key: cord-0933050-r3tu24hr authors: Rozman, Urška; Pušnik, Marko; Kmetec, Sergej; Duh, Darja; Šostar Turk, Sonja title: Reduced Susceptibility and Increased Resistance of Bacteria against Disinfectants: A Systematic Review date: 2021-12-10 journal: Microorganisms DOI: 10.3390/microorganisms9122550 sha: 8bba08b944ade3b33520c9a9b83dd9858d9007b0 doc_id: 933050 cord_uid: r3tu24hr Disinfectants are used to reduce the concentration of pathogenic microorganisms to a safe level and help to prevent the transmission of infectious diseases. However, bacteria have a tremendous ability to respond to chemical stress caused by biocides, where overuse and improper use of disinfectants can be reflected in a reduced susceptibility of microorganisms. This review aims to describe whether mutations and thus decreased susceptibility to disinfectants occur in bacteria during disinfectant exposure. A systematic literature review following PRISMA guidelines was conducted with the databases PubMed, Science Direct and Web of Science. For the final analysis, 28 sources that remained of interest were included. Articles describing reduced susceptibility or the resistance of bacteria against seven different disinfectants were identified. The important deviation of the minimum inhibitory concentration was observed in multiple studies for disinfectants based on triclosan and chlorhexidine. A reduced susceptibility to disinfectants and potentially related problems with antibiotic resistance in clinically important bacterial strains are increasing. Since the use of disinfectants in the community is rising, it is clear that reasonable use of available and effective disinfectants is needed. It is necessary to develop and adopt strategies to control disinfectant resistance. Disinfectants, defined as biocides "Main group 1" [1] , are an essential tool in combatting the spread of infectious diseases. When used properly and according to the instructions, disinfectants can help prevent pathogens' transmission and spread, especially in nosocomial infections. With the rise of life-threatening infections with antibiotic-resistant bacteria and newly emerging viruses, the use of disinfectants and virucidal sanitizing agents has increased [2, 3] . Disinfectants contain one or more biocidal active substances by which harmful organisms are chemically or biologically deterred, rendered harmless or destroyed [4] . In the healthcare sector, in addition to hand hygiene, the disinfection of surfaces is just as crucial to effectively protect patients, healthcare workers and visitors from the transmission of pathogens [5, 6] . Biocidal products are also used in everyday hygiene, where consumers are offered a wide range of antibacterial cleaners, hygienic dishwashers, anti-sweat textiles, hygiene wipes and hand disinfectants. Most of them contain biocidal active substances in various amounts [7, 8] . Although personal and household hygiene is often equated with antimicrobial products, regular handwashing without disinfectants is far more essential and sufficient [9] . However, overuse and improper use of disinfectants can accumulate to be reflected in disinfectant resistance, potentially changing our way of life, from compromising food security to threatening our healthcare systems [6] . Antimicrobial resistance has aroused great interest in the scientific and medical community in the case of antibiotics [10] [11] [12] [13] , but less interest has been paid to disinfectants, We performed a systematic review using the examination, analysis and synthesis of literature and the compilation method. We followed the PRISMA guidelines [36] . The search was performed using search terms in English: (susceptibility OR resistance) AND (disinfectants OR biocides) AND (bacteria OR microorganisms). A literature search was conducted with the databases PubMed, Science Direct and Web of Science. We used the following search limits: research papers published in English related to the research topic until June 2020. We used the same search terms, search limits, inclusion, and exclusion criteria in all the databases. Predetermined inclusion and exclusion criteria were applied as presented in Table 1 . After revision of the databases, the results (n = 11,308) were exported and compiled with Mendeley's reference management software. We also performed hand searching and included 88 articles. Mendeley's automated process removed duplicates (n = 3318), followed by a manual search to identify and remove additional duplicates. The authors screened all abstracts (n = 7990). The search focused on articles describing bacteria that developed a substantial decrease in disinfectant susceptibility with known biocide ingredients. There were multiple reasons for excluding studies, mostly for lacking MIC values or disinfectant concentrations. For the final analysis and the review, 28 sources that remained of interest were included and screened based on their full text by two independent reviewers (See Figure 1 ). After revision of the databases, the results (n = 11,308) were exported and compiled with Mendeley's reference management software. We also performed hand searching and included 88 articles. Mendeley's automated process removed duplicates (n = 3318), followed by a manual search to identify and remove additional duplicates. The authors screened all abstracts (n = 7990). The search focused on articles describing bacteria that developed a substantial decrease in disinfectant susceptibility with known biocide ingredients. There were multiple reasons for excluding studies, mostly for lacking MIC values or disinfectant concentrations. For the final