© 2013 John Wiley & Sons A/S

Transplant Infectious Disease, ISSN 1398-2273

Case report

Brucellosis in a renal transplant recipient

I.-W. Ting, M.-W. Ho, Y.-J. Sung, N. Tien, C.-Y. Chi, H.-C. Ho,
C.-C. Huang. Brucellosis in a renal transplant recipient.
Transpl Infect Dis 2013: 15: E191–E195. All rights reserved
Abstract: Brucellosis is one of the most common systemic zoonotic
diseases transmitted by consumption of unpasteurized dairy
products or by occupational contact with infected animals.
Brucellosis is rare in renal transplant recipients. Only 3 cases have
been reported in the literature. We report a case of brucellosis with
hematologic and hepatobiliary complications in a patient 3 years
after renal transplantation. The mean time from transplantation to
the diagnosis of brucellosis in these 4 reported patients was
5.1 years (range 17 months to 13 years). All patients had fever and
constitutional symptoms, and all attained clinical cure after
combination antibiotic therapy. Given the small number of patients,
further study is needed to identify the characteristics of brucellosis
in renal transplant recipients. Drug interactions and acute renal
failure developed in our patient during antibiotic treatment.
Therefore, we should monitor the levels of immunosuppressive
agents frequently. Several studies have shown in vitro
susceptibilities of Brucella melitensis to tigecycline. In our patient,
fever finally subsided after tigecycline administration. The minimum
inhibitory concentration of tigecycline using Etest was 0.094 lg/mL.
Tigecycline may be a potential option for treatment of brucellosis in
the setting of transplantation.
I.-W. Ting1,2, M.-W. Ho2,3, Y.-J.
Sung2,4, N. Tien2,4, C.-Y. Chi2,3,
H.-C. Ho2,3, C.-C. Huang1,2
1
Kidney Institute, China Medical University Hospital,
Taichung, Taiwan, 2School of Medicine, China Medical
University, Taichung, Taiwan, 3Department of Internal
Medicine, China Medical University Hospital, Taichung,
Taiwan, 4Department of Laboratory Medicine, China
Medical University Hospital, Taichung, Taiwan
Key words: brucellosis; Brucella melitensis; renal
transplantation; tacrolimus; tigecycline
Correspondence to:
Chiu-Ching Huang, MD, The Kidney Institute and
Division of Nephrology, China Medical University
Hospital, China Medical University, No. 2, Yuh Der
Road, Taichung 40402, Taiwan
Tel: +886 4 22052121 (ext. 7387)
Fax: +886 4 22331691
E-mail: cch@mail.cmuh.org.tw
Received 15 January 2013, revised 19 April 2013,
accepted for publication 27 May 2013
DOI: 10.1111/tid.12125
Transpl Infect Dis 2013: 15: E191–E195

Brucellosis is one of the most common systemic Case report

zoonotic diseases with 500,000 new cases annually
(1). It is an intracellular bacterial infection endemic in
Latin America, Central and South America, the Middle
East, Mediterranean countries, northern Africa, and
central Asia (2). The disease is transmitted by con-
sumption of unpasteurized dairy products or by occu-
pational contact with infected animals. Brucellosis may
involve any organ or system in the body and mimic
various multisystem diseases. The most common
affected systems are the osteoarticular, hematologic,
hepatobiliary, gastrointestinal, genitourinary, cardiovas-
cular, and central nervous systems (3).
Brucellosis is rare in renal transplant recipients. To
the best of our knowledge, only 3 cases have been
reported in the literature (4–6). In this report, we
describe the clinical manifestations, laboratory find-
ings, and successful treatment with the new antibiotic,
tigecycline, in a fourth renal transplant recipient with
brucellosis.
A 58-year-old man who had received a renal transplant
3 years ago was admitted to our hospital because of
intermittent fever.
The patient had been well until 1 week before
admission, when fever with temperatures up to 39°C,
chills, and sweats developed. The associated symptoms
were malaise, anorexia, and left upper quadrant abdom-
inal pain that was intermittent, mild, and dull. He
reported no headache, cough, dyspnea, vomiting,
diarrhea, dysuria, open wound, or pain over the graft.
The patient had a history of type 2 diabetes mellitus,
hypertension, gout, and coronary artery disease. He
received renal transplantation from a deceased donor
3 years ago after hemodialysis for 1½ years. Medica-
tions included tacrolimus 1.5 mg and mycophenolate
sodium 180 mg twice daily, aspirin, bisoprolol, glimepi-
ride, metformin, and atorvastatin. He lived in central
Taiwan with his wife and owned a Chinese herb store.

