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Brucella Endocarditis in Persons Who Inject Drugs

Brucella Endocarditis in Persons Who Inject Drugs Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 1 1 1 John M. Cafardi, MD , Douglas Haas, MD , Thomas Lamarre, MD and Judith Feinberg, MD Working Brucella endocarditis in PWID Contact information: John M. Cafardi, MD* The Christ Hospital Department of Infectious Diseases MOB Suite A44 Cincinnati, OH 45219 (513) 585-2791 (T) (513) 585-3882 (F) john.cafardi@thechristhospital.com Judith Feinberg, MD** © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non- commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Department of Behavioral Medicine and Psychiatry Department of Medicine/Section of Infectious Diseases 930 Chestnut Ridge Road West Virginia University Morgantown, WV 26505 (304) 293-5861 (T) (304) 293-2710 (F) judith.feinberg@hsc.wvu.edu *corresponding author **alternate corresponding author Submitted December 27, 2019, revised February 7, 2020 JC, DH and TL evaluated the patients and directed the diagnostic evaluation. JF and JC prepared the manuscript and literature review. All authors discussed the results, contributed to and approved the final manuscript. The Christ Hospital, Cincinnati, OH USA West Virginia University, Morgantown, WV USA Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Abstract: We report two cases of infective endocarditis in injection drug users due to Brucella infection. While cardiac involvement is a frequent sequela of Brucellosis and endocarditis is often seen with injection drug use, Brucella endocarditis in persons who inject drugs without zoonotic exposure has not been reported to date. Key words: infective endocarditis, Brucella, injection drug use, culture negative endocarditis Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 In the last ten years, the United States has seen a dramatic increase in injection drug use and its associated infectious sequelae. These include HIV, hepatitis B and hepatitis C as well as suppurative complications, including endovascular and musculoskeletal infections. The rate of infective endocarditis, in particular, has risen dramatically, having increased from 6% between 2000 and 2008 to 12% in 2013 (1). Furthermore, endocarditis often serves as a sentinel marker for the introduction of injection drug use in a given area (2). Most cases of infective endocarditis associated with injection drug use are due to Staphylococcus aureus, however streptococci, enterococci, gram negative organisms and Candida spp. are also observed (3). Culture negative disease in this population, while uncommon and typically due to obtaining cultures following administration of antibiotics, has been reported and is most commonly due to infection with Bartonella spp. (4). Here, we present what is to our knowledge the first two cases of culture negative infective endocarditis due to Brucella in injection drug users without identifiable zoonotic exposures. Case 1: A 24-year old woman with a complicated medical history including injection heroin use, tricuspid valve replacement following endocarditis due to Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 methicillin susceptible Staphylococcus aureus and hepatitis C infection was admitted with fever. Multiple blood cultures obtained prior to antibiotic therapy were without growth and transesophageal echocardiography demonstrated a vegetation on the tricuspid prosthesis with associated regurgitation and stenosis. She was evaluated by cardiac surgery and surgical intervention was recommended but was deferred due to injection drug use while hospitalized. She was treated with empiric vancomycin, cefepime and levofloxacin and refused therapy with buprenorphine for opioid use disorder. She left the hospital against medical advice after 11 days. Over the next several months she intermittently presented to multiple facilities with dyspnea and lower extremity edema although repeatedly left against medical advice. Five months after her initial presentation she returned to our institution with ongoing complaints of dyspnea and edema; repeat echocardiogram demonstrated multiple vegetations on the prosthetic tricuspid valve as well as tricuspid stenosis and regurgitation. Cultures of blood obtained on admission for bacterial, fungal and acid-fast pathogens were without growth. Serologic testing for Bartonella henselae, Legionella pneumophilia and Coxiella burnettii were negative while serologic testing for Brucella spp at Quest Diagnostics (San Juan Capistrano, CA) demonstrated a positive IgM, negative IgG, and a positive serum agglutination test (SAT) at 1:640. The SAT was repeated two weeks after the initial test and was again positive with a titer of 1:320. Serologic and nucleic acid testing for HIV were negative while additional testing showed immunity to hepatitis B without evidence of prior infection, positive hepatitis C antibody and