Novel approaches to the treatment of bacterial biofilm infections

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Abstract

Bacterial infection remains a major challenge to healthcare and is responsible for significant morbidity and mortality. This situation is becoming complicated by an increasingly ageing and susceptible population and large numbers of bacterial isolates, which have developed resistance to antibiotics. Bacteria that form biofilms and colonize or infect medical devices or wounds are particularly hard to treat as biofilms are inherently highly antibiotic resistant. Most infections have a component where bacteria exist as a biofilm and as a result, prevention or treatment of biofilm-associated infections is highly important. A number of novel strategies to kill biofilms have been in development; these include the use of weak organic acids, photo irradiation and the application of bacteriophage. All have promise and are able to effectively kill biofilms in model systems, but for each there are still unanswered questions. This review summarizes the main features of biofilm infections, each of these novel approaches and the evidence that is still lacking before these potential treatments can be incorporated into clinical usage.

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A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy.

A. Wright, C Hawkins, E Anggård … (2009)

To evaluate the efficacy and safety of a therapeutic bacteriophage preparation (Biophage-PA) targeting antibiotic-resistant Pseudomonas aeruginosa in chronic otitis. Randomised, double-blind, placebo-controlled Phase I/II clinical trial approved by UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Central Office for Research Ethics Committees (COREC) ethical review process. A single specialist university hospital. 24 patients with chronic otitis with a duration of several years (2-58). Each patient had, at the time of entry to the trial, an ear infection because of an antibiotic-resistant P. aeruginosa strain sensitive to one or more of the six phages present in Biophage-PA. Participants were randomised in two groups of 12 treated with either a single dose of Biophage-PA or placebo and followed up at 7, 21 and 42 days after treatment by the same otologist. Ears were thoroughly cleaned on each occasion and clinical and microbiological indicators measured. Physician assessed erythema/inflammation, ulceration/granulation/polyps, discharge quantity, discharge type and odour using a Visual Analogue Scale (VAS). Patients reported discomfort, itchiness, wetness and smell also using a VAS. Bacterial levels of P. aeruginosa and phage counts from swabs were measured initially and at follow-up. At each visit patients were asked about side effects using a structured form. Digital otoscopic images were obtained on days 0 and 42 for illustrative purposes only. Relative to day 0, pooled patient- and physician-reported clinical indicators improved for the phage treated group relative to the placebo group. Variation from baseline levels was statistically significant for combined data from all clinic days only for the phage treated group. Variation from baseline levels was statistically significant for the majority of the patient assessed clinical indicators only for the phage treated group. P. aeruginosa counts were significantly lower only in the phage treated group. No treatment related adverse event was reported. The first controlled clinical trial of a therapeutic bacteriophage preparation showed efficacy and safety in chronic otitis because of chemo-resistant P. aeruginosa.

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George P. C. Salmond, Peter Fineran (2015)

Viruses that infect bacteria (bacteriophages; also known as phages) were discovered 100 years ago. Since then, phage research has transformed fundamental and translational biosciences. For example, phages were crucial in establishing the central dogma of molecular biology - information is sequentially passed from DNA to RNA to proteins - and they have been shown to have major roles in ecosystems, and help drive bacterial evolution and virulence. Furthermore, phage research has provided many techniques and reagents that underpin modern biology - from sequencing and genome engineering to the recent discovery and exploitation of CRISPR-Cas phage resistance systems. In this Timeline, we discuss a century of phage research and its impact on basic and applied biology.

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Biofilm dispersion and quorum sensing.

Cristina Solano, Maite Echeverz, Iñigo Lasa (2014)

Biofilm development and quorum sensing (QS) are closely interconnected processes. Biofilm formation is a cooperative group behaviour that involves bacterial populations living embedded in a self-produced extracellular matrix. QS is a cell-cell communication mechanism that synchronizes gene expression in response to population cell density. Intuitively, it would appear that QS might coordinate the switch to a biofilm lifestyle when the population density reaches a threshold level. However, compelling evidence obtained in different bacterial species coincides in that activation of QS occurs in the formed biofilm and activates the maturation and disassembly of the biofilm in a coordinate manner. The aim of this review is to illustrate, using four bacterial pathogens as examples, the emergent concept that QS activates the biofilm dispersion process. Copyright © 2014 Elsevier Ltd. All rights reserved.