Resistance Toward Chlorhexidine in Oral Bacteria – Is There Cause for Concern?

Abstract

The threat of antibiotic resistance has attracted strong interest during the last two decades, thus stimulating stewardship programs and research on alternative antimicrobial therapies. Conversely, much less attention has been given to the directly related problem of resistance toward antiseptics and biocides. While bacterial resistances toward triclosan or quaternary ammonium compounds have been considered in this context, the bis-biguanide chlorhexidine (CHX) has been put into focus only very recently when its use was associated with emergence of stable resistance to the last-resort antibiotic colistin. The antimicrobial effect of CHX is based on damaging the bacterial cytoplasmic membrane and subsequent leakage of cytoplasmic material. Consequently, mechanisms conferring resistance toward CHX include multidrug efflux pumps and cell membrane changes. For instance, in staphylococci it has been shown that plasmid-borne qac (“quaternary ammonium compound”) genes encode Qac efflux proteins that recognize cationic antiseptics as substrates. In Pseudomonas stutzeri , changes in the outer membrane protein and lipopolysaccharide profiles have been implicated in CHX resistance. However, little is known about the risk of resistance toward CHX in oral bacteria and potential mechanisms conferring this resistance or even cross-resistances toward antibiotics. Interestingly, there is also little awareness about the risk of CHX resistance in the dental community even though CHX has been widely used in dental practice as the gold-standard antiseptic for more than 40 years and is also included in a wide range of oral care consumer products. This review provides an overview of general resistance mechanisms toward CHX and the evidence for CHX resistance in oral bacteria. Furthermore, this work aims to raise awareness among the dental community about the risk of resistance toward CHX and accompanying cross-resistance to antibiotics. We propose new research directions related to the effects of CHX on bacteria in oral biofilms.

Tolerance and Persister Formation in Oral Streptococci

“…The cationic biguanidine CHX, introduced in 1954, is a widely used antimicrobial substance in dentistry and is considered to be the 'gold standard' of oral hygiene due to its ideal antimicrobial spectrum and remnant effect. However, adverse effects such as taste disturbance or tooth staining were noticed early on and allergic reactions including serious anaphylactic reactions have been described [18,43]. Although no clear definition for the term 'resistance' exists so far for antimicrobials such as CHX, intrinsic and acquired mechanisms conferring reduced susceptibility toward CHX have been described in various microorganisms as well as the potential risk of cross-resistance against other biocides or antibiotics [43].…”

Spontaneously Arising Streptococcus mutans Variants with Reduced Susceptibility to Chlorhexidine Display Genetic Defects and Diminished Fitness

“…Adaptations to CHX may also lead to cross-resistance to other antimicrobials, as was noted recently with clinical strains of Klebsiella pneumoniae that acquired resistance to the last-resort antibiotic colistin after exposure to CHX (21). To date, the emergence of tolerant or resistant oral bacteria due to repeated use of CHX in the dental practice has not been fully studied, although the determination of whether exposure to CHX can result in the acquisition of resistance to other antimicrobials and the molecular mechanisms by which CHX may confer resistance in these organisms are of growing interest (22). In this study, we focused on the caries-associated pathogen S. mutans, showed that passage on increasing concentrations of CHX gives rise to variants that display reduced susceptibility to CHX, and began to examine the genetic basis for reduced CHX susceptibility.…”

The Antibacterial Effects of Quaternary Ammonium Salts in the Simulated Presence of Inhibitors in Root Canals: A Preliminary In-Vitro Study

“…In the present study, the inhibitory effect of dentine, dentine matrix and dead bacteria against four antimicrobial compounds were detected, with CHX and NaOCl as control group. CHX and NaOCl are the most studied root canal irrigants in endodontics and they were found to be the most effective irrigants against Gram-positive and negative oral pathogens including yeast, because CHX could damage the bacterial cytoplasmic membrane, which subsequent cause the leakage of cytoplasmic material [26]. The antimicrobial effect of NaOCl is based on causing biosynthetic alterations in cellular metabolism and phospholipid destruction, formation of chloramines that interfere in cellular metabolism, oxidative action with irreversible enzymatic inactivation in bacteria, and lipid and fatty acid degradation [27].…”