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Tigecycline: Its potential for treatment of brucellosis
To cite this Article: , 'Tigecycline: Its potential for treatment of brucellosis',
Scandinavian Journal of Infectious Diseases, 39:5, 432 - 434
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Scandinavian Journal of Infectious Diseases, 2007; 39: 432 434
ORIGINAL ARTICLE
Tigecycline: Its potential for treatment of brucellosis
MURAT DIZBAY1, SELCUK KILIC2, KENAN HIZEL1 & DILEK ARMAN1
From the 1Department of Clinical Microbiology and Infectious Diseases, Gazi University School of Medicine, and 2Refik
Saydam National Hygiene Centre, Department of Communicable Diseases Research, Ankara, Turkey
Abstract
The in vitro efficacy and synergistic activity of tigecycline in comparison with other antimicrobials used in brucellosis, were
tested for 16 Brucella melitensis strains by the E-test method. Tigecycline had the lowest minimal inhibitory concentration
levels, and rifampin the highest, in the study. Tigecycline also provided the better synergistic activity compared to
doxycycline according to the fractional inhibitory concentration index. The results of this in vitro study suggest tigecycline
as a therapeutic alternative for brucellosis. These observations need to be supported with clinical studies.
Introduction
Brucellosis is a multisystemic disease leading to
chronic, recurrent infections and relapses. The
World Health Organization (WHO) Expert Committee on Brucellosis recommended, in 1986, treatment with a doxycycline (DOX) and rifampin (RIF)
combination for a 6-week period [1]. Another
combination commonly used is DOX and streptomycin (STR), which is also a WHO endorsed
regimen. Both regimens are cheap and convenient
for dosing schedule. The treatment still remains
problematic because of side-effects from the antibiotics, duration of treatment, and poor compliance.
Moreover, clinicians may be faced with therapeutic
failures and relapses related to the pharmacokinetic
and pharmacodynamic properties of the antibiotics
used. These problems have led to the investigation of
new drugs for the treatment of brucellosis.
Tigecycline (TIG) is a novel glycylcycline derivative of a tetracycline, minocycline. TIG has demonstrated
activity
against
most
species
of
Enterobacteriaceae and selected species of nonfermentatives, as well as Gram-positives, atypicals
and anaerobes [2]. TIG is indicated for the treatment of a variety of complicated intra-abdominal
and skin-soft tissue infections. Additionally, TIG
should have a role in the treatment of infections due
to extended-spectrum beta-lactamase producing
Enterobactericeae, pan-resistant Acinetobacter spp.
and multiresistant Gram-positive cocci. However,
there are no data about its in vitro activity on
brucella strains.
The aim of this study was to investigate in vitro
activity of TIG on Brucella melitensis strains. We
also studied the in vitro synergistic effect of TIG in
combination compared to classical combinations.
Materials and methods
16 strains of B. melitensis were obtained from blood
cultures from patients admitted to Gazi University
Hospital during 2004 and 2005. All strains were
identified as Brucella melitensis using the following
tests: CO2 requirement, H2S production, urease
positivity, dye sensitivity and growth in thionine.
MIC50 and MIC90 levels of DOX, TIG, RIF and
STR were determined by the E-test (AB Biodisk,
Sweden). Four different antibiotic combinations
(DOX-RIF, DOX-STR, TIG-RIF, and TIG-STR)
were evaluated for in vitro synergistic effect by the Etest method according to the manufacturer’s recommendations. E-test strip of an antibiotic (drug A)
was applied to the surface of 5% sheep blood agar
plates and left for 1 h at room temperature. Subsequently, the strip was removed and another strip
(drug B) was applied onto the imprint of strip A.
Correspondence: M. Dizbay, Department of Clinical Microbiology and Infectious Diseases, University School of Medicine, 06510, Besevler, Ankara, Turkey.
