S YS T E M AT I C R E V I E W

Treatment of Madura foot: a systematic review

Amos Omondi Salim 1,2  Clifford Chacha Mwita 1,3  Samson Gwer 1,4
1
Afya Research Africa (ARA): a Joanna Briggs Institute Centre of Excellence, 2Department of Orthopaedic Surgery, School of Medicine, University of
Nairobi, Nairobi, Kenya, 3Department of Surgery and Anaesthesiology, School of Medicine, Moi University, Eldoret, Kenya, and 4Department of
Medical Physiology, School of Medicine, Kenyatta University, Nairobi, Kenya

ABSTRACT

Review question/objective: The objective of this review was to determine the best available evidence on the
most effective treatment of Madura foot.
Introduction: Madura foot or mycetoma is a chronic granulomatous soft-tissue infection that is endemic to several
regions of Africa and Asia. It may be of fungal (eumycetoma) or bacterial (actinomycetoma) origin, warranting
Downloaded from http://journals.lww.com/jbisrir by BhDMf5ePHKbH4TTImqenVHXBtH07/PgUIJCyDbnlCpBN1BrD/hk2rAVt0MkTuDJSnV3ppD+LM6g= on 02/13/2019

therapy with either antifungal or antibacterial medication as well as surgery. Without timely intervention, it often
results in lifelong disability. However, it is unclear what regimes are most effective for treatment.
Inclusion criteria: This review considered studies that included individuals of all ages with Madura foot (actino-
mycetoma or eumycetoma) as confirmed by microbiological or histological studies. Studies that evaluated antibiotic
and antifungal regimens (any drug, dosage, frequency, duration) as well as surgical interventions (wound debride-
ment, advanced excision or limb amputation) for Madura foot were included. Outcomes of interest were disease
resolution (as determined by complete healing of mycetoma lesion after treatment), recurrence (return of mycetoma
lesion after successful treatment) and mortality. Although this review considered both experimental and epidemio-
logical study designs for inclusion, only case series and individual case reports were identified and were therefore
included in the review.
Methods: A three-step search strategy, involving an initial search, a second more comprehensive search using
identified keywords and a third search involving the reference lists of included articles, was utilized. Ten databases
were searched. An additional 13 sources were searched for gray and/or unpublished literature. Included studies were
assessed by two independent reviewers for methodological validity prior to inclusion in the review using
standardized critical appraisal instruments from the Joanna Briggs Institute. Disagreements were resolved through
discussion or with a third reviewer. A data extraction tool was used to extract data on interventions, populations,
study designs and outcomes of significance to the review question. Statistical pooling was not possible, therefore a
narrative synthesis was performed.
Results: Thirty-one studies were included in the review (27 case reports and four case series). A total of 47 patients
with Madura foot were analyzed. Twenty-five had eumycetoma, 21 actinomycetoma and one had both. Therapy
involved varying dosages of sulfa drugs (co-trimoxazole and dapsone), amikacin and tetracyclines administered for
the therapy of actinomycetoma with resolution of disease in all affected patients. The azole derivatives (itraco-
nazole, ketoconazole, voriconazole, fluconazole and miconazole) as well as co-trimoxazole were the most
commonly employed drugs for eumycetoma, with resolution of disease in 88% of included patients. Surgery
was performed in a total of 21 patients with resolution of disease in all cases. The overall resolution rate following
therapy was 95.7%.
Conclusion: Therapy for Madura foot is informed by case series and case reports which provide low level evidence
for practice. Antimicrobials in conjunction with surgery lead to resolution of disease.
Keywords Mycetoma; Madura foot; actinomycetoma; eumycetoma; antifungal
JBI Database System Rev Implement Rep 2018; 16(7):1519–1536.

Correspondence: Amos Omondi Salim, usalem97@yahoo.com

There is no conflict of interest in this project.
DOI: 10.11124/JBISRIR-2017-003433

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SYSTEMATIC REVIEW A.O. Salim et al.

GRADE Summary of Findings

Treatment of Madura foot: a systematic review
Bibliography: Salim AO, Mwita CC, Gwer S. Treatment of Madura foot: a systematic review. JBI Database
System Rev Implement Rep 2018; 16(7):1519–1536.
Outcomes № of participants Certainty Impact
(studies) of the evi-
Follow-up dence
(GRADE)

Antibiotics for actinomycetoma

Disease resolution assessed with:
clinician assessment
Antifungals for eumycetoma
Disease resolution assessed with:
clinician assessment
21 All patients who received
(12 observational studies) VERY antibiotics for actinomycetoma
LOWa had resolution of disease
25 Disease resolution was high (22
(19 observational studies) VERY out of 25 participants; 88%) with
LOWa the use of various antifungal
agents for eumycetoma

Surgerical intervention for actinomycetoma

Disease resolution assessed with: 6 All patients with actinomycetoma
clinician assessment (5 observational studies) VERY undergoing surgery had resolution
LOWa of disease
Surgical intervention for eumycetoma

Disease resolution assessed with: 15 All patients with eumycetoma who

clinician assessment (13 observational studies) VERY underwent surgery had resolution
LOWa of disease
* The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison
group and the relative effect of the intervention (and its 95%CI).
CI: Confidence interval
a. Although included studies were well conducted case reports/series, the small sample sizes involved increase the risk of
bias
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of
the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the
estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different
from the estimate of effect

