Mini ReviewAntibiotic resistance in Pseudomonas aeruginosa and alternative therapeutic options
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.
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