Cited by 313Antibiotic Resistance in BacteriaBacterial Genetics and BiotechnologyAntimicrobial agents and applications

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Mechanisms of Increased Resistance to Chlorhexidine and Cross-Resistance to Colistin following Exposure of Klebsiella pneumoniae Clinical Isolates to Chlorhexidine

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Wand, Matthew E., Bock, Lucy J., Bonney, Laura C., Sutton, J. Mark·2017·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.01162-16PMC PMC5192135

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Abstract

Klebsiella pneumoniae is an opportunistic pathogen that is often difficult to treat due to its multidrug resistance (MDR). We have previously shown that K. pneumoniae strains are able to “adapt” (become more resistant) to the widely used bisbiguanide antiseptic chlorhexidine. Here, we investigated the mechanisms responsible for and the phenotypic consequences of chlorhexidine adaptation, with particular reference to antibiotic cross-resistance. In five of six strains, adaptation to chlorhexidine also led to resistance to the last-resort antibiotic colistin. Here, we show that chlorhexidine adaptation is associated with mutations in the two-component regulator phoPQ and a putative Tet repressor gene ( smvR ) adjacent to the major facilitator superfamily (MFS) efflux pump gene, smvA . Upregulation of smvA (10- to 27-fold) was confirmed in smvR mutant strains, and this effect and the associated phenotype were suppressed when a wild-type copy of smvR was introduced on plasmid pACYC. Upregulation of phoPQ (5- to 15-fold) and phoPQ -regulated genes, pmrD (6- to 19-fold) and pmrK (18- to 64-fold), was confirmed in phoPQ mutant strains. In contrast, adaptation of K. pneumoniae to colistin did not result in increased chlorhexidine resistance despite the presence of mutations in phoQ and elevated phoPQ , pmrD , and pmrK transcript levels. Insertion of a plasmid containing phoPQ from chlorhexidine-adapted strains into wild-type K. pneumoniae resulted in elevated expression levels of phoPQ , pmrD , and pmrK and increased resistance to colistin, but not chlorhexidine. The potential risk of colistin resistance emerging in K. pneumoniae as a consequence of exposure to chlorhexidine has important clinical implications for infection prevention procedures.

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Background
Chlorhexidine Digluconate
Kampf, G. (2018) · Springer eBooks · doi:10.1007/978-3-319-98785-9_13 · Cited by 13
The Transcriptional Repressor SmvR Is Important for Decreased Chlorhexidine Susceptibility in Enterobacter cloacae Complex
Guérin, F., Gravey, F., Plésiat, P., Aubourg, M., Beyrouthy, R., Bonnet, R., Cattoir, V., & Giárd, J.-C. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01845-19 · Cited by 13
“showed that SmvR acted as a repressor of smvA transcription, and mutation in the sequence of the regulator was correlated with the CHX adaptation (16).”
BackgroundInfluential
Tailoring the immobilization and release of chlorhexidine using dopamine chemistry to fight infections associated to orthopedic devices
Alves, D. F., Borges, P., Grainha, T., Rodrigues, C. F., & Pereira, M. O. (2020) · Materials Science and Engineering C · doi:10.1016/j.msec.2020.111742 · Cited by 14
Potential of lytic bacteriophages as disinfectant to control of Pseudomonas aeruginosa on fomites
Rahimzadeh, G., Zazouli, M. A., & Rezai, M. S. (2022) · Journal of Environmental Health Science and Engineering · doi:10.1007/s40201-021-00770-2 · Cited by 12
“The use of biocides can be an appropriate method acting against the prevalence of nosocomial infections [10].”
Background
Reduced Chlorhexidine Susceptibility Is Associated with Tetracycline Resistance tet Genes in Clinical Isolates of Escherichia coli
Royer, G., de la Rosa, J. M. O., Vuillemin, X., et al. (2022) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01972-21 · Cited by 12
“Some of these authors also reported cross-resistance to colistin (COL) (11, 12), a polypeptide antibiotic with activity against most Gram-negative bacteria (14).”
