eMedicine Specialties > Infectious Diseases > Bacterial Infections

Brucellosis

Wafa Al-Nassir, MBBS, Infectious Diseases Consultant, Saad Specialist Hospital, Al-Khobar, Saudi Arabia
Michelle V Lisgaris, MD, Assistant Professor of Medicine, Case Western Reserve University; Associate Medical Director, Infection Control, Department of Internal Medicine, Division of Infectious Diseases, University Hospitals of Cleveland; Robert A Salata, MD, Chief and Clinical Program Director of Division of Infectious Diseases, Vice Chair for International Affairs, Professor, Department of Medicine, Case Western Reserve University School of Medicine

Updated: Feb 3, 2009

Introduction

Background

Brucellosis is believed to be an ancient disease that was described more than 2000 years ago by the Romans. Bruce first isolated Brucella melitensis in 1887. Since then, brucellosis has become an emerging disease in many parts of the world.

Brucellosis is a worldwide zoonosis caused by infection with the bacterial genus Brucella. These 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. Exposure to infected animals and animal products causes brucellosis in humans.

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

The 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.^{[1 ]}(For more information, see the article CBRNE - Brucellosis in eMedicine’s Emergency Medicine volume.) Familiarity with the manifestations of brucellosis and the optimal laboratory studies is essential for physicians to recognize this re-emerging zoonosis.

Recently, B melitensis, Brucella abortus, and Brucella suis have been completely sequenced, which will help improve our understanding of the complex pathogenesis and the diverse manifestations of this complex disease.

The traditional classification of Brucella species is based largely on the preferred hosts.

Table 1. The 7 Currently Recognized Brucella Species

Among 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. B melitensis is also the most prevalent worldwide. A prolonged course of illness, often associated with suppurative destructive lesions, is associated with B suis infections. B abortus is associated with mild-to-moderate sporadic disease that rarely causes complications. B canis infection has a disease course that is indistinguishable from B abortus infection. B canis infection has an insidious onset, causes frequent relapses, and does not commonly cause chronic brucellosis. B pinnipediae and B cetaceae are distinctive species that typically affect marine animals; however, these strains were recently described to cause disease in humans, mainly neurobrucellosis.

Definitive diagnosis of brucellosis is based on culture, serologic techniques, or both. Clinically, identification to the genus level is adequate to initiate therapy, and the type of Brucella species involved does not alter the therapeutic agents used; however, speciation is necessary for epidemiologic surveillance and requires more detailed biochemical, metabolic, and immunologic testing.

Pathophysiology

Brucella species have a unique ability of invading both phagocytic and nonphagocytic cells and surviving in the intracellular environment by avoiding the immune system in different ways, explaining why brucellosis is a systemic disease and can involve almost every organ system.

After ingestion by phagocytes, approximately 15-30% of Brucella organisms survive. In polymorphonuclear or mononuclear phagocytic cells, the bacteria use numerous mechanisms to avoid or suppress bactericidal responses. Based on animal models, the lipopolysaccharide (LPS; smooth in B melitensis, B abortus, and B suis and rough in B canis) was found likely to play a substantial 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 a poor inducer of some inflammatory cytokines such as tumor necrosis factor (TNF) and interferons. Also, the bacteria do not activate the alternative complement system. Finally, it is thought to inhibit programmed cell death.

After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis.

Susceptibility to intracellular killing differs among species, with B abortus readily killed and B melitensis rarely affected; this might explain the differences in pathogenicity and clinical manifestations in human cases of brucellosis.^{[2 ]}

Frequency

United States

Brucellosis has become a rare disease because of the institution of veterinary control measures (eg, routine screening of domestic livestock, vaccination programs). Now, fewer than 100 cases are reported annually to the Centers for Disease Control and Prevention (CDC). The most common reporting states include California, Florida, Texas, and Virginia.

International

Brucellosis causes more than 500,000 infections per year worldwide. 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 have effectively controlled brucellosis, new areas of human brucellosis have emerged in areas such as central Asia. Disease incidence and prevalence rates vary widely among nations. Because of variable reporting, true estimates in endemic areas are unknown. Incidence rates of 1.2-70 cases per 100,000 people are reported.

