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CLINICAL MICROBIOLOGY REVIEWS, Jan. 2006, p. 50–62 0893-8512/06/$08.00ϩ0 doi:10.1128/CMR.19.1.50–62.2006Copyright 2006, American Society for Microbiology. All Rights Reserved.
Melaleuca alternifolia (Tea Tree) Oil: a Review of Antimicrobial C. F. Carson,1 K. A. Hammer,1 and T. V. Riley1,2* Discipline of Microbiology, School of Biomedical and Chemical Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia 6009,1 and Division of Microbiology and Infectious Diseases, Western Australian Centre for Pathology and Medical Research, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009,2 Australia INTRODUCTION .50
COMPOSITION AND CHEMISTRY .50
PROVENANCE AND NOMENCLATURE .51
COMMERCIAL PRODUCTION .52
Oil Extraction.52
ANTIMICROBIAL ACTIVITY IN VITRO .52
Antibacterial Activity.52
Mechanism of antibacterial action.53
Antifungal Activity .54
Mechanism of antifungal action .54
Antiviral Activity .55
Antiprotozoal Activity.55
Antimicrobial Components of TTO.55
Resistance to TTO .55
CLINICAL EFFICACY.56
ANTI-INFLAMMATORY ACTIVITY.58
SAFETY AND TOXICITY .59
Oral Toxicity.59
Dermal Toxicity.59
PRODUCT FORMULATION ISSUES .59
CONCLUSIONS .59
ACKNOWLEDGMENTS .60
REFERENCES .60
INTRODUCTION
and 48 (142) components. The seminal paper by Brophy andcolleagues (25) examined over 800 TTO samples by gas chro- Many complementary and alternative medicines have en- matography and gas chromatography-mass spectrometry and joyed increased popularity in recent decades. Efforts to vali- reported approximately 100 components and their ranges of date their use have seen their putative therapeutic properties come under increasing scrutiny in vitro and, in some cases, in TTO has a relative density of 0.885 to 0.906 (89), is only vivo. One such product is tea tree oil (TTO), the volatile essential sparingly soluble in water, and is miscible with nonpolar sol- oil derived mainly from the Australian native plant Melaleuca vents. Some of the chemical and physical properties of TTO alternifolia. Employed largely for its antimicrobial properties, TTO is incorporated as the active ingredient in many topical Given the scope for batch-to-batch variation, it is fortunate formulations used to treat cutaneous infections. It is widely avail- that the composition of oil sold as TTO is regulated by an able over the counter in Australia, Europe, and North America international standard for “Oil of Melaleuca—terpinen-4-ol and is marketed as a remedy for various ailments.
type,” which sets maxima and/or minima for 14 components ofthe oil (89) (Table 1). Notably, the standard does not stipulate COMPOSITION AND CHEMISTRY
the species of Melaleuca from which the TTO must be sourced.
TTO is composed of terpene hydrocarbons, mainly mono- Instead, it sets out physical and chemical criteria for the de- terpenes, sesquiterpenes, and their associated alcohols. Ter- sired chemotype. Six varieties, or chemotypes, of M. alternifolia penes are volatile, aromatic hydrocarbons and may be consid- have been described, each producing oil with a distinct chem- ered polymers of isoprene, which has the formula C H . Early ical composition. These include a terpinen-4-ol chemotype, a reports on the composition of TTO described 12 (65), 21 (3), terpinolene chemotype, and four 1,8-cineole chemotypes (83).
The terpinen-4-ol chemotype typically contains levels of terpi-nen-4-ol of between 30 to 40% (83) and is the chemotype used * Corresponding author. Mailing address: Microbiology and Immu- in commercial TTO production. Despite the inherent variabil- nology (M502), School of Biomedical and Chemical Sciences, The ity of commercial TTO, no obvious differences in its bioactivity University of Western Australia, 35 Stirling Hwy, Crawley, Western either in vitro or in vivo have been noted so far. The suggestion Australia 6009, Australia. Phone: 61 8 9346 3690. Fax: 61 8 9346 2912.
E-mail: triley@cyllene.uwa.edu.au.
that oil from a particular M. alternifolia clone possesses en- ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL TABLE 1. Composition of M. alternifolia (tea tree) oil and mucous membrane irritant, fuelling efforts to minimize itslevel in TTO. This reputation was based on historical anec- dotal evidence and uncorroborated statements (20, 55, 98, 126, 153, 156–158), and repetition of this suggestion appears to have consolidated the myth. Recent data, as discussed later in this review, do not indicate that 1,8-cineole is an irritant. Al- though minimization of 1,8-cineole content on the basis of reducing adverse reactions is not warranted, it remains an important consideration since 1,8-cineole levels are usually inversely proportional to the levels of terpinen-4-ol (25), one of the main antimicrobial components of TTO (36, 48, 71, 126).
The composition of TTO may change considerably during stor- age, with ␳-cymene levels increasing and ␣- and ␥-terpinene levels declining (25). Light, heat, exposure to air, and moisture all affect oil stability, and TTO should be stored in dark, cool, dry condi- tions, preferably in a vessel that contains little air.
a IOS 4730, International Organization for Standardization standard no. 4730 PROVENANCE AND NOMENCLATURE
c No upper limit is set, although 48% has been proposed.
d No lower limit is set.
