The emergence of multiple antibiotic resistant organisms in the general community is a potentially serious threat to public health. The emergence of antibiotic resistance has not yet prompted a radical revision of antibiotic utilisation. Instead it has prompted the development of additional antibiotics. Unfortunately, this does not relieve the underlying selection pressure that drives the development of resistance. A paradigm shift in the treatment of infectious disease is necessary to prevent antibiotics becoming obsolete and, where appropriate, alternatives to antibiotics ought to be considered. There are already several non-antibiotic approaches to the treatment and prevention of infection including probiotics, phages and phytomedicines. There is some evidence that probiotics such as Lactobacillus spp. or Saccharomyces boulardii are useful in the prevention and treatment of diarrhoea, including Clostridium difficile-associated diarrhoea that can be difficult to treat and recurs frequently. Bacteriophages have received renewed attention for the control of both staphylococcal and gastrointestinal infections. Phytomedicines that have been utilised in the treatment of infections include artesunate for malaria, tea tree oil for skin infections, honey for wound infections, mastic gum for Helicobacter pylori gastric ulcers and cranberry juice for urinary tract infections. Many infections may prove amenable to safe and effective treatment with non-antibiotics. Commun Dis Intell 2003;27 Suppl:S143-S146.
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Introduction
Increased use of alternative medicines has come about largely as a result of the general community's interest in alternative therapies rather than by demand from healthcare professionals for alternative agents. Both groups have their own prejudices; lay people often assume natural products are completely safe and effective while many health professionals dismiss therapeutic agents or methods that do not fit the conventional paradigm. Both groups often maintain their biases in the face of contradictory evidence, or view the absence of evidence as evidence in its own right. A survey published in 1996 indicated that nearly 50 per cent of the Australian population had used at least one non-medically prescribed alternative medicine.1 With specific regard to antimicrobials, there are several non-antibiotic approaches to the treatment and prevention of infection including probiotics, bacteriophages and phytomedicines.
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Probiotics
Probiotics have been suggested as an alternative therapy for the treatment of infectious gastroenteritis, or the treatment and prevention of antibiotic-associated diarrhoea due to Clostridium difficile. Probiotics are preparations of ostensibly non-pathogenic organisms known to have a beneficial effect on the digestive and other systems by conferring resistance to infection or eliminating infectious agents. Both bacteria and yeasts have been used as probiotics. The mechanisms of action of probiotics have been summarised by Filho-Lima et al.2 Four possibilities exist: 1. antagonism through production of inhibitory substances; 2. competition with the pathogen for adhesion sites or nutrients; 3. immunomodulation of the host; and 4. inhibition of toxins.
Lactobacillus GG has been the most widely studied of probiotic agents. In addition to having been used, with varying degrees of success, for treating or preventing urinary tract infections, vulvo-vaginal candidiasis and bacterial vaginosis,3Lactobacillus GG, in the form of a milk preparation, was recently reported as having some modest but consistent benefits in terms of preventing and reducing the severity of respiratory infections at day care centres.4 While the relevance of this latter observation to the prevention of antibiotic resistance may not be immediately apparent, any intervention which results in reduced use of antibiotics in a particular setting will eventually lead to a decline in antibiotic resistance. Another well-studied probiotic is Saccharomyces boulardii, a yeast that is effective in preventing relapses of Clostridium difficile-associated diarrhoea and treating various types of infectious diarrhoea.5 Several other possible probiotics have been looked at, such as non-toxigenic strains of C. difficile and a strain of Enterococcus faecium. However, enthusiasm for enterococci as probiotics has waned since the emergence of vancomycin resistant enterococci.
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Bacteriophages as antimicrobial agents
An old idea ignored since the beginning of the antibiotic era by all but a few former Soviet block countries is bacteriophage therapy where phages are used to lyse bacterial pathogens. There has been renewed interest in bacteriophage therapy with the emergence of antibiotic resistance as a major problem in modern medicine.6 Several reports from Poland in the 1980s described the treatment of various infections, the majority of which were staphylococcal and included bacteraemia. In vitro testing indicated that bacteriophages were active against specific pathogens. Efficacy in vivo was assessed on a clinical basis alone and positive results were obtained in over 90 per cent of cases, however, there were no untreated controls.7 Similar studies were carried out in the former Soviet Union from the early 1970s. In those studies where staphylococci (presumably Staphylococcus aureus) were involved, bacteria were eliminated after phage therapy in the majority of cases.6 Phages were applied either topically, sub-cutaneously, or via irrigation or drains.
Studies in the United Kingdom have predominantly concentrated on the treatment of diarrhoeal disease, mainly caused by Escherichia coli, using animal models.8 Soothill9 treated experimental S. aureus infections in mice with bacteriophage. Bacteriophage and S. aureus (the same strains as had been used in some of the Polish studies) were injected intraperitoneally simultaneously. In this situation bacteriophage was not protective although infections involving Acinetobacter baumanii and Pseudomonas aeruginosa could be prevented by their respective bacteriophages.
