Has resistance to chlorhexidine increased among clinically-relevant bacteria? A systematic review of time course and subpopulation data

Chlorhexidine (CHX) was introduced for use as an antimicrobial more than 70 years ago. CHX has been and continues to be used broadly for disinfecting surfaces in medical and food service facilities as well as directly on skin of humans and animals. Considering its widespread use over many decades, questions of resistance to CHX have been raised. Additionally, questions of possible coincident resistance to the biocide and resistance to clinically relevant antibiotics have also been raised. A number of important questions remain, including is there consistent evidence of resistance, what is the degree of resistance, especially among clinically isolated microbial strains, and what is the degree of resistance compared to the typical concentrations of the biocide used? Data for microbial species isolated over the last 70+ years were compiled to construct as complete a picture as practical regarding possible resistance, especially among species in which resistance to commonly used antibiotics has been noted to be increasing. This is a compilation and analysis of individual MIC values for CHX reported in the literature, not a compilation of the conclusions individual authors reached. The data were analyzed using straight-forward and robust statistical procedures to detect changes in susceptibility to CHX over time, i.e. linear regression. Linear regression was supplemented with the use of nonlinear least squares regression analysis to detect the presence of population parameters associated with subpopulations of microbial strains which exhibit increased resistance to CHX. Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii were all found to have an increased resistance to CHX over time with the most profound change detected in A. baumannii. Additionally, subpopulations with log-normal distributions were found consistent with the presence of a baseline subpopulation of susceptible strains and a subpopulation with increased resistance to CHX. However, the CHX-resistant subpopulations did not correlate exactly with antibiotic resistance, so details of the relationship remain to be addressed. Increased resistance over time was not detected for Escherichia coli, Enterobacter faecalis, Staphylococcus aureus, or Candida albicans, although a subpopulation with greater than baseline resistance to CHX was detected among strains of E. faecalis and C. albicans. A difference in susceptibility to CHX was also detected between methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) S. aureus strains. The levels of resistance to CHX detected were all markedly lower than concentrations routinely used in medical and food service applications. Reaching conclusions regarding the relationship between antibiotic and CHX resistance was complicated by the limited overlap between tests of CHX and antibiotic resistance for several species. The results compiled here may serve as a foundation for monitoring changes in resistance to CHX and possible relationships between the use of CHX and resistance to antibiotics commonly used in clinical medicine.