Towards Rational Use of Antibiotics for Suspected
Secondary Infections in Buruli Ulcer Patients
Yves T. Barogui1,2, Sandor Klis2, Honore ´ Sourou Bankole ´3, Ghislain E. Sopoh1, Solomon Mamo4,
Lamine Baba-Moussa5, Willem L. Manson6, Roch Christian Johnson7, Tjip S. van der Werf2,
1Programme National de Lutte Contre la Le `pre et l’Ulce `re de Buruli, Ministe `re de la Sante ´, Cotonou, Be ´nin, 2University of Groningen, University Medical Center
Groningen, Department of Internal Medicine/Infectious Diseases, Groningen, The Netherlands, 3De ´partement de Ge ´nie de Biologie Humaine, Ecole polytechnique de
l’Universite ´ d’Abomey-Calavi, Cotonou, Be ´nin, 4Agogo Presbyterian Hospital, Department of Surgery, Agogo, Ghana, 5Laboratoire de biologie et de typage mole ´culaire
en microbiologie, de ´partement de biochimie et biologie cellulaire, Faculte ´ des sciences et techniques, Universite ´ d’Abomey-Calavi, Cotonou, Be ´nin, 6University of
Groningen, University Medical Center Groningen, Department of Medical Microbiology, Groningen, The Netherlands, 7Fondation Raoul Follereau, Cotonou, Be ´nin
Background: The emerging disease Buruli ulcer is treated with streptomycin and rifampicin and surgery if necessary.
Frequently other antibiotics are used during treatment.
Methods/Principal Findings: Information on prescribing behavior of antibiotics for suspected secondary infections and for
prophylactic use was collected retrospectively. Of 185 patients that started treatment for Buruli ulcer in different centers in
Ghana and Be ´nin 51 were admitted. Forty of these 51 admitted patients (78%) received at least one course of antibiotics
other than streptomycin and rifampicin during their hospital stay. The median number (IQR) of antibiotic courses for
admitted patients was 2 (1, 5). Only twelve patients received antibiotics for a suspected secondary infection, all other
courses were prescribed as prophylaxis of secondary infections extended till 10 days on average after excision, debridement
or skin grafting. Antibiotic regimens varied considerably per indication. In another group of BU patients in two centers in
Be ´nin , superficial wound cultures were performed. These cultures from superficial swabs represented bacteria to be
expected from a chronic wound, but 13 of the 34 (38%) S. aureus were MRSA.
Conclusions/Significance: A guide for rational antibiotic treatment for suspected secondary infections or prophylaxis is
needed. Adherence to the guideline proposed in this article may reduce and tailor antibiotic use other than streptomycin
and rifampicin in Buruli ulcer patients. It may save costs, reduce toxicity and limit development of further antimicrobial
resistance. This topic should be included in general protocols on the management of Buruli ulcer.
Citation: Barogui YT, Klis S, Bankole ´ HS, Sopoh GE, Mamo S, et al. (2013) Towards Rational Use of Antibiotics for Suspected Secondary Infections in Buruli Ulcer
Patients. PLoS Negl Trop Dis 7(1): e2010. doi:10.1371/journal.pntd.0002010
Editor: Pamela L. C. Small, University of Tennessee, United States of America
Received May 13, 2012; Accepted December 1, 2012; Published January 24, 2013
Copyright: ? 2013 Barogui et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Netherlands Organisation for Scientific Research [‘VENI’ grant to YS, http://www.nwo.nl]. The funder had no role in
study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Buruli ulcer (BU) is a neglected, emerging disease caused by
Mycobacterium ulcerans. BU usually starts as a nodule, papule,
plaque, or oedema. When left alone, the lesion breaks open and a
typical painless ulcer with undermined edges appears which can
progress to a large necrotic lesion. Sometimes the bone can be
affected and amputation may be necessary. Until 2004, the only
available treatment was surgical removal of affected tissue. Since
2004, streptomycin and rifampicin have been used to treat BU [1–
Secondary infection is often thought to be responsible of severe
complications in BU [4–6]. In chronic diabetic foot ulcers and
thermal burn wounds, secondary infections increase time to
healing and prolong hospital stay [7–10]. The Infectious Diseases
Society of America (IDSA) guidelines on diabetic foot infections
states that infection should be diagnosed clinically on the basis of
the presence of purulent secretions (pus) or at least 2 of the
cardinal manifestations of inflammation (redness, warmth, swelling
or induration, and pain or tenderness) [11,12].
