Brucellosis

Background

Brucellosis is a zoonotic infection caused by the bacterial genus Brucella. The bacteria are transmitted from animals to humans by ingestion through infected food products, direct contact with an infected animal, or inhalation of aerosols. The disease is an old one that has been known by various names, including Mediterranean fever, Malta fever, gastric remittent fever, and undulant fever. Humans are accidental hosts, but brucellosis continues to be a major public health concern worldwide and is the most common zoonotic infection.^[1]

Brucella organisms, which are small aerobic intracellular coccobacilli, localize in the reproductive organs of host animals, causing abortions and sterility. They are shed in large numbers in the animal’s urine, milk, placental fluid, and other fluids. To date, 8 species have been identified, named primarily for the source animal or features of infection. Of these, the following 4 have moderate-to-significant human pathogenicity:

• Brucella melitensis (from sheep; highest pathogenicity)
• Brucella suis (from pigs; high pathogenicity)
• Brucella abortus (from cattle; moderate pathogenicity)
• Brucella canis (from dogs; moderate pathogenicity)

Although domesticated animals are of particular importance, brucellosis is also found in wild animals that exist in herds (eg, bison or elk in North America and wild boar in Germany^[2] ). Humans have only a limited risk from wild animals, mainly because of lack of proximity or intimate contact and infrequent use of milk and meat products from these animals. Concerns have been voiced that interaction of wild animals with domesticated ones may lead to infection of agricultural herds, though supportive evidence is quite limited.

The global burden of human brucellosis remains enormous. The organism causes more than 500,000 infections per year worldwide. The annual number of reported cases in United States (now about 100) has dropped significantly because of aggressive animal vaccination programs and milk pasteurization. Most US cases are now due to the consumption of imported unpasteurized dairy products from Mexico. Approximately 60% of human brucellosis cases in the United States now occur in California and Texas.

Interest in brucellosis has been increasing because of the growing phenomena of international tourism and migration, in addition to the potential use of Brucella as a biological weapon.^[3] Familiarity with the manifestations of brucellosis and knowledge of the optimal laboratory studies are essential for the recognition of this reemerging zoonosis. B melitensis, B abortus, and B suis have been completely sequenced, and these sequencing data will help improve our understanding of the pathogenesis and the manifestations of this complex disease.

Definitive diagnosis of brucellosis is based on culture, serologic techniques, or both. Clinically, identification to the genus level is sufficient to warrant initiation of therapy. The particular Brucella species involved does not affect the choice of therapeutic agents; however, speciation is necessary for epidemiologic surveillance and requires more detailed biochemical, metabolic, and immunologic testing.

• References

Pathophysiology

Brucellae are aerobic gram-negative coccobacilli that possess a unique ability to invade both phagocytic and nonphagocytic cells and to survive in the intracellular environment by finding ways to avoid the immune system. This ability helps explain why brucellosis is a systemic disease and can involve almost every organ system.

Brucella can gain entry into the human body through breaks in the skin, mucous membranes, conjunctivae, and respiratory and gastrointestinal (GI) tracts. Sexual transmission has not been convincingly documented. Ingestion usually occurs by way of unpasteurized milk; meat products often have a low bacterial load. In the United States, percutaneous needlestick exposure, conjunctival exposure through eye splash, and inhalation are the most common routes of entry.

Once within the bloodstream, the organisms quickly become intracellular pathogens contained within circulating polymorphonuclear cells (PMNs) and macrophages, making use of numerous mechanisms to avoid or suppress bactericidal responses. Animal data suggest that the lipopolysaccharide (LPS) coat (smooth in B melitensis, B abortus, and B suis; rough in B canis) is likely to play a role in intracellular survival, perhaps because of adenine and guanine monophosphate production, which inhibits phagosomal fusion and oxidative burst activity.

In addition, Brucella species have relatively low virulence, toxicity, and pyrogenicity, making them poor inducers of some inflammatory cytokines, such as tumor necrosis factor (TNF) and interferons. Furthermore, the bacteria do not activate the alternative complement system. Finally, they are thought to inhibit programmed cell death.

After ingestion by phagocytes, about 15-30% of brucellae survive. Susceptibility to intracellular killing differs among species, with B abortus readily killed and B melitensis rarely affected; these differences might explain the differences in pathogenicity and clinical manifestations in human cases of brucellosis.^[4]

Brucellae that survive are transported into the lymphatic system and may replicate there locally; they also may replicate in the kidney, liver, spleen, breast tissue, or joints, causing both localized and systemic infection. Any organ system can be involved (eg, central nervous system [CNS], heart, joints, genitourinary system, pulmonary system, and skin); localization of the process may cause focal symptoms or findings. After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis.

Development of cell-mediated immunity is the principal mechanism of recovery. The host response to infection with B abortus is characterized by the development of tissue granulomas indistinguishable from those of sarcoidosis. In contrast, infection with the more virulent species (B melitensis and B suis) more commonly results in visceral microabscesses.

Although Brucella infection is primarily controlled through cell-mediated immunity rather than antibody activity, some immunity to reinfection is provided by serum immunoglobulin (Ig). Initially, IgM levels rise, followed by IgG titers. IgM may remain in the serum in low levels for several months, whereas IgG eventually declines. Persistently elevated IgG titers or second rises in IgG usually indicate chronic or relapsed infection. IgA antibodies are elaborated late and also may persist for very long intervals.

• References

Etiology

Brucellosis is caused by infection with Brucella species. The traditional classification of these species is based primarily on the preferred hosts (see Table 1, below).

Table 1. Currently Recognized Brucella Species

View Table

See Table

Of the 4 Brucella species known to cause disease in humans (B abortus, B melitensis, B canis, B suis), B melitensis is thought to be the most virulent and causes the most severe and acute cases of brucellosis; it is also the most prevalent worldwide. B melitensis may be acquired via exposure to animals or animal products or, in the case of laboratory technicians, to specimens from animals (including humans) whose tissues are operated upon or submitted for culture or pathologic analysis.^[5]

B abortus is more widely distributed throughout the world than B melitensis is, but it is less pathogenic for both animals and humans. It has, however, been the most common cause of brucellosis in North America. This species gives rise to mild-to-moderate sporadic disease that rarely causes complications.

B suis has been the second most common cause of brucellosis in North America. Infection with this species gives rise to a prolonged course of illness, often associated with suppurative destructive lesions.

B canis infection has a disease course that is indistinguishable from that of B abortus infection. It infection has an insidious onset, causes frequent relapses, and does not commonly cause chronic brucellosis.

Although B pinnipediae and B cetaceae typically affect marine animals, they are now known to be capable of causing disease in humans (mainly neurobrucellosis).

Ingestion of unpasteurized goat milk and related dairy products is the main route by which B melitensis is transmitted to humans.

Slaughterhouse workers, primarily those in the kill areas, become inoculated with brucellae through aerosolization of fluids, contamination of skin abrasions, and splashing of mucous membranes. Farmers and shepherds have similar exposure risks, and they also have exposure to aborted animals. Veterinarians are usually infected by inadvertent inoculation of animal vaccines against B abortus and B melitensis. Laboratory workers (microbiologists) are exposed by processing specimens (aerosols) without special precautions.