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Ting et al: Brucellosis in renal transplant
One month ago, he visited China for sightseeing. He
denied animal contact or raw food ingestion during the
travel. None of his family had similar symptoms.
On examination, the patient was alert, oriented, and
acutely ill. The temperature was 37.8°C, the blood
pressure 138/75 mmHg, the pulse 84 beats/min, and
the respiratory rate 20 breaths/min. The abdomen was
distended, soft, without tenderness or guarding. The
remainder of the physical examination was normal. The
white blood cell count was 3160/lL (with 67% neu-
trophils and 23% lymphocytes), hemoglobin 12.2 g/dL,
and platelet count 74,000/lL. The serum level of
aspartate aminotransferase was 100 U/L, alanine ami-
notransferase 156 U/L, alkaline phosphatase 142 U/L,
gamma-glutamyl transpeptidase 136 U/L, and creati-
nine 1.25 mg/dL. Urinalysis revealed a pH of 5.5 and 1+
protein; it was otherwise normal. Radiography of the
chest was normal. Ultrasonography of the abdo-
men showed parenchymal liver disease and mild
splenomegaly.
Cytomegalovirus (CMV) infection was suspected in
the beginning. Ganciclovir and ampicillin-sulbactam
were administered, and mycophenolate sodium was
temporarily stopped. Blood tests for CMV antigen,
hepatitis B and C viruses, cryptococcal antigen, and
Aspergillus antigen were all negative. Cultures of blood
obtained at admission grew unidentified tiny gram-
negative coccobacilli. We changed antibiotics to imi-
penem-cilastatin and colistin on admission day 6. Fever
occurred daily after admission, with temperatures up to
39.5°C and accompanied by excessive sweats. We kept
imipenem-cilastatin and replaced colistin with levoflox-
acin on admission day 10. Fever did not subside and
blood cultures sent on days 5, 10, and 17 after
admission were positive for the unidentified tiny
gram-negative coccobacilli. The transthoracic echocar-
diography showed normal valves without vegetation.
Cultures of the bone marrow for bacteria, mycobacte-
ria, and fungi were negative. Tigecycline and levoflox-
acin were used since admission day 17. He became
afebrile after the administration of tigecycline, and the
bacteremia cleared. The white blood cell count, platelet
count, and liver function tests turned normal. The
serum creatinine and tacrolimus levels were stable
during admission. The patient was discharged with
minocycline, clarithromycin, and levofloxacin, after
2 weeks of intravenous tigecycline use.
Brucella melitensis was identified based on conven-
tional biochemical tests including positive oxidase,
urease, and H2S production. We used the BD Phoenix
NMIC/ID-2 commercial kit (Becton Dickinson Diag-
nostic Systems, Sparks, Maryland, USA). Inoculation
was performed according to the manufacturer’s instruc-
E192 Transplant Infectious Disease 2013: 15: E191–E195
tions. The API 20E and 32 GN systems (bioM
erieux SA,
Marcy l’Etoile, France) were also performed to identify
the strain. The offending bacteria were confirmed
by analysis of partial 16S rRNA gene sequencing. 8FPL
(5′-AGAGTTTGATCCTGGCTCAG-3′) and 1492RPL
(5′-GGTTACCTTGTTACGACTT-3′) were used as prim-
ers. We compared the consensus sequences with
GenBank database by using the BLAST analysis. The
closest match was B. melitensis (GenBank accession
number JF939174.1) with maximal identity of 99%. The
minimum inhibitory concentration (MIC) value of
tigecycline was determined by the Etest (bioM
erieux,
Solna, Sweden). Mueller-Hinton agar supplemented
with 5% sheep blood (Oxoid, Basingstoke Hampshire,
UK) was inoculated with suspensions of B. melitensis
equivalent 0.5 McFarland turbidity and was interpreted
2 days after incubation in ambient air at 35°C. The
result was 0.094 lg/mL.
After identification of B. melitensis as the causative
organism, we kept minocycline, added trimethoprim-
sulfamethoxazole (TMP-SMZ), and discontinued clari-
thromycin and levofloxacin. The course after discharge
was complicated by elevated tacrolimus level (15.6 ng/
mL) and acute renal failure (creatinine 2.73 mg/dL). It
was speculated that acute renal failure was caused by
drug interaction between clarithromycin and tacroli-
mus that necessitated a decrease in tacrolimus dose.
Upon discontinuing clarithromycin, the tacrolimus level
dropped. The creatinine level decreased to 1.26 mg/dL
gradually. He took minocycline and TMP-SMZ for a
total of 3 months. No relapse of fever was observed
after discontinuation of antibiotics for a year.
Discussion
Human brucellosis is a common zoonotic disease in
endemic areas. It may be difficult to diagnose because
of its wide clinical polymorphism. Taiwan has been free
of this disease since 1980 after an eradication program
(7). However, 4 imported cases acquired from North
Africa and Malaysia occurred in 2011. Our patient had
visited Henan province of China, which was endemic
for brucellosis (2), 1 month before this illness.
Although he denied animal or raw food exposure, we
speculated that he probably got infected during the
travel. Therefore, the disease may become important
given the high frequency of traveling abroad in this
global village.
The common clinical and laboratory features of
complicated brucellosis are fever (66%), sweats (15%),
malaise (35%), arthralgia (38%), back pain (36%),
abdominal pain, hepatosplenomegaly, anemia (34%),
 Ting et al: Brucellosis in renal transplant