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SYSTEMATIC REVIEW
Introduction
adura foot or mycetoma is a chronic granulo-
M matous soft-tissue infection caused by either
true fungi (eumycetoma) or gram-positive aerobic
bacteria (actinomycetoma).1-3 Although data on the
global burden of this disease are lacking, the infection
is known to be endemic to equatorial, tropical or sub-
tropical regions of the world.1 The highest reported
prevalence of the disease is in Mauritania in the
northwestern part of Africa with 3.49 cases per
100,000 inhabitants while Sudan has the highest
number of cases reported per year (106 cases reported
annually).4 Sporadic cases have been reported in the
Western world, mostly in the migrant population. The
disease affects individuals of all ages but is common
among adult males aged 20 to 50 years.3,5 Owing to
its socioeconomic impact, the World Health Organi-
zation (WHO) now considers Madura foot one of the
neglected tropical diseases (NTDs).6
Madura foot develops after traumatic inoculation
of subcutaneous tissues with contaminated soil and
the infection thereafter progresses to adjacent tissues
or bone. The foot, hand and lower leg regions are the
most commonly affected areas.4 The disease follows a
slow progression from the time of traumatic inocula-
tion to presentation of symptoms. Although this
period is variable, it may be as long as 12 years.7
Affected patients typically present with a chronic
indurated swelling on the affected site, draining
sinuses and discharging granules. The granules are
diagnostic as they represent collections of fungal
hyphae or bacterial filaments.1 An adequate diagnos-
tic procedure is essential in guiding appropriate choice
of therapy. A deep biopsy for histology appears to give
a more substantial contribution to identification of
the causal organism when compared to culture.8
Patients with actinomycetoma are treated with an
antibiotic and can expect to have clinical cure with
little chance of recurrence. There appears to be no
standards in choice of antibiotics and duration of
treatment, although, admittedly, considerations for
therapy may be tampered by the apparent extent of
the disease.9 If not identified and treated early enough,
actinomycetoma may have a rapid course and can
lead to amputation or death secondary to systemic
spread. In contrast, eumyecetoma has a more insidi-
ous course, is less responsive to even new antifungal
agents, has a high recurrence rate, and often results in
amputation.10 It is not clear whether the choice of
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A.O. Salim et al.
antifungal agents and duration of treatment can alter
the subsequent need for surgical amputation. Early
detection and prompt treatment may have better
outcomes. This limits the extent of amputation and
leads to a shorter hospital stay, both of which are
associated with greater cost-effectiveness.11,12
There is unclear guidance on the most appropriate
treatment strategy for Madura foot. A search of the
Cochrane Library and the JBI Database of Systematic
Reviews and Implementation Reports showed no
reviews addressing treatment of Madura foot. In this
systematic review, we examined available literature
for the best available evidence on the most effective
antimicrobial choices for Madura foot as well as the
most appropriate sequence and timing of surgical
intervention for eumycetoma and actinomycetoma.
The review was conducted following procedures out-
lined in a published protocol.13 It is reported accord-
ing to the Preferred Reporting Items for Systematic
Reviews and Meta-analysis (PRISMA) guidelines.14
Review question/objective
The objective of this review was to determine the best
available evidence on the treatment of Madura foot.
More specifically, the objectives were to identify:
1. The most effective antibiotics for treatment
of actinomycetoma.
2. The most effective antifungal agents for treat-
ment of eumycetoma.
3. The most appropriate stage or timing for surgi-
cal intervention for eumycetoma.
Inclusion criteria
Participants
This review considered studies that included individ-
uals of all ages with Madura foot (actinomycetoma
or eumycetoma) as confirmed by histological stud-
ies. However, as a slight deviation from the review
protocol, we also considered studies in which
Madura foot was confirmed by microbiological
methods as well as studies in which patients with
mycetoma of other body regions were mixed with
those who had Madura foot but from which data on
foot involvement could be abstracted.
Intervention
This review considered studies that evaluated anti-
biotic and antifungal regimes (any drug, dosage,
frequency, duration) as well as surgical interventions
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SYSTEMATIC REVIEW
(wound debridement, advanced excision or limb
amputation) for Madura foot. Although studies in
which these interventions were compared to each
other (at different doses, duration, routes of admin-
istration or alternative surgical interventions) were
envisaged in the protocol, no comparative studies
were identified and therefore no comparators could
be specified.
Outcomes
This review considered studies that assessed antimi-
crobial regimes and/or surgical intervention for
Madura foot using the following outcomes:
i) Resolution of disease (absence of mycetoma
lesion following intervention as determined
by a health professional at time of follow-up).
ii) Recurrence of disease (recurrence of mycetoma
lesion after a period of resolution following
therapy as determined by a health professional
at time of follow-up).
iii) Mortality.
As a deviation from the review protocol, limb ampu-
tation was omitted asan outcome because it is one of the
surgical interventions available for Madura foot.
Types of studies
This review considered both experimental and epide-
miological study designs including randomized con-
trolled trials, non-randomized controlled trials, quasi-
experimental, before and after studies, prospective and
retrospective cohort studies, case-control studies and
analytical cross-sectional studies for inclusion. How-
ever, only case series and individual case reports were
identified and were therefore included in the review.
Methods
Search strategy
The search strategy aimed to find both published and
unpublished studies. A three-step search strategy was
utilized in this review. An initial limited search of
MEDLINE was undertaken followed by analysis of
the text words contained in the title and abstract, and of
the index terms used to describe the article. A second
search using all identified keywords and index terms
was then undertaken across all included databases.
Thirdly, the reference lists of all identified reports
and articles were searched for additional studies.
The databases searched were MEDLINE (via
PubMed), Cumulative Index to Nursing and Allied
Health Literature (CINAHL via EBSCOhost),
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A.O. Salim et al.
Cochrane CENTRAL and Embase (Elsevier plat-
form). Other databases searched included Current
Controlled Trials, The Trials Register of Promoting
Health Interventions (TRoPHI), Australian Clinical
Trials Registry (ACTR), Clinical Medicine Net
Prints Collection, Bandolier Evidence Based Health
Care, and The Center for Clinical Trials and Evi-
dence-based Healthcare at Brown Medical School.
The search for unpublished studies and gray liter-
ature included WHO, United Nations High Commis-
sioner for Refugees (UNHCR) and International
Organiszation of Migration (IOM) records, Centers
for Disease Control and Prevention reports, Disserta-
tion Abstracts International, WHO Library, Agency
for Healthcare Research and Quality, Grey Literature
Report, National Library of Medicine, Theses
Canada Portal, ProQuest Digital Theses, Australasian
Digital Theses Program and the British Library.
Since Madura foot is an uncommon diagnosis,
we opted to devise an exhaustive search so as to
increase the chances of finding as many relevant
studies as possible. The terms used were both
medical subject headings (MeSh) terms and free
terms using the words ‘mycetoma’, ‘Madura foot’,
eumycetoma, actinomycetoma and ‘foot diseases’.
These terms were combined using Boolean opera-
tors and the same search strategy was used across
all databases with relevant modifications, where
necessary. The search strategy employed across the
major databases searched is shown in Appendix I.
Only studies published from the January 1, 1950
(being the first date of systematic indexing in the
primary search database [MEDLINE]) and avail-
able in the English language were considered for
inclusion in this review. The last search was per-
formed in December 2016.
Assessment of methodological quality
Papers selected for retrieval were assessed by two
independent reviewers for methodological validity
prior to inclusion in the review using standardized
critical appraisal instruments from the Joanna
Briggs Institute for case series and case reports.15
Any disagreements that arose between the reviewers
were resolved through discussion or with a third
reviewer.
Data extraction
Data were extracted from papers included in the
review using a data extraction tool specifically
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SYSTEMATIC REVIEW A.O. Salim et al.