The provenance of TTO is not always clear from its common name or those of its sources. It is known by a number ofsynonyms, including “melaleuca oil” and “ti tree oil,” the latter hanced microbicidal activity has been made (106), but the being a Maori and Samoan common name for plants in the genus Cordyline (155). Even the term “melaleuca oil” is poten- The components specified by the international standard were tially ambiguous, since several chemically distinct oils are dis- selected for a variety of reasons, including provenance verifi- tilled from other Melaleuca species, such as cajuput oil (also cation and biological activity. For example, with provenance, cajeput or cajaput) from M. cajuputi and niaouli oil from M. the inclusion of the minor components sabinene, globulol, and quinquenervia (often misidentified as M. viridiflora) (51, 98).
viridiflorol is potentially helpful, since it may render the for- However, the term has been adopted by the Australian Ther- mulation of artificial oil from individual components difficult apeutic Goods Administration as the official name for TTO.
or economically untenable. With biological activity, the anti- The use of common plant names further confounds the issue.
microbial activity of TTO is attributed mainly to terpinen-4-ol, In Australia, “tea trees” are also known as “paperbark trees,” a major component of the oil. Consequently, to optimize an- and collectively these terms may refer to species in the Melaleuca timicrobial activity, a lower limit of 30% and no upper limit or Leptospermum genera, of which there are several hundred. For were set for terpinen-4-ol content. Conversely, an upper limit instance, common names for M. cajuputi include “swamp tea of 15% and no lower limit were set for 1,8-cineole, although tree” and “paperbark tea tree,” while those for M. quinquenervia the rationale for this may not have been entirely sound. For include “broad-leaved tea tree” and “broad-leaved paperbark” many years cineole was erroneously considered to be a skin (98). Many Leptospermum species are cultivated as ornamentalplants and are often mistakenly identified as the source of TTO.
In addition, the essential oils kanuka and manuka, derived fromthe New Zealand plants Kunzea ericoides and Leptospermum sco- parium, respectively, are referred to as New Zealand TTOs (42) although they are very different in composition from Australian TTO (125). In this review article, the term TTO will refer only to As explained above, the international standard for TTO does not specify which Melaleuca species must be used to produce oil. Rather it sets out the requirements for an oil chemotype. Oils that meet the requirements of the standard have been distilled from Melaleuca species other than M. al- ternifolia, including M. dissitiflora, M. linariifolia, and M. unci- nata (113). However, in practice, commercial TTO is produced from M. alternifolia (Maiden and Betche) Cheel. The Melaleuca genus belongs to the Myrtaceae family and contains approximately 230 species, almost all of which are native to Australia (51). When left to grow naturally, M. alternifolia grows to a tree reaching heights of approximately 5 to 8 meters (45). Trees older than 3 years typically flower in October and b Kow, octanol-water partition coefficient, from reference 62.
November (12, 98), and flowers are produced in loose, white to creamy colored terminal spikes, which can give trees a “fluffy” were inhaled to treat coughs and colds or were sprinkled on wounds, after which a poultice was applied (135). In addition,tea tree leaves were soaked to make an infusion to treat sorethroats or skin ailments (101, 135). The oral history of Austra- COMMERCIAL PRODUCTION
lian Aborigines also tells of healing lakes, which were lagoons The commercial TTO industry was born after the medicinal into which M. alternifolia leaves had fallen and decayed over properties of the oil were first reported by Penfold in the 1920s time (3). Use of the oil itself, as opposed to the unextracted (121–124) as part of a larger survey into Australian essential plant material, did not become common practice until Penfold oils with economic potential. During that nascent stage, TTO published the first reports of its antimicrobial activity in a was produced from natural bush stands of plants, ostensibly M. series of papers in the 1920s and 1930s. In evaluating the alternifolia, that produced oil with the appropriate chemotype.
antimicrobial activity of M. alternifolia oil and other oils, he The native habitat of M. alternifolia is low-lying, swampy, sub- made comparisons with the disinfectant carbolic acid or phe- tropical, coastal ground around the Clarence and Richmond nol, the gold standard of the day, in a test known as the Rivers in northeastern New South Wales and southern Rideal-Walker (RW) coefficient. The activity of TTO was com- Queensland (142), and, unlike several other Melaleuca species, pared directly with that of phenol and rated as 11 times more it does not occur naturally outside Australia. The plant mate- active (121). The RW coefficients of several TTO components rial was hand cut and often distilled on the spot in makeshift, were also reported, including 3.5 for cineole and 8 for cymene mobile, wood-fired bush stills. The industry continued in this (122), 13 for linalool (123), and 13.5 for terpinen-4-ol and 16 fashion for several decades. Legend has it that the oil was for terpineol (121). As a result, TTO was promoted as a ther- considered so important for its medicinal uses that Australian apeutic agent (5–7). These publications, as well as several soldiers were supplied oil as part of their military kits during others (60, 70, 84, 102, 120, 124, 152), describe a range of World War II and that bush cutters were exempt from national medicinal uses for TTO. However, in terms of the evidence service (35). However, no evidence to corroborate these ac- they provide for the medicinal properties of TTO, they are of counts could be found (A.-M. Conde and M. Pollard [Austra- limited value, since by the standards of today the data they lian War Memorial, Canberra, Australia], personal communi- provide would be considered mostly anecdotal.
cation). Production ebbed after World War II as demand for In contrast, contemporary data clearly show that the broad- the oil declined, presumably due to the development of effec- spectrum activity of TTO includes antibacterial, antifungal, tive antibiotics and the waning image of natural products. In- antiviral, and antiprotozoal activities. Not all of the activity has terest in the oil was rekindled in the 1970s as part of the been characterized well in vitro, and in the few cases where general renaissance of interest in natural products. Commer- clinical work has been done, data are promising but thus far cial plantations were established in the 1970s and 1980s, allow- ing the industry to mechanize and produce large quantities of Evaluation of the antimicrobial activity of TTO has been a consistent product (25, 93). Today there are plantations in impeded by its physical properties; TTO and its components Western Australia, Queensland, and New South Wales, al- are only sparingly soluble in water (Table 2), and this limits though the majority are in New South Wales around the Lis- their miscibility in test media. Different strategies have been more region. Typically, plantations are established from seed- used to counteract this problem, with the addition of surfac- lings sowed and raised in greenhouses prior to being planted tants to broth and agar test media being used most widely (11, out in the field at high density. The time to first harvest varies 13, 15, 31, 32, 61). Dispersion of TTO in liquid media usually from 1 to 3 years, depending on the climate and rate of plant results in a turbid suspension that makes determination of end growth. Harvesting is by a coppicing process in which the points in susceptibility tests difficult. Occasionally dyes have whole plant is cut off close to ground level and chipped into been used as visual indicators of the MIC, with mixed success smaller fragments prior to oil extraction.
