Chemical Disinfectants, Antiseptics and Preservatives PDF

343 18 Chemical Disinfectants, Antiseptics and Preservatives Sean P. Gorman1 and Brendan F. Gilmore2 1 Emeritus Professor of Pharmaceutical Microbiology, Queen’s University Belfast, Belfast, UK 2 Professor of Pharmaceutical Microbiology, School of Pharmacy, Queen’s University Belfast, Belf...

343 18 Chemical Disinfectants, Antiseptics and Preservatives Sean P. Gorman1 and Brendan F. Gilmore2 1 Emeritus Professor of Pharmaceutical Microbiology, Queen’s University Belfast, Belfast, UK 2 Professor of Pharmaceutical Microbiology, School of Pharmacy, Queen’s University Belfast, Belfast, UK CONTENTS 18.1 Introduction, 344 18.1.1 European Union Regulation, 344 18.1.2 Definitions, 345 18.1.2.1 Disinfectant and Disinfection, 345 18.1.2.2 Antiseptic and Antisepsis, 345 18.1.2.3 Preservative and Preservation, 346 18.1.3 Economic Aspects, 346 18.2 Factors Affecting Choice of Antimicrobial Agent, 346 18.2.1 Properties of the Chemical Agent, 346 18.2.2 Microbiological Challenge, 346 18.2.2.1 Vegetative Bacteria, 347 18.2.2.2 Mycobacterium tuberculosis, 347 18.2.2.3 Bacterial Spores, 347 18.2.2.4 Fungi, 347 18.2.2.5 Viruses, 347 18.2.2.6 Protozoa, 349 18.2.2.7 Prions, 349 18.2.3 Intended Application, 350 18.2.4 Environmental Factors, 350 18.2.5 Toxicity of the Agent, 350 18.3 Types of Compound, 352 18.3.1 Acids and Esters, 352 18.3.1.1 Benzoic Acid, 352 18.3.1.2 Sorbic Acid, 352 18.3.1.3 Sulphur Dioxide, Sulphites and Metabisulphites, 352 18.3.1.4 Esters of p-­Hydroxybenzoic Acid (Parabens), 354 18.3.2 Alcohols, 354 18.3.2.1 Alcohols Used for Disinfection and Antisepsis, 354 18.3.2.2 Alcohols as Preservatives, 354 18.3.3 Aldehydes, 355 18.3.3.1 Glutaraldehyde, 355 18.3.3.2 Ortho-­phthalaldehyde, 355 18.3.3.3 Formaldehyde, 356 18.3.3.4 Formaldehyde-­releasing Agents, 356 18.3.4 Biguanides, 356 18.3.4.1 Chlorhexidine, 356 18.3.4.2 Polyhexamethylene Biguanides, 357 18.3.5 Halogens, 357 18.3.5.1 Chlorine, 357 18.3.5.2 Hypochlorites, 357 18.3.5.3 Organic Chlorine Compounds, 357 Hugo and Russell’s Pharmaceutical Microbiology, Ninth Edition. Edited by Brendan F. Gilmore and Stephen P. Denyer. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: https://www.wiley.com/go/HugoandRussells9e 344 18 Chemical Disinfectants, Antiseptics and Preservatives 18.3.5.4 Chloroform, 358 18.3.5.5 Iodine, 358 18.3.5.6 Iodophors, 358 18.3.6 Heavy Metals, 359 18.3.6.1 Silver, 359 18.3.6.2 Copper, 359 18.3.6.3 Mercurials, 359 18.3.7 Hydrogen Peroxide and Peroxygen Compounds, 359 18.3.8 Phenols, 360 18.3.8.1 Phenol (Carbolic Acid), 361 18.3.8.2 Clear Soluble Fluids, Black Fluids and White Fluids, 361 18.3.8.3 Synthetic Phenols, 361 18.3.8.4 Bisphenols, 361 18.3.9 Surface-­active Agents, 361 18.3.9.1 Cationic Surface-­active Agents, 361 18.3.10 Other Antimicrobials, 362 18.3.10.1 Diamidines, 362 18.3.10.2 Dyes, 362 18.3.10.3 Quinoline Derivatives, 362 18.3.11 Antimicrobial Combinations and Systems, 363 18.4 Disinfection Policies, 363 References, 364 Further Reading, 364 18.1 ­Introduction ‘active substances and preparations containing one or more active substances, put up in the form in which they are sup- Disinfectants, antiseptics and preservatives are chemical plied to the user, intended to destroy, deter, render harm- agents that have the ability to destroy, inactivate or inhibit less, prevent the action of, or otherwise exert a controlling the growth of microorganisms. They play a major role in effect on any harmful organism by chemical or biological the control of infection and contamination in medical and means’. The BPD had been transposed into domestic UK health care, and also find widespread use in the law by the Biocidal Products Regulation (BPR) 2001 ([SI management of livestock, the environment, paints and 2001/880] as amended). The BPD was superseded by the coatings, plastics, pharmaceutical, food and beverage EU BPR (Regulation (EU) 528/2012), the text of which was manufacture, textiles, the catering industry and consumer adopted in May 2012, entered into force in July 2012 and products. The term biocide is typically used to describe took effect in member states from September 2013, repeal- chemical agents employed to control harmful organisms ing and replacing the BPD (Directive 98/8/EC). The EU more broadly; this term is used widely throughout BPR concerns the placing on the market, and the use, of European Union (EU) directives. Microbicides, agents biocidal products intended to protect humans, animals, specifically used to control microorganisms, fall under this materials or articles against harmful pests or bacteria, general definition of biocide. through the action of active substances contained in a bioc- idal product. The BPR aims to improve the functioning of 18.1.1 European Union Regulation the biocidal products market within the EU member states, and ensure high levels of protection of human and animal Regulation of biocides continues to develop in the health and the environment, and applies within the European Union and many other countries wherein European Economic Area (EEA), including Iceland, guidance is defined for both the manufacturers and the Liechtenstein and Norway alongside EU member states. users of these products. Between 2000 and 2012, the The EU BPR aims to harmonise the internal market for Biocidal Products Directive (BPD) 98/8/EC and the related biocidal products, introducing several important changes directives – Medicinal Products for Human Use Directive to the previous regulations which include: 2001/83/EC and the Veterinary Medicinal Products Directive 2001/82/EC – governed the production, extending the scope of the regime to cover treated arti- marketing and use of non-­agricultural products intended cles and materials containing biocides; for biocidal purposes. Additionally, ‘agricultural pesticides’ adopting a community authorisation scheme for certain were regulated by the Plant Protection Products Directive types of products; 91/414/EC. The BPD regulated biocides are defined as requiring mandatory data-­sharing;  18.1 ­Introductio 345 Table 18.1 Levels of disinfection attainable when products are used according to manufacturer’s instructions. Disinfection level Low Intermediate High Microorganisms killed Most vegetative bacteria Vegetative bacteria including All microorganisms unless an Some viruses M. tuberculosis extreme challenge or resistance Some fungi Most viruses including hepatitis exhibited B virus (HBV) Most fungi Microorganisms surviving M. tuberculosis Bacterial spores Extreme challenge of resistant Bacterial spores Prions bacterial spores Prions Prions reducing the burden of data collection requirements; microorganisms but reducing them to a level acceptable for harmonising fee structures across member states. a defined purpose, for example, a level that is harmful nei- ther to health nor to the quality of perishable goods. The EU BPR defines a treated article as ‘any substance, Chemical disinfectants are capable of different levels of mixture or article which has been treated with, or action (Table 18.1). The term high-­level disinfection intentionally incorporates, one or more biocidal products’. indicates destruction of all microorganisms, but not Following the end of the ‘transition period’ on 31 necessarily bacterial spores; intermediate-­level disinfection December 2020, Great Britain no longer participates in the indicates destruction of all vegetative bacteria including EU scheme for biocidal products regulation. Prior to the Mycobacterium tuberculosis, but may exclude some United Kingdom’s exit from the European Union, the UK resistant viruses and fungi and implies little or no sporicidal Government Health and Safety Executive (HSE) was activity; low-­level disinfection can destroy most vegetative engaged in negotiations with all EU member states, the bacteria, fungi and viruses, but this will not include spores European Commission and the European Parliament in and some of the more resistant microorganisms. Some the development of a new directly acting EU law, and con- high-­level disinfectants have good sporicidal activity and tributed to the drafting and approval of the EU Biocidal are described as liquid chemical sterilants or chemosterilants Products Regulation (EU BPR 528/2012). As a result, on to indicate that they can effect a complete kill of all leaving the European Union, the existing EU BPR was microorganisms, as in sterilisation. In defining each of copied into British law, as the GB Biocidal Products these disinfection levels, the activity and outcome are Regulation (GB BPR) 2020. The GB BPR controls biocidal determined by correct use of the disinfectant product in products in Great Britain (England, Scotland and Wales), regard to concentration, time of contact and prevailing while the EU