Efflux systems of
1. Introduction
Antibiotic resistance is a worldwide problem of major importance. Isolations in some countries of multi-drug-resistant (resistant to three or more classes of antimicrobials), extensively-drug-resistant (resistant to all but one or two classes) or even pan-drug-resistant (resistant to all available classes) Gram-negative pathogens are causing therapeutic problems and- in the same time- are posing infection control issues in many hospitals. In fact, numerous studies highlight the link between multi-drug-resistance and increased morbidity and mortality, increased length of hospital stay and higher hospital costs [1-4].
Generally, antibiotic resistance mechanisms of
2. Intrinsic resistance of Pseudomonas aeruginosa
2.1. Outer membrane permeability
The outer membrane of Gram-negative bacteria is a barrier which prevents large hydrophilic molecules to pass through it. Aminoglycosides and colistin interact with lipopolysaccharides changing the permeability of the membrane in order to pass whereas beta-lactams and quinolones need to diffuse through certain porin channels.
Bacteria produce two major classes of porins: general; which allow almost any hydrophilic molecule to pass [7] and specific; which have binding sites for certain molecules, allowing them to be oriented and pass in the most energy-efficient way [8].
Most bacteria posses lots of general porins and relatively few specific ones. However, the exact opposite occurs for
2.2. Efflux systems
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MexAB-OprM | Resistance Nodulation Division (RND) | Fluoroquinolones Aminoglycosides β-Lactams (preferably Meropenem, Ticarcillin) Tetracycline Tigecycline Chloramphenicol |
[17] |
MexCD-OprJ | Resistance Nodulation Division (RND) | Fluoroquinolones β-Lactams (preferably Meropenem, Ticarcillin) Tetracycline Tigecycline Chloramphenicol Erythromycin Roxythromycin |
[17] |
MexEF-OprN | Resistance Nodulation Division (RND) | Fluoroquinolones β-Lactams (preferably Meropenem, Ticarcillin) Tetracycline Tigecycline Chloramphenicol |
[17] [18] |
MexXY-OprM | Resistance Nodulation Division (RND) | Fluoroquinolones Aminoglycosides β-Lactams (preferably Meropenem, Ticarcillin, Cefepime) Tetracycline Tigecycline Chloramphenicol |
[17] |
AmrAB-OprA | Resistance Nodulation Division (RND) | Aminoglycosides | [19] |
PmpM | Multidrug And Toxic compound Extrusion (MATE) | Fluoroquinolones | [17] |
Mef(A) | Major Facilitator Superfamily (MFS) | Macrolides | [20] |
ErmEPAF | Small Multidrug Resistance (SMR) | Aminoglycosides | [21] |
Most antibiotics- except polymyxins- are pumped out [9,10] by these efflux systems (Table 1) therefore their first two components are named multidrug efflux (Mex) along with a letter (e.g. MexA and MexB). The outer membrane porin is called Opr along with a letter (e.g. OprM) [11].
2.3. Antibiotic-inactivating enzymes
Another endogenous beta-lactamase produced by
3. Antipseudomonal treatment
Despite the intrinsic resistance of
3.1. Beta-lactams
Beta-lactams bind to and inactivate penicillin-binding proteins (PBPs) that are transpeptidases involved in bacterial cell wall synthesis [15]. The group of beta-lactam antibiotics includes penicillins, cepholosporins, monobactams and carbapenems. The beta-lactams that are most active against
3.2. Quinolones
Quinolones are synthetic antimicrobials that block DNA replication by inhibiting the activity of DNA gyrase and topoisomerase IV [16]. The fluorquinolones with anti-pseudomonal activity are ciprofloxacin, levofloxacin and ofloxacin.
