# 57 - 174 Brucellosis

### 174 Brucellosis

develop hypotension, which is often apparent at admission. Cutaneous 
manifestations develop in most cases (usually within 36 h of onset) 
and characteristically involve the extremities (the lower more often 
than the upper). In a common sequence, erythematous patches are 
followed by ecchymoses, vesicles, and bullae. In fact, sepsis and hem­
orrhagic bullous skin lesions suggest the diagnosis in appropriate set­
tings. Necrosis and sloughing also may be evident. Laboratory studies 
reveal leukopenia more often than leukocytosis, thrombocytopenia, 
or elevated levels of fibrin-split products. V. vulnificus can be cultured 
from blood or cutaneous lesions. The mortality rate approaches 50%, 
with most deaths due to uncontrolled sepsis (Chap. 315). Accord­
ingly, prompt treatment is critical and should include empirical 
antibiotic administration, aggressive debridement, and general sup­
portive care. V. vulnificus is sensitive in vitro to a number of antibiot­
ics, including tetracycline, fluoroquinolones, and third-generation 
cephalosporins. Optimal treatment usually involves administration of 
a third-generation cephalosporin such as ceftazidime with doxycycline 
or a fluoroquinolone and wound debridement.
V. vulnificus–associated soft tissue infection can complicate either a 
fresh or an old wound that comes into contact with seawater; the patient 
may or may not have underlying disease. After a short incubation 
period (4 h to 4 days; mean, 12 h), the disease begins with swelling, ery­
thema, and (in many cases) intense pain around the wound. These signs 
and symptoms are followed by cellulitis, which spreads rapidly and is 
sometimes accompanied by vesicular, bullous, or necrotic lesions. Meta­
static events are uncommon. Most patients have fever and leukocytosis. 
V. vulnificus can be cultured from skin lesions and occasionally from the 
blood. Prompt antibiotic therapy and debridement are usually curative.
V. alginolyticus 
First identified as a pathogen of humans in 1973, V. 
alginolyticus occasionally causes eye, ear, and wound infections. This 
species is the most salt-tolerant of the vibrios and can grow in salt 
concentrations of >10%. Most clinical isolates come from superinfected 
wounds that presumably become contaminated at the beach. Although 
its severity varies, V. alginolyticus infection tends not to be serious and 
generally responds well to antibiotic therapy and drainage. Cases of 
otitis externa, otitis media, and conjunctivitis due to this pathogen have 
been described. Tetracycline treatment usually results in cure. V. algi­
nolyticus is a rare cause of bacteremia in immunocompromised hosts.
■
■FURTHER READING
Brumfield KD et al: Environmental parameters associated with inci­
dence and transmission of pathogenic Vibrio spp. Environ Microbiol 
23:7314; 2021.
Collins JP et al: Preliminary incidence and trends of infections with 
pathogens transmitted commonly through food—Foodborne Dis­
eases Active Surveillance Network, 10 U.S. Sites, 2016–2021. MMWR 
Morb Mortal Wkly Rep 71:1260, 2022.
Domman D et al: Integrated view of Vibrio cholerae in the Americas. 
Science 358:789, 2017.
Global Task Force on Cholera Control: Early detection and response 
to contain outbreaks. www.gtfcc.org. Accessed December 6, 2023.
Huang Y et al: New variant of Vibrio parahaemolyticus, sequence type 
3, serotype O10:K4, China, 2020. Emerg Infect Dis 28:1261; 2022.
Kayembe HC et al: Drivers of the dynamics of the spread of cholera 
in the Democratic Republic of the Congo, 2000–2018: An ecoepidemiological study. PLoS Negl Trop Dis 17:e0011597, 2023.
Mavian CN et al: Ancestral origin and dissemination dynamics of reemerg­
ing toxigenic Vibrio cholerae, Haiti. Emerg Infect Dis 29:2073, 2023.
Weill FX et al: Genomic history of the seventh pandemic of cholera in 
Africa. Science 358:785, 2017.
World Health Organization: Cholera vaccines: WHO position 
paper. Wkly Epidemiol Rec 92:477, 2017.