Oil Extraction
Antibacterial Activity
TTO is produced by steam distillation of the leaves and terminal branches of M. alternifolia. Once condensed, the clear The few reports of the antibacterial activity of TTO appear- to pale yellow oil is separated from the aqueous distillate. The ing in the literature from the 1940s to the 1980s (11, 15, 100, yield of oil is typically 1 to 2% of wet plant material weight.
153) have been reviewed elsewhere previously (35). From the Alternative extraction methods such as the use of microwave early 1990s onwards, many reports describing the antimicrobial technology have been considered, but none has been utilized activity of TTO appeared in the scientific literature. Although there was still a degree of discrepancy between the methodsused in the different studies, the MICs reported were oftenrelatively similar. A broad range of bacteria have now been ANTIMICROBIAL ACTIVITY IN VITRO
tested for their susceptibilities to TTO, and some of the pub- Of all of the properties claimed for TTO, its antimicrobial lished susceptibility data are summarized in Table 3. While activity has received the most attention. The earliest reported most bacteria are susceptible to TTO at concentrations of use of the M. alternifolia plant that presumably exploited this 1.0% or less, MICs in excess of 2% have been reported for property was the traditional use by the Bundjalung Aborigines organisms such as commensal skin staphylococci and micro- of northern New South Wales. Crushed leaves of “tea trees” cocci, Enterococcus faecalis, and Pseudomonas aeruginosa (13, ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL TABLE 3. Susceptibility data for bacteria tested against Mechanism of antibacterial action. The mechanism of action
of TTO against bacteria has now been partly elucidated. Prior to the availability of data, assumptions about its mechanism of ac- tion were made on the basis of its hydrocarbon structure and attendant lipophilicity. Since hydrocarbons partition preferen- tially into biological membranes and disrupt their vital functions (138), TTO and its components were also presumed to behave in this manner. This premise is further supported by data showing that TTO permeabilizes model liposomal systems (49). In previ- ous work with hydrocarbons not found in TTO (90, 146a) and with terpenes found at low concentrations in TTO (4, 146), lysis and the loss of membrane integrity and function manifested by the leakage of ions and the inhibition of respiration were dem- onstrated. Treatment of S. aureus with TTO resulted in the leak- age of potassium ions (49, 69) and 260-nm-light-absorbing mate- rials (34) and inhibited respiration (49). Treatment with TTO also sensitized S. aureus cells to sodium chloride (34) and produced morphological changes apparent under electron microscopy (127). However, no significant lysis of whole cells was observed spectrophotometrically (34) or by electron microscopy (127). Fur- thermore, no cytoplasmic membrane damage could be detected using the lactate dehydrogenase release assay (127), and only modest uptake of propidium iodide was observed (50) after In E. coli, detrimental effects on potassium homeostasis (47), glucose-dependent respiration (47), morphology (67), and abil- ity to exclude propidium iodide (50) have been observed. A modest loss of 280-nm-light-absorbing material has also been reported (50). In contrast to the absence of whole-cell lysis seen in S. aureus treated with TTO, lysis occurs in E. coli treated with TTO (67), and this effect is exacerbated by co-treatment with EDTA (C. Carson, unpublished data). All ofthese effects confirm that TTO compromises the structural and 79). TTO is for the most part bactericidal in nature, although functional integrity of bacterial membranes.
it may be bacteriostatic at lower concentrations.
The loss of viability, inhibition of glucose-dependent respi- The activity of TTO against antibiotic-resistant bacteria has ration, and induction of lysis seen after TTO treatment all attracted considerable interest, with methicillin-resistant occur to a greater degree with organisms in the exponential Staphylococcus aureus (MRSA) receiving the most attention rather than the stationary phase of growth (67; S. D. Cox, J. L.
thus far. Since the potential to use TTO against MRSA was Markham, C. M. Mann, S. G. Wyllie, J. E. Gustafson, and J. R.
first hypothesized (153), several groups have evaluated the Warmington, Abstr. 28th Int. Symp. Essential Oils, p. 201–213, activity of TTO against MRSA, beginning with Carson et al.
1997). The increased vulnerability of actively growing cells was (31), who examined 64 MRSA isolates from Australia and the also apparent in the greater degree of morphological changes United Kingdom, including 33 mupirocin-resistant isolates.
seen in these cells by electron microscopy (S. D. Cox et al.
The MICs and minimal bactericidal concentrations (MBCs) Abstr. 28th Int. Symp. Essential Oils, p. 201–213). The differ- for the Australian isolates were 0.25% and 0.5%, respectively, ences in susceptibility of bacteria in different phases of growth while those for the United Kingdom isolates were 0.312% and suggest that targets other than the cell membrane may be 0.625%, respectively. Subsequent reports on the susceptibility of MRSA to TTO have similarly not shown great differences com- When the effects of terpinen-4-ol, ␣-terpineol, and 1,8-cin- pared to antibiotic-sensitive organisms (39, 58, 68, 106, 115).
eole on S. aureus were examined, none was found to induce For the most part, antibacterial activity has been determined autolysis but all were found to cause the leakage of 260-nm- using agar or broth dilution methods. However, activity has light-absorbing material and to render cells susceptible to so- also been demonstrated using time-kill assays (34, 48, 80, 106), dium chloride (34). Interestingly, the greatest effects were seen suspension tests (107), and “ex vivo”-excised human skin (108).
with 1,8-cineole, a component often considered to have mar- In addition, vaporized TTO can inhibit bacteria, including ginal antimicrobial activity. This raises the possibility that while Mycobacterium avium ATCC 4676 (105), Escherichia coli, Hae- cineole may not be one of the primary antimicrobial compo- mophilus influenzae, Streptococcus pyogenes, and Streptococcus nents, it may permeabilize bacterial membranes and facilitate pneumoniae (85). There are anecdotal reports of aerosolized the entry of other, more active components. Little work on the TTO reducing hospital-acquired infections (L. Bowden, Abstr.
effects of TTO components on cell morphology has been re- Infect. Control Nurses Assoc. Annu. Infect. Control Conf., p.
