Research
Improving malodour management
1
Palliative Care Unit, Christian
Medical College, Vellore, Tamil
Nadu, India
2
Nuclear Medicine Department,
Christian Medical College,
Vellore, Tamil Nadu, India
Correspondence to
Reena George, Palliative Care
Unit, Christian Medical College,
Ida Scudder Road, Vellore,
Tamil Nadu 632004, India;
reena.vellore@gmail.com
Received 28 April 2016
Revised 7 December 2016
Accepted 19 January 2017
To cite: George R,
Prasoona TS, Kandasamy R,
et al. BMJ Supportive &
Palliative Care Published
Online First: [ please include
Day Month Year]
doi:10.1136/bmjspcare-2016-
001166
in advanced cancer: a 10-year
retrospective study of topical,
oral and maintenance metronidazole
Reena George,1 Thotampuri Shanthi Prasoona,1 Ramu Kandasamy,1
Renitha Cherian,1 Thangarathi Celine,1 Jenifer Jeba,1 Shakila Murali,1
David Mathew2
ABSTRACT BACKGROUND
Objectives To explore the relative effectiveness In the initial years of our palliative care
of topical or oral metronidazole used for service in India, the most difficult
malodour in necrotic cancers and to propose a symptom was malodour. Unlike other
protocol for metronidazole usage in managing symptoms, malodour could not be
malodour. adequately controlled by standard clinical
Methods A retrospective case note review of the protocols. The consequences of persistent
management of malodour over 10 years malodour in small homes, without
comparing outcomes with topical, intermittent running water or attached toilets,1 could
and maintenance oral metronidazole. sometimes be horrific as illustrated by
Results Among 179 patients treated for two of our early cases (box 1).
malodour, the commonest primaries were cervical
(45%), and head and neck cancers (40%).
Outcomes were poor during the period when Box 1
only topical or intermittent oral metronidazole
was used. Topical use gradually decreased (97%
Case 1
vs 55%) and the proportion of patients receiving
In 2002, a man was found face down,
maintenance oral metronidazole increased (0% in
abandoned near the oncology department
2003–2004 vs 93% in 2011). Concurrently, there
with maggots crawling out of his neck. He
was reduction in documented malodour (12.5%
had hypopharyngeal cancer and had previ-
of visits per patient in 2003–2004 vs 1.5% in
ously come regularly for radiotherapy
2011, p<0.01).
accompanied by a relative. When malodour
Conclusions Our data support formulary
increased, the family began to withdraw.
guidelines recommending maintenance
Flies laid eggs on the open fungating neck
metronidazole for recurrent malodour. Dimethyl
node, maggots developed and the patient
trisulfide, a product of anaerobic necrosis causes
was turned out of the house. He was
malodour and can attract maggot-producing flies
admitted, and the maggots were removed.
to decaying tissues. Therefore, to reduce
Since the family was unwilling to take him
anaerobic malodour in vulnerable settings, we
back, the patient was transferred to a long-
propose a ladder for metronidazole titration.
term charitable facility in another city.
High-risk patients should start with 400 mg thrice
Case 2
daily ×7 days and continue 200 mg once daily.
In 2003, a woman with recurrent cervical
The SNIFFF severity (Smell-Nil, Faint, Foul or
cancer would attend the palliative care
Forbidding) can guide follow-up dosage: 200 mg
clinic. Pain was easily controlled, but
once daily to continue for nil or faint smell;
severe malodour persisted. The patient was
breakthrough courses of 400 mg thrice daily
distressed that she was causing discomfort
×1 week for foul smell and 2 weeks for
to her daughter, son-in-law and young
forbidding smell, followed by 200 mg once daily.
grandchildren, who shared the one-room
The effectiveness and limitations of
hut. One evening, when the family was
maintenance metronidazole and the SNIFFF
away, the patient hanged herself.
ladder should be prospectively evaluated.
