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 ventilation7 and charcoal dressings that absorb these fatty acids8 seldom adequately control this odor.   The deodorizing effect of metronidazole9–13 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.


  Study medication. 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®, 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.   Study design. The study was a prospective, single-center, open (uncontrolled) trial. Sixteen consecutive consenting patients presenting with malodorous wounds were enrolled for this clinical study (Table 1). 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.   Treatment protocol and dressings. 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®, 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, 1–1.5mm) 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.   Cost. 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.   Statistical analysis. 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).   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 Table 2. The cost for the compounded formulation was $1.68 for a 2oz jar (or $0.028/g) and the cost of MetroGel® (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.


  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 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 Fitzgerald24 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® [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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