Clinical and Antibiofilm Efficacy of Antimicrobial Hydrogels
Clinical and Antibiofilm Efficacy of Antimicrobial Hydrogels
of Antimicrobial Hydrogels
pare the antimicrobial efficacy of each dressing, three pare and contrast currently available antimicro-
different antimicrobial tests were used: disc diffu- bial dressings. The dressings that were evaluated
sion, broth culture, and the Live/Dead Baclight included Cadesorb, Idoflex, Alisite, Acticoat,
bacterial viability assay against P. aeruginosa, Medihoney, Curity, Tegaderm, SilvaSorb,
Meticillin-sensitive Staphylococcus aureus, Acineto- Prontosan, Triadine, and Aquacel. The bio-
bacter baumannii, Candida albicans, Meticillin- film was subjected to pretreatment with gentami-
resistant S. aureus, and vancomycin-resistant cin for 24 h to gain antibacterial resistance. The
enterococci. Acticoat was reported to be the most study was conducted over a 24 h time period. The
efficacious dressing, with a zone of inhibition rang- study concluded that the ability of antimicrobial
ing from 13.9 to 18.4 mm. Acticoat reduced the mi- wound dressings to kill mature biofilms varies
crobial inocula below the limit of detection and widely with time of exposure, number of applica-
reduced microbial viability by 99% within 4 h. Poly- tions, moisture level, and release profile. However,
Mem Silver had no zone of inhibition for most of the researchers did conclude that taking into ac-
the evaluated test microorganisms, and it also count the large degree of variables SilvaSorb and
showed poor antimicrobial activity in the broth cul- Iodoflex were the most effective in reducing the
ture and Live/Dead Baclight assays. The silver mature biofilm by a log of five.28
hydrogel reduced most of the tested microbes below
Iodine hydrogels and biofilms
the detection limit and decreased bacterial viability
Vogt et al.29 undertook a monocentric, random-
by 94–99% after 24 h exposure.23
ized, observer-blinded, phase III study of a poly (N-
Shuffitt et al. reported on the ability of SilvaSorb
vinylpyrrolidone) (PVP)–iodine preparation hydro-
to deliver ionic silver and moisture to the wound
gel containing a 3% iodine concentration (Repithel)
bed, as a result the dressing only required changing
to study the effect on epithelialization in patients
three days after application. The increase in appli-
receiving meshed skin grafts. Grafts of 167 patients
cation time resulted in an overall reduced bioburden.
(donor site defects, burn wounds, or chronic defects)
This case series demonstrated a cost-effective and
were dressed either with Repithel (n = 83) covered
clinically effective method of treatment.24 Glat et al.
with a gauze ( Jelonet), or Jelonet-gauze only (n = 84)
also presented a study on SilvaSorb (Medline
until healing. The grafts that received Repithel
Industries, Inc.) compared with silvadene (King
healed significantly earlier (9.4 vs. 12.4 days;
Pharmaceuticals), a silver sulfadiazine cream, dem-
p < 0.0001) and faster than controls, as measured by
onstrating the efficacy of SilvaSorb in the treatment
neo-epithelialization of mesh holes between days 7
of partial-thickness burns.25 Recently Simcock and
and 11 (91.20 – 22.8% vs. 82.3% – 28.6, p < 0.001).29
May conducted a study on split-skin graft recon-
Further, Beukelman et al.30 tested PVP-ILH, Re-
struction of scalp defects using a decellularized ex-
pithel, on its ability to reduce the inflammatory re-
tracellular matrix biomaterial, with application of
sponse. The study showed that PVP-ILH reduced
SilvaSorb after application to successfully stop in-
the amount of free superoxide anions and helped
fection at the site of reconstruction.26
promote ‘‘normal’’ wound healing.30
Zelen et al.27 compared the healing characteris-
Mishra and Chaudhary tested numerous hy-
tics of diabetic foot ulcers treated with dehydrated
drogels that had incorporated povidone-iodine
human amniotic membrane allografts (EpiFix;
(PVP-I) showing that its release could be tailored by
MiMedx) versus SilvaSorb ( Medline Industries,
hydrogel composition leading to improved wound
Inc.). An international review board–approved,
healing.31 Homann et al. demonstrated the efficacy
prospective, randomized, single-center clinical
of a novel PVP-I-loaded liposome hydrogel in a
trial was performed. Included were patients with
randomized controlled trial compared with silver
a diabetic foot ulcer of at least 4-week duration,
sulfadiazine cream treatment. The liposome PVP-I
without infection, and having adequate arterial per-
hydrogel resulted in significantly faster, complete
