Tea Tree Oil Treatment of MRSA

The prevalence of Methicillin-resistant Staphyloccocus aureus (MRSA) MRSA as a pathogen in hospitals and other community settings underscores the importance of eradicating the infection.¹ As MRSA is not susceptible to commonly used antibiotics, alternative antimicrobial agents are being sought for its eradication. One area of interest involves the use of tea tree oil, which studies have shown to effectively treat infections of drug-resistant bacteria, including MRSA.

Introduction

Figure 1. This colorized scanning electron micrograph (SEM) depicts a grouping of methicillin resistant Staphylococcus aureus (MRSA) bacteria. Public through the CDC

Staphyloccocus aureus, more commonly known as staph bacteria or MRSA, is a Gram-positive coccus-shaped anaerobic bacterium pictured in Figure 1.¹ MRSA is a type of staph bacteria that is resistant to beta-lactam antibiotics, such as penicillin, amoxicillin, oxacillin, and methicillin. MRSA often colonizes on the skin or nostrils of healthy individuals, and is relatively harmless at these sites.¹ If S. aureus enters the body (e.g., wounds, cuts), it may cause infections. In such instances, the MRSA infection may range from mild (e.g., pimples) to life-threatening (e.g., infection of bloodstream, joints, or bones).¹ MRSA is spread through contact and most commonly contracted in public settings, namely hospitals.

Tea tree oil (TTO) is the essential oil derived through steam distillation from the Australian native plant Melaleuca alternifolia. Tea tree oil has been used for centuries as a topical antiseptic. TTO is believed to have antibacterial, antifungal, antiviral, and anti-inflammatory properties.² Although historical anecdotes endorse TTO's medicinal properties, few clinical studies have been conducted to support such claims. Clinical studies, however few, indicate that tea tree oil can treat the skin infection caused by MRSA. Tea tree oil's anti-microbial properties are attributed to belonging to a class of chemicals known as terpenes, specifically terpinen-4-ol.² Tea tree oil's bactericidal effects make this plant extract a plausible addition or supplement to a MRSA treatment plan.

Tea Tree Oil Composition and Chemistry

Figure 2. Chemical structure of the terpenic derivative, terpinen-4-ol. It is one of nearly 100 tea tree oil compounds identified through gas chromatography-mass spectrometry. Public through Wikimedia Commons

Commercially available TTO is a composition of nearly 100 chemical compounds determined by gas chromatography-mass spectrometry.³ TTO is primarily composed of a class of chemicals called terpenes. Specifically, monoterpenes, sesquiterpenes, and other terpene alcohols dominate this composition. Terpenes are volatile, aromatic hydrocarbons and are typically soluble with nonpolar solvents.² While research indicates that terpene alcohols are generally effective anti-microbial agents, terpinen-4-ol, pictured in Figure 2, is the specific terpenic compound believed primarily responsible for TTO's anti-microbial activity. Other terpenic compounds in TTO include 1,8-cineole, terpinolene, and α-terpineol, which have less reputable medicinal properties than terpinen-4-ol.²

TTO composition is commercially available in various chemotypes. The most common chemotype is the terpinen-4-ol chemotype where terpinen-4-ol comprises between 30 to 40% of TTO's commercial composition.² A relatively high composition of terpinen-4-ol is more common in commercial production due to its historical medicinal properties.^2,3

Treatment and Effectiveness

Efforts to validate the therapeutic properties of tea tree oil (TTO) have yielded in vitro (i.e. laboratory) and clinical studies showing that TTO treatment eradicates and reduces MRSA infection, respectively. The demonstrated effectiveness of TTO treatment after MRSA infection has led to preliminary research regarding TTO application as a way to prevent MRSA infection. While TTO displays in vitro and clinical efficiency, TTO has not been demonstrated to prevent initial MRSA colonization. Several studies (as shown below and in Figure 3) support the claims upheld by traditional healers that TTO is an effective antimicrobial agent.

Potency

Figure 3. The potency and effectiveness of tea tree oil (TTO), as described by May et al.,Caelli et al. and Dryden et al..^4,5,6 Image created by Karen Leung.

The efficacy of tea tree oil (TTO) against MRSA has been demonstrated in laboratory studies using cultured S. aureus samples. An in vitro study by May et al. showed that MRSA was eradicated after 6 hours of continuous exposure to 5% TTO. These results imply that TTO is able to eradicate MRSA and has strong health implications for clinical usage.

