BRUCELLOSIS

Introduction & History

Brucellosis:

Disease of domestic and wild

animals (zoonosis): communicable to humans.
It has different non-specific symptoms and
signs
Marston Surgeon serving with Royal Artillery
during Crimean war-reported first accurate
description of human brucellosis.
1886, Bruce isolated Micrococcus (later
Brucella) Melitensis from spleens of Malta
fever victims.
victims
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THE PATHOGEN

Brucellae: Small, Gram negative cocobacilli, nonmotile, non-spore forming.

Brucellae grow aerobically.
Some spp. require supplemental carbon dioxide
for primary isolation.
Any high-quality peptone-based media enriched
with blood or serum serve for in vitro cultivation.
Isolation form clinical specimens require prolonged
( 30 days) incubation.
Brucella strains always catalse-positive; but
oxidase and urease and H2S production may vary.
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The Pathogen (contd.)

Major Brucellae species and their biovars

differentiated by selective inhibition of growth on
media containing dyes- thionin and basic fuchsine.
Genus Brucella divided into six (possibly seven)
spp. on basis of preferred hosts and cultural,
metabolic and antigenic characteristics.
DNA-DNA hybridization studies shown remarkable
( >95%) homology between strains, suggesting
mono-specific gems with subspecies
corresponding evolutionary lineage adapted to
specific hosts.
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Epidemiology

Brucellosis zoonosis all infections, derive

directly or indirectly from animals exposure.
Disease exists world-wide, esp. Mediterranean,
Arabic Peninsula, Indian subcontinent, parts of
Mexico and Central South America.
B. abortus found mainly in cattle, but others spp.
like buffalo, camels, tales can be affected.
B. Melitensis primary affects goats and sheep.
Camels can be important source in some
countries.
B. Suis biovars 1-3 in domestic and feral swine,
cause abattoir-assoc. human disease.
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Epidemiology (Contd.)

B. Canis:
Least common cause of human
disease.
Animals: Brucellosis, Ch. Infection, persisting for
life.
Brucellae localization in reproductive organs,
accounts for major manifestations abortion and
sterility.
Brucellae shed in large numbers in: Milk, urine,
cyetic products of infected animals.

Epidemiology (Contd.)

Thus, Brucellosis constitutes occupational risk for:

farmers, veterinarians, abattoirs and laboratory
personnel.
Routes of transmission to human include:
- Direct contact with animals or their secretions,
through cuts and skin abrasions.
- Infected aerosols inhaled or inoculated into eye
conjunctive sac.
- Ingestion of unpasteurized dairy products.
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Epidemiology (Contd.)
- Meat products: rare source of infection
because: Meat is rarely eaten raw and
organisms are present in low number of
muscle tissue.
- Blood and bone marrow may transmit
disease when ingested in some cultures.
- Human-to-human transmission: Unusual, but
rare cases suspected to be sexually
transmitted.
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Pathogenesis

B. melitensis and B. suis, more virulent than B.

abortus and B. canis.
Infection with any B. species, including attenuated
vaccine strains can cause serious human disease.
Disease determined by:
- Host nutritional and immune status.
- Size of infectious inoculums.
- Route of transmission.
Ex: -Low gastric juice PH, more effective in
preventing B. abortus than B. melitensis
infection when administered by oral route.
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 Pathogenesis

-Therefore, drugs that decrease gastric

acidity were implicated in food borne
brucellosis.
Once brucellae gain entry to body: PMN
Leukocytes attracted to inoculation site by
chemotaxis.
Normal human serum has limited bactericidal
activity against brucellae, but it effectively
opsonizes bacteria for phagocytosis by PMN
Leukocytes.
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Pathogenesis (contd.)
Brucellae:

Facultative intracellular, slowly

dividing pathogens with capacity to survive
and multiply within host phagocytic cells.
Mechanism by which brucellae evade
intracellular killing by PMN-Leukocytes
incompletely under-stood, it is possible that
bacteria property enable them to escape
detection.

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Host Immunity

Major determinant of virulence and immunodominant antigen of Brucella is LPS.

S-Lps is major deter of virulence of brucellae and
dominates antibody response. Humoral antibodies to S-Lps confer short-term protection as
shown by passive transfer experiments using
monoclonal and polyclonal antibodies. Antibodies
to S-Lps used for diagnosis when bacterial
isolation is unsuccessful.
Variety of serologic tests used to measure antibodies to brucellae. Earliest was serum agglutination test (SAT), devised by Wright and Smith 1897.