Mortality/Morbidity

Human brucellosis carries a low mortality rate (<5%), mostly secondary to endocarditis, which is a rare complication of brucellosis. However, brucellosis can cause chronic debilitating illness with extensive morbidity.

Sex

Worldwide, brucellosis is more common in males than in females, with a ratio of 5:2-3 in endemic areas.

Age

• In multiple large series, persons in their third to fifth decades of life were most commonly affected.
• Brucellosis in children comprises 3-10% of reported cases worldwide, with a heavier burden in endemic areas. (For more information on pediatric brucellosis, see the article Brucellosis in eMedicine’s Pediatrics: General Medicine volume.)
• Elderly persons typically develop chronic brucellosis.

Clinical

History

Symptoms of brucellosis are protean in nature, and none is specific enough to support the diagnosis. Table 2 lists symptoms and signs compiled from large studies that were conducted in regions hyperendemic for brucellosis.

• 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. It is associated with chills in almost 80% of cases.
• Constitutional symptoms of brucellosis include anorexia, asthenia, fatigue, weakness, and malaise and are very common (>90% of cases).
• Bone and joint symptoms include arthralgias, low back pain, spine and joint pain, and, rarely, joint swelling. These symptoms affect as many as 55-80% of patients.
• 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.
• Gastrointestinal symptoms, present in 50% of patients, include abdominal pain, constipation, diarrhea, and vomiting.
• 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 CNS involvement. For more information on neurologic manifestations of brucellosis, see the article Brucellosis in eMedicine’s Neurology volume.
• 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.^{[3 ]}

Physical

• Subclinical, acute, subacute, and chronic infections are the classic categorizations of brucellosis. Localized and relapsing forms have also been described. This classification system is subjective and has limited clinical use.
  • 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 or subacute brucellosis: Disease can be mild and self-limited (eg, B abortus) or fulminant with severe complications (eg, B melitensis). Associated symptoms can develop at 2-3 months and 3-12 months prior to diagnosis, respectively. The most common symptoms and signs are listed in Table 2.
  • Chronic brucellosis: The diagnosis 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 complications of brucellosis are typically observed in patients with acute disease or chronic untreated infection. Osteoarticular, genitourinary, and hepatosplenic involvement are most common. Cultures of involved tissue sites and serology can be diagnostic. (See Complications.)
  • 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 in patients with brucellosis vary and are nonspecific for the disease.
• The most common findings include hepatosplenomegaly (or isolated hepatomegaly or splenomegaly) and osteoarticular involvement. Table 2 displays the range of signs observed.
• Osteoarticular findings can include tenderness and swelling over affected joints, bursitis, decreased range of motion, and joint effusion (rare). Maneuvers that isolate the sacroiliac joint may cause pain.
• Neurologic findings vary according to the presentation of neurologic disease, as follows:
  • Acute meningoencephalitis (most common neurological manifestation) - Depressed level of consciousness, meningeal irritation, cranial nerve involvement, coma, seizure, and respiratory depression
  • 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 are as follows:^{[17 ]}
  • Erythema nodosum, abscesses, and papulonodular eruptions (most common)
  • Impetigo, psoriatic, eczematous, and pityriasis rosea –like lesions
  • Macular, maculopapular, and scarlatiniform rashes
  • Vasculitic lesions (eg, petechiae, purpura, thrombophlebitis)
• Ocular findings can include the following:^{[18 ]}
  • Uveitis^{[19 ]}
  • Keratoconjunctivitis
  • Iridocyclitis
  • Nummular keratitis
  • Choroiditis
  • Optic neuritis^{[20 ]}
  • Metastatic endophthalmitis
  • Cataracts

Causes

• Ingestion of unpasteurized goat milk and related dairy products is the main route of B melitensis transmission to humans.
• Slaughterhouse workers, primarily those in the kill areas, become inoculated 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.