Occupational exposures tend to be isolated. A large-scale outbreak of the infection should raise suspicion that a biologic weapon has been released, most likely via an infectious aerosol.

• References

Epidemiology

United States statistics

Although brucellosis is still a reportable disease, it has become rare as a result of the institution of veterinary control measures (eg, routine screening of domestic livestock and vaccination programs). Currently, fewer than 100 cases are reported annually to the Centers for Disease Control and Prevention (CDC), mostly from California, Florida, Texas, and Virginia. Incidental cases arise as a result of relaxation of surveillance standards or because of the increasing international exchange of foodstuffs and animals that may harbor Brucella organisms.

At present, most human cases of brucellosis in the United States are due to B melitensis. The B abortus and B suis species that have accounted for most brucellosis in North America are less likely to engender clinical disease in humans than B melitensis is. When disease develops in North Americans, it often does so with greater latency to onset and milder manifestations.

International statistics

Brucellosis causes more than 500,000 infections per year worldwide. Its geographic distribution is limited by effective public and animal health programs, and the prevalence of the disease varies widely from country to country.^[1] Overall, the frequency of brucellosis is higher in more agrarian societies and in places where handling of animal products and dairy products is less stringent.

European Union (EU) data suggest that there is a clear (though nonlinear) association between gross domestic product (GDP) and rates of brucellosis. According to these data, no countries with a GDP above 90% of the mean had an annual incidence of brucellosis higher than 10 cases per million population.

The heaviest disease burden lies in countries of the Mediterranean basin and Arabian Peninsula, and the disease is also common in India, Mexico, and South and Central America. Although some countries (eg, the United Kingdom and Ireland) have effectively controlled brucellosis, new areas of human brucellosis have emerged in areas such as central and southwest Asia.

Because of variable reporting, true estimates in endemic areas are unknown. Incidence rates of 1.2-70 cases per 100,000 people are reported. In very resource-poor countries (such as some African countries) in which brucellosis is endemic, control through animal slaughter is a poor option because of the fragile nature of the food supply.

In a systematic review was commissioned by the World Health Organization (WHO) with the goal of determining a disability weight for clinical manifestations of human brucellosis, the investigators proposed a disability weight of 0.150 for chronic localized brucellosis and 0.190 for acute brucellosis.^[6] These estimates were based on disability weights from the 2004 Global Burden of Disease Study. Further study is required before a consensus can be reached.

Age-related demographics

Brucellosis in the Mediterranean, chiefly due to B melitensis, has the highest age/sex-related incidence in males in their mid-20s. A report from northern Saudi Arabia found that 60% of cases of brucellosis occurred in individuals aged 13-40 years, whereas 21% occurred in those younger than 13 years, 16% in those aged 40-60 years, and 2.5% in those older than 60 years.^[7]

For unknown reasons, men aged 13-40 years are particularly vulnerable to the manifestation of illness due to B melitensis. Possible explanations include engaging in activities that increase exposure to Brucella organisms (eg, animal husbandry) and less diligent personal hygiene. The predilection is not universal, given that 60% of cases in Jordan occur in individuals younger than 24 years.

Elderly individuals with acute localized brucellosis are particularly likely to manifest destructive localized brucellosis of the spine.^[8]

Brucellosis is generally uncommon in infants. The international literature suggests that brucellosis may be more common in children in developing countries because of lack of pasteurization and working in an agrarian society. Transmission to infants may occur through breastfeeding^[9] or ingestion of raw milk. Prepubertal children account for less than 2% of all cases of neurobrucellosis; fewer than 50 such cases have been described in the peer-reviewed medical literature over the past 50 years.

Sex-related demographics

Worldwide, brucellosis is more common in males than in females. Young adult males predominate in most series of patients with brucellosis compiled in areas of endemic disease. A report from northern Saudi Arabia found a male-to-female ratio of 1.7:1, chiefly individuals aged 13-40 years.^[7] The cases represented in such series are caused chiefly by B melitensis.

Occupational exposure to animals likely plays an important role in the enhanced vulnerability of men to the development of brucellosis. Whether the increased risk manifested by males is additionally influenced by aspects of personal hygiene, immunologic factors, or other circumstances is not known. Food-borne brucellosis is not limited according to age or sex and is found in women and men in equal numbers.

Race-related demographics

Exposures tend to be primarily occupational; accordingly, no racial predilection has been identified in the United States.

• References

Prognosis

The prognosis is generally excellent. Although initial symptoms of brucellosis may be debilitating, if they are treated appropriately and within the first few months of onset, the disease is easily curable, with a low risk of relapse or chronic disease. However, the prognosis is poor in persons who present with congestive heart failure due to endocarditis, in whom mortality approaches 85%. In some patients, brucellosis can cause chronic debilitating illness with extensive morbidity.

In uncomplicated cases of acute brucellosis, fever, malaise, and many other manifestations improve rapidly with bed rest, whereas sustained physical activity may prolong or worsen the degree of illness. Considerable improvement from the symptoms of the acute phase of illness typically occurs within a few weeks, with or without treatment. In many cases, this is followed by complete remission within 2-6 months. Recovery tends to be more rapid with B abortus infection than with B melitensis or B suis infection.

Overall mortality in recognizably symptomatic acute or chronic cases of brucellosis is very low, certainly less than 5% and probably less than 2%. It is usually the result of the rare instance of Brucella endocarditis or is the result of severe CNS involvement, often as a complication of endocarditis. Postmortem analysis confirms that the burden of acute brucellotic infection is borne by tissues of the lymphoreticular system.

Recurrence of symptoms of acute brucellosis is not uncommon. The recurrent disease may be systemic or localized. In some of these patients, the condition evolves into chronic brucellosis, which may be progressive if untreated. Chronic brucellosis includes systemic and specific localized forms (including various types of neurobrucellosis). These various forms are due to continued infectious disease, for which additional treatment is indicated and effective.

Objective clinical and laboratory evidence for ongoing disease is demonstrable. Patients who do not have such evidence and who complain of occasional mild symptoms similar to those found in acute brucellosis are likely to have psychoneurosis. This complication of acute brucellosis does not usually resolve with anti-brucellosis treatments, although such treatments may exert placebo effects for individual bouts. Psychiatric treatment may be indicated.

The likelihood of recurrence is greater in individuals who are not treated or who are inadequately treated for acute brucellosis. However, recurrence is possible even in properly treated patients who have had acute brucellosis. Addition of oral rifampicin to oral tetracycline may reduce the recurrence risk for patients who are treated with that combined therapy for acute brucellosis.

Chronic brucellosis may continue to trouble patients for as long as 25 years, but such cases are quite rare.

