Nebuliser hygiene in cystic fibrosis: evidence-based recommendations

Jane Bell; Lauren Alexander; Jane Carson; Amanda Crossan; John McCaughan; Hazel Mills; Damian O'Neill; John E. Moore; B. Cherie Millar

doi:10.1183/20734735.0328-2019

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Figure 1
Summary of recommendations as a flow diagram.

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Table 1

Key terms and definitions

Term	Definition
Acquisition	In the context of CF, an organism is acquired when it is first detected in a respiratory sample (e.g. sputum or cough swab)
Active drying	In relation to drying of nebulisers, this term means to proactively promote drying by physical means such as drying with a cloth or forced hot air by means of a fan (e.g. in the case of a dishwasher)
Adherence	Patients' compliance with the correct drug prescription and their individualised routines
Aerosolised	The changing of a liquid medication into a mist that is subsequently delivered to the lungs by an appropriate device (e.g. nebuliser)
Air drying	Leaving respiratory devices including nebulisers to passively dry in air
Aseptic technique	Sterile manipulation to minimise risk of contamination
Antibiotic	A substance that acts specifically to kill bacteria (bactericidal) or to inhibit growth of bacteria (bacteriostatic) Ideally, the antibiotic should have minimal action on human cells Antibiotics are chosen to target different classes of bacteria and the various antibiotic groups act on the bacteria in different ways Antibiotics may be delivered orally, by injection into a muscle or vein or nebulised via the airways
Antifungal	A substance designed to kill or inhibit the growth of fungi
Biofilm	When microorganisms grow attached to a surface, they may produce a charged extracellular matrix with a high water content composed of polysaccharides and protein The resultant biofilm can protect the organisms from the normal host defence mechanisms and, since the components are polar in nature, the matrix may be impenetrable to antibiotics In mature biofilm, the oxygen tension may be low, allowing the growth of a mixed population of aerobic and anaerobic bacteria Such biofilm in the lumen of the bronchi in the CF lung may be the source of a periodic surge of bacteria in the airways precipitating a pulmonary exacerbation requiring intravenous antibiotic treatment
*Burkholderia cenocepacia*	B. cenocepacia is Gram-negative bacterium responsible for chronic respiratory disease in CF patients
Burkholderia cepacia complex	A group of ≥20 closely related bacterial species, many of which have been associated in the pathology of lung disease in CF patients The most important members of this complex include B. cenocepacia, B. multivorans and B. vietnamiensis
COPD	A lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible
Colonisation	Physical persistence of microorganisms in the airways, even in the presence of antibiotics This can subsequently lead to a state of chronic colonisation when a microorganism can be repeatedly detected in specimen from a body site Chronic colonisation may be marked by the finding of “mucoid” colonies of Pseudomonas aeruginosa or slow-growing “small-colony variants” of Staphylococcus aureus and such organisms may be impossible to eradicate using antibiotics In CF, chronic colonisation of the lungs by such organisms is usually associated with a clinical deterioration
Compressor	This is a device that compresses room air and forces it, by increased pressure and at a high velocity, through a liquid medicine to turn it into a mist of fine droplets which is then inhaled via a nebuliser
Contamination	The addition of microorganisms from the environment, other patients, healthcare workers or the patients themselves to a surface or object that did not previously contain such organisms
Detergent	A chemical that solubilises soil and dirt and helps clean (e.g. dishwashing liquid) Detergents generally have no antibacterial properties, unless antibacterial substances are specifically incorporated into their formulation and are marketed accordingly
Disinfectant	A chemical that is antimicrobial (e.g. chlorine tablets) and destroys vegetative forms of harmful microorganisms at the proper concentration (e.g. bacteria and fungi), especially on inanimate objects, but which may be less effective in destroying spores
Disinfection	The process (chemical, heat, ozone or ultraviolet light) by which a high percentage of the microorganisms are removed or killed from an object or surface This process will not inactivate bacterial/fungal spores and is less effective than sterilisation
Distilled water	Water that has been purified through boiling/evaporation and allowed to condense back into a liquid, thus removing many impurities