May et al. conducted in vitro experiments to explore the TTO's bactericidal activity in laboratory-grown cultures of MRSA.⁴ May found that 99.9% of the MRSA isolate was killed by TTO within 4 hours and that all was killed by TTO within 6 hours.⁴ This finding demonstrates TTO's potency against MRSA and suggests that TTO's antimicrobial properties make this a good agent to control MRSA and reduce its transmission among humans.

Clinical Efficiency

Figure 4. Impetigo, a skin infection resulting from staph infection. Caelli et al. and Dryden et al. found that tea tree oil could effectively treat a similar MRSA-related ailment.^{5, 6} Public through the CDC.

The efficiency of TTO in eradicating MRSA cultures in vitro led to clinical testing with human patients using products enhanced with TTO. TTO may be added to commercial products, such as body wash, skin cream, and nasal ointment due to its antimicrobial properties. Such products can be incorporated into a daily regimen to treat MRSA. The clinical efficacy of TTO body wash and creams as a decolonization agent for MRSA has been supported by Caelli et al. and Dryden et al..^{5, 6} Both researchers found that TTO treatment is as effective as the conventional treatment regimen against MRSA infection. These studies indicate that TTO treatment may enhance a MRSA eradication regimen.

Caelli et al. compared the effectiveness of TTO treatment to that of standard treatments against MRSA, as measured by post-treatment MRSA concentrations on the skin and within the nose.⁵ In Caelli’s clinical study, 30 MRSA-infected adult hospital inpatients were randomly assigned to receive either the standard treatment (2% antibiotic nasal ointment and triclosan body wash) or tea tree oil regimen (4% TTO nasal ointment and 5% TTO body wash) for three days. Compared to the standard treatment, the tea tree oil topical regimen reduced or eradicated MRSA infection in more subjects. Despite this optimistic finding, the small sample size prevented this result from being statistically significant. Consequently, Caelli concluded that TTO treatment was just as effective at eradicating MRSA as the standard medical treatment.⁵

Dryden et al. conducted a similar study regarding TTO's effectiveness against MRSA-related skin infection.⁶ Dryden's clinical study, which involved 236 MRSA patients, found that the daily application of 5% TTO body wash and 10% TTO cream was more effective than standard treatment at clearing skin lesions and variations in skin texture or color associated with MRSA infection.⁶ However, the TTO regimen did not eradicate the MRSA infection entirely. Dryden concluded that TTO was effective at clearing topical infections commonly found in MRSA patients.⁶

Although research suggests the efficacy of TTO against MRSA, more clinical studies would have to be performed in order to comprehensively assess TTO's effects on MRSA patients. From these experiments, TTO was deemed to be sufficiently effective, safe, and well-tolerated to be considered part of a MRSA eradication regimen.⁶

Antimicrobial Activity: Cytoplasmic Membrane Damage

Figure 5. Membrane permeability is disrupted after tea tree oil (TTO) treatment. A physiologically normal cytoplasmic membrane (A) excludes foreign substances, like NaCl and propidium iodide. A membrane treated with TTO (B) cannot properly exclude foreign material and water, which may lead to cell lysis.^8,9 Image created by Karen Leung.

The target of TTO's antimicrobial activity, and the primary reason for its laboratory and clinical effectiveness, is reported to be the cytoplasmic membrane of MRSA. The bacterial cell membrane physically separates the cell's internal environment from the external environment. It is selectively permeable to organic molecules and ions. As such, it regulates the movement of water and other substances into and out of the cell.⁷ If the membrane is compromised, the cell may rupture due to osmotic pressure (as shown in Figure 5). Research indicates that this is the likely mechanism of TTO’s antimicrobial activity against MRSA.

Studies that have examined membrane integrity after TTO treatment indicate that the essential oil disrupts the membrane permeability. If the membrane permeability is compromised, the barrier between the internal and external environment is weakened. Consequently, foreign material would be able to enter the cell more easily while cytoplasmic material would be able to leave it more easily. A study found that TTO treatment disturbed the MRSA membrane permeability in vitro, which allowed propidium iodide, a foreign substance, to enter the cell and potassium ions, part of the cytoplasmic material, to leave the cell.⁸ Another in vitro study demonstrated that TTO-treated MRSA had increased susceptibility to sodium chloride (NaCl), a cell toxin.⁹ From this evidence, researchers believe that TTO alters the cell membrane.

