Increased usage of antiseptics is associated with reduced susceptibility in clinical isolates of S. aureus

Abstract

22Hospital acquired infection is a major cause of morbidity and mortality and regimes to 23 prevent infection are crucial in infection control. These include decolonisation of at-risk 24 patients of carriage of MRSA which is commonly achieved by protocols that include the use 25 of chlorhexidine, or octenidine as biocidal agents. There is however no standardised single 26 decolonisation regime agreed upon in the UK or other countries and protocols include a 27 variety of active agents. Antibiotic resistant bacteria cause major problems in hospital 28 medicine and concern has been raised regarding the development of biocide resistance 29 which would cause decolonisation regimes to become unreliable. In this study, we 30 assembled a panel of isolates of S. aureus including isolates collected before the 31 development of chlorhexidine and octenidine through to a contemporaneous panel of 32 isolates from a major hospital trust in the UK during a period when the decolonisation regime 33 was altered. We observed significant increases in the MIC and MBC of chlorhexidine in 34isolates collected from periods of high usage of chlorhexidine. No isolates had a significantly 35 altered MIC or MBC of octenidine apart from those collected after octenidine was introduced 36into the trust where isolates with four-fold decreases in susceptibility emerged. There was no 37 suggestion of cross-resistance between the two biocidal agents. A combination of VNTR, 38 PCR for qac genes and whole genome sequencing was used to type isolates and examine 39 possible mechanisms of resistance. The typing data showed no expansion of a single strain 40 was associated with decreased biocide tolerance and isolates with increased chlorhexidine 41 MIC and MBCs were found from different clonal complexes; CC8, CC22 and CC30. Biocide 42 susceptibility did not correlate with carriage of qac efflux pump genes -carriage of qacA and 43 qacB was detected but, with one exception was restricted to isolates of CC8. Analysis of 44 genome sequence data for closely related pairs of strains with differential biocide 45 susceptibility revealed no common mutations or carriage of accessory elements that 46 correlated with biocide tolerance. Mutations with the NorA or NorB efflux pumps, previously 47 associated with chlorhexidine export were identified suggesting this may be an important 48 mechanism of biocide tolerance. The clinical relevance of decreased biocide tolerance in 49 terms of efficacy of decolonisation therapies remains to be established but we present 50 evidence here that isolates are evolving in the face of biocide challenge in patients and that 51 changes to decolonisation regimes are reflected in changes in susceptibility of isolates. More 52 work is needed to assess the impact of these changes to ensure effective and robust 53 decolonisation protocols remain in place. 54 55 56 not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.or...

Priming with biocides: A pathway to antibiotic resistance?

“…Specifically, the ability of biocides to prime for antibiotic resistance without the usual observation of stable biocidal tolerance. Exposure of S. aureus to CHG did not reduce its susceptibility to the biocide, contrasting the findings of Hardy et al where prolonged exposure of S. aureus isolates to CHG led to reduced susceptibility (Hardy et al, 2017).…”

“…Exposure of S. aureus to CHG did not reduce its susceptibility to the biocide, contrasting the findings of Hardy et al where prolonged exposure of S . aureus isolates to CHG led to reduced susceptibility (Hardy et al, 2017). Here, cross‐resistance to oxacillin was observed with no corresponding tolerance to the biocide.…”

“…As previously demonstrated by several studies, prolonged exposure of bacteria to biocides under laboratory conditions can generate less susceptible mutants which can often display reduced susceptibility to various antibiotics (Fernández Márquez et al, 2017; Hardy et al, 2017; Karatzas et al, 2007, 2008; Randall et al, 2007; Whitehead et al, 2011).…”

Lipopolysaccharide structure modulates cationic biocide susceptibility and crystalline biofilm formation in Proteus mirabilis

“…These antimicrobials are integral to strategies aimed at reducing antibiotic use through enhanced infection control (Maillard, 2005). Accordingly, biocide use in clinical settings is increasing, particularly for prophylactic decolonization of newly admitted patients (Gilbert and Moore, 2005;Wand et al, 2017Wand et al, , 2019Hardy et al, 2018). This raises important questions about the impact of increased biocide use on bacterial pathogens, and there is evidence that sub-lethal biocide exposure can select for problematic species, reduced biocide susceptibility, and other undesirable traits (Hayden et al, 2015;Hardy et al, 2018;Wand et al, 2019).…”

“…Accordingly, biocide use in clinical settings is increasing, particularly for prophylactic decolonization of newly admitted patients (Gilbert and Moore, 2005;Wand et al, 2017Wand et al, , 2019Hardy et al, 2018). This raises important questions about the impact of increased biocide use on bacterial pathogens, and there is evidence that sub-lethal biocide exposure can select for problematic species, reduced biocide susceptibility, and other undesirable traits (Hayden et al, 2015;Hardy et al, 2018;Wand et al, 2019). In particular, there is increasing concern that inappropriate, or overuse, of biocides could lead to the emergence of "resistant" strains and select for crossresistance to antibiotics (Wand et al, 2017;Hashemi et al, 2019;Stein et al, 2019).…”