fusion. Patients were randomized to receive Silva-
healing of the burn wounds compared with silver
Sorb alone or with the addition of EpiFix. In the
sulfadiazine cream (9.9 – 4.5 vs. 11.3 – 4.9 days;
SilvaSorb group alone (n = 12) and the EpiFix group
p < 0.015). Local tolerability was also noted to be
(n = 13), wounds reduced in size by a mean of
good; handling and change of dressing were also
32.0% – 47.3% versus 97.1% – 7.0% ( p < 0.001) after 4
rated as easy.32
weeks. Patients treated with EpiFix achieved supe-
rior healing rates over standard treatment alone.27 PHMB hydrogels and biofilms
In a recent comprehensive comparative study on The antimicrobial activity of PHMB owes itself
biofilms, Phillips et al.28 used an ex vivo porcine to its molecular shape and charge. Where PHMB
skin explant, P. aeruginosa biofilm model to com- causes an irreversible loss of essential cellular
402 FINNEGAN AND PERCIVAL
components due to damage caused to the cytoplasm was used for 3 days to prevent pes equinus and to
membrane. PHMB has also been found to prevent let the ankle joint rest. Change in wound size (cm2),
the efflux pump and so the microbe is unable to incidence of local infection, wound bed character-
reduce the levels of antimicrobial present within istics, and pain levels (measured on a 0–10 pedi-
it.33 Therefore, microorganisms are not known to atric pain scale) were assessed at 3-day intervals
adapt to PHMB and no known resistance has yet during the 14-day treatment period. Satisfaction
been documented.34 with the dressing was also evaluated. Twenty chil-
The precise mechanism of action of PHMB on dren (mean age = 5.6 – 1.33 years) were recruited
bacteria still remains unclear.34 An example of into the study and included in the analysis. The
a PHMB-containing hydrogel is Suprasorb X + mean baseline wound area was 8.60 – 6.57 cm2. The
PHMB.35 Bruckner et al.36 performed a study on 40 mean time to complete wound closure was 12.95 –
patients, each suffering from delayed wound healing 7.69 days with a mean total of 4.70 – 1.56 visits. The
for at least 3 weeks, and signs of critical colonization/ mean pain score was 9.55 – 0.69, compared with
infection to determine the efficacy of Suprasorb X + 0.15 – 0.37 on day 14 ( p < 0.003). At the second visit
PHMB. The progress of wound healing was evaluated (after 3 days), 17 of the 20 children were reported to
by a colorimetric method. In 32 out of 40 patients, the be free of pain. No cases of local infection were noted.
share of granulation tissue was increased, as a result The evaluation also showed that it was well toler-
of sufficient reduction of bacterial colonization (gran- ated and achieved good healing outcome.37
ulation tissue start point is 12% – 18% and endpoint is Galitz et al.38 compared the potency of pain and
79% – 24% in 27 – 25 days; n = 40). However, in five the microbial reduction of chronic wounds in a
patients no progress was measured, all of these controlled, randomized, multicentric comparative
wounds were infected with P. aeruginosa with signs of study over a period of 28 days on 21 patients using
biofilm formation.35 BWD-PHMB and a typical silver dressing as a
Consultants36 undertook a cohort study to evalu- comparison. The results of which were inconclusive
ate the clinical efficacy of a polyhexanide-containing in terms of reduction in microbial burden. The pain
biocellulose dressing, Suprasorb X + PHMB (Loh- in changing dressings was noted to be reduced when
mann and rauscher GmbH), for the eradication of using the Suprasorb X + PHMB dressing. Haem-
biofilms in nonhealing wounds. The study consisted merle et al. compared treatment of a polihexanide-
of 28 patients, aged over 18 years, who presented at containing biocellulose wound dressing (BWD +
an outpatient wound clinic with nonhealing, locally PHMB) to silver dressings (Ag) in 38 painful, criti-
infected, and/or critically colonized wounds of various cally colonized or locally infected wounds. Although
etiologies that showed clinical signs of biofilm. The BWD + PHMB and Ag were effective in reducing
patients were prospectively followed for a maximum pain and bacterial burden, the BWD + PHMB was
of 24 weeks or until healing for analysis of safety and stated as being significantly faster at removing the
efficacy endpoints. critical bacterial load from the colonized wounds.39
Evolution of wound size was conducted with Lenselink and Andriessen,40 however, conducted
tracings and standardized digital photographs as a study on the efficacy of Suprasorb X + PHMB on
