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BRUCELLOSIS
Meral SÖNMEZOĞLU, MD
Yeditepe University Hospital
Professor of
Department of Infectious Diseases and Microbiology
Learning Objectives
 Appreciate the importance for our country and
epidemiology
 Know clinical features of brucellosis
 Understand laboratory diagnosis of brucellosis
 Describe the treatment of brucellosis
BRUCELLOSIS
 Known as “undulant fever”, “Mediterranean fever” or
“Malta fever”
 Is a zoonosis and the infection is almost invariably
transmitted by direct or indirect contact with infected
animals or their products.
 It affects people of all age groups and of both sexes.
 There still remain regions where the infection persists in
domestic animals and, consequently, transmission to
the human population frequently occurs.
 It is an important human disease in many parts of the
world especially in the Mediterranean countries of
Europe, north and east Africa, the Middle East, south
and central Asia and Central and South America
BRUCELLOSIS
 Brucellosis is probably the commonest
anthropozoonotic infection worldwide
 A zoonotic infection of domesticated and wild
animals, caused by organisms of the genus
Brucella.
 Humans become infected by ingestion of animal
food products, direct contact with infected animals,
or inhalation of infectious aerosols.
 Brucella melitensis remains the major cause of human
disease worldwide,
 followed by B. abortus and B. suis,
 while rare but persisting cases of B.canis human
infection
BRUCELLOSIS
 Humans, who are usually infected incidentally by
contact with infected animals or ingestion of dairy
foods, may develop numerous symptoms in
addition to the usual ones of fever, malaise, and
muscle pain.
 Disease frequently becomes chronic and may
relapse, even with treatment
 In an era of rapid emergence of antimicrobial
resistance, controversies regarding the
prolonged use of antibiotics with established
activity against Brucella pose special problems.
 In some endemic regions, especially in the
developing world, brucellosis and tuberculosis
coexist in the same communities.
Microbiology
 Brucellae are small, nonmotile, nonsporulating,
nontoxigenic, nonfermenting, aerobic, Gram-negative
coccobacilli that may, based on DNA homology,
represent a single species.
 Conventionally, however, they are classified into six
species, each comprising several biovars
Brucella
Species
Animal Host Human
Pathogenicity
B suis
Swine
High
B melitensis
Sheep, goats
High
B abortus
Cattle, bison
Intermediate
B canis
Dogs
Intermediate
B ovis
Sheep
None
B neotomae
Rodents
None
The 7 Currently Recognized Brucella Species
Organism
Animal Reservoir
Geographic Distribution
B melitensis
Goats, sheep, camels
Mediterranean, Asia, Latin
America, parts of Africa and
some southern European
countries
B abortus
Cows, buffalo, camels, yaks
Worldwide
B suis
Pigs (biotype 1-3)
South America, Southeast Asia, United
States
Brucella canis
Brucella ovis
Canines
Cosmopolitan
Sheep
No known human cases
Brucella neotomae
Rodents
Not known to cause human disease
Brucella pinnipediae and
Brucella cetaceae
Marine animals, minke whales, dolphins,
seals
Recent case reports describing some
human cases (mainly neurobrucellosis
Microbiology
 Brucellae grow best on trypticase, soy-based, or other
enriched media with a typical doubling time of 2 hours.
 Most biovars of B abortus require incubation in an
atmosphere of 5% to 10% carbon dioxide for growth.
 Brucellae may produce urease, oxidize nitrite to nitrate,
and are oxidase and catalase positive.
 Species and biovars are differentiated by their carbon
dioxide requirements
Microbiology
 The lipopolysaccharide (LPS) component of the
outer cell membranes of brucellae is quite
different— both structurally and functionally—
from that of other Gram-negative organisms
 The complete sequencing of the B. melitensis
was achieved in 2002.
 B. suis and abortus recently.
Pathogenesis
 Brucella species have a unique ability of invading both
phagocytic and nonphagocytic cells and surviving in the
intracellular environment by avoiding the immune
system in different ways,
 explaining why brucellosis is a systemic disease and