analysis and the review, 28 sources that remained of interest were included and screened based on their full text by two independent reviewers (See Figure 1) . The relevant data were first extracted by MP and checked by UR. The characteristics of the identified relevant sources were presented in a table, where we described the findings from the review and analysis of the relevant literature. The main findings from the identified sources were highlighted. The extracted data included: (1) disinfectant category; (2) publication author(s), year, country, journal; (3) study aim/purpose; (4) main results of the identified research study. Articles describing the resistance of bacteria against seven different disinfectants were identified, namely: triclosan (10 articles), peracetic acid (2 articles), hydrogen peroxide (3 articles), ethanol and isopropanol (1 article), formaldehyde and glutaraldehyde (2 articles), chlorhexidine (4 articles), benzalkonium chloride and didecyldimonium chloride (5 articles). For this review, the definition of bacterial resistance to a disinfectant is based on an importantly decreased susceptibility in different tests (e.g., disk diffusion test, minimum inhibitory concentration MIC) reported by the clinical microbiology or research laboratories described in the reviewed studies. All 28 selected publications that met the search criteria are classified in Table 2 . In the study, the authors compared the proteomic profile of the susceptible serovar S. enterica Typhimurium with its isogenic triclosan tolerant strain to decode cellular mechanisms that promote biocide tolerance. Changes in the proteome of Salmonella were observed when exposed to sublethal concentrations of triclosan, which gave insights into mechanisms for the response and tolerance. Resistance to benzalkonium chloride is higher in single and mixed-species biofilms than in planktonic grown cells. After exposure for 15 min to 100 µg/mL, mixed-species biofilms are more resistant to benzalkonium chloride than single-species biofilms. The resistance against peracetic acid treatments (15 min to 100 µg/mL) is also higher in single and mixed-species biofilms than planktonic grown cells, but the differences are less pronounced. Spoering and Lewis (2001), USA, Journal of Bacteriology Studying biofilms of P. aeruginosa wild-type strain PAO1 and comparing its resistance against biocide when comparing it to planktonic cells. When comparing biofilms to logarithmic-phase planktonic cells, biofilms were considerably tolerant to the biocide. On the other hand, stationary-phase planktonic cells were more tolerant of peracetic acid than biofilms. The MBC for all three populations was 400 g/mL. Newer clinical isolates of E. faecium were more resistant to alcohol than their predecessors. Using a 70% isopropanol surface disinfectant, mutated E. faecium isolates were ten times more tolerant to disinfectant than isolates from decades ago. Strain ST796 had a reduced tolerance to isopropanol of 1.14 log 10 . Four hundred nucleotide positions mutated on two or more pairs of sequences. The study's main objective was to perform a preliminary examination to detect apparent differences between Salmonella serotypes and isolates, to link them with the resistance to disinfectants, for which there are extensive data regarding Danish fattening flocks. In MICs of five disinfectants commonly used in the Danish or English poultry sector, few variations were observed. Most differences from the isolates having high MICs were determined when using formaldehyde, but only a few isolates differed from the high MIC isolates when using the other four disinfectants. The aim was to investigate the effects of sub-MIC concentrations of CHX on gram-negative bacteria, particularly the P. aeruginosa strain, which is known to have an intrinsic resistance to CHX, and the susceptibility of CHX-resistant strains to antibiotics. After the fourth subculture, growth occurred within 24 h with a further increase in the MIC in P. aeruginosa strains NCIMB 10421; the MIC was significantly increased from the original 10 µg/mL to more than 70 µg/mL. The significance of these findings is still unclear, as the concentration of CHX in clinical use is much higher than that at which the authors obtained resistance. Multiple studies have shown an increased MIC from approximately 4-to 60-fold for specific bacteria for the disinfectant triclosan, making it epidemiologically relevant for increased bacterial adaptability and resistance [16, [37] [38] [39] [40] [41] [42] [43] [44] [45] . The mechanisms for the elevated MIC were various mutations at the genetic level. For E. coli these were: deletion of the ycjD gene [45] , mutation at codon 93 of the fabI gene, and mutation of the MarR transcription activator within the marRAB operon c, which regulates the operation of efflux pumps [41, 43] . For P. aeruginosa, there was deletion of the fabV gene, leading to a decreased fatty acid synthesis and consequent inhibition of the production of acyl-homoserine lactones and other virulence factors, such as LasA/LasB, alkaline proteases, phospholipases, lipases, exotoxin A, rhamnolipid and pyocyanin, and a reduced pathogenicity [46] . It also affects the MexCDOprJ gene, PAO1, which encodes 12 RND pumps [47, 48] . For S. aureus, intracellular malonyl-CoA inhibits the activity of the transcriptional repressor FapR, which directly interacts with the fabI gene, physiologically regulating its expression. This results in the most common mutations, polymorphisms, within the coding regions of C34T and MO035 in the sa-FabI region [49, 50] . For S. enterica there was: a mutation