ported. Electron microscopy of terpinen-4-ol-treated S. aureus cells (34) revealed lesions similar to those seen after TTO TABLE 4. Susceptibility data for fungi tested against test methods differ, MICs generally range between 0.03 and 0.5%, and fungicidal concentrations generally range from 0.12 to 2%. The notable exception is Aspergillus niger, with minimal fungicidal concentrations (MFCs) of as high as 8% reported for this organism (74). However, these assays were performed with fungal conidia, which are known to be relatively impervi- ous to chemical agents. Subsequent assays have shown that germinated conidia are significantly more susceptible to TTO than nongerminated conidia (74), suggesting that the intact conidial wall confers considerable protection. TTO vapors have also been demonstrated to inhibit fungal growth (86, 87) Mechanism of antifungal action. Studies investigating the
mechanism(s) of antifungal action have focused almost exclu- sively on C. albicans. Similar to results found for bacteria, TTO also alters the permeability of C. albicans cells. The treatment of C. albicans with 0.25% TTO resulted in the uptake of pro- pidium iodide after 30 min (50), and after 6 h significant staining with methylene blue and loss of 260-nm-light-absorb- ing materials had occurred (72). TTO also alters the perme- ability of Candida glabrata (72). Further research demonstrat- ing that the membrane fluidity of C. albicans cells treated with 0.25% TTO is significantly increased confirms that the oil sub- stantially alters the membrane properties of C. albicans (72).
TTO also inhibits respiration in C. albicans in a dose-depen- dent manner (49). Respiration was inhibited by approximately 95% after treatment with 1.0% TTO and by approximately 40% after treatment with 0.25% TTO. The respiration rate of Fusarium solani is inhibited by 50% at a concentration of 0.023% TTO (88). TTO also inhibits glucose-induced medium acidification by C. albicans, C. glabrata, and Saccharomycescerevisiae (72). Medium acidification occurs largely by the ex-pulsion of protons by the plasma membrane ATPase, which is treatment (127), including mesosome-like structures.
fuelled by ATP derived from the mitochondria. The inhibition Mechanism of action studies analogous to those described of this function suggests that the plasma and/or mitochondrial above have not been conducted with P. aeruginosa. Instead, membranes have been adversely affected. These results are research has concentrated on how this organism is able to consistent with a proposed mechanism of antifungal action tolerate higher concentrations of TTO and/or components.
whereby TTO causes changes or damage to the functioning of These studies have indicated that tolerance is associated with fungal membranes. This proposed mechanism is further sup- the outer membrane by showing that when P. aeruginosa cells ported by work showing that the terpene eugenol inhibits mi- are pretreated with the outer membrane permeabilizer poly- tochondrial respiration and energy production (46).
myxin B nonapeptide or EDTA, cells become more susceptible Additional studies have shown that when cells of C. albicans to the bactericidal effects of TTO, terpinen-4-ol, or ␥-terpinene are treated with diethylstilbestrol to inhibit the plasma mem- brane ATPase, they then have a much greater susceptibility to In summary, the loss of intracellular material, inability to TTO than do control cells (72), suggesting that the plasma maintain homeostasis, and inhibition of respiration after treat- membrane ATPase has a role in protecting cells against the ment with TTO and/or components are consistent with a destabilizing or lethal effects of TTO.
mechanism of action involving the loss of membrane integrity TTO inhibits the formation of germ tubes, or mycelial con- version, in C. albicans (52, 78). Two studies have shown thatgerm tube formation was completely inhibited in the presenceof 0.25 and 0.125% TTO, and it was further observed that Antifungal Activity
treatment with 0.125% TTO resulted in a trend of blastospores Comprehensive investigations of the susceptibility of fungi changing from single or singly budding morphologies to mul- to TTO have only recently been completed. Prior to this, data tiply budding morphologies over the 4-h test period (78).
were somewhat piecemeal and fragmentary. Early data were These cells were actively growing but were not forming germ also largely limited to Candida albicans, which was a commonly tubes, implying that morphogenesis is specifically inhibited, chosen model test organism. Data now show that a range of rather than all growth being inhibited. Interestingly, the inhi- yeasts, dermatophytes, and other filamentous fungi are suscep- bition of germ tube formation was shown to be reversible, since tible to TTO (14, 42, 52, 61, 116, 128, 140) (Table 4). Although cells were able to form germ tubes after the removal of the ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL TTO (78). However, there was a delay in germ tube formation, indications from RW coefficients were that much of the activity indicating that TTO causes a postantifungal effect.
could be attributed to terpinen-4-ol and ␣-terpineol (121).
Data available today confirm that these two components con-tribute substantially to the oil’s antibacterial and antifungal Antiviral Activity
activities, with MICs and MBCs or MFCs that are generally the The antiviral activity of TTO was first shown using tobacco same as, or slightly lower than values obtained for TTO (36, 42, mosaic virus and tobacco plants (18). In field trials with Nico- 48, 71, 117, 126). However, ␣-terpineol does not represent a tiniana glutinosa, plants were sprayed with 100, 250, or 500 ppm significant proportion of the oil. Additional components with TTO or control solutions and were then experimentally in- MICs similar to or lower than those of TTO include ␣-pinene, fected with tobacco mosaic virus. After 10 days, there were ␤-pinene, and linalool (36, 71), but, similar to the case for significantly fewer lesions per square centimeter of leaf in ␣-terpineol, these components are present in only relatively plants treated with TTO than in controls (18). Next, Schnitzler low amounts. Of the remaining components tested, it seems et al. (132) examined the activity of TTO and eucalyptus oil that most possess at least some degree of antimicrobial activity against herpes simplex virus (HSV). The effects of TTO were (36, 71, 126), and this is thought to correlate with the presence investigated by incubating viruses with various concentrations of functional groups, such as alcohols, and the solubility of of TTO and then using these treated viruses to infect cell the component in biological membranes (63, 138). While monolayers. After 4 days, the numbers of plaques formed by some TTO components may be considered less active, none TTO-treated virus and untreated control virus were deter- can be considered inactive. Furthermore, methodological is- mined and compared. The concentration of TTO inhibiting sues have been demonstrated to have a significant influence on 50% of plaque formation was 0.0009% for HSV type 1 (HSV-1) and 0.0008% for HSV-2, relative to controls. These The possibility that components in TTO may have synergis- studies also showed that at the higher concentration of 0.003%, tic or antagonistic interactions has been explored in vitro (48), TTO reduced HSV-1 titers by 98.2% and HSV-2 titers by but no significant relationships were found. The possibility that 93.0%. In addition, by applying TTO at different stages in the TTO may act synergistically with other essential oils, such as virus replicative cycle, TTO was shown to have the greatest lavender (38), and other essential oil components, such as effect on free virus (prior to infection of cells), although when ␤-triketones from manuka oil (43, 44), has also been investi- TTO was applied during the adsorption period, a slight reduc- gated. Given the numerous components of TTO, the scope for tion in plaque formation was also seen (132). Another study such effects is enormous, and much more work is required to evaluated the activities of 12 essential oils, including TTO, for activity against HSV-1 in Vero cells (110). Again, TTO wasfound to exert most of its antiviral activity on free virus, with1% oil inhibiting plaque formation completely and 0.1% TTO Resistance to TTO
reducing plaque formation by approximately 10%. Pretreat-ment of the Vero cells prior to virus addition or posttreatment The question of whether true resistance to TTO can be with 0.1% TTO after viral absorption did not significantly alter induced in vitro or may occur spontaneously in vivo has not been examined systematically. Clinical resistance to TTO has Some activity against bacteriophages has also been reported, not been reported, despite the medicinal use of the oil in with exposure to 50% TTO at 4°C for 24 h reducing the Australia since the 1920s. There has been one short report of number of SA and T7 plaques formed on lawns of S. aureus induced in vitro resistance to TTO in S. aureus (114). Stepwise and E. coli, respectively (41).
