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EU Derogation Application Form For Copper Appendix C Information on Efficacy APPENDIX C Contents: Page 1: Preamble Page 4: Mode of Action / Efficacy – Legionella Page 5: Efficacy – Additional Pathogenic Organisms CAS No 7440-50-8 EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 Preamble: Copper has been known for its antifungal and biocidal properties for centuries. The historic use of copper has been well documented Egyptian papyrus written between 2600 and 2200 BC describes the application of copper to treat chest wounds and to purify drinking water. Later, Hippocrates recommended the topical application of copper to treat leg ulcers, and, in the pre-antibiotic era of the nineteenth and twentieth centuries, copper preparations were widely used in the treatment of skin conditions, syphilis and tuberculosis.(1) As a fungicide copper sulfate has been used in agriculture from the 1800’s for the control of potato blight and is still used today in the vine industry as the preferred method of fungal control. The use of copper is further illustrated by recent studies and trials into the use of copper surfaces in hospitals and health care settings in infection prevention and control. As the prevalence of hospital acquired infections increases the interest in this particular method of infection control has risen. Studies on the use of copper surfaces abound and all show benefits albeit with limited effect. During a study in the UK “A toilet seat, a set of tap handles and a ward entrance door push plate each containing copper were sampled for the presence of micro-organisms and compared to equivalent standard, non-copper-containing items on the same ward. Items were sampled once weekly for 10 weeks at 07:00 and 17:00. After five weeks, the copper-containing and non-copper-containing items were interchanged. The total aerobic microbial counts per cm2 including the presence of ‘indicator micro-organisms’ were determined. Median numbers of microorganisms harboured by the coppercontaining items were between 90% and 100% lower than their control equivalents at both 07:00 and 17:00.” (2) A similar study from Norway found that “Bacterial cells use different efflux systems to detoxify the metal from the cytoplasm or periplasm. Despite this ability, bacteria are rapidly killed on dry metallic copper surfaces.” (3) Despite these promising findings there is little doubt that although beneficial, copper as a surface it is only successful in augmenting existing infection control measures. Copper as a disinfectant has been used to treat and sterilize water. It is vital to note, however, that regardless of efficacy that copper is not by any means the most effective biocide available. Oxidizing agents such as Chlorine have far quicker killing times and agents such as peracetic acid will kill spores of “difficult” microorganisms such as Clostridium difficile, which will resist both Chlorine and Copper. Copper silver ionization is effective against waterborne pathogens, it is a wide ranging and basically safe method of disinfection but nevertheless should only be viewed as one weapon in the ever decreasing armory of defense against pathogenic and life threatening microbes. A review from 2010 pointed out that ”Hospital-acquired infections are a major challenge to patient safety. It is estimated that in 2002, a total of 1.7 million hospital-acquired infections occurred (4.5 per 100 admissions), and Page 1 EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 almost 99,000 deaths resulted from or were associated with a hospital-acquired infection, making hospital-acquired infections the sixth leading cause of death in the United States; similar data have been reported from Europe. The estimated costs to the U.S. health care budget are $5 billion to $10 billion annually. Approximately one third or more of hospital-acquired infections are preventable.” (4) Further the continued emergence of bacterial resistance to antibiotics coupled with a sever lack of new anti-microbial drugs must mean that any and all available methods of disinfection should be used or at least be available for use should circumstance require. The number of new antibacterial drugs approved in the USA between the years of 1983 and 1987 was 16, between the years 2003 and 2007 the number was 5 (5). This trend is worrying enough but the medical community is now being forced to revert to treatment using polymyxins (polymyxin B, colistin) and pentacationic lipopeptides to attempt to control the continued emergence of drug resistant gram negative bacteria in spite of their nephrotoxicity. (6) The