in the fabI gene, mutation of the AcrAB and TolC genes that regulate efflux pumps, and inactivation of the transcriptional regulators ramA and marA [51] [52] [53] . For the disinfectant peracetic acid, the MIC was raised four-fold in one of the three bacteria tested (P. aeruginosa), while in the others, there were no significant changes in susceptibility. According to the described example, it could be classified as relevant in the indication of resistance, although the results are currently deficient due to the lack of multiple studies and unequal conditions [54, 55] . For E. coli, mutations in the genes erm (B), tet (M), and tet (L) were observed [56] . For the disinfectant hydrogen peroxide, the MIC was also relevantly elevated in only one of the three bacteria studied (A. baumannii) and can be treated as a possible indicator of resistance here as well. However, due to deficient studies and unequal conditions, no conclusion regarding resistance can be made [57] [58] [59] . The cause of the elevated MIC were gene mutations. In all bacteria, mutations were in genes that regulate catalase (Kat), alkyl hydroperoxide reductase, and DNA-binding proteins that allow the catalase-reversible mechanism's inhibitory effect on SpxB expression [60, 61] . For the disinfectant chlorhexidine, the MIC has risen by almost 32-150 times in multiple relevant studies reviewed, making it epidemiologically relevant for increased bacterial adaptability and resistance, and a research/clinically relevant biocide [62] [63] [64] [65] [66] . The causes of the elevated MICs were gene mutations. For Enterococcus, mutation of the efrA and efrB genes that alter the expression of the EfrAB efflux pump of the ABC family, and hydrophobicity of the bacterial surface were observed [67, 68] . For S. aureus and MRSA, mutations of qacA, qacB, smr and norA genes were observed [69] [70] [71] [72] . For P. aeruginosa, mutation of efflux pump genes, such as MexCD-OprJ and oprH-phoPQ initiated by the stress response factor AlgU [69] [70] [71] [72] [73] [74] , and a decreased regulation of genes that encode proteins involved in membrane transport, oxidative phosphorylation, electron transport, and DNA repair were observed [75] [76] [77] . For the disinfectant benzalkonium chloride in multiple relevant studies reviewed, in three of the four bacteria, the MIC rises only 1-4-fold. This could make it epidemiologically relevant for increased bacterial adaptability and resistance, and a research/clinically relevant biocide [68, [78] [79] [80] [81] . The cause of the elevated MIC were gene mutations. For P. aeruginosa, mutations of efflux pump genes such as MDR mexA-mexB-oprM and mexC-mexD-oprJ were observed [82, 83] . For E. coli, a mutation in the sugE gene located in the 94 regions of a chromosome that phenotypically inhibits a groEL mutation were observed [84, 85] . For S. aureus, mutations of six different genes (i.e., qacA / B, qacC (smr), qacG, qacH and qacJ) that contribute to the development of resistance to QAC were observed [86] [87] [88] [89] . For disinfectants containing alcohols, aldehydes and iodine compounds, no relevant changes of MIC values were reported [90] [91] [92] [93] [94] . The MIC values for most commonly used biocides against clinically important bacteria are presented in Table 3 . The bacteria considered resistant had an increased MIC at least two times the average MIC in the first column. In order to understand resistance, there is an emphasis to distinguish between intrinsic and extrinsic resistance. Inherent resistance, known as natural resistance, is chromosomally encoded resistance, which determines the basic spectrum of effects of a disinfectant and the phenotypic resistance, e.g., biofilms. Extrinsic or acquired resistance develops through mutation by incorporating mobile genetic elements (horizontal gene transfer), transferable plasmids and other cell elements [114, 115] . A clear distinction also needs to be made between phenotypic adaptation, which is reversible when exposure to the biocides ends, and acquired resistance, being genetically determined and usually stable [115] . When studying antibiotic resistance, the European Committee on Antimicrobial Susceptibility Testing has decided to: "define separate dividing points for the detection of bacteria with resistance mechanisms and the monitoring of resistance development using wild-type cut-off values (WCV) or epidemiological cut-off values (ECOFF or ECV) and the guidance of therapy via clinical breakpoints" [101, 116] . As defined by the European Committee on Antimicrobial Susceptibility Testing, the ecological concept of antibiotic resistance states that ECOFFs are defined based on the normal distribution of MICs in a given bacterial species. Any isolate with a MIC above the epidemiological cut-off value (ECOFF), which is the upper limit of the normal distribution of the MIC for a given antimicrobial agent and a particular species, is considered resistant [43, 96] . In the case of studying biocide resistance, however, no limits have been set so far, and there are no clear criteria to determine whether a microbe is susceptible to the biocide or not. Therefore, we can use the average MIC values obtained from individual laboratory studies conducted under relatively similar conditions. The observed relevant increase in the MIC value can indicate a decreased susceptibility or even resistance. When interpreting the results, the in-use concentration of the disinfectants used must be considered since the in-use concentration may also be higher than the actual measured MIC values. In this case, we cannot talk about the resistance