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The Centers for Disease Control and Prevention (CDC) has estimated that health care-associated infections account for an estimated 1.7 million infections, 99,000 deaths, and $4.5 billion in excess health care costs annually (16). The key interventions used to control health care-associated infections include surveillance (27, 33), isolation of patients with communicable diseases (26) or multidrug-resistant pathogens (81), proper skin antisepsis prior to invasive procedures and hand hygiene by health care workers (12), and appropriate disinfection and sterilization of medical devices and environmental surfaces (73, 75, 79).
Multiple nosocomial outbreaks have resulted from inadequate antisepsis or disinfection. Inadequate skin antisepsis may result from a lack of intrinsic antimicrobial activity of the antiseptic, a resistant pathogen, overdilution of the antiseptic, or the use of a contaminated antiseptic. The inadequate disinfection of medical devices or environmental surfaces may result from a lack of intrinsic antimicrobial activity of the disinfectant, an incorrect choice of a disinfectant, a resistant pathogen, overdilution of the disinfectant, an inadequate duration of disinfection, a lack of contact between the disinfectant and the microbes, or the use of a contaminated disinfectant. Editorials have noted that contaminated antiseptics and disinfectants have been the occasional vehicles of hospital infections for more than 50 years (20, 72, 76). This paper concisely reviews nosocomial outbreaks associated with the use of a microbiologically contaminated germicide and focuses on the currently recommended germicides.
A precise understanding of terminology is important to understanding the uses of germicides in modern health care. Germicides are biocidal agents that inactivate microorganisms and include antiseptics, disinfectants, and preservatives. Antiseptics are antimicrobial substances that are applied to the skin or mucous membranes to reduce the microbial flora. Disinfectants are substances that are applied to inanimate objects to destroy harmful microorganisms, although they may not kill bacterial spores. Decontamination is a procedure that removes pathogenic microorganisms from objects so they are safe to handle, use, or discard. Finally, preservatives are incorporated into medications or fluids to prevent microbial growth. Germicides may become contaminated as a result of improper manufacturing techniques or during shipping (intrinsic contamination) or during manipulation or use within the health care facility (extrinsic contamination).
Microbial resistance to germicides has been reviewed previously (37, 49, 62, 68, 71). As with antibiotic resistance, resistance to germicides may be an intrinsic property or may arise either by chromosomal gene mutation or by the acquisition of genetic material in the form of plasmids or transposons (49, 68, 71). Importantly, although microbes may display intrinsic resistance to specific antiseptics, antibiotic-resistant pathogens (e.g., methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci) do not demonstrate resistance to germicides at the currently used contact times and concentrations (29, 66, 67, 69, 70, 92).
Antiseptics are used in health care to reduce the transient microbial flora on the hands of health care providers, to reduce the person-to-person transmission of microbes (e.g., methicillin-resistant Staphylococcus aureus), to prepare the skin of patients prior to invasive procedures, and to achieve surgical hand antisepsis. The products commonly used in the United States include alcohols, chlorhexidine, chloroxylenol, iodine and iodophors, quaternary ammonium compounds (e.g., benzethonium chloride), and triclosan (12). The antimicrobial spectra of the currently used antiseptics are displayed in Table Table2.2. More than 40 outbreaks and pseudo-outbreaks due to contaminated antiseptics have been reported (Table (Table3)3) (4, 5, 8, 10, 11, 13-15, 17, 19, 20, 24, 25, 28, 30, 32, 34, 36, 38, 39, 43, 45-47, 50, 52-54, 58, 59, 61, 63, 78, 83-86, 89-91, 93).
The majority of alcohol-based hand antiseptics contain isopropanol, ethanol, or N-propanol. The latter agent, N-propanol, is not currently approved for use for hand hygiene in the United States. Antiseptic agents are available that combine two alcohols or alcohol solutions and another agent (e.g., hexachlorophene, quaternary ammonium compounds, povidone-iodine, triclosan, or chlorhexidine gluconate). Waterless alcohol foams, liquids, and gels are now widely used in health care to improve compliance with hand hygiene (35, 60, 65). Importantly, alcohols have poor activity against bacterial spores, protozoan oocysts, and certain nonlipophilic (nonenveloped) viruses.
The contamination of alcohol-based solutions has rarely been reported. One pseudoepidemic of bacteremia (34) and one outbreak of bacteremia (54) have been traced to contaminated alcohol used for skin antisepsis. These were traced to the use of intrinsically contaminated alcohol (34) and dilution of the alcohol with contaminated water (54).
Chlorhexidine gluconate is widely used in the United States for hand hygiene. Its antimicrobial activity occurs more slowly than that of alcohols.
