Health care-associated infections inflict a huge clinical and economic burden on public health worldwide. Bacterial resistance to antibiotics continues to escalate, and antimicrobial stewardship initiatives have yet to make a major impact. Additionally, the ability of bacteria to evade environmental threats by living within a self-produced protective biofilm and/or producing resistant spores further challenges effective infection control. The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has also amplified the burden significantly. Amidst a particularly challenging infection era, the demand for meticulous infection control and prevention practices is paramount, a key component of which is the use of appropriate disinfectants that can combat a wide variety of microbial pathogens, including diverse forms of viruses and bacteria, particularly highly tolerant spore-forming and biofilm-forming microorganisms. This review addresses the advantages and disadvantages of commonly used disinfectants such as alcohols, hypochlorite, and quaternary ammonium compounds, together with oxidizing agents such as chlorine dioxide and peracetic acid, which are gaining increasing acceptance in routine infection control practices today. Given the increasing requirements for rapid-acting disinfectants that are effective against the toughest of microorganisms (e.g. spores and biofilm), are environmentally friendly, and remain active under diverse environmental conditions, emerging oxidizing agents warrant further consideration, particularly chlorine dioxide, which offers most requirements for an ideal disinfectant, including retention of activity over a broad pH range. Given the critical importance of infection control and antimicrobial stewardship in public health and health care facilities today, consideration of chlorine dioxide as a safe, selective, highly effective, and environmentally friendly disinfectant is warranted.

Infections inflict a major clinical and economic burden on public health on a global scale. Within an alarmingly short timeframe, SARS-CoV-2 has disseminated uncontrollably with devastating speed and effect, infecting approximately 230 million people and accounting for more than 4.7 million deaths at the present time. While SARS-CoV-2 wreaks havoc across the globe, a longer-term, underlying, and escalating threat of bacterial resistance to antibiotics continues. Those most seriously affected by SARS-CoV-2 requiring intensive care become more susceptible to serious bacterial infections that antibiotics are increasingly less effective against. This combination exacerbates the threat to human health.

Health care-associated infections (HCAIs), that is, those acquired while in a health care setting (e.g. hospital, clinic, and long-term care), have a huge impact on patient morbidity and mortality, and on costs to health care. Prevalent HCAIs include catheter-related blood stream infections, surgical site infections, urinary tract infections, and respiratory tract infections (1). A particular spore-forming bacterium, Clostridiodes (Clostridium) difficile, has been reported to be responsible for 5.6% of all infections within the National Health Service (NHS) in England (2), and for a ~$1.5 billion cost burden to US health care annually (1). In a recent analysis of the impact of HCAIs on cost to the NHS in England, Guest et al. estimated 834,000 HCAIs during the period 2016/2017, costing the NHS £2.7 billion and accounting for 28,500 patient deaths (3). This study highlighted the need for strict adherence to infection control practices and guidelines.

While the global impact of antibiotic resistance and more recently the SARS-CoV-2 pandemic are widely acknowledged, another largely unappreciated factor that contributes significantly to the spread of infection is biofilm. This review will expand on the implications of biofilm – what it is, how it contributes to HCAIs and antibiotic resistance, and why biofilm should be acknowledged and targeted in infection control practices.

In an era of continuing bacterial resistance to antibiotics and a viral pandemic, the demand for meticulous infection control practices is greater than ever. In this respect, disinfectants and disinfection procedures are critical, and it is extremely important that disinfectants can combat a wide variety of pathogens that cause such devastating infections – including different forms of viruses and bacteria, particularly spore-forming and biofilm bacteria, which are the most difficult to kill.

Biofilm is an extracellular matrix produced by bacteria to protect themselves from the outside world. Although bacteria are widely acknowledged as existing as actively dividing single cells (sometimes referred to as planktonic or vegetative cells), they much prefer to exist as surface-attached communities. Once attached to a surface (which could be a viable tissue surface or a non-viable surface), bacteria secrete an extracellular polymeric substance around themselves to provide protection from external environmental threats such as extreme temperature, desiccation, immune cells, and antimicrobial agents. This is biofilm, and it is the natural and prevalent form of bacterial life. Biofilm dominates all habitats on the Earth’s surface and has been reported to account for an estimated 80% of the approximate 1.2 × 1030 bacterial cell population (4). We see biofilm in everyday life: dental plaque on the surface of teeth, the scum in a blocked drain, and the slime in a vase of flowers are all examples of bacterial biofilm. Since the 1980s, the implications of biofilm in chronic diseases have been well-documented, and infections such as otitis media, catheter-associated urinary tract infections, and those associated with chronic, non-healing wounds are now recognized as biofilm infections (5, 6). In 2002, the United States National Institutes for Health reported that biofilms account for over 80% of human infections (7). Typically, biofilm is difficult to remove and protects bacteria from the effects of antimicrobial agents; the minimal bactericidal concentration (MBC) of bacteria protected by biofilm has been reported to be 100–1,000 times higher than that of planktonic (unprotected) bacteria (8). Consequently, biofilm infections invariably manifest as difficult-to-treat, persistent, and recurrent infections. More recently, viruses have been shown to exist within biofilm communities in flowing freshwater habitats (9), but in contrast to self-produced bacterial biofilm, viral biofilm forms via acquisition of matrix components from the infected host cell (10). The formation and existence of SARS-CoV-2 (COVID-19) biofilm has recently been hypothesized (10).