can involve almost every organ system
Pathogenesis
 Although humoral antibodies appear to play some role
in resistance to infection, the principal mechanism of
recovery from brucellosis is cell-mediated.
 Cellular immunity involves the development of specific
cytotoxic T lymphocytes and activation of
macrophages, enhancing their bactericidal activity,
through the release of cytokines
Pathogenesis
Pathogenesis
Cultured human monocyte-derived macrophage
infected with Brucella melitensis. The bacteria, which
replicate in phagolysosomes, have a coccobacillary
appearance
Pathogenesis
 Brucella species have relatively low virulence, toxicity,
and pyrogenicity, making them a poor inducer of some
inflammatory cytokines such as tumor necrosis factor
(TNF) and interferons
 After replication in the endoplasmic reticulum, the
brucellae are released with the help of hemolysins and
induced cell necrosis
Epidemiology
 Brucellosis causes more than 500,000 infections per
year worldwide.
 The heaviest disease burden lies in countries of the
Mediterranean basin and Arabian Peninsula,
 Also common in India, Mexico, and South and Central
America
 Because of variable reporting, true estimates in
endemic areas are unknown. Incidence rates of 1.2-70
cases per 100,000 people are reported.
The Global Incidence of Human Brucellosis
Morbidity and Mortality
 Human brucellosis carries a low mortality rate (< 5%),
mostly secondary to endocarditis, which is a rare
complication of brucellosis.
 However, brucellosis can cause chronic debilitating
illness with extensive morbidity.
 Worldwide, brucellosis is more common in males than
in females, with a ratio of 5:2-3 in endemic areas
 Persons in their third to fifth decades of life were most
commonly affected.
Clinical Presentation
 Fever is the most common symptom and sign of brucellosis,
occurring in 80-100% of cases. It is intermittent in 60% of
patients with acute and chronic brucellosis and undulant in
60% of patients with subacute brucellosis. Fever can be
associated with a relative bradycardia
Clinical Presentation
 Constitutional symptoms of brucellosis include anorexia,
asthenia, fatigue, weakness, and malaise and are very
common (>90% of cases).
 Bone and joint symptoms include arthralgias, low back pain,
spine and joint pain, and, rarely, joint swelling. These
symptoms affect as many as 55-80% of patients
Physical
The most common findings include hepatosplenomegaly
(or isolated hepatomegaly or splenomegaly) and osteoarticular involvement.
Physical
 Osteoarticular findings can include tenderness and
swelling over affected joints, bursitis, decreased range
of motion, and joint effusion (rare).
 Maneuvers that isolate the sacroiliac joint may cause
pain
Symptoms and Signs of Brucellosis
Complications
 Osteoarticular complications
 Bone and joint involvement are the most frequent complications of
brucellosis, occurring in up to 40% of cases
 Gastrointestinal complications
 Foodborne brucellosis resembles typhoid fever, in that systemic
symptoms predominate over gastrointestinal complaints
 Hepatobiliary complications
 The liver is commonly involved in brucellosis, although liver function
tests can be normal or only mildly elevated
 Genitourinary complications
 Orchitis and epididymitis are the most frequent genitourinary
complications of brucellosis in men
Complications
 Cardiovascular complications
 Infective endocarditis is the most common cardiovascular
manifestation, and it is said to be the most common cause of death
from brucellosis
 Aortic valve is involved more often than the mitral valve
 Neurological complications
 Neurobrucellosis refers to a variety of neurological complications
associated with brucellosis, meningitis or meningoencephalitis are
the most common manifestations.
 Cutaneous complications
 Opthalmic complications
Complications
 Cutaneous manifestations develop in 5-10% of patients, are transient
and nonspecific, resolve with therapy, and do not alter the prognosis.
Lesions reported in association with brucellosis are as follows:[17]
Erythema nodosum, abscesses, and papulonodular eruptions (most
common)

