Colistin resistance emerging in K. pneumoniae following exposure to chlorhexidine

[Gert van der Hoek]

31 October 2016

Mechanisms of increased resistance to chlorhexidine and cross-resistance to colistin following 2 exposure of Klebsiella pneumoniae clinical isolates to chlorhexidine

Abstract


Klebsiella pneumoniae is an opportunistic pathogen which is often difficult to treat due to its multidrug resistance (MDR). We have previously shown that K. pneumoniae strains are able to "adapt to" (become more resistant) to the widely used bisbiguanide antiseptic chlorhexidine. Here we investigated the mechanisms responsible and the phenotypic consequences for 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 chlorhexidineadaptation is associated with mutations in the two component regulator phoPQ and a putative tet-repressor gene (smvR), adjacent to the MFS family efflux pump smvA Up-regulation of smvA (10-27 fold) was confirmed in smvR mutant strains and this effect and the associated phenotype was suppressed when a wild type copy of smvR was introduced on plasmid pACYC. Up-regulation of phoPQ (5-15 fold) and phoPQ-regulated genes, pmrD (6-19 fold) and pmrK (18-64 fold), were 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 in infection prevention procedures.

[Gert van der Hoek]

01 November 2016

CHLORHEXIDINE USE MAY SELECT FOR COLISTIN RESISTANCE


Infection control is a vital part of maintaining a safe healthcare facility, and the use of biocides and disinfectants to eliminate potential pathogens is an important part of infection control strategy. Pathogens can spread among patients via transfer to surfaces like doors, floors, and countertops and then to healthcare workers, so these environments are cleaned with various antimicrobial treatments that include compounds such as bleach or chlorhexidine.

Chlorhexidine is a common disinfectant used not only in hospitals, but also in home settings. Its use isn’t limited to inanimate surfaces; chlorhexidine is used to clean injuries and prepare skin surfaces before surgery. Chlorhexidine works by disrupting the cell membrane. The positively charged chlorhexidine first interacts with the negatively charged bacterial cell wall. After internalization, the compound binds phospholipids of the inner cell membrane and causes cytoplasmic contents to leak out. Chlorhexidine is effective against both gram-positive and -negative bacteria as well as many pathogenic fungi.

Like other stresses (such as antibiotics), the use of chlorhexidine can select for resistant variants. A new study in Antimicrobial Agents and Chemotherapy suggests a frightening finding: exposure to chlorhexidine may select for chlorhexidine-resistant bacteria, and these resistance mechanisms may confer cross-resistance against antibiotics.

Read more

[Gert van der Hoek]

FIRST STUDY TO LINK ANTIBIOTIC RESISTANCE WITH EXPOSURE TO THE DISINFECTANT CHLORHEXIDINE

Washington, DC – October 31, 2016 -Klebsiella pneumoniae bacteria exposed to chlorhexidine-containing disinfectants can become resistant to colistin, a last resort antibiotic often used against multidrug resistant pathogens. This is the first study to link exposure to chlorhexidine with resistance to colistin in this clinically important pathogen. The research is published this week in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

In the study, the investigators tested the hypothesis that K. pneumoniae could survive exposure to increased concentrations of chlohexidine, and that these exposures might cause resistance to commonly used antibiotics. They selected specific strains of K. pneumoniae that were representative of isolates routinely found in the clinic.

Chlorhexidine is a common ingredient in a number of disinfectants used widely in the home and in healthcare settings, where it is a critical part of many infection control practices.

While some strains died on exposure, others were able to survive at much higher concentrations of chlorhexidine than their parental strains. Some also gained resistance to colistin. The investigators also found gene mutations in the exposed K. pneumoniae that conferred resistance to both compounds.

“Chlorhexidine is a critical part of current infection control practices, and the development of increased resistance to this compound has potential implications for our ability to prevent infections during routine and emergency surgery, and during admission to hospitals,” said coauthor J. Mark Sutton, PhD, Scientific Leader, National Infections Service, Public Health England, Salisbury, UK.

The study data, and other ongoing work in Sutton’s laboratory suggest that many bacterial pathogens may share the same, or similar metabolic pathways. Specific selective pressures from antiseptics, such as chlorhexidine, may result in similar mutations in these pathways conferring increased resistance in these different species of bacteria, he said. “If the same response is seen in hospitals, this might mean that we need to rethink how and where some types of critical disinfectants or antiseptics are used in the clinic.”