OVERVIEW: What every clinician needs to know

Pathogen name and classification

Brucella species are small, aerobic, Gram-negative coccobacilli that are animal pathogens of worldwide distribution. Four species, B. melitensis, B. abortus, B. suis, and B. canis, have been described as zoonotic pathogens in humans.

What is the best treatment?

  • The tetracyclines are the most active agents, and are usually combined with at least one other drug to reduce the risk of relapse. The most commonly recommended first line regimen is doxycycline for at least 6 weeks, combined with either gentamicin for 1-2 weeks or streptomycin for 2-3 weeks. Doxycycline plus rifampin, both for at least 6 weeks, is a more convenient, all-oral regimen but is somewhat less effective (higher risk of relapse). Rifampin accelerates the hepatic clearance of doxycycline, so co-administration of these drugs results in reduced blood levels of the former, perhaps explaining the poorer performance of this combination compared to that of doxycycline plus an aminoglycoside. The combination of rifampin plus minocycline, whose levels are not reduced by rifampin, is promising and merits further study.

  • The optimal duration of therapy for uncomplicated infection is 42-45 days. Shorter courses (e.g., 21 or 30 days) have been demonstrated inferior, particularly in terms of relapse.

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  • Triple therapy, using doxycycline plus rifampin for 42-45 days, plus an aminoglycoside for the first 1-2 weeks, may yield better outcomes but needs further study before it can be recommended routinely.

  • Many experts advocate longer treatment courses (e.g., 12 weeks) for complicated infections, such as those with osteoarticular involvement.

  • The need for parenteral administration is a barrier to aminoglycoside treatment in many settings, and the use of rifampin may inadvertently treat unrecognized tuberculosis with monotherapy. Some experts argue that a prolonged (e.g., 8 week) course of doxycycline monotherapy may be considered for uncomplicated infection with low risk of relapse (not more than one of the following: positive culture, T >38.3°C, <10 days of symptoms before treatment), although this issue requires further study.

  • Optimal treatment for those in whom tetracyclines are contraindicated, notably young children and pregnant women, is less well established. Trimethoprim-sulfamethoxazole and rifampin are the most commonly used drugs in these groups, either alone or in combination. Although head-to-head studies are lacking, rifampin monotherapy appears more effective than trimethoprim-sulfamethoxazole monotherapy, which is not recommended. Limited data support the combination of trimethoprim-sulfamethoxazole and rifampin as a reasonable regimen in children. Either trimethoprim-sulfamethoxazole or rifampin can be combined with 1-3 weeks of an aminoglycoside, although the optimal combination is unknown. In any case, the total duration of the regimen should be at least 6 weeks.

  • Fluoroquinolones (ciprofloxacin and ofloxacin have been studied) are active but have performed poorly as monotherapy. When combined with rifampin, some studies have fluoroquinolones to be comparable to doxycycline (plus rifampin), whereas others suggest inferiority.

  • Acquired resistance to antibiotics is very uncommon and is rarely seen even with relapsed disease.

    Rifampin resistance, mediated by mutations in the RNA-dependent DNA polymerase, has been described.

    Resistance to trimethoprim-sulfamethoxazole has been reported.

    Resistance testing is not routinely performed.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Brucella spp. are concentrated in the genital tract and milk of infected animals. B. melitensis infects primarily goats, sheep, and cattle; B. abortus, primarily cattle, also bison, buffalo, camels, dogs, and yaks; B. suis serovars 1-3, pigs; B. suis serovar 4, reindeer and caribou; B. canis, dogs.

  • B. melitensis is the most common cause of human brucellosis.

  • Humans contract brucellosis from infected animals, primarily by consuming unpasteurized dairy products (e.g., raw milk and soft cheeses), and less commonly via undercooked or raw meat products. Direct contact with an infected animal, via (especially nonintact) skin, mucous membrane exposure, or inhalation of contaminated aerosols, can also transmit infection. Transmission from a heavily contaminated environment, via skin, mucous membrane, or inhalation, can also occur.

