Disinfectants are chemical agents or physical procedures that inhibit or kill microorganisms (Table 50–1). Antiseptics are disinfecting chemical agents with sufficiently low toxicity for host cells that they can be used directly on skin, mucous membranes, or wounds. Sterilants kill both vegetative cells and spores when applied to materials for appropriate times and temperatures. Some of the terms used in this context are defined in Table 50–2.
TABLE 50–1Activities of disinfectants. ||Download (.pdf) TABLE 50–1 Activities of disinfectants.
| ||Bacteria ||Viruses ||Other |
|Gram-Positive ||Gram-Negative ||Acid-Fast ||Spores ||Lipophilic ||Hydrophilic ||Fungi ||Amebic Cysts ||Prions |
|Alcohols (isopropanol, ethanol) ||HS ||HS ||S ||R ||S ||V ||— ||— ||R |
|Aldehydes (glutaraldehyde, formaldehyde) ||HS ||HS ||MS ||S (slow) ||S ||MS ||S ||— ||R |
|Chlorhexidine gluconate ||HS ||MS ||R ||R ||V ||R ||— ||— ||R |
|Sodium hypochlorite, chlorine dioxide ||HS ||HS ||MS ||S (pH 7.6) ||S ||S (at high conc) ||MS ||S ||MS (at high conc) |
|Hexachlorophene ||S (slow) ||R ||R ||R ||R ||R ||R ||R ||R |
|Povidone, iodine ||HS ||HS ||S ||S (at high conc) ||S ||R ||S ||S ||R |
|Phenols, quaternary ammonium compounds ||HS ||HS ||MS ||R ||S ||R ||S ||— ||R |
TABLE 50–2Commonly used terms related to chemical and physical killing of microorganisms. ||Download (.pdf) TABLE 50–2 Commonly used terms related to chemical and physical killing of microorganisms.
|Antisepsis ||Application of an agent to living tissue for the purpose of preventing infection |
|Decontamination ||Process that produces marked reduction in number or activity of microorganisms |
|Disinfection ||Chemical or physical treatment that destroys most vegetative microbes and viruses, but not spores, in or on inanimate surfaces |
|Sanitization ||Reduction of microbial load on an inanimate surface to a level considered acceptable for public health purposes |
|Sterilization ||A process intended to kill or remove all types of microorganisms, including spores, and usually including viruses, with an acceptably low probability of their survival |
|Pasteurization ||A process that kills nonsporulating microorganisms by hot water or steam at 65–100°C |
Disinfection prevents infection by reducing the number of potentially infective organisms by killing, removing, or diluting them. Disinfection can be accomplished by application of chemical agents or use of physical agents such as ionizing radiation, dry or moist heat, or superheated steam (autoclave, 120°C) to kill microorganisms. Often a combination of agents is used, eg, water and moderate heat over time (pasteurization); ethylene oxide and moist heat (a sterilant); or addition of disinfectant to a detergent. Prevention of infection also can be achieved by washing, which dilutes the potentially infectious organism.
Hand hygiene is probably the most important means of preventing transmission of infectious agents from person to person or from regions of high microbial load, eg, mouth, nose, or gut, to potential sites of infection. Alcohol-based hand rubs and soap and warm water are used to remove bacteria. Skin disinfectants along with detergent and water are usually used preoperatively as a surgical scrub for surgeons’ hands.
Evaluation of effectiveness of antiseptics, disinfectants, and sterilants, although seemingly simple in principle, is very complex. Factors in any evaluation include the intrinsic resistance of the microorganism, the number of microorganisms present, mixed populations of organisms, amount of organic material present (eg, blood, feces, tissue), concentration and stability of disinfectant or sterilant, time and temperature of exposure, pH, and hydration and binding of the agent to surfaces. Specific, standardized assays of activity are defined for each use. Toxicity for humans also must be evaluated. In the USA, the Environmental Protection Agency (EPA) regulates disinfectants and sterilants and the FDA regulates antiseptics.
Users of antiseptics, disinfectants, and sterilants need to consider their short-term and long-term toxicity because they may have general biocidal activity and may accumulate in the environment or in the body. Disinfectants and antiseptics may also become contaminated by resistant microorganisms—eg, spores, P aeruginosa, or Serratia marcescens—and actually transmit infection. Most topical antiseptics interfere with wound healing to some degree. Cleansing of wounds with soap and water may be less damaging than the application of antiseptics.