George R, et al. BMJ Supportive & Palliative Care 2017;0:1–6. doi:10.1136/bmjspcare-2016-001166 1
 Research
We struggled for many years to find inexpensive
and effective interventions to reduce severe recurrent
malodour, a common problem for many palliative
care services in the developing world. Even in well-
resourced settings, uncontrolled malodour can cause
embarrassment, isolation, guilt and revulsion.
Eighty-five per cent of caregivers dealing with difficult
wounds rated malodour, rather than pain or bleeding,
as the most distressing wound-related symptom.2
The goal of our research was to improve the man-
agement of malodour. We aimed to do this by retro-
spectively reviewing our data. We also wished to
understand the biochemical mechanisms underlying
refractory malodour as described in recent literature,
and summarised below.
Bacterial and biochemical aspects of malodour
Malodour is a characteristic clinical feature of anaer-
obic necrosis.3 The human body contains millions of
anaerobic bacteria. Many are useful commensals that
guard against disease-causing microbes. Anaerobes
can, however, become pathogenic when there is
mucosal injury, ischaemia or a change in the micro-
environment.3 Oral malodour, for example, is caused
mainly by indigenous mucosal bacteria.4 Anaerobic
cultures from fungating wounds have grown
Bacteroides, Fusobacterium, Peptostreptococci and
Veillonella.5
The chemicals responsible for malodour can now
be individually studied. The gas chromatography-
mass-spectroscopy-olfactometer (GC-MS-O) enables
researchers to separate volatile compounds by gas
chromatography, identify individual compounds
through mass spectroscopy and correlate each chem-
ical thus identified with the odour it emits.6 Using
GC-MS-O, Shirasu et al analysed samples from fun-
gating breast, and head and neck cancers. They
described a range of smells caused by various organic
acids: a sour odour (acetic acid), a cheese odour (iso-
butyric acid), ‘cheese and vomit’ odour (butyric acid)
and ‘cheese and foot’ odour (isovaleric acid).6 These
organic fatty acids, the products of lipid catabolism,
were earlier thought to be the main chemicals causing
malodour.5 7 None of these descriptions, however,
quite capture the nauseating smell of a putrid
tumour.2 Shirasu et al6 showed that the dominant
odourant in fungating cancers was dimethyl trisulfide
(DMTS) which had a strong ‘rotting sulfide’ odour.
DMTS is a product of decomposition and has been
found in the volatiles emitted from rotting flesh, stale
alcohol, human faeces, the stinkhorn fungus and
cooked cabbage.6 8 9 It attracts flies, including
Calliphordiae or carrion flies, which are a major cause
of maggots in decomposing mammalian tissues.10 11
The link between DMTS and maggots in fungating
cancers has not, to the best of our knowledge, been
described in clinical literature. But it probably explains
why, in our community settings, flies are quickly
2 George R, et al. BMJ Supportive & Palliative Care 2017;0:1–6. doi:10.1136/bmjspcare-2016-001166
attracted to a patient having malodourous discharge
or an open wound.12
Metronidazole for malodour
Since DMTS is produced during anaerobic necrosis,
antianaerobic microbials play a therapeutic role in
reducing malodour. In a large international survey,
wound care specialists rated metronidazole application
as more effective than expensive commercial dres-
sings.2 Metronidazole is a nitroimidazole antibiotic.
Its metabolites damage DNA strands and cause cell
death in anaerobic bacteria.13 In 1980, Ashford14
reported that oral metronidazole reduced malodour in
a patient with breast cancer who was subsequently
able to return to her job as a teacher. In a subsequent
double-blind trial,15 the same authors reported that
oral metronidazole reduced anaerobic growth and
malodour.
