Evolving resistance among Gram-positive pathogens

Abstract

Antimicrobial therapy is a key component of modern medical practice and a cornerstone for the development of complex clinical interventions in critically ill patients. Unfortunately, the increasing problem of antimicrobial resistance is now recognized as a major public health threat jeopardizing the care of thousands of patients worldwide. Gram-positive pathogens exhibit an immense genetic repertoire to adapt and develop resistance to virtually all antimicrobials clinically available. As more molecules become available to treat resistant gram-positive infections, resistance emerges as an evolutionary response. Thus, antimicrobial resistance has to be envisaged as an evolving phenomenon that demands constant surveillance and continuous efforts to identify emerging mechanisms of resistance to optimize the use of antibiotics and create strategies to circumvent this problem. Here, we will provide a broad perspective on the clinical aspects of antibiotic resistance in relevant gram-positive pathogens with emphasis on the mechanistic strategies used by these organisms to avoid being killed by commonly used antimicrobial agents.

Keywords: antimicrobial resistance; methicillin-resistant; multidrug-resistant; penicillin-resistant; vancomycin-resistant.

Figure 1.

Schematic representation of the mechanism of action and resistance to linezolid. A, Linezolid interferes with the positioning of aminoacyl transfer RNA (tRNA) by interactions with the peptidyl transferase center. Ribosomal proteins L3 and L4, associated with resistance, are shown. B, Representation of domain V of 23S ribosomal RNA (rRNA) showing mutations associated with linezolid resistance. Position A2503, the target of Cfr (chloramphenicol-florfenicol resistance) methylation, is highlighted. Abbreviation: mRNA, messenger RNA.

Figure 2.

Proposed mechanisms of action and resistance to daptomycin in Gram-positive organisms. A, The daptomycin-calcium complex interacts with the cell membrane mainly at septal areas. B, In Enterococcus faecalis, the antibiotic is diverted from the septum (black arrow) in a process associated with redistribution of anionic phospholipid microdomains (eg, cardiolipin) away from the septal plane. C, In Staphylococcus aureus and Enterococcus faecium, the positively charged daptomycin-calcium complex is “repelled” from the cell surface in a process associated with increase in the net positive charge of the cell envelope (not all strains). Abbreviations: DAP-R, daptomycin-resistant; DAP-S, daptomycin-susceptible.