Although the incidence of secondary infections in BU is
unknown, antibiotics may be frequently prescribed for this
indication. It is equally unknown which bacteria these antibiotics
should target and what the susceptibility of these bacteria is.
Furthermore, the prescribing behaviour of antibiotics used as
prophylaxis after surgery or skin grafting is unknown. Only limited
data are available on resistance of microbes in Be ´nin and Ghana; a
study in Ghana found that 18% of the S. aureus were MRSA .
The few studies published on the prevalence of MRSA in Be ´nin,
showed percentages varying from 17–36% depending on the type
of samples studied [13,14]. Resistance patterns of E. coli were
described in faeces from healthy volunteers and patients with
diarrhea. No Extended-Spectrum beta-lactamase (ESBL) produc-
ing enterobacteriaceae were found in these two studies, but there
PLOS Neglected Tropical Diseases | www.plosntds.org1 January 2013 | Volume 7 | Issue 1 | e2010
was a high resistance to locally used antibiotics [15,16]. In a 500
bed hospital in Abomey 22% of the E. coli were ESBL positive
. An antibiotic policy that is adjusted to the expected microbes
and resistance of these microbes can make antibiotic use more
effective, with lower daily defined doses of antibiotics per person,
leading to less side-effects, and with less resistance. Such policy will
also save resources in an environment where resources are scarce.
The prescribing behaviour of antibiotics for secondary infec-
tions or as prophylaxis in BU interventions was studied, and
cultures of ulcers were taken to provide data for the development
of future guidelines for the use of antibiotics for this indication.
Data were retrieved from files of patients that started treatment
with streptomycin and rifampicin in the period August–October
2009 in the ‘centre de de ´pistage et de traitement de l’ulce `re de
Buruli’, Lalo, Be ´nin. The same data were retrieved from hospital
files on patients that started treatment in the period August–
December 2009 in the ‘centre de ´pistage et de traitement de
l’ulce `re de Buruli’, Allada, Be ´nin, and in the period March 2008–
March 2009 in Agogo Presbyterian Hospital, Agogo, Ghana.
Records were studied in August and September 2010, so that
follow-up of these patients was already completed. Patient
characteristics and the type of lesion were recorded. Data on
antibiotic use different from rifampicin/streptomycin, as well as
the indication for these prescriptions, the dosage and duration as
well as the clinical presentation at the start of treatment were
Between October and December 2010, 20 consecutive patients
with an ulcerative lesion reporting for BU treatment were enrolled
after consent and followed longitudinally. Before the start of
treatment, and before washing or the application of antiseptics, a
swab was taken both from the undermined edge and from the
center of the ulcer. Swabs were also taken at 6 weeks after start of
treatment and at 12 weeks (this is 4 weeks after finishing the 8
weeks rifampicin/streptomycin). Apart from these 20 patients
followed in time, we intended to enrol 25 patients in the villages
and 25 patients admitted in the hospitals after consent with only
one culture taken at a random moment during or after treatment.
The clinical presentation (including local and/or systemic signs of
a secondary infection) and previous use of antibiotics was recorded
for all patients.
Results of the cultures were not reported to the treating
physicians in order to avoid interference with antibiotic prescrib-
ing that would be based on superficial cultures.
Samples were cultured on a medium of Trypcase Soy Agar+5%
Sheep Blood and Chapman Agar (both Biomerieux EMB agar).