World Health Organization: Cholera, 2022. Wkly Epidemiol Rec 
38:432, 2023.
World Health Organization: Outbreak response field manual, 
Global Task Force on Cholera Control. https://www.gtfcc.org/wp-content/
uploads/2020/05/gtfcc-cholera-outbreak-response-field-manual-2024.pdf. 
Accessed March 21, 2024.

Nicholas J. Beeching

Brucellosis
■
■DEFINITION
Brucellosis is a bacterial zoonosis transmitted directly or indirectly to 
humans from infected animals, predominantly domesticated rumi­
nants and swine. The disease is known colloquially as undulant fever 
because of its remittent character. Although brucellosis commonly 
presents as an acute febrile illness, its clinical manifestations vary 
widely, and definitive signs indicative of the diagnosis may be lacking. 
Thus, the clinical diagnosis usually must be supported by the results of 
bacteriologic and/or serologic tests.
■
■ETIOLOGIC AGENTS
Human brucellosis is caused by strains of the genus Brucella, with 
several species groups defined by differences in chromosomal struc­
ture, host preference, and epidemiologic patterns of infection. Brucella 
melitensis is the most common cause of symptomatic disease in humans, 
for which the main sources are sheep, goats, and camels; B. abortus is 
usually acquired from cattle or buffalo; B. suis is generally acquired 
from swine but has one variant that is enzootic in reindeer and caribou 
and another in rodents; B. canis is acquired from dogs. B. ovis causes 
reproductive disease in sheep but has not been clearly implicated in 
human disease. Rare human infections have been reported with B. 
neotomae, which is found in desert rodents. Two species, B. ceti and B. 
pinnipedialis, have been identified in marine mammals, including seals 
and dolphins. At least one case of laboratory-acquired human disease 
due to one of these species has been described, and several cases of 
natural human infection have been reported. As infections in marine 
mammals appear to be widespread, more cases of zoonotic infection in 
humans may be identified. Other reported species include B. microti 
(isolated from field voles), B. papionis (from baboons), B. vulpis (from 
foxes), and B. inopinata (from a patient with a breast implant). Addi­
tional novel strains have been described in diverse species, including 
frogs, bats, and various rodents, and the genus likely will expand 
further in forthcoming years. The genus Brucella is closely related to 
the genus Ochrobactrum, which includes free-living environmental 
bacteria that can occasionally cause opportunistic infections. Recent 
changes in taxonomy now place Ochrobactrum spp. as subspecies of 
Brucella on genetic grounds, although the ecology, physiology, clinical 
niche, and antimicrobial sensitivity of these organisms are completely 
different.
CHAPTER 174
Brucellosis
All brucellae are small, gram-negative, unencapsulated, nonsporu­
lating rods or coccobacilli. They grow aerobically on peptone-based 
medium incubated at 37°C; the growth of some types is improved by 
supplementary CO2. In vivo, brucellae behave as facultative intracel­
lular parasites. The organisms are sensitive to sunlight, ionizing radia­
tion, and moderate heat; they are killed by boiling and pasteurization 
but are resistant to freezing and drying. Their resistance to drying 
renders brucellae stable in aerosol form, facilitating airborne transmis­
sion. The organisms can survive for up to 2 months in soft cheeses 
made from goat’s or sheep’s milk; for at least 6 weeks in dry soil con­
taminated with infected urine, vaginal discharge, or placental or fetal 
tissues; and for at least 6 months in damp soil or liquid manure kept 
in cool dark conditions. Brucellae are easily killed by a wide range of 
common disinfectants used under optimal conditions but are likely to 
be much more resistant at low temperatures or in the presence of heavy 
organic contamination.
■
■EPIDEMIOLOGY
Brucellosis is a zoonosis whose occurrence and control are closely 
related to its prevalence in domesticated animals. Its distribution is 
worldwide apart from the few countries where it has been eradicated 
from the animal reservoir. The true global prevalence of human bru­
cellosis is unknown because of the imprecision of diagnosis and the 
inadequacy of reporting and surveillance systems in many countries.

