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Table 1: Reporting Known Brucella spp. Human PathogensReporting Notification StatusDSATSelect AgentDesignationBrucella speciesBrucella melitensisSelect AgentBrucella suisIdentification(Form 4)24 hours7 daysFor a abortusExposure(Form 3)LRNNationallyNotifiableCondition7 days2 hours24 hours or 7 days7 days2 hours24 hours or 7 days7 days2 hours24 hours or 7 daysNot a Select AgentN/AN/A2 hours24 hours or 7 daysBrucella ceti, pinnipedialis Not a Select AgentN/AN/A2 hours24 hours or 7 daysBrucella canisCase Report FormHealth departments and providers are strongly encouraged to use the approved case report form to reportbrucellosis cases to the Bacterial Special Pathogens Branch. This mechanism will ensure improved collectionof standardized data needed to assess risk factors and trends associated with brucellosis, so that targetedpreventive strategies can be implemented. Patient identifiers such as full name, address, phone number,hospital name, and medical record number should not be included in forms sent to CDC. Instructions forcompletion and submission are included in pages 1 and 2 of the form.DIAGNOSTIC TESTINGCDC/CSTE Laboratory Criteria for Diagnosis1Definitive Culture and identification of Brucella spp. from clinical specimensEvidence of a four-fold or greater rise in Brucella antibody titer between acute and convalescent phaseserum specimens obtained greater than or equal to 2 weeks apartPresumptive Brucella total antibody titer of greater than or equal to 1:160 by standard tube agglutination test (SAT)or Brucella microagglutination test (BMAT) in one or more serum specimens obtained after onset ofsymptomsDetection of Brucella DNA in a clinical specimen by PCR assayNOTE: Evidence of Brucella antibodies by nonagglutination-based testsDOES NOT meet the current CDC/CSTE case definition for aPresumptive Diagnosis of brucellosis. However, ANY quantitative test can be used for confirmation ifthere is a four-fold or greater rise in Brucella antibody titer.Brucellosis Reference Guide: Exposures, Testing, and Prevention4

Testing Performed at CDCThe Zoonotic and Select Agent Laboratory (ZSAL) at CDC performs CLIA-approved Brucella spp. diagnostictesting on human and animal samples.Table 2: Diagnostic Testing Provided by onsCultureTissue, wholeblood, sera,plasmaGold standard; allowsfor genotypingmolecular epidemiologyRequires BSL-3See Appendix 1:Submission ofBrucella IsolatesLRN PCR(for suspectBT andresponse use)Environmentalsamples, swabs,powders, wholeblood, sera, tissueRapid detection; canbe used on isolates andclinical specimensRequires technical expertiseto perform assay; reagentsand equipment can becostly; optimal specimentype not clearSee Appendix 1:Submission ofBrucella IsolatesSeraCheap, assay ofchoice in acute noncomplicated cases; onlyequipment needed isreading apparatusMay not diagnose chronicor complicated cases;subjectiveSee Appendix 1:Submission of Serumfor Brucella SerologyMAT(serology)Not available forB. canis or RB51Results and Notification BMAT results take 2 to 3 weeks, depending on when your sample was received at CDC’s Zoonotic andSelect Agent Laboratory (ZSAL), which is part of the Bacterial Special Pathogens Branch (BSPB). Our labwill generally test your sample within 1 week; however, it can take longer to report results. Results will besent to your State Laboratory.After checking with your State Laboratory, you can contact ZSAL or the BSPB epidemiology team if resultsare not received within 2 to 3 weeks.PCR results from primary specimens can be obtained within 24 hours.Testing Performed Elsewhere CDC does not provide medical consultation on individual patients, and cannot comment on results fromlaboratory assays that we have not performed.We recommend that you consult both with an infectious disease specialist assigned to the patient and themedical director for the diagnostic laboratory that ran the tests for interpretation of results, as they havethe available parameters for the specific assay used.Brucellosis Reference Guide: Exposures, Testing, and Prevention5