well as for determining healing rates. At 24 weeks, patients visiting an outpatient clinic with nonheal-
12 wounds (75%) had healed (complete epithelial- ing wounds of various etiologies that showed clinical
ization with no drainage). Of those wounds that signs of biofilm inhabitancy.40,41 Suprasorb X +
had not closed, the mean wound area had reduced PHMB dressing changes took place two to three
by 61% by week 24. Ten patients (63%) had a good times per week, depending on the wound condition
reduction in biofilm presence, 5 (32%) scored mod- and exudate production, and patients were followed
erate, and 1 (6%) had no reduction noted at week until healing. Reduction of the biofilm was scored on
24, concluding that the PHMB-containing bio- a three-point scale (good/moderate/poor). Reduction
cellulose dressing seems to be suitable for lightly- in wound size was also scored on a three-point scale,
to-moderately exuding wounds.36 using planimetry and photographs. Interestingly
Spits and Van Gent37 conducted a similar study 60% of the 25 patients included in the study had a
to evaluate the clinical benefits, primarily tolera- good reduction in biofilm size and a good reduction in
bility and reduction in pain levels, associated with wound area. These results indicated that Suprasorb
the use of a PHMB-impregnated biosynthetic cel- X + PHMB has the ability to reduce biofilm burden in
lulose dressing (Suprasorb X + PHMB) on pediatric patients with chronic wounds.40 Further, Lenselink
heel lacerations in particular. A PHMB-impreg- and Andriessen performed a similar study in 201142
nated biocellulose dressing was applied and left in that reinforced the efficacy of Suprasorb X + PHMB
situ until epithelialization occurred. A cork splint toward biofilm eradication. Twenty-eight patients,
ANTIBIOFILM EFFICACY OF ANTIMICROBIAL HYDROGELS 403
again from an outpatient wound clinic with non- taining propyl and benzyl side chains with vitamin E
healing, locally infected, and/or critically colonized moiety into physically crosslinked networks of
wounds of various etiologies that showed clinical ‘‘ABA’’-type polycarbonate and poly(ethylene glycol)
signs of biofilm were included in the study. Sixteen triblock copolymers. In vitro antimicrobial stud-
patients (9 women), with a mean age of 60.9 – 21.6 ies revealed that the more hydrophobic [VE/
years, were included in the analysis. The patients BnCl(1:30)]-loaded hydrogels generally exhibited
were prospectively followed for a maximum of 24 better antimicrobial/antifungal effects compared
weeks or until healing for analysis of safety and ef- with their counterpart VE/PrBr(1:30) as lower
ficacy endpoints. Wound size was conducted with minimum bactericidal concentrations (MBCs) were
standardized digital photographs for determining observed in Staphylococcus, Escherichia coli, and C.
healing rates. After 24 weeks, 75% had healed albicans. Similar trends were observed for the
(complete epithelialization with no drainage) and of treatment of biofilms where VE/BnCl(1:30)-loaded
those wounds that had not closed, the mean wound hydrogels displayed better efficiency with regards to
area had reduced by 61% at week 24, 63% had a good eradication of biomass and reduction of microbe vi-
reduction of the biofilm, 32% scored moderate, and ability of the biofilms. These hydrogels also dis-
one had no reduction noted at week 24.42 played excellent compatibility with human dermal
fibroblasts with cell viability > 80% after treatment
New-generation hydrogels and biofilms
with hydrogels loaded with cationic polymers at
Hydrogels containing endopeptidase enzymes,
minimum biocidal concentrations (MBCs).44
which are used to cleave denatured proteins and
Other hydrogels have been reported with prom-
superoxide-dismutase-containing hydrogels, have
ising results, which include oxygen-generating hy-
demonstrated positive effects on wound healing.
drogels,45 thermoresponsive hydrogels,46 semi-inter
Further, a biphosphonate-functionalized hydrogel
penetrating networks hydrogel silver nanocompos-
was reported to inhibit the action of MMPs in
ities,47 and hydrogels incorporating synergistic
chronic wound fluid.43
agents for enhanced antibiofilm activity.48
Lee et al.44 reported on the development of
novel biodegradable hydrogels from vitamin E-
functionalized polycarbonates for antimicrobial SUMMARY
applications. These hydrogels were formed by in- Within this review a host of hydrogels as a
corporating positively charged polycarbonates con- platform containing a variety of antimicrobials in
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PVP ¼ poly(N-vinylpyrrolidone)