    Brucellosis is distributed worldwide but is now rare in the United States and northern Europe. It is more common in the Mediterranean basin, the Middle East, and elsewhere in the developing world. Human brucellosis is particularly common where control of animal brucellosis is poor and the consumption of unpasteurized dairy products widespread. Therefore, in parts of the world with improving farm animal health and hygiene and with increasing use of milk pasteurization, brucellosis is declining.

    In temperate or cold climates, increased incidence of infection correlates with the spring and summer birthing season for farm animals.

Infection control issues

  • Standard precautions should be observed when providing care for patients with brucellosis. Laboratory cultures of Brucella spp. confer a high risk of transmission via aerosolization and should be handled with BIosafety Level 3 protocol.

  • Live, attenuated vaccine strains of B. melitensis and B. abortus are available, but only for use in animals.

  • Post-exposure prophylaxis is recommended for laboratory workers with high risk exposure to Brucella. The Centers for Disease Control and Prevention (CDC)-recommended regimen is a 3 week course of doxycycline (100 mg twice daily) and rifampin (600 mg once daily). When doxycycline is contraindicated (e.g., during pregnancy), trimethoprim/sulfamethoxazole 160mg/800 mg twice daily should be substituted. Rifampin should be omitted if the exposure is to Brucella abortus strain RB51, which is resistant to rifampin. For accidental exposure (percutaneous or conjunctival) to live veterinary Brucella vaccines, the World Health Organization (WHO) recommends a 6 week course of doxycycline.

What host factors protect against this infection?

  • Brucella species are facultative intracellular pathogens that proliferate within cells of the reticuloendothelial system. Therefore, cell-mediated immunity is especially important in controlling the infection.

  • Given this aspect of its pathophysiology, one would expect brucellosis to be much more common in patients with HIV and in recipients of organ transplants; so far, such increased incidence has not been described.

  • Liver histopathology in patients with hepatic involvement can show a spectrum of changes, from scattered small foci of inflammation, to larger foci of inflammation and necrosis, to well-formed granulomas.

What are the clinical manifestations of infection with this organism?

  • Brucellosis usually manifests as an acute or subacute febrile illness, often without localizing signs or symptoms. Nonspecific symptoms, such as chills, sweats, headache, myalgias, arthralgias, anorexia, and generalized asthenia, are common. The illness can persist for weeks to months without treatment, and fever can wax and wane over a period of several days.

What common complications are associated with infection with this pathogen?

  • Osteoarticular disease is the most common complication of brucellosis, particularly sacroileitis and spondylitis. Prolonged (at least 12 weeks) treatment is usually recommended.

  • Hepatic involvement is common but rarely severe; liver function tests are usually either normal or mildly abnormal.

  • Genital tract infection can occur in humans, as it does characteristically in animals. These potential manifestations can mimic tuberculosis or malignancy and include orchitis, epididymitis, and salpingitis. Renal involvement is rare.

  • Infective endocarditis, usually of the aortic valve, is an uncommon complication but may be the most common cause of death from brucellosis. Although the optimal regimen has not been established, successful treatment usually requires valve replacement and prolonged combination antibiotic treatment (e.g., at least 6 weeks before surgery and at least 6 months after).

  • Central nervous system (CNS) disease can occur, including meningitis, meningoencephalitis, cerebral abscess, epidural abscess, and cerebral vasculitis. Cerebrospinal fluid (CSF) examination usually reveals a lymphocytic pleocytosis, elevated protein, and normal or low glucose.

How should I identify the organism?

  • Definitive diagnosis requires the isolation of the organism from blood or infected tissues, although sensitivity is suboptimal. Brucella spp. grow relatively slowly, generally requiring 7-21 days to appear using classic biphasic blood cultures. Lysis centrifugation and newer automated technologies detect organisms more quickly and with higher sensitivity. Bone marrow cultures may be more sensitive in patients with prolonged symptoms but are invasive and infrequently performed.

