Effectiveness of a Topical Formulation

Containing Metronidazole for Wound Odor

and Exudate Control
Cathy Kalinski, RN, BSN, CWCN, COCN, Mary Schnepf, RNC, MPH, ET, Debbie Laboy,
RPh, Lucy Hernandez, MS, APRN, BC, Jeanne Nusbaum, RN, Brian McGrinder, RPh,
Christopher Comfort, MD, Oscar M. Alvarez, PhD
Wounds. 2005;17(4):84-90.
In chronic wound patients with advanced disease, endpoints other than closure offer
improvements in quality of life. Odor management and exudate control are realistic wound
care goals that have not received a great deal of attention. Sixteen cancer patients with
malodorous wounds were treated with a compounded topical formulation consisting of
metronidazole 0.75% in a gel vehicle. Treatments were performed daily or twice a day at
dressing changes consisting of a nonadherent primary dressing and an absorbent (gauze or
nonwoven) secondary dressing. Wound odor was evaluated both by the patient and
investigator using a subjective assessment scale of 0-10 (0=no odor detectable, 5=moderate,
noticeable but not offensive, 10=offensive, putrid). The amount of wound exudate and skin
maceration was evaluated clinically. Safety evaluations included wound volume (to
determine if the test agent deteriorated the wound) and monitoring of unexpected adverse
events. Complete elimination of odor (rating of 0) was reported in 10 patients (62.5%) 24
hours after the initial application. There was significant odor control (>3 units in the odor
scale) in the remaining 6 patients (37.5%). Of the 6 patients that noticed odor control
(improvement without elimination), 5 (83.3%) had wounds in the perineal and rectal areas. In
this limited survey, topically applied metronidazole 0.75% gel did not cause wound
deterioration or an adverse effect. Topical metronidazole 0.75% gel was effective in
controlling wound odor and reducing drainage in large (clinically challenging) fungating
wounds.
Fungating tumors, pressure ulcers, and other chronic wounds are frequently the source of
offensive odors that distress patients, family, and healthcare professionals. These odors often
limit the patients' contact with others and have a negative psychological impact on all
concerned. The social embarrassment caused by a malodorous wound heightens the misery of
advanced and uncontrolled disease, deepening the person's sense of helplessness,
worthlessness, and social isolation at the time when support of family and friends is crucial.
[1]

Smell carries a social stigma and may cause a patient to feel guilty and ashamed. It can
inhibit sexuality and intimacy with a loved one resulting in depression.
[2]

Fungating wounds are the visible markers of underlying malignant disease.
[3]
The wound
develops from a local tumor extending into the epithelium and its supporting lymph and
blood vessels. As the mass increases and loses its vascularity, capillaries rupture, and necrosis
and subsequent infection develop. This produces a malodorous purulent wound.
[4]
For
patients, odor is often the most distressing complication of their wounds and poses a
considerable challenge to caregivers.
Nonsporing anaerobes that colonize cutaneous lesions release volatile fatty acids as metabolic
end products that are responsible for the characteristic putrid odor.
[5,6]
Deodorizers and
ventilation
[7]
and charcoal dressings that absorb these fatty acids
[8]
seldom adequately control
this odor.
The deodorizing effect of metronidazole
[9-13]
has been shown to correlate with eradication of
anaerobic infection,
[9]
but systemic administration is often associated with adverse events,
such as nausea and vomiting, and the ban on alcohol necessary with oral metronidazole may
further impair patients' quality of life.
[14]
Topical application of metronidazole for the
treatment of malodorous skin ulcers has been studied previously. Finlay et al.
[7]
conducted a
multicenter trial that prospectively evaluated metronidazole 0.75% gel on 47 patients with
benign and malignant malodorous wounds. Decreased odor was reported on 95% of the
patients after 14 days of treatment. There was a significant decrease in anaerobic organism
cultured but no significant changes in the growth of aerobic bacteria. In this same study,
patients also reported significantly less pain, but there was no control for the gel vehicle or
wound dressing used. In a double-blind placebo-controlled trial,
[11]
metronidazole 0.8% gel
was reported to be beneficial in the reduction of odor from fungating primary or metastatic
tumors. The difference in odor between the active and placebo-treated wounds was clinically
evident but not statistically significant because of the study's small sample size (11 patients).
There are numerous other articles (case studies or anecdotal experience) reporting the
reduction of wound odor with topically applied metronidazole.
[15-19]

