Technological advancements in the
fight against antimicrobial resistance
Authors:
xxxxx
Authors:
Valerie EdwardsJones, Madeleine
Flanagan,
Randall Wolcott
Intro
Over-prescription and misuse of antibiotics has contributed to the global crisis of
antimicrobial resistance (AMR)[1]. In order to manage this growing crisis, it is crucial that
new technologies and techniques are developed to deal with infection. Infection in
chronic wounds is a common problem, which is often targeted ineffectively by antibiotics.
In addition, biofilms in chronic wounds contribute to prolonged morbidity. There are
now alternative means of fighting infection and biofilms in chronic wounds with topical
antimicrobials rather than systemic antibiotics. Wound irrigation with a topical antimicrobial
is an effective technique that should be used to prevent and combat biofilms and potential
infection, as well as promote healing, without contributing to the growing AMR crisis.
A
Valerie Edwards-Jones is
Emeritus Professor of Medical
Microbiology, Manchester
Metropolitan University, UK; Clinical
Director, MelBec Microbiology Ltd
Madeleine Flanagan is
Principal Lecturer, Postgraduate
Medicine, School of Life and
Medical Sciences, University of
Hertfordshire, UK
Randall D. Wolcott is
Medical Director, Southwest
Regional Wound Care Center,
Lubbock, Texas, USA
ntibiotic or antimicrobial resistance
(AMR) poses a ‘catastrophic threat’[2]. The
Department of Health has issued a UK
Antimicrobial Resistance Strategy, which sets
out how it will meet this growing challenge[3].
The strategy states: ‘There are few public health
issues of greater importance than antimicrobial
resistance in terms of impact on society.’
The wide availability of antibiotics has
contributed to misuse and overuse, allowing
bacteria to develop resistance mechanisms. The
UK’s Department of Health (DH)[3] and World
Health Organization[1] have both warned of the
serious dangers of multi-resistant ‘superbugs’
continuing to develop if interventions are not
put into place to combat the rising levels of
AMR. There is serious concern that the rising
prevalence of multiply-antibiotic resistant
bacteria will result in a post-antibiotic era,
where previously treatable infections (e.g.
infections in chronic wounds) will become
untreatable — resulting in dramatically rising
death levels. Professor John Watson, deputy
chief medical officer at the DH in the UK, said:
‘Antimicrobial resistance is one of the biggest
threats to health security facing the world
today and everybody must take action’[2]
— recommendations that are reflected in
international policy[4].
Antibiotic-resistant bacteria are responsible
for 5,000 deaths per year in the UK, and levels
are rising alarmingly —10 million people will die
due to antibiotic resistance by 2050 if no new
advancements are made[2]. Furthermore, the
Department of Health strategy stated: ‘Coupled to
this, the development pipeline for new antibiotics
is at an all-time low... The process of developing
new antimicrobials and new technologies to allow
quicker diagnosis and facilitate targeted treatment
must be accelerated[3].’
In wound management (whether acute or
chronic wounds), it is crucial to assess and diagnose
infection correctly, and to use products and
techniques that do not contribute to the growing
problem of AMR[5]. Therefore, where possible,
infection in wounds should be managed locally
rather than systemically. In chronic wounds,
where there may be large numbers of bacteria
in the wound without overt signs of infection
(colonisation), it is important that antibiotics are
not used and the reduction in colonisation is
managed locally, through wound cleansing and
debridement regimens.
Chronic wounds and infection
Infection is one of the most common complications
in chronic wounds, and also delays healing
further[6]. Diagnosing and treating an infection
in a chronic wound is often more complex than
in an acute wound, as acute wounds are more
likely to display classic symptoms of infection[5].
Correct diagnosis and appropriate management
of bacterial infection in chronic wounds remains a
major challenge.
Wound colonisation and biofilm
When a microbe attaches to the wound bed,
biofilm begins to form — a complex structure of
microorganisms that forms a thick, slimy barrier
to protect bacteria and block the penetration of
antibodies and other immune responses[7]. Biofilms
may consist of a single or multiple bacterial species,
and in chronic wounds where biofilm is present,
the likelihood of systemic antibiotics working is
very low for several reasons[8], including inability of
the antibiotic to penetrate through the biofilm. In
one study using electron microscopy, biofilm was
identified in 60% of chronic wounds[9]. Bacteria exist
in two states within biofilms: those that are firmly
attached to the surface or the matrix (sessile state),
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or those that are free floating (not attached) and
capable of invading further tissue (planktonic state).