Environmental organism	Bacteria or fungi commonly detected from soil or water sources Although such organisms are often highly resistant to antibiotics, they are not usually included in the panel of clinically significant pathogens and not the target of bacterial culture in the clinical laboratory They do not usually colonise and cause infection except when there is a breach in the normal body defence against microorganisms In the CF lung, the proper function of the ciliary epithelium is compromised and CF patients are subject to colonisation by a succession of environmental bacteria and fungi To detect such organisms, extra resources are used by the clinical bacteriology laboratory processing CF respiratory samples
Eradication	After the initial acquisition of certain bacteria, concerted attempts are made to eliminate the bacteria, usually by means of repeated courses of antibiotics Early detection is the key to successful elimination and ideally, the treatment should be commenced as soon as possible after the organism is detected The declaration that a patient has been cleared of an organism is always retrospective and requires a period (e.g. 1 year) during which only negative samples are obtained
Evidence-based practice (EBP)	The conscientious, explicit and judicious use of current best evidence in making decisions about the care of patients EBP integrates best available external clinical evidence from systematic research
Microbiome	The sum of all the organisms in a region of the body Using molecular methods including PCR and genetic sequencing, hundreds of groups may be identified Studies of the microbiome in respiratory samples from CF patients show dynamic diversity of bacterial species When chronic colonisation occurs, species diversity decreases with high concentrations of the relatively few organisms, such as P. aeruginosa or B. cepacia
Mucociliary clearance	The removal of particles from the airways as the result of the movement of mucus due to the beating of the underlying cilia
Nebulised	Administering a drug to the airways or lungs in the form of an aerosolised mist of fine droplets
Nebuliser	A device that delivers aerosol droplets suitable for patient inhalation
Adaptive Aerosol Delivery	Small, quick devices that give improved deposition of medications by delivering an aerosol on inhalation during the individual’s breathing cycle (e.g. I-neb; Philips Respironics, Murrysville, PA, USA)
Disposable nebuliser	Discarded every 24 h
Jet nebuliser	Compressed air or oxygen used to aerosolise liquid medications
Reusable nebuliser	Can be used more than once
Vibrating mesh nebuliser	Moves liquid medication through a metal mesh to break up into a mist where each drop is a similar size, delivering a mist of medication constantly (e.g. E-flow; Pari, Byfleet, UK)
Nonpathogens	Organisms that do not cause disease, harm or death
Nosocomial infection	A hospital-acquired infection
Opportunistic organisms	Organisms that take advantage of certain opportunities to cause disease (e.g. a weakened immune system)
Pathogens/pathogenic organisms	Disease causing microorganisms, such as bacteria, fungi and viruses
*Pseudomonas aeruginosa*	A Gram-negative bacterium, commonly found in the environment, which is a significant pathogen in patients with CF
Potable water	Drinking water
Pulmonary exacerbation	An increase in respiratory symptoms (e.g. increased cough, sputum production or shortness of breath) accompanied by an acute decrease in lung function
Pulmonary infection	Worsening clinical symptoms or signs, caused by pathogens identified in respiratory secretion samples
Source/reservoir of infection	The principal habitat in which a specific infectious agent lives and multiplies The reservoir is necessary for the infectious agent either to survive or to multiply in sufficient amount to be transmitted to a susceptible host
*Stenotrophomonas maltophilia*	A Gram-negative bacterium identified in people with CF Although its clinical significance is a matter of debate, it is sometimes seen persistently in combination with other more significant pathogens such as P. aeruginosa or S. aureus In a few cases, this bacterium is the sole culminating organism in a CF patient with chronic pulmonary infection
Sterilisation	The process by which all microorganisms, including bacterial and fungal spores, are destroyed
Sterile water	Water is sterilised when it has been treated to destroy all microorganisms including bacterial and fungal spores
Transmission	The process of passing microorganisms from one person or place to another

Table 2

Organisms which have been recovered from the nebulisers of patients with CF[10–22]

