Discerning the role of polymicrobial biofilms in the ascent, prevalence, and extent of heteroresistance in clinical practice

Abstract

Antimicrobial therapy is facing a worrisome and underappreciated challenge, the phenomenon of heteroresistance (HR). HR has been gradually documented in clinically relevant pathogens (e.g. Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia spp., Acinetobacter baumannii, Klebsiella pneumoniae, Candida spp.) towards several drugs and is believed to complicate the clinical picture of chronic infections. This type of infections are typically mediated by polymicrobial biofilms, wherein microorganisms inherently display a wide range of physiological states, distinct metabolic pathways, diverging refractory levels of stress responses, and a complex network of chemical signals exchange. This review aims to provide an overview on the relevance, prevalence, and implications of HR in clinical settings. Firstly, related terminologies (e.g. resistance, tolerance, persistence), sometimes misunderstood and overlapped, were clarified. Factors generating misleading HR definitions were also uncovered. Secondly, the recent HR incidences reported in clinically relevant pathogens towards different antimicrobials were annotated. The potential mechanisms underlying such occurrences were further elucidated. Finally, the link between HR and biofilms was discussed. The focus was to recognize the presence of heterogeneous levels of resistance within most biofilms, as well as the relevance of polymicrobial biofilms in chronic infectious diseases and their role in resistance spreading. These topics were subject of a critical appraisal, gaining insights into the ascending clinical implications of HR in antimicrobial resistance spreading, which could ultimately help designing effective therapeutic options.

An integrated transcriptomic and metabolomic approach to investigate the heterogeneous Candida albicans biofilm phenotype

“…Indeed, it has been reported that the tolerance phenotype was predictive of how effective fluconazole can be if started early [ 40 ]. It is possible that these phenotypes may have some relevance to the heteroresistance phenotypes recently described in C. glabrata and in polymicrobial infection [ 25 , 41 ]. Together, these data imply the importance of discovering the molecular differences between these isolates.…”

Antibiotic Heteroresistance in Klebsiella pneumoniae

“…Although it has been well documented that bacterial biofilms are highly heterogeneous populations that are more drug-resistant than planktonic bacteria, little is known about the influence of biofilm’s environment on heteroresistance. The presence of colistin-heteroresistant subpopulations in K. pneumoniae biofilms is the only example described so far [ 52 , 73 ]. It was found that planktonic cells were susceptible to colistin, whereas colistin resistance exclusively detected within the biofilm population was linked with the small colony variant phenotype.…”

“…It has been demonstrated that these slow-growing colistin-resistant bacteria were absent in a planktonic population that was colistin-susceptible. Biofilms are multicellular communities embedded in extracellular polymeric substances that may constitute a physical barrier for antibiotics and other stress factors [ 72 , 73 , 74 ]. The complex structure of the biofilm facilitates the formation of heterogeneous subpopulations with different gene expression patterns.…”

Strategies to Promote the Journey of Nanoparticles Against Biofilm‐Associated Infections

“…[226] It was reported that biofilms exhibited 10-1000 folds higher recalcitrance to antibiotic than planktonic bacteria, [92] which favored the acquired-resistance of embedded bacteria either through continuous low levels of exposure to antibiotics or through acquisition of resistant genes from other bacteria cells. [227,228] Polymicrobial biofilms mediate greater tolerance than monomicrobial ones in clinical chronic infections, [229] because different bacteria induce each other to become less sensitive to antibiotics by their network of chemical signals exchange. [230,231] Particularly, the bacterial populations in biofilms stochastically generate persisters, which are dormant variants of conventional bacterial cells, and exhibit reduced metabolism and multidrug tolerance.…”