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Background: The management of recalcitrant chronic rhinosinusitis (CRS) is challenged by difficult-to-treat polymicrobial biofilms and multidrug resistant bacteria. This has led to the search for broad-spectrum non-antibiotic antimicrobial therapies. Colloidal silver (CS) has significant antibiofilm activity in vitro and in vivo against S. aureus, MRSA, and P. aeruginosa. However, due to the lack of scientific efficacy, it is only currently used as an alternative medicine. This is the first study looking at the safety and efficacy of CS in recalcitrant CRS. Methods: Patients were included when they had previously undergone endoscopic sinus surgery and presented with signs and symptoms of sinus infection with positive bacterial cultures. Twenty-two patients completed the study. Patients were allocated to 10–14 days of culture directed oral antibiotics with twice daily saline rinses (n = 11) or 10 days of twice daily 0.015 mg/mL CS rinses (n = 11). Safety observations included pre- and post-treatment serum silver levels, University of Pennsylvania Smell Identification Test (UPSIT) and adverse event (AE) reporting. Efficacy was assessed comparing microbiology results, Lund Kennedy Scores (LKS) and symptom scores using Visual Analog Scale (VAS) and Sino-Nasal Outcome Test (SNOT-22). Results: CS demonstrated good safety profile with no major adverse events, no changes in UPSIT and transient serum silver level changes in 4 patients. CS patients had 1/11 (9.09%) negative cultures, compared to 2/11 (18.18%) in the control group upon completion of the study. Whilst not statistically significant, both groups showed similar improvement in symptoms and endoscopic scores. Conclusion: This study concludes that twice daily CS (0.015 mg/mL) sinonasal rinses for 10 days is safe but not superior to culture-directed oral antibiotics. Further studies including more patients and looking at longer treatment or improving the tonicity of the solution for better tolerability should be explored.
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ORIGINAL RESEARCH
published: 11 April 2018
doi: 10.3389/fmicb.2018.00720
Frontiers in Microbiology | www.frontiersin.org 1April 2018 | Volume 9 | Article 720
Edited by:
Maria Olivia Pereira,
University of Minho, Portugal
Reviewed by:
Debora Barros Barbosa,
São Paulo State University-UNESP,
Brazil
Massimo Triggiani,
Università degli Studi di Salerno, Italy
*Correspondence:
Peter-John Wormald
peterj.wormald@adelaide.edu.au
Specialty section:
This article was submitted to
Antimicrobials, Resistance and
Chemotherapy,
a section of the journal
Frontiers in Microbiology
Received: 03 December 2017
Accepted: 27 March 2018
Published: 11 April 2018
Citation:
Ooi ML, Richter K, Bennett C,
Macias-Valle L, Vreugde S, Psaltis AJ
and Wormald P-J (2018) Topical
Colloidal Silver for the Treatment of
Recalcitrant Chronic Rhinosinusitis.
Front. Microbiol. 9:720.
doi: 10.3389/fmicb.2018.00720
Topical Colloidal Silver for the
Treatment of Recalcitrant Chronic
Rhinosinusitis
Mian L. Ooi 1, Katharina Richter 1,2 , Catherine Bennett 1, Luis Macias-Valle 1,3,
Sarah Vreugde 1, Alkis J. Psaltis 1and Peter-John Wormald 1
*
1Department of Surgery-Otolaryngology, Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research,
The University of Adelaide, Adelaide, SA, Australia, 2Adelaide Biofilm Test Facility, Sansom Institute for Health Research,
University of South Australia, Adelaide, SA, Australia, 3Facultad Mexicana de Medicina Universidad La Salle, Department of
Otolaryngology Head and Neck Surgery, Spanish Hospital of Mexico, Granada, Mexico
Background: The management of recalcitrant chronic rhinosinusitis (CRS) is challenged
by difficult-to-treat polymicrobial biofilms and multidrug resistant bacteria. This has led
to the search for broad-spectrum non-antibiotic antimicrobial therapies. Colloidal silver
(CS) has significant antibiofilm activity in vitro and in vivo against S. aureus,MRSA, and
P. aeruginosa. However, due to the lack of scientific efficacy, it is only currently used as
an alternative medicine. This is the first study looking at the safety and efficacy of CS in
recalcitrant CRS.
Methods: Patients were included when they had previously undergone endoscopic
sinus surgery and presented with signs and symptoms of sinus infection with positive
bacterial cultures. Twenty-two patients completed the study. Patients were allocated to
10–14 days of culture directed oral antibiotics with twice daily saline rinses (n=11)
or 10 days of twice daily 0.015 mg/mL CS rinses (n=11). Safety observations
included pre- and post-treatment serum silver levels, University of Pennsylvania Smell
Identification Test (UPSIT) and adverse event (AE) reporting. Efficacy was assessed
comparing microbiology results, Lund Kennedy Scores (LKS) and symptom scores using
Visual Analog Scale (VAS) and Sino-Nasal Outcome Test (SNOT-22).
Results: CS demonstrated good safety profile with no major adverse events, no
changes in UPSIT and transient serum silver level changes in 4 patients. CS patients
had 1/11 (9.09%) negative cultures, compared to 2/11 (18.18%) in the control group
upon completion of the study. Whilst not statistically significant, both groups showed
similar improvement in symptoms and endoscopic scores.
Conclusion: This study concludes that twice daily CS (0.015 mg/mL) sinonasal rinses
for 10 days is safe but not superior to culture-directed oral antibiotics. Further studies
including more patients and looking at longer treatment or improving the tonicity of the
solution for better tolerability should be explored.