Impetigo, psoriatic, eczematous, and pityriasis rosea –like lesions

Macular, maculopapular, and scarlatiniform rashes

Vasculitic lesions (eg, petechiae, purpura, thrombophlebitis)

Ocular findings can include the following:[18] Uveitis[19]

Keratoconjunctivitis

Iridocyclitis

Nummular keratitis

Choroiditis

Optic neuritis[20]

Metastatic endophthalmitis

Cataracts
Differential diagnoses

Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

Cryptococcosis

Hepatitis, Viral

Histoplasmosis

Infectious Mononucleosis

Infective Endocarditis

Influenza

Leptospirosis

Malaria

Tuberculosis

Tuberculosis of the Genitourinary System

Typhoid Fever
Diagnosis
 Culture
 blood cultures with improved techniques such as the
Castaneda bottles
 Subcultures are still advised for at least 4 weeks
 Bone marrow culture is thought to be the criterion
standard
 Any fluid can be cultured (eg, synovial, pleural,
cerebrospinal
 CSF evaluation
Culture
Diagnosis
 Serology Serological testing is the most commonly
used method of brucellosis diagnosis.
 Serum tube agglutination test
 Tray agglutination (TAT) and modified TAT are also popular. Titers of
more than 1:160 in conjunction with compatible clinical presentation
is considered highly suggestive of infection
 ELISA: cytoplasmic proteins as antigens and measures
IgM, IgG, and IgA,
 Polymerase chain reaction (PCR):
Imaging
 Chest radiography :hilar and paratracheal lymphadenopathy,
pulmonary nodules, pleural thickening, and pleural effusion.
 Spinal radiography :
 sacroiliitis, the most commonly observed abnormalities include
blurring of articular margins and widening of the sacroiliac spaces
 Spondylitis-related abnormalities include anterosuperior vertebral
angle epiphysitis, spinal straightening, narrowing of the intervertebral
disc spaces, end-plate sclerosis, and osteophytes
 Radionuclide scintigraphy
Histology
Histologic findings in brucellosis usually include mixed
inflammatory infiltrates with lymphocytic predominance
and granulomas (in up to 55% of cases) with necrosis
Well-formed hepatic granuloma from a patient with brucellosis
Treatment
 The goal of medical therapy in brucellosis is to control
symptoms as quickly as possible to prevent
complications and relapses.
 Multidrug antimicrobial regimens are the mainstay of
therapy because of high relapse rates reported with
monotherapeutic approaches.
 The risk of relapse is not well understood, as resistance
is not a significant issue in treating brucellosis
Treatment
 A meta-analysis performed in 1995 evaluated the
efficacy of the two WHO-recommended regimens
and concluded that the efficacy of the
doxycycline-streptomycin (DOX-STR) regimen
was superior to that of the doxycycline-rifampicin
(DOX-RIF) regimen, as already suggested by
previous studies
Treatment
 In November 2006, a consensus meeting aimed at
reaching a common specialist statement on the
treatment of brucellosis was held in Ioannina, Greece
under the auspices of the International Society of
Chemotherapy and the Institute of Continuing
Medical Education of Ioannina
Recommendations of Ioannina Concensus
Treatment
Treatment
 The essential element in the treatment of all forms of human
brucellosis is the administration of effective antibiotics for an
adequate length of time.
 Treatment of uncomplicated cases in adults and children
eight years of age and older:
 Doxycycline 100 mg twice a day for six weeks +
streptomycin 1 g daily for two to three weeks.
 OR
 Doxycycline 100 mg twice a day for six weeks +
rifampicin 600– 900 mg daily for six weeks.
Treatment
Treatment
 Doxycycline
 Gentamicin
 Streptomycin
 Rifampin
 Trimethoprim-sulfamethoxazole (TMP-SMZ)
Other agents with potential roles include the following:
 Chloramphenicol
 Imipenem-cilastatin
 Tigecycline
 Fluoroquinolones
Treatment
 Children younger than 8 years: The use of rifampin and
trimethoprim-sulfamethoxazole (TMP-SMX) for 6 weeks
 Pregnant women: rifampin alone or in combination with TMP-SMX.
However, TMP-SMX use associated with kernicterus
 Patients with meningoencephalitis may require doxycycline in
combination with rifampin, TMP-SMX, or both
 Patients with endocarditis require aggressive therapy.
Aminoglycoside therapy in conjunction with doxycycline, rifampin, and
TMP-SMX for at least 4 weeks followed by at least 2-3 active agents for
another 8-12 weeks is preferred.
Surgery
 The role of surgery in patients with brucellosis lies in
the treatment of endocarditis or drainage of focal
abscesses.
 Previously healthy native valves, diseased native
valves, and prosthetic valvular structures have been
involved in brucellosis.
 Valvular lesions are typically large and destructive,
regardless of the organism involved
Follow-up
 Relapse rate %10, usualy occur in the first year after 1
infection
 Often milder in severity than initial
 Most cases of relapse are caused by inadequate
treatment
 Can be treated by repeated course
KEY POINTS ON THE DISEASE IN HUMANS
 Human brucellosis usually presents as a febrile illness.
 Most cases are caused by B. melitensis.
 All age groups are affected.
 Complications may affect any organ system.
 The disease may persist as relapse, chronic localized
infection or delayed convalescence
TUS 2012
 Güneydoğu Anadolu’da yaşayan, 45 yaşında hayvancılıkla uğraşan bir
hasta son bir aydır devam eden ateş, eklem ağrıları, gece terlemeleri,
iştahsızlık ve hâlsizlik yakınmalarıyla başvuruyor. Yapılan fizik
muayenede hepatosplenomegali ve radyolojik incelemelerde sakroileitis
tespit ediliyor.
Bu hastanın tedavisinde aşağıdaki ilaçlardan hangisi kullanılmaz?
A) Tetrasiklin
B) Amoksisilin / klavulanat
C) Trimetoprim-sulfametoksazol
D) Rifampisin
E) Siprofloksasin
TUS 2012
 Güneydoğu Anadolu’da yaşayan, 45 yaşında hayvancılıkla uğraşan bir
hasta son bir aydır devam eden ateş, eklem ağrıları, gece terlemeleri,
iştahsızlık ve hâlsizlik yakınmalarıyla başvuruyor. Yapılan fizik
muayenede hepatosplenomegali ve radyolojik incelemelerde sakroileitis
tespit ediliyor.
Bu hastanın tedavisinde aşağıdaki ilaçlardan hangisi kullanılmaz?
A) Tetrasiklin
B) Amoksisilin / klavulanat
C) Trimetoprim-sulfametoksazol
D) Rifampisin
E) Siprofloksasin
TUS 2012
 Aşağıdakilerden hangisi, bruselloz tedavisinde
kullanılan antibiyotiklerden biri değildir?
 A) Doksisiklin
 B) Streptomisin
 C) Rifampin
 D) Trimetoprim-sulfametoksazol
 E) Fusidik asit
TUS 2012
 Aşağıdakilerden hangisi, bruselloz tedavisinde
kullanılan antibiyotiklerden biri değildir?
 A) Doksisiklin
 B) Streptomisin
 C) Rifampin
 D) Trimetoprim-sulfametoksazol
 E) Fusidik asit
TUS 2012

