable human food, as well as a sacred material and medicine, it has been used to treat diverse illnesses ranging from respiratory and enteric infections to eye disorders, burns and wounds. Modern practitioners, however, were reluctant to use it on wounds until regulated products were available. The development of modern wound-care products has changed attitudes and clinical use has increased since regulated, CE-marked products attained drug-tariff status in the UK in 2004.
A marked increase in the publication of scientific articles and reviews has also occurred. The therapeutic potential of honey has been attributed to its ability to promote wound healing and inhibit wound pathogens. This article focuses only on its antimicrobial properties.
Chemical composition of honey
Chemically, honey is a complex substance that has been estimated to contain at least 600 components (Bogdanov et al, 2004). Essentially, it is a supersaturated solution of four main sugars – fructose, glucose, sucrose and maltose. Water molecules comprise less than 20% of the weight of honey and it contains low levels of other sugars, organic acids, proteins and minerals (White, 1979). Honey is acidic and its pH ranges from 3.2 to 4.5 (the average is 3.9) (White, 1979).
Even though it is an easily recognisable product, simple observation of the range of honeys on supermarket shelves readily demonstrates that all honeys are not identical. Flora origin, bee species, geographical source and post-harvesting conditions influence its characteristics. Ancient physicians must have recognised subtle differences because specific types of honey were carefully selected for distinct medicinal purposes (Jones, 2001), yet the underlying principles of this selection are not yet fully understood today.
Evaluation of the antimicrobial activity of honey samples
The high sugar content, low water content and marked acidity of all honeys provide unsuitable conditions to promote the active growth of micro-organisms and explain why honey infrequently spoils at room temperature, despite prolonged storage in the home. Its antimicrobial activity has interested scientists for more than a century, but not all honeys display the same potency.
Some honeys (peroxide honeys) exhibit enhanced antimicrobial activity on dilution due to the activation of an enzyme known as glucose oxidase, which oxidises glucose to gluconic acid and hydrogen peroxide (Molan, 1991). This happens when honey mixes with exudates in a wound.
A laboratory test to evaluate antibacterial activity was used in a survey of 345 honey samples in New Zealand (Allen et al, 1991). In this agar well diffusion assay, honey samples diluted in water or in catalase (an enzyme that destroys hydrogen peroxide) were dispensed into wells cut into agar that had been impregnated with Staphylococcus aureus and the plate was incubated overnight. Inhibition of bacterial growth was observed as concentric zones around wells and then compared with inhibition zones produced by known concentrations of phenol (a reference antiseptic). The test allowed honeys to be divided into three categories of samples:
Those that produced zones of inhibition;
Those whose zones of inhibition were destroyed in the presence of catalase;
Those whose zones of inhibition were unaffected by the presence of catalase.
Hence honeys were identified as:
Those whose activity was confined to their high sugar content, low moisture content and acidity;
Those that generated low levels of hydrogen peroxide on dilution;
Those that retained activity that was independent of the synthesis of hydrogen peroxide on dilution (non-peroxide honeys).
The study showed a wide variation in the antibacterial activity of the selected New Zealand honeys. If honey is intended to be used clinically as an antimicrobial agent, it seems logical to select samples of high potency. Both peroxide and non-peroxide honeys have potential as topical agents, but the activity in non-peroxide honeys is unlikely to be inactivated by catalase present in human tissue or plasma.
Leptospermum honeys, such as jellybush and manuka, produced in Australia and New Zealand respectively, are examples of non-peroxide honeys. Their non-peroxide activity is often expressed as a unique manuka factor (UMF) and it is thought to be derived from plant components that are, as yet, unidentified (Molan, 1992). Honeys that possess non-peroxide antibacterial activity equivalent to 10% phenol (weight/volume or w/v) have been recommended for clinical use (Molan and Betts, 2004). They should be produced under hygienic conditions by trained bee-keepers and come from hives uncontaminated by antibiotics, pesticides or pollutants.
Not all modern wound-care products specify the type of honey used. Honeys from Africa and Oman (Al-Jabri et al, 2003), Canada (Brudzynski, 2006) and Portugal (Henriques et al, 2006) have been investigated for their potential in treatment, but do not meet the recommendations suggested above.
Susceptibility of micro-organisms to honey in laboratory tests
The broad-spectrum antimicrobial activity of honey has been demonstrated by many studies and more than 80 species of micro-organisms have been shown to be susceptible to a diverse range of honeys in laboratory tests (Molan, 1992). Although all undiluted honeys prevent the growth of micro-organisms, the relative susceptibilities of different pathogens can be determined by laboratory tests on a series of diluted honey solutions. Often microbial inhibition is expressed as the minimum inhibitory concentration (MIC), which is the lowest concentration that prevents growth of micro-organisms in the laboratory.
A sensitive method for determining microbial sensitivity to honey was published recently (Patton et al, 2006) and will, in time, generate much reliable information. However, reviews of existing data show inconsistencies as different methods with various environmental or reference strains of organisms and honey samples varying in flora source and potency were used. A more consistent picture emerges when a specific type of honey is applied to a range of organisms. To explore the potential of honey in treating and preventing wound infection, clinical isolates should be tested.
To date, most information has been derived from tests using manuka honey on bacteria capable of causing wound infections. By comparing the efficacy of three Australian honeys with three commercial therapeutic honeys on 13 bacteria and Candida albicans, it was reported that local Australian honeys had inhibitory activity equivalent to commercial samples for some but not all species (Lusby et al, 2005).