Keywords: chronic rhinosinusitis, recalcitrant, infection, antimicrobial, topical agent, safety, efficacy
Ooi et al. Colloidal Silver in Recalcitrant Chronic Sinusitis
INTRODUCTION
The management of recalcitrant chronic rhinosinusitis (CRS)
is increasingly challenged by difficult-to-treat polymicrobial
biofilms and multidrug resistant bacteria which antibiotics often
cannot effectively eradicate. For recalcitrant patients, antibiotics
often alleviate symptoms in acute exacerbations but fail to
eradicate the biofilm nidus which periodically sheds planktonic
organisms resulting in a relapsing and remitting course of
disease (Foreman et al., 2011). This has fuelled a continuous
search for broad-spectrum topical non-antibiotic anti-biofilm
therapies. Topical agents allow increased concentration, localized
action, less systemic side effects and lessen the risk of antibiotic
resistance.
To date, numerous topical agents have been tested and
although some have shown anti-biofilm activity (Chiu et al., 2008;
Le et al., 2008; Alandejani et al., 2009; Jardeleza et al., 2011; Jervis-
Bardy et al., 2012; Paramasivan et al., 2014; Richter et al., 2016,
2017a,b), none have been widely accepted as a treatment option
in recalcitrant CRS. Recent evidence suggests that colloidal
silver (CS) may be effective against bacterial biofilms. We have
previously shown that CS showed significant anti-biofilm activity
in vitro and in vivo against S. aureus (Goggin et al., 2014; Rajiv
et al., 2015), and against methicillin-resistant S. aureus (MRSA)
and P. aeruginosa biofilms. Spherical nanoparticles were also
shown to be non-toxic in human cell culture (THP-1, Nuli-1)
(Richter et al., 2017c) and safe in a sheep sinusitis model (Rajiv
et al., 2015). Moreover, they were physically stable for over 6
months in storage with no observed loss in anti-biofilm activity
(Richter et al., 2017c).
However, due to the lack of evidence for their efficacy, it is
only currently used as an alternative medicine. This is the first
study investigating the safety and efficacy of CS in recalcitrant
CRS patients.
METHODS AND MATERIALS
Participants and Study Design
This was a prospective, open-label, single-blinded, pilot study
looking at the safety and efficacy of CS sinonasal rinses in
patients with recalcitrant CRS between December 2016 to July
2017. Ethics approval was granted by the Central Northern
Adelaide Health Service, Ethics of Human Research Committee
(TQEH/LMH/MH HREC) to conduct the trial within its network
of teaching hospitals in Adelaide, Australia. All subjects gave
written informed consent in accordance with the Declaration of
Helsinki.
A total of 22 patients were enrolled in the study (8 females,
14 males, aged 27–86). Patients were allocated to either the
colloidal silver arm (CS) (n=11) or control arm (CON) (n=11)
depending on availability of silver stock and patient’s adverse
reaction to culture-sensitive oral antibiotics (Figure 1). Full
Abbreviations: CRS, chronic rhinosinusitis; INC, intranasal corticosteroid; CON,
control; CS, Colloidal Silver; VAS, Visual Analog Scale; SNOT-22, Sino-Nasal
Outcome Test-22; LKS, Lund Kennedy Scores; UPSIT, University of Pennsylvania
Smell Identification Test; AE, Adverse Event.
inclusion and exclusion criterias are outlined in Table 1. Baseline
demographic and clinical characteristic are demonstrated in
Table 2.
CS patients were provided with 20 sealed bottles of pre-
filled 120 mL CS solution in standard nasal irrigation squeeze
bottles. Patients were instructed to store these bottles away from
light and in the refrigerator. Prior to use, patients were asked
to warm the solution to room temperature, fill the rinse bottle
to 240 mL with cooled boiled water, then perform the rinses
twice daily for 10 days. Patients are to apply gentle pressure
onto squeeze bottles which delivers the solution through the
inner tube and out of the tip of the bottle into the nostril.
CS patients were specifically instructed not to add the usual
proprietary buffered salts sachets to avoid chemical interaction
with the CS nanoparticles. All squeeze bottles were provided by
NeilMed Pharmaceuticals (Santa Rosa, CA). If there were signs
of persistent infection on endoscopic examination and a positive
culture swab post-treatment, CS patients exited the study and
resumed treatment based on clinical grounds.
CON patients received a 10 to 14-day course of culture-
directed oral antibiotics and were instructed to perform twice
daily saline rinses similar to the delivery of CS. If the patient had
persistent infection on endoscopic examination and a positive
culture swab at the end of treatment, they received CS.
Those taking INCs on enrolment were instructed to continue
throughout the duration of the study.
Synthesis of Silver Nanoparticles
Spherical silver nanoparticles were prepared as previously
described (Richter et al., 2017c). Briefly, a mixture of 6.25 mL
water, 1.25 mL sodium citrate (1% wt.), 1.25 mL silver nitrate
(1% wt.) and 50 µl potassium iodide (300 µM) was prepared
under stirring at room temperature and incubated for 5 min. This
mixture was added to 237.5 mL of boiling water that included 250
µl ascorbic acid (0.1M). The colorless solution changed to yellow
and finally slightly orange, indicating particle formation. The
silver nanoparticles were further boiled for 1 h under reflux and
stirring at 1,500 rpm. After cooling, the silver nanoparticles were
characterized by UV-Vis spectrometry and transmission electron
microscopy (quality control). This confirmed a spherical particle
shape and size of approximately 40 nm. Silver nanoparticles were
stored in amber glass flasks under dark condition at 4C prior to
utilization as a nasal rinse.