Aside from bacterial biofilm causing chronic infections, environmental biofilm is also a major concern in health care facilities. Given the ubiquity of biofilm, it will form and enable bacterial survival on non-viable surfaces such as toilet basins, sink units, drains, beds, and medical devices (e.g. endoscopes) over prolonged periods of time. A study conducted in German hospitals with high antibiotic consumption regularly detected antibiotic residues in toilets, sink siphons, and shower drains (11). Although flushing was shown to remove antibiotic residues, biofilm quickly reformed, and antibiotics were detected again. This study confirmed the ability of the biofilm to act as a reservoir for the accumulation of antibiotics in hospital sanitary units. Additionally, the transfer of antibiotic resistance genes between bacterial cells has been shown to occur 700 times more efficiently within biofilm than among free-living planktonic bacterial cells (12). Consequently, the presence of environmental biofilm in health care facilities is highly likely to enhance the spread of antibiotic resistance, in addition to facilitating bacterial survival and spread of infection (13).

Although biofilm grows most abundantly in wet conditions (i.e. wet surface biofilm), dry surface biofilm (DSB) is also a major concern in health care facilities. Biofilm containing antibiotic-resistant bacteria has been shown to persist for up to 12 months on equipment and furnishings in an intensive care unit, despite prior terminal cleansing involving detergent and bleach (14). In a UK study in three hospitals, DSBs were recovered from the surfaces of keyboards, patient folders, and hand sanitizing bottles, despite prior cleaning (15).

The ubiquity and implications of environmental biofilm within health care facilities and the criticality of effective biofilm control within infection control and prevention practices are clear.

Cleaning and disinfection are critical components in the control and prevention of HCAIs. Together with antibiotics and antiseptics, disinfectants are antimicrobial agents. The term ‘antimicrobial agent’ is broad-ranging and captures agents that can kill microorganisms (essentially bacteria, yeasts, fungi, and viruses) or prevent their growth. Antibiotics are primarily natural chemical substances produced by microorganisms to provide competitive advantage over other microorganisms. Antibiotics exhibit antimicrobial activity against specific microorganisms, for example, Gram-positive or Gram-negative bacteria, and are most commonly administered orally or intravenously to treat serious infections. Antiseptics are broad-spectrum chemical agents that are safe to use on viable tissues such as skin and mucous membranes but are generally too toxic to be used within the body. Disinfectants are similarly broad-spectrum chemical agents that are widely used on non-viable surfaces for infection control; they are too toxic to be used on or within the body. Some disinfectants may also function as antiseptics at lower, non-toxic concentrations, examples of which are included in Table 1. In health care facilities, disinfectants are routinely used to sanitize non-viable surfaces such as beds, mattresses, trolleys, toilets, bedpans, baths, incubators, ventilators, walls, floors, and ceilings, and to sterilize equipment such as endoscopes.

It is important to bear in mind that different types of microorganisms have different tolerances to antimicrobial agents such as disinfectants. As indicated in Fig. 1, bacterial spores are among the most tolerant and prevalent of microorganisms in health care facilities. The ability of some bacteria to produce spores is of clinical significance because it allows the bacteria to survive under hostile environmental conditions, and the spores will germinate to form actively dividing vegetative/planktonic cells when conditions become more favorable (e.g. within the body). The most important and clinically significant spore-forming bacterium is Clostridioides difficile. C. difficile is found in the gut and can cause conditions ranging from diarrhea to life-threatening C. difficile infection (CDI). The bacteria readily grow in the gut (colon) and are excreted in spore-form, which can then disseminate rapidly throughout a health care facility unless effectively controlled.

