Low-level antibacterial resistance: a gateway to clinical resistance.

The huge amount of antibiotic substances released in the human environment has probably resulted in an acceleration in the rate of bacterial evolution. It is to note that most interactions between chemotherapeutic agents and microbial populations occur at very low antibiotic concentrations. Thus, natural selection is expected to act on very small increases in the bacterial ability to resist to antibiotic inhibitory effects. On the other hand, there is a wealth of mechanisms to resist to these low antibiotic concentrations. The progressive enrichment in low-level resistant populations favours secondary selections for more specific and effective mechanisms of resistance, particularly in treated patients. These adaptations may have a biological cost in the absence of antibiotics, but frequently compensatory mutations occur, minimizing such genetic burden. In this way, a phenomenon of directional selection takes place, with low possibilities of return to susceptibility. Moreover, low antibiotic concentrations are not only able to select low-level antibiotic resistant variants, but may produce a substantial stress in bacterial populations, that eventually influences the rate of genetic variation and the diversity of adaptive responses. More attention should be devoted to the mechanisms of low-level resistance in microorganisms, as they can serve as stepping stones to develop high level, clinically relevant resistance. These mechanisms should be identified early in the development of drugs in order to adapt the therapeutic strategies (for instance dosage) to minimize the selection of low-level resistant variants, as frequently they emerge by means of concentration-specific selection. At the same time, conventional susceptibility testing should probably be able to detect low-level resistance, and not only clinically-relevant resistance. We should be vigilant of the evolutionary trends of microorganisms; for that a purpose, knowledge of the biology and epidemiology of low-level resistance is becoming a real need.