undetectable Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 hepatitis C RNA. Testing for Tropheryma whipplei, Histoplasma or Aspergillus was not performed. She reported living in urban areas in the Midwest and repeatedly denied any zoonotic exposures, including cats, dogs, sheep or goats as well as consumption of unpasteurized milk or cheeses. She denied any visits or periods of residence in rural areas or exposures to farm animals. She was unwilling to discuss her source of opioids or injection equipment despite repeated requests. Therapy for brucellosis with rifampin and doxycycline was initiated. She again refused buprenorphine therapy for opioid use disorder and was discharged on oral doxycycline and rifampin, as outpatient parenteral therapy with gentamicin was judged to be unacceptably high risk. She has followed up intermittently with cardiology, cardiac surgery and infectious diseases. At her most recent follow-up visit two months after discharge she reported ongoing adherence to doxycycline and rifampin although she has refused follow-up serologic testing. She has not returned for further visits. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Case 2: Approximately 8 months following the initial presentation of Case 1 and six months after her second admission, a 44-year old man with a history of injection drug use and chronic hepatitis C presented with several months of subjective fevers, malaise, night sweats, back pain, weight loss, and intermittent abdominal pain. Evaluation revealed anemia, thrombocytopenia and hepatosplenomegaly with enlargement of portocaval and porta hepatis lymph nodes. Transesophageal echocardiography demonstrated mitral valve vegetation with associated mitral regurgitation. Multiple sets of blood cultures obtained prior to initiation of antibiotics were negative. Testing for HIV, hepatitis B and syphilis was negative while infection with hepatitis C, genotype 3, was confirmed. Rheumatoid factor was elevated at 58 IU/ml while anti-nuclear antibody testing was negative. He was evaluated by Hematology and started on glucocorticoids for presumed autoimmune hemolytic anemia and thrombocytopenia. Vertebral MRI showed no evidence of osteomyelitis or discitis and CSF analysis revealed normal glucose and protein levels without pleocytosis. Serologic testing for Brucella species was performed at Quest Diagnostics (San Juan Capistrano, CA) and demonstrated positive IgM, negative IgG, and positive serum agglutination titer (SAT) at 1:320. Further testing for culture negative endocarditis, including Bartonella, Coxiella, Aspergillus, Histoplasma, Legionella or Tropheryma whipplei, was not performed. He reported living in urban areas in the Midwest and repeatedly denied any zoonotic exposures, including cats, dogs, sheep or goats. He denied any Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 visits or periods of residence in rural areas or exposures to farm animals as well as consumption of unpasteurized milk or cheeses. He was unwilling to discuss the source of his opioids or injection equipment despite repeated requests. Therapy with doxycycline, rifampin and gentamicin was initiated, however he left against medical advice after 10 days of antibiotic treatment. He was not considered a candidate for outpatient parenteral antibiotic therapy or cardiac surgery due to his poor compliance and ongoing injection drug use. He subsequently returned to the hospital after approximately 24 hours and was restarted on doxycycline, rifampin and gentamicin to complete an additional 7 days of aminoglycoside therapy. He was discharged to complete six weeks of doxycycline and rifampin as well as a prednisone taper and has since been lost to follow-up. Discussion Brucellosis is the most common zoonotic infection worldwide and is acquired by ingestion of contaminated food or contact with infected tissues (5). It is endemic in Western Europe, North and sub-Saharan Africa, Central and South America and the United States (6), with approximately 2.5 billion people living in regions where Brucella is endemic and a worldwide burden of disease of approximately 500,000 cases annually (7). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Brucellosis typically presents with non-specific symptoms, including fevers, malaise, arthralgia and night sweats. After this initial prodrome, focal disease with osteoarticular, genitourinary, neurologic or cardiovascular involvement develops in 30% to 90% of infected individuals (5). Endocarditis is a rare complication of systemic Brucella infection, occurring in 2-3% of cases, with fewer than 400 cases reported in the literature since 1966 (8), and no reported cases in which injection drug use was the sole risk factor for endovascular infection. Despite its rarity, infective endocarditis is responsible for 80% of the deaths due to brucellosis (9). To date, infective endocarditis due to Brucella has been exclusively reported in individuals with a clear history of exposure to animal sources. Definitive