Recent estimates suggest there may be more than 2 million cases of 
human infection a year worldwide. There has been increased recog­
nition of brucellosis in India, Pakistan, Sri Lanka, and China, and of 
importations to countries in Oceania, such as Fiji, and in Asia, such 
as Thailand and Vietnam. In Europe, the incidence of brucellosis in 
a country is inversely related to gross domestic product, and in both 
developed and less well-resourced settings, human brucellosis is related 
to rural poverty and inadequate access to medical care. Failure of 
veterinary control programs due to conflicts or for economic reasons 
contributes further to the emergence and re-emergence of disease, as 
seen currently in some eastern Mediterranean countries.

Even in well-resourced settings, the true incidence of brucellosis in 
domesticated animals may be 10–20 times higher than the reported 
figures. Bovine brucellosis has been the target of control programs in 
many parts of the world and has been eradicated from the cattle popula­
tions of much of northern Europe, Australia, New Zealand, and Canada, 
among other nations. Its incidence has been reduced to a low level in the 
United States and most western European countries, with a varied pic­
ture in other parts of the world. Efforts to eradicate B. melitensis infec­
tion from sheep and goat populations have been much less successful. 
These efforts have relied heavily on vaccination programs, which have 
tended to fluctuate with changing economic and political conditions. In 
some countries (e.g., Israel), B. melitensis has caused serious outbreaks 
in cattle. Infections with B. melitensis still pose a major public health 
problem in Mediterranean countries; in western, central, and southern 
Asia; and in parts of Africa and South and Central America. Infections 
with B. abortus are common in cattle-rearing communities in African 
countries such as Kenya and Uganda. Canine infection with B. canis is 
present on most continents—the incidence appears to be increasing in 
North America and in several European countries, often associated with 
importation of dogs from an endemic area.
PART 5
Infectious Diseases
Human brucellosis is usually associated with occupational or 
domestic exposure to infected animals or their products. Farmers, 
shepherds, goatherds, veterinarians, and employees in slaughterhouses 
and meat-processing plants in endemic areas are occupationally 
exposed to infection. Feral pig hunters are at risk of infection with 
B. suis in several countries, including Australia. Family members of 
individuals involved in animal husbandry may be at risk, although it 
is often difficult to differentiate food-borne infection from environ­
mental contamination under these circumstances. Laboratory workers 
who handle cultures or infected samples also are at risk. Travelers and 
urban residents usually acquire the infection through consumption 
of contaminated foods. In countries that have eradicated the disease, 
new cases are most commonly acquired abroad. Dairy products, espe­
cially soft cheeses, unpasteurized milk, and ice cream, are the most 
frequently implicated sources of infection; raw meat and bone marrow 
may be sources under exceptional circumstances. Infections acquired 
through cosmetic treatments using materials of fetal origin have been 
reported. Person-to-person transmission is extremely rare, as is trans­
fer of infection by blood or tissue donation. Although brucellosis is 
a chronic intracellular infection, there is no evidence for increased 
prevalence or severity among individuals with HIV infection or with 
immunodeficiency or immunosuppression of other etiologies.
Brucellosis may be acquired by ingestion, inhalation, or mucosal or 
percutaneous exposure. Accidental injection or ingestion of the live 
vaccine strains of B. abortus (S19 and RB51) and B. melitensis (Rev 1) 
can cause disease. B. melitensis and B. suis have historically been devel­
oped as biological weapons by several countries and could be exploited 
for bioterrorism (Chap. S4). This possibility should be borne in mind 
in the event of sudden unexplained outbreaks.