designed for the review (Appendix II). The data Results

extracted included specific details about the inter-
ventions, populations, study design and outcomes of
significance to the review question and specific
objectives. Where there was missing information
or lack of clarity in available data, an attempt was
made to contact authors of primary studies although
no response was received.
Data synthesis
A meta-analysis could not be performed as this
review only identified case series/reports with a wide
range of interventions, therefore the results of these
studies have been synthesized in narrative and
tabular form.
Study selection
A total of 304 articles were identified through data-
base searching. No additional studies were identified
through other sources. The 304 studies were
screened and 243 of the studies were excluded,
236 of which did not meet the inclusion criteria
and seven could not be retrieved for full text review.
The remaining 61 studies underwent full text review
and 30 were excluded for various reasons (Appendix
III). The remaining 31 articles met the eligibility
criteria and were included in the review. No addi-
tional studies were identified from searching the
reference lists of identified studies. Figure 1 depicts
the Preferred Reporting Items for Systematic

Studies idenfied through Addional studies idenfied

database searching through other sources
(n = 304) (n = 0)

Studies aer duplicates removed

(n = 304)

Studies screened Studies excluded

(n = 304) (n = 236)

Full-text arcles assessed Full-text arcles excluded,

for eligibility with reasons
(n = 68) (n = 30)
Full-text arcles could not
be retrieved
(n=7)
Studies included in
narrave synthesis
(n = 31)

Studies included in
quantave synthesis
(meta-analysis)
(n = 0)

Figure 1: PRISMA flowchart of study selection and inclusion process14

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SYSTEMATIC REVIEW A.O. Salim et al.

Reviews and Meta-Analyses (PRISMA) flowchart
showing the study selection process.
Characteristics of included studies
Of the 31 included studies, 27 were case reports and
four were case series, all published in English between
197516 and 201517 and describing patients with
Madura foot in whom pharmacotherapy or surgery
(alone or in combination) were admnistered. Studies
were from India,18-23 Europe,1,2,7,17,24-30 North
America,5,10,31-36 Latin America,37,38 Middle East,39
Australasia40,41 and Africa.16 A total of 47 partic-
ipants (age range eight to 71 years; 15 females) were
studied. Of these, 25 had eumycetoma, 21 had
actinomycetoma while one had both fungal and
bacterial etiology. The overall duration of illness
ranged from 48 hours to 23 years. Outcomes of
therapy included either resolution (95.7% of par-
ticipants) or recurrence (2.1% of participants). No
study reported mortality as a direct outcome of
Madura foot. The characteristics of individual stud-
ies are shown in Tables 1 and 2.