but only about a decreased susceptibility. Bacteria control and overcome the effect of disinfectants in different ways (Table 4) , such as restricted permeability of the cell wall, the expression of efflux systems, enzymatic degradation, changes in target sites, and the formation of biofilms [23, 117] . Changes in cell surface hydrophobicity, ultrastructure, protein composition, and fatty acid modifications appear to occur [118, 119] . For example, inactivation of the lipooligosaccharide biosynthesis genes causes resistance in A. baumannii [120] . Modifying the outer membrane proteins and an increased expression of cellular structures may increase the sensitivity to disinfectants [118, 119, 121] . Impermeability of the outer membrane occurs because of the lipopolysaccharide component, which increases the penetration of disinfectants and affects the size and expression of pores, thereby preventing entry and affecting sensitivity [122] . The hydrophilic porin channels on the outer membrane regulate the passage of solutes and are a significant barrier to hydrophilic substance penetration [123] . They also have a negative charge, which can cause the disinfectant molecules to bounce away from the bacterial cell. Bacteria can also grow as biofilms, endospores, and within cellular macrophages. In most natural habitats, microorganisms grow and survive as associated biofilms [124] . Monocultures of several different species or mixed phenotypes of a particular species can form biofilms. It is a community of nonmobile microorganisms that are irreversibly attached to a surface and inserted into a polymeric extracellular matrix. The insensitivity of biofilms to disinfectants is due to altered microbial growth rates, which can be attributed to nutrient depletion in the biofilm, and disinfectant binding to the biofilm, which is neutralized or degraded [35] . Such an organization may moderate the concentration of antimicrobial disinfectants and antibiotics to which deeper biofilm cells are exposed. Such cells accidentally grow slowly, starve, and express stress phenotypes, including regulating efflux pumps and flushing out disinfectants [125] . Slightly less effective mechanisms involve the enzymatic degradation or inactivation of disinfectants when concentrations of agents, such as formaldehyde, chlorhexidine, and quaternary ammonium compounds, are lower than those used in clinical trials practice [126] . The exposure of bacteria to minimal inhibitory concentrations of disinfectants results in the induced expression of neutralizing enzymes, which is crucial for the biodegradation of disinfectants [127] . Examples of the neutralization of disinfectants have been given in several species of bacteria, for example, Pseudomonas fluorescens TN4 isolated from sludge was able to degrade DDAC, which belongs to the group of quaternary ammonium compounds. The isolate was also able to degrade other QACs by the N-dealkylation process [128] . One major cause of bacterial resistance is the active transport of substances to the cell exterior, the so-called efflux with proteins. Efflux pump mechanisms perform essential physiological functions [97] . Although existing in all living cells, those found in bacterial and mammalian cells are especially important for clinicians and pharmacologists since they constitute an important cause of antimicrobial resistance. Multidrug Resistance (MDR) efflux pumps present an ongoing research topic in antibiotic resistance and are also responsible for disinfectant resistance mechanisms [129] . One of the fundamental mechanisms of action is the efflux pump's influence and the modulation of its genes. These efflux systems existed in bacteria long before the use of disinfectants and antibiotics in humans to treat infections. The mechanism involves the secretion of toxic compounds through a bacterial cell wall with a membrane-bound protein composed of at least three components. The increased expression of these pumps can raise the minimum inhibitory concentration to a high level, resulting in resistance to disinfectants [130] and greater sensitivity and crossresistance to antibiotics [40] . Research data show that pump expression reduces the efficacy of various classes of disinfectants, including chlorhexidine digluconate, hydrogen peroxide, benzalkonium chloride, chloroxylenol, iodine compounds, triclosan, quaternary ammonium compounds, phenolic parabens and intercalates [131, 132] . Among the best-studied systems of genes that regulate the secretion of biocides are mexAB-oprM, mexCD-oprJ and mexEF-oprN in P. aeruginosa [133] , acrAB-tolC, acrEF-tolC and emrE in E. coli [134] , smeDEF in bacteria Stenotrophomonas maltophilia [135] , and norA and mepA in S. aureus. In the highly resistant nosocomial bacterium A. baumannii, the efflux activity is regulated by the quacA and quacB genes [57, 77, 136] . Bacteria use the same pumps to remove antibiotics and biocides. Thus, they can select antibiotic-resistant mutants that over-regulate such pumps [137] . Another important factor contributing to the development of disinfectant resistance is the mode of action of disinfectants. Biocides have a broader spectrum of activity and may have multiple targets, while antibiotics tend to have specific intracellular targets [29] . However, in the case of biocides with a particular antimicrobial mechanism (e.g., quaternary ammonium compounds-QAC's), the development of antimicrobial resistance against disinfectants, and cross-resistance to antibiotics, are especially well documented [138] . Denaturation of bacterial membrane proteins and dissolving lipid components such as