importance of water borne pathogens in this emerging problem of nosocomial infections is high. Of the organisms know to be capable of infecting patients through contact with hospital water supplies the bacterial organisms excluding Legionella are: Pseudomonas aeruginosa, Stenotrophmonas maltophilia, Serratia marcescens, Acinetobacter baumannii, Aeromonas hydrophila,Burkholderia, Enterobacter,Flavobacterium, Serratia and Chyseobacterium species. Of the Mycobacterium organisms: Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium xenopi, Mycobacterium kansasii and Mycobacterium chelonae. Of Fungal organisms: Fusarium solani, Exophiala jeansemei, and Aspergillus fumigatus (7). It is becoming more obvious and essential that any method of dealing with these types of infections which is both effective and cost efficient be kept available. With the rise in bacterial resistance to antibiotics, the urgency in dealing with water borne pathogens at root source is now more than ever pressing. Techniques such as staff education and improving standards of hand washing training can only go so far. Patients exposure to the above pathogens occurs while showering, bathing and drinking (water or ice) and through contact with contaminated medical equipment (e.g. tube feeds, endoscopes and respiratory equipment) rinsed with water (7) .These forms of contact cannot reasonably be counteracted other than by dealing with the issue at source. Furthermore recent findings indicate that the incorrect or under use of disinfection agents can induce antibiotic resistance in bacteria. In a study from Galway it was shown that sub lethal doses of benzalkonium chloride, the active ingredient in common hand wipes, eye and ear drops, cleaning EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 products and house hold names such as Detol ® Lysol ® and Bactine ®, can induce bacterial resistance to antibiotics in Pseudomonas aeruginosa (8). All this points to a vital need to maintain all and any disinfection modalities. Bacteria evolve more quickly than science or mankind can adapt to. They have the ability rapidly mutate and adapt so that they can ameliorate the biocidal effect of antimicrobial agents. The conditions required for such evolution are common knowledge: allow some to live and they will adapt. It is therefore wise to allow all safe methods of microbial control to remain available. In addition to uses in pathogenic control in health care settings copper silver ionisation has been well established as an alternate method of maintaining bacteria quality in bathing water. For over thirty years copper silver has been used effectively in both public and private swimming pools as a bactericide, fungicide and algaecide. Many other effective means of ensuring safe quality bathing water exist .Chlorine, bromine, ozone, ultra violet, chlorine dioxide and natural filtration using aquatic plants are all viable means of keeping bathing water safe and copper silver by no means is the most effective alternative. It is however a viable alternative and one which has benefits many others simply do not. Chlorine is by far the most used active in the swimming pool market and with good reason. As an oxidising disinfectant it kills quickly and effectively the majority of bacteria with the noted exception of Cryptosporidium (9). Chlorine is also known to cause health issues with long term exposure. Chlorine is an accepted carcinogen. The WHO states that “in a 2-year bioassay, F344 rats and B6C3F1 mice were given chlorine in drinking-water at levels of 0, 70, 140, or 275 mg/litre (8, 13, or 24 mg/kg of body weight per day for male rats; 5, 7, or 15 mg/kg of body weight per day for female rats; 8, 15, or 24 mg/kg of body weight per day for male mice; and 1, 13, or 22 mg/kg of body weight per day for female mice). Although there was a marginal increase in mononuclear-cell leukaemia in the groups of female rats given 140 and 275 mg/litre, it was considered to be equivocal evidence of carcinogenic activity because the incidence was significantly elevated compared with controls only for the middle dose and the incidence of leukaemia in the concurrent controls was lower than the mean in historical controls” and further states “It has been reported that asthma can be triggered by exposure to chlorinated water. Episodes of dermatitis have also been associated with exposure to chlorine and hypochlorite” and yet further states “An increased risk of bladder cancer appeared to be associated with the consumption of chlorinated tapwater in a population-based, case–control study of adults consuming chlorinated or non-chlorinated water for half of