Resisting resistance: The need for next-generation disinfectants A new silver-based disinfectant could rise to challenges presented by resistant bacteria in health care environments By Michael L. Krall, PURE Bioscience Two million patients in the U.S. become infected each year while hospitalized, and more than 70% of the bacteria causing these infections are resistant to antibiotics, with approximately 90,000 patients a year dying as a result of their infections.1 Three of the most common hospital acquired infections (HAIs) are Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. Hospitals becoming risky business The growing bias toward outpatient care has made hospitals the repository of acutely ill and vulnerable patients, and performance of more aggressive operative techniques on an ever-aging population increases the age/acuity target mix for infections. Antimicrobial resistance continues to develop in those treatment environments demonstrating the highest patient risk, with intensive care units at the center of antibiotic resistance generation.2 Cost estimates of HAIs range from $5 billion to $30 billion in the United States each year.3-5 The economic impact of these infections will be felt even more dramatically within the next 12 months as hospitals will be forced to completely absorb the cost of the majority of HAIs. The Centers for Medicare and Medicaid Services (CMS) has recently published regulations that indicate that beginning in 2008, Medicare will not compensate hospitals for HAI-related claims because CMS considers such infections preventable. Approximately 57% of patients contracting HAIs are Medicare patients.6 Increasing governmental and consumer pressure will drive hospitals to seek improved infection control technologies. One impetus is that HAI reporting will soon become mandatory in all states. The Healthy Hospitals Act of 2007 amends title XVIII of the Social Security Act to require public reporting of health care-associated infections data by hospitals and ambulatory surgical centers; it also permits the Secretary of Health and Human Services to establish a pilot program to provide incentives to hospitals and ambulatory surgical centers to eliminate the rate of occurrence of such infections. Deficiencies of widely used products Procedure and routine form the backbone of hospital infrastructure; however, even a perfectly executed maintenance schedule cannot overcome the constant introduction of microorganisms to the hospital environment. Hospital visitors, accidental cross-contamination by staff, quick room turnovers, and growing resistance to antimicrobials remain constant challenges to a well run hospital. Assuming that precautionary procedures are universally and accurately applied, yet observing that HAI rates are still rising, another variable in the hospital setting must be examined: the products employed during implementation of the maintenance routines. Hospitals rely on sodium hypochlorite (bleach) or quaternary ammonia-based products for disinfection of environmental surfaces in all areas of the facility-from procedure, critical, and ambulatory care areas to common and administrative spaces. Dependence on these “traditional” disinfectants has become increasingly problematic as awareness of their dangers has risen. Bleach and quaternary ammonia products are not ideal for many areas of the hospital because they are toxic and produce harsh fumes. Dermal, ocular, and inhalation exposure to quaternary ammonia fumes can result in a variety of reactions, ranging in intensity from skin irritation/burning, redness, and blistering; eye irritation/burning, pain, and swelling; to respiratory irritation/burning, irritation to mouth, throat, and nose, flu-like symptoms, and headache, among others.7 In addition, allergic-type reactions including hives and contact dermatitis have been reported. Click here to enlarge image Bleach-based products pose similar challenges in that they are corrosive and can cause severe chemical burn damage to eyes and skin and may release harmful vapors. Inadvertent, yet unfortunately common, mixing of bleach with acids or ammonia releases dangerous chlorine or chloramine gas, which can cause acute respiratory irritation and, in extreme cases, asphyxiation.8,9 Quaternary ammonia and bleach-based products are obviously problematic for use near health-compromised-especially respiratory-compromised-patients. Restrictions related to toxicity of and exposure to traditional disinfectants often require hospitals to displace patients in order to properly disinfect facilities, resulting in increased turnover time (and lost revenue) for procedure areas and patient rooms. Hospitals must frequently re-apply these traditional disinfectants because the products require long contact times and do not provide residual protection against re-contamination of surfaces. Also, more strains of organisms are developing resistance to quaternary ammonias as well as other common disinfectants and sanitizing agents. Researchers have observed strains of methicillin-resistant Staphylococcus aureus (MRSA) and other resistant bacteria that have shown an increasing tolerance to common biocides including quaternary ammonias.10,11 In spite of the use limitations and innate health risks posed by these products, when used under strict protocols, bleach and quaternary ammonias have adequately controlled the transmission of disease-causing organisms in closed population environments like hospitals. Until now. A new solution