■
■IMMUNITY AND PATHOGENESIS
Exposure to brucellosis elicits both humoral and cell-mediated 
immune responses. The mechanisms of protective immunity against 
human brucellosis are presumed to be similar to those documented in 
laboratory animals, but such generalizations must be interpreted with 
caution. The response to infection and its outcome are influenced by 
the virulence, phase, and species of the infecting strain. Differences 
have been reported between B. abortus and B. suis in modes of cellular 

entry and subsequent compartmentalization and processing. Antibod­
ies promote clearance of extracellular brucellae by bactericidal action 
and by facilitation of phagocytosis by polymorphonuclear and mono­
nuclear phagocytes; however, antibodies alone cannot eradicate infec­
tion. Organisms taken up by macrophages and other cells can establish 
persistent intracellular infections. The key target cell is the macro­
phage, and bacterial mechanisms for suppressing intracellular killing 
and apoptosis result in very large intracellular populations. Opsonized 
bacteria are actively phagocytosed by neutrophilic granulocytes and by 
monocytes. In these and other cells, initial attachment takes place via 
specific receptors, including Fc, C3, fibronectin, and mannose-binding 
proteins. Opsonized—but not unopsonized—bacteria trigger an oxida­
tive burst inside phagocytes. Unopsonized bacteria are internalized via 
similar receptors but at much lower efficiency. Smooth strains enter 
host cells via lipid rafts. Smooth lipopolysaccharide (LPS), β-cyclic glu­
can, and possibly an invasion–attachment protein (Alb) are involved 
in this process. Tumor necrosis factor α (TNF-α) produced early in 
the course of infection stimulates cytotoxic lymphocytes and activates 
macrophages, which can kill intracellular brucellae (probably mainly 
through production of reactive oxygen and nitrogen intermediates) 
and may clear infection. However, virulent Brucella cells can suppress 
the TNF-α response, and control of infection in this situation depends 
on macrophage activation and interferon γ (IFN-γ) responses. Cyto­
kines such as interleukin (IL) 12 promote production of IFN-γ, which 
drives TH1-type responses and stimulates macrophage activation. 
Inflammatory cytokines, including IL-4, IL-6, and IL-10, downregulate 
the protective response. As in other types of intracellular infection, it 
is assumed that initial replication of brucellae takes place within cells 
of the lymph nodes draining the point of entry. Subsequent hematog­
enous spread may result in chronic localizing infection at almost any 
site, although the reticuloendothelial system, musculoskeletal tissues, 
and genitourinary system are most frequently targeted. Both acute 
and chronic inflammatory responses develop in brucellosis, and the 
local tissue response may include granuloma formation with or with­
out necrosis and caseation. Abscesses may also develop, especially in 
chronic localized infection.
The determinants of pathogenicity of Brucella have not been fully 
characterized, and the mechanisms underlying the manifestations of 
brucellosis are incompletely understood. The organism is a “stealth” 
pathogen whose survival strategy is centered on several processes 
that avoid triggering innate immune responses and that permit 
survival within monocytic cells. These processes include evasion of 
intracellular destruction by restricting the fusion of type IV secre­
tion system–dependent Brucella-containing vacuoles with lysosomal 
compartments, inhibition of apoptosis of infected mononuclear cells, 
and prevention of dendritic cell maturation, antigen presentation, and 
activation of naïve T cells. The smooth Brucella LPS, which has an 
unusual O-chain and core-lipid composition, has relatively low endo­
toxin activity and plays a key role in pyrogenicity and in resistance to 
phagocytosis and serum killing in the nonimmune host. In addition, 
LPS is believed to play a role in suppressing phagosome–lysosome 
fusion and diverting the internalized bacteria into vacuoles located 
in endoplasmic reticulum, where intracellular replication takes place. 
Specific exotoxins have not been isolated, but a type IV secretion sys­
tem (Vir) that regulates intracellular survival and trafficking has been 
identified. In B. abortus, this system can be activated extracellularly, 
but in B. suis, it is activated (by low pH) only during intracellular 
growth. Brucellae then produce acid-stable proteins that facilitate the 
organisms’ survival in phagosomes and may enhance their resistance 
to reactive oxygen intermediates. A type III secretion system based on 
modified flagellar structures also has been inferred, although not yet 
confirmed. Virulent brucellae are resistant to defensins and produce a 
Cu-Zn superoxide dismutase that increases their resistance to reactive 
oxygen intermediates. A hemolysin-like protein may trigger the release 
of brucellae from infected cells.