The purpose of this study was 2-fold: 1) to evaluate the effectiveness of 0.75% metronidazole
on the eradication of odor in patients with large fungating tumors and 2) to compare the costs
associated with using a commercial product versus a formulation compounded by the authors'
hospital pharmacy.
The Calvary Hospital Pharmacy formulated metronidazole 0.75% gel as follows: 3.6g of
metronidazole USP (Gallipot Inc., St Paul, Minn) were blended with 10mL of propylene
glycol (Paddock Labs, Minneapolis, Minn) to produce a gelatin. Upon dispersion, 480mL of
hydroxypropyl methylcellulose (Liqua-Gel
TM
, Paddock Labs) was added and slowly blended
until the metronidazole powder dissolved. The metronidazole 0.75% gel was packaged in
either 2 or 4oz jars and labeled.
The study was a prospective, single-center, open (uncontrolled) trial. Sixteen consecutive
consenting patients presenting with malodorous wounds were enrolled for this clinical study (
). All patients received treatment with the topical formulation. Upon initiation and prior to
initial application, wounds were assessed for odor, exudate, and signs of infection. Wound
odor was evaluated before initial application (baseline Day 0) and once daily by the patient
and 1 investigator. A 10cm visual analog scale rating the odor score from 0-10 was used
(0=no wound odor, 1-4=mildly offensive, 5-8=moderately offensive, and 9-10 extremely
offensive). The patients were followed for 2 weeks. No debridement was undertaken, as it is
not usually performed on fungating tumors. Patients on systemic antibiotics, currently
receiving chemotherapy or radiotherapy, or with known sensitivity to metronidazole were
excluded from the study. All wounds were clinically assessed for general appearance, signs
of infection, degree of exudation, skin maceration, wound size (volume), and local pain.
Patients were also asked to provide comments about their treatment.
Wound Characteristics
Location, Type of Cancer Size, cm (LxWxD)
Right axilla, Merkel cell (breast) 11x2.5x7
Vagina-rectum, vulvar 13x2
Groin-inguinal area, pelvic neoplasm 12x7
Face, squamous cell (skin) 14x13
Head-neck, larynx 7x10
Right chest, lung 14x9
Right face, squamous cell (maxillary sinus) 5x4
Right face, squamous cell (larynx) 7.5x6
Right axilla, breast 5x9
Left chest, breast 10x5x13
Supra pubic, colon-rectum 20x8, 8x3
Right neck, squamous cell (maxillary sinus) 5x3 (4cm sinus)
Right ear, squamous cell (skin) 10x9, 5x3, 1x1
Left neck, squamous cell (oropharynx) 9x7
Buttocks, rectal 2x1
Scrotum-groin, Kaposi sarcoma 26x36
Wounds were cleansed with sterile normal saline before treatment. There were no forceful
irrigation techniques and no other cleansing agents utilized. The same dressing technique was
used throughout the study. It consisted of a nonadherent primary dressing (Adaptic
TM
,
Johnson & Johnson Wound Management, Somerville, NJ) and an absorbent (gauze or
nonwoven) secondary dressing. Treatment with metronidazole gel was performed once daily.
Using a tongue depressor, enough study medication (about the thickness of a dime, 1-.5mm)
was applied over the entire surface of the wound. If the dressing came off or became soiled,
only 1 additional application of the test agent was allowed.
Costs associated with metronidazole powder and formulation ingredients were compared to
the costs of purchasing the commercially available topical formulation. The number of empty
jars was counted as an approximation of total amount of product used throughout the study.
Summarized odor and exudate scores were evaluated using Winks Basic Edition Statistics
Software (TexaSoft, Inc., Cedar Hill, Tex). The mean baseline scores were compared to mean
scores following treatment with metronidazole 0.75% gel using a nonparametric test
(Friedman's Test) for the comparison of repeated measures.
[20]
Unlike the parametric repeated
measures ANOVA or paired t-test, Friedman's test does not assume the distribution of the
data (eg, normality).
Treatment with metronidazole 0.75% gel was easy and convenient. The application of this
topical medication was not associated with any pain or discomfort. The effect of
metronidazole 0.75% gel on wound odor is presented in Figures 1 and 2. Figure 1
summarizes the odor scores as determined by the investigator, and Figure 2 presents the
scores determined by the patients. There was a statistically significant ( p <0.05) decrease in
wound odor 24 hours after just 1 (initial) application in both investigator and patient data sets.
Statistical significance ( p <0.05) was also noted on Days 7 and 14 after the initiation of
therapy. Metronidazole 0.75% gel was effective throughout the entire 2-week treatment
period. For the most part, there was a close correlation between the investigator and patient
odor score. With 2 exceptions (Day 6 and Day 8), the score variation between patient and
investigator was <30% (Figure 3). The response to topical metronidazole on wound odor was
dramatic with a 100% response rate (10 patients reported complete odor elimination, and 6
reported marked improvement [Figure 4]). Wounds treated with topical metronidazole
exhibited less drainage. The decrease in the amount of wound exudate was noticeable after
just 2 applications (48 hours) and persisted throughout the study period. The effect of topical
metronidazole gel on the amount of wound exudate is presented in Figure 5. Although the
differences in wound drainage before and after treatment were clinically evident, they were
not statistically significant ( p =0.096).

