**5. Treatment options for MDR** *Pseudomonas aeruginosa*

Different combinations of the aforementioned mechanisms may be present in a single *P. aeruginosa* isolate leading to simultaneous resistance to various anti-pseudomonal compounds. The most potent combination is obviously that of a carbapenemase producing isolate usually enriched by resistance to quinolones and aminoglycosides leaving very limited options for antimicrobial treatment.

As far as newer carbapenem compounds are concerned, data suggest that doripenem does not offer advantages over other carbapenems against carbapenemase producing strains [126].

In fact, polymyxins and colistin in particular, are quite effective in the treatment of MDR *P. aeruginosa* infections [129,130]. The target of colistin is the bacterial cell membrane. More precisely, colistin interacts with the lipid A of lipopolysaccharides, allowing penetration through the outer membrane by displacing Ca2+ and Mg2+. The insertion between the phos‐ pholipids leads to loss of membrane integrity and consequent bacterial cell death [131]. There are reports of resistance to polymyxin B [132-134] and colistin [135-137] in clinical isolates but they remain to date relatively rare for *P. aeruginosa* [24]. While in many cases the mechanism of clinical polymyxin resistance is unknown, substitution of the lipopolysaccharide lipid A with aminoarabinose has been shown to contribute to polymyxin resistance *in vitro* [138] and

APH(2΄΄) Gentamicin

**Table 6.** Aminoglycoside-modifying enzymes found in *P. aeruginosa* isolates.

**Category Enzymatic**

Acetyltransferases

Nucleotidyltransferases

Phosphoryltransferases

(ANT)

(APH)

(AAC)

**family**

**Subfamily Substrates References**

*Pseudomonas aeruginosa*: Multi-Drug-Resistance Development and Treatment Options

Tobramycin

Tobramycin

Tobramycin

Amikacin

Gentamicin

Tobramycin

Amikacin

Amikacin

Neomycin

IIb Kanamycin [117]

(weakly)

Isepamicin

Tobramycin

[48] [108,109]

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43

[108,109]

[109]

[109] [116]

[113]

[110]

[110-112]

[114,115]

AAC(3) I Gentamicin [11]

II Gentamicin

III Gentamicin

IV Gentamicin VI Gentamicin

II Tobramycin

IIb Tobramycin

ΑΝΤ(3΄) Streptomycin [108]

IIb-like Amikacin

VI Amikacin

AAC(6΄) I Tobramycin

ANT(2΄) Ι Gentamicin

ΑΝΤ(4΄) IIa Tobramycin

APH(3΄) ΙΙ Kanamycin

Tigecycline is an option for Gram-negative MDR pathogens but it cannot be used against *P. aeruginosa*, *Morganella morganii*, *Proteus* spp. and *Providencia* spp. because it is intrinsically vulnerable to their chromosomal-encoded efflux pumps [127].

Furthermore, time-kill studies on 12 MBL-producing *P. aeruginosa* isolates performed with aztreonam alone and in combination with ceftazidime and amikacin, showed bactericidal activity against one and eight isolates respectively. In the same study, colistin was bactericidal against all 12 isolates [128].


**Table 6.** Aminoglycoside-modifying enzymes found in *P. aeruginosa* isolates.

Among the nucleotidyltransferases, ANT(2')-I is the most frequently encountered in *P. aerugiosa.* This enzyme is present in isolates showing resistance to gentamicin and tobramycin

Almost all phosphoryltransferases of *P. aeruginosa* act in the 3' position of the aminoglycoside molecule [24]. However, they have less clinical importance because of the fact that they inactivate aminoglycosides that are not routinely used for the treatment of *P. aeruginosa* infections such as kanamycin and neomycin [109]. The enzymes of this family that inactivate anti-pseudomonal aminoglycosides are APH(3')-VI [110-112], APH(3')-IIb-like [113] and APH(2'') [110]. Despite being reported in some cases, these enzymes remain rare for clinical

Resistance to aminoglycosides in *P. aeruginosa* can occur independently of aminoglycosidemodifying enzymes in cystic fibrosis patients. This type of resistance has been reported in several studies [99,118-120] and is attributable to over-expression of the MexXY-OprM

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 aminoglyco‐ sides [24]. Different 16S rRNA methylases have been described for *P. aeruginosa*: RmtA [112,121], RmtB [122], ArmA [122,123] and RmtD which is commonly found together with the

Different combinations of the aforementioned mechanisms may be present in a single *P. aeruginosa* isolate leading to simultaneous resistance to various anti-pseudomonal compounds. The most potent combination is obviously that of a carbapenemase producing isolate usually enriched by resistance to quinolones and aminoglycosides leaving very limited options for

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 *P. aeruginosa*, *Morganella morganii*, *Proteus* spp. and *Providencia* spp. because it is intrinsically

Furthermore, time-kill studies on 12 MBL-producing *P. aeruginosa* isolates performed with aztreonam alone and in combination with ceftazidime and amikacin, showed bactericidal activity against one and eight isolates respectively. In the same study, colistin was bactericidal

**5. Treatment options for MDR** *Pseudomonas aeruginosa*

vulnerable to their chromosomal-encoded efflux pumps [127].

but not to amikacin [109].