At the other end of the antimicrobial tolerance spectrum, lipid-enveloped viruses such as SARS-CoV-2 are among the most susceptible to disinfectants (Fig. 1). Since bacteria may be up to 100–1,000 times more tolerant to antimicrobial agents in biofilm form (8), biofilm must be considered as one of the most highly tolerant microbial forms that cannot be overlooked. All vegetative (planktonic) bacteria have the capability to exist in the much more tolerant biofilm form; examples of such pathogens include Staphylococcus aureus, Pseudomonas aeruginosa, and many antibiotic-resistant strains of bacteria.

Bearing in mind that spore-forming bacteria and biofilm bacteria are among the most difficult to treat, disinfectants should ideally provide both sporicidal and anti-biofilm activities.

In 2019, the US Centers for Disease Control and Prevention (CDC) and Infection Control Africa Network (ICAN) published a document entitled ‘Best Practices for Environmental Cleaning in Healthcare Facilities: in Resource-Limited Settings (version 2)’ (16). This document provided information on the ideal properties of disinfectants used for environmental sanitation in health care facilities, and the key requirements are summarized as follows:

Simpson et al. (17) also stated ideal criteria for a disinfectant: performance (including activity against biofilm), environment (selective reactivity and non-toxic by-products), safety, and economics (16). Based on these characteristics, chlorine dioxide was rated most highly in comparison with hypochlorous acid, hypobromous acid, and ozone (17).

In Rutala and Weber’s review of disinfection practices in health care facilities, advantages and disadvantages of commonly used disinfectants were listed (Table 2) (18). Despite its widespread use in hospital antisepsis and disinfection, alcohol has limited antimicrobial activity (i.e. not effective against bacterial spores) and exhibits other drawbacks including reduced activity in the presence of organic matter, absence of residual activity, limited activity against non-enveloped viruses, and being flammable. Additionally, both ethanol and isopropyl alcohol have been shown to increase biofilm production in S. aureus and Staphylococcus epidemidis at concentrations ranging from 40 to 95% (19). Sodium hypochlorite (household bleach) is a more effective antimicrobial agent against a broader range of microorganisms (including bacterial spores), but again its activity is compromised by organic matter, it is most effective over a narrow (acidic) pH range, and it has the potential to produce environmentally hazardous by-products and can be corrosive to metals. Quaternary ammonium compounds such as benzalkonium chloride provide a reasonable spectrum of antimicrobial activity, they exhibit detergent properties, and they provide residual activity, but they are ineffective against bacterial spores and non-enveloped viruses, and their activity is compromised by organic matter. Like sodium hypochlorite, peracetic acid and hydrogen peroxide are oxidizing agents with superior characteristics that include a broad spectrum of antimicrobial activity (including bacterial spores), environmentally friendliness (i.e. no hazardous by-products), absence of compromise by organic matter, and surface compatibility.

Another oxidizing agent that has significant advantages over sodium hypochlorite is chlorine dioxide (ClO2). Although ClO2 is a chlorine compound, its chemical behavior is quite different to that of chlorine. The advantages of ClO2 are listed as follows (17, 18) (also see Table 3):

Table 3 also includes peracetic acid, another potent oxidizing disinfectant that captures many of the desirable benefits associated with chlorine dioxide, although its optimum activity is confined to a narrow pH range (25, 26).

Bacterial and viral infections are a huge threat to global public health, and today, this is exemplified by the devastation caused by the recent SARS-CoV-2 pandemic and the continuing escalation of bacterial resistance to antibiotics. Infection control and prevention, therefore, become paramount, and disinfectants have a major role to play in our quest to prevent the spread of infections.

This review has highlighted the inadequacies of commonly and widely used disinfectants such as alcohols, hypochlorite, and quaternary ammonium compounds when considering characteristics such as spectrum of antimicrobial activity, surface compatibility, reactivity, stability, and environmental impact. In contrast, oxidizing agents such as peracetic acid and chlorine dioxide are gaining greater acceptance because they meet optimum requirements for disinfectants to a much greater extent than some of the established disinfectants. In particular, chlorine dioxide meets many of the optimum requirements and is unique in its ability to remain effective over a broad pH range.

Given the critical importance of infection control and antimicrobial stewardship in public health and health care facilities today, consideration of chlorine dioxide as a safe, selective, highly effective, and environmentally friendly disinfectant is warranted.

The author provides consultancy services to LifeClean International AB. Preparation of this manuscript was supported by LifeClean International AB, a provider of disinfectant solutions. The sponsor was not involved in the content of the manuscript.

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