Efficacy Assessment
Endoscopic guided sinonasal swabs were taken at every
scheduled visit for microbiological evaluation. All patients
completed symptoms score questionnaire at every visit, using
Sino-Nasal Outcome Test-22 (SNOT-22) (Kennedy et al., 2013)
(22 items, each scored from 0 to 5; total score range 0 to 110) and
Visual Analog Scale (VAS) (Walker and White, 2000) (average of
6 items and an overall symptom score; each scored from 0 to 100,
total score range 0 to 100). At each visit, all patients had entry and
exit endoscopic videos recorded and scored by a blinded surgeon
using the Lund Kennedy Score (LKS) (Lund and Kennedy, 1995;
Kennedy et al., 2013) (score range, 0–20).
Frontiers in Microbiology | www.frontiersin.org 2April 2018 | Volume 9 | Article 720
Ooi et al. Colloidal Silver in Recalcitrant Chronic Sinusitis
FIGURE 1 | Flow diagram describing patients allocated to (1) Culture-directed oral antibiotics with twice daily saline flush (CON) and (2) Colloidal silver (CS) with
twice-daily saline flush. CON, Control; CS, Colloidal silver.
TABLE 1 | Inclusion and exclusion criteria.
Inclusion Criteria Exclusion criteria
Ongoing symptoms of CRS despite at least
one trial of oral antibiotics
Allergy to silver
ESS >12 weeks prior to enrolment Antibiotics in previous 2 weeks
Positive bacterial microbiology swab Taking oral corticosteroids
Over 18 years of age AND able to give written
informed consent
Pregnant or breastfeeding
Willing to return to this center for postoperative
follow-up care
Immunocompromised
ESS, Endoscopic sinus surgery; CRS, Chronic rhinosinusitis.
Safety Assessment
All patients on CS treatment were required to have pre- and post-
treatment serum silver levels and completed the University of
Pennsylvania Smell Identification Test (UPSIT). If serum silver
level post-treatment was above normal limits, a repeat serum
silver level was performed 7 days later to confirm return to
baseline. Patients were advised to report any adverse outcomes
while on the study.
Data Analysis
Statistical power was calculated for the primary end-point
of culture negativity post-treatment. Power analysis estimates
determined a sample size of 11 patients per group would be
required to achieve statistical significance (80%, p<0.05) based
on response rates of 25 and 90% in the control and silver groups,
respectively.
All results were statistically analyzed at the completion of the
study using 2-way analysis of variance (ANOVA) and student’s
t-test, with a significance value set at p<0.05.
TABLE 2 | Baseline patient demographics and clinical characteristics.
CON (n=11) CS (n=11)
Age, year 61 (52–72) 60 (47–73)
Gender, male 7 (63.6%) 7 (63.6%)
History of polyposis 9 (81.82%) 8 (72.73%)
Frontal drillouts 7 (63.64%) 9 (81.82%)
Visual analog scale 38.29 (22.14–51.86) 49.72 (28.75–65)
SNOT-22 score 38.55 (23–59) 58.01 (43–75)
Lund-Kennedy score 6.82 (4–10) 8.57 (6–10)
Data are medians (interquartile range) or numbers (%). CON, Control; CS, Colloidal silver;
SNOT-22, Sino-Nasal Outcome Test-22.
RESULTS
Efficacy
Microbiology Result
2/11 (18.18%) patients in CON group had negative swabs while
1/11 (9.09%) CS patients had negative swabs upon completion of
treatment. List of pathogens treated in both cohorts are described
in Table 3.
Visual Analog Scale (VAS)
VAS scores in both CON and CS groups showed a similar trend
of improvement post-treatment, but both were not statistically
significant (CON 1.728 [95% CI 7.785 to 11.24] vs. CS 3.536
[95% CI 5.977 to 13.05]) (Figure 2).
Sino-Nasal Outcome Test22 (SNOT-22)
Patients in the CON group showed no change in SNOT-22
scores post- treatment while CS group showed a trend toward
an improvement in SNOT-22 scores, but it was not statistically
Frontiers in Microbiology | www.frontiersin.org 3April 2018 | Volume 9 | Article 720
Ooi et al. Colloidal Silver in Recalcitrant Chronic Sinusitis
TABLE 3 | Standard semi-quantitative analysis of bacterial load reported as scant, light, moderate or heavy (equivalent to 1+, 2+, 3+, or 4+) by laboratory.