antiparallel β and 3 10 helical turns of proteins, C-H deformations in lipids, inhibition of nutrient transport via membrane-bound ATPases, alteration of membrane pH and membrane potential. Horizontal gene transfer, transformation and transduction and core genome mutations in the chromosome nucleotide position on the rpoB gene β subunit of RNA polymerase. Alcohol working mechanism: [6, [139] [140] [141] Alcohol adaptation: [91, 142] and stress factors, biofilm formation, and biodegradation by dealkylation. Benzalkonium chloride releasing agents working mechanism: [29, 78, 158] Benzalkonium chloride releasing agents adaptation: [82, 159] Antimicrobial resistance in healthcare facilities has been occurring and regularly increasing over the last ten years. Growing evidence from in vitro studies has shown that bacteria have a tremendous ability to respond to chemical stress caused by biocides by several different mechanisms [160] . The main reason for emerging resistance is attributed mainly to the overuse, abuse and misuse of disinfectants [160] [161] [162] . Relevant increases in MIC concentrations, changes at the genetic level, and clearly altered mechanisms were observed in studies of several bacterial species in the presence of disinfectants. Through the most relevant of the reviewed articles, we can define the results for disinfectants based on triclosan and chlorhexidine, where the critical deviation of the MIC was observed in multiple studies. Given the ongoing problems with multiple antibiotic resistance in clinically important bacteria strains and the potential for increased resistance to disinfectants, the use of which is rising in the community, it is clear that the prudent use of available and effective antimicrobials is needed. It is essential to develop and adopt strategies to control disinfectant resistance, for which the following factors will make a significant contribution. To solve the disinfectant resistance problem, it is essential to comprehensively summarize the disinfectant resistance mechanisms and to understand the resistance influencing factors [163] . It is also necessary to establish ECOFF values for biocides, without which any research is challenging and, to some extent, inaccurate. Harmonized methods for biocide susceptibility testing need to be developed. Further studies are needed to establish a link between disinfectant exposure and resistance development, as many studies in clinical or external settings are currently limited. The rotation of disinfectants, where one disinfectant should be replaced by another having a different mechanism of action, is recommended [164] . The same types of disinfectants are used both in healthcare institutions and among the general population; therefore, their prudent use and consumption, as we know in the case of antibiotics, are complicated to control. Since selective pressure caused by disinfectants is exerted on both commensal and pathogenic bacteria [165, 166] , monitoring for resistant genes in nonpathogenic or commensal bacteria would make sense. Health-related infections acquired in the community need to be researched annually. More attention should be paid to the correct use of disinfectants by the general public, although supervising the proper use of disinfectants among the general population is very difficult to implement. The risks and benefits of using disinfectants in the environment need to be weighed to determine whether additional precautions are required to guide the development and use of disinfectants [167] . If bacterial resistance increases and develops against many regularly used disinfectants in clinical and industrial settings, overuse in reflection of the COVID-19 pandemic could place an additional burden on global public health [168] . Author Contributions: U.R.: substantial contributions to conception and design, data acquisition, analysis and interpretation; drafting the article and revising it critically for important intellectual content; final approval of the version to be published. M.P.: substantial contributions to conception and design, data acquisition, analysis and interpretation; drafting the article. S.K.: substantial contributions to conception and design, critically revising the article. D.D.: substantial contributions to conception and design, data acquisition, analysis and interpretation; drafting the article and revising it critically for important intellectual content; final approval of the version to be published. S.Š.T.: substantial contributions to conception and design; final approval of the version to be published. All authors have read and agreed to the published version of the manuscript. We are very grateful to Sanlas Holding GmbH, Austria who acted as a co-financer of the project. The research was also financially supported by the national research program (P2-0118). Institutional Review Board Statement: Not applicable. Data Availability Statement: Not applicable. The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Biocidal Products Regulation-Product Types Bacterial resistance to biocides in the healthcare environment: Should it be of genuine concern? Bacterial target sites for biocide action Environmental monitoring of biocides in Europe: Compartment-specific strategies-Workshop report Determinants of disinfectant use among nurses in US healthcare facilities Disinfection and sterilization in health care facilities: What clinicians need to know Consumer exposure to biocides-identification of relevant sources and evaluation of possible health effects Korean consumers' awareness of the risks of chemicals in daily consumer products A systematic review of hand-hygiene and environmental-disinfection interventions in settings with children Alternative antimicrobial approach: Nano-antimicrobial materials. Evid.