Long-Term Safety of Topical Bacteriophage Application to the Frontal Sinus Region.

Amanda J Drilling,Dijana Miljkovic,Sarah Vreugde,Peter Speck,Mian L Ooi,Jason Clark,Peter-John Wormald,Craig James

doi:10.3389/fcimb.2017.00049

Abstract

Background: Staphylococcus aureus biofilms contribute negatively to a number of chronic conditions, including chronic rhinosinusitis (CRS). With the inherent tolerance of biofilm-bound bacteria to antibiotics and the global problem of bacterial antibiotic resistance, the need to develop novel therapeutics is paramount. Phage therapy has previously shown promise in treating sinonasal S. aureus biofilms.Methods: This study investigates the long term (20 days) safety of topical sinonasal flushes with bacteriophage suspensions. The bacteriophage cocktail NOV012 against S. aureus selected for this work contains two highly characterized and different phages, P68 and K710. Host range was assessed against S. aureus strains isolated from CRS patients using agar spot tests. NOV012 was applied topically to the frontal sinus region of sheep, twice daily for 20 days. General sheep wellbeing, mucosal structural changes and inflammatory load were assessed to determine safety of NOV012 application.Results: NOV012 could lyse 52/61 (85%) of a panel of locally derived CRS clinical isolates. Application of NOV012 to the frontal sinuses of sheep for 20 days was found to be safe, with no observed inflammatory infiltration or tissue damage within the sinus mucosa.Conclusion: NOV012 cocktail appears safe to apply for extended periods to sheep sinuses and it could infect and lyse a wide range of S. aureus CRS clinical isolates. This indicates that phage therapy has strong potential as a treatment for chronic bacterial rhinosinusitis.

Highlights

S. aureus isolates from 61 patients diagnosed with chronic rhinosinusitis (CRS) were examined (Table 1)
We found that phage K710 was effective against 59% of the S. aureus strains in our panel of isolates, which was increased to 85% with addition of phage P68
This work confirms that the Novolytics bacteriophage cocktail (NOV012) phage cocktail infects a broad range of S. aureus isolates, including a number of methicillin-resistant S. aureus (MRSA) isolates, from CRS patients

Summary

Introduction

Staphylococcus aureus is an opportunistic bacterial pathogen forming biofilms, which are known to be involved in a number of infective chronic diseases (Petti and Fowler, 2003; Ziran, 2007; Baldoni et al, 2009; Foreman and Wormald, 2010; Singhal et al, 2010, 2011; Jervis-Bardy and Wormald, 2012). Safety of Long-Term Intranasal Bacteriophage Application biofilms of S. aureus are known to impact negatively in chronic rhinosinusitis (CRS) The presence of such infections in CRS reportedly leads to more frequent out-patient visits (Singhal et al, 2011), increased risk of recurrent infections and antibiotic use (Jervis-Bardy and Wormald, 2012) as well as poorer postoperative progression (Foreman and Wormald, 2010; Singhal et al, 2010). Such biofilms are up to 1000-fold more tolerant of current antibiotic therapies than their planktonic counterparts (Anwar et al, 1990). Phage therapy has previously shown promise in treating sinonasal S. aureus biofilms

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