Before colloidal silver After colloidal silver
Heavy MRSA +Light P. aeruginosa Heavy MRSA +Scant P. aeroginosa
Heavy S. aureus Moderate S. aureus
Heavy S. aureus +Heavy P. aeruginosa Moderate S. aureus +Moderate P. aeroginosa
Moderate S. aureus Light S. aureus +Light S. pneumoniae
Scant K. oxytoca, Scant H. influenza No growth
Heavy H. influenza Heavy S. aureus +Light E. cloacae +Light H. influenzae
Moderate K. oxytoca +Moderate P. aeruginosa Heavy K. oxytoca +Moderate P. aeruginosa
Light P. aeruginosa Moderate S. aureus
Heavy S. aureus Moderate S. aureus
Heavy S. aureus +Heavy P. aeruginosa Heavy S. aureus
Heavy S. aureus Heavy S. aureus +Moderate M. morganii
Before oral antibiotics Antibiotics After oral antibiotics After colloidal silver
Heavy S. aureus Augmentin DF Moderate P. aeruginosa +Heavy S. aureus Moderate S. pneumoniae +Moderate S. aureus
Moderate P. aeruginosa Ciprofloxacin Light P. stutzeri Withdrew due to other commitments
Heavy H. influenzae Bactrim DS No growth
Heavy S. aureus Augmentin DF Heavy S. maltophilia No growth
Moderate S. aureus Augmentin DF No growth
Heavy E. coli Augmentin DF Moderate E. coli Withdrew due to flush discomfort
Heavy S. aureus Cephalexin Moderate S. aureus +Light H. influenzae Withdrew due to lack of efficacy
Moderate S. aureus Augmentin DF Moderate S. aureus +Light H. influenzae Heavy S. aureus +Light E. coli
Moderate E. aerogenes Ciprofloxacin Moderate E. aerogenes +Scant S. aureus Withdrew due to due to external injury
Moderate S. pneumoniae +Scant S. aureus Augmentin DF Light S. aureus Light S. aureus
Moderate S. pneumoniae +Scant S. aureus Bactrim DS Moderate S. aureus +Scant Alternaria sp. Light S. aureus
P. aeruginosa, Pseudomonas aeruginosa; MRSA, Methicllin resistant staphylococcus aureus; S. aureus, Staphylococcus aureus; H. influenza, Haemophilus Influenzae; E. cloaca,
Enteroboacter cloacae; S. pneumonia, Streptococcus pneumonia; K. oxytoca, Klebsiella oxytoca; M. Morganii, Morganella Morganii; P. stutzeri, Pseudomonas stutzeri; S. maltophilia,
Stenotrophomonas maltophilia; E. coli, Escherichia coli; E. aerogenes, Enterobacter aerogenes.
FIGURE 2 | Bar graph showing no significant difference in VAS scores
between CON and CS treated groups. VAS, Visual Analog Scale; CON,
Control; CS, Colloidal silver.
significant (CON 0.6364 [95% CI 6.673 to 5.4] vs. CS 5.818
[95% CI 0.2183 to 11.85]) (Figure 3).
Lund Kennedy Score (LKS)
Both CON and CS group showed trends of similar improvements
in Lund Kennedy Scores but this was not statistically significant
(CON 1.818 [95% CI 1.373 to 5.009] vs. CS 2.167 [95% CI
2.154 to 6.488]) (Figure 4).
FIGURE 3 | Bar graph showing no change in SNOT-22 scores in CON group,
while CS group showed a trend of improved SNOT-22 scores, but not
statistically significant. SNOT-22, Sino-Nasal Outcome Test-22; CON, Control;
CS, Colloidal silver.
Subgroup Analyses: Crossover Silver Arm
Five patients completed the crossover CS arm after failing oral
antibiotics. Subgroup analyses were performed comparing VAS,
SNOT-22, and LKS scores of patients while on either treatment.
The mean score difference post antibiotic treatment vs. post CS
treatment were compared using Wilcoxon matched-pairs signed
rank tests. However, due to the small sample size of our subgroup
analyses, data presented is focused on describing observed trends.
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Ooi et al. Colloidal Silver in Recalcitrant Chronic Sinusitis
FIGURE 4 | Bar graph showing similar improvements in LKS in both CON and
CS groups, but not statistically significant. LKS, Lund Kennedy Scores; CON,
Control; CS, Colloidal silver.
Microbiology Result of Crossover arm
1/5 patient had successful infection eradication from CS
treatment after failing culture-sensitive oral antibiotics.
Visual Analog Scale (VAS) of Crossover Arm
There were slight improvements in VAS scores after culture
sensitive oral antibiotics and CS treatment. There was a trend
of greater improvement in VAS while on CS compared to when
patients were treated with culture sensitive oral antibiotics. It is
also observed that patients’ VAS scores appeared to return to
baseline after completing course of oral antibiotics and before
commencing CS which is consistent with what is observed in
clinical practice (Figure 5). Mean difference in VAS scores when
patients were on culture sensitive oral antibiotics 4.546 [95% CI
8.156 to 17.25] vs. CS treatment 5.94 [95% CI 3.347 to 15.23],
p=0.4750.
Sino-Nasal Outcome Test22 (SNOT-22) of
Crossover Arm
There were no changes in SNOT-22 scores after culture sensitive
oral antibiotics treatment but showed trends of improvement
when patients were crossed over to CS treatment (Figure 6).
Mean difference in SNOT-22 scores when patients were on
culture sensitive oral antibiotics 0.2 [95% CI 2.021 to 2.421] vs.
CS treatment 13 [95% CI 22.42 to 3.585], p=0.06.
Lund Kennedy Score (LKS) of Crossover Arm
Patients demonstrated an improvement in LKS post antibiotic
treatment and further improvements were observed after
completion of CS treatment (Figure 7). Mean difference in LKS
scores when patients were on culture sensitive oral antibiotics
2.8 [95% CI 7.311 to 1.711] vs. CS treatment 1.4 [95% CI
4.259 to 1.459], p=0.50.
