Challenges and Promises for Planning Future Clinical Research Into Bacteriophage Therapy Against Pseudomonas aeruginosa in Cystic Fibrosis. An Argumentative Review.

Martina Rossitto,Paola Rosati,Ersilia V Fiscarelli

doi:10.3389/fmicb.2018.00775

Abstract

Although early aggressive and prolonged treatment with specific antibiotics can extend survival in patients with cystic fibrosis (CF) colonized by opportunistic Pseudomonas aeruginosa (PA), antibiotics fail to eradicate the infecting multidrug-resistant (MDR) PA strains in CF. Century-long research has suggested treating patients with bacteriophages (phages, prokaryotic viruses) naturally hosted by bacteria. Although the only phage types used in therapy, lytic phages, lyse PA aggregated in biofilm matrix by depolymerase degrading enzymes, how they can effectively, safely, and persistently do so in patients with CF is unclear. Even though advanced techniques for formulating phage cocktails, training phages and collecting phage libraries have improved efficacy in vitro, whether personalized or ready-to-use therapeutic approaches or phages and antibiotics combined are effective and safe in vivo, and can reduce PA biofilms, remains debatable. Hence, to advance clinical research on phage therapy in clinical trials, also involving mucoid and non-mucoid multidrug-resistant PA in CF, and overcome problems in Western international regulations, we need reliable and repeatable information from experiments in vitro and in vivo on phage characterization, cocktail selection, personalized approaches, and phages combined with antibiotics. These findings, challenges, and promises prompted us to undertake this argumentative review to seek up-to-date information from papers describing lytic phage activity tested in vitro on PA laboratory strains, and PA strains from chronic infections including CF. We also reviewed in vivo studies on phage activity on pulmonary and non-pulmonary animal host models infected by laboratory or CF PA strains. Our argumentative review provides essential information showing that future phage clinical research in CF should use well-characterized and selected phages isolated against CF PA, tested in vitro under dynamic conditions in cocktails or combined with antibiotics, and in vivo on non-pulmonary and pulmonary host models infected with mucoid and non-mucoid CF MDR PA. Our findings should encourage pharmaceutical industries to conduct clinical trials in vitro and in vivo testing patented genomic engineered phages from phage libraries combined with antibiotics to treat or even prevent multidrug-resistant PA in CF, thus helping international regulatory agencies to plan future clinical research on phage therapy in CF.

Highlights

Pseudomonas aeruginosa (PA), an opportunistic environmental pathogen, typically colonizes 30% of children, and up to 80% of 25-year-old and older adults with cystic fibrosis (CF) (Gibson et al, 2003; Stuart et al, 2010), inexorably causing chronic lung infection, pulmonary function decline, and death (Frederiksen et al, 1997; Murray et al, 2007; Moreau-Marquis et al, 2008)
To do so we reviewed, appraised and synthesized information from publications describing lytic phages tested in vitro in PA from various sources, and phage activity, resistance and safety in vivo on non-pulmonary and pulmonary host models infected by various laboratory and clinical CF PA strains
Our findings provide new insights that will prompt renewed clinical research in CF PA to test wellselected lytic phages to include in cocktails, develop personalized phage therapy, address phage-antibiotic combinations, and envisage even genomic engineered phages combined with antibiotics to treat MDR and XDR PA in patients with CF (Figure 2)

Summary

Introduction

Pseudomonas aeruginosa (PA), an opportunistic environmental pathogen, typically colonizes 30% of children, and up to 80% of 25-year-old and older adults with cystic fibrosis (CF) (Gibson et al, 2003; Stuart et al, 2010), inexorably causing chronic lung infection, pulmonary function decline, and death (Frederiksen et al, 1997; Murray et al, 2007; Moreau-Marquis et al, 2008). Surface motile planktonic PA cells leave the biofilm, colonize new lung sites, and initiate new sessile PA micro-colonies triggering repeated lung infections requiring antibiotics (Supplementary Table 1; Costerton et al, 1999, 2003). Despite international recommendations on CF infections, including MDR organism prevention and control (Saiman et al, 2014), and recent findings on PA evolutionary adaptation, diversification, and resistance factors in CF lungs (Supplementary Table 1; Winstanley et al, 2016), research interest is waning on new antibiotics to include in pipeline programs (Theuretzbacher, 2009; Bassetti et al, 2011). As a new weapon to treat CF lung infection caused by MDR PA and other multi-resistant superbugs, extensive research has reappraised bacteriophage (phage) therapy (Sulakvelidze et al, 2001; Thiel, 2004; Hurley et al, 2012)

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