Table 1: Characteristics of included studies on actinomycetoma

Patient Total follow-
Author/date Country Study design characteristics Intervention Outcome up period
Sharma 200321 India Case report 24 y.o. male Trimethoprim 160 mg – Resolution as Not reported
with actinomyce- 800 mg BD for 5 weeks with determined by a
toma for 5 years no response followed by IM clinician
Amikacin 15 mg/kg OD and
dapsone 100 mg OD for 21
days. Dapsone 100 mg OD
given for a further 2 weeks –
all constituting 1 cycle. 5 cycles
given. Dapsone given for 6
weeks after last cycle.
Pulikot 200220 India Case report 10 y.o. male with Sulphamethoxazole (75mg/ Tri- Resolution as 6 months
actinomycetoma for methoprim 15mg), Dapsone determined by a
6 years (1mg/kg BD) and rifampicin clinician
(10mg/kg OD) for 8 months
Tilak 200922 India Case report 45 y.o. male with Oral Dapsone (100 mg OD), Resolution as Not reported
actimomycetoma for Bactrim (1 tablet BD) and determined by a
15 years rifampicin (100 mg OD) for 5 clinician
months
Giavedoni 201426 Spain Case report 39 y.o. male with IM Amikacin (500 mg OD for Resolution as Not reported
actinomycetoma for 21 days) then trimethoprim/Sul- determined by a
1 year phamethoxazole (2g OD for 6 clinician
months).
Saraca 199338 Brazil Case report 23 y.o. male with Dapsone, Trimethoprim Resolution as 9 years
actinomycetoma of Sulfamethoxazole, Sulfadiazine determined by a
unknown duration followed by amputation. clinician
Freed 197516 South Africa Case report 40 y.o. male with Tetracycline (500 mg QID) Resolution as Not reported
actonomycetoma for 5 months followed by determined by a
for 1 year amputation clinician
Gyotoku 200241 Japan Case report 65 y.o. male with Oral Minocycline (100 mg OD) Resolution as 1 year
actinomycetoma for and oral Trimethoprim/ determined by a
5 years Sufamethoxazole (4g OD) for clinician
1 month followed by surgical
excision
Foltz 20045 USA Case report 38 y.o. male with Wound excision followed by Resolution as 1 year
actinomycetoma trimethoprim/Sulfamethoxazole determined by a
for 6 months (160/800 mg BD) and Rifampin clinician
(300mg) for 6 months
Davis 199910 USA Case report 24 y.o. male with Wound excision followed by Resolution as Not reported
actinomycetoma for doxycycline 100 mg BD determined by a
8 years clinician
Pelzer 200028 Germany Case report 65 y.o. male with Itraconazole 200 mg OD and Resolution as Not reported
actinomycetoma 320 mg Trimethoprim/ Sulfa- determined by a
and eumycetoma methoxazole 600 mg OD for clinician
7 months

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SYSTEMATIC REVIEW A.O. Salim et al.

Table 1. (Continued)
Patient Total follow-
Author/date Country Study design characteristics Intervention Outcome up period
Kamalam 198718 India Case series 10 patients (age Tetracycline for up to 6 years. Resolution in all 6 months to
range 17–40 years; 2 patients had surgery 10 subjects as 6 years
3 females) with determined by a
actinomycetoma for clinician
between 6 months
and 20 years
Buonfrate 20147 Italy Case series 2 male patients Trimethprim-Sulfamethoxazole Resolution in both 2 and 16 years
(43 and 46 y.o.) for 2 years subjects as deter-
with actinomyce- mined by a clini-
toma for up to cian
12 years
OD: once daily; BD: twice daily; QID: four times daily; IM: intramuscular; mg: milligram; g: gram; kg: kilogram; y.o.: years old

Table 2: Characteristics of included studies on eumycetoma

Study Patient Total follow–

Author/date Country design characteristics Intervention Outcome up period
Gunduz 200627 Turkey Case report 29 y.o. female with Itraconazole 200 mg OD for Resolution as Not reported
eumycetoma for 4 months and 160 mg determined by a
15 years Trimethoprim/ 800 mg clinician
sulfamethoxazole BD for
10 months
Asly 201024 France Case report 50 y.o. female with Below knee amputation Resolution as 6 months
eumycetoma for determined by a
23 years clinician
Burkus 198532 USA Case report 44 y.o. female with En block excision Resolution as 4 months
eumycetoma for determined by a
6 months clinician
Porte 200630 France Case report 49 y.o. female with Oral Voriconazole 400 mg BD Resolution as 9 months
eumycetoma for for 2 days then 200 mg BD determined by a
unknown for 18 months clinician
duration
Lindsley 200833 USA Case report 29 y.o. male with Voriconazole for 6 weeks as Resolution as 4 months
eumycetoma for well as unspecified broad determined by a
3 years. spectrum antibiotics clinician
Bonifaz 200937 Mexico Case report 57 y.o. Itraconazole 300 mg OD Resolution as 18 months
male with tapered off to 100 mg OD for determined by a
eumycetoma 20 months. clinician
for 3 years
Turiansky 199535 USA Case report 29 y.o. Oral Ketoconazole 200 mg BD No resolution 6 months
female with for 1 year as well as intrale- of disease as
eumycetoma sional miconazole for 8 weeks determined by a
for 7 years clinician at time
of follow-up
Cunningham 199625 UK Case report 71 y.o. male Amphotericin B 1mg/kg daily Resolution as 3 months
with eumycetoma then alternate days for 1 determined by a
for 48 hours month then oral itraconazole clinician
300 mg BD later tapered to
100 mg BD for 2 months