BackgroundInfluential
Applying fluorescent dye assays to discriminate Escherichia coli chlorhexidine resistance phenotypes from porin and mlaA deletions and efflux pumps
Gregorchuk, B. S. J., Reimer, S. L., Slipski, C. J., Milner, K. A., Hiebert, S. L., Beniac, D. R., Booth, T. F., Zhanel, G. G., & Bay, D. C. (2022) · Scientific Reports · doi:10.1038/s41598-022-15775-6 · Cited by 13
Mutant selection window of disinfectants for Staphylococcus aureus and Pseudomonas aeruginosa
Kawamura, M., Fujimura, S., Tokuda, K., et al. (2019) · Journal of Global Antimicrobial Resistance · doi:10.1016/j.jgar.2019.01.015 · Cited by 12
Profiling the resistome and virulome of Bacillus strains used for probiotic-based sanitation: a multicenter WGS analysis
Bini, F., Soffritti, I., D’Accolti, M., Mazziga, E., Caballero, J. D., David, S., Argimon, S., Aanensen, D. M., Volta, A., Bisi, M., et al. (2025) · BMC Genomics · doi:10.1186/s12864-025-11582-1 · Cited by 11
“Indeed, AMR has become one of the major threats to human health, emerging and spreading, particularly in hospital environments, as a result of the selective pressures exerted by the widespread use of disinfectants and antibiotics in these settings [16].”
Octenidine effectively reduces Candida auris colonisation on human skin
Cerbu, D., Seiser, S., Phan-Canh, T., Moser, D., Freystätter, C., Matiasek, J., Kuchler, K., & Elbe‐Bürger, A. (2025) · Scientific Reports · doi:10.1038/s41598-025-11914-x · Cited by 11
“…37,38 , and the meanwhile frequently described manifestations of reduced susceptibility to this antiseptic, including even cross-resistance to antibiotics (e.g. colistin) and antifungals (e.g. azoles), raises concerns among healthcare professionals about its use in infection control 39–44 .”
Molecular typing of reduced susceptibility of Acinetobacter calcoaceticus–baumannii complex to Chlorhexidine in Turkey by pulsed-field gel electrophoresis
Tozluyurt, A. (2024) · Journal of Medical Microbiology · doi:10.1099/jmm.0.001882 · Cited by 11
Unraveling Antimicrobial Resistance Dynamics in Mycoplasma gallisepticum : Insights Into Antibiotic and Disinfectant Interactions
Kamal, M. A., Salem, H. M., Alhotan, R. A., Hussein, E. O., Gálik, B., Saleh, A. A., & Kaoud, H. A. H. E.-S. (2025) · Veterinary Medicine and Science · doi:10.1002/vms3.70181 · Cited by 12
Selection of a Gentamicin-Resistant Variant Following Polyhexamethylene Biguanide (PHMB) Exposure in Escherichia coli Biofilms
Cuzin, C., Houée, P., Lucas, P., Blanchard, Y., Soumet, C., & Bridier, A. (2021) · Antibiotics · doi:10.3390/antibiotics10050553 · Cited by 13
“Previous studies ve shown a decrease in susceptibilities toward antibiotics in various bacterial species after expos re to sublethal concentr tions of chlorhexidine, another member of the biguanide molecul f mily [17,18].”
Result
Vinegar inhibits the formation of oral biofilm in situ
Liu, Y., & Hannig, M. (2020) · BMC Oral Health · doi:10.1186/s12903-020-01153-z · Cited by 11
Characteristics and genomic epidemiology of colistin-resistant Enterobacterales from farmers, swine, and hospitalized patients in Thailand, 2014–2017
Boonyasiri, A., Brinkac, L. M., Jauneikaite, E., et al. (2023) · BMC Infectious Diseases · doi:10.1186/s12879-023-08539-8 · Cited by 10
“Previously reported disruptions and mutations in mgrB [8, 40] and pmrB (D150Y) [41] conferring colistin resistance were observed in four of the five iso-lates: KPCTRPRTH01 ( mgrB : Q30*), KPCTRPRTH02 ( pmrB : D150Y), KPCTRPRTH03 ( mgrB : W20*), and KPCTRPRTH04 ( pmrB : D150Y) (Suppl.”