In an attempt to reduce systemic effects, topical
metronidazole solutions and gels were introduced,
and reported to be effective in up to 95% of cases, as
summarised in a recent systematic review.16–18 A
placebo-controlled trial of metronidazole gel (n=11)
was stopped within 2 weeks because the authors felt it
was unethical to deny a beneficial intervention to ter-
minally ill patients.19
Although collated tables indicate that metronidazole
has benefitted the majority of patients with fungating
cancers in individual studies, systematic reviews point
out that adequately powered trials with objective mea-
sures are lacking.16 20 To the best of our knowledge,
the most recent randomised trial was published
20 years ago,5 and the largest randomised controlled
trial to date has 12 patients.15 Most observational
studies of metronidazole in fungating wounds have
recruited fewer than 50 patients.21 In particular, there
is a paucity of reports with systemic metronidazole,
and of treatment outcomes in resource-poor
countries.
Thus, there are limitations in the size, duration and
generalisability of the studies on metronidazole for
malodour. We wished to study outcomes with metro-
nidazole in patients with longer term follow-up, in
economically disadvantaged settings by reviewing
retrospective data.
METHODS
Our research started with the observation that our
clinic was having fewer ‘smelly days’ during its second
decade. All the members of the interdisciplinary team
were in agreement that refractory malodour and
maggots had become much less common among our
patients on follow-up. Since we had not introduced
expensive wound care products, or new topical treat-
ments, we wondered if this improvement was asso-
ciated with changes in the way we had prescribed
metronidazole. This observation and hypothesis
prompted a retrospective study. We obtained ethical
 Research

clearance from Institutional Review Board of the Table 1 Patient characteristics

Christian Medical College, Vellore, India, to study the N (%)
case notes of patients who had been treated for Total 179 100
malodour. Gender
Our institution is a tertiary hospital in South India.
Male 53 29.6
The majority of our new registrations during the first
Female 126 70.4
decade came from over a 1000 km away, and those
Primary site
patients were excluded. We identified patients whose
Cervix 80 44.7
residence was near Vellore through our database. We
Head and neck 71 39.7
then hand-searched these 2013 case notes to identify
patients who met the inclusion criteria. We included Buccal mucosa 23
patients who had been prescribed metronidazole for Tongue 11
either malodour or discharge, and had subsequently Oral cavity, other subsites 9
come to the clinic for at least two visits. We excluded Oropharynx, other subsites 3
patients who were prescribed metronidazole for other Larynx 11
conditions such as giardiasis. Patients who did not Hypopharynx 9
report malodour or stopped coming once they devel- Maxilla 3
oped malodour would have been inadvertently Nasopharynx 1
excluded. The entire case notes of each eligible External auditory canal 1
patient were studied to note the dates when malodour Breast 6 3.5
was documented, and the dose, frequency and routes Rectum/anal canal 5 2.8
by which oral or topical metronidazole were Vulva/vagina 4 2.2
prescribed. Others 13 7.3
A major limitation of our study was that we had not
used any validated tool to serially record the severity
of malodour. Consequently, we could not estimate the
prevalence of malodour in the population, or the adenocarcinoma and about 4% had infiltrating duct
quantitative response to treatment. Gethin et al2 carcinomas. Only two patients had non-epithelial
report that fewer than 5% of wound care specialists (connective tissue) tumours. Head and neck cancer,
score the severity of malodour. and cancers of the uterine cervix were the most
As a surrogate indicator for the recurrence of mal- common primary tumours; and were significantly
odour, we calculated the proportion of visits with more likely to have recurrent malodour than other
smell (PVS) for individual patients. The median PVS cancers (table 2).
was a measure of what proportion of visits were docu- Between 2003 and 2004, malodour was managed
mented as ‘smelly’ for the average (median) patient, mainly with topical metronidazole (table 2). As metro-
during a particular time period. We also noted the nidazole gel is expensive and difficult to apply in
number of metronidazole prescriptions—topical, oral deep-seated pelvic and oral cancers, powdered metro-
full course (400 mg thrice daily for 5–7 days) or oral nidazole or parenteral preparations of metronidazole
maintenance (200 mg once daily) for each patient. were used for vaginal douches, oral rinses and topical
We compared the changing pattern of metronida- application over fungating wounds.