Safety
Serum Silver Levels
Four patients who had received CS had serum silver levels that
were above normal limits measured within 24 h after receiving
final silver dose. 3 patients had a repeat test 10 days after
study exit which saw serum silver levels had returned to normal
parameters. One patient had serum silver levels which were above
normal ranges pre-treatment and on repeat test had returned to
FIGURE 5 | Bar graph comparing VAS scores of patients following failed
culture sensitive oral antibiotics and crossed-over to CS treatment. VAS, Visual
Analog Scale; CS. Colloidal silver.
baseline. Our laboratory reference indicates that argyria can be
present at serum silver levels of approximately 100 nmol/L, the
highest level of serum silver level recorded in our study was 57.3
nmol/L.
Smell Test
There were no significant changes in smell pre- and post-
treatment between both groups measured using the University
of Pennsylvania Smell Identification Test (UPSIT).
Adverse Events
There were no serious adverse events reported.
DISCUSSION
In this study, looking at the primary end-point of culture
negativity post-treatment, CS has not been shown to be superior
to culture-directed oral antibiotics. Although interesting to note,
CS patients had more severe baseline disease when compared to
CON, but demonstrated comparable improvement in subjective
symptoms and objective endoscopic scores suggesting it may
be more than just a placebo effect. It is possible that CS
treatment over 10 days is sufficient to demonstrate symptomatic
and endoscopic improvement but insufficient time to achieve
bacterial eradication. Indeed, when compared with topical
mupirocin rinses which have been one of the more successful
topical treatments for recalcitrant patients (Solares et al., 2006;
Uren et al., 2008; Jervis-Bardy and Wormald, 2012; Jervis-Bardy
et al., 2012; Seiberling et al., 2013), mupirocin has been used as a
twice-daily rinse over 3–4 weeks. We believe that this reflects the
duration of CS treatment needs to be further optimized. A longer
study period including a larger number of study participants
would be needed to assess the safety and efficacy of CS topical
application in these patients.
The spherical CS nanoparticles used in this study has been
shown to have substantial anti-biofilm activity in vitro with
96, 97, and 98% biofilm reduction of S. aureus, MRSA, and
P. aeruginosa respectively (Richter et al., 2017c). It has been
postulated that CS exerts its antimicrobial properties via multiple
mechanisms. It can act on bacterial cell membranes by disrupting
phosphate (Schreurs and Rosenberg, 1982) and sodium channels
(Semeykina and Skulachev, 1990), inhibits mitochondrial ATPase
Frontiers in Microbiology | www.frontiersin.org 5April 2018 | Volume 9 | Article 720
Ooi et al. Colloidal Silver in Recalcitrant Chronic Sinusitis
FIGURE 6 | Bar graph comparing SNOT-22 scores of patients following failed
culture sensitive oral antibiotics and crossed-over to CS treatment. SNOT-22,
Sino-Nasal Outcome Test-22; CS, Colloidal silver.
FIGURE 7 | Bar graph comparing LKS scores of patients following failed
culture sensitive oral antibiotics and crossed-over to CS treatment. LKS, Lund
Kennedy Scores; CS, Colloidal silver.
(Chappell and Greville, 1954) and interacts with bacterial DNA to
form dissociable complexes (Rosenkranz and Rosenkranz, 1972;
Modak and Fox Jr., 1973).
Some immunomodulatory functions of CS have also been
observed in the literature. It has the ability to inhibit matrix
metalloproteinases (MMPs) which is pro-inflammatory (Wright
et al., 2002) and metallothionein (Wright et al., 2002) (MT) which
promotes resistance to immune-mediated apoptosis (Dutsch-
Wicherek et al., 2006). Both MTs and MMPs have been found at
increased levels in patient with CRS with nasal polyps (CRSwNP)
(Wicherek et al., 2007; Eisenberg et al., 2008; Sauter et al., 2008).
CS has also been shown to induce inflammatory cells apoptosis
by TNF-αand IL-12 suppression (Bhol and Schechter, 2005). An
improved host response might be able to account for the efficacy
observed in the CS cohort even though there was no eradication
of bacteria.
However, one of the limitations of this study is the time-
consuming process of manufacturing CS rinses using small scale
equipment. Currently, to prepare sufficient CS for a 10-day
treatment course a full-time laboratory personnel requires over
10–15 h. If production cannot be upscaled, CS could be evaluated
as an adjunct to oral antibiotics.
In the literature, silver has been described to exhibit low
toxicity with minimal risks expected from clinical exposure.
Silver is absorbed into the systemic circulation as a protein
complex and eliminated by the liver and kidneys (Lansdown,
2006). Prolonged silver exposure commonly associated with
occupational and/or systemic administration can lead to
deposition of silver particles in skin (argyria), eye (argyrosis), and
other organs (Tomi et al., 2004). Argyria is a cosmetic concern
with irreversible blue-gray skin discoloration in sun-exposed
areas, but not life-threatening.
Reported cases of silver toxicity are limited. In the literature,
very little data exists correlating serum silver levels with
symptomatic presentation of argyria and at present there are
no medical guidelines available regarding its use. The World
Health Organisation reported that a person can have a total
lifetime oral intake of approximately 10 g of silver with no
observed adverse effects (World Health Organisation, 1996). The
United States Environmental Protection Agency’s has reported
that a maximum acceptable oral dose of silver to be 0.005
mg/kg/day or about 0.35 mg for a 70 kg person a day, every
day during their lifetime (Fung and Bowen, 1996). In this study
patients will be exposed to a total of 72 mg of topical CS rinses,
which is well under the total lifetime amount of 10 g and to an
equivalent of 7.2 mg/day of topical silver treatment for 10 days.
Our laboratory reference of serum silver levels indicates argyria
could be present when serum silver levels exceed 100 nmol/L.
