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Sweetening Inhaled Antibiotic Treatment for Eradication of Chronic Respiratory Biofilm Infection

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Abstract

Purpose

The failure of chronic therapy with antibiotics to clear persistent respiratory infection is the key morbidity and mortality factor for patients with chronic lung diseases, primarily due to the presence of biofilm in the lungs. It is hypothesised that carbon sources, such as mannitol, could stimulate the metabolic activity of persister cells within biofilms and restore their susceptibility to antibiotics. The aims of the current study are to: (1) establish a representative in vitro model of Pseudomonas aeruginosa biofilm lung infection, and (2) investigate the effects of nebulised mannitol on antibiotic efficacy, focusing on ciprofloxacin, in the eradication of biofilm.

Method

Air interface biofilm was cultured onto Snapwell inserts incorporated into a modified pharmacopeia deposition apparatus, the Anderson Cascade Impactor (ACI). Three different formulations including mannitol only, ciprofloxacin only and combined ciprofloxacin and mannitol were nebulised onto the P. aeruginosa biofilm using the modified ACI. Antibacterial effectiveness was evaluated using colony-forming units counts, biofilm penetration and scanning electron microscopy.

Results

Nebulised mannitol promotes the dispersion of bacteria from the biofilm and demonstrated a synergistic enhancement of the antibacterial efficacy of ciprofloxacin compared to delivery of antibiotic alone.

Conclusions

The combination of ciprofloxacin and mannitol may provide an important new strategy to improve antibiotic therapy for the treatment of chronic lung infections. Furthermore, the development of a representative lung model of bacterial biofilm could potentially be used as a platform for future new antimicrobial pre-clinical screening.

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Abbreviations

ACI:

Anderson cascade impactor

ATCC:

American type cell culture collection

BE:

Bronchiectasis

CAMHB:

Cation adjusted Mueller-Hinton broth

Cipro:

Ciprofloxacin only

Cipro-man:

Ciprofloxacin and mannitol

CDC:

Centers for disease control

CF:

Cystic fibrosis

CFU:

Colony-forming unit count

COPD:

Chronic obstructive pulmonary disease

CV:

Crystal violet

DMEM:

Dulbecco’s Modified Eagle’s Medium

DMSO:

Dimethyl sulfoxide

EPS:

Extracellular polymeric substances

EVOM:

Epithelial voltohmmeter

f 1 :

Difference factor

f 2 :

Similarity factor

FBS:

Fetal bovine serum

FPF:

Fine particle fraction

GSD:

Geometric standard deviation

HBSS:

Hank’s balanced salt solution

HPLC:

High performance liquid chromatography

LB:

Luria-Bertani

MMAD:

Mass median aerodynamic diameter

P. aeruginosa :

Pseudomonas aeruginosa

PBS:

Phosphate buffered saline

PCF:

Primary ciliary dyskinesia

RID:

Refractive index detector

RTIs:

Respiratory tract infections

SEM:

Scanning electron microscope

TEER:

Transepithelial electrical resistance

USP:

United States Pharmacopoeia

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Author information

Authors and Affiliations

  1. Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Sydney, NSW, 2037, Australia

    Ching-Yee Loo, Wing-Hin Lee, Gianluca Lauretani, Daniela Traini, Paul Young & Hui Xin Ong

  2. Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur (RCMP UniKL), Ipoh, Perak, Malaysia

    Ching-Yee Loo & Wing-Hin Lee

  3. Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy

    Gianluca Lauretani & Santo Scalia

  4. Pharmaceutical Sciences, Aradigm Corporation, Hayward, California, USA

    David Cipolla

  5. Discipline of Pharmacology, Sydney Medical School, Camperdown, NSW, 2006, Australia

    Daniela Traini, Paul Young & Hui Xin Ong

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  1. Ching-Yee Loo
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Correspondence to Hui Xin Ong.

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Loo, CY., Lee, WH., Lauretani, G. et al. Sweetening Inhaled Antibiotic Treatment for Eradication of Chronic Respiratory Biofilm Infection. Pharm Res 35, 50 (2018). https://doi.org/10.1007/s11095-018-2350-4

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  • DOI: https://doi.org/10.1007/s11095-018-2350-4

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