zole use over the decade with the median PVS at dif- Between 2005 and 2008, courses of oral metronida-
ferent periods during the first decade of our service. zole (400 mg thrice daily for 5–7 days) were increas-
The above surrogate markers only indicate how clin- ingly prescribed for problematic smell. Despite the
ical practice evolved in response to the problem of increasing use of oral metronidazole for breakthrough
malodour. The proportion of visits with malodour malodour, a significant proportion of visits by these
would probably have been higher if we had prospect- patients continued to be smelly (figure 1).
ively screened for the symptom. Starting in 2005, about a third of patients received
1–2 prescriptions of 200 mg metronidazole once daily
RESULTS until the next visit. By 2011, 93% of patients had
We identified 179 patients who met the inclusion cri- been advised to continue low-dose metronidazole
teria (table 1). (This is likely to be an underestimation 200 mg once daily (table 2). With the regular use of
because many patients do not report the symptom or low-dose metronidazole, the proportion of visits
stop coming to hospital when they develop mal- during which smell was documented dropped signifi-
odour.) The median duration of follow-up was cantly (figure 1). In summary, over the first decade,
3 months (range 2 weeks–28 months). Patients were there had been a significant increase in the use of
seen for a median of eight visits (range 2–37 visits). maintenance oral metronidazole 200 mg once daily
The biopsy reports of 133 patients were available. Of (0% in 2003–2004 vs 93% in 2011); a reduction in
these, 82% had squamous cell carcinoma, 5% had topical use (97% vs 55%) ( p=0.001, Kruskal-Wallis

George R, et al. BMJ Supportive & Palliative Care 2017;0:1–6. doi:10.1136/bmjspcare-2016-001166 3

 Research

Table 2 Proportion of visits with malodour and the use of smells that come from inside the patient, and some-
metronidazole times the whole ward smells.” Nurses in Africa speak
Primary Site n Median PVS of applying a vaginal pack soaked in thick slurry made
Cervix 80 14.3% of many powdered metronidazole tablets. This is a
Head and neck 71 12.5% challenging task for a lay caregiver when the tumour
Other 28 4.8%, p=0.025* is associated with bleeding, fistulae or hazardous dis-
charge. It also needs a considerable amount of metro-
Number of visits when nidazole each day. Early studies in gynaecological
metronidazole was prescribed, cancers used oral, not topical, metronidazole.7 In
Years Patients median and IQR more recent studies, where topical metronidazole was
Topical 400 mg thrice 200 mg used, complete malodour control was less likely in
daily oral once daily oral perineal and rectal lesions than in the more superficial
2003–2004 29 3 (2–5) 0 (0–1) 0 (0) cutaneous, breast or nodal cancers.21 In our data set,
2005–2006 34 4 (1–7) 1 (0–1.25) 0 (0–2) gynaecologic or head and neck cancers were asso-
2007–2008 45 2 (0–3) 1 (1–2) 1 (0–3) ciated with more smelly visits than other cancers
2009–2010 49 1 (0–2) 1 (1–2) 2 (0.5–3) (table 2). A single oral dose has been shown to have
2011 22 1 (0–3) 1 (1–3) 5 (2.75–11.5) greater bioavailability than topical or vaginal adminis-
*Independent-samples Kruskal-Wallis test. tration.13 In bulky or deep-seated tumours the oral
PVS, proportion of visits with smell. route is probably simpler and less expensive than
topical metronidazole.