.
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Clinical Manifestation
Symptoms

of Brucellosis: non-specific, e.g.

fever, sweats, malaise, anorexia, headache,
backpain.
Onset: acute or insidious, beginning within 2
to 4 weeks after inoculation.
An Undulant fever pattern observed if
patients go untreated for long periods.
Some patients c/o malodorous sweat and
peculiar mouth taste.
Mild lymphadenopathy reported in 10 to
20% of cases.
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Clinical Manifestation

Splenomegaly or hepatomegaly in 20 to 30% of

cases.
Brucellosis: systemic infection in which any organ
or system of the body can be involved.
Attempts to categorize the disease into acute,
subacute and chronic, according to symptoms,
length and severity are purely arbitrary.
Disease referred to focal or localized when
involvement of specific organ predominates.
However, there is little evidence that such
complication represent distinct subset of patients.
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Clinical Manifestation

Patients with delayed convalescence: poorly understood,

some
authorities
attribute
that
to
pre-existing
psychoneurosis exacerbated by brucellosis.
Such patients present diagnostic dilemma, because their
complaints resemble brucellosis, but further antimicrobial
therapy, ineffective, and patients often believe they suffer
from incurable brucellosis.
Most relapses occur within 3 to 6 months of discontinuing
therapy.
Disease considered chronic if infection persists
more than 12 months (arbitrary definition).

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 Respiratory System

- Airborne transmission of brucellosis common

in abbatoirs.
- Respiratory tract involvement ranges from flulike illness with normal chest radiograph results
to bronchitis, broncopneumonia, lung nodules,
miliary lesions, hilar adenopathy and pleural
effusions.
- Rarely brucellae identified by stain or culture
of expectorated sputum.
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 Diagnosis

- Because brucellosis nonspecific, it is

important to:
Obtain detailed history including:
- Occupation, exposure to animals, travel to
enzootic areas, and ingestion of high-risk
foods, as unpasteurized dairy products.
- WBC: normal or low, and may not suggest
infectious process.
- Anemia, leukopenia, and thrombocytopenia,
common findings.
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 Diagnosis

- Diagnosis of brucellosis made with certainty,

when brucellae recovered from blood, bone
marrow, or other tissues.
- Rate of isolation from blood ranges from 1570% depending on methods used and
incubation period.
- When brucellosis is suspected, Lab. should be
informed to maintain cultures for minimum of
4 weeks.
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 Diagnosis (cont;d.)

- Bone marrow cultures have higher yield than

blood.
- Most Labs. Now use rapid isolation techniques;
are satisfactory for recovering brucellae.
- Faster isolation time reported for lysis
concentration method.
- Preliminary studies using PCR, with random or
selected primers, are promising, but require
additional evaluation.
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 Diagnosis

- Presumptive identification of brucella spp.

Made
on the basis of morphologic, cultural, and
serologic features, but confirmation requires:
- Oxidative metabolism
- Phage-typing, or genotyping
procedures.
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 Diagnosis (contd.)

- In the absence of bacteriologic confirmation,

presumptive diagnosis made on the basis of
high or rising titers of specific antibodies.
- Variety of serologic tests applied to
brucellosis
- No single titer of brucella antibodies always
diagnostic, but, most cases of active
infection, have titer higher than 1:160.
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 Treatment (contd.)

- Intracellular localization of brucellae, believed to

offer some protection against antimicrobials, thus
drugs with good intra-cellular penetration are
necessary for cure.
- Tetracyclines among most active drugs for
treating brucellosis, but, relapse rate unacceptably high with single-drug therapy, thus combination therapy is recommended.
- Many studies showed tetracycline (500 mg PO x
4 times daily combined with streptomycin
(1 g/day I.M.) for three weeks is the most
effective treatment.
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 Treatment

- Doxycycline + Rifampicin, especially for pts. with

complications such as spondylitis.
- Rifampicin reported effective for treating
brucellosis during pregnancy.
- Inclusion of aminoglycosides in treatment
regimen suggested, by studies, to be synergistic
with other agents in vitro and clinical use.

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 Treatment (contd.)

- Streptomycin used as preferred aminoglycoside

by most studies, reasons exist to use Gentamin
instead, because Gentamicin is more active in
vitro, less toxic, and can be given as single daily
dose (SDD). However, more studies needed to
establish optimal schedule and compare both
agents (Strept. & Genta.)
- Cotrimoxazole (TMP + SMX), gained initial
enthusiasm, but subsequent comparative
studies revealed unacceptable relapse rate.
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 Treatment (contd.)

- Most authorities recommend: Doxycycline in

combination with two or more other drugs with
treatment continued for many months
depending
on response.
- Doxycycline crosses BBB, better than generic
Tetracycline, and use successfully with
Cotrimoxazole (TMP/SMX) and Rifampicin for
brucella meningitis and endocarditis.
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 Treatment (contd.)

- Third generation cephalosporins achieve high

concentration in CSF, but brucella spp.
susceptibility variable, thus in vitro sensitivity
should be ensured.
- Despite cure of brucella endocarditis, cases
with antibiotic alone, most cases require
combined medical-surgical approach.
- Corticosteroids often recommended from
neurobrucellosis, but, in the absence of
controlled studies, their efficacy is unproved.
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