Effect of metronidazole 0.75% gel on wound odor as determined by investigator. Results
represent mean odor scores. A score of 0=no odor, 1-4=minimally offensive, 5-8=moderately
offensive, and 9-10=extremely offensive. *Indicates a statistically significant difference
between the means when compared to baseline, Day 0 (prior to treatment) at p<0.05.

Effect of metronidazole 0.75% gel on wound odor as determined by patients. Results
represent mean odor scores. A score of 0=no odor, 1-4=minimally offensive, 5-8=moderately
offensive, and 9-10=extremely offensive. *Indicates a statistically significant difference
between the means when compared to baseline, Day 0 (prior to treatment) at p <0.05.

Effect of metronidazole 0.75% gel on wound odor: summary of investigator and patient
scores. Results represent mean odor scores. A score of 0=no odor, 1-4=minimally offensive,
5-8=moderately offensive, and 9-10=extremely offensive.

Twenty-four hour response to metronidazole 0.75% gel.

Amount of wound exudate before and after treatment with metronidazole 0.75% gel. *Wound
exudate assessment performed by investigator (3=heavy, 2=moderate, 1=scant).
The costs associated with metronidazole 0.75% gel compounded by the authors' pharmacists
and the cost to the hospital of the equivalent commercial formulation is shown in . The cost
for the compounded formulation was $1.68 for a 2oz jar (or $0.028/g) and the cost of
MetroGel
TM
(Galderma, Fort Worth, Tex) was $43.50 for 45g (or $0.96/g). A total of 8,640g
(144 2oz jars) were used throughout the study (16 patients for 2 weeks) totaling $241.92.
Based on the 8,640g used, it would have cost $8,294.40 to use the commercially available
formulation. This constitutes a savings of $7,882.74.
Costs of Compounded Metronidazole 0.75% Gel and the Commercial Formulation
(MetroGel)
Agent Cost $ Commercial Formulation
Metronidazole 7.75 (25g) 43.50 (45g)*
LiquiGel 7.00 (pint)
PEG 4.77 (pint)
Package (2oz jar) 0.65
Cost per jar (60g) 1.68
Cost per gram 0.028** 0.966
*Based on the cost to the hospital



**Cost associated with labor not included
The term "fungating" describes a condition of ulceration and proliferation that arises when
malignant tumor cells infiltrate and erode the barrier properties of the skin. Figure 6 shows
both these features in a patient with squamous cell carcinoma who was enrolled in this study.
Areas of tumor growth are visible at the wound margins and on the patient's cheek together
with the central area of ulceration. Fungating tumors may be complicated by sinus or fistula
formation (Figure 7). Tumor infiltration of the skin involves the spread of malignant cells
along pathways that offer minimal resistance between tissue planes, along small blood
vessels (capillaries), lymphatic vessels, and in perineural spaces.
[21]
Fungating wounds may
develop on a number of sites, the breast being the most common.
[3]
Melanoma, lymphoma,
and cancers of the lung, stomach, head, neck, uterus, kidney, ovary, colon, and bladder also
have the potential to invade the skin. The incidence or prevalence of fungating malignant
wounds is unknown, as data are based on estimations rather than derived from population-
based cancer registries. In a retrospective survey based on questionnaires, Thomas et al.
[3,22]

calculated an incidence of more than 2,400 per year (the majority being treated in
radiotherapy and oncology units). The author concluded that these figures reflect a significant
incidence.

The term "fungating" describes a condition of ulceration and proliferation, which arises when
malignant tumor cells infiltrate and erode the barrier properties of the skin. This image shows
both these features in a patient with squamous cell carcinoma. Areas of tumor growth are
visible at the wound margins and on the patient's cheek and forehead, together with the
central area of ulceration.

