Keeping Afloat in a Rising Tide of Waterborne HAIs: 8 Facts Healthcare Leaders Must Know

By Joseph S. Cervia, MD, MBA, FACP, FAAP, FIDSA
        
Abstract

Healthcare-associated infections (HAIs) affect an estimated 1.7 million individuals and result in 99,000 deaths annually in American hospitals. With its role in handwashing accepted as perhaps our most reliable means for reducing HAI risk, hospital tap water has also been recognized as a source of such infections. Peer-reviewed literature has demonstrated that hospital tap water contains microbial pathogens, and that biofilm in water systems resists disinfection and delivers pathogenic organisms to the point of care. At-risk patients are susceptible to infection through direct contact, ingestion, and inhalation of waterborne pathogens. Systemic water treatment technologies reduce levels of recognized waterborne pathogens; however, they cannot eradicate biofilm within healthcare facility plumbing. Existing point-of-use (POU) filtration technologies have been reported to interrupt clinical outbreaks of infection due to recognized waterborne pathogens in the healthcare environment, and can represent a critical component of a comprehensive infection control strategy, particularly when targeted for patients at high risk.

Introduction
According to the Centers for Disease Control and Prevention (CDC), HAIs account for an estimated 1.7 million infections and 99,000 deaths annually in American hospitals.(1)  It has long been accepted that handwashing with water may be the most reliable defense in the battle to reduce HAIs; however, hospital tap water has also been recognized paradoxically as a source of risk for such infections. Navigating the turbulent seas of healthcare payment reform and safeguarding precious resources requires an awareness of these risks and how they may be safely and cost-effectively managed. What follows are eight facts healthcare leaders must know in order to stay afloat.

1. Waterborne HAIs are alarmingly common.
In the wake of what has been described as one of the deadliest outbreaks of Legionnaires Disease (LD) ever reported, one of the 127 recognized victims, which included patients, employees, and visitors initiated a $600 million class-action lawsuit against the nursing facility at the center of the storm.(2) A separate 2006 LD outbreak at an acute care facility, which also killed and injured both patients and visitors alike, resulted in a $5.2 million settlement.(3) Yet another institution, a renowned university teaching hospital, has for years been plagued by repeated lawsuits related to LD contracted from its water system.(4-5) According to experts, healthcare-associated LD nationwide is simply not that unusual.(6)  According to the CDC, an estimated 8,000 to 18,000 cases of LD occur each year in the United States. This is particularly striking as the agency also notes that only 2 percent to 10 percent of estimated LD cases are reported.

2. Waterborne HAIs exact a devastating human and financial toll.
Most LD cases are sporadic; 23 percent are nosocomial and 10 percent to 20 percent can be linked to outbreaks. Death occurs in 10 percent to 15 percent of LD cases; and, a substantially higher proportion of fatal cases occur during nosocomial outbreaks. Disease is often attributed to inhalation of contaminated aerosols from showers and faucets, and aspiration of contaminated water. Nevertheless, in normal hosts, bacterial exposures from such water sources are typically cleared by innate defenses, such as the respiratory tracts mucociliary escalator for elimination of inhaled organisms.(7)  However, immunocompromised individuals, such as pharmacologically immunosuppressed recipients of bone marrow and solid organ transplants, persons with congenital or acquired immunodeficiency syndromes, oncology and burn patients, critically ill patients in intensive care units, smokers, individuals with chronic cardiac and respiratory disorders, and residents of skilled nursing facilities are likely to be at higher risk for LD and infections with other waterborne pathogens (WBP). It is precisely for such at-risk patients that appropriate infection control measure are most important.
Since the causative bacterium, Legionella pneumophila will not grow in routinely utilized culture media, LD has been remarkably under-diagnosed. Nevertheless, urinary antigen, direct fluorescent antibody, and culture-based testing for LD have been available to and utilized by clinicians for many years, and enhanced detection methods such as rapid duplex polymerase chain reaction (PCR) testing have been more recently developed. Despite the likelihood of under-diagnosis, Medicare data presented in the Federal Register indicate that for fiscal year 2007, 351 cases of LD were diagnosed in beneficiaries at a cost of $86,014 per hospital stay. 