exposure of five MRSA isolates to increasing concentrations of The results of these studies indicate that TTO may act TTO yielded three isolates with TTO MICs of 1% and one against enveloped and nonenveloped viruses, although the isolate each with TTO MICs of 2% and 16%, respectively. All range of viruses tested to date is very limited.
isolates showed initial MICs of 0.25%. There has also been onereport suggesting that E. coli strains harboring mutations in themultiple antibiotic resistance (mar) operon, so-called Mar mu- Antiprotozoal Activity
tants, may exhibit decreased susceptibility to TTO (66). Minor Two publications show that TTO has antiprotozoal activity.
changes in TTO and ␣-terpineol susceptibilities have also been TTO caused a 50% reduction in growth (compared to con- seen in S. aureus isolates with reduced susceptibility to house- trols) of the protozoa Leishmania major and Trypanosoma hold cleaners (53). However, in these last two studies the brucei at concentrations of 403 mg/ml and 0.5 mg/ml, respec- changes in susceptibility were marginal and do not represent tively (109). Further investigation showed that terpinen-4-ol strong evidence of resistance (53, 66). With regard to fungi, an contributed significantly to this activity. In another study, TTO attempt to induce resistance to TTO in two clinical isolates of at 300 mg/ml killed all cells of Trichomonas vaginalis (151).
Candida albicans was largely unsuccessful, with isolates failing There is also anecdotal in vivo evidence that TTO may be to grow in 2% (vol/vol) TTO after serial passage in increasing effective in treating Trichomonas vaginalis infections (120).
Resistance to conventional antibiotics has not been demon- strated to influence susceptibility to TTO, suggesting that Antimicrobial Components of TTO
cross-resistance does not occur. For example, antimicrobial- Considerable attention has been paid to which components resistant isolates of S. aureus (31, 58), C. albicans and C. gla- of TTO are responsible for the antimicrobial activity. Early brata (148), P. aeruginosa (106), and Enterococcus faecium (106, 115) have in vitro susceptibilities to TTO that are similar some evidence preliminary suggesting that TTO reduces the levels of several compounds associated with halitosis (144).
Overall, these studies provide little evidence to suggest that Two studies have assessed the efficacy of TTO for the erad- resistance to TTO will occur, either in vitro or in vivo, although ication of MRSA carriage. The effectiveness of a 4% TTO minimal data are available. It is likely that the multicomponent nasal ointment and a 5% TTO body wash was compared to nature of TTO may reduce the potential for resistance to occur that of conventional treatment with mupirocin nasal ointment spontaneously, since multiple simultaneous mutations may be and Triclosan body wash in a small pilot study (28). Of the 15 required to overcome all of the antimicrobial actions of each of patients receiving conventional treatment, 2 were cleared and the components. Furthermore, since TTO is known to affect 8 remained colonized at the end of therapy; in the TTO group cell membranes, it presumably affects multiple properties and of 15, 5 were cleared and 3 remained colonized. The remainder functions associated with the cell membrane, similar to the of patients did not complete therapy. Differences in clearance case for membrane-active biocides. This means that numerous rates were not statistically significant, most likely due to the targets would have to adapt to overcome the effects of the oil.
low patient numbers. Stronger evidence for the efficacy of TTO Issues of potential resistance are important if TTO is to be in decolonizing MRSA carriage comes from a recent trial in used more widely, particularly against antibiotic-resistant or- which 236 patients were randomized to receive standard or TTO treatment regimens (56). The standard regimen consistedof 2% mupirocin nasal ointment applied three times a day, 4%chlorhexidine gluconate soap applied at least once a day, and CLINICAL EFFICACY
1% silver sulfadiazine cream applied to skin lesions, wounds,and leg ulcers once a day, all for 5 days. The TTO regimen In parallel with the characterization of the in vitro antimi- consisted of 10% TTO nasal cream applied three times a day, crobial activity of TTO, the clinical efficacy of the oil has also 5% TTO body wash applied at least once daily and 10% TTO been the subject of investigation. Early clinical studies attempt- cream applied to skin lesions, wounds, and leg ulcers once a ing to characterize the clinical efficacy of TTO (60, 120, 152) day, all for 5 days. The 10% TTO cream was allowed to be used are not considered scientifically valid by today’s standards and as an alternative to the body wash. Follow-up swabs were taken will therefore not be discussed further. Data from some of the at 2 and 14 days posttreatment, with the exception of 12 pa- more recent clinical investigations are summarized in Table 5.