elevated liver function tests (31%), and elevated
C-reactive protein (68%) and erythrocyte sedimentation
rate (73%). Complications include hematologic (55%),
osteoarticular (37%), hepatobiliary (31%), gastrointesti-
nal (12%), genitourinary (5%), central nervous (5%), and
cardiovascular systems (1%) (8). Renal involvement of
brucellosis, presenting as tubulointerstitial nephritis or
glomerulonephritis with or without acute renal failure,
is not common (9, 10). It is worth noting that in patients
with end-stage renal disease, there tend to be more
complaints of arthralgia but fewer complaints of fever
(43%) (11). Up to this date, 6 cases of Brucella
peritonitis have been reported in continuous ambula-
tory peritoneal dialysis patients (12). The catheter
removal rate was 50%. The most common presenting
symptom was abdominal pain, and only 1 patient had a
body temperature >37.5°C. Therefore, in endemic
areas, brucellosis should be kept in mind in patients
with end-stage renal disease, even if they are afebrile.
Only 3 cases have been reported of brucellosis in
renal transplant recipients (4–6). The detailed informa-
tion on these, including our present case, is summa-
rized in Table 1. The mean age of these patients at
presentation was 49.8 years (range 41–58 years). The
male to female ratio was 1.0. The mean time from renal
transplantation to the diagnosis of brucellosis was
5.1 years (range 17 months to 13 years). All patients
were receiving immunosuppressive therapy, and all had
fever and constitutional symptoms. Our patient had
leukopenia, thrombocytopenia, and elevated liver func-
tion tests. Two of the 4 patients had acute-on-chronic
kidney disease at presentation, and renal function
returned to baseline after antibiotic treatment. Compli-
cations reported in these patients were infective endo-
carditis, neurobrucellosis, arthritis, hematologic, and
hepatobiliary manifestations. Our patient had the mild-
est complication, probably because of the new gener-
ation of immunosuppressive agents he was taking. All
patients attained clinical cure after combination antibi-
otic therapy.
Brucellosis is not a common complication after renal
transplantation, even in endemic areas. The possible
explanation for this phenomenon may be the avoidance
of raw food ingestion and animal contact in this group

Brucellosis in renal transplant recipients

Case number 1 2 3 4

Reference Bishara et al. (4) Yousif & Nelson (5) Einollahi et al. (6) Present case
Age in years/gender/ 41/Male/Israel 56/Female/Saudi Arabia 44/Female/Iran 58/Male/Taiwan
country
Time post transplant 3 years 13 years 17 months 3 years
Immunosuppressive Azathioprine, Cyclosporine azathioprine, Cyclosporine, Tacrolimus, mycophenolate
therapy prednisolone prednisolone azathioprine, sodium
prednisolone
Clinical features Fever, weakness Fever, confusion Fever, right knee Fever, sweats, malaise
swelling
WBC (per mm3) 5200 NA 20,000 3160
Platelets (per mm3) 130,000 NA NA 74,000
ALT (U/L) Normal NA NA 156
Creatinine (mg/dL) 1.6 6.0, 2.71 3.8, 1.71 1.25
Diagnosis Blood culture Brucella titer (1:320) Synovial fluid, blood Blood culture (B. melitensis)
(Brucella melitensis) cultures
Complication Infective endocarditis2 Neuro-brucellosis Brucellosis arthritis Hematologic, hepatobiliary
Treatment DOX, RIF, TMP-SMZ DOX, RIF DOX, RIF, CIP TIG 2 weeks; MIN, TMP-SMZ
6 weeks 6 weeks 3 months
Outcome Cure Cure Cure Cure