As with other alternative therapies, there have been concerns about the safety of bacteriophage therapy. One concern has been the development of antiphage antibody during therapy. This was assessed in Poland in 57 patients following oral administration of bacteriophage and found no measurable antibody in 44 patients during treatment. In two cases high titre antibody developed.10 Another major problem has been the presence of various toxins in crude phage lysates, however, this can now be addressed during preparative process.11 The bioavailability of phage administered systemically has also been a concern, with early studies indicating that phage was quickly cleared by the reticuloendothelial system. Mutant phages with the ability to evade the reticuloendothelial system have now been produced.11 It is possible that bacteria will ultimately become resistant to phage lysis in the same way that antibiotic resistance has emerged. However, phage used as a single dose, may be less likely to result in resistance than using antibiotics for a long period. Other problems include the observation that some methicillin-resistant S. aureus (MRSA) seem to be inherently less susceptible to bacteriophages than antibiotic-susceptible S. aureus. Finally, there is concern of the possibility of lysogenic conversion, whereby bacteriophage could acquire various toxin genes and introduce these into susceptible bacteria. The likelihood of this occurring, or of virulence genes being introduced by transduction, is unknown.
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Phytomedicines
Phytomedicines are plant-derived remedies and many, such as tea tree oil (TTO), honey and cranberry juice, are targeted towards infectious diseases. TTO is the essential oil derived from certain species of Australian native plants in the genus Melaleuca, mainly Melaleuca alternifolia.12 Originally developed in the pre-antibiotic era, its antimicrobial properties were first reported in the 1920s when it was shown to be more active than one of the widely used disinfectants of the day, phenol.12 The antimicrobial activity and tolerability of TTO made it a popular skin antiseptic for the next 20 years. The dawn of the antibiotic era precipitated the demise of interest in TTO which could not compete with the potency and selective toxicity of the new agents. Consequently, TTO was discarded as an antimicrobial agent before its properties could be elucidated fully. Sixty years later, the widespread occurrence of multiple antibiotic-resistant organisms in hospital and community settings suggests new antimicrobial agents, preferably with novel mechanisms of action, are required and it seems prudent to re-examine previously superseded products such as TTO. In vitro, TTO has broad spectrum antibacterial activity13 including activity against MRSA.14 Antifungal and antiviral properties have also been demonstrated in vitro and preliminary in vivo work suggests that it may be useful in the treatment of acne15 and oral candidiasis,16 and in the decolonisation of MRSA carriage.17 An understanding of its mechanisms of action against bacteria is being reached18,19 and it appears that multiple mechanisms are involved, perhaps diminishing the rate at which resistance is likely to develop.
In contrast to TTO, honey has a much longer recorded history of medicinal use. Scattered reports in the medical literature describe the antibacterial properties of honey and honey products, and their potential as antimicrobial agents, particularly in wound care.20 More recently, in vitro antibacterial activity has been described and a wide range of organisms is inhibited by honey including E. coli, Proteus mirabilis, Ps. aeruginosa, Enterococcus faecalis21 and Helicobacter pylori.22 The activity of honey has been attributed to the high osmolarity, the low pH and the presence of hydrogen peroxide. However, these factors alone or in combination do not account for all of the antibacterial activity and the identity of the main antimicrobial component of some honeys and its mechanism of action remains unclear.
Cranberries were used by North American Indians for food and medicine and they still enjoy popularity today. Commercially available cranberry juice may be useful in the treatment and prevention of urinary tract infections. Its putative medicinal properties have been partly investigated with occasional papers appearing in the medical literature. In a recent study, the effect of regular cranberry juice consumption on the recurrence of urinary tract infections was examined.23 The time to first recurrence of a symptomatic urinary tract infection was compared in three groups of women randomised to receive daily 50 ml of European cranberry juice, 100 ml of a Lactobacillus GG drink or no intervention. Of the 50 patients randomised to cranberry juice, the cumulative rate of first recurrence of urinary tract infections during the 12-month follow-up was significantly reduced compared to the 50 patients receiving no intervention. In contrast, consumption of the Lactobacillus GG drink offered no benefit. Earlier work by Avorn et al.24 suggested that daily ingestion of 300 ml of cranberry juice reduced the frequency of bacteriuria with pyuria in older women. A number of mechanisms have been postulated although a direct antibacterial effect and acidification of the urine have been excluded as the primary mechanisms of action. Exposure of uropathogenic E. coli to cranberry juice or extracts diminishes expression of P-fimbriae and inhibits their adherence to uroepithelial cells.25 Similar work has shown that a high molecular weight constituent of cranberry juice can inhibit H. pylori adhesion to gastric mucosa.26 While cranberry juice may not prove to be an effective treatment for current urinary tract or H. pylori infections, it may prevent de novo infections or prevent reinfection.