The serum silver levels were well below this concentration and
no symptoms of argyria were observed in any patient of this
study.
Although this study has shown that CS is safe based on serum
silver levels and smell tests, the discomfort of using CS rinses
have been noted. This discomfort is likely due to the tonicity
and temperature of the rinses and possible stinging properties
from silver. To improve the tonicity of the rinse solution for
better tolerability, we are currently looking at mixing CS with 5%
dextrose isotonic solution.
CONCLUSION
This study concludes that twice daily CS (0.015 mg/mL) sinonasal
rinses for 10 days is safe but not superior to culture-directed oral
antibiotics. Future studies looking at optimizing the tolerability,
duration of treatment and investigating the role of CS as an
adjunct treatment to oral antibiotics should be explored and
evaluated in a randomized, double-blinded, placebo-controlled
trial.
AUTHOR CONTRIBUTIONS
MO: project design, data collection and analysis, manuscript
preparation; KR: project design, product manufacture and
quality control, manuscript preparation; CB: product
manufacture and quality control; LM-V: data analysis; AP
project design, manuscript preparation; SV: project design,
manuscript preparation; P-JW: project design, manuscript
preparation.
FUNDING
The University of Adelaide, School of Medicine, Department of
Otolaryngology Head and Neck Surgery, Adelaide, SA, Australia.
Frontiers in Microbiology | www.frontiersin.org 6April 2018 | Volume 9 | Article 720
Ooi et al. Colloidal Silver in Recalcitrant Chronic Sinusitis
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10308.x
Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2018 Ooi, Richter, Bennett, Macias-Valle, Vreugde, Psaltis and
Wormald. This is an open-access article distributed under the terms of the Creative
Commons Attribution License (CC BY). The use, distribution or reproduction in
other forums is permitted, provided the original author(s) and the copyright owner
are credited and that the original publication in this journal is cited, in accordance
with accepted academic practice. No use, distribution or reproduction is permitted
which does not comply with these terms.
Frontiers in Microbiology | www.frontiersin.org 7April 2018 | Volume 9 | Article 720
... With twice-daily colloidal silver sinus rinses for 10 days, there were at best nonsignificant trends towards improvement in a visual-analogue scale and Lund Kennedy and SNOT-22 scores. No adverse effects were identified, though four of eleven patients in the colloidal silver arm had elevated serum silver which normalised upon cessation of treatment (Ooi et al., 2018a). ...
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The role of bacterial biofilms in chronic and recalcitrant diseases is widely appreciated, and the treatment of biofilm infection is an increasingly important area of research. Chronic rhinosinusitis (CRS) is a complex disease associated with sinonasal dysbiosis and the presence of bacterial biofilms. While most biofilm-related diseases are associated with highly persistent but relatively less severe inflammation, the presence of biofilms in CRS is associated with greater severity of inflammation and recalcitrance despite appropriate treatment. Oral antibiotics are commonly used to treat CRS but they are often ineffective, due to poor penetration of the sinonasal mucosa and the inherently antibiotic resistant nature of bacteria in biofilms. Topical non-antibiotic antibiofilm agents may prove more effective, but few such agents are available for sinonasal application. We review compounds with antibiofilm activity that may be useful for treating biofilm-associated CRS, including halogen-based compounds, quaternary ammonium compounds and derivatives, biguanides, antimicrobial peptides, chelating agents and natural products. These include preparations that are currently available and those still in development. For each compound, antibiofilm efficacy, mechanism of action, and toxicity as it relates to sinonasal application are summarised. We highlight the antibiofilm agents that we believe hold the greatest promise for the treatment of biofilm-associated CRS in order to inform future research on the management of this difficult condition.
... The discovery of antibiotics in the early 20 th century led to a cessation in the development of silver as an antimicrobial agent. However, the development of increasing levels of bacterial resistance to most antibiotics in recent years has led to re-examination of the potential of this ancient remedy [20] including studies with patients using colloidal silver and antibiotics [21] . ...
... 13 For example, colloidal Ag nasal spray is used to treat rhinitis. 14 The employment of Ag-containing products may lead to intentional or unintentional human exposure to silver NPs (AgNPs) or Ag + and may have adverse effects on human health. 15−17 Longterm use (months to years) of colloidal Ag products, even as directed, has been reported to result in argyria. ...
... Ooi et al. 13 performed a single-blinded pilot study comparing colloidal silver sinonasal irrigation with saline irrigation and 10-14 days of culture-directed oral antibiotics. While treatment with colloidal silver showed a trend toward SNOT-22 score improvement after 10 days of twice daily washes, this change was not statistically significant (colloidal silver, −5.8 (95 per cent CI: −0.2 to +11.9) vs control, -0.6 (95 per cent CI: −6.7 to +5.40)). ...
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Objective Chronic rhinosinusitis patients with biofilms cultured from their sinonasal cavity have greater symptom burden and risk of recalcitrant disease. A number of non-antibiotic, ‘anti-biofilm’ treatments exist which show anti-biofilm properties in preclinical studies. There is little evidence evaluating their impact on clinical symptom scores in chronic rhinosinusitis. Method A systematic review was performed to assess the literature regarding the efficacy of non-steroid, non-antibiotic, anti-biofilm specific topical therapies in the treatment of chronic rhinosinusitis. The primary outcome assessed was change in validated patient reported outcome measures before and after anti-biofilm treatment. Results Thirteen studies assessing the effect of anti-biofilm therapies in chronic rhinosinusitis through validated patient-reported outcome measures were included. Seven different anti-biofilm specific therapies for chronic rhinosinusitis were identified. None of the seven anti-biofilm therapies was identified as being confidently efficacious beyond placebo. Only one therapy (intranasal xylitol) showed a statistically significant reduction in symptom scores compared with placebo in more than one trial. Conclusion Robust evidence supporting the use of various anti-biofilm therapies in chronic rhinosinusitis is lacking. Further high quality, human, in vivo trials studying the effect of anti-biofilm therapies in chronic rhinosinusitis are needed to address the deficiencies of the current evidence base.