-Based Complementary Altern Alternatives to antibiotics-A pipeline portfolio review Alternatives to overcoming bacterial resistances: State-of-the-art Disinfection and sterilization using plasma technology: Fundamentals and future perspectives for biological applications The role of surface disinfection in infection prevention Comparison of the efficacy of natural-based and synthetic biocides to disinfect silicone and stainless steel surfaces Altered competitive fitness, antimicrobial susceptibility, and cellular morphology in a triclosan-induced small-colony variant of Staphylococcus aureus Biocide use and antibiotic resistance: The relevance of laboratory findings to clinical and environmental situations Susceptibility to disinfectants in antimicrobialresistant and-susceptible isolates of Escherichia coli, Enterococcus faecalis and Enterococcus faecium from poultry-ESBL/AmpCphenotype of E. coli is not associated with resistance to a quaternary ammonium compound Triclosan and antimicrobial resistance in bacteria: An overview Assessment of the Antibiotic Resistance Effects of Biocides Hand hygiene-evaluation of three disinfectant hand sanitizers in a community setting Biocide resistance mechanisms Overview perspective of bacterial strategies of resistance to biocides and antibiotics Resistance to antibiotics, biocides, preservatives and metals in bacteria isolated from seafoods: Co-selection of strains resistant or tolerant to different classes of compounds Use of germicides in the home and the healthcare setting: Is there a relationship between germicide use and antibiotic resistance? Drug resistance and gene transfer mechanisms in respiratory/oral bacteria Mechanisms of bacterial biocide and antibiotic resistance Antiseptics and disinfectants: Activity, action, and resistance The impact of triclosan on the spread of antibiotic resistance in the environment Biocidal agents used for disinfection can enhance antibiotic resistance in gram-negative species Mechanisms of increased resistance to chlorhexidine and cross-resistance to colistin following exposure of Klebsiella pneumoniae clinical isolates to chlorhexidine Resistance toward chlorhexidine in oral bacteria-Is there cause for concern? Development of bacterial resistance to several biocides and effects on antibiotic susceptibility Biofilms in vitro and in vivo: Do singular mechanisms imply cross-resistance? Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement Triclosan resistance in methicillin-resistant Staphylococcus aureus expressed as small colony variants: A novel mode of evasion of susceptibility to antiseptics Functional screening for triclosan resistance in a wastewater metagenome and isolates of Escherichia coli and Enterococcus spp. from a large Canadian healthcare region Comparative proteomic analysis of Salmonella tolerance to the biocide active agent triclosan Prevalence of decreased susceptibility to triclosan in Salmonella enterica isolates from animals and humans and association with multiple drug resistance Triclosan-tolerant bacteria: Changes in susceptibility to antibiotics Functional characterization of triclosan-resistant enoyl-acyl-carrier protein reductase (FabV) in Pseudomonas aeruginosa Active efflux, a common mechanism for biocide and antibiotic resistance Triclosan resistance in Salmonella enterica serovar Typhimurium Signature gene expression profile of triclosan-resistant Escherichia coli Quorum sensing and environmental adaptation in Pseudomonas aeruginosa: A tale of regulatory networks and multifunctional signal molecules Susceptibility of compound 48/80-sensitized Pseudomonas aeruginosa to the hydrophobic biocide triclosan Triclosan resistance of Pseudomonas aeruginosa PAO1 is due to FabV, a triclosanresistant enoyl-acyl carrier protein reductase High-level triclosan resistance in Pseudomonas aeruginosa is solely a result of efflux High-level tolerance to triclosan may play a role in Pseudomonas aeruginosa antibiotic resistance in immunocompromised hosts: Evidence from outbreak investigation A novel resistance mechanism to triclosan that suggests horizontal gene transfer and demonstrates a potential selective pressure for reduced biocide susceptibility in clinical strains of Staphylococcus aureus Efficacy of triclosan as an antimicrobial hand soap and its potential impact on antimicrobial resistance: A focused review Staphylococcus aureus but not Listeria monocytogenes adapt to triclosan and adaptation correlates with increased fabI expression and agr deficiency Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials Mixed species biofilms of Listeria monocytogenes and Lactobacillus plantarum show enhanced resistance to benzalkonium chloride and peracetic acid Defence strategies and antibiotic resistance gene abundance in enterococci under stress by exposure to low doses of peracetic acid Molecular characterization of reduced susceptibility to biocides in clinical isolates of Acinetobacter baumannii Inhibitory and bactericidal effects of hydrogen peroxide production by Streptococcus pneumoniae on other inhabitants of the upper respiratory tract Use of a predictive protocol to measure the antimicrobial resistance risks associated with biocidal product usage Staphylococcus aureus SrrAB affects susceptibility to hydrogen peroxide and co-existence with Streptococcus sanguinis Effect of hydrogen peroxide production and the Fenton reaction on membrane composition of Streptococcus pneumoniae Susceptibility of community