Approach

The mainstay of treatment includes combinations of antibiotics to cure symptoms and prevent relapse. Treatment adherence is the cornerstone of a successful outcome, as relapse is largely due to poor antibiotic compliance, and should be encouraged at every opportunity.

Uncomplicated disease

Brucellosis is considered uncomplicated if there are acute non-specific features in the absence of focal infection. Antibiotic therapy shortens the duration of illness and relieves symptoms.[75] Up to 30% of patients treated with monotherapy experience relapses, and therefore a combination of antibiotics is routinely recommended. However, relapse is not actually related to emergence of antimicrobial resistance but rather to poor antibiotic compliance, and usually occurs within 6 months of completion of therapy.[41][42][126]

The World Health Organization (WHO) recommends that adults and children ≥8 years of age should be treated with a tetracycline for 6 weeks (doxycycline is preferred due to its less frequent dose schedule and lower risk of adverse effects), plus either a parenteral aminoglycoside (streptomycin for 2-3 weeks or gentamicin for 7-10 days) or oral rifampicin for 6 weeks.[75] The US Centers for Disease Control and Prevention (CDC) recommend an oral regimen for uncomplicated disease (a tetracycline or trimethoprim/sulfamethoxazole plus rifampicin for a minimum of 6 weeks).[62]​​

Tetracyclines are generally contraindicated in children <8 years of age due to the risk of tooth discoloration and inhibition of bone growth. Therefore, tetracyclines can be replaced by trimethoprim/sulfamethoxazole in children <8 years of age. The WHO recommends trimethoprim/sulfamethoxazole for 6 weeks, plus either an aminoglycoside (streptomycin for 3 weeks or gentamicin for 7-10 days) or rifampicin for 6 weeks.[75] The CDC recommend an oral regimen for uncomplicated disease (trimethoprim/sulfamethoxazole plus rifampicin for 4-6 weeks).[62]​​

Tetracyclines are contraindicated in pregnant women. Optimum treatment of pregnant and breastfeeding women is based on anecdotal reports.[58] A 6-week course of oral rifampicin is generally recommended.[41][42][75] Rifampicin plus trimethoprim/sulfamethoxazole for 4 weeks is an acceptable alternative.[58] A specialist should be consulted for guidance on antibiotic selection in these patients.

Optimum regimens remain controversial, but the following principles are becoming clearer.[126][127][128][129][130]

  • Regimens containing an injectable aminoglycoside are superior to those with two oral agents, mainly in reducing subsequent relapse.

  • 6 weeks of oral therapy is superior to 4 weeks.

  • Fluoroquinolones are probably not suitable for inclusion in first-line regimens due to reduced efficacy compared with the above and are not usually recommended. However, a fluoroquinolone plus rifampicin is better tolerated than doxycycline plus rifampicin.

  • Triple-therapy regimens (including an aminoglycoside) are probably superior to double antimicrobial regimens and may be preferred in complicated disease.[126][127][128][129][131][132][133]

Regimens incorporating injectable drugs have the advantage that adherence can be confirmed due to daily attendance at a healthcare facility. However, disadvantages include the need for daily attendance at a healthcare facility (or inpatient management) and the possibility of irreversible 8th cranial nerve toxicity, which may occur late as an adverse effect of aminoglycoside administration.

Relapses are usually treated with the same regimen as initially used, as resistance to antimicrobials is rarely the cause. However, most clinicians would use a regimen containing an aminoglycoside for relapses, especially if an aminoglycoside had not been included in the initial regimen.

Complicated disease

Focal disease (orchitis, sacroiliitis, spondylitis, endocarditis, meningoencephalitis, focal brain or cranial nerve lesions) usually requires longer periods of treatment. Most treatment failures are associated with poor compliance, and, therefore, this is a major issue with prolonged courses of antibiotics. There is little evidence regarding optimum duration of treatment in cases of focal disease, but most authors favour triple antibiotic therapy for adults or adolescents, with an injectable aminoglycoside continued for 2 weeks combined with doxycycline and rifampicin, which are continued for at least 3-6 months.[41][42][75][126][127] Most patients with infective endocarditis end up needing valve replacement despite 6 months or more of antibiotic treatment.[5][41] There is evidence that early surgery improves mortality.[134]

In cases of neurological manifestations, streptomycin or gentamicin use is usually discouraged because of questionable ability of aminoglycosides to penetrate the cerebrospinal fluid and the potential for neurotoxicity, which may further complicate the clinical presentation.[135] Ceftriaxone or trimethoprim/sulfamethoxazole may be added as a third drug for better central nervous system penetration.[41][42][48][135][136][137]​ A triple antibiotic regimen is generally recommended for complicated infection, and courses may need to be prolonged for longer periods of time according to clinical and radiological response.[138]

In the absence of evidence (regarding treatment of focal disease with or without neurological manifestations), similar considerations may apply for children and should be evaluated on an individual basis for pregnant or breastfeeding women. Consultation with an infectious-diseases specialist is, therefore, advised before commencing treatment in pregnant or breastfeeding women and in children.

Relapses are usually treated with the same regimen as initially used, as resistance to antimicrobials is rarely the cause.

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