■
■CLINICAL FEATURES
Brucellosis almost invariably causes fever, which may be associated with 
profuse sweats, especially at night. In endemic areas, brucellosis may be

difficult to distinguish from other causes of fever. However, two features 
recognized in the nineteenth century distinguish brucellosis from other 
tropical fevers, such as typhoid and malaria: (1) Left untreated, the fever 
of brucellosis shows an undulating pattern that persists for weeks before 
the commencement of an afebrile period that may be followed by relapse. 
(2) The fever of brucellosis is associated with musculoskeletal symptoms 
and signs in about one-half of all patients.
The clinical syndromes caused by the different species are similar, 
although B. melitensis tends to be associated with a more acute and 
aggressive presentation and B. suis with focal abscess induction. B. abortus 
infections may have a more insidious onset and are more likely to become 
chronic. B. canis infections are generally regarded as less severe but, like 
other species, can cause serious disease such as endocarditis.
The incubation period varies from 1 week to several months, 
and the onset of fever and other symptoms may be abrupt or insidi­
ous. In addition to experiencing fever and sweats, patients become 
increasingly apathetic and fatigued; lose appetite and weight; and have 
nonspecific myalgia, headache, and chills. Overall, the presentation of 
brucellosis often fits one of three patterns: febrile illness that resembles 
typhoid but is less severe; fever and acute monoarthritis, typically of the 
hip or knee, in a young child; and long-lasting fever, misery, and lowback or hip pain in an older person (especially men). In an endemic 
area (e.g., much of the Middle East), a patient with fever and difficulty 
walking into the clinic would be suspected to have brucellosis until it 
was proven otherwise.
Diagnostic clues in the patient’s history include travel to an endemic 
area, employment in a diagnostic microbiology laboratory, consump­
tion of unpasteurized milk products (including soft cheeses), contact 
with animals, accidental inoculation with veterinary Brucella vaccines, 
and—in an endemic setting—a history of similar illness in the family 
(documented in almost 50% of cases). Focal features are present in the 
majority of patients. The most common are musculoskeletal pain and 
physical findings in the peripheral and axial skeleton (~40% of cases). 
Osteomyelitis more commonly involves the lumbar and low thoracic 
vertebrae than the cervical and high thoracic spine. Individual joints 
that are most commonly affected by septic arthritis are the knee, hip, 
sacroiliac, shoulder, and sternoclavicular joints; the pattern may be one 
of monoarthritis or polyarthritis. Osteomyelitis may also accompany 
septic arthritis.
In addition to the usual causes of vertebral osteomyelitis or septic 
arthritis, the most important disease in the differential diagnosis is 
tuberculosis. This point influences the therapeutic approach as well 
as the prognosis, given that several antimicrobial agents used to treat 
brucellosis are also used to treat tuberculosis. Septic arthritis in brucel­
losis progresses slowly, starting with small pericapsular erosions. In the 
vertebrae, anterior erosions of the superior end plate are typically the 
first features to become evident, with eventual involvement and sclero­
sis of the whole vertebra. Anterior osteophytes eventually develop, but 
vertebral destruction or impingement on the spinal cord is rare and 
usually suggests tuberculosis (Table 174-1).
Other systems may be involved in a manner that resembles typhoid. 
About one-quarter of patients have a dry cough, usually with few 
changes visible on the chest x-ray, although pneumonia, empyema, 
intrathoracic adenopathy, or lung abscess can occur. Sputum or pleural 
effusion cultures are rarely positive in such cases, which respond well 
to standard brucellosis treatment. One-quarter of patients have hepa­
tosplenomegaly, and 10–20% have significant lymphadenopathy; the 
differential diagnosis includes glandular fever–like illness such as that 
caused by Epstein-Barr virus, Toxoplasma, cytomegalovirus, HIV, or 
Mycobacterium tuberculosis. Up to 10% of men have acute epididymoorchitis, which must be distinguished from mumps and from surgical 
problems such as torsion. Prostatitis, inflammation of the seminal 
vesicles, salpingitis, and pyelonephritis all occur. There is an increased 
incidence of fetal loss among infected pregnant women, although tera­
togenicity has not been described and the tendency toward abortion is 
much less pronounced in humans than in animals.
