Gastrointestinal complications of brucellosis are relatively common. A diffuse granulomatous hepatitis is commonly seen in brucellosis due to abortus, although whether this is seen in melitensis infections is unclear. 19 In cases where the diagnosis is uncertain, a liver biopsy may afford an opportunity to culture the Brucella organism. Unusual gastrointestinal manifestations of brucellosis include peritonitis, pancreatitis, acute cholecystitis, and acute abdomen. 20–22B. suis, abortus, and melitensis have been reported as a cause of hepatic or splenic abscess. 23 A recent review of suppurative complications of brucellosis noted that patients with abscess could present years or decades after supposed resolution of their disease; in some patients, no previous diagnosis of brucellosis had ever been made. The authors noted that all of their patients had calcium deposits associated with the abscess which were visible on CT or ultrasound; this may imply that abscess formation is a late complication of chronic disease, not a manifestation of new infection. Diagnosis in these patients was complicated by the low rate of positive cultures (from either blood or abscess aspirate) and the relatively low antibody titers (by serum agglutination test). 24
Osteoarticular disease is the most common complication of brucellosis, with an estimated 20% to 30% of all cases having some evidence of an osteoarticular focus. Spondylitis and sacroiliitis are the classic forms of metastatic disease, but bursitis, tenosynovitis, enthesopathies, and arthritis (particularly of weight-bearing joints) are also seen. 25,26 Aspiration of joints is variably sensitive in culture; analysis of fluid usually demonstrates an exudative process, with leukocyte counts ranging from several hundreds to several thousands. 27B. melitensis has been reported as a cause of prosthetic joint infection, treated successfully with removal of hardware and prolonged antibiotic therapy;28 other reports suggest that hardware removal may not be absolutely necessary. 29 Osteomyelitis of the long bones is relatively unusual. Spinal disease most commonly occurs in the lumbar region, followed by cervical and thoracic lesions; multiple sites of spinal disease are not uncommon. Although most cases resolve favorably with prolonged antibiotic therapy, potentially devastating neurologic complications may ensue. A diagnosis of brucellar spondylitis is commonly made based on an elevated sedimentation rate and compatible nuclear medicine or magnetic resonance imaging, in conjunction with significantly elevated serological titers. 30 Compared with tuberculous spondylitis, brucellar spondylitis tends to have less-associated paraspinous inflammation and relatively preserved vertebral architecture. Surgical intervention is, thus, rarely required. 31
Endocarditis is an uncommon manifestation of brucellosis, but it is the most frequently fatal complication. 32 Surgery is considered mandatory if a cure is to be achieved, although cures with medical therapy alone have been reported in patients who have no evidence of congestive heart failure. 33,34 The optimal duration of antibiotic therapy is not well understood, but is probably at least several months.
Although fever, cough and dyspnea are frequently reported among patients with brucellosis, true pulmonary disease is uncommon. Brucella has been reported as a cause of chronic lymphocytic pleural effusions or empyemas. 35
Urinary tract infection per se is relatively rare, but a significant proportion of men with brucellosis will have an associated epididymo-orchitis. In comparison to acute epididymo-orchitis, brucellar epididymo-orchitis may present with a more gradual prodrome, a relatively normal urinalysis and classically undulant fever. 36 Prostatitis has been reported as a complication.
A syndrome of chronic fatigue has long been associated with brucellosis. 17 These patients frequently complain of diverse somatic symptoms, including depression, headaches, and incapacitating fatigue, in the absence of objective findings. A considerable number of these patients have a concomitant psychoneurosis and many have issues of secondary gain (usually relating to workers’ compensation).