Gram-negative bacteria	Achromobacter xylosoxidans Acinetobacter spp. (A. johnsonii, A. junii) Aeromonas hydrophila Burkholderia cepacia complex Chryseobacterium indologenes Comamonas spp. (C. acidovorans, C. testosteroni) Delftia spp. Enterobacter spp. Escherichia coli Flavobacterium spp. (F. indologenes, F. meningosepticum) Haemophilus parahaemolyticus Klebsiella spp. (K. ozaenae, K. pneumoniae) Moraxella spp. (M. osloensis) Neisseria subflava Ochrobactrum anthropi Oligella urethralis Pantoea agglomerans Proteus spp. Pseudomonas spp. (P. aeruginosa, P. aureofaciens, P. fluorescens. P. stuzeri, P. vesicularis) Rhizobium (Agrobacterium) radiobacter Serratia marcescens Shewanella putrefaciens Sphingobacterium spp. (Sphingomonas paucimobilis) Stenotrophomonas maltophilia
Gram-positive bacteria	Actinomyces viscosus Bacillus spp. Corynebacterium spp. Enterococcus faecalis Granulicatella adiacens Microbacterium spp. (M. oxydans, M. paraoxydans) Micrococcus spp. (M. luteus, M. lylae) Rothia spp. (R. dentocariosa, R. mucilaginosa) Staphylococcus spp. (S. aureus (MRSA, MSSA), S. epidermidis, S.saprophyticus, S. pasteuri) Streptococcus spp. (viridans group streptococci)
Other bacteria	Paenibacillus spp.
Yeasts	Candida spp. (C. albicans, C. guilliermondii, C. holmii, C. krusei, C. lipolytica, C. parapsilosis, C. sake, C. zeylanoides) Cryptococcus spp. (C. albidus, C. carnescens, C. unigutatulus)
Filamentous fungi	Aspergillus spp. (A. fumigatus, A niger, A. versicolor) Aureobasidium pullulans Cladosporium spp. (Cladosporium sphaerospermum) Exophiala spp. (E. jeanselmei, E. oligosperumum) Lecanicillium spp. (L. lecanii) Microsporum fulvum Myxotrichum sp. Penicillium spp. (P. commune, P. coryphilum, P. digitatum P. glabrum, P. griseofulvin) Rhizopus oryzae Rhodotorula spp. (R. glutinis, R. minuta, R. mucilaginosa) Scopulariopsis chartarum Ulocladium chartarum Sporobolomyces roseus Trichosporon asahii

MRSA: methicillin-resistant S. aureus; MSSA: methicillin-sensitive S. aureus.

