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1 BRUCELLOSIS Hakan Erdem ESCMID Postgraduate Training Course September 2014, Izmir

2 Presentation Plan The pathogen Epidemiology Transmission Diagnosis Clinical presentation Treatment Outcome HE-2

3 Aerobic The Pathogen Gram (-) coccobacillus Catalase-positive Non-motile Non-spore forming Intracellular reproducing HE-3

4 The Most Frequent Zoonosis Ancient disease Sheep, goat, cattle, swine Half a million cases annually Problematic in developing countries Bosilkovski M, et al. Natural history of brucellosis in an endemic region in different time periods. Acta Clin Croat 2009; 48(1): 41-6 Seleem MN, et al. Brucellosis: a re-emerging zoonosis. Vet Microbiol 2010; 140(3-4): HE-4

5 Mediterranean Balkans Middle East Persian Gulf Endemic Regions Central/South America Former Soviet countries Pappas G, et al. The new global map of human brucellosis. Lancet Infect Dis 2006; 6(2): HE-5

6 The Natural Reservoirs HE-6

7 Survival in Dairy Products Yoghurt, safe 30 days in ice cream 6 weeks at 4ºC in cream days in fresh cheese Safe to consume after 2-3 mos HE-7

8 The Bacterium Dies Boiling and pasteurization When the milk goes sour Heating Ionized radiation Disinfectants HE-8

9 Transmission HE-9

10 Diagnosis HE-10

11 Wide variability exists for ESR, CRP,WBC, and routine biochemical tests HE-11

12 Blood, bone marrow Culture The most suitable specimens Automated culture systems Improved recovery Usually within three days Even in the CSF Erdem H, et al. Diagnosis of chronic brucellar meningitis and meningoencephalitis: The results of Istanbul-2 study. Clinical Microbiology and Infection 2013; 19: E80 E86 Araj GF. Update on laboratory diagnosis of human brucellosis. International Journal of Antimicrobial Agents. 2010; 36 ; S12 S17, HE-12

13 Serology Serum agglutination test Reference technique Rose-Bengal slide test Rapid screening The Coombs antiglobulin test Immunocapture ELISA Araj GF. Update on laboratory diagnosis of human brucellosis. International Journal of Antimicrobial Agents. 2010; 36 ; S12 S17, HE-13

14 Molecular Tests Patients with negative serology Provides early recognition As early as 10 days after inoculation The outbreaks or relapses Colmenero JD, Queipo-Ortuño MI, Reguera JM, et al. Real time polymerase chain reaction: a new powerful tool for the diagnosis of neurobrucellosis. J Neurol Neurosurg Psychiatry. 2005;76(7): HE-14

15 Clinical Presentation Brucellosis is a great imitator HE-15

16 Start of The Disease Incubation 1-4 wks Acute or mostly chronic infection HE-16

17 Brucellosis is one of the leading causes of FUO Sipahi OR, et al. Pooled analysis of 857 published adult fever of unknown origin cases in Turkey between Med Sci Monit 2007; 13(7): CR Ali-Eldin FA, et al. Clinical spectrum of fever of unknown origin among adult Egyptian patients admitted to Ain Shams University Hospitals: a hospital based study. J Egypt Soc Parasitol 2011; 41(2):

18 B. melitensis,b. abortus,b. suis infections are reported to be similar HE-18

19 Frequent Complaints Fever Arthralgia Back Pain Fatigue Symptoms Other Complaints Sweating Malodorous Perspiration Lack of Appetite Myalgia Chills HE-19

20 Undulant Fever HE-20

21 Frequent Liver enlargement Splenomegaly Sacroiliitis Other Findings Other Peripheral arthritis Scrotal swelling Neck stiffness Lymphadenopathy HE-21

22 HE-22

23 Any focal involvement is seen in half of the patients HE-23

24 Ulu-Kilic A, Karakas A, Erdem H, et al. Update on Treatment Options for Spinal Brucellosis. Clinical Microbiology and Infection 2014;20(2):O75-82 HE-24

25 Osteoarticular Involvement Radiodiagnostics HE-25

26 Characteristic Pedro-Pons sign in spondylitis is noteworthy HE-26

27 Brucellosis and Liver Mild elevation to hepatitis Histopathology, reactive hepatitis Cholestasis Granulomatous forms, 5% Tuberculosis? Decompensation, cirrhosis if untreated Ozturk-Engin D, Erdem H, Gencer S, et al. Liver involvement in patients wıth brucellosis: The results of Marmara study. European Journal of Clinical Microbiology & Infectious Diseases. 2014;33(7): HE-27