Some of the chemical classes of antiseptics, disinfectants, and sterilants are described briefly in the text that follows. The reader is referred to the general references for descriptions of physical disinfection and sterilization methods.
The two alcohols most frequently used for antisepsis and disinfection are ethanol and isopropyl alcohol (isopropanol). They are rapidly active, killing vegetative bacteria, Mycobacterium tuberculosis, and many fungi, and inactivating lipophilic viruses. The optimum bactericidal concentration is 60–90% by volume in water. They probably act by denaturation of proteins. They are not used as sterilants because they are not sporicidal, do not penetrate protein-containing organic material, and may not be active against hydrophilic viruses. Their skin-drying effect can be alleviated by addition of emollients to the formulation. Use of alcohol-based hand rubs has been shown to reduce transmission of health care–associated bacterial pathogens and is recommended by the Centers for Disease Control and Prevention (CDC) as the preferred method of hand decontamination in health care settings. Alcohol-based hand rubs are ineffective against spores of C difficile, and handwashing with soap and water is required for decontamination after caring for a patient with infection from this organism.
Alcohols are flammable and must be stored in cool, well-ventilated areas. They must be allowed to evaporate before cautery, electrosurgery, or laser surgery. Alcohols may be damaging if applied directly to corneal tissue. Therefore, instruments such as tonometers that have been disinfected in alcohol should be rinsed with sterile water, or the alcohol should be allowed to evaporate before they are used.
Chlorhexidine is a cationic biguanide with very low water solubility. Water-soluble chlorhexidine digluconate is used in water-based formulations as an antiseptic. It is active against vegetative bacteria and mycobacteria and has variable activity against fungi and viruses. It strongly adsorbs to bacterial membranes, causing leakage of small molecules and precipitation of cytoplasmic proteins. It is active at pH 5.5–7.0. Chlorhexidine gluconate is slower in its action than alcohols, but, because of its persistence, it has residual activity, producing bactericidal action equivalent to alcohols. It is most effective against Gram-positive cocci and less active against Gram-positive and Gram-negative rods. Spore germination is inhibited by chlorhexidine. Chlorhexidine digluconate is resistant to inhibition by blood and organic materials. However, anionic and nonionic agents in moisturizers, neutral soaps, and surfactants may neutralize its action. Chlorhexidine digluconate formulations of 4% concentration have slightly greater antibacterial activity than newer 2% formulations. The combination of chlorhexidine gluconate in 70% alcohol, available in some countries including the USA, is the preferred agent for skin antisepsis in many surgical and percutaneous procedures. The advantage of this combination over povidone-iodine may derive from its more rapid action after application, its retained activity after exposure to body fluids, and its persistent activity on the skin. Chlorhexidine has a very low skin-sensitizing or irritating capacity. Oral toxicity is low because it is poorly absorbed from the alimentary tract. Chlorhexidine must not be used during surgery on the middle ear because it causes sensorineural deafness. Similar neural toxicity may be encountered during neurosurgery.
Iodine in a 1:20,000 solution is bactericidal in 1 minute and kills spores in 15 minutes. Tincture of iodine USP contains 2% iodine and 2.4% sodium iodide in alcohol. It is the most active antiseptic for intact skin. It is not commonly used due to serious hypersensitivity reactions and staining of clothing and dressings.
Iodophors are complexes of iodine with a surface-active agent such as polyvinyl pyrrolidone (PVP; povidone-iodine). Iodophors retain the activity of iodine. They kill vegetative bacteria, mycobacteria, fungi, and lipid-containing viruses. They may be sporicidal with prolonged exposure. Iodophors can be used as antiseptics or disinfectants, the latter containing more iodine. The amount of free iodine is low, but it is released as the solution is diluted. An iodophor solution must be diluted according to the manufacturer’s directions to obtain full activity.
Iodophors are less irritating and less likely to produce skin hypersensitivity than tincture of iodine. They require drying time on skin before becoming active, which can be a disadvantage. Although iodophors have a somewhat broader spectrum of activity than chlorhexidine, including sporicidal action, they lack its persistent activity on skin.