1
At admission and discharge.
2
A 3 mm vegetation on mitral valve.
WBC, white blood cell count; NA, not available; ALT, alanine aminotransferase; DOX, doxycycline; RIF, rifampin; TMP-SMZ, trimethoprim-
sulfamethoxazole; CIP, ciprofloxacin; TIG, tigecycline; MIN, minocycline.

Table 1

Transplant Infectious Disease 2013: 15: E191–E195 E193

Ting et al: Brucellosis in renal transplant
of patients. Given the small number of patients, further
study is needed to identify the characteristics of
brucellosis in renal transplant recipients.
Two cases have been reported of transmission of
brucellosis by bone marrow transplantation (13, 14). In
the literature, brucellosis occurred in a 20-year-old man
4 months after successful allogeneic hematopoietic
stem cell transplant (15). Relapsing brucellosis also
developed in a 15-year-old boy 2 months after liver
transplantation (16). To the best of our knowledge, no
cases of Brucella infection after heart, lung, or pancreas
transplantation have been reported.
The aims of antibiotic therapy for brucellosis are to
relieve symptoms, reduce complications, and prevent
relapses. The recommended first-line combination
therapy is 6 weeks of doxycycline plus 2 weeks of
gentamycin or streptomycin (17). The second-line
combination therapy is 6 weeks of doxycycline and
rifampin. Alternatively, 6 weeks of doxycycline and
TMP-SMZ is also effective. We did not choose
gentamycin or streptomycin because our patient was
a renal transplant recipient with a creatinine level of
1.25 mg/dL. In addition, he took tacrolimus as immu-
nosuppressive therapy, which was metabolized mainly
by the cytochrome P-450 3A system (18). Rifampin is a
strong inducer of the cytochrome P-450 3A isozymes.
Simultaneous use of rifampin and tacrolimus may
result in marked reduction in tacrolimus level and
acute rejection. Therefore, we used minocycline and
TMP-SMZ as the therapeutic regimen. Macrolide
antibiotics such as clarithromycin form inactive com-
plexes with cytochrome P-450 3A isozymes and
inhibit the metabolism of other drugs. This was seen
in our patient, who developed acute renal failure
and high tacrolimus level after the administration of
clarithromycin.
Several studies have shown in vitro susceptibilities
of B. melitensis to tigecycline (19–21). The MIC
ranges of tigecycline using Etest was 0.019–0.25 lg/
mL. The result was 0.094 in this study. This low value
suggested tigecycline as a therapeutic option in the
treatment of brucellosis. Only 1 case report was found
in the literature demonstrating in vivo efficacy of
tigecycline for brucellosis (22). The patient was a 41-
year-old man with hepatic failure. Brucellosis recurred
soon after 6 weeks of doxycycline and ciprofloxacin,
and was successfully treated with tigecycline plus
gentamycin. In our patient, fever persisted despite the
use of several antibiotics, and fever finally subsided
after tigecycline administration. One report described
increased tacrolimus levels necessitating a decrease in
tacrolimus dose during tigecycline therapy (23). How-
ever, in our patient, tigecycline was well tolerated and
E194 Transplant Infectious Disease 2013: 15: E191–E195
the tacrolimus levels were stable during the treatment
course.
In conclusion, although brucellosis is rare in renal
transplant recipients, we should maintain a high index
of suspicion. During antibiotic treatment, we should
be aware of the potential drug interactions and
monitor the levels of immunosuppressive agents
frequently. Tigecycline did not alter tacrolimus levels
in our patient. Tigecycline was used successfully to
treat brucellosis in our patient and should be consid-
ered for use in treatment of brucellosis in transplant
patients.
References
1. World Health Organization. Fact Sheet N173. Geneva,
Switzerland: World Health Organization, 1997.
2. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV.
The new global map of human brucellosis. Lancet Infect Dis 2006;
6: 91–99.
3. Buzgan I, Karahocagil MK, Irmak H, et al. Clinical manifestations
and complications in 1,028 cases of brucellosis: a retrospective
evaluation and review of the literature. Int J Infect Dis 2010; 14:
469–478.
4. Bishara J, Robenshtok E, Weinberger M, Yeshurun M, Sagie A,
Pitlik S. Infective endocarditis in renal transplant recipients.
Transpl Infect Dis 1999; 1: 138–143.
5. Yousif B, Nelson J. Neurobrucellosis – a rare complication of
renal transplantation. Am J Nephrol 2001; 21: 66–68.
6. Einollahi B, Hamedanizadeh AK, Alavian SM. Brucellosis
arthritis – a rare complication of renal transplantation: a case
report. Transplant Proc 2003; 35: 2698.
7. Lu YS, Lee YL, Lin DF, Tsai HJ. Case study on human brucellosis
of bovine-origin in Taiwan. Taiwan Prov Res Inst Anim Hlth Exp
Rep 1994; 30: 127–134.
8. Mermut G, Ozgencß O, Avci M, et al. Clinical, diagnostic and
therapeutic approaches to complications of brucellosis: an
experience of 12 years. Med Princ Pract 2012; 21: 46–50.
9. Bakri FG, Wahbeh A, Mahafzah A, Tarawneh M Brucella
glomerulonephritis resulting in end-stage renal disease: a case
report and a brief review of the literature. Int Urol Nephrol 2008;
40: 529–533.
10. Ceylan K, Karahocagil MK, Soyoral Y, et al. Renal involvement in
Brucella infection. Urology 2009; 73: 1179–1183.
11. Turuncß T, Demirog lu YZ, Alisßkan H, et al. Brucellosis in cases of
end-stage renal disease. Nephrol Dial Transplant 2008; 23:
2344–2349.
12. Solak Y, Biyik Z, Demircioglu S, et al. Brucella peritonitis in
peritoneal dialysis: a case report and review of the literature. Perit
Dial Int 2012; 32: 126–130.
13. Naparstek E, Block CS, Slavin S. Transmission of brucellosis by
bone marrow transplantation. Lancet 1982; 1: 574–575.
14. Ertem M, Ku €rekcßi AE, Aysev D, Unal E, Ikinciog ullari A.
Brucellosis transmitted by bone marrow transplantation. Bone
Marrow Transplant 2000; 26: 225–226.
15. Al-Anazi KA, Jafar SA, Al-Jasser AM, Al-Omar H, Al-Mohareb
FI. Brucella bacteremia in a recipient of an allogeneic
hematopoietic stem cell transplant: a case report. Cases J 2009; 2:
91.