3.The costs of HAIs are progressively being shifted to providers.
Whereas historically such additional treatment costs have been shifted to payors, with current trends in U.S. healthcare payment reform, it is likely that this burden will be increasingly borne by hospitals. Considering the aforementioned estimates, savings for prevention of LD in Medicare beneficiaries alone would be estimated to be over $30 million per year, substantially higher than that for other healthcare-associated conditions (e.g., air embolism, blood incompatibility, and surgical site infection after coronary artery bypass grafting) recently selected by the Centers for Medicare and Medicaid Services (CMS) in its 2008 Final Rule for exclusion from additional hospital reimbursement. Acknowledging these data, CMS is continuing to consider healthcare-associated LD and infections attributable to other WBP in its subsequent rulemaking.(8)

4. A startling number of HAIs may be attributed to WBPs.
Indeed, while LD outbreaks in healthcare facilities often command headlines, clinicians struggle with other WBP, such as Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter spp. among many others on a daily basis in their hospitalized patients. In fact, some of the most frequently isolated Gram-negative bacteria have been found to persist in hospital water for extended periods and have been responsible for nosocomial outbreaks.(9) A recent review of prospective studies published between 1998 and 2005 indicated that between 9.7 percent and 68.1 percent of random intensive care unit water samples were positive for P. aeruginosa, and between 14.2 percent and 50 percent of patient infections with this organism were due to genotypes found in intensive care unit water.(10) 

According to the CDC, the overall incidence of P. aeruginosa infections alone in U.S. hospitals averages about 0.4 percent (4 per 1,000 discharges), and the bacterium is the fourth most commonly isolated nosocomial pathogen accounting for 10.1 percent of all hospital-acquired infections.(11) In fact, up to 42 percent of P. aeruginosa infections in hospitalized patients have been linked to water;(12-13) and one investigation has estimated that 1,400 deaths occur each year as a result of waterborne nosocomial pneumonias attributable to P. aeruginosa alone.(8) 

All of these infections result in huge costs to our healthcare system, as well as a tremendous human toll in excess morbidity and mortality. Moreover, numerous clinical studies published in peer-reviewed medical literature demonstrate the clinical efficacy and cost-effectiveness of regular water testing, appropriate systemic water disinfection, and POU hospital water filtration as a comprehensive strategy for reducing infections with Legionella and other WBP in hospitals.(14)  CDC, the World Health Organization (WHO), the Occupational Safety and Health Administration (OSHA), the Veterans Health Administration (VHA), and other recognized standards organizations have established guidelines for the prevention of LD and other WBP that have been available and widely distributed for years.(15-22) Yet, tragically, many healthcare facilities fail to establish effective prevention strategies, exposing patients and their institutions to unnecessary risk.

5. WBP risk may be astonishingly difficult to detect.
Despite concerns regarding the increasing incidence of serious HAI due to multi-drug resistant Gram-negative pathogens, the risk of waterborne transmission of these microbes has received relatively little attention. Dr. Bruce Dixon, director of the Allegheny County Health Department has summed up the problem succinctly: If you dont look for it, you wont find it. If you dont find it, you dont think you have a problem. If you dont think you have a problem, you dont do anything about it.(23)  

Even when healthcare facilities do look, a better understanding of the ecology of WBP in the healthcare environment is necessary in order to gain further insight into why this risk may go largely unrecognized. Waterborne microbes thrive to varying degrees in both hot and cold water.  Yet, whereas cold water is delivered directly to the POU (e.g., taps, showers), hot water in large buildings such as hospitals is supplied via a recirculation loop, which contains organic and inorganic nutrients to nourish waterborne microbes, maintains favorable temperatures for microbial growth, and promotes the formation of biofilm on internal surfaces of pipes and fixtures. Waterborne microbes may be shed from biofilm only intermittently, complicating efforts at detection. Moreover, WBP, adapted to life in a relatively nutrient-poor environment, may be difficult to culture using nutrient-rich media for short incubation periods (e.g., 24 to 48 hours at 37 degrees C) as is standard practice for the culturing of specimens obtained from patients by clinical microbiology laboratories. Successful culturing of Legionella and other WBP may require special media and extended incubation periods at lower temperatures (e.g., 20 degrees C for 14 to 28 days).(24)

6. WBPs may be intractably resistant to control.
Ubiquitous in hospital plumbing as in nature, biofilm may be recognized as the slippery material coating wet surfaces, like the slimy material on stones that one may feel between ones toes when wading barefoot in a body of water.  Scientists define biofilm as a microbially-derived sessile community characterized by cells that are irreversibly attached to a substratum or to one another, are embedded in a matrix of extracellular polymeric substances that they have produced, and exhibit altered characteristics with respect to growth rate and gene transcription.(25) Biofilm affords microbial pathogens protection from adverse environmental conditions outside the host;(26)  and, it has been established that biofilm bacteria display a higher level of resistance to antimicrobial agents(27-31) and environmental controls (e.g. ultraviolet light, metals, and acid pH) (32-34) than do planktonic (free-floating) bacteria. Interestingly, for clinically important organisms such as P. aeruginosa, a single genetic locus has been identified to be associated with both the ability to form biofilm and antimicrobial resistance.(35)

The ability to form and maintain biofilm communities for protection from adverse environmental conditions has permitted WBP to survive, thrive, and to evolve further mechanisms for resistance to outside threats across millennia. Thus, our difficulties in detecting and eradicating these organisms by means of altering environmental conditions in our water distribution systems should come as no surprise. 

