Journal of APPLIED BIOMEDICINE
ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)
Volume 9 (2011), No 3, p 143-149
DOI 10.2478/v10136-009-0033-5
Gentamicin bound to the nanofibre microdispersed oxidized cellulose in the treatment of deep surgical site infections
etr Lochman, Jiri Paral, Jaromir Koci
Address: Petr Lochman, Department of Field Surgery, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
ochmpet@seznam.cz; lochmpet@yahoo.com
Received 7th June 2011.
Revised 17th September 2011.
Published online 12th November 2011.
Full text article (pdf)
Abstract in xml format
Summary
Key words
Introduction
Materials and methods
Results
Discussion
Conclusions
Acknowledgement
References
SUMMARY
The aim of this experimental in vivo study was to examine the effect of topically-used gentamicin bound to microdispersed oxidized cellulose (MDOC) in nanofibre form in the treatment of deep surgical site infections and to compare it with Garamycin Schwamm®. Twelve domestic swine were used in a model of a full-thickness infected dermal wound. The effectiveness of both forms of gentamicin were tested in wound infections caused by Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. The effectiveness of gentamicin-MDOC and Garamycin Schwamm® were comparable according to microbiological culture findings, with no statistically significant differences. When macroscopically assessed, 100% of the infected wounds treated by gentamicin-MDOC were without signs of infection, compared with only 16.7% when Garamycin Schwamm® was used and this was of statistical significance. Therefore when combined with a nanofibre MDOC carrier, topically-used gentamicin is rendered more effective for the treatment of full-thickness skin infections.
KEY WORDS
gentamicin; microdispersed oxidized cellulose; surgical site infections; Garamycin Schwamm
INTRODUCTION
Surgical site infections (SSI) are the second or third
most frequent healthcare-associated infections and the
subject of extensive research for the development of
new woundcare products and technologies for wound
healing (Smyth et al. 2008).
Microdispersed oxidized cellulose (MDOC), a
trademark of HemCon Medical Technologies, Inc., is
a random copolymer of polyanhydroglucose and
polyanhydroglucuronic acid. It has been produced as
SEAL-ONTM (HemCon Medical Technologies, Inc.,
Portland, U.S.A.) for its haemostatic effect and its
ability to facilitate blood clot formation. MDOC is
also believed to have an influence on wound healing
but no clear results have as yet been shown. Therefore
we chose to examine its efficacy as a topical carrier
for gentamicin in the healing of acute wound
infections in comparison to Garamycin Schwamm®
(Essex Chemie AG, Luzern, Switzerland). For this
purpose, an experimental in vivo model of a
full-thickness infected dermal wound in pigs was
created; the wound infections caused by
Staphylococcus aureus, Pseudomonas aeruginosa and
Escherichia coli - the three most often cultivated
pathogens from surgical site infections in the
Teaching Hospital in Hradec Kralove. All these
pathogens are among the most common in SSI
according to the literature within last decades (CDC
NNIS 1996, Nooyen et al. 1994).
MATERIALS AND METHODS
Preparation of gentamicin-MDOC
MDOC in the form of sodium-calcium salt of
polyanhydroglucuronic acid (PAGA) has several
biologically useful properties (active haemostasis,
immunostimulation, quick absorption, and
anti-adhesion). From the physico-chemical point of
view, this ionogenic polysaccharide, which functions
as a carboxylate ion exchanger, is fully absorbed by
the organism. But it is not a film-forming or
fibre-forming substance in and of itself. Depending
on its concentration, it creates salts or gels in water as
colloido-dispersed systems. However in gels without
a biocompatible non-toxic stabiliser the CaNaPAGA
solution separates from the gel, and therefore, in order
to prepare fibres from MDOC, modifying components
such as biocompatible carrier-polymers, softening
agents, etc. should be included in the preparation.
MDOC as a carboxylate polymer (as well as
hyaluronic or alginic acid) creates intermolecular
complexes (IMC) with positively-charged low-
molecular substances or polymers, i.e. it can work as
a carrier of substances such as basic antibiotics
including gentamicin.
For the production of MDOC nanofibres (ø of
fibres is 50-500 nm) it is necessary to use
biocompatible and absorbable fibre-forming polymers
that would create nanofibres together with MDOC or
be used as a binding material for the preparation of
nanofibres. Medicinal glycerine, which has an impact
on the physical properties of micro or nanofibres, has
been successfully used as a softening agent for these
systems. The nanofibres were always fully absorbable
after their application.