16. Polat KY, Tosun MS, Ertekin V, Aydinli B, Emre S. Brucella
infection with pancytopenia after pediatric liver transplantation.
Transpl Infect Dis 2012; 14: 326–329.
17. Skalsky K, Yahav D, Bishara J, Pitlik S, Leibovici L, Paul M.
Treatment of human brucellosis: systematic review and
meta-analysis of randomized controlled trials. BMJ 2008; 336:
701–704.
18. Paterson DL, Singh N. Interactions between tacrolimus and
antimicrobial agents. Clin Infect Dis 1997; 25: 1430–1440.
19. Kilic S, Dizbay M, Cabadak H. In vitro activity of tigecycline,
tetracycline and fluoroquinolones against Brucella melitensis.
J Chemother 2008; 20: 33–37.
Transplant Infectious Disease 2013: 15: E191–E195
Ting et al: Brucellosis in renal transplant
20. Bayram Y, Korkoca H, Aypak C, et al. Antimicrobial
susceptibilities of Brucella isolates from various clinical
specimens. Int J Med Sci 2011; 8: 198–202.
21. Chuang YC, Chen SC, Mu JJ, et al. Brucellosis, Taiwan, 2011.
Emerg Infect Dis 2011; 12: 2374–2375.
22. Cocchi S, Bisi L, Codeluppi M, et al. Brucellosis in a patient with
end-stage liver disease undergoing liver transplantation:
successful treatment with tigecycline. Liver Transpl 2010; 16:
1215–1216.
23. Pavan M, Chaudhari AP, Ranganth R. Altered bioavailability of
tacrolimus following intravenous administration of tigecycline.
Am J Kidney Dis 2011; 57: 354.
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