Background
Genomic and Transcriptomic Adaptation to Chlorhexidine in Streptococcus spp.
Daller, B., Auer, D. L., Buchalla, W., et al. (2025) · Journal of Dental Research · doi:10.1177/00220345251320912 · Cited by 10
“Concomitantly, the MICs of several antibiotics also increased, suggesting the development of cross-resistances in the adapted strains (Wand et al. 2017; Laumen et al. 2021).”
Extensively-drug-resistant Klebsiella pneumoniae ST307 outbreak strain from north-eastern Germany does not show increased tolerance to quaternary ammonium compounds and chlorhexidine
Hornschuh, M., Zwicker, P., Krämer, A., et al. (2021) · Journal of Hospital Infection · doi:10.1016/j.jhin.2021.01.032 · Cited by 10
Hygiene requirements for cleaning and disinfection of surfaces: recommendation of the Commission for Hospital Hygiene and Infection Prevention (KRINKO) at the Robert Koch Institute
Commission For Hospital Hygiene And Infection Prevention (KRINKO) (2024) · PubMed Central · doi:10.3205/dgkh000468 · Cited by 13
“…sub-bactericidal concentrations, such as triclosan, BAC, chlorhexidine, silver and copper, presents a risk of developing tolerance and resistance that correlates with antibiotic resistance [149], [162], [166], [324], [333], [334], [335], [336], [337], [338], [339]40] and the loss of biodiversity.”
Time for biocide stewardship?
Zamudio, R., Oggioni, M. R., Gould, I. M., et al. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0360-6 · Cited by 10
Tolerance and Persister Formation in Oral Streptococci
Suppiger, S., Astasov‐Frauenhoffer, M., Schweizer, I., Waltimo, T. M. T., & Kulik, E. M. (2020) · Antibiotics · doi:10.3390/antibiotics9040167 · Cited by 10
In vitro activity of six biocides against carbapenemase-producing Klebsiella pneumoniae and presence of genes encoding efflux pumps
Gual-de-Torrella, A., Delgado-Valverde, M., Pérez‐Palacios, P., et al. (2022) · Enfermedades infecciosas y microbiologia clinica (English ed ) · doi:10.1016/j.eimce.2021.05.016 · Cited by 9
Implementation of 2% Chlorhexidine Bathing to Reduce Healthcare-Associated Infections Among Patients in the Intensive Care Unit
Chang, H.-L., Liu, T.-Y., Huang, P.-S., et al. (2025) · Microorganisms · doi:10.3390/microorganisms13010065 · Cited by 9
“Wand et al. showed that the adaptation of Klebsiella pneumoniae isolates to CHG exposure led to an increase in minimal inhibitory concentration values for colistin from 2–4 mg/L to >64 mg/L [33].”
Antimicrobial Stewardship Lessons From Mupirocin Use and Resistance in Methicillin-Resitant Staphylococcus Aureus
Peterson, L. R., Samia, N. I., Skinner, A. M., et al. (2017) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofx093 · Cited by 9
“Compounding the risk from universal decolonization is the potential for widespread chlorhexidine use leading to colistin resistance in Gram-negative bacteria, as the linkage between chlorhexidine exposure and colistin resistance in Klebsiella pneumonia was recently demonstrated by Wand and colleagues [27].”