7. Reducing WBP risk to patients and healthcare institutions requires a proactive and multi-dimensional approach.
Methods used to protect patients and water systems must adequately address biofilm in order to be effective. A number of preventive strategies have been employed by healthcare facilities, usually in response to an outbreak. They include: hot water flushing of the plumbing system, chlorination, chlorine dioxide, monochloramine (used exclusively at the municipal treatment level in the U.S.), copper-silver ionization, ultraviolet light (UV), ozonation, and POU water filtration. Each method has advantages and disadvantages related to ease of implementation, cost, maintenance issues, and short- and long-term effectiveness. Aside from POU filtration, these methods are often incompletely effective in the long-term. Maintenance of systemic disinfection agents at levels that consistently prevent recolonization and biofilm elaboration despite variability in water quality due to seasonal changes and facility construction is difficult. Once reestablished, biofilm effectively protects microbes against the harsh effects of systemic disinfection strategies.

Of these preventive methods, flushing all parts of the plumbing system at temperatures of greater than 65 degrees C is perhaps the easiest to implement, but precludes the use of water outlets during the procedure, occupies substantial facility management staff resources, and presents a risk of scalding. Recent data corroborate earlier observations that hot water flushing is inadequate in eliminating Legionella from plumbing systems over the longer term,(36) even though temperatures above 59 degrees C were associated with an inability to culture Legionella.(37-38)  One study disclosed that a system flush using hot water at 80 degrees C was incapable of eradicating Legionella serogroup 5.39  In fact, one published observation documented the presence of a persistent strain of Legionella in a hospital over the course of 15 years.(40) 

Chlorination is also relatively simple to establish; however, it can be challenging to maintain adequate levels of chlorine throughout a hospital water system.  Electrolytic chlorine generation systems in large-scale studies appear to be no better than sodium hypochlorite.(41) However, chlorination is not free of risk for possible byproduct-associated genotoxicity, which is an emerging concern.(42) Bench-scale chlorination compared with UV irradiation showed that both methods were effective in reducing levels of indicator organisms; however, pathogens of clinical concern were less affected by chlorination.(43) Published data demonstrate that waterborne pathogens are protected against chlorination by biofilm.(44-45)  These findings suggest that chlorination may be less effective than other alternatives, despite its relative cost efficiencies.

Chlorine dioxide effectively reduces, but may not eliminate Legionella.(46) Testing of multiple disinfection strategies has indicated that chlorine dioxide may arguably be the most effective systemic disinfection method for the control of Legionella.(44) In simulated potable water system testing, chlorine dioxide was shown to be more effective in reducing heterotrophic bacterial counts, with reduced levels of some but not all organic halogenated byproducts.(47) However, chlorine dioxide systems are more costly to install than chlorination.

Efficacy studies of chloramines alone or in combination with free chlorine indicate that neither alone is adequate as a disinfectant.(48) In addition, the spectrum of potentially harmful halogenated byproducts left by combination chlorination regimens(49) will take some time to assess.  Chlorine and chloramines also differ in their spectrum of antimicrobial activity. For example, Klebsiella pneumoniae appears to be more sensitive to chloramines than to free chlorine under certain conditions.(50)

Studies of copper-silver ionization used either alone or in combination with other systemic disinfection strategies have demonstrated this technology to be effective to varying degrees.(51) However, it is likely to be more effective when used in combination with another disinfection technology.  Importantly, none of these studies was able to demonstrate sustained eradication of Legionella; however, acutely, copper and silver ions alone and in combination have demonstrated bactericidal activity of greater than 99.999 percent against the clinically relevant WBP, such as P. aeruginosa, A. baumannii, and S. maltophilia, in addition to Legionella.(52-53)