Table 3 ‘SNIFFF’ ladder: Smell-Nil, Faint, Foul or
Forbidding? Titrating metronidazole for malodour Intermittent versus maintenance metronidazole
We had better malodour control when maintenance
Patients at high-risk of recurrent malodour/inadequate wound care:
metronidazole was used. Cervical and head and neck
▸ Give a course of oral metronidazole 400 mg thrice daily for
cancers arise in tissues with large populations of com-
7 days. Consider maintaining on 200 mg once daily*.
mensal anaerobes. The cancer changes the microenvir-
▸ Teach low-cost, home-based wound care and environmental
onment, anaerobes proliferate, histolytic enzymes
hygiene.
destroy tissues releasing necrotic malodourous discharge
On follow-up, rate severity of smell to titrate metronidazole dosage
which acts as a trigger to further microenvironment
Nil or faint smell Continue metronidazole 200 mg
once daily as maintenance. changes3 (figure 2). It is unlikely that intermittent doses
Foul smell (definite unpleasant Add 400 mg thrice daily of metronidazole will suffice in these damaged tissues
smell) metronidazole for 7 days. Then with ongoing proliferation of indigenous commensals.
continue 200 mg once daily. Dankert et al7 continued oral metronidazole 200 mg
Forbidding smell (unbearable Add 400 mg thrice daily for thrice daily in gynaecological cancers. The Palliative
smell/smell makes it difficult to 2 weeks and maintain on 200 mg Care Formulary recommends 200 mg twice daily indef-
provide care) twice daily.22
initely for recurrent malodour.22 Pharmacodynamic
*If there is a concern that caregivers might not follow up,
maintenance metronidazole could be recommended on the first visit to
studies suggest that metronidazole may have prolonged
reduce the risk of patient abandonment. activity after a single loading dose.13

Cost-effectiveness, adherence and limitations of the study

test) and a reduction in the proportion of visits with
documented smell (12.5% of visits per patient vs
1.5%) ( p=0.007, Kruskal-Wallis test). Malodour was
better controlled during the period when regular
low-dose metronidazole was administered than when
intermittent courses of standard-dose metronidazole
were used. Adherence was satisfactory within the limi-
tation of a retrospective analysis.
DISCUSSION
Topical versus oral metronidazole
Treatment outcomes were disappointing when topical
application was the mainstay of treatment. It is diffi-
cult to apply adequate doses in deep-seated head and
neck, and cervical cancers. A senior nurse in a large
inpatient facility in India said, “With good nursing
care we can control the smells that come from near
the surface of the body. It is difficult to control the
A retrospective study has many limitations. We had
not measured the serial severity of malodour; hence
we could not estimate the percentage response in indi-
vidual patients. The actual prevalence of malodour
too, would probably have been higher than is
reported here. We could only compare the pattern of
care with the overall outcome, and generate a hypoth-
esis that needs to be validated prospectively.
Another limitation is that we had not systematically
screened for undesirable effects. Nausea and vomiting
were not common symptoms. Patients on low-dose
maintenance generally did not complain of a bitter
taste, and adherence was good. Low-dose metronida-
zole is less likely than full course metronidazole to
cause major disulfiram reactions with alcohol. Some
metronidazole syrups even contain alcohol.22 Williams
and Woodcock23 have reviewed literature to report
that disulfiram-like effects with metronidazole are

4 George R, et al. BMJ Supportive & Palliative Care 2017;0:1–6. doi:10.1136/bmjspcare-2016-001166


Figure 1 Malodour recurrence versus maintenance metronidazole.
Figure 2 The vicious cycle of malodour and necrotic discharge in cancer.
rare, and that the link is not conclusively proven.
With the limitations of our data set, we cannot draw a
definite conclusion regarding disulfiram-like effects
with low-dose metronidazole. A dose of 200 mg is
generally safe in liver and renal failure.22
Oral metronidazole is much less expensive than the
gel and hence affordable to poor patients.22 The total
cost of 6 weeks of metronidazole 200 mg once daily
or 1 week of 400 mg thrice daily is <US$1 (about 25
Indian rupees).