Gentamicin sulphate was attached to PAGA
during the process. Therefore, instead of the sulphuric
acid in gentamicin sulphate, the anion (polyanhydroglucuronate of gentamicine) was created by
PAGA.
At the start of these studies when nanofibres were
prepared, it was impossible to achieve a higher
surface density than the max. amount of 15 g/m2. This
meant that, upon a concentration of 14.3% w/w of
gentamicin in the MDOC nanofabrics, the content of
gentamicin sulphate per 100 cm2 of the area was a
maximum of 21.45 mg, a concentration insufficient
for its intended effect. It is noted that Garamycin
Schwamm® contains 130 mg of gentamicin for the
same area. Therefore, microfibres were prepared from
long-fibrous medicated cotton-wool. These
microfibres were transferred to raw cellulose through
nitrogen oxides in the HNO3 medium, followed by
hydrolysis of the cellulose in the medium of H2O2 and
Ca salts. After hydrolysis, gentamicin sulphate was
added to the reaction mixture during homogenization
at a temperature of 20 °C. The suspension of fibres
was filtered through a filter divider. The fibres were
created by being washed with aqueous alcohol and
dehydrated using concentrated ethylalcohol.
Afterwards, they were dried in a laminar box to a
constant weight.
The technology for the production procedure for
MDOC nanofabrics with a surface density of up to
150 g/m2 was developed and controlled. Thus, a
uniform concentration of gentamicin in an amount up
to 150 mg on an area of 100 cm2 was achieved; i.e. a
concentration comparable to Garamycin Schwamm®.
Experimental design and treatment
Twelve female domestic swine (35-45 kg of weight)
were used in this study; each experiment taking seven
days. After intramuscular premedication by ketamine
30 mg/kg (Narkamon®, Zentiva, Czech Republic),
azaperone 40 mg/kg (Stressnil®, Janssen
Pharmaceutica, Belgium) and atropine 0,5 mg
(Atropin Biotika A.U.V.®, Biotika, Slovakia) the
animal was put under general intravenous anesthesia
and maintained with ketamine. After preparation of
the operation field, eight full-thickness dermal defects
5 cm long with side incisions and fascial injury were
created in the paravertebral area (four wounds on
each side - on the left marked L1 to L4, on the right
marked R1 to R4). Contusion of skin margins using
Pean forceps was performed to imitate the most
common wound type in routine practice. After that,
0.5 ml of the microbiological agent suspension in a
density of 108 CFU/ml was injected into seven
wounds, the last one left clean without infection
(always marked R4) as a control. The comparative
effectiveness of gentamicin-MDOC and Garamycin
Schwamm® was tested against each microbiological
agent infection separately in two animals (also in 12
treated infected wounds). In every animal there were
2 controls - one infected non-treated wound (marked
L1) and one clean wound without infection (marked
R4). After 45 minutes, pieces of gentamicin-MDOC
or Garamycin Schwamm® (5x1.6 cm size containing
10.83 mg of gentamicin) were always placed into six
infected wounds (L2 to L4 and R1 to R3). The entire
operation area was covered by gauze and a surgical
towel. After 24, 48 and 168 hours, swabs were made
for cultivation on blood agar, macroscopic assessment
of wounds divided in 3 groups according to the
absorption of the carrier and the presence of signs of
local infection was performed and photodocumentations were carried out. A very similar
experimental design has already been used in an
experimental study performed by Plodr (2004).
Presence of pus in the wound bed was considered
to be an indicator of local infection. At the end of the
experiment the animals were sacrificed by
intravenous application of T-61® (Intervet Canada
Ltd., Canada). During the experiment, the animals
received humane care according to the criteria
outlined in the "Guide for the Care and Use of
Laboratory Animals". The animals were kept in
specific boxes (each animal separately) during the
whole experiment with unrestricted access to water
and were fed by mixture A1 for laboratory animals.
Statistical analysis was carried out using Fisher's
exact test, at the significance level alpha2=0.05.