tients who were lost to follow-up. Evaluation of the remaining One of the first rigorous clinical studies assessed the efficacy 224 patients showed no significant differences between treat- of 5% TTO in the treatment of acne by comparing it to 5% ment regimens, with 49% of patients receiving standard ther- benzoyl peroxide (BP) (14). The study found that both treat- apy cleared versus 41% of patients in the TTO group.
ments reduced the numbers of inflamed lesions, although BP For many years there has been considerable interest in the performed significantly better than TTO. The BP group possibility of using TTO in handwash formulations for use in showed significantly less oiliness than the TTO group, whereas hospital or health care settings. It is well known that hand- the TTO group showed significantly less scaling, pruritis, and washing is an effective infection control measure and that lack dryness. Significantly fewer overall side effects were reported of compliance is related to increased rates of nosocomial in- by the TTO group (27 of 61 patients) than by the BP group (50 fections. The benefits of using TTO in a handwash formulation include its antiseptic effects and increased handwashing com- The efficacy of TTO in dental applications has been as- pliance. A recent handwash study using volunteers showed that sessed. An evaluation of the effect of a 0.2% TTO mouthwash either a product containing 5% TTO and 10% alcohol or a and two other active agents on the oral flora of 40 volunteers solution of 5% TTO in water performed significantly better suggested that TTO used once daily for 7 days could reduce the than soft soap, whereas a handwash product containing 5% number of mutans streptococci and the total number of oral bacteria, compared to placebo treatment. The data also indi- Occasional case reports of the use of TTO have also been cated that these reductions were maintained for 2 weeks after published. In one, a woman self-treated successfully with a the use of mouthwash ceased (64). In another study, compar- 5-day course of TTO pessaries after having been clinically ison of mouthwashes containing either approximately 0.34% diagnosed with bacterial vaginosis (19). In a second, a combi- TTO, 0.1% chlorhexidine, or placebo on plaque formation and nation of plant extracts of which TTO was a major component vitality, using eight volunteers (9), showed that after TTO was inserted percutaneously into bone to treat an intractable treatment, both plaque index and vitality did not differ from MRSA infection of the lower tibia, which subsequently resolved those of subjects receiving placebo mouthwash on any day, (136). This same essential oil solution has now been shown to aid whereas the results for the chlorhexidine mouthwash group in the healing of malodorous malignant ulcers (154).
differed significantly from those for the placebo group on all With regard to fungal infections, TTO has been clinically days (9). Lastly, a study comparing a 2.5% TTO gel, a 0.2% evaluated for the treatment of onychomycosis (26, 143), tinea chlorhexidine gel, and a placebo gel found that although the pedis (131, 145), dandruff (130), and oral candidiasis (92, 149).
TTO group had significantly reduced gingival index and pap- Although much has been made of the potential for TTO to be illary bleeding index scores, their plaque scores were actually used in the treatment of vaginal candidiasis, no clinical data increased (139). These studies indicate that although TTO may have been published. However, results from an animal (rat) cause decreases in the levels of oral bacteria, this does not model of vaginal candidiasis support the use of TTO for the necessarily equate to reduced plaque levels. However, TTO may have a role in the treatment of gingivitis, and there is also In the first of the onychomycosis trials (26), 60% of patients ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL treated with TTO and 61% of patients treated with 1% clo- one had deteriorated. Of patients receiving the alcohol-free trimazole had full or partial resolution. There were no statis- solution, five were cured, two improved, two were unchanged, tically significant differences between the two treatment groups and one had deteriorated. Three patients were lost to fol- for any parameter. The second onychomycosis trial (143) com- low-up and were considered nonresponders.
pared two creams, one containing 5% TTO alone and the Support for TTO possessing in vivo antiviral activity comes other containing 5% TTO and 2% butenafine, both applied from a pilot study investigating the treatment of recurrent three times daily for 8 weeks. The overall cure rate was 0% for herpes labialis (cold sores) with a 6% TTO gel or a placebo gel patients treated with 5% TTO alone, compared to 80% for (30). Comparison of the patient groups (each containing nine patients treated with both butenafine and TTO. Unfortunately, evaluable patients) at the end of the study showed that reepi- butenafine alone was not evaluated. The observation that TTO thelialization after treatment occurred after 9 days for the may be useful adjunct therapy for onychomycosis has been TTO group and after 12.5 days for the placebo group. Other made by Klimmek et al. (95). However, onychomycosis is con- measures, such as duration of virus positivity by culture or sidered to be largely unresponsive to topical treatment of any PCR, viral titers, and time to crust formation, were not signif- kind, and a high rate of cure should therefore not be expected.
icantly different, possibly due to small patient numbers. Inter- The effectiveness of TTO in treating tinea pedis has been estingly, when TTO was evaluated for its protective efficacy in evaluated in two trials. In the first trial, patients were treated an in vivo mouse model of genital HSV type 2 infection, it did with 10% TTO in sorbolene, 1% tolnaftate, or placebo (sor- not perform well (21). In contrast, the oil component 1,8-cineole bolene) (145). At completion of treatment, patients treated performed well, protecting 7 of 16 animals from disease.
with TTO had mycological cure and clinical improvement rates There are a number of limitations to the clinical studies of 30% and 65%, respectively. This compares to mycological described above. Several had low numbers of participants, cure rates of 21% in patients receiving placebo and 85% in meaning that statistical analyses could not be performed or patients receiving tolnaftate. Similarly, clinical improvement differences did not reach significance. Many studies had am- was seen in 41% of patients receiving placebo and 68% of biguous and/or equivocal outcomes. Of those studies with patients receiving tolnaftate. In a second tinea trial, the efficacy larger numbers of patients, few reported 95% confidence in- of solutions of 25% and 50% TTO in ethanol and polyethylene tervals or relative risk values. While most studies compared the glycol was compared to treatment with placebo (vehicle) (131).
efficacy of TTO to a placebo, many did not compare TTO to a Marked clinical responses were seen in 72% and 68% of pa- conventional therapy or treatment regimen, again limiting the tients in the 25% and 50% TTO treatment groups, respec- conclusions that could be drawn about efficacy. Several publi- tively, compared to 39% of patients in the placebo group.