Brucellosis infrequently involves the central nervous system (< 5–7% of all cases), but the consequences of neurobrucellosis can be severe. 37,38 Symptoms can develop at any stage, during acute or chronic disease, and may present as acute or chronic meningoencephalitis, polyradiculopathy, radiculitis, or acute demyelinating disease. 39–41 On rare occasions, neurologic symptoms may be the presenting complaint. Peripheral neuropathy alone is rarely associated with neurobrucellosis, although in some reports an 8th cranial nerve deficit is cited as being characteristic. Optic neuritis with papilledema has also been reported. 42 Some patients have experienced cerebral ischemia due to meningovascular disease (arteritis), similar to that seen in syphilis. In addition to these findings, there are reports of both brain abscess and chronic subdural empyema in patients with brucellosis. 43 All cases of CNS involvement appear to be complicated by meningitis at some point; however, for unclear reasons, <50% of patients with documented brucellar meningitis will have meningeal signs or symptoms (headache, stiff neck, etc). The CSF is characterized by a lymphocytic pleocytosis in most of cases, although the WBC count rarely exceeds 500. Hypoglycorrhachia is present in about 50% of cases, but the protein is invariably elevated. Bouza et al 44 state that from their experience, the Coombs test is the most reliable serologic test for the diagnosis of meningitis;45 others claim that the ELISA, performed on CSF, is the most sensitive. The organism itself (most commonly melitensis) will only rarely be cultured from spinal fluid. Treatment of meningitis usually reverses most neurologic deficits, although some patients have permanent sequelae, particularly if myelopathy is present.
Children with brucellosis have much the same clinical presentation as adults: fever, hepatosplenomegaly, and arthralgias predominate, although the symptoms may be milder. 46,47 Because of the association between brucellosis and spontaneous abortion in animals, there has always been concern as to whether pregnant women with brucellosis might have a higher risk of miscarriage. A recent study found that 46% of pregnant patients with brucellosis (diagnosed based on serum agglutinin tests and/or bacteremia) had spontaneous abortions; the risk appeared to be much higher in the first and second trimesters. 48 Antibiotic therapy was associated with a much-reduced rate of miscarriage. Little is published on the natural history of brucellosis in HIV-positive patients. However, it is not recognized as an opportunistic infection even in areas of high endemicity, and its clinical course, including response to therapy, seems similar to that in HIV-negative patients. 49 HIV does not seem to affect the clinical accuracy of anti-Brucella antibody detection (by ELISA). 50
The diagnosis of brucellosis should be entertained in any patient with chronic fever and a history of travel to the Middle East, Central or South America, or other endemic areas. It should be remembered that brucellosis is not an unusual disease in Spain, the Balkans, and the eastern Mediterranean. A compatible occupational history (veterinarians, sheep or goat herders, or abattoir workers) should also prompt consideration of brucellosis. Lastly, a significant number of patients with brucellosis-type symptoms should raise the suspicion of a local outbreak, most likely in relation to contaminated food but also potentially due to a bioterrorist attack.
Blood cultures have very variable sensitivity, anywhere from 53% to 90%. Traditionally, to rule out brucellosis, it was necessary to hold blood cultures for up to 30 days, performing blind subcultures on a periodic basis to maximize yield. Yagupsky 51 describes the various methods in use to isolate Brucella, and concludes by noting that automated systems (such as the BACTEC 9000 series systems) are capable of diagnosing over 95% of cultures within 7 days of incubation, without the need for subculturing. However, if cultures remain negative despite high clinical suspicion, it seems reasonable to continue to hold the blood culture bottles for the full 30 days, and perhaps perform weekly blind subculturing, incubating the subcultures in 10% CO2 environments.
In patients with negative blood cultures and a high clinical suspicion of brucellosis, bone marrow biopsy and culture is advisable, as it has a sensitivity in excess of 90%, and cultures may be positive even when the patient has been treated with antibiotics. 52 Bone marrow cultures also may become positive more rapidly than blood cultures, perhaps reflecting the higher inoculum of bacteria in reticuloendothelial cells of the bone marrow.