BPR controls biocidal products in Northern environmental conditions as described in subsequent Ireland. A number of minor differences between GB BPR sections of this chapter. and the EU BPR exist, which essentially allow GB to make different decisions to the EU, EEA and Switzerland and 18.1.2.2 Antiseptic and Antisepsis develop its own programmes for review of existing active Antisepsis, a specific type of disinfection, is defined as substances; however, the core regulatory instruments are destruction or inhibition of microorganisms on living largely identical. tissues having the effect of limiting or preventing the harmful results of infection. It is not a synonym for disinfection. The chemicals used are applied to skin and 18.1.2 Definitions mucous membranes, so as well as having adequate Some key definitions relevant to chemical microbicides are antimicrobial activity they must not be toxic or irritating given below. Other terms used to describe antimicrobial for these tissues. Antiseptics are mostly used to reduce the activity are considered in Chapter 19. microbial population on the skin before surgery or on the hands to help prevent spread of infection by this route. 18.1.2.1 Disinfectant and Disinfection Sanitisation, a regulated term, refers to the use of Disinfection is the process of removing microorganisms, disinfectants for reduction, not necessarily elimination, of including pathogens, from the surfaces of inanimate microorganisms from surfaces to levels considered objects. The British Standards Institution (BSI) further acceptable or safe as determined by public health regula- defines disinfection as not necessarily killing all tions. Therefore, sanitisation has a specific meaning with 346 18 Chemical Disinfectants, Antiseptics and Preservatives respect to disinfection applications or antisepsis, namely, ammonium compounds [QACs] and amine compounds), the removal or inactivation of microorganisms that pose a organometallics, organosulphurs, chloroisocyanurates threat to public health. The use of alcohol-­based hand sani- and phenolics. There are around 250 chemicals that have tisers has become increasingly common globally as an been identified as active components of microbicidal infection control measure during the COVID-­19 pandemic. products in the EU. Antiseptics are sometimes formulated as products contain- The aim of this chapter is to introduce the range of ing significantly lower concentrations of agents used for chemicals in common use and to indicate their activities disinfection. and applications. 18.1.2.3 Preservative and Preservation Preservatives are included in pharmaceutical and many 18.2 ­Factors Affecting Choice other types of formulations, both to prevent microbial of Antimicrobial Agent spoilage of the product and to minimise the risk to the consumer of acquiring an infection when the preparation Choice of the most appropriate antimicrobial compound is administered (see Chapter 17). Preservatives must be for a particular purpose depends on many factors and the able to limit proliferation of microorganisms that may be key parameters are described below. introduced unavoidably into non-­sterile products such as oral and topical medications during their manufacture and use. In sterile products, where multiuse preparations 18.2.1 Properties of the Chemical Agent remain available, preservatives should kill any microbial The process of killing or inhibiting the growth of contaminants introduced inadvertently during use. It is microorganisms using an antimicrobial agent is basically essential that a preservative is not toxic in relation to the that of a chemical reaction and the rate and extent of this intended route of administration of the preserved reaction will be influenced by concentration of agent, preparation. Preservatives tend to be employed at very low temperature, pH and formulation. The significance of concentrations and consequently levels of antimicrobial these factors on activity is considered in Chapter 19, and is action also tend to be of a lower order than for disinfectants referred to when discussing the individual agents in or antiseptics. This is illustrated by the British, European Section 18.3. Tissue toxicity will influence whether a and US pharmacopoeial requirements for preservative chemical can be used as an antiseptic or preservative, and efficacy where a degree of bactericidal activity is necessary, this limits the range of agents for these applications or although this should be obtained within a few hours or necessitates the use of lower concentrations of that agent. over several days of microbial challenge depending on the This is discussed further in Section 18.2.5. type of product to be preserved. 