Anti-pseudomonad Activity of Manuka Honey and Antibiotics in a Specialized ex vivo Model Simulating Cystic Fibrosis Lung Infection.

Aled E L Roberts,Rowena E Jenkins,David W Thomas,Manon F Pritchard,Lydia C Powell

doi:10.3389/fmicb.2019.00869

Abstract

Pseudomonas aeruginosa causes problematic chronic lung infections in those suffering from cystic fibrosis. This is due to its antimicrobial resistance mechanisms and its ability to form robust biofilm communities with increased antimicrobial tolerances. Using novel antimicrobials or repurposing current ones is required in order to overcome these problems. Manuka honey is a natural antimicrobial agent that has been used for many decades in the treatment of chronic surface wounds with great success, particularly those infected with P. aeruginosa. Here we aim to determine whether the antimicrobial activity of manuka honey could potentially be repurposed to inhibit pulmonary P. aeruginosa infections using two ex vivo models. P. aeruginosa isolates (n = 28) from an international panel were tested for their susceptibility to manuka honey and clinically relevant antibiotics (ciprofloxacin, ceftazidime, and tobramycin), alone and in combination, using conventional antimicrobial susceptibility testing (AST). To increase clinical applicability, two ex vivo porcine lung (EVPL) models (using alveolar and bronchiolar tissue) were used to determine the anti-biofilm effects of manuka honey alone and in combination with antibiotics. All P. aeruginosa isolates were susceptible to manuka honey, however, varying incidences of resistance were seen against antibiotics. The combination of sub-inhibitory manuka honey and antibiotics using conventional AST had no effect on activity against the majority of isolates tested. Using the two ex vivo models, 64% (w/v) manuka honey inhibited many of the isolates where abnormally high concentrations of antibiotics could not. Typically, combinations of both manuka honey and antibiotics had increased antimicrobial activity. These results highlight the potential of manuka honey as a future antimicrobial for the treatment of pulmonary P. aeruginosa isolates, clearing potential infection reservoirs within the upper airway.

Highlights

Pseudomonas aeruginosa is an opportunistic pathogen, capable of causing infections in various immunocompromised patient groups (de Bentzmann and Plésiat, 2011)
Pulmonary P. aeruginosa infections are difficult to treat, due to its various antimicrobial resistance (AMR) and antimicrobial tolerance (AMT) capabilities and the constraints surrounding the effective delivery of antimicrobial agents (Lee and Yoon, 2017)
This study demonstrates that manuka honey was effective at inhibiting a wide range of P. aeruginosa isolates (22) associated with Cystic Fibrosis (CF) infection; building on the findings of a previous study (Jenkins et al, 2015)

Summary

Introduction

Pseudomonas aeruginosa is an opportunistic pathogen, capable of causing infections in various immunocompromised patient groups (de Bentzmann and Plésiat, 2011). Up to 80% of CF patients will acquire a pulmonary P. aeruginosa infection, an event that is linked to poor patient prognosis and infection chronicity (Schelstraete et al, 2013). This link between P. aeruginosa and persistence, is due, in part, to the formation of biofilms by mucoid strains (Høiby et al, 2010). Biofilm formation in P. aeruginosa leads to increased antimicrobial tolerance (AMT), an extra defensive strategy on top of the innate and acquired antimicrobial resistance (AMR) mechanisms it possesses (El Zowalaty et al, 2015). There are few effective therapeutic options for pulmonary P. aeruginosa infections, with many patients harboring multidrug resistant strains (López-Causapé et al, 2017). In order to provide respite care for these patients, novel antimicrobial agents with effective anti-biofilm effects must be identified (Worthington and Melander, 2013)

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