UV irradiation, which is rarely used in the hospital setting in the U.S., has poor penetrating power, is only effective at the source of irradiation, and remains prone to fouling of the quartz sleeves surrounding the UV lamp.(54)  One notable advance is the use of light emitting diodes to deliver UVA radiation, which has been shown to be effective as a bactericidal treatment. However, this technology awaits further characterization.(55)  Like other combinations of systemic disinfection strategies, it should not be surprising that UV and ozonation used in combination have been shown to be better than either used alone.(56)  

POU water filtration offers the potential benefit of immediate and complete effectiveness against waterborne bacteria, fungi, and protozoa.  Although the implementation of POU water filtration for at-risk patient populations in the healthcare setting is a relatively new phenomenon in the U.S., this technology has been used extensively in Europe for over a decade. POU filtration studies have appeared extensively in the scientific literature and have repeatedly addressed the role of filtration technology in both reducing infections due to WBP and reducing costs for healthcare institutions.(14)
Laboratory and clinical studies have validated the efficacy of POU filters in removing WBP.  In one such validation study, two counter-top goose neck faucets were attached to a laboratory model plumbing system. A 0.005 µm point-of-use filter (Nephros Inc., River Edge, New Jersey) was attached to a test faucet. Environmental isolates of Legionella, Pseudomonas, Stenotrophomonas, Acinetobacter, Klebsiella, and Mycobacterium were added to the model plumbing system to reach the starting bacterial concentration for each organism at above 3x103 cfu/mL. Water and swab samples were withdrawn at T = 1, 2, 3, 4, 5, 7 and 14 days from both the test faucet (after filtration) and control faucet (no filtration). A standardized microbiological method was followed for cultures of each organism.  During the 14-day study, more than 30,000 liters of water was run through the filter. Results showed that the point-of-use filter successfully removed L. pneumophila, P. aeruginosa, S. maltophilia, A. baumannii, K. pneumoniae, and M. abcessens from the model plumbing system. No test pathogens were cultured in both water and swab samples from the test faucet. Approximately 2,500,000 cfu/mL of test pathogens, on average, were recovered from the control faucet.(57)  Sheffer, et al.(58)  conducted a study during which it was demonstrated that POU filters labeled for a maximum use life of seven days completely eliminated L. pneumophila and Mycobacterium gordonae from hot tap water over an eight-day period of use. Vonberg, et al.(59)  observed that 99.6 percent of 256 filtered water samples obtained during their study were devoid of Legionella spp. 

After an observation period of 11 months, during which a high incidence of P. aeruginosa bacteremia was observed in a hematology unit with severely neutropenic patients, Vianelli, et al.(60)  performed extensive sampling in an attempt to trace the environmental source of the isolates that were appearing in patient blood cultures. Upon identifying faucets and showers in the unit as the primary environmental sources of those isolates, POU filters were installed on all hematology unit water outlets. Highly statistically significant reductions in bloodstream infections were subsequently observed over the course of the next two years.

In a study spanning a period of two years, Trautmann, et al.(61)  documented a decrease in the monthly rate of P. aeruginosa infections in a surgical intensive care unit (SICU) from 2.5 per month prior to POU filter installation to 0.8 per month after POU filter installation. Van der Mee-Marquet, et al.(62) surveyed pseudomonal infections of blood, urological, and pulmonary origin over 23,611 patient days in an intensive care unit over a period of 7.5 years. During a timeframe of 2.5 years prior to the use of POU filtration, 8.7 infections per 1,000 patient days were observed, while in the five years after installation of POU filters, only 3.2 infections per 1,000 patient days were recorded. 

In a neonatal intensive care unit, La Ferriere(63) employed a variety of infection control interventions, including POU filtration, in order to effect a dramatic decline in HAIs attributable to P. aeruginosa.  More recent clinical studies have demonstrated the efficacy and cost-effectiveness of POU filtration in reducing the risk of infections for bone marrow transplant recipients,(64) and patients in sub-acute care.(65)

Though extremely reliable, potential limitations of a POU water filtration strategy include the risk of possible retrograde contamination of incoming tap water,(66) limited filter use life, and the additional cost of POU filters. With respect to these concerns, it is important to note that not all POU filters are alike. Filters designed for under sink installation are less subject to retrograde splash or touch contamination. In addition, some POU filters are considerably less vulnerable to fouling, and thus labeled for more extended use lives.  Such practical advantages may add considerably to the efficiency and cost-effectiveness of POU filtration for healthcare facilities.