their lifetimes” (10) More recent studies highlight not only the health issues regarding Chlorine but also the sever health risks associated with chlorine by-products in a swimming pool environment. One study showed “Regular attendance at chlorinated pools by young children is associated with an exposure dependent increase in lung epithelium permeability and increase in the risk of developing asthma, especially in association with other risk factors. We therefore postulate that the increasing exposure of children to chlorination products in indoor pools might be an important cause of the rising incidence of childhood asthma and allergic diseases in industrialised countries” (11). Another study summarised as follows: “Disinfection is mandatory for swimming pools: public pools are usually disinfected by gaseous chlorine or sodium hypochlorite and cartridge filters; home pools typically use stabilized chlorine. These methods produce a variety of disinfection byproducts (DBPs), such as Page 2 EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 trihalomethanes (THMs), which are regulated carcinogenic DBPs in drinking water that have been detected in the blood and breath of swimmers and of nonswimmers at indoor pools. Also produced are halogenated acetic acids (HAAs) and haloketones, which irritate the eyes, skin, and mucousmembranes; trichloramine, which is linked with swimmingpool- associated asthma; and halogenated derivatives of UV sun screens, some of which show endocrine effects. Precursors of DBPs include human body substances, chemicals used in cosmetics and sun screens, and natural organic matter. Analytical research has focused also on the identification of an additional portion of unknown DBPs using gas chromatography (GC)/mass spectrometry (MS) and liquid chromatography (LC)/MS/MS with derivatization. Children swimmers have an increased risk of developing asthma and infections of the respiratory tract and ear. A 1.6- 2.0-fold increased risk for bladder cancer has been associated with swimming or showering/bathing with chlorinated water. Bladder cancer risk from THM exposure (all routes combined) was greatest among those with the GSTT1-1 gene. This suggests a mechanism involving distribution of THMs to the bladder by dermal/inhalation exposure and activation there by GSTT1-1 to mutagens. DBPs may be reduced by engineering and behavioral means, such as applying new oxidation and filtration methods, reducing bromide and iodide in the source water, increasing air circulation in indoor pools, and assuring the cleanliness of swimmers.” (12) In addition Chlorine and all other pool disinfectants require the use of additional chemicals such as aluminium sulphate as a flocculent, copper sulphate as an algaecide (yes we are aware of the irony), acids and bicarbonates as pH regulators. Copper silver ionization does not require any additional chemical additions thus reducing both health and environmental risks to two simple actives. All told there is enough evidence to suggest that Chlorine, while being effective, is not without its drawbacks. At the very least viable safe alternatives should remain available. In a final use, that of cooling water, copper silver ionisation is again not the sole or best modality available in the strictest sense of best. It does however present a system where by exact dosages required are controllable to ensure public safety from cooling towers, Air conditioning systems and HVac systems and the inherent risk from airborne Legionella. Again in this instance there are alternatives on the market but copper silver, due to its ability to penetrate and break up biofilm is more effective. In addition to controlling biofilm and Legionella in cooling towers copper silver will also control algae and fungi within cooling systems and it is unique in this multi-faceted ability to control a full spread of microbial contaminants. This ability to control a range of microbial organisms, from fungal to viral, lends the use of copper silver to a further seldom mentioned advantage over other modalities. In being multi active copper silver ionisation can reduce energy consumption dramatically. In the health care setting its use avoids the need for energy expensive thermal treatments; in the cooling tower sector it increases cooling efficiency by biofouling control and in the swimming pool sector has proven to be more cost effective in the long term than the alternatives for an array of reasons not least being extending the life of the pool water and filtration media. In short Copper silver ionisation presents a viable alternative to control pathogenic waterborne diseases and pathogens