Mini Review
Antibiotic resistance in Pseudomonas aeruginosa and alternative therapeutic options

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Abstract

Pseudomonas aeruginosa is a leading cause of nosocomial infections and is responsible for ∼10% of all hospital-acquired infections worldwide. It continues to pose a therapeutic challenge because of the high rate of morbidity and mortality associated with it and the possibility of development of drug resistance during therapy. Standard antibiotic regimes against P. aeruginosa are increasingly becoming ineffective due to the rise in drug resistance. With the scope for developing new antibiotics being limited, alternative treatment options are gaining more and more attention. A number of recent studies reported complementary and alternative treatment options to combat P. aeruginosa infections. Quorum sensing inhibitors, phages, probiotics, anti-microbial peptides, vaccine antigens and antimicrobial nanoparticles have the potential to act against drug resistant strains. Unfortunately, most studies considering alternative treatment options are still confined in the pre-clinical stages, although some of these findings have tremendous potential to be turned into valuable therapeutics. This review is intended to raise awareness of several novel approaches that can be considered further for combating drug resistant P. aeruginosa infections.

Introduction

Pseudomonas aeruginosa is one of the most common pathogens in nosocomial and ventilator-associated pneumonia, cystic fibrosis (CF), meningitis, abscess, soft tissue infections, urinary tract infections, catheter associated infections, corneal infections and conjunctival erythema. In addition to acute infections, P. aeruginosa also causes debilitating chronic lung infections in immunocompromised patients, cystic fibrosis patients, and individuals receiving chemotherapy. It can form biofilms on indwelling medical devices such as catheters and on native airways of the CF patients; these biofilms harbor slow growing bacterial subpopulations that are extremely resistant to antibiotics (Williamson et al., 2012). P. aeruginosa can also colonize through disruption of the normal flora balance caused by administration of broad-spectrum antibiotics or dysfunction of the immune system (Abdelghany et al., 2012).

According to the recent Centers for Disease Control (CDC) report around 51,000 healthcare-associated P. aeruginosa infections occur every year in the United States, of which around 6000 (13%) are caused by multidrug-resistant (MDR) P. aeruginosa strains which account for roughly 400 deaths every year. MDR P. aeruginosa was given a threat level of serious threat in the CDC antibiotic resistance threat report. Colistin (polymyxin E), a cyclic amphipathic antibiotic, although known for its nephrotoxicity and neurotoxiciy, is the last resort of treatment option left against MDR P. aeruginosa strains (Sabuda et al., 2008). Recently, the emergence of colistin resistance has also been reported from several countries including Denmark, United Kingdom and Australia (Denton et al., 2002, Johansen et al., 2008). To address the difficulties in treating P. aeruginosa infections, several approaches were undertaken including intensifying research to develop new antibiotics, use of different antibiotic combinations, and identification of alternative treatment methods using non-antibiotic means. However, the scope for the development of new antibiotics that will be more effective than the existing antibiotics and against which the frequency of resistance development will be lower than the current antibiotics is very limited. Therefore, a lot of research was focused on developing new antibiotic combinations to treat MDR P. aeruginosa infections (Dubois et al., 2001, Rahal, 2006, Sobieszczyk et al., 2004, Waters and Smyth, 2015). In this regard, aerosolized antibiotic formulations of aztreonam, tobramycin, levofloxacin and liposomal amikacin were developed to deliver antibiotics through the pulmonary route of CF patients. Several in vitro experiments and clinical trials were also conducted to identify ideal antibiotic combinations (e.g. combinations of cefepime and amikacin; polymyxin B with carbapenem, aminoglycoside, quinolone or β-lactam) to treat P. aeruginosa infections. In addition to this a lot of research is being carried out to develop non-antibiotic therapeutics against this pathogen using probiotics, phages and phytomedicines. Recent investigations suggest that some of these non-antibiotic therapeutic agents alone or in combination with antibiotics are highly effective against multi-drug resistant P. aeruginosa strains, indicating that non-antibiotic antimicrobial agents in future may play a significant role in the management of P. aeruginosa infections (Veesenmeyer et al., 2009). Here, we attempt to summarize the findings that tackled P. aeruginosa infections by non-antibiotic means. We reviewed the role of different quorum quenchers, lectin inhibitors, iron chelators, efflux pump inhibitors, probiotic organisms, bacteriophages, anti-microbial peptides, bacteriocins and nanoparticles as antimicrobial agents against this pathogen.