This is a fungating tumor (buttocks) in a patient with chondrosarcoma. These tumors are
frequently complicated by sinus or fistula formation. Tumor infiltration of the skin involves
the spread of malignant cells along soft tissue planes (which offer minimal resistance), along
capillaries, lymphatic vessels, and in perineural spaces.
The clinical significance of the problem in relation to physical and psychological distress is
well documented.
[23]
Several case studies describe vividly the embarrassment that a fungating
wound causes the patient, owing principally to the problems of smell, exudate, and soiling of
clothes.
[3]
The isolation endured through not being able to share the problem with
professional caregivers, family members, and friends is also conveyed. Sims and
Fitzgerald
[24]
studied the fear associated with a fungating wound and advancing disease, and
Rutheford et al.
[25]
described the distressing associations of smell that may stay with the
family even after the patient has died.
Most wound odor appears to be associated with the metabolic process of anaerobic bacteria.
Devitalized and necrotic tissue is host to both anaerobic and aerobic bacteria. A vital source
of energy for anaerobes is lipid that has been decomposed by aerobes and facultative
anaerobes. Malodor is caused by the production of volatile fatty acids, ie, propionic,
isobutyric, butyric, isovaleric, and valeric, during lipid catabolism. Acetic acid does not
appear to have the same effect.
[26]
Most significant anaerobic infections involve 5
anaerobes.
[26,27]
These include Bacteroides fragilis, Bacteroides prevotella, Fusobacterium
nucleatum, Clostridium perfringens, and anaerobic cocci. Other pathogenic organisms that
may cause a pungent wound odor belong to the aerobic group of bacteria, the most common
being Proteus, Pseudomonas, and Klebsiella.
[5]
In the authors' experience, fungating lesions
and gangrenous wounds are most commonly associated with malodor. However, odor is very
often a major symptom in other chronic wounds, such as large venous ulcers, pressure ulcers,
neuropathic (diabetic) ulcers, and, less commonly, inflammatory ulcers.
Upon review of the literature, the authors were surprised to find numerous articles describing
the use of metronidazole for malodorous wounds. Also, there is widespread agreement among
wound care professionals that topical metronidazole is effective in controlling wound odor.
Most clinicians that use or prescribe metronidazole for this purpose rely on the commercially
available preparations (MetroGel [0.75% gel], Galderma Laboratories, Fort Worth, Tex, and
Noritate
TM
[1% cream], Dermik, Berwyn, Pa). These commercially available formulations
must be prescribed off label (in the US), since they are indicated for the treatment of
inflammatory lesions and erythema of acne/rosacea. Every article that the authors reviewed
describing the use of metronidazole to control wound odor reported positive results. These
studies and case reports cited benefit from both commercially available and compounded
(home-made) topical metronidazole formulations. Industry leaders cite the cost of clinical
trials and a small market as deterrents to pursue wound odor control as a new indication, but
with the growing chronic wound population, it merits further consideration.
Frequently, the commercially available topical metronidazole formulations are not
reimbursed. Occasionally, it is because of the cost or because it is not indicated for this use.
Ethically, the authors felt that all of the inpatients with fungating wounds should be treated
with topical metronidazole. After studying the purchasing costs involved with the
commercially available formulations, the authors asked the pharmacy to study the feasibility
of compounding a metronidazole gel for the facility. It was agreed that the authors would
study the pharmacy-compounded formulation on 20 consecutive patients with fungating
malodorous wounds. The cost to the hospital for a 45g tube of MetroGel was approximately
$43.50 compared to $1.68 for 60g (2oz jar) if the authors compounded their own.
In the authors' experience, metronidazole 0.75% gel formulated and compounded by the
facility's pharmacists was very effective for the treatment of malodorous wounds. The
response was noticeable just several hours after the initial application and continued
throughout the 2-week study period. In most instances, a once-daily application was
sufficient. In addition, 0.75% metronidazole gel was effective in controlling wound exudate.
Treatment was safe (there were no adverse events related to the use of metronidazole 0.75%
gel), easy, convenient, and cost effective.
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Funding information
This study was supported by a grant to Calvary Hospital's Ostomy and Wound Care Program
from the New York State Department of Health and the offices of New York State Senator
Charles J. Fuschillo, Jr. The authors wish to thank Joseph G. Cairo, Jr. for his assistance in
applying for this grant.
Reprint Address
Cathy Kalinski, RN, BSN, CWCN, COCN Center for Palliative Wound Care Calvary
Hospital, 1740 Eastchester Road, Bronx, NY 10461.
Wounds. 2005;17(4):84-90. 2005 Health Management Publications, Inc.