The different microbial isolates were differentiated and antimi-
crobial susceptibility was performed on Mu ¨ller Hinton agar with
antibiotic discs (Rosco Diagnostica). Detection of methicillin
resistance was done on Mu ˝ller Hinton agar with the addition of
5% NaCl. The results of the antibiograms were reported as either
susceptible, intermediate resistance, or resistant. Apart from the
antibiotics tested in the routine setting, rifampicin and clarithro-
mycin discs were added to the antibiograms of gram positive
microbes, and streptomycin discs were added to antibiograms of
both gram positive and negative microbes. Cultures and antibiotic
susceptibility testing were performed at the National Public health
Laboratory, Cotonou. The method used for susceptibility testing
was the agar medium diffusion method (Kirby Bauer method).
The internal quality control is done with the following reference
strains:E. coli ATCC25922 and S. aureus ATCC25923. The
laboratory participates in international quality control with the
following organizations: Institute Pasteur in Paris, the WHO
Collaborating Centers Faro in Marseilles (France), and MDSC in
Ouagadougou, Burkina Faso.
From the 20 patients with cultures taken at the same time from
the center and the border of the ulcer, only the results of the
border of the ulcer were used for the descriptive analysis.
The protocol and consent forms of the study were approved by
the ethical review committee of the Ministry of Health (Direction
de la Formation et de la Re ´cherche en Sante ´, nr IRB6860). For
participants in the part of the study obtaining swabs from the
Buruli ulcer lesions, written and verbal informed consent or assent
was obtained from all participants aged 12 years or older, and
consent from parents, care takers, or legal representatives of
participants aged between 12 and 18 years of age.
In total, 185 patients started treatment with streptomycin and
rifampicin in the study periods. 147 Patients had an ulcer, 38 had
a plaque as the only lesion. Four patients (2.7%) had both an ulcer
and a nodule. Median age was 12 years old. Two patients were
known to be HIV positive; the other patients did not have a
relevant medical history.
Of these 185 patients, 51 were admitted because of the severity
of the disease or because of distance to health care center. Of the
51 admitted patients, 40 (78%) received at least one course of
antibiotics other than streptomycin and rifampicin during their
admission. The median number (IQR) of antibiotic courses for
admitted patients was 2 (1, 5), with a maximum number of courses
of 13. In Table 1, the different antibiotic strategies for suspected
Buruli ulcer (BU) is a neglected, emerging disease caused
by Mycobacterium ulcerans. BU usually starts as a nodule,
papule, plaque, or oedema. When left alone, the lesion
breaks open and a typical painless ulcer with undermined
edges appears which can progress to a large necrotic
lesion. BU is treated with antibiotics (streptomycin and
rifampicin) and surgery if necessary. Apart from these two
antibiotics, patients frequently receive other antibiotics
during treatment. In files from patients treated in Benin
and Ghana we found that in admitted patients a median of
two antibiotic courses were prescribed. Only twelve
patients received antibiotics for a suspected secondary
infection, all other courses were prescribed as prophylaxis
of secondary infection extended till 10 days on average
after excision, debridement or skin grafting. In another
patient group in Benin, superficial wound swabs from
Buruli ulcers were performed and showed a high rate of
MRSA. We propose a guideline for rational antibiotic
treatment for suspected secondary infections or prophy-
laxis. Adherence to the proposed guideline will have a
major impact on antibiotic use other than streptomycin
and rifampicin in Buruli ulcer patients, saving costs, toxicity
and development of antimicrobial resistance.
Rational Antibiotic Use in Buruli Ulcer
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Table 1. Antibiotic treatment given to patients for different Buruli ulcer related indications.
INDICATION (IN 51 ADMITTED
SECONDARY INFECTION (N=12)
PROPHYLAXIS EXTENDED AFTER
PROPHYLAXIS EXTENDED AFTER SKIN
PROPHYLAXIS EXTENDED AFTER
Penicillin and flucloxacillin
Flucloxacillin and metronidazole
Flucloxacillin and gentamicin
Amoxicillin and metronidazole
Ciprofloxacin and metronidazole
Clindamycin and gentamicin
Ceftriaxone, gentamicin and
C10, G5, M5 -
Penicillin G, flucloxacillin and
P3, F10, G5
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secondary infections and prophylaxis extended after three different
surgical interventions are presented. Apart from the antibiotics
prescribed in Table 1, two patients received treatment for
suspected sepsis with a secondarily infected BU lesion as focus.