RESULTS
The results of cultivations (on blood agar) of
microbiological swabs from the wounds taken at 24,
48 and 168 hours were compared. No significant
differences in E. coli and P. aeruginosa - infected
wounds were noted. In S. aureus infections, 50% of
the wounds treated by nanofibre gentamicin-MDOC
were negative compared with only 8.3% treated by
Garamycin Schwamm®, but the difference was not
statistically significant (Table 1).
All the infected controls had a positive cultivation
finding at the end of the experiment. Approximately
half of the clean controls were found to be
secondarily contaminated, mostly with
Staphylococcus epidermidis. Microbiology observations showed similar results with the two sources of
gentamicin used, with the exception of the S. aureus
infections. However, macroscopic assessments
showed big differences between the wounds treated
with the forms of gentamicin.
Macroscopic assessment is allowed for the
diagnosis of wound infection. According to the CDC
definition of SSI the diagnosis can be made by a
surgeon or attending physician, with no necessity for
having a positive cultivation finding, and is a matter
of subjectivity. Bruce et al. (2001) published a
meta-analysis of 90 studies pertaining to the
definition of SSI; in most of them diagnosis of the
wound infection is made only by macroscopic
assessment. And more, positive cultivation can be due to colonization or contamination only - it is not a sign
of infection without further symptoms.
Nanofibre gentamicin-MDOC was fully absorbed
in 94.4% of the treated wounds at 48 hours and in
100% of those at 168 hours. All the wounds were
macroscopically clean, healed with a crust and at
48 hours and 168 hours showed no signs of local
infection (presence of pus). Garamycin Schwamm®
was fully absorbed in 5.6% of wounds at 48 hours
and in 16.7% at 168 hours. Additionally, 25% of the
wounds at 48 hours and 83.3% at 168 hours showed
local signs of infection, especially if the collagen
carrier of Garamycin Schwamm® was not fully
absorbed. All these differences were statistically
significant (Table 2).
Macroscopic assessment of the infected wounds
treated with gentamicin-MDOC showed, in all cases,
similar results to the uninfected control wounds, i.e.
absence of any evidence of local infection, or
presence of pus.
DISCUSSION
Surgical site infections (SSI) lead to increased
morbidity, mortality, longer hospital stays and higher
hospital costs. Antibiotic prophylaxis is generally
recommended for all clean-contaminated,
contaminated and dirty procedures, mostly by
systemic administration. Topical administration of
antibiotics for prophylaxis is recommended for both
contaminated and clean wounds (Diehr et al. 2007).
Topical antimicrobials can be used in the treatment of
secondarily-infected wounds, and the treatment is
found to be as effective as the systemic administration
of antibiotics in the case of minor infected wounds
(Kraus et al. 1998). More importantly, there is a clear
role for the topical administration of antibiotics in the
treatment of chronic wounds (O'Meara et al. 2001).
One of the most common topically-used
antibiotics in surgery is gentamicin. This is probably
due to its effectiveness on a broad spectrum of gram
positive and gram negative bacteria and, when used
topically, its efficacy against methicillin-resistant
S. epidermidis (MRSE) and methicillin-resistant
S. aureus (MRSA) (Eklund 2007, Friberg et al. 2007).
Other advantages of topical administration of
gentamicin are its high concentration in the wound
and minimal concentration in the serum. High local
gentamicin levels, about 75-200 times higher than
minimum inhibition concentration (MIC), 4mg/l, were
observed in wound fluid compared to that in theserum (1-4 mg/l after 24 hours), both levels being safely below the toxic threshold of 10 mg/l (Leyh et al. 1999, Friberg et al. 2003, Eklund et al. 2005, Eklund 2007).
Table 1. Microbiological cultivation - counts and percentage of treated wounds with negative cultures.
|
E. coli |
S. aureus |
P. aeruginosa | |
24 h |
48 h |
168 h |
24 h |
48 h |
168 h |
24 h |
48 h |
168 h | | Garamycin
Schwamm |
12/12
100% |
12/12
100% |
12/12
100% |
12/12
100% |
0/12
0% |
1/12
8.30% |
12/12
100% |
12/12
100% |
8/12
66.70% | | nanoMDOC |
12/12
100% |
12/12
100% |
12/12
100% |
12/12
100% |
12/12
100% |
6/12
50% |
12/12
100% |
12/12
100% |
6/12
50% |
For both the tested materials - in the first line in fraction number of wounds with negative cultures findings to all treated wounds,
in the second row the ratio expressed as a percentage.