The traditional gold standard of diagnostic testing is the serum agglutination test (SAT), developed in 1897, which measures both IgG and IgM. The SAT uses a standardized reference strain of Brucella abortus 119, which will agglutinate in the presence of anti-abortus, melitensis, and suis antibodies. Young 53 has written an extensive review of the SAT, including pitfalls in its interpretation and comparison with other serological methods of diagnosis. Although IgM titers are the first to rise after infection with brucellosis, IgM paradoxically remains elevated longer than IgG; thus, measures of IgG are traditionally used to monitor effectiveness of therapy. Treatment of serum with 2-mercaptoethanol will cause the IgM antibodies to lose the ability to agglutinate. Thus, the 2-mercaptoethanol modification of the SAT allows the distinction between agglutination due to IgM and that due to IgG. An SAT titer of ≥1:160 is considered evidence of active brucellosis.
A number of phenomena can interfere with proper interpretation of the SAT. Very high titers of antibody will prevent agglutination, as the antibodies will be unable to cross-link due to saturation of all binding sites (the prozone phenomenon); this false-negative result can be avoided by routinely performing dilutions on all negative serum. Infections with other organisms, including cholera, tularemia, and Yersinia, can cause false-positive reactions. Finally, although Brucella canis is only rarely a human pathogen, it cannot be identified with the standard SAT; thus, canis infections require the use of specialized antigen from other strains of Brucella, usually ovis.
Other tests (microagglutination, direct fluorescent antibody, Rose Bengal agglutination test) have been developed to aid in the diagnosis of brucellosis, but none offers any particular advantage over the SAT. An indirect Coombs test has been developed to look for the presence of nonagglutinating anti-abortus antibody in patient’s serum; however, this phenomenon occurs only rarely, if ever, in patients with clinical disease. An ELISA has been developed, which is more sensitive in the detection of Brucella antibody than the SAT. Unfortunately, in the clinical setting, this may not be as advantageous as it seems, as the persistence of IgG and IgM may not correlate with true disease. Most clinicians specializing in the diagnosis and treatment of brucellosis rely on the SAT, using the Coombs test and ELISA primarily in the setting of a negative SAT from a patient with a high clinical likelihood of having brucellosis. 17 A highly sensitive and specific PCR assay has been developed and appears promising, 54,55 although not yet commercially available.
A not uncommon scenario is the patient who presents for evaluation with a “positive Brucella test” but without symptoms compatible with brucellosis. It is important to remember that persons exposed in the past to Brucella, or successfully treated for brucellosis, may have low-level positive SAT titers. Thus, the significance of the SAT should always be interpreted in the light of the pretest clinical likelihood of the patient having active disease (as manifested by signs and symptoms such as fever, hepatosplenomegaly, and so forth). Patients with nonspecific symptoms (such as chronic fatigue) and positive titers should not be treated with antibiotics, but should be carefully evaluated and followed over time with serial SAT titers.
As a rule, therapy with only one drug is contraindicated, as the rate of relapse is unacceptable with monotherapy. Doxycycline and streptomycin in combination are the traditional first line treatment of uncomplicated brucellosis, but streptomycin is difficult to obtain, and its use is frequently complicated by ototoxicity. In a trial attempting to find a less toxic substitute for streptomycin, doxycycline for 45 days plus 5 mg/kg once-daily gentamicin for the first 7 days, was shown to be effective (relapse rate of 5.9%) for uncomplicated brucellosis. However, 30 days of doxycycline in combination with 7 days of gentamicin was associated with a higher relapse rate. 56 Thirty-day courses of doxycycline may have an acceptably low relapse rate if combined with a longer course of aminoglycosides (2 to 3 weeks). 57 Gentamicin may be given either intravenously or intramuscularly.