Background
Evaluation of a Newly Developed Vacuum Dried Microtiter Plate for Rapid Biocide Susceptibility Testing of Clinical Enterococcus faecium Isolates
Roedel, A., Dieckmann, R., Makarewicz, O., et al. (2020) · Microorganisms · doi:10.3390/microorganisms8040551 · Cited by 9
Resistome Analysis of Klebsiella pneumoniae Complex from Residential Aged Care Facilities Demonstrates Intra-facility Clonal Spread of Multidrug-Resistant Isolates
Blaikie, J. M., Sapula, S. A., Siderius, N. L., et al. (2024) · Microorganisms · doi:10.3390/microorganisms12040751 · Cited by 9
“Given the increasingly published links between antimicrobial resistance and biocide tolerance [31,32], tolerance to the biocides benzalkonium chloride, chlorhexidine and triclosan was also assessed using the same method and was determined by comparison with re-ported ECOFF values for K. pneumoniae…”
BackgroundMethod
Changes in resistome profile of potential probiotic Lactiplantibacillus pentosus in response to edible oil adaptation
García, E. A., Benomar, N., Lerma, L. L., Ordoñez, J. J. D. L. F., Knapp, C. W., & Abriouel, H. (2022) · Food Microbiology · doi:10.1016/j.fm.2022.104148 · Cited by 9
Correction to: Susceptibility of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) to chlorhexidine digluconate, octenidine dihydrochloride, polyhexanide, PVP-iodine and triclosan in comparison to hospital-acquired MRSA (HA-MRSA) and community-aquired MRSA (CA-MRSA): a standardized comparison
Dittmann, K., Schmidt, T., Müller, G., et al. (2019) · Antimicrobial Resistance and Infection Control · doi:10.1186/s13756-019-0601-8 · Cited by 9
Functional screening of a human saliva metagenomic DNA reveal novel resistance genes against sodium hypochlorite and chlorhexidine
Wigand, J., Tansirichaiya, S., Winje, E., & Al‐Haroni, M. (2021) · BMC Oral Health · doi:10.1186/s12903-021-02000-5 · Cited by 8
“The mode of action is dose-dependent; bacteriostatic at low concentrations, bactericidal in higher, both through binding to negatively charged membrane phospholipids, resulting in reduced membrane fluidity and osmoregulation [50, 51].”
Background
Smart control of agricultural water wells in western Iran: Application of the Q-methodology
Gholamrezai, S., Azadi, H., Karamian, F., et al. (2023) · Journal of Soil and Water Conservation · doi:10.2489/jswc.2023.00066 · Cited by 8
“These results are consistent with the findings of Wand et al. (2017) who have shown that, despite many advantages of using smart meters to manage water use on agricultural land, the crop will face yield loss in some irrigated lands. for farmers (10: +3).”
Result
Evaluation of activity and potential for development of antimicrobial resistance to a new tinted 2% chlorhexidine gluconate/70% isopropyl alcohol film-forming sterile preoperative skin preparation
Dormstetter, K. K. N., Olson, L. K. M., Bennaars-Eiden, A., et al. (2018) · Journal of Global Antimicrobial Resistance · doi:10.1016/j.jgar.2018.12.008 · Cited by 8
Needle-free connectors catheter-related bloodstream infections: a prospective randomized controlled trial
Koeppen, M., Weinert, F., Oehlschlaeger, S., et al. (2019) · Intensive Care Medicine Experimental · doi:10.1186/s40635-019-0277-7 · Cited by 8
Influence of Abiotic Factors in the Emergence of Antibiotic Resistance
Dutta, S., & Ramamurthy, T. (2020) · Springer eBooks · doi:10.1007/978-981-15-3658-8_4 · Cited by 8
The role of MfsR, a TetR-type transcriptional regulator, in adaptive protection of Stenotrophomonas maltophilia against benzalkonium chloride via the regulation of mfsQ
Chittrakanwong, J., Charoenlap, N., Vanitshavit, V., et al. (2021) · FEMS Microbiology Letters · doi:10.1093/femsle/fnab098 · Cited by 8
Transcriptomic signature of bacteria exposed to benzalkonium chloride
McCarlie, S. J., du Preez, L. L., Castillo, J., Boucher, C. E., & Bragg, R. R. (2023) · Research in Microbiology · doi:10.1016/j.resmic.2023.104151 · Cited by 8
Prevention of Staphylococcus aureus Ventilator-Associated Pneumonia: Conventional Antibiotics Won’t Cut It
Burnham, J. P., & Kollef, M. H. (2017) · Clinical Infectious Diseases · doi:10.1093/cid/cix060 · Cited by 8
“Klebsiella pneumoniae isolates exposed to chlorhexidine [29].”