Tel: /90 312 2025432. Fax: /90 312 2136333. E-mail: [email protected]
(Received 4 September 2006; accepted 7 November 2006)
ISSN 0036-5548 print/ISSN 1651-1980 online # 2007 Taylor & Francis
DOI: 10.1080/00365540601105756
Downloaded By: [ANKOS 2007 ORDER Consortium] At: 14:05 1 May 2007
Susceptibility of Brucella strains to tigecycline
The plates were incubated at 35oC for 48 h under
anaerobic conditions and then MIC levels of each
drug and combination were read. The fractional
inhibitory concentration (FIC) index was calculated
as FIC /MICAB/MICA/MICBA/MICB. The results
of combination tests according to FIC index were
interpreted as follows: synergistic (FIC 5/0.5), additive (FIC /0.5 and 5/1), indifferent (FIC /1
and 5/4), and antagonistic (FIC /4).
Results
MIC50 and MIC90 values were lowest for TIG and
highest for rifampin against B. melitensis isolates
among 4 antibiotics (Table I).
By E-test, the combinations with RIF (TIG-RIF
and DOX-RIF) were synergistic for all strains. TIGSTR and DOX-STR combinations revealed additive
activity in 6.25% and 12.5%, indifference in 81.25%
and 68.75%, and antagonism in 12.5% and 18.75%
of the isolates, respectively. No synergy was detected
in combinations with STR. There was no difference
between the DOX-RIF and TIG-RIF combinations
according to the FIC index. The TIG-STR combination, however, had a lower FIC index than the
DOX-STR combination (Table II).
Discussion
Combination therapy is recommended in the treatment of brucellosis [1]. The antibiotics used in
combination should be synergistic. Although there
are some studies on in vitro susceptibility of brucella
strains, the standard procedures for in vitro testing
have not been determined [3]. In vitro testing by Etest was suggested for Brucella spp. because it is less
labour-intensive, less time-consuming, and more
practical than the broth microdilution method [4].
Checkerboard and E-test methods are commonly
used to detect interaction between antibiotics. The
checkerboard method is more difficult and timeconsuming for routine antimicrobial synergy testing.
Orhan et al. found a correlation between checkerboard and E-test methods for the synergy testing of
brucella strains [5]. We preferred to use the E-test
method which was easier to perform and less timeconsuming than the checkerboard method.
Although tetracyclines are considered very active
drugs against Brucella and DOX is the drug of
choice, antibiotic susceptibility patterns of Brucella
appear to vary geographically. Rubinstein et al., in
Israel, found minocycline to be the most effective
antibacterial drug against B. melitensis [6]. In a
Mexican study, Lopez-Merino et al. found fluoroquinolones comparable to tetracycline and doxycycline, and the MIC values for tetracyclines were
higher than in Brucella strains isolated in Turkey [7].
In 4 studies from Turkey, MIC90 values of DOX
were detected between 0.032 and 0.50 mg/ml [5,8 10]. We also found that DOX had lower MIC90
values (0.25 mg/ml) than RIF (2 mg/ml) and STR
(0.75 mg/ml). TIG was superior to DOX, and its
MIC90 values were the lowest in our study. To our
knowledge, this is the first study on tigecycline
activity on Brucella spp., so comparison with any
other study results could not be performed.
As a tetracycline derivative, TIG reaches high
intracellular concentration in the tissue, macrophages, and neutrophils. Therefore, it may be
considered to be of some potential in the treatment
of brucellosis [2]. Pappas et al. suggested that the
enhanced activity of TIG may allow for its use as a
single agent in brucellosis, even with a short timeduration [11]. However, absence of in vitro studies
for Brucella spp., parenteral administration of the
antibiotic requiring hospitalization, the conservation
of TIG because of promising results of its use in the
treatment of multiresistant bacterial infections, and
overall cost were considered as limitations of such a
therapy.
In our study, although RIF had the highest MIC
values, combinations with RIF (TIG-RIF and DOXRIF) demonstrated synergistic activity in all strains.