42 Infection Control

*P. aeruginosa* isolates [24].

*4.3.3. 16S rRNA methylases*

MBL SPM-1 in Brazil [124,125].

antimicrobial treatment.

against all 12 isolates [128].

*4.3.2. Efflux systems*

efflux pump.

In fact, polymyxins and colistin in particular, are quite effective in the treatment of MDR *P. aeruginosa* infections [129,130]. The target of colistin is the bacterial cell membrane. More precisely, colistin interacts with the lipid A of lipopolysaccharides, allowing penetration through the outer membrane by displacing Ca2+ and Mg2+. The insertion between the phos‐ pholipids leads to loss of membrane integrity and consequent bacterial cell death [131]. There are reports of resistance to polymyxin B [132-134] and colistin [135-137] in clinical isolates but they remain to date relatively rare for *P. aeruginosa* [24]. While in many cases the mechanism of clinical polymyxin resistance is unknown, substitution of the lipopolysaccharide lipid A with aminoarabinose has been shown to contribute to polymyxin resistance *in vitro* [138] and cystic fibrosis isolates [139]. Colistin is frequently associated with nephro- and neurotoxicity but both these adverse effects seem to be dose-dependent and reversible [140].

adapt very well to the hospital environment. There are important challenges in the treatment of MDR *P. aeruginosa* strains and their isolation in healthcare settings poses serious infection control issues. For these reasons, the prudent use of antibiotics, mainly those used as last resort treatment like carbapenems is of outmost importance in order to prevent evolutionary pressure

*Pseudomonas aeruginosa*: Multi-Drug-Resistance Development and Treatment Options

http://dx.doi.org/10.5772/55616

45

that may lead to the emergence of highly resistant clones.

\*Address all correspondence to: meletisg@hotmail.com

versary. J Hosp Infect 2009;73. 338–344.

1 Aristotle University of Thessaloniki, School of Medicine,Thessaloniki, Greece

2 Department of Clinical Microbiology, Veroia General Hospital,Veroia, Greece

3 Department of Internal Medicine,Agios Dimitrios General Hospital of Thessaloniki,

[1] Slama TG. Gram-negative antibiotic resistance: there is a price to pay. Crit Care

[2] Kerr KG, Snelling AM. Pseudomonas aeruginosa: a formidable and ever-present ad‐

[3] Mauldin PD, Salgado CD, Hansen IS, et al. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant

[4] Tumbarello M, Repetto E, Trecarichi EM, et al. Multidrug- resistant Pseudomonas aeruginosa bloodstream infections: risk factors and mortality. Epidemiol Infect

[5] Lambert PA. Mechanisms of antibiotic resistance in Pseudomonas aeruginosa. J R

[6] Moore NM, Flaws ML. Antimicrobial resistance mechanisms in Pseudomonas aeru‐

[7] Hancock REW, & Brinkman F. Function of Pseudomonas porins in uptake and efïlux.

Gram- negative bacteria. Antimicrob Agents Chemother 2010;54. 109–115.

**Author details**

Greece

**References**

2008;12. (Sup4) S4.

2011;139. 1740-1749.

Soc Med 2002;95. 22-26.

ginosa. Clin Lab Sci 2011; 24. 47-51.

Annu Rev Microbiol 2002;56. 17-38.

Georgios Meletis1,2 and Maria Bagkeri3

Another interesting option for the treatment of MDR *P. aeruginosa* is fosfomycin, an old antibacteial that has regained attention because of its *in vitro* activity against such isolates [140]. Fosfomycin inactivates the enzyme pyruvil-transferase, which is required for the synthesis of the cell wall peptidoglycan. In a review of the existing fosfomycin studies, 81.1% of 1529 patients were successfully treated for infections caused by *P. aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Enterobacter* spp. and *Klebsiella* spp. Fosfomycin was administered together with aminoglycosides, cephalosporins and penicillines [141]. More studies are needed however to determine the future role of fosfomycin against MDR *P. aeruginosa* isolates.
