Evolution under low antibiotic concentrations: a risk for the selection of Pseudomonas aeruginosa multidrug‐resistant mutants in nature

Abstract

Antibiotic pollution of non-clinical environments might have a relevant impact on human health if resistant pathogens are selected. However, this potential risk is often overlooked, since drug concentrations in nature are usually below their minimal inhibitory concentrations (MICs). Albeit, antibiotic resistant bacteria can be selected even at sub-MIC concentrations, in a range known as the sub-MIC selective window. Using short-term evolution experiments, we have determined the sub-MIC selective windows of the opportunistic pathogen Pseudomonas aeruginosa for seven antibiotics of clinical relevance, finding the ones of quinolones to be the widest, and the ones of polymyxin B and imipenem, the narrowest. Clinically relevant multidrug-resistant mutants arose within the sub-MIC selective windows of most antibiotics tested, being some of these phenotypes mediated by efflux pumps' activity. The fact that the concentration of antibiotics reported in aquatic ecosystemscolonizable by P. aeruginosaare, in occasions, higher than the ones that select multidrug-resistant mutants in our assays, has implications for understanding the role of different ecosystems and conditions in the emergence of antibiotic resistance from a One-Health perspective. Further, it reinforces the importance of procuring accurate information on the sub-MIC selective windows for drugs of clinical value in pathogens with environmental niches.

Rapid Decline of Ceftazidime Resistance in Antibiotic-Free and Sublethal Environments Is Contingent on Genetic Background

“…Because of that, most studies in the field have focused on the study of AR evolution on antibiotic-free environments or inhibitory (hereafter dubbed lethal, to simplify) concentrations of antibiotics. However, subinhibitory (hereafter dubbed sublethal, to simplify) concentrations can also select antibiotic resistant mutants ( Sanz-García et al 2021 ) and they can be present in certain clinical situations (e.g., incomplete treatments or limited drug accessibility) ( Baquero and Negri 1997 ). Therefore, it is possible that sublethal concentrations of antibiotics may be relevant during the evolutionary compensation of fitness costs, a feature that has not been addressed yet.…”

Gold nanocluster adjuvant enables the eradication of persister cells by antibiotics and abolishes the emergence of resistance

“…34–36 For example, sub-MIC of fluoroquinolones can enrich bacterial populations with clinically relevant mutants presenting MICs beyond clinical breakpoint. 37…”

“…[34][35][36] For example, sub-MIC of fluoroquinolones can enrich bacterial populations with clinically relevant mutants presenting MICs beyond clinical breakpoint. 37 Fig. 4 AuNC@CPP enables the eradication of mature biofilms by ofloxacin (OFL).…”

Differential Performance and Lung Deposition of Levofloxacin with Different Nebulisers Used in Cystic Fibrosis

“…Nevertheless, Zirela and I-Neb outperformed the other nebulisers in terms of lung dose, reaching 2- and 4-fold higher intrathoracic levofloxacin deposition than the eFlow rapid and LC Plus, respectively. The lung doses estimated for the eFlow rapid and LC Plus nebulisers can be regarded as low and certainly discourage the off-label use of these devices with the present levofloxacin formulation since local antibiotic doses below the minimum inhibitory concentration increase the risk of generating antibiotic-resistant bacterial strains [ 29 ], which have a negative impact on disease management and progression [ 5 ].…”