Neurologic involvement is common, with depression and lethargy 
whose severity may not be fully appreciated by either the patient or the 
physician until after treatment. A small proportion of patients develop 

TABLE 174-1  Radiology of the Spine: Differentiation of Brucellosis 
from Tuberculosis
 
BRUCELLOSIS
TUBERCULOSIS
Site
Lumbar and others
Dorsolumbar
Vertebrae
Multiple or contiguous
Contiguous
Diskitis
Late
Early
Body
Intact until late
Morphology lost early
Canal compression
Rare
Common
Epiphysitis
Anterosuperior
General: upper and lower 
disk regions, central, 
subperiosteal
Osteophyte
Anterolateral (parrot beak)
Unusual
Deformity
Wedging uncommon
Anterior wedge, gibbus
Recovery
Sclerosis, whole-body
Variable
Paravertebral 
abscess
Small, well-localized
Common and discrete 
loss, transverse process
Psoas abscess
Rare
More likely
lymphocytic meningoencephalitis that mimics mild neurotuberculosis, 
atypical leptospirosis, or noninfectious conditions. Rare manifestations 
include intracerebral abscess, a variety of cranial nerve deficits, or rup­
tured mycotic aneurysms.
Endocarditis occurs in ~1% of cases, most often affecting the aortic 
valve (natural or prosthetic). Any site in the body may be involved in 
metastatic abscess formation or inflammation; the female breast and 
the thyroid gland are affected particularly often. Nonspecific maculo­
papular rashes and other skin manifestations are uncommon and are 
rarely noticed by the patient even if they develop.
CHAPTER 174
■
■DIAGNOSIS
Because the clinical picture of brucellosis is not distinctive, the diagnosis 
must be based on a history of potential exposure, a presentation con­
sistent with the disease, and supporting laboratory findings. Results of 
routine biochemical assays are usually within normal limits, although 
serum levels of hepatic enzymes and bilirubin may be elevated. Periph­
eral leukocyte counts are usually normal or low, with relative lympho­
cytosis. Mild anemia may be documented. Thrombocytopenia and 
disseminated intravascular coagulation with raised levels of fibrinogen 
degradation products can develop. The erythrocyte sedimentation rate 
and C-reactive protein levels are often normal but may be raised.
Brucellosis
In body fluids such as cerebrospinal fluid (CSF) or joint fluid, lym­
phocytosis and low glucose levels are the norm. Elevated CSF levels 
of adenosine deaminase cannot be used to distinguish tubercular 
meningitis, as they may also be found in brucellosis. Biopsied samples 
of tissues such as lymph node or liver may show noncaseating granu­
lomas without acid-fast bacilli. The radiologic features of bony disease 
develop late and are much more subtle than those of tuberculosis or 
septic arthritis of other etiologies, with less bone and joint destruction. 
Isotope scanning is more sensitive than plain x-ray and continues to 
give positive results long after successful treatment.
Isolation of brucellae from blood, CSF, bone marrow, or joint fluid 
or from a tissue aspirate or biopsy sample is definitive, and attempts at 
isolation are usually successful in 50–70% of cases. Blood culture using 
modern nonradiometric or similar signaling systems (e.g., Bactec) usu­
ally become positive within 7 days. Clinicians should alert the labora­
tory to the possibility of brucellosis if suspected, as all cultures should 
be handled under containment conditions appropriate for dangerous 
pathogens. Brucella species may be misidentified as Agrobacterium, 
Ochrobactrum, or Psychrobacter (Moraxella) phenylpyruvicus by the 
gallery identification strips that may still be used in the diagnostic 
laboratory. In recent years, matrix-assisted laser desorption ionization 
time-of-flight mass spectrometry (MALDI-TOF MS) has emerged as 
a powerful tool for bacterial identification in well-resourced labora­
tories. Earlier implementations of MALDI-TOF often failed to identify 
Brucella species correctly as a genus or at species level. Following recent 
changes in taxonomy, Ochrobactrum isolates may now be reported as a

subspecies of Brucella. This can lead to confusion and have important 
clinical and public health consequences, as management differs com­
pletely. Clinicians should confirm the meaning of any culture report 
suggestive of brucellosis with laboratory colleagues before making 
therapeutic decisions.