The practical difficulties of administering parenteral antibiotics in underserved communities make an all-oral treatment regimen desirable. In 1986, the World Health Organization recommended the use of doxycycline in combination with rifampin for 6 weeks as the preferred treatment of adult acute brucellosis. A number of trials have looked at whether rifampin and doxycycline (both for 6 weeks) are comparable to streptomycin (14 days) plus doxycycline (6 weeks). 58–60 These trials show that the 2 treatment arms are roughly equivalent, although in 2 of the trials, the aminoglycoside arm had a slightly lesser relapse rate. Additionally, doxycycline plus an aminoglycoside may be somewhat more effective in the treatment of brucellar spondylitis. 61 Either regimen is superior to short-course therapy with doxycycline (21 days) with another agent. In an open randomized trial, Montejo et al 62 compared 6 different regimens for the treatment of uncomplicated brucellosis. Although there was no statistically significant difference between individual regimens, the 2 regimens including streptomycin (given for 14 days), when grouped together, had greater efficacy than the other 4.
If a rifampin-containing regimen is chosen, it is important to remember that many patients who are at risk for brucellosis are also at risk for tuberculosis, which may likewise present with chronic fevers, fatigue, and evidence of granulomatous disease on tissue specimens. Misdiagnosis of tuberculosis as brucellosis might lead to the inadvertent use of rifampin as monotherapy against Mycobacterium tuberculosis, a situation almost guaranteed to result in rifampin resistance.
Trimethoprim/sulfamethoxazole was thought for many years to be an ideal alternative antibiotic in the treatment of brucellosis, but a trial comparing monotherapy with tetracycline and streptomycin demonstrated unacceptably high rates of relapse. 63 There are relatively less data on the use of trimethoprim/sulfamethoxazole in combination therapy. Extending the duration of therapy (eg, 3 to 6 months) may reduce the rate of relapse. Likewise, azithromycin has proven disappointing; a trial of 21 days of azithromycin in combination with gentamicin showed a relapse rate of 30%. It is possible, however, that a longer duration of therapy might show an effect equivalent to that of combination therapy with tetracyclines. 64
Quinolone antibiotics are active in vitro, and should be highly effective in clinical disease, as these drugs have good intracellular penetration. However, clinical experience is relatively limited. Monotherapy with quinolones, as with other antibiotics, seems to be associated with an unacceptably high rate of relapse. 65,66 One small trial compared a 30-day course of ciprofloxacin (500 mg PO BID) plus rifampin with a 45-day course of doxycycline plus rifampin. This demonstrated comparable efficacy between the 2 arms, with no relapses. 67 Another trial used 6 weeks of ofloxacin plus rifampin in comparison with 6 weeks of doxycycline plus rifampin; again, equivalent efficacy was demonstrated, but with the important additional observation that gastric irritation was much less in the ofloxacin arm, a potentially important consideration in prolonged antibiotic therapy. 68
Patients with brucellar meningitis or osteomyelitis are generally treated for longer periods (eg, months, in the case of meningitis). Meningitis is generally treated with some combination of doxycycline, rifampin, and trimethoprim/sulfamethoxazole, as aminoglycosides do not penetrate well into the CNS. There is no evidence that intrathecal administration of antibiotics is beneficial. Bouza et al 44 advocate the use of steroids in complicated cases of brucellar meningitis, although there is no clear evidence of additional efficacy. Others have used steroids in the setting of arachnoiditis, spinal cord, or cranial nerve lesions. Brucellar endocarditis is generally treated with 3 or 4 agents, one of which is an aminoglycoside.
In the event of relapse, most patients respond to repeated courses of the same medications, but multiple courses may be required. An extensive search should be instituted for occult sites of infection, including endocarditis, hepatic or splenic abscesses, sacroiliitis or spondylitis, or meningitis. Relapses most commonly occur within the first 6 months after completion of therapy. 69 If a suppurative focus is identified, drainage (either percutaneous or surgical) is advisable in addition to prolonged antibiotic therapy.
