Mechanisms of antimicrobial resistance in the intensive care unit

Bacteria have evolved myriad mechanisms to protect themselves from antibiotics (1-4). Antimicrobial resistance can be acquired from diverse genetic events ranging from chromosomal mutation to acquisition of exogenous DNA (e.g., plasmids, transposons, integrins, etc.) (3). Antimicrobial resistance occurs by four general mechanisms: enzymatic inactivation or modification of the antibiotic, alteration in the bacterial target site, permeability barriers to antibiotic infiux, and active and effiux pumps (whereby antibiotics are extruded from the bacterial cells) (1-4). Once genetic mutations conferring resistance emerge, they typically increase over time. Endemic and epidemic outbreaks of resistance clones facilitate spread of these difficultto-treat organisms from hospitals, geographic regions, and countries (5,6). Over the past two decades, resistance rates to a variety of antibiotics have escalated dramatically both globally and within the United States (U.S.A.) (7-10). Clonal spread of organisms carrying antimicrobial resistance determinants between patients, hospitals, cities, states, and countries has fueled the explosive rise in resistance rates globally (7,9,11). Selection pressure from antibiotic use amplifies and perpetuates resistant clones (12). Antimicrobial resistance rates are highest in intensive care units (ICUs), because of the debilitated state of patients, prolonged hospital stays, comorbidities, and liberal use of antimicrobials (13,14). Ventilator-associated pneumonia (VAP) is associated with high rates of multidrug-resistant (MDR) organisms (12,15). Inadequate antimicrobial therapy, as a result of MDR, is an independent risk factor for mortality (16-18). For serious nosocomial infections, broad-spectrum therapy is essential to cover potentially resistant organisms (12,19). Resistance to antibiotics also has been noted in patients with specific risk factors [e.g., bronchiectasis or structural lung disease, immunosuppressive illness or drug therapy, human immunodeficiency virus (HIV) infection, prior antibiotic therapy, cystic fibrosis (CF)]. As patients with CF survive into adulthood, infections with pan-resistant Pseudomonas aeruginosa, Burkholderia cepacia, and Stenotrophomonas maltophilia may emerge (20). In addition, resistance to a variety of classes of antibiotics has emerged among common community pathogens such as Streptococcus pneumoniae (pneumococcus) (7,21) and Haemophilus infiuenzae, important causes of pneumonia, bronchitis, and sinusitis (22). Importantly, a few dominant clones of MDR Str. pneumoniae spread rapidly between countries and continents, limiting therapeutic options. In addition, methicillin-resistant Staphylococcus aureus (MRSA), formerly encountered only in hospitals or long-term care facilities (LTCFs), has now emerged in community settings (23). Recently, strains of vancomycin-resistant Sta. aureus (VRSA) were identified as a result of genetic transfer of resistance determinants from vancomycin-resistant Enterococcus faecium (VREF) (24).