Multiple outbreaks have been linked to contaminated chlorhexidine. Most reports have been traced to the use of contaminated water to prepare diluted preparations and/or the practice of reusing bottles to dispense chlorhexidine without adequate disinfection. Although most outbreaks have occurred with solutions containing less than 2% chlorhexidine, an outbreak has been reported with solutions of 2% to 4% chlorhexidine (90). The inappropriate use of chlorhexidine as a disinfectant has also led to outbreaks. Examples include the use of contaminated chlorhexidine solutions to disinfect glass reservoirs containing urinary bladder irrigants (51), plastic clamps (48), and thermometers (17). Outbreaks due to contaminated chlorhexidine/cetrimide solutions have also been reported (8, 13, 93).
Chloroxylenol, also known as parachlorometaxylenol, is a halogen-substituted phenolic compound that has been used both as a preservative and as an active agent in antimicrobial soaps. An outbreak of Serratia marcescens infection or colonization in a neonatal intensive care unit was traced to extrinsically contaminated 1% chloroxylenol soap (5).
Quaternary ammonium compounds are composed of a nitrogen atom linked directly to four alkyl groups, which may vary in their structure and complexity. Of this large group of compounds, alkyl benzalkonium chlorides are the most widely used as antiseptics. Other agents include benzethonium chloride, cetrimide, and cetylpyridium chloride. The FDA classifies benzalkonium chloride as having insufficient data to classify it as safe and effective for use for antiseptic hygiene.
More outbreaks have been ascribed to contaminated benzalkonium chloride than any other antiseptic (Table (Table3).3). In 2003, Tiwari and colleagues reviewed the literature and referenced multiple reports of outbreaks or pseudo-outbreaks associated with the use of benzalkonium chloride (86). The most common species were aerobic, gram-negative bacilli, including Burkholderia cepacia, S. marcescens, and Enterobacter spp. Most but not all outbreaks were linked to the storage of benzalkonium chloride with cotton or gauze or the improper dilution of the benzalkonium chloride solution. The use of benzalkonium chloride to disinfect endoscopes has also led to urinary tract and pulmonary infections (20), and the use of contaminated spray bottles for environmental disinfection led to S. marcescens infections complicating cardiopulmonary surgery (22). The failure of benzalkonium chloride as a preservative in multidose albuterol bottles led to respiratory tract colonization and infection (31). Contaminated benzalkonium chloride used to disinfect the septa of multidose corticosteroid bottles has led to injection site abscesses with Pseudomonas aeruginosa (56).
Iodine has been used as an antiseptic for more than 100 years. Because iodine often causes irritation and discoloring of the skin, iodophors have largely replaced iodine as the active agent in antiseptics. Multiple outbreaks due to contaminated iodophors have been reported (Table (Table3).3). The prolonged survival of B. cepacia in commercially manufactured providone-iodine has been documented (3), and intrinsic contamination of a povidone-iodine solution led to both infections and pseudoinfections (10, 14, 36, 58-59). These reports of intrinsic microbial contamination of antiseptic formulations of povidone-iodine and poloxamer-iodine caused a reappraisal of the chemistry and use of iodophors. It was found that “free” iodine (I2) contributes to the bactericidal activity of iodophors and that dilutions of iodophors demonstrate more rapid bactericidal action than a full-strength povidone-iodine solution. The reason for the observation that dilution increases bactericidal activity is unclear, but it has been suggested that dilution of povidone-iodine results in a weakening of the iodine linkage to the carrier polymer, with an accompanying increase of free iodine in solution. Therefore, iodophors must be diluted according to the manufacturers' directions to achieve antimicrobial activity.
Although most reports of contaminated iodophors have reported contamination with gram-negative bacilli, O'Rourke and colleagues isolated Staphylococcus aureus from the rims of two bottles containing an iodophor in an operating room (57). No infections were noted as a result of this contamination.
Triclosan at concentrations of 0.2% to 2% has antimicrobial activity and has been incorporated into soaps for use by health care workers and into a variety of commercial products. It has a broad range of antimicrobial activity, but it is often bacteriostatic.
Liquid soap bottles containing 1% triclosan used as an operating room scrub were found to be contaminated with S. marcescens or Candida parapsilosis (7). However, no infections were reported. An outbreak of newborn conjunctivitis due to S. marcescens was associated with the use of intrinsically contaminated 0.5% triclosan antiseptic soap (50).
A variety of chemical agents are used as disinfectants; the choice of an agent depends on its intended use (Table (Table1).1). Disinfectants have not been as commonly involved in outbreaks as antiseptics (Table (Table4)4) (6, 9, 18, 20-23, 41, 42, 44, 55, 56, 64, 80, 82, 87, 88). The agents currently approved for use as high-level disinfectants (e.g., chlorine, peracetic acid, and ortho-phthalaldehyde) have rarely, if ever, been implicated in outbreaks. However, outbreaks may occur when ineffective disinfectants, including iodophors, alcohols, and overdiluted glutaraldehyde, are used for high-level disinfection.