Table 3

A list of documented methods used to disinfect nebulisers

Method	Evidence
Chemical methods
Acetic acid/vinegar	Ineffective against CF pathogens such as B. cenocepacia, S. aureus and MRSA [52]
Benzyl ammonium chloride (Control III; Maril Inc., Tustin, CA, USA)	Not recommended due to narrow spectrum of activity and slow action [26]
Ethyl alcohol/ethanol (70%)	Has been reported to reduce fungal and bacterial contamination of nebulisers but not completely [53]
Isopropyl alcohol/propanol (70%)	Will lose activity over time; therefore, needs to be regularly replaced Saliva and sputa may protect microorganisms from the action of alcohol; therefore, prior washing of devices is required May be ineffective against mycobacteria [54] It has been reported that isopropyl alcohol disinfection does not affect nebuliser output[55]
Hydrogen peroxide (3%)	Although listed in the CFF-IP&C guidelines (3% hydrogen peroxide for 30 min), there is limited evidence supporting disinfection of nebulisers with hydrogen peroxide [26]
Sodium hypochlorite	Although hypochlorite disinfection has been shown to decrease the contamination of nebulisers due to commensal and environmental organisms, a similar reduction has not been observed in the case of CF pathogens [10, 56] Corrosive chemicals such as hypochlorite are prohibited for disinfecting the mesh membrane of the e-Flow rapid nebuliser [5]
Ozone	Commercially available SoClean (Peterborough, NH, USA) ozone machine has been examined with type strains of B. cepacia, P. aeruginosa, S. aureus and S. maltophilia Preliminary findings have shown a 5-min infusion followed by a 120-min dwell time to be effective against these organisms when spiked onto a Pari LCPlus nebuliser, without affecting nebuliser output Further investigation is required in relation to nontuberculous mycobacteria and clinical strains of CF pathogens [57]
Squalamine	Squalamine (a steroid–polyamine conjugate compound with broad spectrum antimicrobial activity) targets membrane integrity, and has potential to reduce levels of S. aureus, P. aeruginosa, Candida albicans and Aspergillus niger on contaminated nebulisers [58] Further work needs to be completed prior to advocating the employment of this molecule
Heat methods
Boiling (continuous boil in water for 5 mins)	The CFF-IP&C guidelines and manufacturers’ guidelines recommend that nebulisers should be disinfected by placing them in boiling water for 5 mins [26] Decrease in nebuliser output with Pari LC Plus® device following repeated disinfection by boiling [55]; however, experimental limitations must be considered [59]
Steam (electric baby bottle steam disinfectors)	See table 4
Steam (microwave) (place in microwave-safe receptacle submerged in water and microwave for 5 mins, 2.45 GHz)	Evidence in CFF-IP&C guideline taken from [65–67]; none of these studies employed nebulisers This method cannot be used with nebulisers that contain metal components (e.g. mesh in the eFlow rapid) Dutch study demonstrated that nebulisers contaminated with Enterococcus faecalis, S. aureus and P. aeruginosa were free of microorganisms after microwave treatment (650 W, 9 min) [68]
Dishwasher disinfection (≥70°C/158°F for 30 min)	Although listed in the CFF-IP&C guidelines [26], there is limited evidence supporting disinfection of nebulisers using high-temperature dishwashers
Autoclave (a maximum of 277°F or 136°C)	Certain nebuliser parts may be sterilised using autoclave methods (e.g. Pari Reusable Nebuliser parts, except mask and tubing) [69]

MRSA: methicillin-resistant S. aureus.

Table 4

Advantages and disadvantages of steam disinfection for nebuliser devices

Advantages	Disadvantages
Effective killing of a wide range of bacterial pathogens [60–62], including: B. cepacia complex B. cepacia Burkholderia multivorans Candida albicans Enterococcus faecium Haemophilus influenzae Mycobacterium abscessus abscessus Mycobacterium abscessus bolletii Mycobacterium abscessus massiliense Mycobacterium abscessus/chelonae Mycobacterium avium intracellulare Mycobacterium chelonae P. aeruginosa (mucoid, nonmucoid) S. aureus (MRSA, MSSA) Steno. maltophilia	Apart from the Wabi Baby disinfector, all other baby bottle disinfector manufacturers have not endorsed their product for nebuliser disinfection None of the steam disinfector units have indicators to show/confirm that unit has successfully completed its full cycle
The commercial Steam Sterilizer Plus Model (Wabi Baby, Frisco, TX, USA) has been examined for its effectiveness in disinfecting nebulisers spiked with CF organisms [63]: Achromobacter xylosoxidans B. cepacia P. aeruginosa MSSA
P. aeruginosa (mucoid, nonmucoid) and nontuberculous mycobacteria were not detected in either wet or dry fully assembled nebulisers following steam disinfection even in the presence of sputa [62]
Different brands of steam disinfectors performed effectively [62]
Terminal (end-stage) disinfection will allow for destruction of above pathogens, which may enter during prior stages (tap water, residual sputum, detergent, handling, etc.)
Relatively cheap (approximately GBP 50, EUR 80, USD 70)
Widely available in electrical shops and from online sellers	Wabi Baby device only available in USA
Simple to operate
No consumable items required, except tap water
Fast cycle speeds (approximately 8–15 min to disinfection)
Disinfected nebuliser can be stored in disinfector units post-cycle until required (≤24 h), thus avoiding post-disinfection contamination from surfaces, hands, environment, tap water
Portable (maybe taken on holiday/travel if voltage compatible)	Voltage compatibility in different countries
Can be used with metal components (e.g. metal vibrating mesh)
No membrane performance effect with Pari e-Flow rapid device [64]	Decrease in nebuliser output with Pari LC Plus device following repeated steam disinfection [55]; however, experimental limitations must be considered [59]

MRSA: methicillin-resistant S. aureus; MSSA: methicillin-sensitive S. aureus.