• References

Patient Education

Patient education should include efforts to address the following issues:

• The nature of the disease and the routes by which it can be transmitted
• The symptoms, complications, and treatment of the disease, as well as the risk of relapse if it is not adequately treated
• The potential adverse effects of the medications administered
• The need for strict compliance with the antibiotic regimen
• In soma case, reassurance concerning recurrent symptoms that are not associated with clinical or laboratory evidence of acute brucellotic disease
• The need to avoid potential sources of infection – This may involve avoiding infected animals, using stricter precautions (eg, gloves and mask) when dealing with a potentially infected animal, or avoiding potentially contaminated foods
• For farmers and ranchers, immunization of their cattle against the disease as necessary
• For laboratory workers, maintenance of the appropriate level of containment

• References

History

A careful history is the most helpful tool in the diagnosis of brucellosis. The history should include both assessment of any risk factors present and evaluation of any symptoms reported. Unless exposure to Brucella is due to a weaponized attack,^[3] almost every case of brucellosis involves exposure to an affected animal in some fashion, either directly or indirectly.

Risk factors

The risk factors for brucellosis differ somewhat, depending upon whether a given individual resides in or has recently visited a region of endemic disease.

Endemic exposure

Brucellosis should be considered in any patient whose place of residence or dietary, travel, or occupational history suggests a risk for the infection and who is experiencing any of the various known neurologic or nonneurologic complications of brucellosis. It must be borne in mind that the latency period from infection to onset of symptoms of primary brucellosis may be as long as months.

The threshold for consideration of brucellosis is low in regions of endemic disease, where diagnostic testing is undertaken for any of the many atypical presentations or unusual complications.

A dietary history is especially helpful for diagnosing brucellosis in individuals who live in or visit regions of endemic disease. Unpasteurized dairy products, especially goat’s cheese, frequently are implicated as sources of human infection. Raw or poorly cooked meats are also important sources of infection in regions of endemic disease.

Occasional person-to-person transmission has been reported, including transmission to infants via breastfeeding. There is a little evidence for sexual transmission of brucellosis.

Laboratory transmission of brucellosis may occur, especially in regions of endemic disease. It is estimated that 12% of laboratory workers in Spain acquire brucellosis.^[5]

Nonendemic exposure

Brucellosis poses a particular diagnostic challenge in persons not from regions of endemic disease. In areas of the world where brucellosis is rare, the diagnosis may be missed even in patients who manifest typical signs, such as otherwise uncomplicated persistent undulating fever. The possibility of brucellosis is even less likely to be recognized promptly in cases that present atypically.

A dietary history is important in evaluating for the possibility of brucellosis among individuals who live in regions where the disease is not endemic because the disease may be acquired through ingestion of infected foods shipped from regions of endemic disease. Ingestion of unpasteurized milk from cows or goats enhances risk of infection in both regions of endemic disease and regions in which the disease is not endemic.

Although various potential intermediate hosts have harbored brucellosis in the extra-Mediterranean world, dairy cattle infected with B abortus have been particularly important hosts in North America. The infection is often symptomatic in cattle. Outbreaks of epizootic bovine abortion due to B abortus should alert health care providers to the possibility of human brucellosis. Some cases in humans in North America have been traced to pork from hogs infected with B suis. In Scandinavia and Alaska, reindeer are an important source of brucellosis.

Brucellosis has developed in infants who have been breastfed from mothers who either visited regions of endemic disease or ingested foodstuffs shipped from such regions.

In nonendemic regions, as in endemic regions, physicians, veterinarians, pathologists, and laboratory personal exposed to tissues from infected animals (including humans) are at particular risk for brucellosis.^[5] Surprisingly, infection with Brucella species accounts for as many as 10% of laboratory-acquired infections, 24% of laboratory-acquired bacterial infections, and 11% of occupational-exposure deaths in the United States.^[10]

Aside from laboratory workers, individuals at greatest risk for brucellosis are those exposed to goats, sheep, cows, camels, pigs, reindeer, rabbits, or hares, both in areas of endemic disease and in areas where the disease is not endemic. Such individuals include herders, hunters, farmers, dairy workers, veterinarians, abattoir workers, and meatpackers.

Brucella has the potential to be used as a biologic weapon,^[3] but to date, these organisms have not been implicated in any major bioterrorism incident. Were they used in such a way, however, patients might not present until several weeks later. Because of this potential, and in view of the rarity of brucellosis in the United States, especially in more urban areas, any clustering of brucellosis cases should be thoroughly investigated and reported to public health officials.

Symptoms

Symptoms of brucellosis are protean in nature, and none is specific enough to support the diagnosis (see Table 2, below).^{[11, 12]}

Table 2. Symptoms and Signs of Brucellosis

View Table

See Table

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. Fever of unknown origin (FUO) is a common initial diagnosis in patients in areas of low endemicity.^[25] It is associated with chills in almost 80% of cases.

Constitutional symptoms of brucellosis include anorexia, asthenia, fatigue, weakness, and malaise, and weight loss 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. Arthralgias may be diffuse or localized, with a predilection for bone ends and the sacroiliac joint. Acute monoarticular arthritis is uncommon but may be part of the presentation.

Neuropsychiatric symptoms of brucellosis are common despite the rare involvement of the nervous system. Headache, depression, and fatigue are the most frequently reported neuropsychiatric symptoms. In patients with advanced disease who have meningoencephalitis, these complaints may include changes in mental status, coma, neurologic deficit, nuchal rigidity, or seizures.

A significant percentage (approximately 50%) of patients have gastrointestinal (GI) complaints, primarily dyspepsia, though abdominal pain from hepatic abscesses may occur. Hepatic abscesses should be suspected in patients with signs of systemic toxicity and persistently elevated liver enzymes. The abscess can serve as a source of bacteremic seeding. Spontaneous bacterial peritonitis secondary to brucellosis infection has been reported. Constipation, diarrhea, and vomiting may occur.

Genitourinary infections with brucellae have been reported and include orchitis, urinary tract infection (UTI), and glomerulonephritis. Frank renal failure or sepsis is rare.

Neurologic symptoms of brucellosis can include weakness, dizziness, unsteadiness of gait, and urinary retention. Symptoms associated with cranial nerve dysfunction may affect persons with chronic central nervous system (CNS) involvement.

Cough and dyspnea develop in up to 19% of persons with brucellosis; however, these symptoms are rarely associated with active pulmonary involvement. Pleuritic chest pain may affect patients with underlying empyema.^[26]

Endocarditis from brucellae is reported, with septic embolization a common complication of this form of brucellosis. Other cardiac complications, such as pulmonary edema or dysrhythmias, are rare. Brucella endocarditis is the form most commonly associated with fatalities.

With the chronic form of brucellosis, in which the illness has lasted longer than 1 year (undiagnosed and untreated brucellosis), an afebrile pattern is typical, with a history of myalgia, fatigue, depression, and arthralgias (chronic fatigue syndrome is the most important disease in the differential diagnosis). The chronic form is primarily caused by B melitensis and usually affects adults older than 30 years. The chronic form is rare in children.