Need for further research
Our findings need to be tested, ideally in a multicentre,
double-blind randomised trial which compares full
course metronidazole followed by oral maintenance
metronidazole, topical metronidazole or placebo. Study
participants with malodourous lesions should be
recruited from high, middle and low-income countries.
Malodour should be measured using a validated score
at baseline and, after a week of non-pharmacological
treatment, to quantify the premetronidazole benefit.
The serial severity of malodour should then be regularly
measured while on the study interventions.
In addition to the primary endpoint of malodour
recurrence, relevant secondary endpoints should also
be studied. These could include drug-related factors
such as adherence, alcohol consumption and adverse
effects; disease-related endpoints such as the incidence
George R, et al. BMJ Supportive & Palliative Care 2017;0:1–6. doi:10.1136/bmjspcare-2016-001166
Research
of necrotic fistulae, abscesses, sepsis and the duration
of survival. Qualitative methods can additionally be
applied to understand the subjective experience of
patients, caregivers and healthcare providers.
If adequately powered, and appropriately stratified
for risk and setting, such a study may identify vulner-
able patients needing maintenance metronidazole and
estimate the number needed to treat.
Simple clinical ‘ladder’ to measure and manage chronic
malodour
The ‘number harmed by not treating’ malodour
remains a matter of immediate concern. This can
happen even when the patient is being looked after by
palliative care services. The son of a patient with mal-
odour said, “Other palliative care services had con-
trolled my mother’s pain, but the smell kept coming
back and it was difficult to go near her. We are very
grateful that the smell could be controlled in her final
weeks.” Less committed caregivers stop bringing mal-
odourous patients to hospital even for anticancer
treatment, and potentially curable tumours like cer-
vical cancer become fatal.24
Cervical, head and neck, rectal and other bulky fun-
gating lesions are a major part of the global cancer
burden.25 Chronic, non-malignant neglected wounds
become malodourous. Many patients do not have access
to skilled community nurses.26 Rather than exhorting
5
 Research
family caregivers to do regular dressings to keep mal-
odour down, clinicians should treat malodour regularly
so that caregivers are willing to undertake dressings.
Figure 2 illustrates the vicious cycle of anaerobic necro-
sis, caregiver withdrawal and worsening smell.
Therefore, integrating formulary recommendations
and our findings, we propose a smell ‘ladder’ that can
be used by busy clinicians. During follow-up visits,
while talking to the patient, the smell can be quickly
graded as SNIFFF (Smell-Nil, Faint, Foul or
Forbidding). The suggested dosage of maintenance or
breakthrough metronidazole for different degrees of
smell is summarised in table 3.
This simple ladder for chronic malodour manage-
ment will, we hope, improve malodour control for
some patients, until better evidence becomes available.
CONCLUSIONS
Our retrospective data suggest that maintenance
metronidazole may reduce the recurrence of mal-
odour in tissues with ongoing anaerobic necrosis. A
simple ladder for treating malodour may help in man-
aging this distressing condition. This needs to be eval-
uated through further research.
Acknowledgements We thank Robert Twycross for his valuable
suggestions, and Vaishali Jayachandran for the statistical
analysis. We thank John Lunn, Sr. Rosemund, Leema Mathew,
MP Thressiamma and Roja Rekha for clinical and
administrative support.
Contributors RG designed the study, interpreted data, drafted
the SNIFFF protocol and wrote the paper. TSP and RK
interpreted and managed data and helped write the paper. RK
screened for cases, extracted data, coordinated data
management, data presentation and patient follow-up. RMC
and TC interpreted and managed data and assisted with data
acquisition. RG, TSP, RMC, TC, JJS, SM and DM contributed
to the evolution of clinical protocols over the decade. All
authors critically reviewed and approved the manuscript.
Competing interests None declared.
Ethics approval The study received ethical approval from the
Institutional Review Board, Christian Medical College, Vellore,
India.
Provenance and peer review Not commissioned; externally
peer reviewed.
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