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Conclusions
Alternative therapies are viewed favourably by many patients because they are often not being helped by conventional therapy and they believe there are fewer detrimental side effects. In addition, many report significant improvement while taking complementary and alternative medicines. Unfortunately, the medical profession has been slow to embrace these therapies and good scientific data are scarce at present.3 However, as we approach the 'post-antibiotic era' the situation is changing. Further research is needed to validate the claims made for alternative therapies.
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References
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2. Filho-Lima JVM, Viera EC, Nicoli JR. Antagonistic effect of Lactobacillus acidophilus, Saccharomyces boulardii and Escherichia coli combination against experimental infections with Shigella flexneri and Salmonella enteritidis subsp. typhimurium in gnotobiotic mice. J Appl Microbiol 2000;88:365-370.
3. Golledge CL, Riley TV. 'Natural' therapies for infectious diseases. Med J Aust 1996;164:94-95.
4. Hatakka K, Savilahti E, Ponka A, Meurman JH, Poussa T, Nase L, et al. Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial. BMJ 2001;322;1327-1331.
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7. Slopek S, Weber-Dabrowska B, Dabrowski M, Kucharewicz-Krukowska A. Results of bacteriophage treatment of suppurative bacterial infections in the years 1981-1986. Arch Immunol Ther Exp 1987;35:569-583.
8. Smith HW, Huggins MB. Successful treatment of experimental Escherichia coli infections in mice using phage: its general superiority over antibiotics. J Gen Microbiol 1982;128:307-318.
9. Soothill JS. Treatment of experimental infections of mice with bacteriophages. J Med Microbiol 1992;37:258-261.
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11. Merril CR, Biswas B, Carlton R, Jensen NC, Creed GJ, Zullo S, et al. Long-circulating bacteriophage as antibacterial agents. Proc Natl Acad Sci USA 1996;93:3188-3192.
12. Carson CF, Riley TV. Antimicrobial activity of the essential oil of Melaleuca alternifolia. Lett Appl Microbiol 1993;16:49-55.
13. Hammer KA, Carson CF, Riley TV. Susceptibility of transient and commensal skin flora to the essential oil of Melaleuca alternifolia (tea tree oil). Am J Infect Control 1996;24:186-189.
14. Carson CF, Cookson BD, Farrelly HD, Riley TV. Susceptibility of methicillin-resistant Staphylococcus aureus to the essential oil of Melaleuca alternifolia. J Antimicrob Chemother 1995;35:421-424.
15. Bassett IB, Pannowitz DL, Barnetson RStC. A comparative study of tea tree oil versus benzoylperoxide in the treatment of acne. Med J Aust 1990;153:455-458.
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17. Caelli M, Porteous J, Carson CF, Heller R, Riley TV. Tea tree oil as an alternative topical decolonization agent for methicillin-resistant Staphylococcus aureus. J Hosp Infect 2000;46:236-237.
18. Cox S, Mann CM, Markham JL, Bell HC, Gustafson JE, Warmington JR, et al. The mode of action of the essential oil of Melaleuca alternifolia (tea tree oil). J Appl Microbiol 2000;88:170-175.
19. Carson CF, Mee BJ, Riley TV. 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 2002;46:1914-1920.
20. Cooper RA, Molan PC, Krishnamoorthy L, Harding KG. Manuka honey used to heal a recalcitrant surgical wound. Eur J Clin Microbiol Infect Dis 2001;20:758-759.
21. Allen KL, Molan PC, Reid GM. A survey of the antibacterial activity of some New Zealand honeys. J Pharm Pharmacol 1991;43:817-822.
22. Al Somal N, Coley KE, Molan PC, Hancock BM. Susceptibility of Helicobacter pylori to the antibacterial activity of manuka honey. J R Soc Med 1994;87:9-12.
23. Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 2001;322:1571-1575.
24. Avorn J, Monane M, Gurwitz JH, Glynn RJ, Choodnovskiy I, Lipsitz LA. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994;271:751-754.
25. Foo LY, Lu Y, Howell AB, Vorsa N. The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro. Phytochemistry 2000; 54:173-181.
26. Burger O, Ofek I, Tabak M, Weiss E I, Sharon N, Neeman I. A high molecular mass constituent of cranberry juice inhibits Helicobacter pylori adhesion to human gastric mucus. FEMS Immunol Med Microbiol 2000;29:295-301.
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Author affiliations
1. Department of Microbiology, The University of Western Australia, Crawley, Western Australia
2. Western Australian Centre for Pathology and Medical Research, Nedlands, Perth, Western Australia
Corresponding author: Professor Thomas V Riley, Department of Microbiology, Queen Elizabeth II Medical Centre, Nedlands, Perth WA 6009. Telephone: +618 9346 3690. Facsimile: +618 9382 8046. Email: triley@cyllene.uwa.edu.au
This article was published in Communicable Diseases Intelligence Volume 27 Suppl, May 2003.