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Table 2. (Continued)
Study Patient Total follow–
Author/date Country design characteristics Intervention Outcome up period
Capoor 200718 India Case report 8 y.o. male with Monthly wound debridement Resolution as Not reported
eumycetoma for followed by co-trimoxazole determined by a
1 year for 5 days and oral Ketocona- clinician
zole 100 mg BD for 2 months
Southern 199634 USA Case report 15 y.o. male with Wound debridement followed Resolution as 16 months
eumycetoma for by amphotericin B, ketocona- determined by a
unknown duration zole 400 mg BD, flucytosine clinician
100mg/ day, ketoconazole and
fluconazole 200 mg OD all for
14 months
Chazan 200439 Israel Case report 45 y.o. male with IV Liposomal Amphotericin B Resolution as 16 months
eumycetoma for 3mg/kg OD for 5 days determined by a
3 months followed by debridement clinician
and oral Itraconazole for
5 months
Gunathilake 201440 Australia Case report 50 y.o. female with Debridement followed by oral Resolution as 2 years
eumycetoma for Itraconazole 200 mg BD for determined by a
5 years 12 months clinician
Mestre 201517 Portugal Case report 43 y.o. female with Wound excision followed by Resolution as Not reported
eumycetoma for oral Itraconazole 400 mg per determined by a
unknown duration day for 16 months clinician
Hood 199728 UK Case report 30 y.o. female with Surgical debridement followed Resolution as 18 months
eumycetoma for by Itraconazole 400mgs OD determined by a
4 months and flucytosine 1g TID for clinician
1 year
Warintarawej 197536 USA Case report 23 y.o. male with Extensive wound debridement Resolution as 3 months
eumycetoma for irrigation and packing with determined by a
6 years gauze containing amphotericin clinician
B at 1mg/ml concentration.
Dressing changes continued
for 6 weeks
Bakerspiegel 198331 Canada Case report 25 y.o. female with Wound excision followed by Resolution as 2 years
eumycetoma for IV Miconazole 600 mg TID determined by a
2 years for 23 days clinician
El Muttardi 20101 UK Case report 16 y.o. female with Wound excision followed by Resolution as 1 year
eumycetoma for fluconazole 400 mg OD for determined by a
4 years 6 months clinician
Venugopal 199323 India Case series 5 patients (age Oral Ketoconazole 200 mg BD Resolution in all 4 months to
range 18–45 years; for between 8 and16 months. five subjects as 2 years
2 females) with Three patients had surgical determined by a
eumycetoma for excision clinician
1.5–4 years
Mattioni 20132 France Case series 3 patients (age Combinations involving Resolution in sub- Up to 9 years
range 16–34 years) amoxicillin þ itraconazole þ ject with surgery;
with eumycetoma fluconazole þ terbinafine therapy failure in
for between 5 and followed by surgery, the remaining
12 years Cotrimoxazole þ two; outcomes
voriconazole þ caspofungin, determined by a
Voriconazole þ itraconazole þ clinician
cotrimoxazole
OD: once daily; BD: twice daily; TID: three times daily; IV: intravenous; mg: milligram; g: gram; kg: kilogram; y.o.: years old

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Methodological quality Review findings

The methodological quality of included studies is The review findings are presented in narrative form
depicted in Tables 3 and 4. Among the four case according to the general class of interventions used
series studies, only one study stated the inclusion for therapy.
criteria clearly.2 Inclusion criteria were unclear in
three studies.7,19,23 The condition of interest was
measured using a valid and reliable method in all
Antibiotics for actionomycetoma
A total of 12 studies reported on the use of anti-
four studies, i.e. presence/absence of Madura foot
biotics for actinomycetoma. Two were case series7,19
was determined using a repeatable, reproducible,
and 10 were case reports.5,10,16,20-22,26,29,38,41 Over-
valid and objective diagnostic method. In all four
all, four antibiotic classes were utilized for the treat-
of these case series, it was unclear whether patient
inclusion was consecutive or not. Further, in three ment of actinomycetoma. The sulfa drugs (Co-
trimoxazole, dapsone and sulfadiazine) and the tet-
of these studies,7,19,23 it was unclear if patient
racyclines (tetracyline, doxycycline and minocy-
inclusion was complete, i.e. it was difficult to
cline) were the most utilized drugs. Rifampicin
determine if all patients with the condition of
and the aminoglycoside amikacin were the other
interest who presented during the study period
drugs employed. The antifungal itraconazole was
were included in the series or whether there were
used for therapy in studies where both actinomyce-
some who were excluded and this affected the
toma and eumycetoma were diagnosed.29 Drug
reliability of individual studies. In all four studies,
there was clear reporting of patient demographic doses, routes of administration and duration of
therapy were variable (Table 1). Out of 21 patients
characteristics, clinical characteristics and the
with actinomycetoma, all had resolution of disease
outcome of therapy. However, none of these
as determined by the absence of Madura foot lesion
studies reported on the demographic character-
after a period of therapy. Although none of the
istics of the presenting site and this may have had
included studies explicitly reported resolution as
an impact on the external validity of included
an outcome, there was sufficient information from
studies.
each study that therapy had led to healing of the
The remaining 27 studies were case
reports.1,5,10,16-18,20-22,24-41 All of them described Madura foot lesion. No disease recurrence was
reported during the six months to 16 years of fol-
clearly the patient demographics, the clinical history
low-up after therapy for actinomycetoma. The out-
and condition of the patient, the diagnostic tests
come of studies on actinomycetoma is shown in
utilized, the interventions applied and the clinical
Table 1.
condition after intervention. However, only eight
studies explicitly reported the adverse events associ-
ated with therapy.17,18,21,25,27-29,31 All 27 reports Antifungals for eumycetoma
highlighted a clinically relevant lesson for clinical A total of 19 studies reported on the use of anti-
practice. Overall, the studies included in this review fungals for eumycetoma. Two were case series2,23
were of good quality. and 17 were case reports.1,17,18,24,25,27,28,30-37,39,40