Membrane integrity is key to maintaining the membrane’s normal function. If the membrane is compromised, the cell is unlikely to survive the damage. TTO has been shown to induce lasting membrane damage in MRSA, which represents a plausible mechanism for TTO’s eradication of MRSA.^8,9 However, the details of TTO’s mode of action are under speculation. One model presented by Carson proposes that TTO impairs the membrane’s ability to osmoregulate the cell adequately.⁹ The subsequent rupture of the cell membrane due to osmotic pressure would cause cell lysis.⁹ Since this area of research remains relatively unexplored, more investigation would be warranted to form a theory.

Susceptibility to Antibiotic Resistance after TTO Exposure

The available forms of TTO range from pure oil to retail products for personal health care, home care, and pet care.¹⁰ Commercial TTO preparations, which may vary in its components' concentrations, provide users more opportunity to apply TTO at ineffective concentrations. The growing use of TTO also implies that a diversity of microbes is coming into contact with sub-lethal TTO concentrations.¹⁰ There is concern that exposing MRSA to sub-lethal concentrations of TTO may lead to decreased antibiotic susceptibility (i.e. increased antibiotic resistance). ¹¹

Similar studies produce conflicting results

Figure 6. A comparison of McMahon and Thomsen's experimental parameters regarding the study of antibiotic susceptibility after TTO exposure. Both researchers performed the same experiment (i.e. same procedure) with the shown differences.^12,13 Although they investigated the same question, the researchers came to different conclusions. Image created by Karen Leung.

Whether TTO exposure decreases antibiotic susceptibility in MRSA remains a subject of investigation. Evidence has been presented for both sides of this debate by McMahon et al and Thomsen et al.^12,13 The two researchers conducted similar studies, but came to different conclusions regarding TTO's effect on antibiotic susceptibility in MRSA.

In their respective studies, McMahon and Thomsen used similar experimental designs to determine whether exposure of MRSA to sub-lethal TTO concentrations increased its resistance to antibiotics.^{12, 13} Both examined the minimal inhibitory concentration (MIC) of antibiotics commonly used to treat MRSA before and after the pathogen was habituated to sub-lethal TTO concentrations. They believed that changes in MIC, the minimal concentration of an antimicrobial needed to inhibit bacterial growth, was an adequate indication of MRSA’s sensitivity to the antibiotic. A positive change in MIC suggested increased antibiotic resistance and vice versa.^{12, 13}

Although McMahon and Thomsen’s experiments were conducted similarly, their overall findings did not match (Figure 5).^{12, 13} McMahon reported that exposing MRSA isolates to a sub-lethal concentration of 0.25% (v/v) TTO increased the average MICs of antibiotics by two-fold or greater.¹² McMahon concluded that TTO exposure increased MRSA’s resistance to antibiotics.¹² On the other hand, Thomsen reported that exposing MRSA isolates to a sub-lethal concentration of 0.075% (v/v) TTO did not increase the MICs of the same antibiotics by more than two-fold, indicating that any changes in MIC were minor.¹² The different sub-lethal concentration used by Thomsen reflects this study's limited ability to reproduce McMahon's experiment.¹³ Thomsen concluded that exposure to sub-lethal concentrations of TTO did not contribute to antibiotic resistance.¹³ Since McMahon and Thomsen produced varying results of unknown clinical significance, clinical studies could be conducted to test the validity of their respective claims.¹³

It is unlikely that the exposure of MRSA to sub-lethal TTO concentrations increases antibiotic resistance. Thomsen et al defended their stance by pointing out that the numerous replicates in McMahon’s study made minor numerical increases and reductions in MIC statistically significant.¹³ A separate study also reported that tea tree oil had little impact on the development of antimicrobial resistance and susceptibility.¹⁴ These reports suggest that TTO exposure does not alter MRSA’s susceptibility to antibiotics.

Implications of TTO-induced antibiotic resistance

Given the unexplored clinical significance regarding TTO-induced antibiotic resistance, the discussion of TTO-induced antibiotic resistance remains relevant.¹² If found to impact antibiotic susceptibility, TTO concentrations in retail products may be increased so that there is less exposure to sub-lethal TTO concentrations.¹² This may be achieved through legislation and/or regulation of commercial TTO products. While sub-lethal TTO concentrations may impact antibiotic susceptibility, they do not necessarily impact TTO's antibacterial properties. Sub-lethal TTO concentrations can still effectively destroy certain bacteria.^12,13

Conclusion

Discovering alternative therapy for the treatment of MRSA is very important as antibiotic resistance becomes more prevalent. MRSA's increasing resistance to mupirocin, the primary antibiotic in standard MRSA eradication treatments, has been noted by Dryden.⁷ Since TTO shows little sign of inducing antibiotic susceptibility in MRSA upon treatment, one alternative treatment is the use of tea tree oil as an antimicrobial agent.¹³