18.2.2 Microbiological Challenge 18.1.3 Economic Aspects The types of microorganism present and the levels of The international antimicrobial chemical market, particu- microbial contamination (the bioburden) both have a larly in the case of disinfectants, is expected to grow sig- significant effect on the outcome of treatment. If the nificantly over the coming years, on the basis of concerns bioburden is high, long exposure times and/or higher about bacterial and other pathogenic threats and the concentrations of antimicrobial may be required. increasing emphasis on hygiene in the home and work- Microorganisms vary in their sensitivity to the action of place. In particular, the SARS-­CoV-­2 pandemic has signifi- chemical agents. Some organisms merit attention either cantly increased demand for disinfectant and antimicrobial because of their resistance to disinfection (for further chemicals; this is expected to continue to drive significant discussion, see Chapter 20) or because of their significance growth in the sector, even post pandemic, as consumer in cross-­infection or healthcare-­associated infections (see and workplace practices with respect to disinfection, sani- Chapter 16). Of particular concern is the significant tisation and hygiene are likely to be altered in the longer increase in resistance to disinfectants resulting from term. The global value of the antimicrobial and disinfect- microbial growth in the biofilm form rather than free ant chemical market was estimated at $9.1 billion in 2019 suspension (see Chapter 8). Microbial biofilms form and is projected to increase to $17.1 billion by 2027, repre- readily on available surfaces, posing a serious problem for senting a combined annual growth rate of 6.7% over hospital infection control committees in advising suitable this period. Key disinfectant products in use contain disinfectants for use in such situations. Recently, the ­aldehydes, iodophors, nitrogen compounds (quaternary description of dry surface biofilms (dehydrated biofilms  18.2 ­Factors Affecting Choice of Antimicrobial Agen 347 which have been shown to exist on dry inanimate sur- contaminated with mycobacteria if the patient is a carrier faces in healthcare, food processing and domiciliary envi- of this organism. It is important to be able to disinfect the ronments) with their demonstrable environmental equipment to a safe level to prevent transmission of persistence and significantly elevated tolerance to infection to other patients (Table 18.2). antimicrobial challenge (even compared with hydrated or 18.2.2.3 Bacterial Spores wet biofilms) highlights yet another potential challenge to selection of an appropriate disinfectant agent or Bacterial spores can exhibit significant resistance to even approach. Dry surface biofilms, as yet, lack a clear or the most active chemical disinfectant treatment. The agreed definition in the literature, or standardised test majority of disinfectants have no useful sporicidal action in methods, further complicating appropriate disinfectant a pharmaceutical context, which relates to disinfection of selection. materials, instruments and environments that are likely to The efficacy of an antimicrobial agent must be be contaminated by the spore-­forming genera Bacillus, investigated by appropriate capacity, challenge and in-­use Clostridioides and Clostridium. However, certain aldehydes, tests to ensure that a standard is obtained which is halogens and peroxygen compounds display very good appropriate to the intended use (Chapter 19). In practice, it activity under controlled conditions and are sometimes is not usually possible to know which organisms are used as an alternative to physical methods for sterilisation present on the articles being treated. Thus, it is necessary to of heat-­sensitive equipment. In these circumstances, categorise agents according to their antimicrobial activity correct usage of the agent is of paramount importance, as and for the user to be aware of the level of antimicrobial safety margins are lower in comparison with physical action required in a