Chlorine is a strong oxidizing agent and universal disinfectant that is commonly provided as a 5.25% sodium hypochlorite solution, a typical formulation for household bleach. Because formulations may vary, the exact concentration should be verified on the label. A 1:10 dilution of household bleach (producing a 0.525% concentration) provides 5000 ppm of available chlorine. The CDC recommends this concentration for disinfection of blood spills. Less than 5 ppm kills vegetative bacteria, whereas up to 5000 ppm is necessary to kill bacterial spores. A concentration of 1000–10,000 ppm is tuberculocidal. One hundred ppm kills vegetative fungal cells in 1 hour, but fungal spores require 500 ppm. Viruses are inactivated by 200–500 ppm. Dilutions of sodium hypochlorite made up in pH 7.5–8.0 tap water retain their activity for months when kept in tightly closed, opaque containers. Frequent opening and closing of the container reduces the activity markedly.
Because chlorine is inactivated by blood, serum, feces, and protein-containing materials, surfaces should be cleaned before chlorine disinfectant is applied. Undissociated hypochlorous acid (HOCl) is the active biocidal agent. When pH is increased, the less active hypochlorite ion, OCl–, is formed. When hypochlorite solutions contact formaldehyde, the carcinogen bischloromethyl is formed. Rapid evolution of irritating chlorine gas occurs when hypochlorite solutions are mixed with acid and urine. Solutions are corrosive to aluminum, silver, and stainless steel.
Alternative chlorine-releasing compounds include chlorine dioxide and chloramine-T. These agents have a prolonged bactericidal action.
Phenol itself (perhaps the oldest of the surgical antiseptics) is no longer used even as a disinfectant because of its corrosive effect on tissues, its toxicity when absorbed, and its carcinogenic effect. These adverse actions are diminished by forming derivatives in which a functional group replaces a hydrogen atom in the aromatic ring. The phenolic agents most commonly used are o-phenylphenol, o-benzyl-p-chlorophenol, and p-tertiary amylphenol. Mixtures of phenolic derivatives are often used. Some of these are derived from coal tar distillates, eg, cresols and xylenols. Skin absorption and skin irritation still occur with these derivatives, and appropriate care is necessary in their use. Detergents are often added to formulations to clean and remove organic material that may decrease the activity of a phenolic compound.
Phenolic compounds disrupt cell walls and membranes, precipitate proteins, and inactivate enzymes. They are bactericidal (including mycobacteria) and fungicidal and are capable of inactivating lipophilic viruses. They are not sporicidal. Dilution and time of exposure recommendations of the manufacturer must be followed.
Phenolic disinfectants are used for hard surface decontamination in hospitals and laboratories, eg, floors, beds, and counter or bench tops. They are not recommended for use in nurseries and especially near infants, where their use has been associated with hyperbilirubinemia. Use of hexachlorophene as a skin disinfectant has caused cerebral edema and seizures in premature infants and, occasionally, in adults. It is no longer available in the United States.
QUATERNARY AMMONIUM COMPOUNDS
The quaternary ammonium compounds (“quats”) are cationic surface-active detergents. The active cation has at least one long water-repellent hydrocarbon chain, which causes the molecules to concentrate as an oriented layer on the surface of solutions and colloidal or suspended particles. The charged nitrogen portion of the cation has high affinity for water and prevents separation out of solution. The bactericidal action of quaternary compounds has been attributed to inactivation of energy-producing enzymes, denaturation of proteins, and disruption of the cell membrane. These agents are fungistatic and sporistatic and also inhibit algae. They are bactericidal for Gram-positive bacteria and moderately active against Gram-negative bacteria. Lipophilic viruses are inactivated. They are not tuberculocidal or sporicidal, and they do not inactivate hydrophilic viruses. Quaternary ammonium compounds bind to the surface of colloidal protein in blood, serum, and milk and to the fibers in cotton, mops, cloths, and paper towels used to apply them, which can cause inactivation of the agent by removing it from solution. They are inactivated by anionic detergents (soaps), by many nonionic detergents, and by calcium, magnesium, ferric, and aluminum ions.
Quaternary compounds are used for sanitation of noncritical surfaces (floors, bench tops, etc). Their low toxicity has led to their use as sanitizers in food production facilities. The CDC recommends that quaternary ammonium compounds such as benzalkonium chloride not be used as antiseptics because several outbreaks of infections have occurred that were due to growth of Pseudomonas and other Gram-negative bacteria in quaternary ammonium antiseptic solutions.
