Emergence of antimicrobial resistance

 Antibiotic exposure

The observation that changes in the incidence of bacterial resistance often mirror prior changes in exposure to antibiotics, has withstood experimental, epidemiologic, and mathematical scrutiny in both animals and humans. Hence, there is an enduring consensus that antibiotic exposure lies at the root of the complex mechanisms through which resistance emerges. The evidence linking antibiotic exposure to resistance is particularly strong for VRE. Most healthy human non carriers administered a glycopeptide antibiotic (Vancomycin or teicoplanin) orally will become colonized with VRE. There is also a consistent association between previous use of vancomycin, the VRE carrier state, and VRE bacteremia. While VRE colonization rates are twofold to ninefold higher in patients who have received vancomycin, prior exposure to this drug is neither required nor sufficient for colonization: third-generation cephalosporins, aminoglycosides, aztreonam, ciprofloxacin, imipenem and the anti-anaerobe antimicrobials clindamycin and metronidazole , have all been independently associated with the VRE carrier state. Antibiotic exposure can cause the emergence of VRE by inducing the expression of resistance genes and by selecting strains already expressing these genes. By altering the competing microbiota in the gastrointestinal tract, thereby increasing VRE concentration in the stools, antibiotic exposure can also facilitate the transmission of VRE.  

Recently, attention has focused on enterococci, not only because of their remarkable role in nosocomial infections, but also due to their remarkable and increasing resistance to antimicrobial agents. These two factors are mutually reinforcing since resistances allow enterococci to survive in an environment in which antimicrobial agents are heavily used. Antimicrobial therapy for enterococcal infections is complicated. Due to intrinsic low-level of resistance in enterococci to many antibiotics (clindamycin, aminoglycosides and β-lactams) a bactericidal effect cannot be reached at clinically relevant concentrations.

Traditionally, treatment of infections caused by enterococci has consisted of a synergistic combination of an aminoglycoside and a cell wall active antibiotic (e.g. ampicillin and vancomycin). However, emergence of resistance to these antibiotics has become a problem in many parts of the world. Antimicrobial resistance can be divided into two general types, that which is an inherent or intrinsic property and that which is acquired. The terms inherent or intrinsic resistance are used here to indicate resistance which is a usual species characteristic present in all or most of the strains of that species.

Antimicrobial resistance can be divided into two general types, that which is an inherent or intrinsic property and that which is acquired. The genes for intrinsic resistance, like other characteristics of the species, appear to reside in the chromosome. The various intrinsic traits exhibited by enterococci include resistances to semisynthetic penicillinase-resistant penicillins, cephalosporins, low levels of aminoglycosides, low levels of clindamycin and polymyxins.

The intrinsic resistance of enterococci to many commonly used antimicrobial agents may have endowed them with a cumulative advantage for further acquisition of genes encoding resistance to tetracycline, erythromycin (plus the newer compounds azithromycin and clarithromycin), chloramphenicol, high levels of trimethoprim, high levels of clindamycin, high levels of aminoglycosides, penicillin (by means of penicillinase), fluoroquinolones and vancomycin. Acquired resistance results from either a mutation in the existing DNA or acquisition of new DNA.

There are at least three major causes for the emergence of multidrug resistant enterococci:

1. Baseline that which is an inherent or intrinsic property to several antimicrobial agents.

2. Acquired resistance via mobile resistance genes on plasmids and transposons, chromosomal exchange, (and transfer of resistance to other bacteria including enterococci).

3. Mutations which lead to higher resistance.