The inhibition of seven species of bacteria, for example, was demonstrated by Willix et al (1992) with manuka honey. Active manuka honey has been shown to inhibit Pseudomonas aeruginosa (Cooper et al, 2002a), S. aureus (Cooper et al, 2002b, 1999), coagulase-negative staphylococci (French et al, 2005) and enterococci (Cooper et al, 2002b) when diluted by a factor of at least 10. Such low concentrations would not be used clinically, but data indicates that the dilution of honey by wound exudate would not readily prevent activity during use.
From using a syrup containing the four main sugars present in honey, it is evident that inhibition at diluted concentrations is not attributable to sugars alone but to one or more components of natural honey (French et al, 2005; Cooper et al, 2002a, 2002b). It is also clear that antibiotic-sensitive strains and their respective antibiotic-resistant strains are equally susceptible to active manuka honey (French et al, 2005; Cooper et al, 2002a, 2002b, 1999). Not only are antibiotic-resistant bacteria inhibited by honey, but also synergistic action of honey with antibiotics has been found (Al-Jabri et al, 2005).
The mode of bacterial inhibition by honey is bactericidal rather than bacteriostatic (Lusby et al, 2005; Cooper et al, 2002a). Cellular target sites have not been identified. Gram-positive bacteria are generally more susceptible than Gram negatives. Staphylococci seem to be the species most susceptible to honey, even though they are known to be most tolerant to elevated levels of sugars.
The antifungal activity of honey has been demonstrated with dermatophytes (Brady et al, 1996) and yeasts (Irish et al, 2006). The inhibition of protozoa has also been reported in laboratory tests (Zeina et al, 1997).
Antiviral activity is not easily tested in laboratory tests but a clinical study has indicated its efficacy in the treatment of recurrent herpes simplex lesions (Al-Waili, 2004). There is, however, much in vitro evidence to confirm the broad-spectrum antimicrobial activity of honey.
Inhibition of pathogens in wounds
Laboratory tests provide estimations of the relative sensitivities of microbial species to honey, but it is important to monitor the effect of the topical application of honey on wound flora. Wound sterilisation is not necessary for healing to proceed, but fast eradication of wound infections has been observed, for example following Caesarean sections and hysterectomies (Al-Waili and Saloom, 1999 ). In this study crude, Yemeni honey collected from villages was compared with antiseptics (Al-Waili and Saloom, 1999).
The eradication of malodour, presumably due to the inhibition of anaerobes, has been noted in leg ulcers (Gethin and Cowman, 2005) and pressure ulcers (Van der Weyden, 2003).
The eradication of antibiotic-resistant bacteria has the potential to reduce the development of wound infection and cross-infection. Examples of this include: MRSA being removed from colonised leg ulcers (Chambers, 2006); from a diabetic foot ulcer in a patient threatened with amputation (Eddy and Giddeonson, 2005); from wounds in patients in paediatric oncology (Simon et al, 2006). In the last example, leptospermum honey has become the first-line treatment, rather than the last.
The prophylactic benefits of honey have been identified in patients with renal illnesses (Johnson et al, 2005). In a randomised controlled trial, the topical exit-site application of Medihoney was compared with mupirocin for the prevention of catheter-associated infections in haemodialysis patients. Thrice-weekly applications of the two agents showed a comparable rate of catheter-associated bacteraemias. The topical honey was considered to be safe, cheap and effective and without the risk of selecting mupirocin-resistant staphylococci.
The effects of medical honey in healing seven consecutive patients whose wounds were either colonised or infected with MRSA has been reported from Germany (Blaser et al, 2007). Despite the use of topical antiseptics and topical antibiotics in some patients, as well as the systemic use of vancomycin in three patients, MRSA had persisted in some wounds for up to five years. Following the daily application of honey, MRSA was eradicated from all wounds and, in most cases, without additional use of antimicrobial treatments.
Despite the growing number of case reports, a randomised, controlled trial to investigate the efficacy of honey in eradicating MRSA from wounds is still required.
Possible mechanism of action?
P. aeruginosa is a difficult organism to inhibit because of its innate and acquired resistance to antimicrobial agents. Although an opportunist pathogen, it can cause persistent wound infections that may be linked to its ability to form biofilms.
The initiation of wound infection and the formation of biofilms by pseudomonas depends on the adhesion of bacterial cells. Several Israeli honeys and royal jelly block these critical events (Lerrer et al, 2007). The most abundant sugar (fructose) is thought to prevent the bacteria from binding to host-cell membrane receptor sites. Without adhesion, neither infection nor biofilms can develop.
Judging from the practice of ancient physicians, the antimicrobial characteristics of honey have long been recognised. Although much of the evidence is anecdotal, observations from laboratory and clinical studies provide suitable evidence to support the claims. Although the mechanisms by which micro-organisms are inhibited are not known, an appreciation of how infection may be prevented through the topical application of honey is forming. It is hoped that further research will advance our understanding
of this process.
After reading this article you will be able to:
List the main components in honey.
Understand that three types of honey can be recognised on the basis of a laboratory test.
Explain which infective agents are inhibited by honey.
Describe selected clinical studies that demonstrate the antimicrobial properties of honey.
Understand a possible mechanism of action for honey.
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