• References

Physical Examination

Generally, physical examination findings are normal or only minimally abnormal (see below), and the diagnosis is made on the basis of the history and serologic studies.

Categorization of disease

Traditionally, brucellosis has been classified as subclinical, acute, subacute, or chronic; localized and relapsing forms have also been described. This classification system, though commonly used, is subjective and of limited clinical utility.

Subclinical brucellosis

Disease is usually asymptomatic, and the diagnosis is usually established incidentally after serologic screening of persons at high risk of exposure. Culture data are usually unrevealing.

Acute and subacute brucellosis

Disease can be mild and self-limited (eg, B abortus) or fulminant with severe complications (eg, B melitensis). Associated symptoms can develop 2-3 months before diagnosis in mild cases and 3-12 months before diagnosis in severe cases.

Usually, acute brucellosis occurs without focal abnormalities. Nonfocal weakness may be noted. The tissues overlying the spine or peripheral nerves may be tender to percussion. Tenderness, swelling, or effusion of joints may be evident. In some instances, orchitis appears after a few days of illness. Testicular swelling and tenderness in the wake of chills and high fever thus resemble mumps orchitis.

Some patients manifest constipation. Occasionally, abdominal tenderness suggests an acute abdomen. In some more severe cases, tender enlargement of the spleen may be detected.

Murmurs, friction rubs, acute-onset blindness or visual field disturbance, tachycardia, oropharyngeal or conjunctival petechiae (some with pale centers), Roth spots, splinter hemorrhages of the nail beds, Osler nodes, Janeway lesions, or hepatosplenomegaly may develop as manifestations of bacterial endocarditis, a complication that is much rarer as an aspect of acute or subacute brucellosis than as an element of focal or diffuse chronic brucellosis.

Rarely, disease of the lungs or pleura is a feature of acute brucellosis, manifestations of which could include rales, wheezes, abnormalities of percussion or egophony, or pleural friction rubs.

Meningismus, papilledema, mental status changes, and long-tract signs are found in a small fraction of cases of acute brucellosis as manifestations of acute neurobrucellosis.

Radicular sensory or motor changes may arise in individuals with brucellotic osteomyelitis with associated epidural abscess. Focal tenderness or pain in the perispinous region may precede fever and objective sensory or motor findings. Brucellotic cervical epidural abscess may produce tenderness and movement restriction without the classic triad (fever, neck pain, and radiculopathy) of streptococcal or other types of epidural abscess. However, such findings may eventually develop, prompting delayed consideration of this diagnostic entity.^[10]

Chronic brucellosis

The diagnosis of chronic brucellosis is typically made after symptoms have persisted for 1 year or more. Low-grade fevers and neuropsychiatric symptoms predominate. Results of serologic studies and cultures are often negative; without confirmatory evidence, many authorities doubt the existence of chronic disease. Many patients have persistent disease caused by inadequate initial therapy, and underlying localized disease may be present.

Localized and relapsing brucellosis

Localized complications of brucellosis are typically observed in patients with acute disease or chronic untreated infection. Osteoarticular, genitourinary, and hepatosplenic involvement are most common (see Complications). Cultures of involved tissue sites and serology can be diagnostic.

Relapsing brucellosis may be difficult to distinguish from reinfection. Presenting symptoms typically reflect the initial disease; however, these symptoms are more severe. Symptoms typically develop 2-3 months after therapy completion. Culture results are typically positive, and serology may be difficult to interpret, but enzyme-linked immunoassay (ELISA) testing may be more helpful.

Physical findings

Physical findings in patients with brucellosis vary and are nonspecific for the disease.

Among the most common findings is hepatosplenomegaly (or isolated hepatomegaly or splenomegaly). Right upper quadrant pain and jaundice may indicate hepatic abscess. Generalized tenderness, rebound tenderness, and sluggish or absent bowel sounds can be expected in patients with peritonitis.

Osteoarticular involvement is also common. Focal infection of bones or joints may present with localized abnormal physical findings (eg, swelling, tenderness, and limited motion) in the affected areas. Arthritis, joint effusions, or, in severe cases, costovertebral angle tenderness may be observed. Focal osteomyelitis of the vertebrae, tibia, and, especially, the knee has also been associated with brucellosis infection even in the absence of other significant systemic symptoms. Maneuvers that isolate the sacroiliac joint may cause pain.

Focal infection of the genitourinary system may also present with localized abnormal physical findings. Epididymo-orchitis has been described in association with brucellosis; a tender, swollen scrotum with erythema is present in these patients. Urethritis has been reported. Testicular abscess, mimicking tumor, has also been known to occur.

Endocarditis may present with new or changing murmurs, and mycotic aneurysms of ventricles, brain, and aorta have been observed. A pericardial rub is present in patients with pericarditis.

Although pulmonary complaints are frequently present in patients with brucellosis, physical examination of this organ system almost always yields normal findings.

Neurologic findings vary according to the presentation of neurologic disease and may include the following:

• Acute meningoencephalitis (most common neurologic manifestation) - Depressed level of consciousness, meningeal irritation, cranial nerve involvement, coma, seizure, and respiratory depression
• Meningitis – Nuchal rigidity, Kerning sign, and Brudzinski sign
• Increased intracranial pressure (ICP) or brain abscess – Papilledema, cranial nerve palsy, and focal neurologic deficits
• Peripheral polyradiculoneuropathy - Hypotonia and areflexia in most cases, paraparesis, and an absence of sensory involvement
• Diffuse CNS involvement - Spasticity, hyperreflexia, clonus, extensor plantar response, sensorineural hearing loss, cranial nerve involvement, and cerebellar signs

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 include the following^[27] :

• Erythema nodosum, abscesses, and papulonodular eruptions (most common)
• Cutaneous ulcerations
• Impetigo, psoriatic, eczematous, and pityriasis rosea –like lesions
• Macular, maculopapular, and scarlatiniform rashes
• Vasculitic lesions (eg, petechiae, purpura, and thrombophlebitis)

Ocular findings can include the following^[28] :

• Uveitis^[29]
• Keratoconjunctivitis
• Iridocyclitis
• Nummular keratitis
• Choroiditis
• Optic neuritis^[30]
• Metastatic endophthalmitis
• Cataracts

• References

Complications

Complications are rare in the patient who is treated appropriately, though relapse of infection may occur in 10% of patients. The major risk factor for the development of focal complications is symptom duration greater than 30 days before diagnosis. The most common focal complications fall into the following categories:

• Osteoarticular^[31]
• Hepatobiliary and GI
• Genitourinary
• Neurobrucellosis
• Cardiovascular
• Pulmonary
• Hematologic^[32]

Other, less common complications include the following:

• Splenic abscess
• Thyroid abscess
• Epidural abscess
• Uveitis

Osteoarticular

Osteoarticular symptoms affect 20-60% of patients with brucellosis and are the most commonly reported complications; sacroiliitis is the most common (though rarer in children). Spondylitis, arthritis, osteomyelitis, bursitis, and tenosynovitis have been reported. Paraspinal pyogenic complications are often associated with spondylitis, especially in elderly persons. Peripheral joint involvement usually includes the knees, hips, ankles, and shoulders and can be monoarticular or polyarticular.