8. Prevention of HAIs related to WBPs is exceedingly cost-effective.
The added cost incurred for HAIs in U.S. hospitals has been conservatively estimated at $15,275 to $38,656 per infection.(67-68) More recent data from the Agency for Healthcare Research and Quality place additional costs for a single HAI closer to $43,000.(69) While scientific studies have supported the use of POU water filters to reduce at-risk patient exposure to WBP, healthcare institutions that adopt this technology can also realize economic benefits. Hall, et al.(70) demonstrated that costs associated with filtered drinking water supplied to immunocompromised patients were drastically lower than those for both bottled sterile water and commercially available bottled water.  In addition, Trautmann, et al.(71) recounted savings realized on the cost of antibiotics used to treat P. aeruginosa infections in a SICU during implementation of POU water filters on faucets.  Finally, it should be noted that these estimates do not take into account the institutional costs inherent in responding to a recognized outbreak of HAIs or of any resulting litigation.

Going with the Flow or Stemming the Tide?
Despite often highly publicized evidence of risk posed by WBP such as Legionella, and the well-documented efficacy of measures to reduce this risk, the control of WBP in U.S. healthcare institutions remains a work in progress. As has been previously stated, the U.S. lags far behind Europe in recognition of tap water as an important source of HAIs. Currently, the approaches taken by many U.S. healthcare institutions to control WBP vary greatly. 

Vigilance with respect to water quality in U.S. hospitals is not uniform.(72) Some facilities respond to an outbreak by culturing water, and temporarily installing some preventive measure such as POU filters. When the outbreak is interrupted, POU filters are removed, leaving the facility unprotected against the inevitable next outbreak.  Still other institutions adopt an undisciplined and haphazard approach to water culturing, installation of a systemic disinfection technology, and fail to implement complementary POU filtration. This approach leaves the facility continually vulnerable to biofilm in the plumbing system, changes in water pressure, and seasonal variations in water quality. It also ignores recent studies indicating that electronic (non-touch) faucets can harbor and promote the proliferation of WBP due to the fact that their electrical solenoid valves remain warm at all times, providing an incubated environment for planktonic and biofilm-based bacteria, fungi, and protozoa.(73-75) More recently, thought-leading facilities have recognized the importance and cost-effectiveness of performing routine microbial analyses of tap water in at-risk patient areas, installing an appropriate systemic disinfection technology, and pro-actively utilizing POU filtration to protect their most vulnerable patients.

Finding a Safe Harbor
It has been suggested that hospital water distribution systems are among the most overlooked, important, and controllable sources of HAI.(8) Available evidence in the peer-reviewed literature has demonstrated that hospital tap water contains microbial pathogens, and that biofilms in water delivery systems resist disinfection and deliver pathogenic organisms into the healthcare environment. At-risk patients are susceptible to infection through direct contact, ingestion, and inhalation of WBP. Systemic water treatment technologies reduce levels of recognized WBP; however, they vary in initial and long-term maintenance costs, efficacy against specific organisms, and compatibility with facility plumbing system materials. Moreover, they do not permanently and completely eradicate biofilms within healthcare facility plumbing. Finally, existing POU filtration technologies have been reported to interrupt clinical outbreaks of infection due to recognized WBP in the healthcare environment, and can represent a critical component of a comprehensive infection control strategy, particularly when pro-actively targeted for patients at high risk.

Joseph S. Cervia, MD, MBA, FACP, FAAP, FIDSA, is clinical professor of medicine and pediatrics at Albert Einstein College of Medicine and Hofstra-North Shore LIJ School of Medicine.