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|
Penicillins | Bacterial cell wall synthesis inhibition | Ticarcillin |
Penicillin / Beta-lactamase inhibitor | Bacterial cell wall synthesis inhibition | Ticarcillin/Clavulanic acid |
Piperacillin/Tazobactam | ||
Cefalosporins | Bacterial cell wall synthesis inhibition | Ceftazidime |
Cefepime | ||
Monobactams | Bacterial cell wall synthesis inhibition | Aztreonam |
Carbapenems | Bacterial cell wall synthesis inhibition | Imipenem |
Meropenem | ||
Doripenem | ||
Fluoroquinolones | Block of DNA synthesis | Ciprofloxacin |
Levofloxacin | ||
Ofloxacin | ||
Aminoglycosides | Protein synthesis inhibition | Gentamycin |
Tobramycin | ||
Amikacin |
3.3. Aminoglycosides
Aminoglycosides inhibit protein synthesis by binding to the 30S or 50S ribosomal subunit [22]. Drugs of this antibiotic class that can be used against
4. Acquired resistance of Pseudomonas aeruginosa
Apart from being resistant to a variety of antimicrobial agents,
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|
Beta-lactams | Endogenous beta-lactamases |
Acquired beta-lactamases | |
Efflux | |
Diminished permeability | |
Fluoroquinolones | Target site mutations |
Efflux | |
Aminoglycosides | Aminoglycoside-modifying enzymes |
Efflux | |
16S rRNA methylases | |
Polymyxins | LPS modification |
4.1. Resistance to beta-lactams
Resistance to beta-lactam antibiotics is multi-factorial but is mediated mainly by inactivating enzymes called beta-lactamases. These enzymes cleave the amide bond of the beta-lactam ring causing antibiotic inactivation and are classified according to a structural [25] and a functional [26] classification.
Among the beta-lactams, carbapenems are the most efficient against
4.1.1. Expression of endogenous beta-lactamases
Resistance to beta-lactams in clinical isolates is commonly due to the presence of AmpC beta-lactamases [29-36]. Furthermore, the production of AmpC beta-lactamases in
AmpC enzymes are not carbapenemases, they posses however a low potential of carbapenem hydrolysis and their overproduction combined with efflux pumps over-expression and/or diminished outer membrane permeability has been proven to lead also to carbapenem resistance in
4.1.2. Acquired beta-lactamases
Acquired beta-lactamases are typically encoded by genes which are located in transferable genetic elements such as plasmids or transposons [39] often on integrons [40-49]. Integrons are genetic elements that capture and mobilize genes [50]. Other genetic elements associated with transferable resistance in
Different types of transferable beta-lactamases have been found in clinical
|
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A | 2b | TEM-1, -2, -90, -110, SHV-1 |
[57,58] |
2be | PER-1, -2 VEB-1, -2, -3 TEM-4, -21, -24, -42, -116 SHV-2a, -5, -12 GES/IBC-1, -2, -5, -8, -9 BEL LBT 802 CTX-M-1, -2, -43 |
[10] [53] [59-62] |
|
2c | PSE-1 (CARB-2), PSE-4 (CARB-1), CARB-3, CARB-4, CARB-like, AER-1 | [10] [63] |
|
2f | KPC-2, -5 | [64,65] | |
B | 3 | IMP-1, -4, -6, -7, -9, -10, -12, -13, -15, -16, -18, -22 VIM-1, -2, -3, -4, -5, -7, -8, -11, -13, -15, -16,-17, -18 SPM-1 GIM-1 AIM-1 NDM-1 |
[10] [47] [66-76] |
C | 1 | AmpC | [77] |
D | 2d | OXA LCR-1 NPS-1 |
[10] [12] [54] [57] [78-80] |
Among them, carbapenemases are of major clinical importance because they inactivate carbapenems together with other beta-lactams. Ambler class A ESBLs hydrolyze penicillins, narrow- and broad-spectrum cephalosporins and aztreonam [54]. Some TEM and SHV enzymes do not possess broad-spectrum cephalosporinase activity and are called restricted-spectrum beta-lactamases. Class D OXA beta-lactamases are a heterogenous group of enzymes and not all share the same properties. Generally, most of them show a preference for cloxacillin over benzylpenicillin. They confer resistance to amino- and carboxypenicillins and narrow –spectrum cephalosporins even though some of them are ESBLs and a few members of the class present carbapenemase activity [24].
4.1.3. Carbapenemases
IMP and VIM type MBLs were first identified in Japan [81] and Italy [82] respectively and have spread though all continents since then. Other metallo-enzymes are more geographically restricted. SPM-1, after causing outbreaks in Brazil [28], has been found in Basel [83] in a single isolate recovered from a patient previously hospitalized in Brazil. GIM-1 and AIM-1 were reported from Germany [41] and Australia [84] and did not spread elsewhere. Finally, the only report for NDM-1 in
Ambler class A carbapenemase KPC was first reported in
Enzymes GES/IBC belong to the same enzymatic class but their carbapenemase activity is not as high as that of the KPCs. It may become important however if combined with diminished outer membrane permeability or efflux over-expression. For
Class D carbapenemases like OXA-198 have been found in
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A | 2f | KPC |
B | 3 | IMP enzymes VIM enzymes SPM-1 GIM-1 AIM-1 NDM-1 |
4.1.4. Efflux systems over-expression
Among the various efflux systems of
4.1.5. Diminished permeability
OprD is a specific porin of the outer membrane of
4.2. Resistance to fluoroquinolones
High-level resistance to fluoroquinolones is mediated by target site modifications. Efflux plays a contributing role as well [96,97] and the two mechanisms often coexist [32,98-100].