Formaldehyde and glutaraldehyde are used for disinfection or sterilization of instruments such as fiberoptic endoscopes, respiratory therapy equipment, hemodialyzers, and dental instruments that cannot withstand exposure to the high temperatures of steam sterilization. They are not corrosive for metal, plastic, or rubber. These agents have a broad spectrum of activity against microorganisms. They act by alkylation of chemical groups in proteins and nucleic acids. Failures of disinfection or sterilization can occur as a result of dilution below the known effective concentration, the presence of organic material, and the failure of liquid to penetrate into small channels in the instruments. Automatic circulating baths are available that increase penetration of aldehyde solution into the instrument while decreasing exposure of the operator to irritating fumes.
Formaldehyde is available as a 40% weight per volume solution in water (100% formalin). An 8% formaldehyde solution in water has a broad spectrum of activity against bacteria, fungi, and viruses. Sporicidal activity may take as long as 18 hours. Its rapidity of action is increased by solution in 70% isopropanol. Formaldehyde solutions are used for high-level disinfection of hemodialyzers, preparation of vaccines, and preservation and embalming of tissues. The 4% formaldehyde (10% formalin) solutions used for fixation of tissues and embalming may not be mycobactericidal.
Glutaraldehyde is a dialdehyde (1,5-pentanedial). Solutions of 2% weight per volume glutaraldehyde are most commonly used. The solution must be alkalinized to pH 7.4–8.5 for activation. Activated solutions are bactericidal, sporicidal, fungicidal, and viricidal for both lipophilic and hydrophilic viruses. Glutaraldehyde has greater sporicidal activity than formaldehyde, but it may have less tuberculocidal activity. Lethal action against mycobacteria and spores may require prolonged exposure. Once activated, solutions have a shelf life of 14 days, after which polymerization reduces activity. Other means of activation and stabilization can increase the shelf life. Because glutaraldehyde solutions are frequently reused, the most common reason for loss of activity is dilution and exposure to organic material. Test strips to measure residual activity are recommended.
Formaldehyde has a characteristic pungent odor and is highly irritating to respiratory mucous membranes and eyes at concentrations of 2–5 ppm. The U.S. Occupational Safety and Health Administration (OSHA) has declared that formaldehyde is a potential carcinogen and has established an employee exposure standard that limits the 8-hour time-weighted average (TWA) exposure to 0.75 ppm. Protection of health care workers from exposure to glutaraldehyde concentrations greater than 0.2 ppm is advisable. Increased air exchange, enclosure in hoods with exhausts, tight-fitting lids on exposure devices, and use of protective personal equipment such as goggles, respirators, and gloves may be necessary to achieve these exposure limits.
Ortho-phthalaldehyde (OPA) is a phenolic dialdehyde chemical sterilant with a spectrum of activity comparable to glutaraldehyde, although it is several times more rapidly bactericidal. OPA solution typically contains 0.55% OPA. Its label claim is that high-level disinfection can be achieved in 12 minutes at room temperature compared with 45 minutes for 2.4% glutaraldehyde. Unlike glutaraldehyde, OPA requires no activation, is less irritating to mucous membranes, and does not require exposure monitoring. It has good materials compatibility and an acceptable environmental safety profile. OPA is useful for disinfection or sterilization of endoscopes, surgical instruments, and other medical devices.
Electrolysis of saline yields a mixture of oxidants, primarily hypochlorous acid and chlorine, with potent disinfectant and sterilant properties. The solution generated by the process, which has been commercialized and marketed as Sterilox for disinfection of endoscopes and dental materials, is rapidly bactericidal, fungicidal, tuberculocidal, and sporicidal. High-level disinfection is achieved with a contact time of 10 minutes. The solution is nontoxic and nonirritating and requires no special disposal precautions.
The peroxygen compounds, hydrogen peroxide and peracetic acid, have high killing activity and a broad spectrum against bacteria, spores, viruses, and fungi when used in appropriate concentration. They have the advantage that their decomposition products are not toxic and do not injure the environment. They are powerful oxidizers that are used primarily as disinfectants and sterilants.