The peripheral blood–based polymerase chain reaction (PCR) 
has enormous potential to detect bacteremia, to predict relapse, and 
to exclude “chronic brucellosis.” This method is more sensitive and 
quicker than blood culture, and it does not carry the attendant biohaz­
ard risk posed by culture. However, it is not perfect, and false-negative 
results are sometimes observed in patients with positive blood cultures. 
Nucleic acid amplification techniques are now quite widely used, 
although no single standardized procedure has been adopted. Prim­
ers for the spacer region between the genes encoding the 16S and 23S 
ribosomal RNAs (rrs-rrl), various outer-membrane protein–encoding 
genes, the insertion sequence IS711, and the protein BCSP31 are sensi­
tive and specific. Blood and other tissues are the most suitable samples 
for analysis. The clinical significance of prolonged PCR positivity, com­
monly seen in blood after successful treatment, remains controversial.
Serologic examination often provides the only positive laboratory 
findings in brucellosis. In acute infection, IgM antibodies appear early 
and are followed by IgG and IgA. All these antibodies are active in 
agglutination tests, whether performed by tube, plate, or microagglu­
tination methods. The majority of patients have detectable agglutinins 
at this stage. As the disease progresses, IgM levels decline, and the 
avidity and subclass distribution of IgG and IgA change. The result 
is reduced or undetectable agglutinin titers. However, the antibodies 
are detectable by alternative tests, including the complement fixation 
test, Coomb’s antiglobulin test, and enzyme-linked immunosorbent 
assays. There is no clear cutoff value for a diagnostic titer. Rather, 
serology results must be interpreted in the context of exposure history 
and clinical presentation. In endemic areas or in settings of potential 
occupational exposure, agglutinin titers of 1:320–1:640 or higher are 
considered diagnostic; in nonendemic areas, a titer of ≥1:160 is consid­
ered significant. Repetition of tests after 2–4 weeks may demonstrate 
a rising titer.
PART 5
Infectious Diseases
In most centers, the standard agglutination test (or a derivative such 
as the microagglutination test) is still the mainstay of serologic diag­
nosis. In an endemic setting, >90% of patients with acute bacteremia 
have standard agglutination titers of at least 1:320 at the time of clinical 
presentation. Some centers rely on the Rose Bengal test, particularly for 
screening, but it has been only partially validated for human diagnostic 
use. A variety of near-patient or point-of-care tests are still in develop­
mental stages.
Antibody to the Brucella LPS O chain—the dominant antigen—is 
detected by all the conventional tests that employ smooth B. abortus 
cells as antigen. Because B. abortus cross-reacts with B. melitensis and 
B. suis, there is no advantage in replicating the tests with these antigens. 
Cross-reactions also occur with the O chains of some other gramnegative bacteria, including Yersinia enterocolitica O:9, Escherichia coli 
O157, Francisella tularensis, Salmonella enterica group N, Stenotroph­
omonas maltophilia, and Vibrio cholerae. The cell-surface antigens of 
rough Brucella strains such as B. canis or B. ovis do not react in these 
serologic tests, which will give false-negative results. Specific antigenbased tests used in veterinary practice to detect B. canis and B. ovis 
produce inconsistent results in human diagnosis and are not validated 
for this purpose. Clinicians should consult with the laboratory about 
test selection if B. canis infection is suspected. Similarly, live B. abortus 
vaccine strain RB51 does not elicit antibody responses in serologic tests 
that use smooth antigens, and this fact must be taken into account if 
serologic tests are employed in attempts to identify or follow the course 
of infections in persons accidentally exposed to the vaccine.