28 1) Franco MP, Mulder M, Gilman RH, Smits HL. Human brucellosis. Lancet Infect Dis. 2007;7(12): ) Demiroğlu YZ, Turunç T, Karaca S, et al. Neurological involvement in brucellosis; clinical classification, treatment and results. Mikrobiyol Bul. 2011;45(3): HE-28

29 Chronic Meningoencehalitis Headache, fever, > half Meningeal irritation, 1/3 Sweating Weight loss Back pain Confusion Hepatomegaly Hypoesthesia Splenomegaly Gul HC, Erdem H, Bek S. Overview of neurobrucellosis: a pooled analysis of 187 cases. Int J Infect Dis ;13(6):e HE-29

30 Neurobrucellosis, Sequelae Erdem H, Ulu-Kilic A, Kilic S, et al. Efficacy and tolerability of antibiotic combinations in neurobrucellosis: results of the Istanbul study. Antimicrob Agents Chemother. 2012;56(3): HE-30

31 Genitourinary Involvement 5-10 % of cases Mostly males Epididymo-orchitis, males Pyelonephritis, females Simulates tumors or tbc Nephritis, with endocarditis Erdem H, Elaldi N, Ak O, Genitourinary brucellosis: results of a multicentric study. Clin Microbiol Infect May 16. doi: / HE-31

32 Scrotal pain and swelling with arthralgia, arthritis should alert for Brucellosis HE-32

33 Cardiovascular System HE-33

34 Endocarditis 1 % of all brucellosis cases Mitral, tricuspid Underlying valvular disorders, 60% Koruk ST, Erdem H, Koruk I, et al. Management of Brucella endocarditis: results of the Gulhane study. Int J Antimicrob Agents 2012; 40(2): HE-34

35 Endocarditis, Mortality 13 % despite treatment Pericardial effusion Congestive heart failure Koruk ST, Erdem H, Koruk I, et al. Management of Brucella endocarditis: results of the Gulhane study. Int J Antimicrob Agents 2012; 40(2): HE-35

36 Similar to Other CAPs Erdem H, Inan A, Elaldi N, and the study group. Respiratory system involvement in brucellosis: The results of the Kardelen study. Chest 2014;145(1):87-94.

37 Pulmonary Brucellosis 10% required ICU admission A mean of 4 days. All responded to standard therapy A benign disease Erdem H, Inan A, Elaldi N, and the study group. Respiratory system involvement in brucellosis: The results of the Kardelen study. Chest 2014;145(1): HE-37

38 Brucellosis in Pregnancy Complicates pregnancy Particularly in the first two trimesters HE-38

39 Complications in Pregnancy Intrauterine infection Fetal death Spontaneous abortion Premature delivery Low birth weight HE-39

40 Treatment Antimicrobials accumulating in the phagocytes Monotherapy is not recommended HE-40

41 Aminoglycoside Based Regimens Doxy 2x100 daily for 6 weeks Plus an aminoglicoside Streptomycin, 1 gr, 2-3 wks Gentamicin, 5 mg/kg, 7 days HE-41

42 Oral Regimen (6 weeks) Doxy 2x100 mg/day combined to Oral rifampin mg or 15 mg/kg HE-42

43 Drug Selection AG based regimens, superior Doxy+Rif, rather cheap Available in most countries HE-43

44 Relapses, 10-15% Antimicribial resistance is not a major issue The same combination can be used HE-44

45 Management of Neurobrucellosis

46 Neurobrucellosis, Treatment Ceftriaxone 1 mo, 2x2 gr/day Doxy+rif 4-5 mos After cessation of ceftriaxone Doxy+Rif Adding SXT, meaningless Erdem H, Ulu-Kilic A, Kilic S, et al. Efficacy and tolerability of antibiotic combinations in neurobrucellosis: results of the Istanbul study. Antimicrob Agents Chemother. 2012;56(3): HE-46

47 Mortality : Endocarditis Morbidity: Neurobrucellosis HE-47

48 Gul HC, Erdem H. Brucellosis (Brucella species) Mandell GL, Bennett JE, Dolin R, eds, Mandell, Douglas, and Bennett s principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone, 8th edition, 2015, 8th edition. HE-48

49 Thanks