Section snippets

Virulence factors

The severity of the P. aeruginosa infections is due to its virulence factors. The virulence factors, especially the exotoxins and proteases cause extensive host tissue damage by disrupting normal cytoskeletal structure, depolymerization of actin filaments and cleavage of the immunoglobulin G (IgG) and A (IgA). P. aeruginosa produced exoenzymes disrupt the normal cytoskeletal structure, depolymerizes the actin filaments and cleaves IgG and IgA; thus facilitates invasion, dissemination and

Mechanisms of antibiotic resistance and need for alternative antimicrobial agents

The mechanism of antibiotic resistance in P. aeruginosa is multi-factorial which include the expression of multiple antibiotic modifying enzymes such as aminoglycoside modifying enzymes, β-lactamases including extended-spectrum β-lactamases and metallo-β-lactamases (Lister et al., 2009); antibiotic efflux pumps such as MexAB-OprM, MexEF-OprN, MexCD-OprJ, and MexXY-OprM (Livermore, 2002, Poole, 2001) and acquisition of chromosomally or plasmid encoded antibiotic resistance genes. Additionally,

Non-antibiotic antimicrobial agents

While the incidence of infections caused by antibiotic resistant strains has increased, the discovery of novel classes of antibiotics has slowed down which made it imperative to search for alternative treatment strategies. Several non-conventional ways of treating P. aeruginosa infections have shown promising results in preclinical studies and few of them have succeeded in demonstrating significant clinical outcomes. The antimicrobial roles of the different non-conventional non-antibiotic

Conclusion

The discovery of penicillin by Alexander Fleming in 1928 and subsequent introduction of antibiotic therapy was undoubtedly one of the greatest medical breakthroughs of all time, which saved millions of lives because infectious disease related mortality was dramatically reduced. However, the easy availability and widespread misuse of antibiotics has come at the price of a sharp increase in different drug resistance bacteria including P. aeruginosa. As there are not many new antibiotics in the

Conflicts of interest

No conflicts.

Acknowledgements

This work was supported by the research grant from the Department of Science and Technology, Kerala (SR/S0/HS/0011/2012). MC is supported by senior research fellowship (3/1/2/16/2013-Nut) from ICMR, India. ACP is supported by Kerala State Council for Science, Technology & Environment (KSCSTE) as junior research fellowship (Order No: 1132/2013/KSCSTE), India.

References (149)

  • J.H. Lee et al.

    ZnO nanoparticles inhibit Pseudomonas aeruginosa biofilm formation and virulence factor production

    Microbiol. Res.

    (2014)
  • D. Lorentzen et al.

    Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions

    Free Radic. Biol. Med.

    (2011)
  • E. Mansouri et al.

    Clinical study to assess the immunogenicity and safety of a recombinant Pseudomonas aeruginosa OprF-OprI vaccine in burn patients

    FEMS Immunol. Med. Microbiol.

    (2003)
  • S. McGrath et al.

    Dueling quorum sensing systems in Pseudomonas aeruginosa control the production of the Pseudomonas quinolone signal (PQS)

    FEMS Microbiol. Lett.

    (2004)
  • R.R. Mohamed et al.

    Synthesis and characterization of antimicrobial crosslinked carboxymethyl chitosan nanoparticles loaded with silver

    Int. J. Biol. Macromol.

    (2014)
  • S. Mohan et al.

    Completely green synthesis of dextrose reduced silver nanoparticles, its antimicrobial and sensing properties

    Carbohydr. Polym.

    (2014)
  • S.M. Abdelghany et al.

    Gentamicin-loaded nanoparticles show improved antimicrobial effects towards Pseudomonas aeruginosa infection

    Int. J. Nanomedicine

    (2012)
  • S.T. Abedon et al.

    Phage treatment of human infections

    Bacteriophage

    (2011)
  • H. Ahmadi et al.

    Immunological evaluation of OMP-F of native Iranian Pseudomonas aeruginosa as a protective vaccine

    J. Infect. Dev. Ctries

    (2012)
  • Y. Alexandre et al.

    Screening of Lactobacillus spp. for the prevention of Pseudomonas aeruginosa pulmonary infections

    BMC Microbiol.

    (2014)
  • J. Azeredo et al.

    The use of phages for the removal of infectious biofilms

    Curr. Pharm. Biotechnol.

    (2008)
  • E. Banin et al.

    Iron and Pseudomonas aeruginosa biofilm formation

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • E. Banin et al.

    The potential of desferrioxamine-gallium as an anti-Pseudomonas therapeutic agent

    Proc. Natl. Acad. Sci. U. S. A.

    (2008)
  • U. Baumann et al.

    Assessment of pulmonary antibodies with induced sputum and bronchoalveolar lavage induced by nasal vaccination against Pseudomonas aeruginosa: a clinical phase I/II study

    Respir. Res.

    (2007)
  • B. Bonev et al.