Table 3: Methodological quality of included case series studies

Condition Valid Clear Outcomes Clear
Clear measured in methods for Clear reporting or follow up reporting of Statistical
inclusion standard, identification Consecutive Complete reporting of of clinical results presenting site(s) analysis
criteria reliable way of condition inclusion inclusion demographics information reported demographics appropriate
Kamalam No Yes Yes Unclear Unclear Yes Yes Yes No N/A
198719
Buonfrate No Yes Yes Unclear Unclear Yes Yes Yes No N/A
20147
Venugopal No Yes Yes Unclear Unclear Yes Yes Yes No N/A
199323
Mattioni Yes Yes Yes Unclear Yes Yes Yes Yes No N/A
20132

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SYSTEMATIC REVIEW A.O. Salim et al.

Table 4: Methodological quality of included case report studies

Current
clinical Post-
Patient’s Patient’s condition of Diagnostic Interventions/ intervention Adverse
demographic history clearly the patient on tests/assessment treatment clinical events Case report
characteristics described and presentation methods and procedures condition identified provides take
clearly presented as clearly results clearly clearly clearly and away
described a timeline described described described described described lessons
Sharma 200321 Yes Yes Yes Yes Yes Yes Yes Yes
Pulikot 200220 Yes Yes Yes Yes Yes Yes No Yes
22
Tilak 2009 Yes Yes Yes Yes Yes Yes No Yes
Giavedoni 201426 Yes Yes Yes Yes Yes Yes No Yes
Saraca 199338 Yes Yes Yes Yes Yes Yes No Yes
Freed 197516 Yes Yes Yes Yes Yes Yes No Yes
41
Gytotku 2002 Yes Yes Yes Yes Yes Yes No Yes
Foltz 20045 Yes Yes Yes Yes Yes Yes No Yes
Davis 199910 Yes Yes Yes Yes Yes Yes No Yes
Pelzer 200029 Yes Yes Yes Yes Yes Yes No Yes
27
Gunduz 2006 Yes Yes Yes Yes Yes Yes Yes Yes
Asly 201024 Yes Yes Yes Yes Yes Yes N/A Yes
Burkus 198532 Yes Yes Yes Yes Yes Yes N/A Yes
Porte 200630 Yes Yes Yes Yes Yes Yes Yes Yes
Lindsley 200833 Yes Yes Yes Yes Yes Yes No Yes
37
Bonifaz 2009 Yes Yes Yes Yes Yes Yes No Yes
Turiansky 199535 Yes Yes Yes Yes Yes Yes No Yes
Cunningham 199625 Yes Yes Yes Yes Yes Yes Yes Yes
Capoor 200718 Yes Yes Yes Yes Yes Yes Yes Yes
34
Southern 1996 Yes Yes Yes Yes Yes Yes No Yes
Chazan 200439 Yes Yes Yes Yes Yes Yes No Yes
Guanthilake 201440 Yes Yes Yes Yes Yes Yes No Yes
Mestre 201517 Yes Yes Yes Yes Yes Yes Yes Yes
28
Hood 1997 Yes Yes Yes Yes Yes Yes Yes Yes
Warintarawej 197536 Yes Yes Yes Yes Yes Yes No Yes
Bakerspiegel 198331 Yes Yes Yes Yes Yes Yes Yes Yes
El Muttardi 20101 Yes Yes Yes Yes Yes Yes No Yes

Seven antimicrobial classes were used for the treat-
ment of eumycetoma. Azole derivatives were the
most widely used drugs. The sulfa drugs (co-trimox-
azole), polyenes (amphotericin B), nucleoside ana-
logs (flucytosine), allylamines (terbinafine),
aminobenzylpenicillins (amoxicillin) and the echino-
candins (caspofungin) were also utilized. Drug
doses, routes of administration and duration of
therapy were variable (Table 1). However, 88%
(22 out of 25) of patients with eumycetoma had
resolution of disease as determined by the absence of
eumycetoma lesion after a period of therapy. One
patient had both actinomycetoma and eumyce-
toma.29 There was resolution of disease after therapy
with both antifungal and antibiotic therapy. Three
out of 25 patients (12%) had a reported recurrence
of the lesion (as determined by the reappearance of
eumycetoma lesion after a period of healing). In one
patient, recurrence occurred within six months of
follow-up, while in the other two, recurrence was
noted within nine years of follow-up. Overall, the
follow-up period ranged from three months to 16