The contribution of antimicrobials and antimicrobial resistance to climate change and a possible way to reverse it whilst still offering high quality healthcare—a conceptual analysis
Sams-Dodd, J., & Sams‐Dodd, F. (2025) · Frontiers in Public Health · doi:10.3389/fpubh.2025.1644086 · Cited by 7
Healthcare Facilities as an Emerging Source of Antimicrobial Resistance: A One Health Perspective
Khan, M. T., Ribeiro‐Almeida, M., Yaman, Ü., & Prata, J. C. (2025) · Environments · doi:10.3390/environments12120470 · Cited by 8
Biofilm Production by Critical Antibiotic-Resistant Pathogens from an Equine Wound
Afonso, A. C., Sousa, M., Pinto, A. R., Cotovio, M., Simões, M. V., & Saavedra, M. J. (2023) · Animals · doi:10.3390/ani13081342 · Cited by 7
An ion metathesis strategy for overcoming therapeutic limitations of rose bengal
Azevedo, A. M. O., Seabra, C. L., Moniz, T., Nunes, C., Ayala, C. E., Rangel, M., Reis, S., Santos, J. L. M., Warner, I. M., & Saraiva, M. L. M. F. S. (2024) · Dyes and Pigments · doi:10.1016/j.dyepig.2024.112050 · Cited by 7
Tackling transmission of infectious diseases: A probiotic‐based system as a remedy for the spread of pathogenic and resistant microbes
D’Accolti, M., Soffritti, I., Bini, F., Mazziga, E., & Caselli, E. (2024) · Microbial Biotechnology · doi:10.1111/1751-7915.14529 · Cited by 7
“As an example, chlorhexidine was reported to favour the onset of bacterial resistance against colistin, ceftazidime and tetracycline (Wand et al., 2017), and benzalkonium chloride was observed to induce adaptation in Gram-negative bacteria, finally inducing resistance to ampicillin and cefotaxime…”
Background
Assessment of the Potential for Inducing Resistance in Multidrug-Resistant Organisms from Exposure to Minocycline, Rifampin, and Chlorhexidine Used To Treat Intravascular Devices
Rosenblatt, J. S., Vargas‐Cruz, N., Reitzel, R. A., et al. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00040-19 · Cited by 7
“Similarly, CHX resistance has been reported to be due to the presence of efflux pumps (34) which”
Background
Comparison of hydroalcoholic rubbing and conventional chlorhexidine scrubbing for aseptic skin preparation in dogs
Asimus, E., Palierne, S., Blondel, M., et al. (2019) · Veterinary Surgery · doi:10.1111/vsu.13222 · Cited by 7
Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development
Wand, M. E., Taylor, H. V., Auer, J. L., et al. (2019) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2019.08.009 · Cited by 7
Self-citation

Authors: Wand, M. E., Bock, L. J., Bonney, L. C., & Sutton, J. M.
Affiliations: Public Health England (GB)
ORCID: Wand, Matthew E.
Bock, Lucy J.
Bonney, Laura C.
Sutton, J. Mark
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2017-01
Volume: 61
Issue: 1
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.01162-16
PMC: PMC5192135
OpenAlex: W2540856562
Cited by: 313
References: 54
Citations by year: 2026: 19 · 2025: 25 · 2024: 23 · 2023: 34 · 2022: 46 · 2021: 43 · 2020: 36 · 2019: 47 · 2018: 19 · 2017: 18
FWCI: 13.87
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Public Health England (GIA 109506)
Topics: Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antimicrobial agents and applications
Keywords: Klebsiella pneumoniae, chlorhexidine, colistin, cross-resistance, PhoPQ two-component system, major facilitator superfamily, multidrug resistance, infection control
MeSH terms: Anti-Bacterial Agents, Bacterial Proteins, Chlorhexidine, Colistin, Klebsiella pneumoniae, Microbial Sensitivity Tests, Mutation, Plasmids, Drug Resistance, Bacterial

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Mechanisms of Increased Resistance to Chlorhexidine and Cross-Resistance to Colistin following Exposure of Klebsiella pneumoniae Clinical Isolates to Chlorhexidine

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