Hydrogen peroxide is a very effective disinfectant when used for inanimate objects or materials with low organic content such as water. Systems that produce hydrogen peroxide vapor or dry mist are now available for room decontamination in healthcare facilities. Organisms that produce the enzymes catalase and peroxidase rapidly degrade hydrogen peroxide. The innocuous degradation products are oxygen and water. Concentrated solutions containing 90% weight per volume H2O2 are prepared electrochemically. When diluted in high-quality deionized water to 6% and 3% and put into clean containers, the products remain stable. Concentrations of 10–25% hydrogen peroxide are sporicidal. Vapor phase hydrogen peroxide (VPHP) is a cold gaseous sterilant that has the potential to replace the toxic or carcinogenic gases ethylene oxide and formaldehyde. VPHP does not require a pressurized chamber and is active at temperatures as low as 4°C and concentrations as low as 4 mg/L. It is incompatible with liquids and cellulose products. It penetrates the surface of some plastics. Automated equipment using vaporized hydrogen peroxide or hydrogen peroxide mixed with formic acid is available for sterilizing endoscopes.
Peracetic acid (CH3COOOH) is prepared commercially from hydrogen peroxide, acetic acid, and a catalyst such as sulfuric acid. It is explosive in the pure form. It is usually used in dilute solution and transported in containers with vented caps to prevent increased pressure as oxygen is released. Peracetic acid is more active than hydrogen peroxide as a bactericidal and sporicidal agent. Concentrations of 250–500 ppm are effective against a broad range of bacteria in 5 minutes at pH 7.0 at 20°C. Bacterial spores are inactivated by 500–30,000 ppm peracetic acid. Only slightly increased concentrations are necessary in the presence of organic matter. Viruses require variable exposures. Enteroviruses require 2000 ppm for 15–30 minutes for inactivation.
An automated machine that uses buffered peracetic acid liquid of 0.1–0.5% concentration has been developed for sterilization of medical, surgical, and dental instruments. Peracetic acid sterilization systems have also been adopted for hemodialyzers. The food processing and beverage industries use peracetic acid extensively because the breakdown products in high dilution do not produce objectionable odor, taste, or toxicity, and rinsing is not necessary.
Peracetic acid is a potent tumor promoter but a weak carcinogen. It is not mutagenic in the Ames test.
Ultraviolet irradiation is used in some health care facilities as an alternate mode of disinfection for patient care areas. It is typically employed via an automated system, allowing for less staff exposure to decontamination products. It has rapid cidal activity against numerous pathogens, providing effective decontamination for most vegetative bacteria in less than 25 minutes and against C. difficile in less than one hour.
Heavy metals, principally mercury and silver, are now rarely used as disinfectants. Mercury is an environmental hazard, and some pathogenic bacteria have developed plasmid-mediated resistance to mercurials. Hypersensitivity to thimerosal is common, possibly in up to 40% of the population. These compounds are absorbed from solution by rubber and plastic closures. Thimerosal 0.001–0.004% is still used safely as a preservative of vaccines, antitoxins, and immune sera. Although a causative link to autism has never been established and the original claim was found to be fraudulent, thimerosal-free vaccines are available for use in children and pregnant women.
Inorganic silver salts are strongly bactericidal. Silver nitrate, 1:1000, had been most commonly used, particularly as a preventive for gonococcal ophthalmitis in newborns. Antibiotic ointments have replaced silver nitrate for this indication. Silver sulfadiazine slowly releases silver and is used to suppress bacterial growth in burn wounds (see Chapter 46).
For many years, pressurized steam (autoclaving) at 120°C for 30 minutes has been the basic method for sterilizing instruments and other heat-resistant materials. When autoclaving is not possible, as with lensed instruments and materials containing plastic and rubber, ethylene oxide—diluted with either fluorocarbon or carbon dioxide to diminish explosive hazard—has been used at 440–1200 mg/L at 45–60°C with 30–60% relative humidity. The higher concentrations have been used to increase penetration.
Ethylene oxide is classified as a mutagen and carcinogen. The OSHA permissible exposure limit (PEL) for ethylene oxide is 1 ppm calculated as a time-weighted average. Alternative sterilants now being used increasingly include vapor-phase hydrogen peroxide, peracetic acid, ozone, gas plasma, chlorine dioxide, formaldehyde, and propylene oxide. Each of these sterilants has potential advantages and problems. Automated peracetic acid systems are being used increasingly for high-level decontamination and sterilization of endoscopes and hemodialyzers because of their effectiveness, automated features, and the low toxicity of the residual products of sterilization.