Hepatobiliary

Hepatobiliary complications include hepatitis, hepatic abscess, and acute cholecystitis. The rarely reported GI complications include ileitis, colitis, and spontaneous peritonitis.

Genitourinary

Genitourinary complications usually manifest as orchitis or epididymo-orchitis.^[33] Renal involvement is rare, although glomerulonephritis and pyelonephritis have been reported.^[34] Infection in pregnant patients is rare and is associated with first-trimester abortions. The frequency of this complication is not substantially different from its frequency when associated with other bacterial infections.

Neurobrucellosis

Neurobrucellosis occurs more frequently in endemic regions and develops in approximately 5% of cases. Meningitis^[35] (1-2%) and, less commonly, papilledema, optic neuropathy, radiculopathy, stroke, and intracranial hemorrhage may be seen.

Acute meningoencephalitis presents with a prehospital symptom duration of less than 7 days, and clinical findings progress rapidly. With appropriate aggressive therapy, symptoms resolve quickly, and patients are rarely left with residual sequelae. Other forms of neurobrucellosis typically present after at least 3 months of gradual symptoms. After successful therapy, residual deficits are not uncommon; however, they are rarely debilitating.

Cardiovascular

Worldwide, endocarditis occurs in less than 2% of patients with brucellosis; however, in endemic areas, it may affect 7-10% of patients. The aortic valve is affected in 75% of patients, and 50% of affected valves were previously healthy. Endocarditis is responsible for most of the mortality associated with brucellosis.

Pericarditis, myocarditis, and mycotic aneurysms of the aorta and cerebral vessels may complicate endocarditis. Primary pericarditis and myocarditis are also reported and have a more favorable outcome.

Pulmonary

Pulmonary complications are reported in 0.3-1% of patients with brucellosis (less commonly in children) and include pneumonia and pleural effusion. These complications are less common in children. Pneumonitis and pleural empyema have been reported.

Hematologic

Hematologic complications are not typically associated with severe sequelae and resolve with appropriate therapy. Reports of disseminated intravascular coagulation (DIC) and the hemophagocytic syndrome have been published. Splenic abscess has been reported.

• References

Approach Considerations

Given that symptoms and signs of brucellosis are nonspecific, cultures and serology are usually necessary for diagnosis. Some general laboratory findings might suggest the diagnosis (eg, leukopenia, relative lymphocytosis, or pancytopenia^{[36, 37]} [in as many as 20% of cases]). The standard test for diagnosis of brucellosis is the isolation of the organism from blood or tissues (eg, through bone marrow biopsy or liver aspiration).

In the United States, federal regulations applicable to clinicians, pathologists, and laboratory staff govern the possession, use, and transport of specimens or cultures containing B abortus, B suis, and B melitensis. These are the select agent rules of the Department of Health and Human Services (DHHS) and the Department of Agriculture (DOA). Isolations of these species and instances of potential laboratory exposure must be reported either to the Centers for Disease Control and Prevention (CDC) or to the Animal and Plant Health Inspection Service.^[10]

Reporting requirements that are at least equally strenuous are in place in other parts of the world, especially those areas that are certified as Brucella -free. That designation carries economic importance of the first degree in Brucella -free countries such as New Zealand. The consequences of importation of Brucella to New Zealand may be extremely severe.

• References

Laboratory Studies

Complete blood count

A complete blood count (CBC) typically is ordered routinely as part of an evaluation for a patient with potential infectious disease. Leukocytosis is rare in brucellosis, and a significant number of patients are neutropenic. Anemia is reported in 75% of patients (particularly with chronic infection), thrombocytopenia is reported in 40% (secondary to hepatosplenomegaly or from immune thrombocytopenia), and pancytopenia is reported in 6% of patients.

Liver enzymes

A slight elevation in liver enzyme levels is a very common finding. These elevated levels may reflect the severity of hepatic involvement and correlate clinically with hepatomegaly.

Culture

Diagnosis of brucellosis is definitive when Brucella organisms are recovered from blood, bone marrow, or other tissue. Some Brucella species require 5-10% carbon dioxide for primary isolation. Because of the ease of aerosol transmission, any potential Brucella specimens should be handled under a biohazard hood.

The sensitivity of blood cultures with improved techniques such as the Castaneda bottles is further improved by the lysis-centrifugation technique. With these methods, the sensitivity is approximately 60%.

Subcultures are still advised for at least 4 weeks; thus, if brucellosis is suspected, the laboratory should be alerted to keep the cultures for 3-4 weeks, which is not done routinely for most bacterial cultures.

Because the reticuloendothelial system holds a high concentration of brucellae, bone marrow culture is thought to be the criterion standard. Sensitivity is usually 80-90%.^[38]

Any fluid (eg, synovial fluid, pleural fluid, or cerebrospinal fluid [CSF]) can be cultured, but the yield is usually low.

CSF analysis

In patients with neurobrucellosis, analysis of CSF reveals a mild-to-modest lymphocytic pleocytosis of 88-98%. Protein levels are elevated in conjunction with normal glucose levels. CSF cultures are positive for brucellosis less than 50% of the time, but antibody testing of the fluid yields a diagnosis. CSF cultures are indicated for suggested meningitis.

Arthrocentesis

Although significant joint effusion is uncommon, arthrocentesis may occasionally be needed to exclude septic arthritis. The joint aspirate demonstrates an exudative fluid with low cell counts and mononuclear predominance. Patients with brucellosis rarely present with acute monoarticular arthritis.

Serology

Serologic testing is the most commonly used method of diagnosing brucellosis. Repeated serologic testing is recommended if the initial titer is low.

The tube agglutination test, developed by Bruce, measures antibodies against smooth lipopolysaccharide (LPS); it remains the most popular test tool for the diagnosis of brucellosis. The 2-mercaptoethanol test detects immunoglobulin G (IgG), and titers higher than 1:80 define active infection. A high IgG antibody titer or a titer that is higher after treatment suggests persistent infection or relapse. Other tests, such as tray agglutination (TAT) and modified TAT, are also popular.

Titers higher than 1:160 in conjunction with a compatible clinical presentation are considered highly suggestive of infection. Titers higher than 1:320 are considered to be more specific, especially in endemic areas. Seroconversion and evolution of the titers can also be used for diagnosis.

The shortcomings of agglutination tests test include potential cross-reactivity with IgM of other organisms such as Francisella tularensis, Salmonella urbana, Yersinia enterocolitica serotype O9, Vibrio cholerae, Afipia clevelandensis, and some other bacteria.

Prozone phenomenon may occur secondary to hyperantigenemia, possibly leading to false-negative results. Accordingly, routine dilution of sera (typically beyond 1:320) is necessary to avoid this problem.