to HAIs must be implemented to prevent further human and economic losses. ‘Silver bullet’ solution? Silver has been recognized for thousands of years as an effective anti-infective agent.12 Hippocrates, the father of modern medicine, wrote that silver had beneficial healing and anti-disease properties, and ancient cultures stored food, water, and other liquids in silver vessels to prevent spoilage. U.S. pioneers at the turn of the 20th century placed silver dollars in milk bottles to prolong freshness. Silver compounds were even used successfully to prevent infection in World War I before the advent of modern antibiotics. Click here to enlarge image Although the widespread use of silver went out of fashion with the development of modern antibiotics, recently there has been renewed interest in silver as a broad-spectrum antimicrobial. Many silver technologies have been successfully commercialized after achieving the appropriate regulatory registrations and approvals for niche uses. In medicine, silver sulfadiazine cream, often used in combination with silver-coated dressings, is the “standard of care” for the antibacterial/antibiotic treatment of serious burns. Additionally, silver-coated catheters and other medical devices are gaining market share, with over-the-counter silver impregnated bandages now available to consumers. Several industries have embraced silver as a natural and effective antimicrobial solution, with silver technologies now prevalent in food processing and packaging materials, water treatment equipment, textiles, construction products, and HVAC systems. Increasing consumer awareness and use of silver as an antimicrobial continues to rise as more and more domestic and international companies are integrating silver technologies into plastics for various products. The safety of silver and silver compounds has been extensively reviewed in the public literature and summarized and interpreted in U.S. Environmental Protection Agency (EPA) and U.S. Food and Drug Administration (FDA) decisions, by other federal agencies, and by international organizations. For example, the EPA has evaluated silver on multiple occasions and has concluded that there are no adverse health effects associated with ingestion of silver. In animal studies, as reported by the Agency for Toxic Substances and Disease Registry (ATSDR) in 1990 and EPA in 1993, silver is of low acute toxicity (no toxic effects reported at the doses tested). Furthermore, there is no evidence of acute or chronic toxicity, mutagenicity, carcinogenicity, neurotoxicity, or reproductive or developmental effects due to silver.13,14 In addition, the EPA Office of Water set a Secondary Maximum Contaminant Level for silver in drinking water of 0.1 mg/L based solely on cosmetic effects; although this is a nonenforceable level offered for guidance purposes, the decision determined that there are no health effects associated with 0.1 mg/L in water.15 Identical conclusions to those reached by EPA and ATSDR were reported by the World Health Organization (2003) and by the National Research Council (NRC, 2004).16,17 Neither WHO nor NRC identified any new data beyond that considered by ATSDR and EPA. Silver’s multiple modes of action are believed responsible for its quick and broad-spectrum efficacy (which depends upon its ionization level) as well as for the low probability of inducing bacterial resistance. Creating a stabilized ionic silver formulation opens the door for its use in a wide array of products and treatments-including hard surface disinfection. Perhaps the most differentiating and salient characteristic of silver is the fact that no clinical evidence exists of the development of ionic silver-resistant microbial strains.18 One ionic silver disinfectant registered with the EPA (EPA registration number 72977‑3) carries claims of broad-spectrum efficacy superior to those of traditional disinfectants (see tables). In addition to antiviral and antifungal claims, the 30-ppm silver dihydrogen citrate (SDC) disinfectant carries a 30-second kill against Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella choleraesuis, and Listeria monocytogenes. The first new disinfectant active to be registered by the EPA in more than 30 years, the SDC-based product also provides 24-hour residual protection against standard indicator bacteria and a two-minute kill claim on MRSA and vancomycin-resistant Enterococcus faecium (VRE). Moreover, SDC-based disinfectants pose little if any health hazard because they are odorless, colorless, non-corrosive, non-flammable, and compatible with other disinfecting cleaners.19 Bacteria are actually attracted to SDC as opposed to being repelled as they are by traditional disinfectants.20 Bacteria utilize carbon, including organic compounds like citrate, as a nutritional source.21,22 Because of the citric acid component of the SDC molecule, bacteria recognize and take in the SDC as a food source (see Fig. 1). After easily entering the microorganism through membrane transport proteins, the ionic silver binds to DNA and intracellular proteins and causes irreversible damage to the DNA and protein structure (see Fig. 2). Metabolic and reproductive functions halt, and the organism dies.23 This unique “Trojan horse” mode of action is in addition to the expected affinity between silver ions and sulfur-containing thiol groups in metabolic and structural proteins bound to the membrane surface.24 In this extracellular attack, SDC targets these critical proteins