associated methicillin resistant Staphylococcus aureus isolated from faeces to antiseptics High-level vancomycin resistant Enterococcus faecium related to humans and pigs found in dust from pig breeding facilities Adaptive bacterial response to low level chlorhexidine exposure and its implications for hand hygiene Development of resistance to chlorhexidine diacetate in Pseudomonas aeruginosa and the effect of a'residual'concentration Biocide and copper tolerance in enterococci from different sources Evolution of resistance to cationic biocides in Streptococcus mutans and Enterococcus faecalis The effect of exposure to sub-inhibitory concentrations of hypochlorite and quaternary ammonium compounds on antimicrobial susceptibility of Pseudomonas aeruginosa Antiseptic resistance in methicillin sensitive and methicillin resistant Staphylococcus aureus isolates from some major hospitals Nanosilberbeschichtete Lebensmittelverpackungsfolie zur Reduktion von Keimen auf Schweinefleisch und Testung der Empfindlichkeit von MRSA-und MSSA-Isolaten gegenüber Silber und sieben weiteren Bioziden Antimicrobial agent of susceptibilities and antiseptic resistance gene distribution among methicillin-resistant Staphylococcus aureus isolates from patients with impetigo and staphylococcal scalded skin syndrome Susceptibilities to antiseptic agents and distribution of antiseptic-resistance genes qacA/B and smr of methicillin-resistant Staphylococcus aureus isolated in Asia during 1998 and 1999 Antimicrobial and toxicological profile of the new biocide Akacid plus® Responses of Pseudomonas aeruginosa to antimicrobials Global transcriptomic response of Pseudomonas aeruginosa to chlorhexidine diacetate Epidemiology and susceptibilities of methicillinresistant Staphylococcus aureus in Taiwan: Emphasis on chlorhexidine susceptibility Distribution of biocide resistant genes and biocides susceptibility in multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii-A first report from the Kingdom of Saudi Arabia The disinfectant effects of benzalkonium chloride on some important foodborne pathogens Detection of benzalkonium chloride resistance in community environmental isolates of staphylococci Effect of subinhibitory concentrations of benzalkonium chloride on the competitiveness of Pseudomonas aeruginosa grown in continuous culture Effect of benzalkonium chloride adaptation on sensitivity to antimicrobial agents and tolerance to environmental stresses in Listeria monocytogenes Long-term exposure to benzalkonium chloride disinfectants results in change of microbial community structure and increased antimicrobial resistance An investigation into the relative resistances of common bacterial pathogens to quaternary ammonium cation disinfectants Overexpression of the Escherichia coli sugE gene confers resistance to a narrow range of quaternary ammonium compounds Analysis of a complete library of putative drug transporter genes in Escherichia coli Exposure to Sublethal Concentrations of Benzalkonium Chloride Induces Antimicrobial Resistance and Cellular Changes in Klebsiellae pneumoniae Clinical Isolates Analysis of genomic diversity and evolution of the low-level antiseptic resistance gene smr in Staphylococcus aureus First report of qacG, qacH and qacJ genes in Staphylococcus haemolyticus human clinical isolates MgrA is a multiple regulator of two new efflux pumps in Staphylococcus aureus Possible associations between Salmonella persistence in poultry houses and resistance to commonly used disinfectants and a putative role of mar Increasing tolerance of hospital Enterococcus faecium to handwash alcohols Antimicrobial effectiveness of povidone-iodine and consequences for new application areas Emergence of glutaraldehyde-resistant Pseudomonas aeruginosa Bacterial resistance to antibiotic alternatives: A wolf in sheep's clothing? PubChem Compound Summary for CID 5564 Evaluation of epidemiological cut-off values indicates that biocide resistant subpopulations are uncommon in natural isolates of clinicallyrelevant microorganisms The importance of efflux pumps in bacterial antibiotic resistance The efficacy of chemical agents in cleaning and disinfection programs Validation of peracetic acid as a sporicide for sterilization of working surfaces in biological safety cabinets Limited association between disinfectant use and either antibiotic or disinfectant susceptibility of Escherichia coli in both poultry and pig husbandry Minimal inhibitory concentration (MIC) determination of disinfectant and/or sterilizing agents. Braz Hydrogen peroxide: A potential wound therapeutic target Co-operative inhibitory effects of hydrogen peroxide and iodine against bacterial and yeast species Bacillus pumilus KatX2 confers enhanced hydrogen peroxide resistance to a Bacillus subtilis P katA:: katX2 mutant strain In vitro antimicrobial activity of glutaraldehyde plus O-phenylphenol association (ratio 2:1) Minimum Inhibitory Concentrations of and Adaptation to Five Disinfectants Commonly Used Against Salmonella in the Poultry Industry A review on biocide reduced susceptibility due to plasmid-borne antiseptic-resistant genes-special notes on pharmaceutical environmental isolates Guideline for Disinfection and Sterilization in Healthcare Facilities Evaluation of Antibacterial Activity of Three Quaternary Ammonium Disinfectants on Different Germs Isolated from the Hospital Environment Antibacterial and resistance-modifying activities of thymoquinone against oral pathogens Postadaptational resistance to benzalkonium chloride and subsequent physicochemical modifications of Listeria monocytogenes Bacterial disinfectant