As well as protecting bacteria, biofilm presence
also delays healing by promoting responses such as
inflammation and increased exudate[7]. In chronic
wounds where biofilm has formed, bacteria play
a critical role in the failure of the wound to heal,
but the wound may not show obvious signs of
infection[10], as the bacteria within the biofilm may
not be activating the immune system. In addition,
a bacterial species behaves differently within a
biofilm, and regulation of bacterial growth and
toxin production is greatly affected.
Although early identification and treatment of a
biofilm in a wound can increase healing rates and
improve patient wellbeing, they are microscopic
structures and difficult to identify with the naked
eye[11]. However, biofilm presence may be indicated
by factors including the following[12]:
■■ Failure to close or progress to healing despite
appropriate therapy
■■ Exudate and malodour
■■ Shiny, slimy wound surface
■■ Persistent necrotic tissue
■■ Persistent slough.
Biofilms start to form quickly (within two
to four hours) and evolve into a fully mature
community within two to four days; they recover
rapidly from mechanical disruption and reform
within 24 hours[13]. Therefore, chronic wounds
that fail to heal and become static, or those
that become infected, need to be treated using
multiple approaches to promote healing and
manage infection. Treatments include:
■■ Wound cleansing/irrigation
■■ Debridement
■■ Antimicrobial soaks/washes
■■ Topical antimicrobials.
The role of wound cleansing/irrigation
Biofilm-based wound care involves breaking up
the biofilm and preventing its redevelopment;
targeting biofilms through wound cleansing is an
important method in managing chronic wounds
and preventing infection[7].
Wound cleansing is defined as the removal
of ‘surface contaminants, loose debris, slough,
softened necrosis, microbes and/or remnants
of previous dressings from the wound surface
and its surrounding skin’[14]. Wound cleansing
assists wound bed preparation by removing
loose material to create optimum conditions
for healing.
Cleansing and preparing the wound bed is
one of the key steps in assessing the wound
and selecting appropriate treatment [Figure 1]
48
for a best practice decision-making algorithm),
using the TIME principle. The TIME principle in
wound healing involves: tissue management
(T); reducing infection and inflammation (I);
maintaining moisture levels (M); encouraging
epithelialisation of the wound edge (E)[15].
The preferred method of wound cleansing is
irrigation, which clears the wound of debris and
microbes, while avoiding wound bed trauma[14]
[Box 1].
Box 1. Tips for wound irrigation.
■■ The choice of solution should be based on both
examination of the wound and a holistic assessment
of the patient
■■ When delivering irrigation, consider the patient’s needs
and the wound itself, taking into account factors such as
levels of pain experienced and general skin fragility
■■ Irrigation solution volumes of 50–100 ml per centimetre
of wound length is the standard rule
■■ To prevent cross-contamination, the clinician should
wear personal protective equipment and make sure not
to use solution that has been opened for longer than
24 hours
■■ For the patient’s comfort, make sure that irrigation is at
room temperature or slightly warmer. Use analgesia for
painful wounds
■■ Position the patient so that the solution runs from the
upper end of the wound downward (unless the upper
end is heavily infected and the lower end is cleaner),
into a clean basin or irrigating pouch
■■ Record all aspects of wound cleansing, including
full assessment, date, skin care performed, dressings
applied and notes on the patient’s adherence to
treatment.
When choosing a wound irrigation solution,
it is vital that the irrigation agent does not
impair the wound healing process. The broad
categories of solutions that can be used for
wound irrigation are: water, saline, highly
reactive solutions and antimicrobial solutions.
Water and saline
Water and saline are not cytotoxic and have not
been found to be harmful to wounds; however,
neither do they actively promote wound healing
or contain antimicrobial properties of any
significance[16]. Water and saline can remove
planktonic bacteria and other wound debris,
but this cleansing may not remove some of the
harmful molecules that may be present, which
delays healing.