cations noted that patient blinding was compromised or im- Similarly, there were mycological cures of 55% and 64% in the practicable due to the characteristic odor of TTO (14, 30, 130, 25% and 50% TTO treatment groups, respectively, compared 131). These studies, while perhaps conducted as double to 31% in the placebo group. Dermatitis occurred in one pa- blinded, are technically only single blinded, which is not ideal.
tient in the 25% TTO group and in three patients in the 50% Perhaps most importantly, few studies have been replicated TTO group. This led to the recommendation that 25% TTO be independently. Therefore, although some of these data indi- considered an alternative treatment for tinea, since it was as- cate that TTO has potential as a therapeutic agent, confirma- sociated with fewer adverse reactions than but was just as tory studies are required. In addition, factors such as the final effective as 50% TTO. These studies highlight the importance TTO concentration, product formulation, and length and fre- of considering the formulation of the TTO product when con- quency of treatment undoubtedly influence clinical efficacy, ducting in vivo work, since it is likely that the sorbolene vehicle and these factors must be considered in future studies. The used in the first tinea trial may have significantly compromised cost-effectiveness of any potential TTO treatments must also be considered. For example, TTO therapy may offer no cost advan- The evaluation of a 5% TTO shampoo for mild to moderate tage over the azoles in the treatment of tinea but is probably more dandruff demonstrated statistically significant improvements in economical than treatment with the allylamines.
the investigator-assessed whole scalp lesion score, total area ofinvolvement score, and total severity score, as well as in the ANTI-INFLAMMATORY ACTIVITY
patient-assessed itchiness and greasiness scores, compared toplacebo. Overall, the 5% TTO was well tolerated and appeared Numerous recent studies now support the anecdotal evi- to be effective in the treatment of mild to moderate dandruff.
dence attributing anti-inflammatory activity to TTO. In vitro TTO has been evaluated as a mouthwash in the treatment of work over the last decade has demonstrated that TTO affects oropharyngeal candidiasis. In a case series, 13 human immu- a range of immune responses, both in vitro and in vivo. For nodeficiency virus-positive patients who had already failed example, the water-soluble components of TTO can inhibit the treatment with a 14-day course of oral fluconazole were lipopolysaccharide-induced production of the inflammatory treated with an alcohol-based TTO solution for up to 28 days mediators tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (92). After treatment, of the 12 evaluable patients, 2 were (IL-1␤), and IL-10 by human peripheral blood monocytes by cured, 6 were improved, 4 were unchanged, and 1 had deteri- approximately 50% and that of prostaglandin E by about 30% orated. Overall, eight patients had a clinical response and after 40 h (81). Further examination of the water-soluble frac- seven had a mycological response. In subsequent work the tion of TTO identified terpinen-4-ol, ␣-terpineol, and 1,8-cin- same TTO solution was compared with an alcohol-free TTO eole as the main components, but of these, only terpinen-4-ol solution (149). Of patients receiving the alcohol-based solu- was able to diminish the production of TNF-␣, IL-1␤, IL-8, tion, two were cured, six improved, four were unchanged, and IL-10, and prostaglandin E by lipopolysaccharide-activated ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL monocytes. The water-soluble fraction of TTO, terpinen-4-ol, Dermal Toxicity
and ␣-terpineol also suppressed superoxide production byagonist-stimulated monocytes but not neutrophils (22). In con- TTO can cause both irritant and allergic reactions. A mean trast, similar work found that TTO decreases the production of irritancy score of 0.25 has been found for neat TTO, based on reactive oxygen species by both stimulated neutrophils and patch testing results for 311 volunteers (10). Another study, in monocytes and that it also stimulates the production of reac- which 217 patients from a dermatology clinic were patch tested tive oxygen species by nonprimed neutrophils and monocytes with 10% TTO, found no irritant reactions (150). Since irritant (29). TTO failed to suppress the adherence reaction of neu- reactions may frequently be avoided through the use of lower trophils induced by TNF-␣ stimulation (2) or the casein-in- concentrations of the irritant, this bolsters the case for discour- duced recruitment of neutrophils into the peritoneal cavities of aging the use of neat oil and promoting the use of well-formu- mice (1). These studies identify specific mechanisms by which lated products. Allergic reactions have been reported (54, 147), TTO may act in vivo to diminish the normal inflammatory and although a range of components have been suggested as response. In vivo, topically applied TTO has been shown to responsible, the most definitive work indicates that they are modulate the edema associated with the efferent phase of a caused mainly by oxidation products that occur in aged or contact hypersensitivity response in mice (23) but not the de- improperly stored oil (82). There is little scientific support for velopment of edema in the skin of nonsensitized mice or the the notion that 1,8-cineole is the major irritant in TTO. No edematous response to UVB exposure. This activity was attrib- evidence of irritation was seen when patch testing was per- uted primarily to terpinen-4-ol and ␣-terpineol. When the ef- formed on rabbits with intact and abraded skin (118), guinea fect of TTO on hypersensitivity reactions involving mast cell pigs (82), and humans (118, 141), including those who had degranulation was examined in mice, TTO and terpinen-4-ol previous positive reactions to TTO (96). Rarely, topically ap- applied after histamine injection reduced histamine-induced plied tea tree oil has been reported to cause systemic effects in skin edema, and TTO also significantly reduced swelling in- domestic animals. Dermal application of approximately 120 ml duced by intradermal injection of compound 48/80 (24). Hu- of undiluted TTO to three cats with shaved but intact skin man studies on histamine-induced wheal and flare provided resulted in symptoms of hypothermia, uncoordination, dehy- further evidence to support the in vitro and animal data, with dration, and trembling and in the death of one of the cats (17).
the topical application of neat TTO significantly reducingmean wheal volume but not mean flare area (97). Erythema PRODUCT FORMULATION ISSUES
and flare associated with nickel-induced contact hypersensitiv-ity in humans are also reduced by neat TTO but not by a 5% The physical characteristics of TTO present certain difficul- TTO product, product base, or macadamia oil (119). Work has ties for the formulation and packaging of products. Its lipophi- now shown that terpinen-4-ol, but not 1,8-cineole or ␣-terpineol, licity leads to miscibility problems in water-based products, modulates the vasodilation and plasma extravasation associ- while its volatility means that packaging must provide an ade- ated with histamine-induced inflammation in humans (94).
quate barrier to volatilization. Since TTO is readily absorbedinto plastics, packaging must cater to and minimize this effect.