Table 5

Summary of evidence-based best practice guidelines relating to nebuliser hygiene in CF

New nebuliser parts should be washed and disinfected before first use (recommendation 2) During hospital admission and at home, wash the nebuliser parts after each use (recommendation 3) Nebulisers should be washed and re-disinfected immediately prior to use after greater than 24 h of inactivity (recommendation 4)
At-home recommendations	Inpatient recommendations
Wash hands thoroughly with soap and water and use hand disinfector gel before starting the cleaning process (Recommendation 1)	Wash hands thoroughly with soap and water and use hand disinfector gel before starting the cleaning process.
	Gloves should be worn by healthcare professionals with hand hygiene performed after removal of gloves (recommendation 1)
Disconnect nebuliser from the compressor unit and dissemble into constituent components (recommendation 11)	Disconnect nebuliser from the compressor unit and dissemble into constituent components (recommendation 11)
Washing Wash nebuliser components in a solution of warm tap water (recommendation 12) and dishwashing liquid in accordance with the detergent manufacturer's guidance (recommendation 14)	Washing Wash nebuliser components in a solution of warm tap water (recommendation 12) and dishwashing liquid in accordance with the detergent manufacturer's guidance (recommendation 14)
Location Do not wash nebuliser parts directly in kitchen or bathroom sinks (recommendation 8) or the dishwasher (recommendation 9) This should be done in a dedicated plastic, glass or metal bowl in the patients' kitchen (recommendation 10)	Location This should be done in a disposable bowl, metal bowl or basin (not directly in a sink; recommendation 5) in the patients' room (recommendation 6)
Rinsing Sterile water must be used during a final rinse when immediate disinfection is not possible (recommendation 13)	Rinsing Sterile water must be used during a final rinse, when immediate disinfection is not possible (recommendation 13).
Disposal of waste water Disposal of waste water should be via the toilet, ensuring the toilet lid is closed prior to flushing (recommendation 17)	Disposal of waste water Metal bowl and waste water should be sent to the ward sluice (recommendation 15). Waste water should be disposed of here and the metal bowl should be sterilised by autoclaving (Recommendation 16).
Disinfection Washed and rinsed nebulisers should be disinfected after each use (recommendation 7) using an electric baby bottle steam disinfector, (recommendation 18)	Disinfection Washed and rinsed nebulisers should be disinfected immediately after each use (recommendation 7) using an electric baby bottle steam disinfector (recommendation 18), or reusable nebulisers may be autoclaved, where the nebuliser manufacturer states that the device can be safely autoclaved (recommendation 19)
Storage Leave the disinfected nebuliser parts undisturbed in the disinfector until the next use (within 24 h) Should the parts be disturbed (i.e. lid lifted off for any reason) then the disinfection process should be repeated and the parts left undisturbed until the next use (within 24 h) (recommendation 20)	Storage Leave the disinfected nebuliser parts undisturbed in the disinfector until the next use (within 24 h) Should the parts be disturbed (i.e. lid lifted off for any reason) then the disinfection process should be repeated and the parts left undisturbed until the next use (within 24 h) (recommendation 20)
After disinfection Wash hands thoroughly with soap and water, and use hand disinfector gel after the cleaning and disinfection process prior to reassembling the nebuliser device (recommendation 1)	After disinfection Wash hands thoroughly with soap and water, and use hand disinfector gel after the cleaning and disinfection process prior to reassembling the nebuliser device (recommendation 1)

Supplementary Material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Figure S1 EDU-0328-2019.figureS1
Table S1 EDU-0328-2019.tableS1
Table S2 EDU-0328-2019.tableS2