... The suspension of submicroscopic silver particles does not directly attack bacteria but leads to the inactivation of enzymes responsible for bacterial respiration, reproduction, and metabolism by forming homo-base pairs with guanine, targeting sulfhydryl group to form S-silver bonds, and mediating membrane alteration [62]. Ooi et al. [63] used a mixture of water, sodium citrate, silver nitrate, and potassium iodide to prepare CS and treated patients with CRS through CS nasal irrigation. Although the Sino-Nasal Outcome Test (SNOT-22) scores and endoscopic scores were improved, they were not better than those of the antibiotic treatment group. ...
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Chronic rhinosinusitis is an upper respiratory disease during which topical drug treatment via the nasal cavity is the most actively utilized therapeutic strategy. In addition to steroids, antibiotics, and antifungal agents, which are widely used in clinical practice, research on novel topical agents to improve the bacterial biofilm or mucociliary clearance remains ongoing. Moreover, owing to the complex structure of the nasal cavity, the effects of nasal drug delivery vary depending on factors related to delivery fluid dynamics, including device, volume, and compounds. In this article, we review methods and compounds that have been applied to chronic rhinosinusitis management and introduce recent advances and future perspectives in nasal drug delivery for upper respiratory diseases.
... Of note, colloidal silver was reported to treat biofilm-related infections by S. aureus [15], methicillin-resistant S. aureus, and P. aeruginosa in vitro and in vivo in a model of Caenorhabditis elegans [16]. In clinical settings, colloidal silver was used topically for treatment of recalcitrant chronic rhinosinusitis, and it demonstrated a good safety profile with no major adverse events [17]. ...
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Due to the emergence of antimicrobial resistance, new alternative therapies are needed. Silver was used to treat bacterial infections since antiquity due to its known antimicrobial properties. Here, we aimed to evaluate the in vitro activity of colloidal silver (CS) against multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria. A total of 270 strains (Acinetobacter baumannii (n = 45), Pseudomonas aeruginosa (n = 25), Escherichia coli (n = 79), Klebsiella pneumoniae (n = 58)], Staphylococcus aureus (n = 34), Staphylococcus epidermidis (n = 14), and Enterococcus species (n = 15)) were used. The minimal inhibitory concentration (MIC) of CS was determined for all strains by using microdilution assay, and time–kill curve assays of representative reference and MDR strains of these bacteria were performed. Membrane permeation and bacterial reactive oxygen species (ROS) production were determined in presence of CS. CS MIC90 was 4–8 mg/L for all strains. CS was bactericidal, during 24 h, at 1× and 2× MIC against Gram-negative bacteria, and at 2× MIC against Gram-positive bacteria, and it did not affect their membrane permeabilization. Furthermore, we found that CS significantly increased the ROS production in Gram-negative with respect to Gram-positive bacteria at 24 h of incubation. Altogether, these results suggest that CS could be an effective treatment for infections caused by MDR Gram-negative and Gram-positive bacteria.
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Background Treatment of recalcitrant chronic rhinosinusitis (CRS) is a challenge with increasing antibiotic resistance, leading to re-emergence of topical therapies. The aim of this study was to assess safety and efficacy of topical colloidal silver solution for the treatment of Staphylococcus aureus biofilms in a sheep model.Methods In the safety study, normal saline (control) and 30-ppm colloidal silver solution (test) was used to flush the frontal sinuses for 14 days in 8 sheep (4 sheep each). In the efficacy study, following frontal sinus infection with Staphylococcus aureus, sheep were treated with either control saline or topical silver solution of varying concentrations (30 ppm/20 ppm/10 ppm/5 ppm) for 5 days, with 4 sheep in each group. Blood silver level, full blood counts, and biochemical parameters were analyzed in both safety and efficacy studies. Sinus tissue was harvested for histological examination and ciliary structure analysis in safety and for biofilm biomass quantification by fluorescence in situ hybridization (FISH) technique and COMSTAT 2 software in the efficacy study. Results were analyzed using appropriate statistical tests.ResultsSheep treated with silver showed a significant decrease in biofilm biomass (0.004, 0.004, 0.004, and 0.007, in the 4 silver-treated groups, respectively) compared to saline control (0.175), p < 0.001. Although average blood silver levels were higher in the treated groups compared to controls (p < 0.05), blood counts and biochemical parameters were normal. Histology and ciliary structure analysis did not show any difference between control and treatment groups.Conclusion Topical colloidal silver solution has effective antibiofilm activity in Staphylococcus aureus CRS in a sheep model and appears safe.