The FIC index of TIG-RIF (mean 0.16) was lower
than DOX-RIF (mean 0.21). When TIG-STR and
DOX-STR combinations were compared, additive
or indifferent activity was found to some extent, but
synergy was not detected in any strain. Furthermore,
antagonism was the result in 12.5% and 18.75% of
the isolates, respectively. Orhan et al., similarly to
our study, found a high rate of synergy in DOX-RIF
combination by E-test, but in contrast to our
findings, they detected 68.7% of synergistic activity
between DOX and STR [5].
Table I. The MIC ranges, MIC50 and MIC90 values of antibiotics.
Antibiotic
Tigecycline (TIG)
Doxycycline (DOX)
Rifampin (RIF)
Streptomycin (STR)
433
MIC ranges (mg/ml)
MIC50 (mg/ml)
MIC90 (mg/ml)
0.064 0.125
0.047 0.25
0.75 2
0.25 0.75
0.064
0.094
1.5
0.50
0.094
0.25
2
0.75
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434
M. Dizbay et al.
Table II. The results of antibiotic combinations by E-test.
DOX-RIF
DOX-STR
TIG-RIF
TIG-STR
Strain No.
FIC
Activity
FIC
Activity
FIC
Activity
FIC
Activity
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
0.18
0.15
0.30
0.19
0.21
0.25
0.16
0.12
0.10
0.38
0.28
0.18
0.31
0.12
0.27
0.40
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
2.32
2.08
2.73
1.57
1.70
2.18
1.70
2.12
3.04
5.50
0.53
0.62
6.05
2.18
4.06
2.75
ID
ID
ID
ID
ID
ID
ID
ID
ID
AG
ADD
ADD
AG
ID
AG
ID
0.21
0.15
0.14
0.16
0.13
0.09
0.15
0.14
0.14
0.26
0.24
0.15
0.15
0.15
0.19
0.24
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
0.81
1.12
2.18
1.82
2.13
1.72
2.13
1.55
1.54
1.5
3.04
2.11
1.58
6.17
6.17
3.05
ADD
ID
ID
ID
ID
ID
ID
ID
ID
ID
ID
ID
ID
AG
AG
ID
FIC: fractional inhibitory concentration; S: synergistic; ADD: additive; ID: indifferent; AG: antagonistic.
In conclusion, the results of this in vitro study
suggest TIG as a therapeutic alternative for brucellosis. These observations need to be supported with
clinical studies.
[5] Orhan G, Bayram A, Zer Y, Balci I. Synergy tests by E-test
and checkerboard methods of antimicrobial combinations
against Brucella melitensis. J Clin Microbiol 2005;43:140 3.
[6] Rubinstein ER, Lang R, Shasha B, et al. In vitro susceptibility of Brucella melitensis to antibiotics. Antimicrob
Agents Chemother 1991;35:1925 7.
[7] Lopez-Merino A, Contreras-Rodriguez A, Migranas-Ortiz
R, et al. Susceptibility of Mexican Brucella isolates to
moxifloxacin, ciprofloxacin and other antimicrobials used
in the treatment of human brucellosis. Scand J Infect Dis
2004;36:636 8.
[8] Bodur H, Balaban N, Aksaray S, et al. Biotypes and
antimicrobial susceptibilities of Brucella isolates. Scand J
Infect Dis 2003;35:337 8.
[9] Baykam N, Esener H, Ergonul O, Eren S, Celikbas AK,
Dokuzoguz B. In vitro antimicrobial susceptibility of Brucella species. Int J Antimicrob Agents 2004;23:405 7.
[10] Yamazhan T, Aydemir S, Tunger A, Serter D, Gokengin D.
In vitro activities of various antimicrobials against Brucella
melitensis strains in the Aegean Region in Turkey. Med Princ
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[11] Pappas G, Solera J, Akritidis N, Tsianos E. New approaches
to the antibiotic treatment of brucellosis. Int J Antimicrob
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