4.2.1. DNA gyrase and topoisomerase IV mutations
Gyrase and topoisomerase are comprised by two subunits each. DNA gyrase (GyrA and GyrB) is the main target of fluoroquinolones in
4.2.2. Efflux pumps contribution
Four efflux pumps contribute to fluoroquinolone resistance: MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY-OprM [105] as a consequence of mutational events in their repressor genes [24]. Among these, MexAB-OprM, MexCD-OprJ, and MexEF-OprN have been associated to fluoroquinolone resistance in clinical isolates [31,105-107] whereas MexXY-OprM has only been linked rarely to such type of resistance [106].
4.3. Resistance to aminoglycosides
Acquired resistance to aminoglycosides is mediated by transferable aminoglycoside-modifying enzymes (AMEs), rRNA methylases and derepression of endogenous efflux systems [24,108,109].
4.3.1. Aminoglycoside-modifying enzymes
Modification and subsequent inactivation of aminoglycosides is achieved by three deferent mechanisms: (1) acetylation, by aminoglycoside acetyltransferases (AACs), (2) adenylation, by aminoglycoside nucleotidyltransferases (ANTs), and (3) phosphorylation, by aminoglycoside posphoryltransferases (APHs) [108].
Genes encoding AMEs are typically found on integrons together with other genes responsible for transferable resistance for other antibiotic classes. This way AMEs become important determinants for the development of multi-drug resistance in
Enzymatic families that acetylate the 3 and 6’ position of the antibiotic are the most common. Five subfamilies of AAC(3) and two of AAC(6’) have been described for
Among the nucleotidyltransferases, ANT(2’)-I is the most frequently encountered in
Almost all phosphoryltransferases of
4.3.2. Efflux systems
Resistance to aminoglycosides in
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Acetyltransferases (AAC) |
AAC(3) | I | Gentamicin | [11] [48] [108,109] |
II | Gentamicin Tobramycin |
|||
III | Gentamicin Tobramycin |
|||
IV | Gentamicin | |||
VI | Gentamicin Tobramycin |
|||
AAC(6΄) | I | Tobramycin Amikacin |
[108,109] | |
II | Tobramycin Gentamicin |
|||
Nucleotidyltransferases (ANT) |
ANT(2΄) | Ι | Gentamicin Tobramycin |
[109] |
ΑΝΤ(4΄) | IIa | Tobramycin Amikacin |
[114,115] | |
IIb | Tobramycin Amikacin |
|||
ΑΝΤ(3΄) | Streptomycin | [108] | ||
Phosphoryltransferases (APH) |
APH(3΄) | ΙΙ | Kanamycin Neomycin |
[109] [116] |
IIb | Kanamycin | [117] | ||
IIb-like | Amikacin (weakly) |
[113] | ||
VI | Amikacin Isepamicin |
[110-112] | ||
APH(2΄΄) | Gentamicin Tobramycin |
[110] |
4.3.3. 16S rRNA methylases
Methylation of the 16S rRNA of the A site of the 30S ribosomal subunit interferes with aminoglycoside binding and consequently promotes high-level resistance to all aminoglycosides [24]. Different 16S rRNA methylases have been described for
5. Treatment options for MDR Pseudomonas aeruginosa
Different combinations of the aforementioned mechanisms may be present in a single
As far as newer carbapenem compounds are concerned, data suggest that doripenem does not offer advantages over other carbapenems against carbapenemase producing strains [126].
Tigecycline is an option for Gram-negative MDR pathogens but it cannot be used against
Furthermore, time-kill studies on 12 MBL-producing
In fact, polymyxins and colistin in particular, are quite effective in the treatment of MDR
Another interesting option for the treatment of MDR
6. Combination therapy
The application of combination therapy instead of monotherapy in cases of non-MDR
Several old and newer studies have showed the increased activity
7. Conclusion
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