which has proven itself on the market and in supported studies to be safe, controllable and effective. EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 Information on Efficacy: Mode of Action: The biocidal and antimicrobial properties of copper have been of interest to science roughly since the mid 1800’s. Many studies on exactly how copper deactivates or kills microbes have been carried out but the exact molecular mechanisms which give copper its antimicrobial properties are still under investigation. What is known is that copper antimicrobial mechanisms are complex and vary in mode of and site of action. To date it has been shown that copper binds with Sulphur based enzyme structures (13), catalyses the generation of reactive oxygen species which in turn damage cell DNA, (14) copper reduces the metabolic capacity of cells, copper will damage bacterial cell walls and cause result in lysis (16 & 17) and more recent studies have shown that copper is also toxic to viruses and bacteriophages and interestingly that water has been shown to mediate in the toxicity (18).Thus copper is toxic to microorganisms in a multifaceted manner and has been shown to be effective against a whole range of organisms for bacteria to virus to fungus. Efficacy against Waterborne Pathogens – Specific Studies: Copper silver ionisation as distinct from copper itself has been the subject of interest for over twenty years in the area of controlling waterborne pathogens. The main topic of research has been the area of Legionella control where copper silver has been well established. Indeed several worldwide health care organisations, including the HSE in Ireland, include copper and silver ionisation as part of recommended practice (19). The following table details some of the studies completed: Reference World Health Organisation (2007) (20) Study Type Real World Lee K. Landeen et al(1989) (22) Laboratory Assay Josep Modol et al (2007) (24) Conclusions N/A Effective when prescribed concentrations are maintained 11 years No cases of hospital-acquired legionnaires’ disease were diagnosed after the installation of the copper–silver ionization system in 94% (15 of 16) of the hospitals. One hospital did report a case of hospital-acquired legionnaires’ disease soon after the installation of the ionization system; however, no cases had occurred from 1995 to 2002 in this hospital Recommendation Janet E. Stout; Victor L. Yu (2003) (21) Zeming Liu et al (1998) (23) Length N/A Real World Trial 8 months Real World Trial 5 Years Enhanced bacterial inactivation rates of agar-grown cultures of L. pneumophila in well water systems were shown when copper and silver were added to chlorinated water In summary, one copper-silver ionization system was successfully used to disinfect two hospital buildings sequentially After implementation of the copper-silver ionization system, environmental colonization with Legionella species decreased significantly, and the incidence of nosocomial legionellosis decreased dramatically, from 2.45 to 0.18 cases per 1000 patient discharges Page 4 EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 Another trial in Germany concluded that copper silver ionisation was not effective in controlling Legionella, and concluded “The effect was not significant (P = .071); therefore, it must be considered that Legionella developed a tolerance to silver ions” (25). This was refuted later in another study which stated “In a study performed in Germany, the failure of copper–silver ionization to control Legionella was attributed by the authors to the emergence of Legionella resistant to copper–silver ionization. However, careful analysis of the article showed that resistance to copper or silver ions was never demonstrated for any Legionella strains isolated following copper–silver disinfection. The apparent failure to control Legionella was more likely due to suboptimal ion levels and not to the development of resistance” (21). Weather or resistance did indeed develop or weather levels of silver were too low to be effective this study raises relevant points regarding the efficacy of copper silver ionization. Bacterial resistance to both copper and silver is known. It is further well accepted that given the correct circumstances and conditions that bacteria will develop resistance to virtually all disinfection modalities. With regard to copper and silver this may yet be the case and it is certainly the experience of this author that the system is not without failings. In the course of installing systems both in Ireland and abroad, factors which require attention during the running of copper silver ionisations