References

  1. Kievens RM, Edwards JR, Richards CL, et al. Estimating Healthcare-Associated Infections and Deaths in U.S. Hospitals 2002. Public Health Reports.2007; 122:160-166.
2. http://www.yourlawyer.com/articles/read/10870  .
  3. http://www.mysanantonio.com/news/local_news/52_million_settles_suit_over_hospital_outbreak.html .
 4. http://www.redorbit.com/news/health/532374/family_of_legionnaires_victim_files_lawsuit/index.html .
 5. http://www.nypost.com/seven/04092007/news/regionalnews/legionnaire_death_suit_regionalnews_denise_buffa.htm .
 6. http://www.nj.com/news/index.ssf/2008/09/legionnaires_disease_strikes_s.html .
  7. Prince A. Biofilms, antimicrobial resistance, and airway infection. N Engl J Med. 2002;347:1110-1111.
8. Federal Register. Part II: Department of Health and Human Services Centers for Medicare & Medicaid Services 42 CFR Parts 411, 412, 413, 422, and 489 Medicare Program; Changes to the Hospital Inpatient Prospective Payment Systems and Fiscal Year 2009 Rates Tuesday, August 19, 2008. 73(161):48471-48487.
9. Anaissie EJ, Penzak SR, Digani MC. The hospital water supply as a source of nosocomial infections: a plea for action. Arch Intern Med. 2002;162:1483-1492.
10. Trautmann M, Lepper P, Haller M. Ecology of Pseudomonas aeruginosa in the intensive care unit and the evolving role of water outlets as a reservoir of the organism. Am J Infect Control. 2005;33(5)(suppl 1):S41-S49.
11. http://www.textbookofbacteriology.net/pseudomonas.html .
12. Reuter S, Sigge A,  Heidemarie W, Trautmann M. Analysis of transmission pathways of Pseudomonas aeruginosa between patients and tap water outlets. Crit Care Med. 2002;30(10):2222-2228.
13. Blanc DS. et al., Faucets as a reservoir of endemic Pseudomonas aeruginosa colonization/infections in intensive care units Intensive Care Med. 2004;30:1964-1968.
14. Cervia JS, Ortolano GA, Canonica FP. Hospital Tap Water: A Reservoir of Risk for Health Care-Associated Infection. Infect Dis in Clin Practice. 2008;16(6):349-353.
15. http://www.lapublichealth.org/ACD/docs/Legionnaires/Legionella_Guidelines_Final.pdf
16. http://www.osha.gov/dts/osta/otm/legionnaires/sampling.html
17. http://www.who.int/water_sanitation_health/emerging/Legionella.pdf 
 18. http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=1654
19.  http://www.cdc.gov/ncidod/dbmd/diseaseinfo/legionellosis_g.htm
20. http://www.Legionella.org.
21. http://www.osha.gov/dts/osta/otm/legionnaires/conf_outbreaks.html#Control
 22. Guidelines for Environmental Infection Control in Health-Care Facilities: Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR. June 6, 2003;52(RR10);1-42.
23. Squier CL, Stout JE, Krsytofiak S, et al. A proactive approach to prevention of health care-acquired Legionnaires' disease: the Allegheny County (Pittsburgh) experience. Am J Infect Control. 2005; Aug;33(6):360-7.
24. Reasoner, D.J., Geldreich, E.E., A new medium for the enumeration and subculture of bacteria from                potable water. Appl and Environ Microbiol. 1985; 49(1):1-7.
25. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev. 2002;15(2):167-193.
26. Lindsay D, von Holy A. Bacterial biofilms within the clinical setting: what healthcare professionals should know. J Hosp Infect. 2006;64:313-325.
27.  Costerton JW, Lewandowski Z, Caldwell DE, et al. Microbial biofilms. Annu Rev Microbiol. 1995;49:711-745.
28. Donlan RM. Biofilms: microbial life on surfaces. Emerg Infect Dis. 2002;8:881-890.
29. Lindsay D, von Holy A. Different responses of planktonic and attached Bacillus subtilis and Pseudomonas fluorescens to sanitizer treatment. J Food Prot.1999;62:368-379.
30. Dodds MG, Grobe J, Stewart PS. Modeling biofilm antimicrobial resistance. Biotechnol Bioeng. 2000;68:456-465.
31.  Meyer B. Approaches to prevention, removal and killing of biofilms. Int Biodeterior Biodegradation. 2003;51:249-253.
32. Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial biofilms: from the natural environment to infectious diseases. Nat Rev Microbiol. 2004;2:95-108.
33. Hall-Stoodley L, Stoodley P. Biofilm formation and dispersal and the transmission of human pathogens. Trends Microbiol. 2005;13:7-10.