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Figure 1: Best practice
decision-making
algorithm[5].
Patient presents with a wound
Conduct a comprehensive assessment of the
patient, wound bed (TIME) and environment
Is healing delayed, and/or does the patient have
clinical signs of critical colonisation/infection?
YES
Is the patient high-risk
(e.g. lymphoedema
with cellulitis/DFU at
risk of amputation)?
YES
Consider systemic
antibiotic therapy and
refer to a specialist if
appropriate
Continue standard
wound care
Continue treating with same
or new topical antimicrobial;
review again at 2 weeks.
Check whether the product
can be used for longer than
4 weeks. If not, reconsider
dressing choice
NO
Consider other factors:
■Is the wound painful?
■Are exudate levels high?
■Is there any odour?
■Is there slough in the
wound bed?
YES
NO
If there are signs of
spreading infection,
consider systemic
antibiotics and topical
antimicrobials
YES
NO
Consider treatment with a topical antimicrobial
Treatment-goal factors:
■ Reducing pain/
exudate/odour
■ Reducing necrotic/
sloughy tissue in
wound bed
■ Reducing wound size
■ Encouraging signs of
healing
Topical antimicrobial
factors:
■Bioburden
reduction method
■Contraindications
■Suitability based on
patient and wound
needs
■Cost and availability
1. Discontinue topical
antimicrobial
2. Revert to standard
wound care
The wound has not improved,
and signs of infection continue.
Discontinue treatment and reassess
underlying conditions to determine
what factors might have changed or
need to be considered
1. Choose topical antimicrobial*
2. Document rationale for choice
3. Prepare wound bed appropriately
4. Apply agent per manufacturer’s
instructions
*Review at each dressing change
The Cochrane review on water and saline as
irrigation agents[17] found no evidence that using
water and saline to cleanse wounds increases
infection; however, the review also found that
there is no strong evidence to indicate that
cleansing with water and saline is better than not
cleansing, and concluded that more research was
needed. It was also noted that even ‘safe’ tap water
can become colonised with microbes, which may
in turn infect wounds irrigated in this way [17].
Highly reactive solutions
The highly reactive solution options such as
peroxide and povidone iodine, as well as some
commercially available products (e.g. foams,
50
NO
The wound
has improved.
Are there also
continuing signs
of infection?
YES
NO
Review at 2 weeks:
■■ Is the wound improving according
to treatment goals?
■■ Have exudate/odour/pain
decreased?
■■ Has necrotic/sloughy tissue
decreased?
■■ Has wound size decreased?
soaps, wipes and solutions with surfactants), can
be cytotoxic[18,14]. The Cochrane review[17] found
that highly reactive solutions have little effect
on controlling wound bacteria; in fact, they may
interfere with healing mechanisms.
Antimicrobial solutions
Common cleansing agents in this category
have been found to be effective while having
a minimally toxic effect when used in low
concentrations[14]. Because they are antiseptic
rather than antibiotic, antimicrobial solutions
also have the advantage of being widely
usable in chronic wounds without resulting
in AMR issues. They also have the ability to
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reduce bioburden, and disrupt and/or prevent
biofilm, effectively[14].
New advances
Hypochlorous acid (HOCI) is a powerful
antimicrobial agent. It is highly active against all
bacterial, viral and fungal human pathogens[19],
while preventing the creation of resistant strains
by attacking bacteria at multiple sites[20,21]. HOCI
has been shown to have specific anti-biofilm
activity, and is able to rapidly penetrate through
biofilm, in order to kill the microorganisms
within the biofilm[19]. This is effective at low
concentrations, while also being non-cytotoxic
and non-irritating[22].
HOCI is naturally produced by the body as a
fundamental immune response against infection
— when white blood cells engulf pathogens, HOCI
is generated, which neutralises bacteria as part of
the oxidative burst process[22]. HOCI demonstrates
antimicrobial properties by targeting DNA
synthesis within bacteria cells, which not only kills
the bacteria but inhibits further bacterial growth
or mutation — crucially, helping to prevent the
development of resistant bacterial strains[22]
HOCI is also commercially available as an
antimicrobial wound cleansing solution (e.g.
