Case Report
Brucellosis in a Renal Transplant Recipient
I-Wen Ting1,4, Mao-Wang Ho2,4, Yun-Ju Sung3,4, Ni Tien3,4, Chih-Yu Chi2,4,
Hung-Chi Ho2,4, Chiu-Ching Huang1,4
Correspondence to:
Chiu-Ching Huang, M.D.
The Kidney Institute and Division of Nephrology
China Medical University Hospital
China Medical University
No. 2, Yuh Der Road, Taichung, Taiwan
Telephone: +886-4-22052121-7387
Fax: +886-4-22331691
E-mail: cch@mail.cmuh.org.tw
__________________________________
1
Kidney Institute, China Medical University Hospital, Taichung, 40402, Taiwan
2
Department of Internal Medicine, China Medical University Hospital, Taichung,
40402, Taiwan
3
Department of Laboratory Medicine, China Medical University Hospital, Taichung,
40402, Taiwan
4
China Medical University, Taichung, 40402, Taiwan
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. There have been only three
case reports in the literature. We reported a case of brucellosis with hematological and
hepatobiliary complications in a patient three years after renal transplantation. The
mean time from transplantation to the diagnosis of brucellosis in these four 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. Giving
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 against tigecycline. In our patient, fever finally
subsided after tigecycline administration. The minimum inhibitory concentration of
tigecycline using Etest was 0.094 microgram per milliliter. According to our study,
tigecycline is a reliable antibiotic against brucellosis.
Key words: brucellosis, renal transplantation, tacrolimus, tigecycline
Abbreviations: U, units; CMV, cytomegalovirus; B. melitensis, Brucella melitensis;
MIC, minimum inhibitory concentration
Introduction
Brucellosis is one of the most common systemic 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 consumption of
unpasteurized dairy products or by occupational 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,
hematological, hepatobiliary, gastrointestinal, genitourinary, cardiovascular, and
central nervous systems [3].
Brucellosis is rare in renal transplant recipients. To the best of our knowledge,
there have been only three case reports in the literature [4-6]. In this report, we
describe the clinical manifestations, laboratory findings, and successful treatment with
the new antibiotic, tigecycline, in a renal transplant recipient with brucellosis.
Case Report
A 58-year-old man who received a renal transplant three years ago was admitted
to this hospital because of intermittent fever.
The patient had been well until one 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 abdominal 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 three
years ago after hemodialysis for one and a half year. Medications included tacrolimus
1.5 milligram and mycophenolate sodium 180 milligram twice daily, aspirin,
bisoprolol, glimepiride, metformin, and atorvastatin. He lived in central Taiwan with
his wife and owned a Chinese herb store. 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 per minute, the
respiratory rate 20 breaths per minute. The abdomen was distended, soft, without
tenderness, or guarding. The remainder of the physical examination was normal. The
white blood cell count was 3160 per microliter (with 67% neutrophils and 23%
lymphocytes), hemoglobin 12.2 gram per deciliter, and platelet count 74000 per
microliter. The serum level of aspartate aminotransferase was 100 units (U) per liter,
alanine aminotransferase 156 U per liter, alkaline phosphatase 142 U per liter,
gamma-glutamyl transpeptidase 136 U per liter, and creatinine 1.25 milligram per
deciliter. Urinalysis revealed a pH of 5.5, 1+ protein; it was otherwise normal.
Radiography of the chest was normal. Ultrasonography of the abdomen 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 imipenem-cilastatin and colistin on the sixth admission day. Fever
occurred daily after admission, with temperatures up to 39.5C and accompanied with
excessive sweats. We kept imipenem-cilastatin and replaced colistin with levofloxacin
on the tenth admission day. Fever did not subside and five sets of blood cultures
collected after admission remained positive. The transthoracic echocardiography
showed normal valves without vegetation. Cultures of the bone marrow for bacteria,
mycobacteria, and fungi were negative. Tigecycline and levofloxacin were used since
the seventeenth admission day. 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 (B. melitensis) was identified based on conventional
biochemical tests including positive oxidase, urease, and H2S production. We used the
BD Phoenix NMIC/ID-2 commercial kit (Becton Dickinson Diagnostic System,
Sparks, MD, USA). Inoculation was performed according to the manufacturer's
instructions. The API 20E and 32 GN systems (bioMérieux 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 primers. 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 (bioMérieux, Sweden). Mueller-Hinton agar supplemented
with 5% sheep blood (Oxoid, 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 microgram per milliliter.