Enzyme-linked immunosorbent assay (ELISA) typically uses the cytoplasmic proteins as antigens and measures IgM, IgG, and IgA, allowing better interpretation, especially in cases of brucellosis relapse.^[39] This is because antibodies against LPS, which are used in agglutination tests, might persist for longer periods and are believed to yield higher sensitivity and specificity. ELISA of CSF also helps diagnose neurobrucellosis. Because levels should decrease with effective treatment, ELISA is also helpful in follow-up.

Rapid point-of-care assays

Point-of-care assays are available that offer fast and accessible diagnostic capabilities, especially in areas were special laboratory resources are lacking.

Polymerase chain reaction

Polymerase chain reaction (PCR) tests have been developed for the detection and rapid diagnosis of Brucella species in human blood specimens.^[40] Two major genetic targets are the Brucella gene BCSP31 and the 16S-23S rRNA operon. The 16S-23S rRNA operon has been shown in studies to be more reliable in terms of sensitivity but is not yet widely used in clinical practice and needs more standardization. Possible applications would include evaluating cases of relapse and monitoring response to therapy.

Other promising tests include nested PCR, real-time PCR,^{[41, 42]} and PCR-ELISA, but the clinical roles for all of these tests remain to be defined.^{[43, 44, 40, 45]}

Urinalysis and urine culture

Urinalysis, urine culture, sensitivity testing, or a combination thereof may be indicated in the presence of symptoms of urinary tract infection (UTI). The most likely finding is a sterile pyuria, similar to that seen with tuberculosis. Urine cultures may be helpful; the organism grows from the urine if the genitourinary tract is infected.

• References

Radiography

A chest radiograph should be obtained if respiratory symptoms are present or if a source of infection is not apparent. Radiographic findings are typically absent in brucellosis, even in patients with prominent respiratory symptoms. Findings that may be observed in patients with active pulmonary involvement include hilar and paratracheal lymphadenopathy, pulmonary nodules, pleural thickening, and pleural effusion.

Spinal radiographic findings in patients with osteoarticular disease occur later in the course of illness, usually 2-3 weeks after the onset of symptoms. In patients with sacroiliitis, the most commonly observed abnormalities include blurring of articular margins and widening of the sacroiliac spaces.^[46] Spondylitis-related abnormalities include anterosuperior vertebral angle epiphysitis, spinal straightening, narrowing of the intervertebral disc spaces, end-plate sclerosis, and osteophytes.^[47]

• References

Other Imaging Studies

Ultrasonography

Echocardiography is used to evaluate for possible endocarditis. The primary site of vegetation is the aortic valve, with the sinus of Valsalva most commonly affected, followed by the mitral valve. Mycotic aneurysms of the aorta or carotids may be observed on duplex arteriography.

Use of ultrasonography to diagnose testicular abscess from brucellosis has been reported; low-resistance flow appears to be characteristic for these tumors.^[48]

Radionuclide scintigraphy

Radionuclide scintigraphy^[49] is more sensitive for revealing skeletal abnormalities, especially early in the disease, when standard radiographic findings are usually normal. This modality may be especially helpful in distinguishing hip involvement from sacroiliitis. To facilitate prompt diagnosis, radionuclide scintigraphy also may have a role in screening for new-onset brucellosis and musculoskeletal symptoms.

Computed tomography

In patients with altered mental status or focal neurologic deficits, cranial computed tomography (CT) is warranted. Although the CT scan is often normal, it may reveal evidence of acute or chronic Brucella leptomeningitis, subarachnoid hemorrhage, or cerebral abscess.

• References

Biopsy

Bone marrow aspiration and biopsy may be required to establish a diagnosis in certain patients. Bone marrow examination may reveal erythrophagocytosis. Microangiopathic hemolytic anemia, thrombocytopenic purpura,^[50] and Coombs-positive hemolytic anemia have been reported in brucellosis.

Percutaneous liver biopsy may be needed in the patient with liver granulomas to obtain a specimen for diagnosis. Analysis of liver biopsy specimens may reveal granulomatous hepatitis and hepatic microabscesses.

• References

Histologic Findings

Histologic findings in brucellosis usually include mixed inflammatory infiltrates with lymphocytic predominance and granulomas (in up to 55% of cases) with necrosis (see the images below).^[51]

View Image

Brucella species are poorly staining, small gram-negative coccobacilli (0.5-0.7 × 0.6-1.5 µm) and are seen mostly as single cells with an appearance r....

View Image

Well-formed hepatic granuloma from patient with brucellosis.

• References

Approach Considerations

The goal of medical therapy in brucellosis is to control symptoms as quickly as possible in order to prevent complications and relapses.

Initial care for brucellosis is supportive. Given the nonspecificity of patient complaints, a diagnosis of brucellosis in the emergency department (ED) is unlikely. With an appropriate history, an astute clinician may suspect it. Appropriate precautions (eg, mask, gloves, and eye protection) should be taken for respiratory procedures or handling body fluids. Specimens from the patient should be handled in the laboratory under biosafety level III conditions.

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; resistance is not a significant issue in treating brucellosis.^[52]

Depending on what other systems are involved, more specialized care may be needed. Transfer to another facility depends on the needs of the patient. Because most patients do not require highly specialized interventions, the need to transfer should not be frequent. Personnel involved in the transfer should maintain respiratory and contact precautions, and the vehicle should be decontaminated after transport as needed.

• References

Initial Supportive Care

Given that the symptoms generally are vague and the presentation is rarely life-threatening, emergency medical service (EMS) care should focus on stabilization, as needed, and transport. As in the care of any patient with a potentially transmissible disease, appropriate precautions (eg, gloves, mask, and gown) should be used.

If a proximate bioterrorist attack is known or strongly suggested at the time of patient contact, appropriate decontamination is warranted. In the event of a covert undiscovered attack, patients may become symptomatic well after the time that decontamination is necessary. If the patient presents as part of a known, immediately proximate bioterrorism incident, EMS providers should notify the hospital to undertake appropriate decontamination and isolation measures.

Respiratory isolation usually is not necessary, provided that close contact with the respiratory tract is not made. Masks should be worn for intubation, suctioning, or other maneuvers that may expose the caregiver to a large concentration of aerosolized particles. Supportive care should be provided for any specific symptoms, and appropriate tests should be targeted to affected organ systems as determined by the history and physical findings.

The development of an effective Brucella vaccine for use in humans would be an important step to controlling and probably eradicating brucellosis. However, the vaccine strategy is currently applicable only in control of livestock disease.

• References

Pharmacologic Therapy

Antibiotics

Although multiple antibiotics display in vitro activity against Brucella species, clinical response has been demonstrated with only a limited number of agents. Drugs that display clinical activity with low relapse rates include the following:

• Doxycycline
• Gentamicin
• Streptomycin
• Rifampin
• Trimethoprim-sulfamethoxazole (TMP-SMZ)

Other agents with potential roles include the following:

• Chloramphenicol
• Imipenem-cilastatin
• Tigecycline
• Fluoroquinolones

In those cases where relapse has occurred, the development of antibiotic resistance does not appear to be the underlying cause.