Diagnostic DifficultiesWhile culture is the gold standard, Brucella spp. can be fastidious, slow growers. Culture from primaryspecimens may require up to 21 days of incubation. Bone marrow culture is more sensitive than blood;however, the invasiveness of the procedure should be considered. Persons with chronic infections are less likelyto be culture-positive.Agglutination is a confirmatory serological test to diagnose brucellosis. The standard tube agglutination test(SAT) is the reference method, of which BMAT is a modified format. Brucella-specific agglutination tests involve direct agglutination of bacterial antigens by specific antibodies.Agglutination tests detect antibodies of IgM, IgG, and IgA classes.IgM antibodies are predominant in acute infection but decline within weeks. Relapses are accompanied bytransient elevations of IgG and IgA antibodies but not IgM.PositiveBloodCulturesAcute ting IgGIgAAcute(up to 3 mo.)nonagglutinating IgASubacute(3 mo. - 1 yr)Chronic(1 yr. onward)Stage of BrucellosisFigure 1: Antibody Responses in Untreated Brucellosis.8IgM detection sensitivities using other EIA formats have been reported between 67% to 100% with limitedspecificity data.9, 10 Such tests are qualitative, making them difficult to interpret in a clinical setting, and mighthave different performance characteristics and utility when used in areas with low disease prevalence, such asthe United States. Results of EIA tests must be confirmed by a quantitative reference method such as BMAT.BMAT Testing DrawbacksCross-reactions and false-positive test results can occur in Brucella antibody tests, mainly with IgM.10The primary immunodeterminant and virulence factor for Brucella species is smooth lipopolysaccharide (S-LPS)on the outer cell membrane, which is antigenically similar to the lipopolysaccharide of other gram-negativerods. False-positive Brucella test results can be caused by cross-reactivity of antibodies to Escherichia coli O157,Francisella tularensis, Moraxella phenylpyruvica, Yersinia enterocolitica, certain Salmonella serotypes, and from personsvaccinated against Vibrio cholerae.BMAT tends to perform better for diagnosing acute cases rather than chronic cases.11 Additionally, BMAT isnot as useful in detecting chronic brucellosis cases or neurobrucellosis. In a suspected chronic case, an IgGELISA would be more informative.12Brucellosis Reference Guide: Exposures, Testing, and Prevention6

Treatment 13, 14The table below provides a summary of the Red Book treatment recommendations, as well as severalrecommended treatment documents. Information about post-exposure prophylaxis is provided below in thesection titled “Laboratory, Surgical, and Clinical Exposures.”Table 3: Brucellosis Treatment OptionsSubjectSummaryCombination therapy to decrease the incidence of relapse: Adults,Children 8 yearsOral doxycycline (2–4 mg/kg per day, maximum 200 mg/day, in 2 divided doses) or oraltetracycline (30–40 mg/kg per day, maximum 2 g/day, in 4 divided doses) -and- Rifampin (15–20 mg/kg per day, maximum 600–900 mg/day, in 1 or 2 divided doses). Recommended for a minimum of 6 weeks.Combination therapy with trimethoprim-sulfamethoxazole (TMP-SMZ) can be used iftetracyclines are contraindicated. Children 8 yearsPregnancyCombination therapy: consider adding rifampin. Consult physician for dosing or ifrifampin is contraindicated. Tetracyclines (such as doxycycline) should be avoided inchildren less than 8 years of age.Tetracyclines are contraindicated for pregnant patients. Consult obstetrician regardingspecific antimicrobial therapy instructions. Complicated Cases(endocarditis,meningitis,osteomyelitis, etc.)Oral TMP-SMZ (trimethoprim, 10 mg/kg per day, maximum 480 mg/day; and sulfamethoxazole,50 mg/kg per day, maximum 2.4 g/day) divided in 2 doses for 4 to 6 weeks. Streptomycin* or gentamicin for the first 14 days of therapy in addition to atetracycline for 6 weeks (or TMP-SMZ if tetracyclines are contraindicated).Rifampin can be used in combination with this regimen to decrease the rate of relapse.For life-threatening complications, such as meningitis or endocarditis, duration oftherapy often is extended for 4 to 6 months.Case-fatality rate is 1%.Surgical intervention should be considered in patients with complications such asdeep tissue abscesses.*May not be readily available in the U.S. Referencesfor TreatmentRecommendations Ariza J et al. 2007. Perspectives for the Treatment of Brucellosis in the 21st Century:The Ioannina Recommendations. PLoS Med. 4(12): e317. 71/journal.pmed.0040317Al-Tawfiq JA. 2008. Therapeutic options for human brucellosis. Expert Rev Anti InfectTher. 6(1): 109-120. http://www.ncbi.nlm.nih.gov/pubmed/18251668Solera J. 2010. Update on brucellosis: therapeutic challenges. Intl J Antimicrob Agent.36S, S18–S20. http://www.ncbi.nlm.nih.gov/pubmed/20692127Note: The B. abortus strain used in the RB51 vaccine was derived by selection in rifampin-enriched media and is resistant to rifampin in vitro.This strain is also resistant to penicillin. If infection is due to this vaccine strain, treatment should be determined accordingly (example:doxycycline and TMP/SMX in place of rifampin). Specifics on the regimen and dose should be established in consultation with the person’shealth care provider in case of contraindications to the aforementioned.Brucellosis Reference Guide: Exposures, Testing, and Prevention7