After identification of B. melitensis as the causative organism, we kept
minocycline, added trimethoprim-sulfamethoxazole, and discontinued clarithromycin
and levofloxacin. The course after discharge was complicated by elevated tacrolimus
level (15.6 nanogram per milliliter) and acute renal failure (creatinine 2.73 milligram
per deciliter). It was speculated that acute renal failure was due to drug interaction
between clarithromycin and tacrolimus that necessitated a decrease in tacrolimus dose.
Upon discontinuing clarithromycin, the tacrolimus level became insufficient. The
creatinine level decreased to 1.26 milligram per deciliter gradually. He took
minocycline and trimethoprim-sulfamethoxazole 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 eradication program [7]. However, there were four
imported cases acquired from North Africa and Malaysia in 2011. Our patient had
visited Henan province of China, which was endemic for brucellosis [2], one 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 giving the high frequency of travelling 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%), elevated liver function tests (31%),
elevated C-reactive protein (68%) and erythrocyte sedimentation rate (73%).
Complications include hematological (55%), osteoarticular (37%), hepatobiliary
(31%), gastrointestinal (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
uncommon [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, there have been six case reports of Brucella peritonitis in
continuous ambulatory peritoneal dialysis patients [12]. The catheter removal rate was
50%. The most common presenting symptom was abdominal pain, and only one
patient had a body temperature over 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.
There have been only three case reports of brucellosis in renal transplant
recipients [4-6]. The detailed information including our case is summarized 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 function tests. Two
of the four patients had acute on chronic kidney disease at presentation, and renal
function returned to baseline after antibiotic treatment. Complications reported in
these patients were infective endocarditis, neurobrucellosis, arthritis, hematological
and hepatobiliary manifestations. Our patient had the mildest complication, probably
because of the new generation immunosuppressive agents he was taking. All patients
attained clinical cure after combination antibiotic 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 of patients. Giving the small number of patients, further
study is needed to identify the characteristics of brucellosis in renal transplant
recipients.
There are two case reports about the 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]. Besides,
relapsing brucellosis developed in a 15-year-old boy 2 months following liver
transplantation [16]. To the best of our knowledge, no case report of Brucella
infection after heart, lung, or pancreas transplantation was found.
The aim of antibiotic therapy for brucellosis is 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 trimethoprim-sulfamethoxazole 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 milligram per deciliter. In
addition, he took tacrolimus as immunosuppressive 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 trimethoprim-sulfamethoxazole as the therapeutic regimen.
Macrolide antibiotics such as clarithromycin form inactive complexes 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 against
tigecycline [19-21]. The MIC ranges of tigecycline using Etest was 0.019 to 0.25
microgram per milliliter. The result was 0.094 in our study. This low value suggested
tigecycline as a therapeutic option in the treatment of brucellosis. Only one 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 successfully treated
with tigecycline plus gentamicin. 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]. However, in our patient, tigecycline was well
tolerated and 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 is a reliable antibiotic against brucellosis. It did not
seem to alter tacrolimus level in our patient.
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Table 1. Brucellosis in renal transplant recipients.
Case
1
2
3
4
Reference
4
5
6
Present case
Age/gender/
41/Male/
56/Female/
44/Female/
58/Male/
country
Israel
Saudi Arabia
Iran
Taiwan
Transplantation
3 years
13 years
17 months
3 years
Immunosuppressive Azathioprine,
Cyclosporine
Cyclosporine,
Tacrolimus,
therapy
azathioprine,
azathioprine,
mycophenolate
prednisolone
prednisolone
sodium
Fever,
Fever,
Fever, right
Fever, sweats,
weakness
confusion
knee swelling
malaise
WBC (per mm3)
5200
NA
20000
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 Synovial fluid,
Blood
(B. melitensis) (1:320)
blood cultures
(B. melitensis)
Infective
Neuro-
Brucellosis
Hematological,
endocarditis2
brucellosis
arthritis
hepatobiliary
DOX, RIF,
DOX, RIF
DOX, RIF, CIP TIG 2 weeks
TMP-SMZ
6 weeks
Clinical features
Complication
Treatment
prednisolone
MIN, TMP-
6 weeks
Outcome
Cure
culture
SMZ 3 months
Cure
Cure
Cure
WBC, white blood cell; NA, not available; ALT, alanine aminotransferase; 1 at admission and discharge;
2
3mm vegetation on mitral valve; DOX, doxycycline; RIF, rifampin; TMP-SMZ, trimethoprim-
sulfamethoxazole; CIP, ciprofloxacin; TIG, tigecycline; MIN, minocycline