The application of a TTO regimen is comparable to standard MRSA treatment in eradicating MRSA.^5,6 The reported mechanism for TTO's bactericidal effects is damage to the cytoplasmic membrane, thus making the membrane more permeable to substances, such as water.⁹ Impaired osmoregulation may lead to cell lysis.⁹

Current research focuses on TTO's mechanism of action, safety, and effect on antibiotic susceptibility. Though cytoplasmic membrane damage is believed to be the major bactericidal effect, the mechanism is still largely unexplored. Other research examines commercial tea tree oil's cytotoxic effects if applied topically to human skin.¹⁵ Such investigations would determine the safety of applying TTO on a regular basis and hopefully, the optimal strength of TTO for pharmaceutical formulation.

References

1. MRSA Infection. National Health Service (NHS) Web site. Last revised on 23/09/2011. Accessed on 21/03/2013.

2. Carson, C. F., Hammer, K. A., Riley, T. V. Malalueca alternifolia (tea tree) oil: a review of antimicrobial and other medicinal properties. Clin. Microbiol. Rev. 19, 50-62 (2006)

3. Brophy, J. J., N. W. Davies, I. A. Southwell, I. A. Stiff, and L. R. Williams. Gas chromatographic quality control for oil of Melaleuca terpinen-4-ol type (Australian tea tree). J. Agric. Food Chem. 37, 1330-1335 (1989)

4. May, J., Chan, C. H., King, A., Williams, L., French, G. L. Time kill studies of tea tree oils on clinical isolates. J. Antimicrob. Chemo. 45, 639-643 (2000)

5. Caelli, M., Porteous, J., Carson, C. F., Heller, R., Riley, T. V. Tea tree oil as an alternative topical decolonization agent for methicillin-resistant Staphylococcus aureus. J. Hosp. Infect. 46, 236-237 (2000)

6. Dryden, M. S., Dailly, S., Crouch, M. A randomized, controlled trial of tea tree topical preparations versus a standard topical regimen for the clearance of MRSA colonization. J. Hosp. Infect. 56, 283-286 (2004)

7. Todar, K. "Structure and function of bacterial cells" Online Textbook of Bacteriology. 2012 Published. 15/04/2013 Accessed.

8. Cox, S. D., et al. The mode of antimicrobial action of the essential oil of Melaleuca alternifolia (tea tree oil). J. Applied Microbiol. 88, 170-175 (2000).

9. Carson, C. F., Mee, B. J., Riley, T. V. Mechanism of action of Melaleuca alternifolia (tea tree) oil on Staphylococcus aureus determined by time-kill, lysis, leakage, and salt tolerance assays and electron microscopy. Antimicrob. Agents Chemother. 46, 1914-1920. (2002)

10. "Tea tree oil" American Cancer Society Web site. 28/11/2008 Revised. 16/04/2013 Accessed.

11. Gilbert, P., McBain A. J. Potential impact of increased use of biocides in consumer products on prevalence of antibiotic resistance. Clin. Microbiol. Rev. 16, 189-208 (2003)

12. McMahon, M. A. S., Blair, I. S., Moore, J. E., McDowell, D. A. Habituation to sub-lethal concentrations of tea tree oil (Melaleuca alternifolia) is associated with reduced susceptibility to antibiotics in human pathogens. J. Antimicrob. Chemother. 59, 125-127. (2007)

13. Thomsen, N. A., Hammer, K. A., Riley, T. V. Belkum, A. V., Carson, C. F. Effect of habituation to tea tree (Melaleuca alternifolia) oil on the subsequent susceptibility of Staphylococcus spp. to antimicrobials, triclosan, tea tree oil, terpinen-4-ol and carvacrol. Int. J. Antimicrob. Agents. 41, 343-351. (2013)

14. Hammer, K. A., Carson, C. F., Riley, T. V. Effects of Malaleuca alternifolia (Tea Tree) essential oil and the major monoterpene component terpinen-4-ol on the development of single- and multistep antibiotic resistance and antimicrobial susceptibility. Antimicrob. Agents Chemother. 56, 909-915 (2012)

15. Loughlin, R., Gilman, B. F., McCarron, P. A., Tunney, M. M. Comparison of the cidal activity of tea tree oil and terpinen-4-ol against clinical bacterial skin isolates and human fibroblast cells. Letters Applied Microb.. 48, 428-433 (2008)

[Edited by Karen Leung, a student of Nora Sullivan in BIOL187S (Microbial Life) in The Keck Science Department of the Claremont Colleges Spring 2013.