particular situation (see Table 18.1). methods of sterilisation (Chapter 21). Clostridioides difficile is a particularly problematic 18.2.2.1 Vegetative Bacteria contaminant in hospital environments, resulting in high At in-­use concentrations, chemicals used for disinfection levels of morbidity and mortality. In addition to stringent should be capable of killing bacteria and other organisms handwashing, meticulous environmental disinfection expected in that environment within a defined contact procedures must be in place, for example, using solutions period. This includes ‘problem’ organisms such as of 5.25–6.15% sodium hypochlorite for routine disinfection. methicillin-­resistant Staphylococcus aureus (MRSA), When high-­level disinfection of C. difficile is required, 2% vancomycin-­resistant enterococci (VRE) and species of glutaraldehyde, 0.55% o-­phthalaldehyde and 0.35% per- Listeria, Campylobacter and Legionella. Antiseptics and acetic acid are effective. preservatives are also expected to have a broad spectrum of The antibacterial activity of some disinfectants and antimicrobial activity, but at their in-­use concentrations, antiseptics is summarised in Table 18.2. after exerting an initial biocidal (killing) effect, their main function may be biostatic (inhibitory). Gram-­negative 18.2.2.4 Fungi bacilli, which are a major cause of healthcare-­associated The vegetative fungal form is often as sensitive as vegetative infections, are often more resistant than Gram-­positive bacteria to chemical antimicrobial agents. Fungal spores species. Pseudomonas aeruginosa, an opportunistic (conidia and chlamydospores; see Chapter 4) may be more pathogen (see also Chapter 7), has gained a reputation as resistant, but this resistance is of much lesser magnitude the most resistant of the Gram-­negative organisms. than that exhibited by bacterial spores. The ability to rapidly However, problems mainly arise when a number of destroy pathogenic fungi – such as the important nosocomial additional factors such as heavily soiled articles or diluted pathogen Candida albicans, filamentous fungi such as or degraded disinfectant solutions are employed. Trichophyton mentagrophytes and spores of common spoilage moulds such as Aspergillus niger – is put to advantage 18.2.2.2 Mycobacterium tuberculosis in many applications of use. Many disinfectants have good M. tuberculosis and other mycobacteria are resistant to activity against these fungi (Table 18.3). In addition, ethanol many bactericides. Resistance is either (i) intrinsic, mainly (70%) is rapidly and reliably active against Candida species. due to reduced cellular permeability, or (ii) acquired, due to mutation or the acquisition of plasmids (Chapter 13). 18.2.2.5 Viruses Tuberculosis remains an important public health hazard, Susceptibility of viruses to antimicrobial agents can depend and indeed the annual number of tuberculosis cases on whether or not the viruses possess a lipid envelope. continues to rise in many countries. The greatest risk of Non-­lipid viruses are frequently more resistant to acquiring infection is from the undiagnosed patient. disinfectants and it is also likely that such viruses cannot Equipment used for respiratory investigations can become be readily categorised with respect to their sensitivities to 348 18 Chemical Disinfectants, Antiseptics and Preservatives Table 18.2 Antibacterial activity of commonly used disinfectants and antiseptics. Activity against Class of compound Mycobacteria Bacterial spores General levela of antibacterial activity Alcohols Ethanol/isopropyl + − Intermediate Aldehydes Glutaraldehyde + + High o-­Phthalaldehyde + + High Formaldehyde + + High Biguanides Chlorhexidine − − Intermediate Halogens Hypochlorite/chloramines + + High Iodine/iodophor + + Intermediate, problems with Ps. aeruginosa Peroxygens Peracetic acid + + High Hydrogen peroxide + + High Phenolics Clear soluble fluids + − Intermediate Chloroxylenol − − Low Bisphenols − − Low, poor against Ps. aeruginosa Quaternary ammonium compounds Benzalkonium − − Intermediate Cetrimide − − Intermediate a Activity expected per manufacturer’s instructions and will depend on environmental conditions and bioburden. Table 18.3 Antifungal activity of disinfectants and antiseptics. Time (minutes) to give >99.99% killa of Antimicrobial agent Aspergillus niger Trichophyton mentagrophytes Candida albicans Phenolic (0.36%)