have become apparent. Just as Chlorine is subject to failure at higher temperatures copper silver requires that pH be maintained and a level below 7.2 to ensure success. Copper solubility is pH dependant and at levels above 6 copper begins to fall from solution and eventually revert to colloidal form. Further ensuring constant levels of copper and silver is vital not only to ensure efficacy but also, and perhaps more importantly, to mitigate against bacterial resistance development. Additional Pathogenic Efficacy: Copper silver ionisation is valuable in more than controlling Legionella. Other waterborne pathogenic organisms are also vulnerable to treatment using copper silver ionisation. A study on planktonic and biofilm forming pathogens in 2010 summarised that “The study was to determine the efficacy of copper-silver ionization against the formation of Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter baumannii in biofilms and planktonic phases. At concentrations below the EPA limits, ionization has potential to control the three waterborne pathogens” (26). All three of the above microorganisms are known to cause disease and fatalities in humans. These pathogenic agents are not limited to bacterial infestations but also include fungal and viral pathogens (29) .Of the organisms know to be capable of infecting patients through contact with hospital water supplies the bacterial organisms excluding Legionella are: Pseudomonas aeruginosa, Stenotrophmonas maltophilia, Serratia marcescens, Acinetobacter baumannoo, Aeromonas hydrophila and Chyseobacterium species. Page 5 EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 Of the Mycobacterium organisms: Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium xenopi, Mycobacterium kansasii and Mycobacterium chelonae. Of Fungal organisms: Fusarium solani, Exophiala jeansemei, and Aspergillus fumigatus (28). A study on fungal pathogens revealed that “The prevalence of fungi was significantly lower in ionized than in nonionized water samples from health care facilities” (27) It is interesting to note that this particular study was carried out in a hospital who had already installed a copper silver system for the control of Legionella and that the study was prompted by the fact that “Since a copper and silver ionization system was installed in our hospital in September 1999 for control of environmental Legionella species, the number of consultations to the Infectious Diseases department regarding fungal infection has markedly decreased” (27). To summarise, a growing number of studies are pointing to copper silver being effective in controlling waterborne pathogens. The technology has been established in the field of Legionella control but has efficacy in the control of a spread of microorganisms. It is accepted that the efficacy is subject to conditions of operation and that further more in-depth research on microorganisms other than Legionella is required to fully prove the full efficacy of the system but copper silver is working and keeping water free from pathogens in a number of applications without risk to human health or the environment and as such is a key tool in the control of pathogenic agents. Page 6 EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 Bibliography: 1. Dollwet H, Sorenson J. Historic uses of copper compounds in medicine. Trace Elements Med 1985;2:80e87. 2. Casey AL et al., Role of copper in reducing hospital environment contamination, J Hosp Infect (2009), doi:10.1016/j.jhin.2009.08.018 3. André Mikolay & Susanne Huggett & Ladji Tikana & Gregor Grass & Jörg Braun & Dietrich H. Nies “Survival of bacteria on metallic copper surfaces in a hospital trial” Appl Microbiol Biotechnol (2010) 87:1875–1879 4. Anton Y. Peleg, M.B., B.S., M.P.H. and David C. Hooper, M.D. “Hospital-Acquired Infections Due to Gram-Negative Bacteria” N Engl J Med. 2010 May 13; 362(19): 1804–1813. 5. Helen W. Boucher, George H. Talbot, John S. Bradley, John E. Edwards Jr, David Gilbert, Louis B. Rice, Michael Scheld, Brad Spellberg, and John Bartlett “Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America” Clinical Infectious Diseases 2009; 48:1–12 6. Marie-Paule Mingeot-Leclercq, Paul M. Tulkens, Sophie Denamur, Timo Vaara, Martti Vaara “Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells” Peptides 35 (2012) 248–252 7. (Elias J. Anasissie et al) The Hospital Water Supply as a source of Nosocomial Infections – A Plea for Action. Arch Intern Med. (2002)162, 1483-1492 8. Gerard T. A. Fleming Paul H. Mc Cay, Alain A. Ocampo-Sosa “Effect of subinhibitory concentrations of benzalkonium chloride on the competitiveness of Pseudomonaaeruginosa