Optimal antibiotic therapy for brucellosis has been studied to some degree; however, recommendations may differ.

For simple infections, doxycycline (100 mg PO twice daily for 6 weeks) may be the most appropriate monotherapy; however, relapse rates with such monotherapy approach 40% and as a result, rifampin (600-900 mg/day) is usually added. Fluoroquinolones (eg, ciprofloxacin) have been used as monotherapy as well but also carry a high relapse rate; adding these agents to doxycycline offers no specific advantages over other combination regimens but may be preferred in areas where resistance to rifampin is high.

For acute brucellosis in adults and children older than 8 years, the World Health Organization (WHO) guidelines recommend the following:

• Doxycycline 100 mg PO twice daily plus rifampin 600-900 mg/day PO – Both drugs are to be given for 6 weeks; this regimen is more convenient but probably increases the risk of relapse
• Doxycycline 100 mg PO twice daily for 6 weeks and streptomycin 1 g/day IM for 2-3 weeks – This regimen is believed to be more effective, mainly in preventing relapse; gentamicin can be used as a substitute for streptomycin and has shown equal efficacy
• Ciprofloxacin-based regimens have shown efficacy equal to that of doxycycline-based regimens

A 2012 Cochrane review found that a regimen consisting of doxycycline for 6 weeks plus streptomycin for 2-3 weeks was more effective than one consisting of doxycycline plus rifampicin for 6 weeks.^[53] The investigators also found that a regimen consisting of a fluoroquinolone plus rifampicin for 6 weeks was as effective overall as doxycycline plus rifampin (though the evidence for this conclusion was of low quality) and was slightly better tolerated.

For brucellosis in children younger than 8 years, administration of rifampin and TMP-SMZ for 6 weeks is the therapy of choice.^{[54, 55]} The relapse rate appears to be approximately 5% or lower.

Treatment of brucellosis in pregnant women is a challenging problem, and the available data are limited. TMP-SMZ has been effective in this population, either as monotherapy or as part of combination therapy with rifampin or gentamicin. The most common recommendation is for rifampin, either alone or in combination with TMP-SMZ. It should be kept in mind that the use of TMP-SMZ by the end of pregnancy is associated with kernicterus.

In patients with spondylitis or sacroiliitis, doxycycline and rifampin combined with an aminoglycoside (gentamicin) for the initial 2-3 weeks, followed by 6 weeks of rifampin and doxycycline, is usually recommended.

Patients with nervous system infections typically require combination therapy. Doxycycline is generally preferred to tetracyclines or aminoglycosides because the latter are less likely to cross the blood-brain barrier in adequate quantities. Many authorities prefer a 3-drug (doxycycline-streptomycin-rifampin or doxycycline−TMP-SMZ−rifampin) regimen to a 2-drug regimen. A brief course of adjunctive corticosteroid therapy has been used to control the inflammatory process, but studies are limited.

Third-generation cephalosporins have been used in Brucella meningitis, but susceptibility is variable and must be ensured by in vitro sensitivity studies. Duration of therapy has ranged in various cases from 1-19 months, with treatment continued until the cerebrospinal fluid (CSF) is found to be without evidence of organisms or inflammation. In the year following cessation of treatment, agglutinins for Brucella should be followed in serum to ensure that relapse does not occur.

Some patients presenting with acute brucellar meningoencephalitis cannot be distinguished reliably from patients with herpes encephalitis, and the presentations of other patients may not be distinguishable from that of bacterial meningitis. In such cases, the initial therapeutic interventions should include agents appropriate for the management of those conditions.

Patients with endocarditis require aggressive therapy. Aminoglycoside therapy in conjunction with doxycycline, rifampin, and TMP-SMZ for at least 4 weeks, followed by at least 2-3 active agents (without aminoglycosides) for another 8-12 weeks, is preferred.

Chronic brucellosis is treated with triple-antibiotic therapy. The combination of rifampin, doxycycline, and streptomycin often is used.

Corticosteroids and other agents

The use of corticosteroids is reserved for symptomatic Brucella meningitis. Although these agents are generally recommended, scientific evidence supporting their use is lacking. No consensus exists on optimal dosing, frequency, or duration of therapy.

Any additional drugs needed for symptomatic treatment (eg, antipyretics, analgesics) must be administered as well. Additional medication is based on the patient’s presenting symptoms.

• References

Surgical Intervention

The main roles of surgery in patients with brucellosis lie in the treatment of endocarditis and in the drainage of pyogenic joint effusions or paraspinal abscesses.^{[56, 57]}

Previously healthy native valves, diseased native valves, and prosthetic valvular structures have been involved in brucellosis.^[58] Valvular lesions are typically large and destructive, regardless of the organism involved. Accordingly, valve replacement surgery is often recommended in addition to a prolonged course of antibiotics.

• References

Diet and Activity

No special diet is required for the treatment of brucellosis. Discuss with patients the importance of consuming pasteurized milk and milk products and avoiding other possible sources of infection. Obviously, the impact of such education will have the greatest effect on family and friends who may be at risk for infection.

Restriction of activity with bed rest appears to confer benefit in the acute phase of brucellosis, increasing the rate of recovery.

• References

Prevention

Prevention of brucellosis in humans depends on eradication or control of the disease in animals and on avoiding potential sources of infection. Better handling of infected animals or animal products is paramount. Public awareness and education play major roles in prevention.

Consumption of unpasteurized milk and milk products, as well as of raw or undercooked meats, should be avoided. Education may be provided to the patient and family concerning risks and should emphasize avoiding anything identified as a specific cause in the case at hand. Should the identified source be a live animal, the herd or flock from which it came should be investigated. In endemic areas, investigation is warranted for all animals.

Scrupulous hygiene may prevent infection, especially when practiced by individuals likely to have close contact with goats, sheep, cows, camels, pigs, reindeer, rabbits, or hares. Obviously, this contact is of greatest importance in areas of endemic disease.

At present, immunization is not an option for patients; the vaccine is attenuated for animals but not for humans and may cause disease in humans.^[59] However, immunization of at-risk animals reduces the number of infected animals and therefore the reservoir of infection. Results from a study of the planned brucellosis control program in Egypt showed that removal of infected animals under the actual implementation of the program would likely permit brucellosis to remain endemic in the goat and sheep population.^[60]

All persons with an occupational risk for brucellosis should be informed about the use of protective devices (eg, goggles, masks, and gloves) to avoid exposure to aerosols, body fluids, or the brucellosis vaccine. In particular, laboratory personnel should be advised of the potential diagnosis so they will use biosafety level-3 precautions when in contact with suspicious specimens.

Bioterrorism

Serious concerns have been expressed concerning the utilization of Brucella species in biologic weapons. Airborne transmission of these bacteria is readily achieved via the mucous membranes of the conjunctivae, nasal passages, oropharynx, and respiratory tract. Infection may occur as the result of lodging of organisms in cuts or abrasions. As few as 10-100 organisms may produce infection via aerosol exposure. The resulting disease may exhibit any of the various manifestations of which Brucella species are capable.