Disinfectants are used as preservatives to prevent the overgrowth of bacteria and fungi in pharmaceutical products, laboratory sera and reagents, cosmetic products, and contact lenses. Multi-use vials of medication that may be reentered through a rubber diaphragm, eye drops, and nose drops require preservatives. Preservatives should not be irritating or toxic to tissues to which they will be applied, they must be effective in preventing growth of microorganisms likely to contaminate solutions, and they must have sufficient solubility and stability to remain active.
Commonly used preservative agents include organic acids such as benzoic acid and salts, the parabens, (alkyl esters of p-hydroxybenzoic acid), sorbic acid and salts, phenolic compounds, quaternary ammonium compounds, alcohols, and mercurials such as thimerosal in 0.001–0.004% concentration.
SUMMARY Miscellaneous Antimicrobials
|Subclass, Drug ||Mechanism of Action ||Effects ||Clinical Applications ||Pharmacokinetics, Toxicities, Interactions |
| • Metronidazole ||Disruption of electron transport chain ||Bactericidal activity against susceptible anaerobic bacteria and protozoa ||Anaerobic infections • vaginitis • C difficile colitis ||Oral or IV • hepatic clearance (t½ 8 h) • disulfiram-like reaction when given with alcohol • Toxicity: Gastrointestinal upset • metallic taste • neuropathy • seizures |
| • Tinidazole: Oral; similar to metronidazole but dosed once daily; approved for trichomonas, giardiasis, and amebiasis |
| • Fidaxomicin ||Inhibits bacterial RNA polymerase ||Bactericidal in Gram-positive bacteria ||C difficile colitis ||Oral • blood levels negligible • Toxicity: Nonspecific gastrointestinal upset |
| • Rifaximin ||Inhibits bacterial RNA polymerase ||Bactericidal activity in Gram-positive and Gram-negative bacteria ||Travelers’ diarrhea, hepatic encephalopathy, C difficile colitis, irritable bowel syndrome ||Oral • blood levels negligible • Toxicity: Nausea |
|URINARY ANTISEPTICS |
| • Nitrofurantoin ||Not fully understood • disrupts protein synthesis and inhibits multiple bacterial enzyme systems ||Bacteriostatic or bactericidal activity against susceptible bacteria ||Uncomplicated urinary tract infections • long-term prophylaxis ||Oral • rapid renal clearance (t½ 0.5 h) • blood levels are negligible • contraindicated in renal failure • Toxicity: Gastrointestinal upset • neuropathies • hypersensitivity pneumonitis |
| • Methenamine hippurate and methenamine mandelate: Oral; release formaldehyde at acidic pH in the urine; used only for prophylaxis, not treatment, of urinary tract infections |
|GENERIC NAME ||AVAILABLE AS |
|MISCELLANEOUS ANTIMICROBIAL DRUGS |
|Colistimethate sodium ||Generic, Coly-Mycin M |
|Fidaxomicin ||Dificid |
|Methenamine hippurate ||Generic, Hiprex |
|Methenamine mandelate ||Generic, Mandelamine |
|Metronidazole ||Generic, Flagyl, Metro |
|Mupirocin ||Generic, Bactroban, Centany |
|Nitrofurantoin ||Generic, Macrodantin, Macrobid |
|Polymyxin B (Polymyxin B sulfate) ||Generic |
|DISINFECTANTS, ANTISEPTICS, & STERILANTS |
|Benzalkonium ||Generic, Zephiran |
|Benzoyl peroxide ||Generic |
|Chlorhexidine gluconate topical ||Generic, Hibiclens, Betasept, others |
|Chlorhexidine gluconate, oral rinse: 0.12% ||Peridex, Periogard |
|Glutaraldehyde ||Cidex |
|Iodine aqueous ||Generic, Lugol’s Solution |
|Iodine tincture ||Generic |
|Nitrofurazone ||Generic, Furacin |
|Ortho-phthalaldehyde ||Cidex OPA |
|Povidone-iodine ||Generic, Betadine |
|Silver nitrate ||Generic |
|Thimerosal ||Generic, Mersol |