grown in continuous culture” Microbiology (2010), 156, 30–38 9. D. G. KORICH, J. R. MEAD, M. S. MADORE, N. A. SINCLAIR,1 AND C. R. STERLING “Effects of Ozone, Chlorine Dioxide, Chlorine, and Monochloramine on Cryptosporidium parvum Oocyst Viability” APPLIED AND ENVIRONMENTAL MICROBIOLOGY, May 1990, p. 1423-1428 10. WHO “Chlorine in Drinking-water Background document for development of WHO Guidelines for Drinking-water Quality” WHO/SDE/WSH/03.04/45 11. A Bernard, S Carbonnelle, O Michel, S Higuet, C de Burbure, J-P Buchet, C Hermans,X Dumont, I Doyle “Lung hyperpermeability and asthma prevalence in schoolchildren unexpected associations with the attendance at indoor chlorinated swimming pools” 12. C H R I S T I A N Z W I E N E R , S U S A N D . R I C H A R D S O N , D A V I D M . D E M A R I N I , T A M A R A G R U M M T, T H O M A S G L A U N E R , A N D F R I T Z H . F R I M M E L “Drowning in Disinfection Byproducts? Assessing Swimming Pool Water” VOL. 41, NO. 2, 2007 / ENVIRONMENTAL SCIENCE & TECHNOLOGY 13. Sterritt, RM; Lester, JN "Interactions of heavy metals with bacteria". The Science of the total environment 14 (1): 5–17 (1980) 14. Isidoros Iakovidis, Ioannis Delimaris, and StylianosM. Piperakis “Copper and Its Complexes inMedicine: A Biochemical Approach” Molecular Biology International Volume 2011 15. Jennifer L. Rowland, Michael Niederweis “Resistance mechanisms of Mycobacterium tuberculosis against phagosomal copper overload” Tuberculosis 92 (2012) 202e210 16. L. P. T. M. Zevenhuizen, J. Dolfing, E. J. Eshuis, and Ineke J. Scholten-Koerselman “Inhibitory Effects of Copper on Bacteria Related to the Free Ion Concentration” Microbial Ecology 5:139-146 (1979) EU Derogation Application Form For Copper Appendix C Information on Efficacy CAS No 7440-50-8 17. Christophe Espírito Santo, Ee Wen Lam, Christian G. Elowsky, Davide Quaranta, Dylan W. Domaille, Christopher J. Chang, and Gregor Grass “Bacterial Killing by Dry Metallic Copper Surfaces” APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Feb. 2011, 18. Jinyu Li and John J. Dennehy “Differential Bacteriophage Mortality on Exposure to Copper” APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Oct. 2011 19. Legionnaires’ Disease Subcommittee of the Scientific Advisory Committee “National Guidelines for the Control of Legionellosis in Ireland, 2009” Health Protection Surveillance Centre 20. World Health Organisation “LEGIONELLA and the prevention of legionellosis” WHO 2007 21. Janet E. Stout, PhD; Victor L. Yu, MD “ Experiences of the first 16 Hospitals using CopperSilver Ionisation for Legionella Control: Implications for the Evaluation of other Disinfection Modalities” INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY August 2003 22. L K Landeen, M T Yahya and C P Gerba “Efficacy of Copper and Silver Ions and Reduced Levels of Free Chlorine in Inactivation of Legionella pneumophila “ Appl. Environ. Microbiol. 1989, 55(12):3045. 23. Zeming Liu, Janet E. Stout, Marcie Boldin, John Rugh, Warren F. Diven, and Victor L. Yu “Intermittent Use of Copper-Silver Ionization for Legionella Control in Water Distribution Systems: A Potential Option in Buildings Housing Individuals at Low Risk of Infection” Clinical Infectious Diseases 1998;26:138–40 24. Josep Modol, Miquel Sabria, Esteban Reynaga, Maria L. Pedro-Botet, Nieves Sopena, Pere Tudela, Irma Casas ,and Celestino Rey-Joly1 “Hospital-Acquired Legionnaires Disease in a University Hospital: Impact of the Copper-Silver Ionization System” Clinical Infectious Diseases 2007; 44:263–5 25. Ute Rohr, Martin Senger, Fidelis Selenka, Ralf Turley, and Michael Wilhelm “Four Years of Experience with Silver-Copper Ionization for Control of Legionella in a German University Hospital Hot Water Plumbing System” Clinical Infectious Diseases 1999;29:1507–11 26. Hsiu-Yun Shih and Yusen E. Lin “Efficacy of Copper-Silver Ionization in Controlling Biofilmand Plankton-Associated Waterborne Pathogens” APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Mar. 2010 27. Marıa Luisa Pedro-Botet, Inma Sanchez, Miquel Sabria, Nieves Sopena, Lourdes Mateu, Marian Garcıa-Nun ez, and Celestino Rey-Joly “Impact of Copper and Silver Ionization on Fungal Colonization of the Water Supply in Health Care Centers: Implications for Immunocompromised Patients” Clinical Infectious Diseases 2007; 45:84–6 28. (Elias J. Anasissie et al) The Hospital Water Supply as a source of Nosocomial Infections – A Plea for Action. Arch Intern Med. (2002)162, 1483-1492 29. (L.T Curtis) Prevention of hospital-acquired infections: review of non-pharmacological interventions. Journal of Hospital Infection (2008) 69, 204-2119