resistance-A challenge for the food industry Current and emergent strategies for disinfection of hospital environments Does microbial resistance or adaptation to biocides create a hazard in infection prevention and control? Inhibition Zone Diameter Distributions of Microorganisms without and with Phenotypically Evident Resistance Mechanisms Cellular impermeability and uptake of biocides and antibiotics in Gram-positive bacteria and mycobacteria Outer membrane changes in Pseudomonas stutzeri resistant to chlorhexidine diacetate and cetylpyridinium chloride Outer membrane protein shifts in biocide-resistant Pseudomonas aeruginosa PAO1 Effect of Subinhibitory Concentrations of Antibiotics and Disinfectants on ISAba-Mediated Inactivation of Lipooligosaccharide Biosynthesis Genes in Acinetobacter baumannii. Antibiotics 2021 Induction of fatty acid composition modifications and tolerance to biocides in Salmonella enterica serovar Typhimurium by plant-derived terpenes Physiological changes induced by the quaternary ammonium compound benzyldimethyldodecylammonium chloride on Pseudomonas fluorescens Molecular basis of bacterial outer membrane permeability revisited. Microbiol Bacterial spore structures and their protective role in biocide resistance Loss of or inhibition of all multidrug resistance efflux pumps of Salmonella enterica serovar Typhimurium results in impaired ability to form a biofilm Antiseptic "resistance": Real or perceived threat? Potential impact of increased use of biocides in consumer products on prevalence of antibiotic resistance Biodegradation of didecyldimethylammonium chloride by Pseudomonas fluorescens TN4 isolated from activated sludge An overview of bacterial efflux pumps and computational approaches to study efflux pump inhibitors Biocides-resistance, cross-resistance mechanisms and assessment Bacterial multidrug efflux pumps: Much more than antibiotic resistance determinants Commonly used farm disinfectants can select for mutant Salmonella enterica serovar Typhimurium with decreased susceptibility to biocides and antibiotics without compromising virulence Induction of mexCD-oprJ operon for a multidrug efflux pump by disinfectants in wild-type Pseudomonas aeruginosa PAO1 Low level of cross-resistance between triclosan and antibiotics in Escherichia coli K-12 and E. coli O55 compared to E. coli O157 The biocide triclosan selects Stenotrophomonas maltophilia mutants that overproduce the SmeDEF multidrug efflux pump Mechanisms of bacterial insusceptibility to biocides Multidrug efflux pump overexpression in Staphylococcus aureus after single and multiple in vitro exposures to biocides and dyes Modes of action of three disinfectant active substances: A review Understanding the antimicrobial activity of selected disinfectants against methicillin-resistant Staphylococcus aureus (MRSA) Very low ethanol concentrations affect the viability and growth recovery in post-stationary-phase Staphylococcus aureus populations Disinfection and Sterilization in Health Care Facilities: An Overview and Current Issues Ethanol tolerance in Escherichia coli DH5-Alpha developed by serial exposure to sublethal doses is conferred to wild strains by horizontal gene transfer Formaldehyde stress responses in bacterial pathogens Resistance mechanisms of bacteria to antimicrobial compounds Formation, accumulation, and hydrolysis of endogenous and exogenous formaldehyde-induced DNA damage Molecular mechanisms of chlorhexidine tolerance in Burkholderia cenocepacia biofilms Inhibition of the Staphylococcus aureus NADPH-dependent enoyl-acyl carrier protein reductase by triclosan and hexachlorophene Non-antibiotic antimicrobial triclosan induces multiple antibiotic resistance through genetic mutation Distribution of triclosan-resistant genes in major pathogenic microorganisms revealed by metagenome and genome-wide analysis Characterization of triclosan-resistant mutants reveals multiple antimicrobial resistance mechanisms in Rhodospirillum rubrum S1H Triclosan: A widely used biocide and its link to antibiotics Povidone iodine in wound healing: A review of current concepts and practices Antiseptics in the era of bacterial resistance: A focus on povidone iodine Efficacy of dilute povidone-iodine against multi-drug resistant bacterial biofilms, fungal biofilms and fungal spores Use of hydrogen peroxide as a biocide: New consideration of its mechanisms of biocidal action Contribution of catalase to hydrogen peroxide resistance in Enterococcus faecalis Mechanisms of biofilm resistance to antimicrobial agents Evaluation of a benzalkonium chloride hand sanitizer in reducing transient Staphylococcus aureus bacterial skin contamination in health care workers Adaptation of a bacterial membrane permeabilization assay for quantitative evaluation of benzalkonium chloride as a membrane-disrupting agent Molecular basis of bacterial disinfectant resistance. Drug Resist. Updates 2020, 48, 100672 Bacterial resistance to Quaternary Ammonium Compounds (QAC) disinfectants The global threat of antimicrobial resistance: Science for intervention. New Microbes New Infect Disinfectant resistance in bacteria: Mechanisms, spread, and resolution strategies Biocide rotation in the healthcare setting: Is there a case for policy implementation? Recent Emergence of Escherichia coli with Cephalosporin Resistance Conferred by blaCTX-M on Washington State Dairy Farms Biology of Microorganisms Increased usage of antiseptics is associated with reduced susceptibility in clinical isolates of Staphylococcus aureus Tackling Drug Resistant Infections Globally-Final Report and Recommendations; Government of the United Kingdom