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SYSTEMATIC REVIEW
years. The outcome of studies on eumycetoma is
depicted in Table 2.
Surgery for Madura foot
Overall, 21 patients from 15 studies had surgery at
various times in the course of their therapy and all had
resolution of disease.1,2,5,10,17,19,23,24,28,31,32,34,36,40,41
The majority of patients (15 patients) considered for
surgery had eumycetoma. Only two cases were treated
exclusively by surgery.24,32 Both patients had eumyce-
toma. Surgery involved limb amputation in one and
wound excision in the other. Overall, three patients
had limb amputation while the rest had wound
debridement in combination with pharmacotherapy.
None of the studies reported explicitly at what point in
the course of therapy surgery was performed.
Discussion
This review set out to examine the available evidence
on the treatment of Madura foot. Currently, there
are no guidelines or controlled trials to inform
appropriate management of Madura foot and to
the best of our knowledge, this is the first attempt
at systematically analyzing therapy for this condi-
tion. Overall, the review findings showed that varied
antibiotic and antifungal treatment regimens were
utilized for the therapy of Madura foot with good
results (95.7% resolution rate).
In this review, therapy for actinomycetoma
involved the use of varied antibiotic regimens all
of which led to complete resolution of disease
(Table 1). This is higher than has been previously
reported.2,19 The commonest antibiotics used for
actionomycetoma were the sulfa drugs co-trimoxa-
zole and dapsone. Equally common was the use of
tetracylines. Amikacin was utilized in two studies in
this review. Although these regimens are based on
susceptibility testing, there are no comparative clini-
cal studies (controlled or uncontrolled) to support
their use or guide duration of therapy. Nonetheless,
these regimens may be successful because actino-
mycetoma granules are smaller compared to eumy-
cetoma granules leading to better drug penetration
and higher cure rates.38 Also, the common species of
bacteria causing actinomycetoma lead to tissue cal-
cification and if this is identified then a regimen
containing tetracyclines is recommended since they
are more readily deposited in calcifying tissues.21
We found that 88% of patients treated for eumy-
cetoma achieved resolution. The regimens used for
JBI Database of Systematic Reviews and Implementation Reports
©2018 Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
A.O. Salim et al.
treatment involved the azole derivatives, particularly
itraconazole, ketoconazole and voriconazole.
Amphotericin B, flucytosine and co-trimoxazole
were also employed. Other drugs recommend in
the literature include Griseofulvin and posacona-
zole.2,5 However, comparative clinical studies to
guide therapy for eumycetoma are lacking. As with
actinomycetoma, choice of regimen should be based
on susceptibility testing, although for fungi, this is
difficult to practice owing to long culture times and
inconsistent results. Drug penetration is also more
difficult with eumycetoma lesions because of exten-
sive fibrosis and larger granules (which represent
micro colonies of fungi).19
A total of 21 patients (15 with eumycetoma) had
surgery in addition to pharmacotherapy. All of these
patients had resolution of disease. The use of surgery
for Madura foot stems from the observation that
drug penetration is poor and resistance is high there-
fore surgery is needed in order to eradicate addi-
tional foci of disease. However, surgery alone is not
recommended since it has a recurrence rate of 20–
90%.2,5 Available surgical options include wound
debridement and limb amputation. There is no lit-
erature to support the use of one over the other.
However, patients with extensive disease (e.g. bone
involvement and destruction) for whom there is loss
of limb function and poor chances of achieving cure
should have limb amputation as was the case in two
studies in this review.24,32 Although no study
assessed the timing of surgical intervention, most
favored surgery followed by antimicrobial therapy.
In cases where lesions are small at presentation or
unresponsive to therapy, surgery may be considered
as a second option.
This review had a number of limitations. First,
some studies were excluded from the review for not
reporting the outcome of therapy as required in the
inclusion criteria. Consequently, there is the possi-
bility that studies with therapeutic failures were
excluded from the review. Further, non-publication
of failures (publication bias) may lead to overesti-
mation of efficacy. Second, only case series and case
reports were included in this review. While this is a
limitation in terms of the level of evidence for rec-
ommendations regarding treatment, it highlights
Madura foot as a neglected disease. Indeed, WHO
has now designated it as one of the NTDs.13 Perhaps
this may lead to funding of better quality observa-
tional or experimental studies on therapy for
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SYSTEMATIC REVIEW
Madura foot. Another limitation with this review is
the fact that only studies published in English were
considered for inclusion which introduced bias in the
review findings.
Conclusion
Antimicrobials in conjunction with surgery lead to
resolution of Madura foot. However, therapy for
this disease is informed by case series and case
reports which provide low level evidence for
practice.
Recommendations for practice
Available evidence shows that antimicrobial therapy
in combination with surgery leads to disease resolu-
tion. However, this practice is based on very low-
quality evidence (based on GRADE ranking) and
therefore the recommendation for its use is weak (JBI
Grades of recommendation: Grade B).
Recommendations for research
Current knowledge on therapy for Madura foot is
informed by case series and case reports. Randomized
clinical trials are warranted in order to determine the
most effective regimen for treating this disease.
Acknowledgments
We acknowledge the Joanna Briggs Institute and its
staff for the help accorded in retrieving the majority
of the studies identified for inclusion in this review.
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Appendix I: Search strategies