Consideration must also be given to the properties of the SAFETY AND TOXICITY
finished product. Early suggestions that the antimicrobial ac- Despite the progress in characterizing the antimicrobial and tivity of TTO may be compromised by organic matter came anti-inflammatory properties of tea tree oil, less work has been from disk diffusion studies in which the addition of blood to done on the safety and toxicity of the oil. The rationale for agar medium decreased zone sizes (8). This observation con- continued use of the oil rests largely on the apparently safe use trasts sharply with historical claims that the activity of TTO of the oil for almost 80 years. Anecdotal evidence over this may in fact be enhanced in the presence of organic matter such time suggests that topical use is safe and that adverse events as blood and pus. A thorough investigation of this claim com- are minor, self-limiting, and infrequent. More concrete evi- prehensively refuted this idea (76) and also showed that prod- dence such as published scientific work is scarce, and much uct excipients may compromise activity.
information remains out of the public domain in the form of Some work on the characteristics and behavior of TTO reports from company-sponsored work. The oral and dermal within formulations has been conducted. Caboi et al. (27) toxicities of TTO are summarized briefly below.
examined the potential of a monoolein/water system as a car-rier for TTO and terpinen-4-ol. The activity of TTO productsin vitro has also been investigated (16, 77, 107). However, very Oral Toxicity
little work has been conducted in this area, and if stable, TTO can be toxic if ingested, as evidenced by studies with biologically active formulations of TTO are going to be devel- animals and from cases of human poisoning. The 50% lethal dose for TTO in a rat model is 1.9 to 2.6 ml/kg (129), and ratsdosed with Յ1.5 g/kg TTO appeared lethargic and ataxic (D.
CONCLUSIONS
Kim, D. R. Cerven, S. Craig, and G. L. De George, Abstr.
Amer. Chem. Soc. 223:114, 2002). Incidences of oral poisoning
A paradigm shift in the treatment of infectious diseases is in children (55, 91, 112) and adults (57, 133) have been re- necessary to prevent antibiotics becoming obsolete, and where ported. In all cases, patients responded to supportive care and appropriate, alternatives to antibiotics ought to be considered.
recovered without apparent sequelae. No human deaths due to There are already several nonantibiotic approaches to the TTO have been reported in the literature.
treatment and prevention of infection, including probiotics, phages, and phytomedicines. Alternative therapies are viewed 22. Brand, C., A. Ferrante, R. H. Prager, T. V. Riley, C. F. Carson, J. J.
favorably by many patients because they are often not being Finlay-Jones, and P. H. Hart. 2001. The water soluble-components of the
essential oil of Melaleuca alternifolia (tea tree oil) suppress the production
helped by conventional therapy and they believe there are of superoxide by human monocytes, but not neutrophils, activated in vitro.
fewer detrimental side effects. In addition, many report signif- Inflamm. Res. 50:213–219.
23. Brand, C., M. A. Grimbaldeston, J. R. Gamble, J. Drew, J. J. Finlay-Jones,
icant improvement while taking complementary and alterna- and P. H. Hart. 2002. Tea tree oil reduces the swelling associated with the
tive medicines. Unfortunately, the medical profession has been efferent phase of a contact hypersensitivity response. Inflamm. Res. 51:236–
slow to embrace these therapies, and good scientific data are 24. Brand, C., S. L. Townley, J. J. Finlay-Jones, and P. H. Hart. 2002. Tea tree
still scarce. However, as we approach the “postantibiotic era” oil reduces histamine-induced oedema in murine ears. Inflamm. Res. 51:
the situation is changing. A wealth of in vitro data now sup- ports the long-held beliefs that TTO has antimicrobial and 25. Brophy, J. J., N. W. Davies, I. A. Southwell, I. A. Stiff, and L. R. Williams.
1989. Gas chromatographic quality control for oil of Melaleuca terpinen- anti-inflammatory properties. Despite some progress, there is 4-ol type (Australian tea tree). J. Agric. Food Chem. 37:1330–1335.
still a lack of clinical evidence demonstrating efficacy against 26. Buck, D. S., D. M. Nidorf, and J. G. Addino. 1994. Comparison of two
bacterial, fungal, or viral infections. Large randomized clinical topical preparations for the treatment of onychomycosis: Melaleuca alter-
nifolia (tea tree) oil and clotrimazole. J. Fam. Pract. 38:601–605.
trials are now required to cement a place for TTO as a topical 27. Caboi, F., S. Murgia, M. Monduzzi, and P. Lazzari. 2002. NMR investiga-
tion on Melaleuca alternifolia essential oil dispersed in the monoolein aque-
ous system: phase behavior and dynamics. Langmuir 18:7916–7922.
28. Caelli, M., J. Porteous, C. F. Carson, R. Heller, and T. V. Riley. 2000. Tea
ACKNOWLEDGMENTS
tree oil as an alternative topical decolonization agent for methicillin-resis- This review was supported in part by a grant (UWA-75A) from the tant Staphylococcus aureus. J. Hosp. Infect. 46:236–237.
29. Caldefie-Che´zet, F., M. Guerry, J. C. Chalchat, C. Fusillier, M. P. Vasson,
Rural Industries Research and Development Corporation.
and J. Guillot. 2004. Anti-inflammatory effects of Melaleuca alternifolia
We are grateful to Ian Southwell (Wollongbar Agricultural Institute, essential oil on human polymorphonuclear neutrophils and monocytes.
NSW) for helpful discussions on oil provenance and to staff at the Free Rad. Res. 38:805–811.
Australian War Memorial (Canberra, ACT) for sharing their knowl- 30. Carson, C. F., L. Ashton, L. Dry, D. W. Smith, and T. V. Riley. 2001.
edge of Australian military history and TTO.
Melaleuca alternifolia (tea tree) oil gel (6%) for the treatment of recurrent
herpes labialis. J. Antimicrob. Chemother. 48:450–451.
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