Issues beyond resistance: inadequate antibiotic therapy and bacterial hypervirulence

Abstract

The administration of antibiotics while critical for treatment, can be accompanied by potentially severe complications. These include toxicities associated with the drugs themselves, the selection of resistant organisms and depletion of endogenous host microbiota. In addition, antibiotics may be associated with less well-recognized complications arising through changes in the pathogens themselves. Growing evidence suggests that organisms exposed to antibiotics can respond by altering the expression of toxins, invasins and adhesins, as well as biofilm, resistance and persistence factors. The clinical significance of these changes continues to be explored; however, it is possible that treatment with antibiotics may inadvertently precipitate a worsening of the clinical course of disease. Efforts are needed to adjust or augment antibiotic therapy to prevent the transition of pathogens to hypervirulent states. Better understanding the role of antibiotic-microbe interactions and how these can influence disease course is critical given the implications on prescription guidelines and antimicrobial stewardship policies.

Keywords: biofilm; hypervirulence; pathogenesis; persister cell; resistance; sub-inhibitory antibiotic concentrations; toxin; virulence.

Figure 1.

Schematic diagram of the various mechanisms utilized by bacteria to induce virulence gene expression and HGT in the presence of antibiotics. RecA and activation of SOS represents a virulence hub, both directly affecting the expression of several genes through various stress responses and indirectly through phage induction (Goerke, Koller and Wolz 2006). In some cases, toxin gene translation can be abrogated via antibiotics which inhibit ribosomal activity (Ohlsen et al. ; Mascini et al. ; Tanaka et al. ; Dumitrescu et al. ; Stevens et al. 2007). Certain pathogenic strains may also respond to therapeutic antibiotic doses by decreasing intracellular levels via resistance mechanisms (e.g. drug efflux systems), promoting virulence gene expression as though sub-inhibitory concentrations were present (Mc Cay, Ocampo-Sosa and Fleming 2010). Lastly, a number of response regulators and two-component signal transduction systems may be involved in directly inducing gene expression (e.g. Arr), or indirectly by inducing general stress responses (e.g. DpiBA and SOS) (Hoffman et al. ; Kelley 2006).