Database Search terms Hits Dates searched

MEDLINE #1) mycetoma [MeSH Terms] OR ‘‘myce- 304 1st January – 31st
toma’’[All Fields] December 2016
#2) madura foot [All Fields]
#3) eumycetoma [All Fields]) OR actino-
mycetoma [All Fields]
#4) foot diseases [MeSH Terms] OR foot
diseases [All Fields]
#5) #1 OR 2# OR 3
#6) #4 AND #5
Cumulative Index to Nurs- Mycetoma OR eumycetoma OR actino- 0 1st January – 31st
ing and Allied Health Liter- mycetoma OR Madura Foot December 2016
ature (CINAHL)
The Cochrane CENTRAL Mycetoma [title, abstract, keywords] OR 6 1st January – 31st
eumycetoma [title, abstract, keywords] December 2016
OR actinomycetoma [title, abstract, key-
words] OR Madura Foot [title, abstract,
keywords]
Embase ’maduromycosis’/exp OR ’maduromyco- 287 1st January – 31st
sis’ December 2016
Current Controlled Trials, Mycetoma 0 1st January – 31st
The Trials Register of Pro- Eumycetoma December 2016
moting Health Interventions Actinomycetoma
(TRoPHI) Madura Foot
Australian Clinical Trials Mycetoma [All Fields] OR eumycetoma 0 1st January – 31st
Registry (ACTR) [All Fields] OR actinomycetoma [All December 2016
Fields] OR Madura Foot [All Fields]
Clinical Medicine Net Prints Mycetoma 0 1st January – 31st
Collection Eumycetoma December 2016
Actinomycetoma
Madura Foot
Bandolier Evidence Based Mycetoma 0 1st January – 31st
Health Care Eumycetoma December 2016
Actinomycetoma
Madura Foot
The Center for Clinical Mycetoma 0 1st January – 31st
Trials and Evidence-based Eumycetoma December 2016
Healthcare at Brown Medi- Actinomycetoma
cal School Madura Foot

JBI Database of Systematic Reviews and Implementation Reports ß 2018 THE JOANNA BRIGGS INSTITUTE 1533

©2018 Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.

SYSTEMATIC REVIEW A.O. Salim et al.

(Continued)

Database Search terms Hits Dates searched

WHO, United Nations High Mycetoma 0 1st January – 31st
Commissioner for Refugees Eumycetoma December 2016
(UNHCR) and International Actinomycetoma
Organization of Migration Madura Foot
(IOM) records, CDC
reports, Dissertation
Abstracts International,
WHO Library, Agency for
Healthcare Research and
Quality, Grey Literature
Report, National Library of
Medicine, Theses Canada
Portal, ProQuest Digital
Theses, Australasian Digital
Theses Program and the
British Library.
Total number of studies 304
after exclusion of duplicates

JBI Database of Systematic Reviews and Implementation Reports ß 2018 THE JOANNA BRIGGS INSTITUTE 1534

©2018 Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.

SYSTEMATIC REVIEW A.O. Salim et al.

Appendix II: Data extraction tool

Data Extraction Form: Effective management of Madura foot

Reviewer________________________ _________Date___________________________________

Author___________________________________ Year___________________________________

Journal_______________________________________

Country_______________________________________

Study Method

RCT Cohort study Case control study Case Series Case Report

Participants

Number_______________ Age_______ Sex__________ Follow up period_____________

Interventions

Surgery (Debridement/amputation)

Antifungals

Drug Dose Duration

Antibiotics

Drug Dose Duration

Results/Outcomes

Resolution/cure

Recurrence

Mortality

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SYSTEMATIC REVIEW A.O. Salim et al.

Appendix III: Characteristics of excluded studies

Author/date Country Reason for exclusion

42
Suttner 1990 Germany No specific treatment modality
4
Van de Sande 2013 Netherlands No focus on treatment
43
Kamalam 1976 India No focus on treatment
44
Badali 2010 Netherlands Outcome not clearly reported
45
Fielder 2004 Kenya Outcome not reported
46
Fletcher 2001 UK No report on final outcome
47
Hemashettar 2006 India Outcome not reported
48
Motswaledi 2009 South Africa Outcome not reported
49
Iriat 2011 France Outcome not reported
50
Tilak 2012 India Final outcome and follow-up not indicated
51
Gupta 2013 India Outcome not reported
52
Desobeaux 2013 France Outcome not reported
53
Pilsczek 2007 Jamaica No report on follow-up and final outcome
54
Kamalam 1975 India Outcome not reported
55
Parker 2009 UK Unclear diagnosis
56
Jiminez 2011 USA Unclear diagnosis
57
Culligan 1985 South Africa Outcome not reported
58
Thammayya 1980 India Treatment not mentioned
Hemashettar 200059 India No focus on treatment
60
Biasoli 1986 Argentina Outcome not reported
61
Sampaio 2015 Brazil No report on final outcome
62
Vilela 2004 Brazil Outcome not reported
63
Rouphael 2007 USA No report on final outcome and follow- up
64
Brownell 2005 USA No report on follow-up and final outcome
65
White 2014 Mexico No report on outcome and follow-up
66
Brufman 2015 Israel No report on final outcome and follow-up
67
Samaila 2007 Nigeria No clear report of treatment and follow-up
12
Fahal 2015 Sudan Specific treatment for specific lesions not reported
8
Ten Broeke 1998 Netherlands Outcome not reported
68
Develoux 1988 Niger Specific treatment modalities not reported

JBI Database of Systematic Reviews and Implementation Reports ß 2018 THE JOANNA BRIGGS INSTITUTE 1536

©2018 Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.