TREATMENT
Brucellosis
The broad aims of antimicrobial therapy are to treat and relieve the 
symptoms of current infection and to prevent relapse. Focal disease 

presentations may require specific intervention in addition to more 
prolonged and tailored antibiotic therapy. In addition, tuberculosis 
must always be excluded, or—to prevent the emergence of resistance—
therapy should be tailored to specifically exclude drugs active 
against tuberculosis (e.g., rifampin used alone) or to include a full 
antituberculous regimen.
Early experience with streptomycin or tetracycline monotherapy 
showed that relapse was common; thus dual therapy with both 
agents became the norm. This is still the most effective combina­
tion, but alternatives may be used, with the options depending on 
local or national policy about the use of rifampin for the treatment 
of nonmycobacterial infection. For the several antimicrobial agents 
that are active in vivo, efficacy can usually be predicted by in vitro 
testing. However, numerous Brucella strains show in vitro sensitiv­
ity to a whole range of antimicrobials that are therapeutically inef­
fective, including assorted β-lactams. The use of fluoroquinolones 
remains controversial despite the good in vitro activity and whitecell penetration of most agents of this class. Low intravacuolar pH is 
probably a factor in the poor performance of these drugs.
For adults with acute nonfocal brucellosis (duration <1–2 months), 
a 6-week course of therapy incorporating at least two antimicro­
bial agents is required. Complex or focal disease may necessitate 

≥3 months of therapy. Adherence to the therapeutic regimen is very 
important, and poor adherence underlies almost all cases of appar­
ent treatment failure; such failure is rarely due to the emergence of 
drug resistance, although increasing resistance to trimethoprimsulfamethoxazole (TMP-SMX) is being reported.
The gold standard for the treatment of brucellosis in adults is IM 
streptomycin (0.75–1 g daily for 14–21 days) together with doxy­
cycline (100 mg twice daily for 6 weeks). In both clinical trials and 
observational studies, relapse follows such treatment in 5–10% of 
cases. The usual alternative regimen favored by the World Health 
Organization and many national guidelines consists of rifampin 
(600–900 mg/d) plus doxycycline (100 mg twice daily) for 6 weeks. 
This is easier for the patient and health care provider but requires 
sustained treatment adherence. The relapse/failure rate of this 
regimen is ~10% in trial conditions but can rise to >20% in many 
nontrial situations, possibly because doxycycline levels are reduced 
and clearance rates increased by concomitant rifampin administra­
tion. Patients who cannot tolerate or receive tetracyclines (children, 
pregnant women) can be given high-dose TMP-SMX instead (two 
or three standard-strength tablets twice daily for adults, depending 
on weight).
Good evidence supports the use of an aminoglycoside such as 
gentamicin (5–6 mg/kg per day for 1–2 weeks) instead of strep­
tomycin, and this is recommended in U.S. and U.K. guidelines. 
Shorter courses of gentamicin have been associated with high fail­
ure rates in adults. Early experience with fluoroquinolone mono­
therapy was disappointing, but it has been suggested that ofloxacin 
or ciprofloxacin, given together with rifampin for 6 weeks, might be 
an acceptable alternative to the other 6-week regimens for adults. 
A substantial meta-analysis did not support the use of fluoroqui­
nolones in first-line treatment regimens, and these drugs were 
not recommended by an expert consensus group (the Ioannina 
Recommendations) except in the context of well-designed clinical 
trials. However, a more recent meta-analysis is more supportive of 
the efficacy of these drugs, and adequately powered prospective 
studies will be needed to resolve their role in standard combination 
therapy. Although triple-drug regimens are superior to double-drug 
regimens in meta-analyses, they are not indicated for uncompli­
cated brucellosis. A triple-drug regimen such as doxycycline and 
rifampin, enhanced by initial aminoglycoside, should be considered 
for all patients with complicated disease and for those for whom 
treatment adherence is likely to be a problem.
Focal neurologic disease due to Brucella species requires pro­
longed treatment (i.e., for 3–6 months), usually with ceftriaxone 
supplementation of a standard regimen. Brucella endocarditis is 
treated with at least three drugs (an aminoglycoside, a tetracy­
cline, and rifampin), and many experts add ceftriaxone and/or a