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Colloidal silver is an alternative medicine consisting of silver particles suspended in water. After using this solution as a nasal spray, the symptoms of a previously recalcitrant Staphylococcus aureus (S. aureus)-infected chronic rhinosinusitis patient were observed to have improved markedly. The aim of this study was to determine whether colloidal silver has any direct bactericidal effects on these biofilms in vitro. S. aureus biofilms were grown from the ATCC 25923 reference strain on Minimum Biofilm Eradication Concentration (MBEC) device pegs, and treated with colloidal silver. Concentrations tested ranged from 10 to 150 μL colloidal silver diluted to 200 μL with sterile water in 50 μL cerebrospinal fluid (CSF) broth. Control pegs were exposed to equivalent volumes of CSF broth and sterile water. The sample size was 4 biomass values per treatment or control group. Confocal scanning laser microscopy and COMSTAT software were used to quantify biofilms 24 hours after treatment. Significant differences from control were found for all concentrations tested bar the lowest of 10 μL colloidal silver in 200 μL. At 20 μL colloidal silver, the reduction in biomass was 98.9% (mean difference between control and treatment = -4.0317 μm(3) /μm(2) , p < 0.0001). A maximum biomass reduction of 99.8% was reached at both 100 and 150 μL colloidal silver (mean differences = -4.0681 and -4.0675μm(3) /μm(2) , respectively, p < 0.0001). Colloidal silver directly attenuates in vitro S. aureus biofilms.
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Bacterial biofilms are thought to contribute to recalcitrance in chronic rhinosinusitis (CRS) patients. Manuka honey (MH) and its active component methylglyoxal (MGO) have demonstrated antibiofilm activity in vitro. This study evaluated the safety and efficacy of these agents in an in vivo model. To assess safety, ovine frontal sinuses were flushed twice daily for 14 days. In each sheep, 1 sinus was flushed with a panel of MGO concentrations ranging from 0.5 to 7.2 mg/mL alone and flushed with a panel of with 16.5% wt/vol MH enriched with MGO at the same range of concentrations (0.5-7.2 mg/mL; designated MH/MGO). Contralateral sinuses were flushed with saline control. Tissue morphology was assessed histologically and with scanning electron microscopy. Efficacy was tested by developing Staphylococcus aureus biofilms in sheep sinuses. Twice-daily irrigation for 5 days was commenced with either saline, MGO (0.5-3.6 mg/mL) alone, or MH/MGO (with 0.5-3.6 mg/mL MGO). Biofilm biomass was compared between the groups (n = 4) using LIVE/DEAD BacLight staining and confocal scanning laser microscopy. The results of the safety assessment, for normal sinuses treated with MGO alone or with MH/MGO (≤1.8 mg/mL) showed normal pseudostratified epithelium and cilia structure; however, higher concentrations caused cilia denudation and squamous metaplasia. As for efficacy, when compared to saline flush, treatment with MH/MGO at 0.9 mg/mL (0.608 ± 0.110 vs 0.316 ± 0.197 μm(3) /μm(2) , respectively; p = 0.015) and 1.8 mg/mL (0.676 ± 0.079 vs 0.114 ± 0.033 μm(3) /μm(2) , respectively; p = 0.001) significantly reduced biofilm biomass. Sinus irrigation with MH/MGO at MGO concentrations between 0.9 and 1.8 mg/mL is both safe to mucosa and efficacious against S. aureus biofilm. MH/MGO irrigation could represent a viable treatment option for recalcitrant CRS.
Article
A number of factors are critical when considering the expected benefit of surgical intervention in patients with chronic rhinosinusitis (CRS) who have failed medical therapy. To evaluate the Sino-nasal Outcome Test (SNOT-22) and other patient demographic characteristics as predictors of postsurgical improvement in patients with CRS. Consecutive adult subjects presenting to the Otolaryngology Clinics at the University of Virginia with refractory CRS that required surgery were included. Patients were excluded if they had not completed both preoperative and postoperative SNOT-22 evaluations. Demographic and baseline measures, including asthma and smoking status, total immunuglobulin E (IgE), absolute eosinophil counts, and Lund-Mackay computed tomography (CT) scoring were also obtained for each subject. Regression analyses were performed. One hundred four subjects met criteria and were included. These subjects showed a 51% overall improvement in postsurgical SNOT-22 evaluations (95% confidence interval [CI]: [45, 57%], P < .001). Multivariate regression analysis revealed that SNOT-22 items related to "runny nose," "cough," and "sadness" were independent predictors of postsurgical SNOT-22 improvement (P < .05, for all). Although "runny nose" had a direct correlation with improvement, more severe "sadness" and "cough" scores had a negative impact on degree of improvement. Similarly, analyses indicated that questions categorized as pertaining to nasal or ear symptoms were uniquely associated with postsurgical improvement in SNOT-22 scores (P < .001 and P = .015, respectively). Neither Lund-Mackay CT scoring, total IgE, nor absolute eosinophil counts correlated with improvement in postsurgical SNOT-22 scores. Physicians can use components of the SNOT-22 to predict likelihood of symptom improvement after surgical intervention in subjects with CRS.
Introduction Matrix metalloproteinases (MMP) are a family of endopeptidases involved in extracellular matrix degradation and which could potentially explain specific histological changes in nasal polyposis. The aim of this study is to determine whether MMP-2 and 9 are involved in chronic rhinosinusitis with polyposis. Material and method Specimens were collected from 15 patients affected by nasal polyposis and 15 control patients (with turbinoplasty performed). Specimens were processed for determination of protein expression levels by Western-blot and for determination of their enzymatic activity by zymography for both MMPs. Results Results showed a higher expression and activity of MMP-9 but not of MMP-2 in specimens from patients with polyposis when compared with controls. Conclusions These results support the involvement of MMP-9 in the tissue remodelling characteristic of this disease.