Differential Diagnoses

Other Problems to Be Considered

Collagen-vascular disease
Chronic fatigue syndrome
Malignancy
Osteomyelitis

Workup

Laboratory Studies

As mentioned above, symptoms and signs of brucellosis are unspecific; cultures and serology are usually necessary for diagnosis. Some general laboratory findings might suggest the diagnosis (eg, leukopenia, relative lymphocytosis, pancytopenia^{[21,22 ]}[in up to 20% of cases]). Slight elevation in liver enzymes is a very common finding. The criterion standard test for diagnosis of brucellosis is the isolation of the organism from the blood or tissues (eg, bone marrow, liver aspiration).

• Culture
  • 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.
  • Bone marrow culture is thought to be the criterion standard, since the reticuloendothelial system holds a high concentration of brucellae. Sensitivity is usually 80-90%.^{[23 ]}
  • Any fluid can be cultured (eg, synovial, pleural, cerebrospinal), but the yield is usually low.
• CSF evaluation: This reveals a mild-to-modest lymphocytic pleocytosis in 88-98% of in patients with neurobrucellosis. Protein levels are elevated in conjunction with normal glucose levels.
• Serology
  • Serological testing is the most commonly used method of brucellosis diagnosis.
  • Serum tube agglutination test: This test, developed by Bruce, measures antibodies against smooth LPS; it remains the most popular test tool for the diagnosis of brucellosis.
  • Other tests such as tray agglutination (TAT) and modified TAT are also popular. Titers of more than 1:160 in conjunction with compatible clinical presentation is considered highly suggestive of infection. Titers of more 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 this test include cross-reactivity with immunoglobulin M (IgM) of other organisms such as Francisella tularensis, Salmonella urbana, Yersinia enterocolitica, Vibrio cholera, Afipia clevelandensis, and some other bacteria.
  • Prozone phenomenon may occur secondarily to hyperantigenemia, possibly leading to false-negative results, so routine dilution of the serum beyond 1:320 would help to prevent such a problem.
• ELISA: This technique has been gaining popularity in the last few years. ELISA typically uses the cytoplasmic proteins as antigens and measures IgM, IgG, and IgA, allowing for better interpretation, especially in cases of brucellosis relapse.^{[24 ]}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 titers is also helpful in diagnosing neurobrucellosis. Because levels should decrease with effective treatment, ELISA is also helpful in follow-up.
• Rapid point-of-care assays: These are available and enable fast and accessible diagnostic capabilities, especially in areas were special laboratory resources are lacking.
• Polymerase chain reaction (PCR): PCR testing for brucellae is a recent advance with promising potential. It would allow for rapid and accurate diagnosis of brucellosis. PCR was first developed in the early 1990s. 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,^{[25,26,27 ]}and PCR-ELISA, but the clinical role for these tests remains to be defined.^{[28,29,30,31 ]}

Imaging Studies

• Chest radiography
  • Radiographic findings are typically absent in brucellosis, even in patients with prominent respiratory symptoms.
  • Findings observed in patients with active pulmonary involvement include hilar and paratracheal lymphadenopathy, pulmonary nodules, pleural thickening, and pleural effusion.
• Spinal radiography
  • 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.^{[32 ]}
  • Spondylitis-related abnormalities include anterosuperior vertebral angle epiphysitis, spinal straightening, narrowing of the intervertebral disc spaces, end-plate sclerosis, and osteophytes.^{[33 ]}
• Radionuclide scintigraphy^{[34 ]}
  • This study is more sensitive for revealing skeletal abnormalities, especially early in the disease, when standard radiographic findings are usually normal.
  • Radionuclide scintigraphy may be especially helpful in distinguishing hip involvement from sacroiliitis.
  • To facilitate prompt diagnosis, this study also may have a role in screening for newly onset brucellosis and musculoskeletal symptoms.

Histologic Findings

Histologic findings in brucellosis usually include mixed inflammatory infiltrates with lymphocytic predominance and granulomas (in up to 55% of cases) with necrosis.^{[35 ]}

See image below.

Well-formed hepatic granuloma from a patient with brucellosis.

Treatment

Medical Care

The goal of medical therapy in brucellosis is to control symptoms as quickly as possible to prevent complications and relapses. Multidrug antimicrobial regimens are the mainstay of therapy because of high relapse rates reported with monotherapeutic approaches. The risk of relapse is not well understood, as resistance is not a significant issue in treating brucellosis.