    Principles of assessing bacterial susceptibility to antibiotics using the agar diffusion method

    J. Antimicrob. Chemother.

    (2008)
  • D. Bumann et al.

    Systemic, nasal and oral live vaccines against Pseudomonas aeruginosa: a clinical trial of immunogenicity in lower airways of human volunteers

    Vaccine

    (2007)
  • V.L. Campodonico et al.

    Evaluation of flagella and flagellin of Pseudomonas aeruginosa as vaccines

    Infect. Immun.

    (2010)
  • A.W. Carpenter et al.

    Dual action antimicrobials: nitric oxide release from quaternary ammonium-functionalized silica nanoparticles

    Biomacromolecules

    (2012)
  • C. Chemani et al.

    Role of LecA and LecB lectins in Pseudomonas aeruginosa-induced lung injury and effect of carbohydrate ligands

    Infect. Immun.

    (2009)
  • J. Chen et al.

    Effect of silver nanoparticle dressing on second degree burn wound

    Zhonghua Wai Ke Za Zhi

    (2006)
  • P. Cornelis et al.

    Pseudomonas aeruginosa adapts its iron uptake strategies in function of the type of infections

    Front. Cell. Infect. Microbiol.

    (2013)
  • S.J. Cryz et al.

    Vaccine potential of Pseudomonas aeruginosa O-polysaccharide-toxin A conjugates

    Infect. Immun.

    (1987)
  • S.J. Cryz et al.

    Immunization of cystic fibrosis patients with a Pseudomonas aeruginosa O-polysaccharide-toxin A conjugate vaccine

    Behring Inst. Mitt.

    (1997)
  • D. De et al.

    Antibacterial effect of lanthanum calcium manganate nanoparticles against Pseudomonas aeruginosa ATCC 27853

    J. Biomed. Nanotechnol.

    (2010)
  • L. Debarbieux et al.

    Bacteriophages can treat and prevent Pseudomonas aeruginosa lung infections

    J. Infect. Dis.

    (2010)
  • I. Deguise et al.

    Synthesis of glycodendrimers containing both fucoside and galactoside residues and their binding properties to Pa-IL and PA-IIL lectins from Pseudomonas aeruginosa

    New J. Chem.

    (2007)
  • K. DeLeon et al.

    Gallium maltolate treatment eradicates Pseudomonas aeruginosa infection in thermally injured mice

    Antimicrob. Agents Chemother.

    (2009)
  • Y. Deng et al.

    Cis-2-dodecenoic acid signal modulates virulence of Pseudomonas aeruginosa through interference with quorum sensing systems and T3SS

    BMC Microbiol.

    (2013)
  • M. Denton et al.

    Transmission of colistin-resistant Pseudomonas aeruginosa between patients attending a pediatric cystic fibrosis center

    Pediatr. Pulmonol.

    (2002)
  • B. Deslouches et al.

    Activity of the de novo engineered antimicrobial peptide WLBU2 against Pseudomonas aeruginosa in human serum and whole blood: implications for systemic applications

    Antimicrob. Agents Chemother.

    (2005)
  • E. Deziel et al.

    Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • G. Doring et al.

    A double-blind randomized placebo-controlled phase III study of a Pseudomonas aeruginosa flagella vaccine in cystic fibrosis patients

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • V. Dubois et al.

    Nosocomial outbreak due to a multiresistant strain of Pseudomonas aeruginosa P12: efficacy of cefepime-amikacin therapy and analysis of beta-lactam resistance

    J. Clin. Microbiol.

    (2001)
  • C. Forestier et al.

    Oral probiotic and prevention of Pseudomonas aeruginosa infections: a randomized, double-blind, placebo-controlled pilot study in intensive care unit patients

    Crit. Care

    (2008)
  • W. Fu et al.

    Bacteriophage cocktail for the prevention of biofilm formation by Pseudomonas aeruginosa on catheters in an in vitro model system

    Antimicrob. Agents Chemother.

    (2010)
  • M. Galle et al.

    The Pseudomonas aeruginosa type III secretion system has an exotoxin S/T/Y independent pathogenic role during acute lung infection

    PLoS ONE

    (2012)
  • J. Garbe et al.

    Characterization of JG024, a pseudomonas aeruginosa PB1-like broad host range phage under simulated infection conditions

    BMC Microbiol.

    (2010)
  • R. Garcia-Contreras et al.

    Gallium induces the production of virulence factors in Pseudomonas aeruginosa

    Pathog. Dis.

    (2014)
  • M. Geiszt et al.

    Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense

    FASEB J.

    (2003)
  • A. Giacometti et al.

    In-vitro activity of cationic peptides alone and in combination with clinically used antimicrobial agents against Pseudomonas aeruginosa

    J. Antimicrob. Chemother.

    (1999)
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