Children with brucellosis may be treated with trimethoprim/sulfamethoxazole in combination with aminoglycosides and/or rifampin. Although tetracyclines are not approved for pediatric use in the United States, they have been used with success in the treatment of childhood brucellosis. In a large multicenter study of children with brucellosis, no difference was seen between 3-week and 8-week treatment courses with combination therapy; thus, the authors recommend that trimethoprim/sulfamethoxazole for 3 weeks, in combination with gentamicin for 5 days, be used. 70
Although antimicrobial resistance among Brucella isolates has been reported, it is not clear from the literature that there is a strong link between in vitro resistance and clinical failure. In vitro trimethoprim/sulfamethoxazole resistance is most commonly reported, although there are reports of rifampin and ciprofloxacin resistance as well. 71,72 One study comparing relapse rates of susceptible versus nonsusceptible B. melitensis isolates found no correlation between resistance and likelihood of relapse. 73 Resistance trends do not appear to be changing over time. Given the difficulties and dangers in performing antimicrobial susceptibility testing with Brucella, most clinicians elect to treat with standard first line regimens.
In summary, single-agent regimens are contraindicated; for optimal results, a dual-agent regimen for at least 6 weeks seems indicated for most cases of uncomplicated adult brucellosis. There may be a slightly lower relapse rate, however, with the use of doxycycline for 6 weeks and an aminoglycoside for the first 2 weeks. Complicated cases may require longer courses; in contrast, the relapse rate in children may be acceptably low after only 3 to 4 weeks of therapy. Deep-seated infection (hepatic abscess, empyema) may require surgical or other drainage in addition to prolonged antibiotics. In all cases, follow up for at least 6 months is indicated, as most relapses occur within this period. Risk factors for relapse include suboptimal therapy, bacteremia, and perhaps, also, the early institution of treatment (which may be due to decreased antigenic stimulation of the host immune response among such patients). Of note, a significant percentage of patients who relapse may not have fever, and their symptoms are frequently milder; thus, the clinician must maintain a high level of vigilance. PCR testing, if available, may be helpful in this setting.
The routine pasteurization of milk and milk products has been the single factor most responsible for the control of brucellosis in the United States. However, the importation of unpasteurized products from other countries does pose a potential risk to United States residents, a risk that may grow as international travel increases.
There is little data on the role of routine screening for Brucella in populations at risk. Use of the SAT as a screening test is complicated by the uncertain significance of a low positive titer in an asymptomatic person. However, in certain populations, particularly the medically underserved, it may be reasonable to screen family or other community members of brucellosis patients, as they may share the same risk factors and if sick may not spontaneously present for diagnosis and treatment. 74
Numerous attempts have been made to develop a killed Brucella vaccine for use in humans; however, to date, they have not gained widespread use, as long-lasting immunity does not develop. Live Brucella vaccine (using attenuated strains) is widely used in areas where brucellosis is common, such as the former Soviet Union. Due to the rarity of human brucellosis, Brucella vaccine is not routinely available in the United States. Diagnosis of Brucella infection after accidental inoculation with the RB51 vaccine is difficult, as the SAT will be negative; furthermore, the strain is resistant to rifampin in vitro. The MMWR has suggested postexposure prophylaxis with 21 days of twice daily doxycycline in the event of a needlestick exposure to RB51; the efficacy of this regimen has not been tested. 75
If clinicians suspect brucellosis, the laboratory should be notified so that it can take the maximal precautions available. Brucella should only be manipulated by trained laboratory personnel in biosafety level II cabinets (ie, HEPA filters on both incoming and outgoing air), ideally in a BSL-3 level laboratory. Furthermore, additional workup of Brucella (eg, strain typing or antimicrobial sensitivities) should probably only be done in public health laboratories accustomed to working with aerosolized pathogens, and cultures should be kept sealed when not in active use. In the event of an accidental exposure, it seems reasonable to screen all workers in the involved area for the presence of agglutinating antibodies and to treat presumptively all those who are positive, as treatment of latent disease may result in a milder course.
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