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Antimicrobial resistance

Antimicrobial resistance is a concept that arose from the necessity to predict if an antimicrobial is efficient in the treatment of a specific infection and/or pathogen. Therefore, clinical definitions have been developed, such as those from European Committee on the Antimicrobial Susceptibility Testing (EUCAST). In this case, microorganisms can be classified as susceptible, intermediate, or resistant to a certain antimicrobial if the minimum inhibitory concentration is higher or lower than the standardized value (Jones and Howe, 2014). Susceptibility testing is useful once it gives some information about the resistance and therefore helps to predict clinical outcome (Doern and Brecher, 2011). Some microorganisms are inherently susceptible or resistant to a specific antimicrobial due to a lack of target or even impermeability. For instance, Gram-positive bacteria are inherently resistant to colistin due to the absence of an outer membrane (Li et al., 2005). In addition, Gram-negative bacteria are inherently resistant to large molecules such as vancomycin (glyco- peptide), since they are not able to penetrate the outer membrane (Russell, 2003). Contrarily, bacteria that are inherently susceptible can also acquire antimicrobial resistance, which, according to EUCAST, gives rise to microbial definition as wild type and non-wild type. The microorganism is considered as wild type for a species by applying the appropriate cut-off value in a specific phenotypic test system. In this case, the cut-off value remains unchanged regardless of the circumstances. Contrarily, the non-wild type microorganisms are defined by the presence of an acquired or mutational mechanism of resistance to the antimicrobial in test, which makes the clinical response to the antimicrobial uncertain (Jones and Howe, 2014).

Infections caused by biofilms are hard to treat especially due to the characteristics of the colonizing community that leads always to a large increase of resistance to antimicrobial chemicals (around 1000-fold decrease in susceptibility) when compared with planktonic cells (Taraszkiewicz et al., 2013; Percival et al., 2015; Desai et al., 2014). Infections associated with biofilms are often recalcitrant to several antimicrobials, and the most common mechanisms include: diffusion limitation by the influence of the biofilm matrix; development of physiological gradients, which leads to the formation of microenvironments and consequently to heterogeneity of cell phenotypes and phenotypes associated with biofilms, such as bacterial persistence or dormancy as well as genetic adaptation to different conditions (Humphreys and McBain, 2014; Percival et al., 2015; Taraszkiewicz et al., 2013). Target site modification, antimicrobial-modifying enzymes, and efflux pumps are also three important mechanisms of microorganism resistance, which can be considered as phenotypic alterations when their expression is up- or downregulated depending on the surrounding microenvironment or a genetic adaptation when the modification/ enzyme/efflux pump is not present in the wild-type microorganism; therefore, their expression occurs after a mutation or a genetic acquisition from other microorganisms (Joes and Howe, 2014).

The matrix is a heterogeneous layer composed of enzymes and extracellular polymers that comprise 90% of the biofilm (Taraszkiewicz et al., 2013; Suleman et al., 2014). The matrix is a contributor for the biofilm recalcitrance since it is capable to interact directly with the majority of antimicrobials, by delaying their diffusion (reaction diffusion limitation), inactivate antimicrobials by enzymatic action (enzyme-mediated diffusion limitation), and act as a quenching agent of cationic antimicrobials and antibiotics (Stewart, 1996; Humphreys and McBain, 2014). In addition, it is also a defense mechanism against UV light and dehydration, therefore, the matrix can act as a physical and chemical barrier (Percival et al., 2015; Desai et al., 2014).

The heterogeneity of the biofilm results in microenvironments with different availabilities of nutrients and oxygen, which may affect the rate of growth and metabolism that leads to the existence of microorganisms with different metabolic states (Percival et al., 2015). This is reflected by quorum-sensing signals and toxic products accumulation (Subramanian et al., 2012). Some of the microorganisms are in stationary phase that may reduce their susceptibility to antimicrobials. In fact, these bacteria are considered persister cells that are not intrinsically resistant to antibiotics, but their association with the biofilm allows their prevalence over antibiotic treatments (Subramanian et al., 2012; Humphreys and McBain, 2014; Kim et al., 2009).

The last hypothesis embraces the genetic adaptation to different conditions since the mutation frequency and plasmid exchange within the cells in biofilm is higher than when in planktonic state. Therefore, another important antimicrobial resistance mechanism is target site modification that corresponds to the modification of the target so that the chemical binds less efficiently (Lewis, 2008). In another mechanism, the microorganism is able to produce aminoglycoside-modifying enzymes and therefore they are able to inactivate or modify the antimicrobial (Gordon and Wareham, 2010). Impermeability mechanism is based on the modification of the bacterial envelop so that the chemical is not able to penetrate to its action site. The existence of efflux pumps is also an important mechanism of biofilm antimicrobial resistance since the chemical is actively removed from the bacterial cytoplasm through an efflux pump (Jones and Howe, 2014; Sun et al., 2013; Sheldon, 2005). Currently, efflux pumps can be divided into five families: multidrug and toxic extrusion, ATP-binding cassette (ABC), staphylococcal multiresistance (SMR), resistance modulation division (RND), and major facilitator superfamily (MFS) (Humphreys and McBain, 2014). Several other mechanisms are also responsible for bacterial resistance to antimicrobials, but they are not so frequent. In fact, bacteria are able to protect the target site or may fail the formation of the active drug (Jones and Howe, 2014; Sheldon, 2005).

Table 4.1 Summary of major medical devices used in each human system

Medical device

Central nervous system

Central venous catheters

Sensory organs

Contact lenses

Respiratory system

Endotracheal tubes

Cardiovascular system

Intravenous catheters Mechanical heart valves Pacemakers

Bone tissue

Prosthetic joints

Urinary tract

Urinary catheters

Others

Peritoneal dialysis catheters

Adapted from Mihai, M.M., Holban, A.M., Giurcaneanu, C., Popa, L.G., Oanea, R.M., Lazar, V., Chifiriuc, M.C., Popa, M., Popa, M.I., 2015. Microbial biofilms: impact on the pathogenesis of periodontitis, cystic fibrosis, chronic wounds and medical device-related infections. Curr. Top. Med. Chem. 15, 1552-1576.

 
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