and destroys their structure (see Fig. 3). Disruption of the organism’s membrane function and integrity lyses the membrane and the organism dies. Figure 1. Silver dihydrogen citrate’s (SDC’s) rapid and broad spectrum efficacy is largely attributed to its dual mechanisms of action and unique characteristics. These two mechanisms, alone or in combination, make SDC a powerful antimicrobial while mitigating microbial resistance. Image courtesy of PURE Bioscience.Click here to enlarge image null Figure 2. Bacteria are actually attracted to SDC because they recognize citric acid as a food source. SDC easily enters the microorganism like a “Trojan horse” through membrane transport proteins, binds to DNA and intracellular proteins, and causes irreversible damage to the DNA and protein structure. Metabolic and reproductive functions halt and the organism dies. Image courtesy of PURE Bioscience.Click here to enlarge image null Figure 3. Silver ions are attracted to sulfur-containing thiol groups in metabolic and structural proteins bound to the membrane surface. SDC targets these critical proteins and destroys their structure in an extracellular attack. Disruption of the organism’s membrane function and integrity lyses the membrane and the organism dies. Images courtesy of PURE Bioscience.Click here to enlarge image null In this time of rapidly growing human and economic costs of HAIs, including resistant strains of bacteria, solutions must be developed and implemented to prevent such infections. The burden of loss will continue to grow for patients who suffer from HAIs, families who feel the impact of fatalities from the infections, and the economy that has been absorbing up to $30 billion annually (and growing) for a largely preventable epidemic in our hospitals. Michael L. Krall is CEO of PURE Bioscience, which develops and markets technology-based bioscience products (www.purebio.com). References U.S. CDC, “Campaign to Prevent Antimicrobial Resistance in Healthcare Settings: Why a Campaign?”, www.cdc.gov/drugresistance/healthcare/problem.htm, 2001. J.D. Siegel, MD, et al., Healthcare Infection Control Practices Advisory Committee, “Management of Multidrug-Resistant Organisms in Healthcare Settings,” pp. 8-10, 2006. U.S. CDC Office of Enterprise Communication, “Hospital Infections Cost U.S. Billions of Dollars Annually,” Mar. 2006. R.W. Haley, “Incidence and Nature of Endemic and Epidemic Nosocomial Infections,” Hospital Infections, Boston: Little, Brown, pp. 359-74, 1985. R.R. Roberts et al., “The Use of Economic Modeling to Determine the Hospital Costs Associated with Nosocomial Infections,” Clinical Infectious Diseases (36:11), pp. 1424-1432, 2003. D. Murphy, RN, BSN, MPH, CIC, et al, “Dispelling the Myths: The True Cost of Healthcare-Associated Infections,” An APIC Briefing, Feb. 2007. U.S. EPA Office of Pesticide Programs Antimicrobials Division, “Incident Reports Associated with Quaternary Ammonium Compounds (Quats),” http://pi.ace.orst.edu/search/getDocketDocument.s?document=EPA-HQ-OPP-2006-0339-0009, Feb. 15, 2006. U.S. EPA Pesticides and Toxic Substances (7508W), “Sodium and Calcium Hypochlorite Salts,” R.E.D Facts 738-F-91-108, www.epa.gov/oppsrrd1/REDs/Factsheets/0029fact.pdf, Sept. 1991. U.S. Dept. of Health and Human Services Agency for Toxic Substances & Disease Registry, “Calcium Hypochlorite (CaCl2O2)/Sodium Hypochlorite (NaOCl) CAS 7778-54-3/7681-52-9;UN 1748/1791,” Medical Management Guidelines, www.atsdr.cdc.gov/MHML/mmg184.html. A.P. Fraise, “Susceptibility of Antibiotic-Resistant Cocci to Biocides,” J. Appl. Microbiology Symp. Suppl. (92), 185X-162S, 2002. G. Sundheim et al., “Bacterial Resistance to Disinfectants Containing Quaternary Ammonium Compounds,” International Biodeterioration & Biodegradation (41:3-4), pp. 235-239, 1998. J.L. Clement, P.S. Jarrett, “Antimicrobial Silver,” Metal-Based Drugs (1), pp. 467-482, 1994. National Toxicology Prog., NIEHS, Research Triangle Park, NC, NTIS #PB2002-109208, 2002. U.S. EPA, Office of Pesticide Prog., Re-registration Eligibility Decision for Silver, case 4082, 1993. U.S. EPA, Silver, Integrated Risk Information Systems, last rev. Oct. 28, 2003 (1996). . WHO, “Silver in Drinking Water,” Geneva (WHO/SDE/WSH/03.04/14). NRC, Spacecraft Water Exposure Guidelines for Selected Contaminants (1:9), The National Academies Press, 2004. A.B. Lansdown, “Silver I: Its Antibacterial Properties and Mechanism of Action,” J. Wound Care (11:4), pp. 125-30, Apr. 2002. PURE Bioscience web site, www.purebio.com/technolo gies/silver_dihydrogen_citrate. L. Benov, I. Fridovich, “Escherichia coli Exhibits Negative Chemotaxis in Gradients of Hydrogen Peroxide, Hypochlorite, and N-chlorotaurine: Products of the Respiratory Burst of Phagocytic Cells,” Proc. Natl. Academy of Sci. of the United States of America (93:10), pp. 4999-5002, May 1996. K. Todar, “Nutrition and Growth of Bacteria,” Todar’s Online Textbook of Bacteriology, University of Wisconsin-Madison Dept. of Bacteriology, 2004. G. Molin, “Mixed Carbon Source Utilization of Meat-Spoiling Pseudomonas fragi 72 in Relations to Oxygen limitation and Carbon dioxide Inhibition,” Appl. and Environ. Microbiology (49:6), pp. 1442-1447, 1985. Q.L. Feng et al., “A Mechanistic Study of the Antibacterial Effect of Silver Ions on Escherichia coli and Staphylococcus aureus,” J. Biomedical Mat. Research (52:4), pp. 662-668, 2000. A.D. Russell, W.B. Hugo, “Antimicrobial Activity and Action of Silver,” Progress in Medicinal Chemistry (31), pp. 351-70, 1994.