Woundox® Irrigation Solution, Martindale Pharma).
Woundox Irrigation Solution was specifically
designed with the aim of preventing the
development of resistant bacteria.
In vitro studies showed that Woundox Irrigation
Solution has rapid, broad-spectrum antimicrobial
action against the bacterial species commonly
found in chronic wounds. Application of
Woundox Irrigation Solution to microbes known
to inhibit wound healing successfully reduced
25 of the 27 microbes tested by 99.99% (4-log)
or more, within 15 seconds of exposure[23,24]. Of
the two organisms that were not reduced by
99.99% or more, Aspergillus brasiliensis (a fungus)
was reduced by 99.3% (2-log) and K. pneumoniae
by 93.3% (1.2-log). In vitro studies for longer
exposure time (30 seconds/1 minute/3 minutes)
are currently ongoing.
It was also demonstrated that Woundox
Irrigation Solution is effective in destroying
19.Sakarya S, Gunay N, Karakulak M et al. Hypochlorous acid: an
ideal wound care agent with powerful microbicidal, antibiofilm,
and wound healing potency. Wound Res 2014;26(12): 342–50
20.Shetty N, Srinivasan S, Holton J, Ridgway GL. Evaluation of
microbicidal activity of a new disinfectant: Sterilox® 2500
against Clostridium difficile spores, Helicobacter pylori,
vancomycin resistant Enterococcus species, Candida albicans
and several Mycobacterium species. J Hospital Infection 1999;46:
101–5
21.Zinkevich V, Beech IB, Tapper R, Bogdarina I. The effect of superoxidized water on Escherichia coli. J Hospital Infection 2000;46:
153–6
biofilms — following 3-minute treatment with
Woundox Irrigation Solution on 72-hour preformed biofilms, a biofilm assay showed that no
viable bacteria were recovered[23,24]. Woundox
Irrigation Solution demonstrated clinical efficacy
within 3 minutes, compared to 10–15 minutes
for comparable solutions. Clinical studies have
reported generally improved wound-healing
outcomes with HOCI-based products such as
Woundox Irrigation Solution[25,26]. New approaches
to wound cleansing should include an agent that
contains a tolerable and efficacious antimicrobial
that reduces microbial bioburden within the
wound bed, promotes an optimal healing
environment and the development of healthy
tissue, making Woundox Irrigation Solution an
ideal option in current clinical practice, while
fitting in with important new strategies for
combating the crisis of antimicrobial resistance.
Conclusion
Inappropriate prescription and overuse of
antibiotics in managing chronic wounds, together
with their inability to easily penetrate and act
within biofilms, have contributed to the increasing
development of resistant microbial strains[8].
To combat this, irrigation with an antimicrobial
solution should be used as standard practice for
chronic wounds. Healthcare professionals can now
harness the natural, concentrated power of HOCI
for the effective management of chronic wounds
and wound bed preparation. Treating infection
with a HOCI-based topical antimicrobial, such as
Woundox Irrigation Solution, rather than systemic
antibiotics, will reduce bacterial bioburden
without contributing to the development of
resistant microbial strains, while promoting an
optimal healing environment[22].
In vitro studies[23,24] have demonstrated that
Woundox Irrigation Solution is a powerful,
rapidly acting, broad-spectrum, topical
antimicrobial solution that does not cause
bacterial resistance, making it an ideal option in
WINT
current clinical practice.
Acknowledgment
This article has been supported by Martindale Pharma
22.Eryilmaz M, Palabruyik IM. Hypochlorous acid – analytical
methods and antimicrobial activity. Topical J Pharm Res 2013;12(1):
123–6
23.Martindale Pharma, Clinical evaluation report. Data on file
24.Martindale Pharma, Biological evaluation report. Data on file
25.Crew J, Varilla R, Rocas TA et al. NeutroPhase in chronic nonhealing wounds. Int J Burns Trauma 2012;2(3): 126–34
26.Robson MC, Payne WG, Ko F. Hypochlorous acid as a potential
wound care agent: Part II. Stabilized hypochlorous acid: Its role
in decreasing tissue bacterial bioburden and overcoming the
inhibition of infection on wound healing. J Burns Wounds 2007;
6: e6
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