Table 2. Macroscopic assessment of the wounds at 7 days - counts and percent of wounds.
|
E. coli |
S. aureus |
P. aeruginosa | |
I |
II |
III |
I |
II |
III |
I |
II |
III | | Garamycin
Schwamm |
0/12
0% |
0/12
0% |
12/12
100% |
3/12
25% |
0/12
0% |
9/12
75% |
2/12
16.70% |
0/12
0% |
10/12
83.30% | | nanoMDOC |
12/12
100% |
0/12
0% |
0/12
0% |
12/12
100% |
0/12
0% |
0/12
0% |
12/12
100% |
0/12
0% |
0/12
0% |
For both the tested materials - in the first line in fraction number of wounds classified in each group according to the presence
of infection and complete/incomplete resorption to all treated wounds, in the second row the ratio expressed in percentage.
group I - clean wound, tested material fully absorbed;
group II - clean wound, tested material not fully absorbed;
group III - wound with signs of infection, tested material not absorbed.
Table 3. Resorption of the carrier - counts and percent of wounds.
|
Complete resorption |
Incomplete resorption | |
24 h |
48 h |
168 h |
24 h |
48 h |
168 h | | Garamycin
Schwamm |
2/36
5.6% |
2/36
5.6% |
6/36
16.7% |
34/36
94.4% |
34/36
94.4% |
30/36
83.3% | | nanoMDOC |
21/36
58.3% |
34/36
94.4% |
36/36
100% |
15/36
41.7% |
2/36
5.6% |
0/36
0% |
For both the tested materials - in the first line in fraction number of wounds with complete/incomplete resorption of the carrier
to all infected treated wounds with specific material (3x12 wounds with S. aureus, P. aeruginosa and E. coli infection), in the
second row the ratio expressed in percentage.
Most published articles involving topically-administered gentamicin with a collagen carrier
describe the results of the prophylaxis of SSI in
cardiac surgery (Leyh et al. 1999, Friberg et al. 2003,
2007, Eklund et al. 2005, Eklund 2007, Friberg 2007,
Schersten 2007). Gentamicin-collagen implants with
various brand names (Collatamp-G®, Gentacoll®,
Sulmycin Implant®), containing 130 mg of gentamicin
and 280 mg of collagen are placed underneath the
sternum or between its edges before sternotomy
closure. In some studies, more than one implant of
gentamicin-collagen was applied (Leyh et al. 1999,
Friberg et al. 2005, Friberg 2007).
In the first randomized controlled study published
by Friberg et al. in 2005, the sternal wound infection
rate was 4% in the gentamicin group and 5.9% in the
control group, this was not statistically significant.
The data presented showed a slight reduction in
infection rate in gentamicin-collagen groups, but the
study population was too small to make a statistically
reliable conclusion.
In the next randomized control study, the
incidence of SSI in 2000 patients undergoing
open-heart surgery was significantly reduced from
9% to 4.3% in the gentamicin group, but without
effect as to the occurrence of osteitis or mediastinitis
(Friberg et al. 2005). The difference in all groups
involving deep SSI was not of statistical significance,
except in groups of patients with either a BMI (body
mass index) >25 kg/m2 or diabetes mellitus, or both
(Friberg et al. 2005, Friberg 2007). On the other hand,
there were significantly more reoperations for
bleeding in the gentamicin-collagen group (4.0% vs.
2.3%). This result was not explained, but it can be
argued that the difference may be due to bleeding
from the bone marrow from a gap between the two
sternum halves when two gentamicin-collagen layers
were inserted (Friberg et al. 2005). A similar increase
in the number of cases with postoperative bleeding
with dehiscence was noted by Leyh et al. (1999). In
general, topically-administered gentamicin-collagen
implants are recommended for antibiotic prophylaxis
in cardiac surgery.
The use of topical gentamicin as a prophylaxis is
also recommended in some clean procedures in
orthopaedic and general surgery. Eveillard et al.
proved the effectiveness of gentamicin- impregnated
cement in the prevention of deep wound infection
after primary total knee arthroplasty. The infection
rates were 1.21% for patients who had antimicrobial
cement and 9.52% for those who had not (Eveillard et
al. 2003). Musella et al. (2001) recommended the use
of gentamicin-laced collagen tampons in groin hernia
patients if polypropylene mesh is inserted under
aponeurosis of the external oblique muscle. In the
gentamicin group, 1/301 patients (0.3%) developed a
postoperative wound infection compared with 6/294
in the control group (2.0%).
