Antibiotic Heteroresistance in Klebsiella pneumoniae

Abstract

Klebsiella pneumoniae is one of the most common pathogens responsible for infections, including pneumonia, urinary tract infections, and bacteremias. The increasing prevalence of multidrug-resistant K. pneumoniae was recognized in 2017 by the World Health Organization as a critical public health threat. Heteroresistance, defined as the presence of a subpopulation of cells with a higher MIC than the dominant population, is a frequent phenotype in many pathogens. Numerous reports on heteroresistant K. pneumoniae isolates have been published in the last few years. Heteroresistance is difficult to detect and study due to its phenotypic and genetic instability. Recent findings provide strong evidence that heteroresistance may be associated with an increased risk of recurrent infections and antibiotic treatment failure. This review focuses on antibiotic heteroresistance mechanisms in K. pneumoniae and potential therapeutic strategies against antibiotic heteroresistant isolates.

Keywords: Klebsiella pneumoniae; antibiotic heteroresistance; multidrug resistance.

Figure 1

Heteroresistance detection methods and the difference between persister, resistant, and heteroresistant bacteria. (a) In the PAP assay, bacteria are spread on agar plates with increasing concentrations of antibiotics. Heteroresistance is determined as the growth of colonies at ≥8 × MIC of the main cell population. In the Etest assay, heteroresistance is determined by visible growth of colonies within the zone of clearing around the strips with a preformed continuous gradient of antibiotic concentrations. (b) Resistant bacteria that emerge before or during antibiotic treatment can grow in the presence of the antibiotic. They give rise to new populations distinct from the original ones. In the case of heteroresistance, resistant cells revert to the susceptible phenotype after the antibiotic treatment, usually due to high fitness costs. Persister cells can survive antibiotic treatment, but they cannot grow in the presence of the antibiotic. After the treatment, persisters can resume growth, switching back to the sensitive phenotype.

Figure 2

Two-component systems PhoPQ, PmrAB, and CrrAB control lipid A modifications by adding 4-amino-4-deoxy-l-arabinose (L-Ara4N) and phosphoethanolamine (PEtN). The modifications decrease the net negative charge of the lipid A, resulting in colistin resistance. See the text for more details.