One of them received ampicillin, gentamicin and metronidazole
and the other received ceftriaxone and metronidazole. Another
patient received ampicillin and metronidazole as prophylaxis
extended after bone surgery for disseminated BU.
Different antibiotic combinations were started during the
treatment with streptomycin and rifampicin sixteen times. Median
number of days passed between start of streptomycin and
rifampicin and the first time other antibiotics were prescribed
was 63 days.
The clinical signs reported when starting a course of antibiotics
to treat a Buruli ulcer related infection were diverse (Table 2).This
prescribing behaviour resulted in a high number of antibiotics
prescribed per 100 patient days of hospitalization (Table 3).
Microbiological results of Buruli ulcer lesions in Be ´nin
In 71 patients (20 patients with follow-up
cultures, 26 hospitalized patients and 25 outpatients) 106 cultures
were taken from a BU lesion. S. aureus was less frequently found
during therapy with streptomycin and rifampicin, further distri-
bution (Table 4) of results seemed similar before, during or after
antibiotic therapy. Looking separately at the 20 patients that were
followed longitudinally (before the start of antibiotics, after 6 and
after 12 weeks), showed a similar pattern with less frequently S.
aureus found in the culture after 6 weeks of antibiotic therapy. In
these 20 patients cultures were taken from the center of the lesion,
and from the undermined edges of the ulcers before the start of
treatment. Isolates did not significantly differ between these two,
but cultures from the undermined edges were more often negative
than from the center of the ulcer (18% vs. 9%, p=0.34 Chi-
square). None of the cultures was taken during antibiotic treatment
other than streptomycin or rifampicin.
Clinical presentation at moment of culture.
moment the culture was performed, 38 patients had one local
sign of a secondary infection and 12 patients had two local signs of
a secondary infection. Of these 12 patients with two local
symptoms, only one culture turned out to be negative. Only one
of these 12 patients was clinically considered to have a secondary
infection and started treatment with additional antibiotics after the
cultures were taken. In the other positive cultures, a distribution of
bacteria similar to Table 4 was found. At the moment cultures
were taken none of the patients showed a systemic sign of a
Susceptibility pattern of bacteria cultured.
microorganisms were cultured, including the follow-up cultures
and the cultures at the border and at the center of the lesion. The
susceptibility pattern of the cultured microorganisms is presented
in Table 5, susceptibility of the cultured MRSA in Table 6.
Thirteen of the 34 (38%) S. aureus isolates were resistant to oxacillin
In total 124
Table 2. Clinical signs reported before start of antibiotics for
a suspected secondary infected BU.
OOZING, PUS, ‘WOUND LOOKS DIRTY’3
Raised WBC or fever2
Fever with a local sign (swelling, warmth, tenderness)2
Warmth, swelling or tenderness2
Oozing and swelling1
WBC=White Blood cell Count.
Table 3. Number of days of prescribed antibiotics per 100
days in hospital.
DAYS ANTIBIOTICS USED IN
THERAPEUTIC DOSAGE PER 100
DAYS IN HOSPITAL.
Penicillin G 0.1
Total apart from SR 23.0
*Standard treatment of M. ulcerans with 56 days of rifampicin and streptomycin
not included in this table.
Table 4. Results of cultures in 71 patients before, during or after treatment with streptomycin and rifampicin.
before SR (59cultures)during SR (16cultures) after SR (31cultures)Total (106 cultures)
Group A streptococcus 4026
Group B or C streptococcus2103
S. aureus150 1126
Pseudomonas aeruginosa 135 1230
Negative culture19 (32%)4(25%)7(23%)30(28%)
For patients followed longitudinally, only cultures from the center of the ulcer were included at inclusion (cultures from border gave similar results).
Rational Antibiotic Use in Buruli Ulcer
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and were therefore probably MRSA. This percentage was not
substantially different in patients before admission or before start
of antibiotic treatment. Based on resistance to ceftriaxone and
susceptibility to amoxicillin/clavulanic acid, we expect that there
was one ESBL producing Klebsiella pneumoniae.