LABORATORY, SURGICAL, AND CLINICAL EXPOSURESLaboratory Exposures4, 15Once a potential exposure is recognized, the first task is to determine the activities performed that may haveled to the exposure. Then identify:1. who was in the laboratory during the suspected time(s) of exposure2. where they were in relation to the exposure3. what they did with the isolatesThe identified individuals should be assessed for exposure risk using the descriptions in Table 4.Table 4. Laboratory Risk Assessment and Post-Exposure Prophylaxis (PEP): Minimal (but not zero) RiskSpecimenhandlingRoutine clinicalspecimen (e.g.,blood, serum,cerebrospinalfluid)Exposure scenarioPEPFollow-up/monitoringPerson who manipulates a routineclinical specimen (e.g., blood, serum,cerebrospinal fluid) in a certified ClassII biosafety cabinet, with appropriatepersonal protective equipment (i.e.,gloves, gown, eye protection).N/APerson present in the lab while someonemanipulates a routine clinical specimen(e.g., blood, serum, cerebrospinal fluid)in a certified Class II biosafety cabinet,or on an open bench where manipulationdid not involve occurrence of aerosolgenerating events (e.g., centrifugingwithout sealed carriers, vortexing,sonicating, spillage/splashes).May consider symptom watch forfollowing scenarios: NoneEnriched material(e.g., a Brucellaisolate, positiveblood bottle)or reproductiveclinical specimen(e.g., amnioticfluid, placentalproducts)Person who manipulates enriched material(e.g., a Brucella isolate, positive bloodbottle) or reproductive clinical specimen(e.g., amniotic fluid, placental products)in a certified Class II biosafety cabinet,with appropriate personal protectiveequipment (i.e., gloves, gown, eyeprotection).Person present in the lab while someonemanipulates enriched material (e.g., aBrucella isolate, positive blood bottle)or reproductive clinical specimen (e.g.,amniotic fluid, placental products) ina certified Class II biosafety cabinet.Brucellosis Reference Guide: Exposures, Testing, and Prevention Person who manipulates a routineclinical specimen (e.g., blood,serum, cerebrospinal fluid) onan open bench with or withoutappropriate personal protectiveequipment (i.e., gloves, gown,eye protection), or in a certifiedClass II biosafety cabinet withoutappropriate personal protectiveequipment.Person present in the lab whilesomeone manipulates a routineclinical specimen (e.g., blood,serum, cerebrospinal fluid) onan open bench, resulting inoccurrence of aerosol-generatingevents (e.g., centrifuging withoutsealed carriers, vortexing,sonicating, spillage/splashes).8

Table 4. Laboratory Risk Assessment and Post-Exposure Prophylaxis (PEP): Low RiskSpecimenhandlingEnriched material(e.g., a Brucellaisolate, positiveblood bottle)or reproductiveclinical specimen(e.g., amnioticfluid, placentalproducts)Exposure scenarioPerson present in the lab at a distanceof greater than 5 feet from someonemanipulating enriched material (e.g., aBrucella isolate, positive blood bottle)or reproductive clinical specimen (e.g.,amniotic fluid, placental products),on an open bench, with no occurrenceof aerosol-generating events (e.g.,centrifuging without sealed carriers,vortexing, sonicating, spillage/splashes).Brucellosis Reference Guide: Exposures, Testing, and PreventionPEPMay consider ifimmunocompromisedor pregnant.Discuss with healthcare provider (HCP).Note: RB51 isresistant to rifampinin vitro, and thereforethis drug should notbe used for PEP ortreatment courses.Follow-up/monitoringRegular symptomwatch (e.g., weekly)and daily self-feverchecks through24 weeks postexposure, after lastknown exposure.Sequentialserologicalmonitoring at 0(baseline), 6, 12, 18,and 24 weeks postexposure, after lastknown exposure.Note: no serologicalmonitoringcurrently availablefor RB51 and B.canis exposures inhumans.9

Table 4. Laboratory Risk Assessment and Post-Exposure Prophylaxis (PEP): High RiskSpecimenhandlingRoutine clinicalspecimen (e.g.,blood, serum,cerebrospinalfluid)Exposure scenarioPEPPerson who manipulates a routine clinicalspecimen (e.g., blood, serum, cerebrospinalfluid), resulting in contact with broken skin ormucous membranes, regardless of workingin a certified Class II biosafety cabinet, withor without appropriate personal protectiveequipment (i.e., gloves, gown, eye protection).Doxycycline 100mgtwice daily, andrifampin 600 mg oncedaily, for three weeks.Person who manipulates (or is 5 feet fromsomeone manipulating) enriched material(e.g., a Brucella isolate, positive blood bottle)or reproductive clinical specimen (e.g.,amniotic fluid, placental products), outside ofa certified Class II biosafety cabinet.Enrichedmaterial (e.g., aBrucella isolate,positive bloodbottle) orreproductiveclinical specimen(e.g., amnioticfluid, placentalproducts)Person who manipulates enriched material(e.g., a Brucella isolate, positive blood bottle)or reproductive clinical specimen (e.g.,amniotic fluid, placental products), within acertified Class II biosafety cabinet, withoutappropriate personal protective equipment(i.e., gloves, gown, eye protection).All persons present during the occurrence ofaerosol-generating events (e.g., centrifugingwithout sealed carriers, vortexing, sonicating,spillage/splashes) with manipulation ofenriched material (e.g., a Brucella isolate,positive blood bottle) or reproductive clinicalspecimen (e.g., amniotic fluid, placentalproducts) on an open bench.For patients withcontraindicationsto doxycycline orrifampin: TMPSMZ, in addition to

Presumptive laboratory evidence, but without definitive laboratory evidence, of Brucella infection Confirmed—A clinically compatible illness with definitive laboratory evidence of Brucella infection Please refer to the CSTE Laboratory Criteria for Diagnosis section for specifications regarding "presumptive"