34. Jefferson KK. What drives bacteria to produce a biofilm? FEMS Microbiol Lett. 2004;236:163-173.
35. Drenkard E, Ausubel FM. Pseudomonas biofilm formation and antimicrobial resistance are linked to phenotypic variation. Nature. 2002;416:740-743.
36. Mouchtouri V, Velonakis E, Hadjichristodoulou C.  Thermal disinfection of hotels, hospitals, and athletic venues hot water distribution systems contaminated by Legionella species. Am J Infect Control. 2007 Nov;35(9):623-7.
  37. Lasheras A, Boulestreau H, Rogues AM, Ohayon-Courtes C, Labadie JC, Gachie JP.  Influence of amoebae and physical and chemical characteristics of water on presence and proliferation of Legionella species in hospital water systems. Am J Infect Control. 2006 Oct;34(8):520-5.
  38. Saby S, Vidal A, Suty H.  Resistance of Legionella to disinfection in hot water distribution systems. Water Sci Technol. 2005;52(8):15-28.
  39. Perola O, Kauppinen J, Kusnetsov J, Kärkkäinen UM, Lück PC, Katila ML Persistent Legionella pneumophila colonization of a hospital water supply: efficacy of control methods and a molecular epidemiological analysis. APMIS. 2005 Jan;113(1):45-53.
  40. Scaturro M, Dell'eva I, Helfer F, Ricci ML.  Persistence of the same strain of Legionella pneumophila in the water system of an Italian hospital for 15 years. Infect Control Hosp Epidemiol. 2007 Sep;28(9):1089-92. Epub 2007 Jul 3.
  41. Clevenger T, Wu Y, Degruson E, Brazos B, Banerji S.  Comparison of the inactivation of Bacillus subtilis spores and MS2 bacteriophage by MIOX, ClorTec and hypochlorite.  J Appl Microbiol. 2007 Dec;103(6):2285-90.
  42. Richardson SD, Plewa MJ, Wagner ED, Schoeny R, Demarini DM.  Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: A review and roadmap for research.  Mutat Res. 2007 Nov-Dec;636(1-3):178-242
  43. Blatchley ER 3rd, Gong WL, Alleman JE, Rose JB, Huffman DE, Otaki M, Lisle JT.  Effects of wastewater disinfection on waterborne bacteria and viruses.  Water Environ Res. 2007 Jan;79(1):81-92
  44. Berry D, Xi C, Raskin L.  Microbial ecology of drinking water distribution systems.  Curr Opin Biotechnol. 2006 Jun;17(3):297-302. Epub 2006 May 15.
  45. Loret JF, Robert S, Thomas V, Cooper AJ, McCoy WF, Lévi Y.  Comparison of disinfectants for biofilm, protozoa and Legionella control.  J Water Health. 2005 Dec;3(4):423-33.
  46. Zhang Z, McCann C, Stout JE, Piesczynski S, Hawks R, Vidic R, Yu VL.  Safety and efficacy of chlorine dioxide for Legionella control in a hospital water system.  Infect Control Hosp Epidemiol. 2007 Aug;28(8):1009-12.
 47.  Rand JL, Hofmann R, Alam MZ, Chauret C, Cantwell R, Andrews RC, Gagnon GA.  A field study evaluation for mitigating biofouling with chlorine dioxide or chlorine integrated with UV disinfection.  Water Res. 2007 May;41(9):1939-48
  48. Chen C, Zhang XJ, He WJ, Han HD.  Simultaneous control of microorganisms and disinfection by-products by sequential chlorination. Biomed Environ Sci. 2007 Apr;20(2):119-25.
 49.  Hua G, Reckhow DA.  Characterization of disinfection byproduct precursors based on hydrophobicity and molecular size. Environ Sci Technol. 2007 May 1;41(9):3309-15.
  50. Goel S, Bouwer EJ.  Factors influencing inactivation of Klebsiella pneumoniae by chlorine and chloramine.  Water Res. 2004 Jan;38(2):301-8. 
  51. Cachafeiro SP, Naveira IM, García IG.  Is copper-silver ionisation safe and effective in controlling Legionella?  J Hosp Infect. 2007 Nov;67(3):209-16.
  52. Huang HI, Shih HY, Lee CM, Yang TC, Lay JJ, Lin YE.  In vitro efficacy of copper and silver ions in eradicating Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter baumannii: Implications for on-site disinfection for hospital infection control. Water Res. 2007 Jul 12.
  53. Mòdol J, Sabrià M, Reynaga E, Pedro-Botet ML, Sopena N, Tudela P, Casas I, Rey-Joly C. Hospital-acquired legionnaires disease in a university hospital: impact of the copper-silver ionization system.  Clin Infect Dis. 2007 Jan 15;44(2):263-5.
  54. Nessim Y, Gehr R. Fouling mechanisms in a laboratory-scale UV disinfection system. Water Environ Res. 2006 Nov;78(12):2311-23.