  • Brucella spp. are small, Gram-negative coccobacilli.

  • Whenever cultivation of Brucella spp. from blood, bone marrow, or other tissues is attempted, it is essential to notify the microbiology laboratory of the diagnostic suspicion, both to maximize yield and to alert the lab to take appropriate precautions to prevent transmission.

    Standard, biphasic or lysis-centrifugation blood culture systems may be used. Suspicious blood cultures should be subcultured to sheep blood agar, chocolate agar, and MacConkey or EMB agar plates, incubated at 35°C with 5-10% CO2.

    Colonies are smooth and convex, non-pigmented and non-hemolytic.

    Colonies are positive for oxidase, catalase and urea (B. canis may be oxidase-variable)

    Usually grows in 2-4 days using the BACTEC 9240 system. Punctate colonies on sheep blood agar plates usually by 48 hours.

    Cultures are relatively insensitive; therefore, serologic testing usually is also performed.

  • Serology is commonly used to diagnose brucellosis and is generally more sensitive than cultures. Most available assays detect antibodies against the smooth lipopolysaccharide (S-LPS) of the outer membrane. Titers of agglutinins should decrease after successful treatment.

  • Polymerase chain reaction (PCR) assays for Brucella spp. have been developed, but their role in clinical care has not been defined.

How does this organism cause disease?

  • Brucella spp. enter hosts via ingestion, inhalation, or inoculation through mucous membranes or non-intact skin. The bacteria are taken up by, and multiply within, phagocytic cells of the reticuloendothelial system and are able to resist intracellular killing. The virulence factors conferring the capacity for cell entry and intra-phagocytic survival and propagation are not well understood, although the smooth lipopolysaccharides of the outer membrane appear to play a key role in evading host defenses.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

“Sentinel laboratory guidelines for suspected agents of bioterrorism: species”.

Ariza, J, Bosch, J, Gudiol, F. “Relevance of in vitro antimicrobial susceptibility of to relapse rate in human brucellosis”. Antimicrob Agents Chemother. vol. 30. 1986. pp. 958-60. (In the context of a clinical trial of tetracycline/streptomycin, doxycycline/streptomycin and doxycycline/rifampin, pre-treatment minimum inhibitory concentration (MIC) of the drugs given did not predict the risk of relapse, and the MICs of relapse-associated isolates did not differ significantly from pre-treatment.)

Ariza, J, Bosilkovski, M, Cascio, A. “Perspectives for the treatment of Brucellosis in the 21st century: the Ioannina recommendations”. PLoS Med. vol. 4. 2007. pp. e317(Expert panel recommendations for the treatment of uncomplicated Brucellosis. Doxycycline/gentamicin regarded as "gold standard" [good evidence, high quality], doxycycline/rifampin as slightly inferior but more convenient [good evidence, high quality], doxycycline/gentamicin as the preferred alternative [moderate evidence, high quality]. Ofloxacin and ciprofloxacin recommended only as second or third agents in regimens containing doxycycline [poor evidence]. Trimethoprim-sulfamethoxazole recommended only as the third drug of a combination regimen [poor evidence].)

Cascio, A, Scarlata, A, Giordano, S. “Treatment of human brucellosis with rifampin plus minocycline”. J Chemother. vol. 15. 2003. pp. 248-52. (This is a retrospective review of 239 adults and children treated with a 3-week course of oral minocycline and intravenous rifampin. 100% response, less than 2% relapse.)

“Laboratory-acquired Brucellosis—Indiana and Minnesota, 2006”. MMWR. vol. 57. 2008. pp. 39-42. (This source includes recommendations for post-exposure prophylaxis and serologic monitoring in exposed laboratory workers.)

Franco, MP, Mulder, M, Gilman, RH, Smits, HL. “Human brucellosis”. Lancet Infect Dis. vol. 7. 2007. pp. 775-786. (This is a comprehensive review article.)