• The World Health Organization recommends the following for adults and children older than 8 years:
  • Doxycycline 100 mg PO bid and rifampin 600-900 mg/d PO: Both drugs are to be given for 6 weeks (more convenient but probably increases the risk of relapse).
  • Doxycycline 100 mg PO bid for 6 weeks and streptomycin 1 g/d IM daily 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 equal efficacy to doxycycline-based regimens.
• Children younger than 8 years: The use of rifampin and trimethoprim-sulfamethoxazole (TMP-SMX) for 6 weeks is the therapy of choice. Relapse rate appears to be approximately 5% or less.
• Pregnant women: Brucellosis treatment is a challenging problem with limited studies. The recommendation is a regimen of rifampin alone or in combination with TMP-SMX. However, TMP-SMX use by the end of pregnancy is associated with kernicterus.
• In patients with spondylitis, 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 meningoencephalitis may require doxycycline in combination with rifampin, TMP-SMX, or both. A brief course of adjunctive corticosteroid therapy has been used to control the inflammatory process, but studies are limited.
• Patients with endocarditis require aggressive therapy. Aminoglycoside therapy in conjunction with doxycycline, rifampin, and TMP-SMX for at least 4 weeks followed by at least 2-3 active agents (without aminoglycosides) for another 8-12 weeks is preferred.
• Many other drugs have good in vitro activity against Brucella, including, but not limited to, chloramphenicol, imipenem-cilastin, and tigecycline. Gentamicin-loaded microparticles and immune-response stimulates may hold future promise. 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.

Surgical Care

• The role of surgery in patients with brucellosis lies in the treatment of endocarditis or drainage of focal abscesses.^{[36 ]}
• Previously healthy native valves, diseased native valves, and prosthetic valvular structures have been involved in brucellosis.^{[37 ]}Valvular lesions are typically large and destructive, regardless of the organism involved.

Consultations

• Infectious disease specialist
• Cardiothoracic surgery specialist if endocarditis is suspected or documented

Diet

• No special diet is required for the treatment of brucellosis.

Medication

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 doxycycline, gentamicin and streptomycin, rifampin, and TMP-SMX. Other agents with potential roles include chloramphenicol, imipenem-cilastatin, and fluoroquinolones. When relapse has occurred, the development of antibiotic resistance does not appear to be the underlying cause.

Antibiotics

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

Doxycycline (Vibramycin)

Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Dosing

Adult

100 mg PO/IV q12h

Pediatric

<8 years: Not recommended
>8 years: 2-5 mg/kg/d PO/IV qd or divided bid; not to exceed 200 mg/d

Interactions

Bioavailability decreases minimally with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Streptomycin

Aminoglycoside antibiotic. Although studied in combination with other agents in brucellosis, largely replaced by gentamicin (less adverse events).

Dosing

Adult

1 g IM q12h

Pediatric

20-40 mg/kg/d IM in divided doses bid/qid

Interactions

Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics; prolongs effects of neuromuscular blocking agents

Contraindications

Documented hypersensitivity; non–dialysis-dependent renal insufficiency

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Narrow therapeutic index; not intended for long-term therapy; caution in renal failure not on dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; can cause vestibular and cochlear toxicity

Gentamicin (Garamycin)

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be administered IV/IM.

Dosing

Adult

5 mg/kg/d IV/IM in divided doses; once daily dosing advocated by many

Pediatric

2 mg/kg IV/IM q8h

Interactions

Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents, thus prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)

Contraindications

Documented hypersensitivity; non–dialysis-dependent renal insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Trimethoprim-sulfamethoxazole (Bactrim, Septra)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Dosing

Adult

160 mg TMP-800 mg SMX PO q12h (1 double strength tab q12h)

Pediatric

<2 months: Do not administer
>2 months: 10-12 mg/kg/d, based on TMP, PO divided bid (50-60 mg/kg/d, based on SMX, divided bid)

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, people who are chronic alcoholics, elderly patients, those receiving anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in individuals deficient in G-6-PD; patients with AIDS may not tolerate or respond to TMP-SMX; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation

Rifampin (Rifadin)

Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.