 55.  Mori M, Hamamoto A, Takahashi A, Nakano M, Wakikawa N, Tachibana S, Ikehara T, Nakaya Y, Akutagawa M, Kinouchi Y.  Development of a new water sterilization device with a 365 nm UV-LED. Med Biol Eng Comput. 2007 Dec;45(12):1237-41.
  56. Oh BS, Park SJ, Jung YJ, Park SY, Kang JW.  Disinfection and oxidation of sewage effluent water using ozone and UV technologies. Water Sci Technol. 2007;55(1-2):299-306.
 57.  Lin, Y.E., Shih, H.Y., Stout, J.E. Efficacy of Point-of-Use Water Filter in Removing Nosocomial Infection-Associated Waterborne Pathogens in a Laboratory Model Plumbing System.  Society of Healthcare Epidemiology of America Annual Meeting 2009; Poster 101.
 58. Sheffer, P., J. Stout, M. Wagener, and R. Muder. Efficacy of new point-of-use water filter for preventing exposure to Legionella and waterborne bacteria.  Amer. J. Infect. Cont. 2005;33(5) Supplement 1:S20-S25.
59. Vonberg, R.P., T. Eckmanns, J. Bruderek, H. Ruden, and P. Gastmeier. Use of terminal tap water filter systems for prevention of nosocomial legionellosis. J. Hosp. Infect. 2005;60:159-162.
60. Vianelli, N. et al Resolution of a Pseudomonas aeruginosa outbreak in a hematology unit with the use of disposable sterile water filters. Haematologica.2006;91(7):983-985.
61. Trautmann, M., H. Royer, E. Helm, W. May, and M. Haller. Pseudomonas aeruginosa: new insights into transmission pathways between hospital water and patients. Filtration. 2004;1(Supplement 1): 63-70.
62. Van der Mee-Marquet, N et al. Water microfiltration: a procedure to prevent Pseudomonas aeruginosa infection.  XVI Congres Nat. Soc. Franc. DHyg. Hospitaliere, Water and Hospital Symposium.2005;Reims, France. Abstract S.137.
 63. LaFerriere, C. Infection control measures vs. waterborne microbes in the NICU. SHEA Annual Meeting Poster Session. 2006;Chicago.
64. Cervia J.S., Farber B., Armellino D., Klocke J., Bayer R.L., McAlister M., Stanchfield I., Canonica F.P.,  Ortolano G.A.  Point-of-use water filtration reduces healthcare-associated infections in bone marrow transplant recipients. Transpl Infect Dis. 2010 Jun;12(3):238-41. Epub 2009 Sep 25.
65. Holmes C., Cervia J.S., Ortolano G.A., Canonica F.P. Preventive efficacy and cost-effectiveness of point-of-use water filtration in a subacute care unit. Am J Infect Control. 2010 Feb;38(1):69-71. Epub 2009 Aug 25.
 66. Rogues, A-M,  H. Boulestreau,, A. Lashe´ras, A. Boyer, D. Gruson , C. Merle, Y. Castaing, C.M. Be´bear, J.-P. Gachie. Contribution of tap water to patient colonization with Pseudomonas aeruginosa in a medical intensive care unit. J Hosp Infect. 2007; 67:72-78.
67. Roberts, R.R., R.D. Scott II, R. Cordell et al. The use of economic modeling to determine the hospital costs associated with nosocomial infections.  Clin. Infect. Dis. 2003;36(11):1424-1432.
68. Zahn, C. and M.R. Miller. Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. JAMA. 2003;290(14):1868-1874.
 69. Lucado, J., Paez, K., Andrews, R., Steiner, C. Adult Hospital Stays with Infections Due to Medical Care, 2007. Agency for Healthcare Research and Quality, Healthcare Cost and Utilization Project. Statistical Brief #94. August 2010.
70. Hall, J., G. Hodgson, and K.G. Kerr. Provision of safe potable water for immunocompromised patients in hospital. J. Hosp. Infect. 2004;58:155-158.
71. Trautmann, M., T. Michalsky, H. Wiedeck, V. Radosavljevic, and M. Ruhnke. Tap water colonization with Pseudomonas aeruginosa in a surgical intensive care unit (ICU) and relation to Pseudomonas infections of ICU patients. Infect. Control Hosp.Epidemiol. 2001;22(1):49-52.
72. Kozicki, Z. A. A call for a new standard for water quality in health care facilities. 12th World Congress on Public Health. Istanbul, Turkey. April 29, 2009.
73. Halabi, M., M. Weisholzer-Pittl, J. Dchoberj, and H. Mittermeyer. Non-touch fittings in hospitals: a possible source of P. aeruginosa and Legionella spp. J Hosp Infect. 2001;49(2):117-21.
74.  Merrer, J., E. Girou, and D. Ducellier. Should electronic faucets be used in intensive care and hematology units?  Intensive Care Med. 2005;31:1715-1718.
75. Chaberny, I., and P. Gastmeier. Should electronic faucets be recommended in hospitals? Infect. Cont. Hosp. Epidemiol. 2004;25:997-1000.