In clean-contaminated and contaminated
procedures, the results are ambivalent. Buimer et al.
(2008) describe a significant reduction in
postoperative complications (dehiscence, infection),
after one week of treatment, in a group of patients
treated with enclosure of gentamicin after primary
excision in case of hidradenitis suppurativa (35%)
compared with patients treated with primary excision
only (52%). However, after 3 months, complications
in both groups were comparable.
In the case of pilonidal sinus treatment,
bacteriological culture findings were not statistically
different when treated by excision, gentamicin-
collagen implantation and primary closure, or open
treatment alone (Holzer et al. 2003). This study
indicates that the use of gentamicin-collagen shortens
the time of wound healing in patients with a primary
closure.
In the case of repair of an anal fistula, using an
advancement flap, gentamicin-collagen did not
decrease the infection rate, and there was no
difference in the recurrence rate (Gustafsson et al.
2006). A number of studies evaluate the effectiveness
of topical administration of gentamicin in colorectal
surgery procedures. Wounds after stoma closure, and
perineal wounds after abdominoperineal excisions,
were contaminated and the incidence of SSI was high.
Haase et al. did not find any differential effect
between subcutaneously-used gentamicin implants
with regard to the prevention of wound infections
after loop-ileostomy closure (Haase et al. 2005).
However, very good results were achieved with the
topical administration of gentamicin in randomized
controlled studies (Rosen et al. 1992, Gomez et al.
1999, Grussner et al. 2001). Grussner et al. (2001)
found a reduction of pathogens in cultures and a
lower infection rate in perineal wounds after
abdominoperineal excisions. In total, the
bacteriological efficacy amounted to 83.7% in the
treated group vs. 60.4% in the controls. The
difference in infection rates was also significant; 6%
vs. 20.8%. Similar results were reported in the studies
of Rosen et al. (1992) and Gomez et al. (1999) -
though with a significantly higher percentage of
primary wound healing in the gentamicin treated
group, 87% vs. 46% for the control group, and an
infection rate of 9% vs. 44%, respectively.
In our study reported here, we used a new
biodegradable carrier formed by microdispersed
oxidized cellulose in nanofibre form. This cellulose
has a good haemostatic effect and facilitates blood
clot formation, in agreement with previous tests of
product SEAL-ONTM (HemCon Medical
Technologies, Inc., Portland, USA).
The collagen matrix is fully biodegradable and
resorbed within 1 to 8 weeks, depending on the
vascularization of the tissue (Gustafsson et al. 2006,
Buimer et al. 2008). In contrast, microdispersed
oxidized cellulose is fully resorbed within the first
48 hours in 94% of wounds (Table 3). When
gentamicin is attached to the carrier
(gentamicin-MDOC, 130 mg gentamicin/100 cm2),
we found superior inhibition of infection by
comparison to the topical administration of
gentamicin (Garamycin Schwamm®). In this study,
Garamycin Schwamm® was not fully absorbed in
83.3% of the wounds at 7 days, and, like a foreign
body in the wound bed, could increase the rate of SSI.
In agreement with previously published data we
found no adverse effects due to treatment with
gentamicin.
There were no macroscopic differences between
infected treated wounds with nanofibre MDOC and
infected and clean controls. To conclude, no treatment
has similar macroscopic results as the treatment with
MDOC, but the advantage of nanofibre MDOC with
gentamicin is in the better cultivation results
compared to the infected controls. We proved quicker
resorption of MDOC than collagen-gentamicin in
Garamycin Schwamm.
So, when gentamicin is attached to the carrier
formed by MDOC in comparable amount (130
mg/100 cm2), we find this superior for administration.
CONCLUSIONS
Topically-used gentamicin, attached to nanofibrous
microdispersed oxidized cellulose is effective in the
treatment of soft tissue infections, due to its
antimicrobial activity, excellent resorption of the
MDOC carrier in comparison to collagen, and its
promotion of blood clot formation.
ACKNOWLEDGEMENT
The study was supported by the Faculty of Military
Health Sciences, University of Defense, research
project No. 0000503.
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