Currently there is no specific guideline for the prescription of
additional antibiotics to BU patients suspected to have secondary
infection. However, our findings indicate that prescribing addi-
tional antibiotics is widespread among BU patients that are
admitted to the hospital because of the severity of their BU or
distance to health care. Moreover, the type and duration of these
antibiotic courses is highly variable, even within the same
indication. Antibiotics were most frequently prescribed as
prophylaxis of secondary infections extended after surgical
procedures rather than for the treatment of suspected secondary
infections. Surprisingly, duration of this prophylaxis was even
longer than for actual treatment of secondary infections. This
frequent use of antibiotics leads to unnecessary costs, antibiotic
resistance, and side-effects for the patients with possible long term
consequences. For example, prescribing gentamicin during the
therapy with rifampicin and streptomycin imposes a serious risk of
In general, skin surgery is not an indication for antimicrobial
prophylaxis, therefore prophylaxis after excision and after
debridement  is not considered as indicated. However, there
is some inconclusive evidence that in skin grafts systemic
perioperative antibiotic prophylaxis contributes to the autograft
survival . Ramos et al. found a rate of autograft survival for the
group of patients with burns using two days of perioperative
antibiotic prophylaxis of 97% versus 87% in the group without
prophylaxis . In patients with arterial and venous ulcers no
differences in graft survival was observed with perioperative use of
As stated by the IDSA guidelines it is unlikely that benefit is
conferred by the administration of additional doses after the
patient has left the operating room [18,22,23]. Antimicrobial
prophylaxis should certainly be discontinued within 24 hours of
the operative procedure since prolonged antibiotic prophylaxis
contributes to antimicrobial resistance [18,24,25]. In case clini-
cians decide to give perioperative antibiotics in skin grafting,
advice for use of appropriate antibiotics is given in Figure 1.
Although MRSA is frequent and community acquired, suggested
antibiotic therapy as prophylaxis in skin grafting in Figure 1 does
not cover MRSA. The alternatives vancomycin or ofloxacin/
ciprofloxacin are not appropriate as prophylaxis due to resistance
development to these antibiotics and/or costs. Studies on the use
of vancomyin as prophylaxis in medical centers with high MRSA
prevalence are controversial in preventing surgical site infections
Report of clinical symptoms of secondary infections may not
always have been complete in the files, but different clinical signs
were reported in patients receiving antibiotics for suspected
secondary infection. These clinical signs seem nonspecific; in
patients not clinically suspected to have a secondary infection, the
same local and systemic signs were frequent as well. The diagnosis
of a secondary infection of the BU therefore remains difficult to
ascertain. A paradoxical response may be an alternative diagnosis
Table 5. Susceptibility of cultured organisms (other than M. ulcerans) in Buruli ulcer lesions in Benin.
S. aureus, n=34
Amoxicillin/clavulanic acid 11522
Ceftriaxone13 146 2638
Gentamicin 3400200 2607 3405
Streptomycin76 2000262 1768 22
Chloramphenicol210 13002716 12323
Nalidixic acid21 161126
Cultures taken from both the center and the border of the ulcer at start of treatment in patients followed longitudinally were included, leading to a different number of
cultures than in Table 4.
Table 6. Sensitivity of the cultured MRSA.
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Figure 1. Suggested guideline for use of antibiotics in prophylaxis and suspected secondary infections. * Ciprofloxacin is not generally
recommended for use in children, but appears relatively safe .
Rational Antibiotic Use in Buruli Ulcer
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in patients suspected of a secondary infection . A superficial
culture of the wound as done in the study is certainly not helpful in
the diagnosis of a secondary infection and can not guide individual
care [29,30,31]. Superficial cultures as done in this study, can not
guide individual care. In this study, we performed cultures to make
an inventory of isolates and local resistance patterns to enable the
first steps to an antibiotic guideline. Superficial swabs yield a
greater range of organisms than do deeper tissue material due to
contaminants not involved in the secondary infection and yet may
fail to identify some of the deep-seated organisms. If a culture is
needed to guide antibiotic therapy, tissue specimens obtained by
biopsy, ulcer curettage or aspiration are preferred . Such
cultures would have been preferable for this study but were not
performed for ethical reasons. Such procedures are more invasive,
and moreover, most included patients were not suspected to have
a secondary infection and they would therefore not benefit from a
deep tissue biopsy.