Bichat guidelines have been established for the management of individuals at risk for or manifesting evidence of brucellosis after bioterroristic exposure. Treatment regimens combining doxycycline with either streptomycin or rifampin are thought adequate in such situations; the combination of ofloxacin with rifampin is also cited. To date, however, no studies have conclusively established the efficacy of postexposure prophylaxis as a method of preventing brucellosis.^[61]

• References

Consultations

The primary specialist to consult is an infectious disease specialist. Proper serologic tests, cultures, further diagnostic evaluations, and the correct antibiotic therapy should be determined in collaboration with this specialist.

Depending on the clinical manifestations of the disease and the degree of damage to individual organ systems, additional specialists may be consulted, such as the following:

• Orthopedic or neurologic surgeon (for management of inflammatory disturbances of vertebrae and spinal disks)
• Cardiothoracic surgeon (if endocarditis is suspected or documented)

• References

Long-Term Monitoring

Outpatient care consists of completing the prescribed course of antibiotic therapy, treating any exposed patients, and avoiding contact with the initial source of infection. Care is continued until the infection is cured and laboratory findings return to reference ranges. Serologic studies and enzyme-linked immunosorbent assay (ELISA) can be used to document patient response to therapy. After an adequate course of therapy, persistent or recurrent symptoms of brucellosis should prompt a search for localized suppurative lesions.

Careful follow-up is essential for ensuring that the patient complies with the full 6-week antibiotic regimen and for determining whether a relapse has occurred. In some instances, the disease takes a relapsing and remitting course. In such cases, triple-drug therapy may be undertaken for periods as long as 6 months or more.

Relapsing brucellosis must be distinguished from instances of reinfection. The degree of immunity induced by an initial attack of brucellosis may be inadequate to prevent reinfection. Second, third, or even more instances of reinfection may occur, especially in veterinarians and other individuals who are continually exposed to animals.

Some individuals acquire infection-induced hypersensitivity to Brucella antigens. This may result in a severe local reaction caused by accidental self-inoculation with Brucella vaccines. Reactions of this sort are especially likely to be experienced by veterinarians and others who are responsible for inoculating animal herds.

• References

Medication Summary

Although many antibiotics display in vitro activity against Brucella species, clinical response has been demonstrated with only a few of them. Drugs that display clinical activity with low relapse rates include doxycycline, gentamicin, streptomycin, rifampin, and trimethoprim-sulfamethoxazole (TMP-SMZ). Other agents with potential roles are chloramphenicol, imipenem-cilastatin, and various fluoroquinolones. When relapse occurs, the development of antibiotic resistance does not appear to be the underlying cause.

Corticosteroids are indicated to reduce inflammation and improve neurologic outcome in patients with neurobrucellosis.

• References

Doxycycline (Doryx, Vibramycin, Adoxa)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline is a synthetic broad-spectrum antibiotic derived from oxytetracycline. It inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Its activity, like that of other tetracyclines, is essentially bacteriostatic. Doxycycline is readily absorbed and is eliminated by biliofecal and urinary excretion. Dosage must be adjusted in patients with impaired renal function.

Trials have established the efficacy of doxycycline as treatment for brucellosis. Because of concerns regarding treatment failures, combination therapy with rifampin or an aminoglycoside now is recommended, although doxycycline remains approved for use as monotherapy.

• References

Streptomycin

• Dosing, Interactions, etc.

Clinical Context:  Streptomycin is an aminoglycoside antibiotic that exerts a bacteriostatic effect by inhibiting protein synthesis through binding to 30S ribosomal subunits. It typically achieves peak serum concentration within 1 hour of being injected intramuscularly (IM). It achieves good penetration of all organ systems except the central nervous system (CNS), and it readily passes through placental membrane barriers. Streptomycin is excreted by renal glomerular filtration; dosage adjustment is necessary in patients with diminished renal function.

Streptomycin is indicated as a cotherapeutic agent to augment the antibacterial actions of other agents used to treat brucellosis.

• References

Gentamicin

• Dosing, Interactions, etc.

Clinical Context:  Gentamicin is an aminoglycoside antibiotic that exerts a bacteriostatic effect by inhibiting protein synthesis through binding to 30S ribosomal subunits. It is commonly used to treat brucellosis in combination with either TMP-SMZ or doxycycline. Dosing regimens are numerous. Either a single daily dose or multiple daily doses may be used for adults. The dose should be adjusted on the basis of creatinine clearance and changes in volume of distribution and may be administered either intravenously (IV) or IM.

• References

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra DS)

• Dosing, Interactions, etc.

Clinical Context:  TMP-SMZ (also referred to as cotrimoxazole) inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. It is used adjunctively in children younger than 8 years and is used either as monotherapy or in combination with rifampin or gentamicin to treat infection in pregnant women.

• References

Rifampin (Rifadin)

• Dosing, Interactions, etc.

Clinical Context:  Rifampin inhibits DNA-dependent bacterial (but not mammalian) RNA polymerase activity in susceptible cells. No known cross-resistance of microbes occurs, except when other rifamycins are involved. Rifampin is readily absorbed after oral dosing. Renal and hepatobiliary routes of elimination are active. Rifampin is used as a component of combination therapy for brucellosis. It may exhibit bacteriostatic or bactericidal activity, depending on its concentration at the site of infection.

• References

Tetracycline

• Dosing, Interactions, etc.

Clinical Context:  Tetracycline is a readily absorbed antibiotic with bacteriostatic effects produced by inhibition of microbial protein synthesis. It is concentrated by the liver in bile and is excreted in feces and urine. Dosage must be adjusted for patients with renal impairment; excessive systemic accumulation may occur, which can result in possible hepatic toxicity or worsening of azotemia, hyperphosphatemia, and acidemia. In patients with significantly abnormal renal function, monitoring of serum concentrations may be warranted.

• References

Ciprofloxacin (Cipro)

• Dosing, Interactions, etc.

Clinical Context:  Ciprofloxacin is a synthetic broad-spectrum antimicrobial agent of the fluoroquinolone class. It exerts bactericidal activity by interfering with microbial DNA gyrase activity. It is well absorbed orally and is largely cleared unchanged in urine.

• References

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

• References

Dexamethasone (Baycadron)

• Dosing, Interactions, etc.

Clinical Context:  The use of corticosteroids is reserved for symptomatic Brucella meningitis. Although these agents are generally recommended, scientific evidence supporting their use is lacking. No consensus exists on optimal dosing, frequency, or duration of therapy.

• References

Methylprednisolone (A-Methapred, Medrol, Depo-Medrol, Solu-Medrol)

• Dosing, Interactions, etc.

Clinical Context:  Methylprednisolone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

• References

Class Summary

In patients with brucellosis, corticosteroids are indicated to reduce inflammation and improve neurologic outcome. The addition of anti-inflammatory therapy with methylprednisolone or another corticosteroid may be beneficial in patients with severe or diffuse CNS involvement, cranial neuropathies, optic neuritis, or arachnoiditis.

• References