Alcohol is widely used for the environmental disinfection of small areas (i.e., “spot” disinfection). Flammability precludes its use on large surfaces. Multiple outbreaks have resulted from the use of alcohols as “high-level” disinfectants for semicritical medical devices. Rarely, contaminated alcohol used as a surface disinfectant has been linked to outbreaks. For example, Berger reported an epidemic of pseudobacteremia with Bacillus cereus that was traced to contaminated cotton pads maintained in 70 to 90% ethanol that were used to disinfect the top of blood culture bottles before inoculation (9). Alcohol is not effective as a surface disinfectant against adenovirus, and its use to disinfect tonometer tips has been associated with epidemic keratoconjunctivitis (40).
The biocidal activity of glutaraldehyde is a consequence of its alkylation of the sulfydryl, hydroxy, carboxyl, and amino groups of microorganisms, which alters RNA, DNA, and protein synthesis. There have been reports of microorganisms with resistance to glutaraldehyde, including some mycobacteria (e.g., Mycobacterium chelonae and Mycobacterium xenopi), Methylobacterium mesephilicum, Trichosporon, fungal ascospores, and Cryptosporidium (73). A pseudo-outbreak caused by Mycobacterium chelonae and Methylobacterium mesophilicum due to contamination of an automated endoscope washer was reported (41). M. chelonae grew from the endoscopes, the automated washers, and the glutaraldehyde from the washers.
The bactericidal action of the quaternary ammonium compounds has been attributed to the inactivation of energy-producing enzymes, denaturation of essential cell proteins, and disruption of the cell membrane. A pseudo-outbreak of B. cepacia bacteremia was traced to the use of a contaminated quaternary ammonium compound to disinfect the rubber stoppers of blood culture bottles (21).
Formaldehyde inactivates microorganisms by alkylating the amino and sulfhydryl groups of proteins and the ring nitrogen atoms of purine bases. The aqueous solution is virucidal, bactericidal, tuberculocidal, fungicidal, and sporicidal. An outbreak of Klebsiella oxytoca sepsis in a neonatal and pediatric intensive care unit was traced to a contaminated solution of formaldehyde (8.0 g/dl) used for disinfection of surfaces and infusion pumps (64), while an outbreak of Pseudomonas sepsis due to deficient formaldehyde mixing used to disinfect dialyzers was reported (88).
The contamination of phenolics used for disinfection has been reported previously (Table (Table44).
Outbreaks and pseudo-outbreaks related to contaminated germicides have most commonly been reported with contaminated antiseptics. Outbreaks from contaminated high-level disinfectants have rarely, if ever, been reported. Outbreaks from contaminated intermediate- and low-level disinfectants have occasionally been reported. All outbreaks associated with contaminated germicides have occurred due to gram-negative bacilli or mycobacteria. This is felt to be due to the fact that the outer membrane of gram-negative bacteria or the complex cell wall of mycobacteria acts as a barrier to germicides (49).
Both outbreaks and sporadic failures of germicides may be due to user error rather than microbial contamination. Common errors include the use of overdiluted solutions, the use of outdated products, the use of tap water to dilute the germicide, the refilling of small-volume dispensers from large-volume stock containers, and the improper selection of an appropriate product (e.g., the use of a low-level disinfectant rather than a high-level disinfectant to disinfect an endoscope). Because multiple outbreaks have resulted from the refilling of small-volume dispensers from large-volume stock containers, small-volume containers should be used until they are completely empty (i.e., do not “top off” the containers), rinsed with tap water, and then air dried before they are refilled. When a potential failure of proper disinfection or sterilization occurs, we recommend the use of a standardized risk assessment for determining patient risk and the need to inform patients (74).
A critical component of disinfection is prior cleaning. Prior cleaning is necessary to remove proteinaceous material and biofilms to allow the germicide to achieve adequate microbial inactivation. Experimental studies have demonstrated that the physical thickness of the cellular and extracellular material that forms on surfaces (i.e., biofilms) can protect imbedded organisms from the microbicidal actions of disinfectants and antiseptics (1, 2). For example, the bacteria growing in a biofilm can be up to 1,500 times more resistant to germicides than the same bacteria growing in liquid culture (77). The failure to properly clean medical devices may lead to inadequate microbial inactivation for all chemical germicides.
With the use of more effective agents and newer guidelines, the number of outbreaks due to contaminated germicides had decreased over the past 50 years. However, in order to prevent future outbreaks associated with contaminated germicides, it is critical to follow the standard recommendations, which are as follows: (i) use only CDC-recommended and FDA-cleared antiseptics; (ii) use only CDC-recommended and EPA-registered or FDA-cleared disinfectants; (iii) use all germicides at their recommended use dilution, and do not overdilute products; (iv) use sterile water to dilute antiseptics; (v) use all germicides for the recommended contact times; (vi) do not use germicides labeled only as antiseptics for the disinfection of medical devices or surface disinfection; (vii) follow the recommended procedures in the preparation of products to prevent extrinsic contamination; (viii) small-volume dispensers that are refilled from large-volume stock containers should be used until they are entirely empty, and then they should be rinsed with tap water and air dried before they are refilled; and (ix) store stock solutions of germicides as indicated on the product label.
Published ahead of print on 1 October 2007.