Another limitation of the study is the limited number of positive
cultures, yet we think this number of isolates reflects the micro-
organisms in the superficial swabs in general and this information
guides antibiotic treatment suggestion. Further studies are needed
to gather more information on the susceptibility of the highly
prevalent MRSA. Patients treated in the out-patient setting did not
have reported use of antibiotics apart from streptomycin and
rifampicin, but we are not informed on antibiotics that may have
been used by these patients prescribed by other doctors than the
The high percentage of MRSA cultured is worrisome. The
prevalence of MRSA was equally high among patients before start
of treatment, suggesting this MRSA may be community acquired.
In Benin, antibiotics are freely available, and are often used
without prescription, and a recent study showed that BU patients
often use left-over antibiotics to reduce pain and inflammation
before reporting to the hospital . Improved wound care and
antibiotic therapies in case of clinical suspicion of a secondary
infection of the BU are suggested in Figure 1. This figure is based
on availability, WHO Essential Drug Lists 2011, costs and the
high prevalence of community acquired MRSA.
If treatment contains gentamicin, treatment with streptomycin
and rifampicin should be stopped temporarily, to limit toxicity.
Dosage of different antibiotics are given in Text S1.
Even though secondary infections were not frequent, the high
prevalence of MRSA complicates treatment. Further studies are
needed to have a more precise susceptibility pattern of S. aureus in
this patient population. To deal with the currently found high
prevalence of MRSA, facilities at the BU treating centers will have
to be improved. Laboratory facilities that enable cultures and
testing for MRSA are highly necessary along with knowledge
about rational prescribing and the possibility to consult clinical
microbiologists or infectious diseases specialist to help interpreting
the results. In case patients are suspected to have a secondary
infection not responsive to appropriate wound care, a deep tissue
biopsy should be sent for culture before the start of antibiotic
treatment. In case of systemic signs, blood cultures should also be
performed if possible. Vancomycin is on the complementary list of
the WHO Essential drug list 2011but it is not available in most
centers. However, with the MRSA prevalence as found, it seems
an essential drug. Its use is complicated by high costs and need for
plasma drug concentration monitoring to limit toxicity.
Treatment of osteomyelitis is not included in the figure; in the
year 2000 a study showed that only in 16% of the osteomyelitis
patients another germ than M. ulcerans was involved  Whether
this percentage is still accurate is unknown and this should be
studied during ongoing drug studies. Especially because of long
treatment duration, in case of osteomyelitis, cultures should be sent
from bone debridement/biopsy to guide antibiotic therapy for
potential non-MU organisms, if possible.
Strategies to optimize wound care in Buruli ulcer patients should
be studied, as no information is currently available. However,
all measures to prevent healthcare associated infections should be
actively implemented in all facilities implementing wound care.
Periodic routine culturing of wounds should be performed (e.g.
once every 2 years) to remain updated on the prevalence of MRSA
and possible development of resistance. Rational antibiotic
prescribing behaviour should be stimulated in centers treating
BU ,  Adherence to Figure 1 in prescribing antibiotics
different from the streptomycin and rifampicin will have a major
impact on antibiotic use in the BU treatment centers, saving
money and toxicity and limiting of further antimicrobial resistance
development. This topic should be included in general protocols
on the management of BU.
Dosage of antibiotics in Figure 1.
We would like to thank Didier Agossadou for his leadership of the National
Buruli ulcer Program in Be ´nin and Hounsou Franc ¸ois from LNSP for his
Conceived and designed the experiments: YTB SK GES WLM RCJ TSW
YS. Performed the experiments: YTB HSB GES SM LBM. Analyzed the
data: YTB SK WLM YS. Wrote the paper: YTB HSB GES SM LBM SK
GES WLM RCJ TSW YS.
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PLOS Neglected Tropical Diseases | www.plosntds.org8January 2013 | Volume 7 | Issue 1 | e2010