Hayvancılıkla uğraşan 40 yaşındaki bir erkek hasta, son 2 aydır devam eden
ateş, bol terleme, kas ağrıları, sol dizinde ağrı ve şişlik yakınmalarıyla
başvuruyor. Öyküsünden ateşinin aralıklarla geldiği; 7-10 gün ateşli dönemleri,
7-10 gün normal dönemlerin izlediği öğreniliyor. Fizik muayenesinde
konjunktivada solukluk ve 6 cm splenomegali saptanıyor. Laboratuvar
incelemelerinde hematokrit: % 30, lökosit: 6000/mm3 (% 60 parçalı, % 40
lenfosit) ve trombosit: 150.000/mm3 olarak bulunuyor.
Bu hasta için en olası tanı aşağıdakilerden hangisidir?
A) Tifo
B) Sıtma
C) Bruselloz
D) Q ateşi
E) Hodgkin hastalığı
TUS 2012

Hayvancılıkla uğraşan 40 yaşındaki bir erkek hasta, son 2 aydır devam eden
ateş, bol terleme, kas ağrıları, sol dizinde ağrı ve şişlik yakınmalarıyla
başvuruyor. Öyküsünden ateşinin aralıklarla geldiği; 7-10 gün ateşli dönemleri,
7-10 gün normal dönemlerin izlediği öğreniliyor. Fizik muayenesinde
konjunktivada solukluk ve 6 cm splenomegali saptanıyor. Laboratuvar
incelemelerinde hematokrit: % 30, lökosit: 6000/mm3 (% 60 parçalı, % 40
lenfosit) ve trombosit: 150.000/mm3 olarak bulunuyor.
Bu hasta için en olası tanı aşağıdakilerden hangisidir?
A) Tifo
B) Sıtma
C) Bruselloz
D) Q ateşi
E) Hodgkin hastalığı
TUS 2013
 Mezbahada et kesimi ile uğrasan kişide eklem ağrısı
var. katalaz ve oksidaz + üreme etkeni var.
a) Brucella melitensis
b) Listeria monocytogenesis
c) Tuberculosis
TUS 2013
 Brusellozda, aşağıdaki örneklerin hangisinden
bakteri izolasyonu yapılmaz?
A) Kan
B) Kemik iliği
C) İdrar
D) Gaita
E) Sinovyal sıvı
TUS 2013
 Brusellozda, aşağıdaki örneklerin hangisinden
bakteri izolasyonu yapılmaz?
A) Kan
B) Kemik iliği
C) İdrar
D) Gaita
E) Sinovyal sıvı
TUS 2013
 Sekiz yaşından büyük çocuklarda bruselloz
tedavisinde kullanılan en etkili antibiyotik
kombinasyonu aşağıdakilerden hangisidir?
A) Sikloserin ve aminoglikozid
B) 3. kuşak sefalosporin ve aminoglikozid
C) Tetrasiklin ve 3. kuşak sefalosporin
D) Doksisiklin ve aminoglikozid
E) Kloramfenikol ve amoksisilin
TUS 2013
 Sekiz yaşından büyük çocuklarda bruselloz
tedavisinde kullanılan en etkili antibiyotik
kombinasyonu aşağıdakilerden hangisidir?
A) Sikloserin ve aminoglikozid
B) 3. kuşak sefalosporin ve aminoglikozid
C) Tetrasiklin ve 3. kuşak sefalosporin
D) Doksisiklin ve aminoglikozid
E) Kloramfenikol ve amoksisilin