Dosing

Adult

900 mg/d PO/IV divided bid

Pediatric

15-20 mg/kg PO/IV; not to exceed 600 mg/d

Interactions

Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Follow-up

Further Outpatient Care

• Encourage patient compliance with the antimicrobial regimen used.
• After an adequate course of therapy, persistent or recurrent symptoms of brucellosis should prompt a search for localized suppurative lesions.
• Serologic testing with serologic studies and ELISA methods can be used to document patient response to therapy.

Deterrence/Prevention

• Inform persons with an occupational risk for brucellosis about the use of protective devices (eg, goggles, masks, gloves) to avoid exposure to aerosols, body fluids, and inadvertent vaccine exposure.
• Inform travelers to endemic areas about appropriate dietary hygiene.
• Advise laboratory personnel about the potential diagnosis so they will use biosafety level-3 precautions when in contact with suspicious specimens.

Complications

• Osteoarticular^{[38 ]}
  • These symptoms affect 20-60% of patients with brucellosis and are the most commonly reported complications; sacroiliitis is the most common.
  • 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
  • These complications include hepatitis, hepatic abscess, and acute cholecystitis.
  • The rarely reported gastrointestinal complications include ileitis, colitis, and spontaneous peritonitis.
• Genitourinary
  • These complications usually manifest as orchitis or epididymo-orchitis.^{[39 ]}
  • Renal involvement is rare, although glomerulonephritis and pyelonephritis have been reported.^{[40 ]}
  • Infection in pregnant patients is rare and is associated with first-trimester abortions. The frequency of this complication is not substantially different than when it is associated with other bacterial infections.
• Neurobrucellosis
  • This complication occurs more frequently in endemic regions and develops in approximately 5% of cases. See Workup.
  • 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
  • Endocarditis occurs in less than 2% of patients with brucellosis worldwide; 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.
  • 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
  • These complications are reported in 0.3-1% of patients with brucellosis and include pneumonia and pleural effusion.
  • These complications are less common in children.
• Hematologic^{[41 ]}
  • 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.

Prognosis

• Although initial symptoms of brucellosis may be debilitating, if they are treated appropriately and within the first few months of onset, this disease is easily curable with a low risk of relapse or chronic disease. The prognosis is poor in persons who present with congestive heart failure due to endocarditis, with a mortality rate approaching 85%.

Patient Education

• Stress the importance of patient medical compliance to prevent persistent disease and clinical relapse.

Multimedia

Media file 1: Well-formed hepatic granuloma from a patient with brucellosis.

References

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Keywords

brucellosis, Malta fever, Brucella melitensis, human brucellosis, bang disease, Brucella abortus, undulant fever, B melitensis, B abortus, Brucella suis, B suis, Brucella canis, B canis, bacterial zoonosis, neurobrucellosis, chronic brucellosis, acute brucellosis, subclinical brucellosis, subacute brucellosis, localized brucellosis, relapsing brucellosis

Contributor Information and Disclosures

Author

Wafa Al-Nassir, MBBS, Infectious Diseases Consultant, Saad Specialist Hospital, Al-Khobar, Saudi Arabia
Wafa Al-Nassir, MBBS is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Coauthor(s)

Michelle V Lisgaris, MD, Assistant Professor of Medicine, Case Western Reserve University; Associate Medical Director, Infection Control, Department of Internal Medicine, Division of Infectious Diseases, University Hospitals of Cleveland
Michelle V Lisgaris, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America, and Society for Healthcare Epidemiology of America
Disclosure: Nothing to disclose.

Robert A Salata, MD, Chief and Clinical Program Director of Division of Infectious Diseases, Vice Chair for International Affairs, Professor, Department of Medicine, Case Western Reserve University School of Medicine
Robert A Salata, MD is a member of the following medical societies: American Association of Immunologists, American Federation for Medical Research, American Medical Association, Central Society for Clinical Research, Infectious Diseases Society of America, Ohio State Medical Association, and Society for Healthcare Epidemiology of America
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey D Band, MD, Clinical Professor of Medicine, Wayne State University School of Medicine; Director, Division of Infectious Diseases and International Medicine, William Beaumont Hospital Corporation
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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
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Ronald A Greenfield, MD, Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine
Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist  Speaking and teaching

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
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