Moreno, S, Ariza, J, Espinosa, FJ. “Brucellosis in patients infected with the human immunodeficiency virus”. Eur J Clin Microbiol Infect Dis. vol. 17. 1998. pp. 319-26. (This is a clinical presentation similar to those uninfected with HIV, although only 12 patients are described in this study.)

Sasmazel, A, Baysal, A, Fedakar, A. “Treatment of Brucella endocarditis: 15 years of clinical and surgical experience”. Ann Thorac Surg. vol. 89. 2010. pp. 1432-6. (This is a retrospective analysis of 13 cases over 15 years at a specialty care hospital in Istanbul. All cases involved the aortic and/or mitral valve, and, in 2 cases, prosthetic valves. All patients received triple antibiotic therapy [mostly doxycycline/tetracycline plus rifampin plus streptomycin or trimethoprim-sulfamethoxazole]. Ten patients underwent elective valve replacement surgery after 6 weeks of antibiotics, another two patients required urgent valve replacement for heart failure. The duration of post-operative antibiotic therapy was guided by agglutination titers, usually several months. Mean follow-up was 95 months (range, 10-184 months); two patients died, but more than 10 years after surgery [stroke, congestive heart failure]. One patient had endocarditis of his prosthetic mitral valve, refused surgery, and had a good outcome after 10 months of antibiotics.)

Skalsky, K, Yahav, D, Bishara, J. “Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials”. BMJ. vol. 336. 2008. pp. 701-4. (This source included 30 trials. The authors concluded that first line regimens should be doxycycline for 6 weeks plus rifampin for 6 weeks plus gentamicin for 2 weeks OR doxycycline for 6 weeks plus gentamicin for 2 weeks. Doxycycline for 6 weeks plus streptomycin for 2 weeks was considered the first alternative. Recommended second-line regimens were doxycycline for 6 weeks plus rifampin for 6 weeks OR tetracycline [less convenient than doxycycline] plus gentamicin/streptomycin for 2 weeks. Trimethoprim-sulfamethoxazole plus either doxycycline or rifampin, both for 6 weeks, was considered an optional regimen poorly supported by evidence. Regimens not recommended included any monotherapy, any regimen for less than 30 days, and fluoroquinolone plus either rifampin or doxycycline.)

Solera, J. “Update on brucellosis: therapeutic challenges”. Int J Antimicrob Agents. vol. 36S. 2010. pp. S18-S20. (This is a review article focusing on challenging scenarios: pregnancy [rifampin for 45 days with or without trimethoprim-sulfamethoxazole recommended, avoiding the latter before week 13 or after week 36], children under age 8 [1 week of gentamicin plus either rifampin or trimethoprim-sulfamethoxazole for 45 days], resource limited settings [monotherapy with doxycycline for 6-8 weeks acceptable if low risk for relapse]).

Solera, J, Martinez-Alfaro, E, Espinosa, A. “Multivariate model for predicting relapse in human brucellosis”. J Infect. vol. 36. 1998. pp. 85-92. (Independent predictors of relapse were baseline T greater than 38.3°C, positive culture at baseline, and duration of symptoms before treatment less than 10 days.)

Solis Garcia del, Pozo, Solera, J. “Systematic review and meta-analysis of randomized clinical trials in the treatment of human brucellosis”. PLoS ONE. vol. 7. 2012. pp. e32090(Included 22 trials of treatment of uncomplicated brucellosis published since 1985. The authors concluded that the most effective regimen is doxycyline for 45 days plus either streptomycin for 14 days or gentamicin for 7 days, and recommended doxycyline plus rifampin as the first alternative. In contrast to the meta-analysis of Skalsky et al. 2008, the authors did not reject fluoroquinolone-containing regimens, citing them as alternatives meriting further study; did not dismiss monotherapy with doxycycline; and did not find sufficient evidence to recommend triple therapy [doxycycline, rifampin, plus an aminoglycoside] for uncomplicated brucellosis.)