diagnosis requires isolation of Brucella species in culture of blood, body fluid or tissue samples or a four-fold increase in antibody titer, obtained two or more weeks apart while a presumptive diagnosis is made by isolation of Brucella DNA in a tissue sample or a SAT  1:160 in a symptomatic individual (10). The preferred treatment of brucellosis is six weeks of doxycycline with either three weeks of streptomycin, one week of gentamicin, or six weeks of rifampin. The treatment of Brucella infective endocarditis is complex and, due to the limited number of cases, poorly defined. In general, a combination of medical and surgical therapy is required for cure (11), although management via successful medical therapy alone has been reported (12). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 We believe these are the first cases of Brucella infective endocarditis associated with injection drug use without identifiable zoonotic risk factor. Although the possibility of false positive serologic testing or unidentified zoonotic exposure exists, we were unable to identify any zoonotic risk factor despite repeated inquiry. While attempts to determine the source of the drugs and/or injection equipment were unavailing, it is possible that there was a zoonotic source for these infections that occurred in the same area and during a narrow timeframe and that may have been connected to the source of the drugs and/or injection equipment. Given these cases, we suggest consideration of brucellosis when evaluating culture-negative infective endocarditis in persons who inject drugs. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 5U54GM104942-04 (Co-Investigator Feinberg) and the National Institute on Drug Abuse Award Number DA 2UG3DA044825-02 (P.I. Feinberg). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 References 1. Wurcel AG, Anderson JE, Chui KK, Skinner S, Knox TA, Snydman DR, et al. Increasing Infectious Endocarditis Admissions Among Young People Who Inject Drugs. Open Forum Infect Dis. 2016;3(3):ofw157. 2. Keeshin SW, Feinberg J. Endocarditis as a Marker for New Epidemics of Injection Drug Use. Am J Med Sci. 2016;352(6):609-14. 3. Mathew J, Addai T, Anand A, Morrobel A, Maheshwari P, Freels S. Clinical features, site of involvement, bacteriologic findings, and outcome of infective endocarditis in intravenous drug users. Arch Intern Med. 1995;155(15):1641-8. 4. Moss R, Munt B. Injection drug use and right sided endocarditis. Heart. 2003;89(5):577-81. 5. Pappas G, Akritidis N, Bosilkovski M, Tsianos E. Brucellosis. N Engl J Med. 2005;352(22):2325-36. 6. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis. 2006;6(2):91-9. 7. Jennings GJ, Hajjeh RA, Girgis FY, Fadeel MA, Maksoud MA, Wasfy MO, et al. Brucellosis as a cause of acute febrile illness in Egypt. Trans R Soc Trop Med Hyg. 2007;101(7):707-13. 8. Keshtkar-Jahromi M, Razavi SM, Gholamin S, Keshtkar-Jahromi M, Hossain M, Sajadi MM. Medical versus medical and surgical treatment for brucella endocarditis. Ann Thorac Surg. 2012;94(6):2141-6. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 9. Colmenero JD, Reguera JM, Martos F, Sanchez-De-Mora D, Delgado M, Causse M, et al. Complications associated with Brucella melitensis infection: a study of 530 cases. Medicine (Baltimore). 1996;75(4):195-211. 10. Prevention CfDCa. Brucellosis Reference Guide: Exposures, Testing and Prevention 2017 [Available from: https://www.cdc.gov/brucellosis/pdf/brucellosi-reference-guide.pdf. 11. Mert A, Kocak F, Ozaras R, Tabak F, Bilir M, Kucukuglu S, et al. The role of antibiotic treatment alone for the management of Brucella endocarditis in adults: a case report and literature review. Ann Thorac Cardiovasc Surg. 2002;8(6):381-5. 12. Fonseca JP, Pereiro T, Dos Santos DP, Correia JM, Capelo J, Carragoso A. Successful Management of Prosthetic Valve Brucella Endocarditis with Antibiotherapy Alone. Eur J Case Rep Intern Med. 2018;5(4):000808. Accepted Manuscript http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Brucella Endocarditis in Persons Who Inject Drugs

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© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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Abstract

Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 1 1 1 John M. Cafardi, MD , Douglas Haas, MD , Thomas Lamarre, MD and Judith Feinberg, MD Working Brucella endocarditis in PWID Contact information: John M. Cafardi, MD* The Christ Hospital Department of Infectious Diseases MOB Suite A44 Cincinnati, OH 45219 (513) 585-2791 (T) (513) 585-3882 (F) john.cafardi@thechristhospital.com Judith Feinberg, MD** © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non- commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Department of Behavioral Medicine and Psychiatry Department of Medicine/Section of Infectious Diseases 930 Chestnut Ridge Road West Virginia University Morgantown, WV 26505 (304) 293-5861 (T) (304) 293-2710 (F) judith.feinberg@hsc.wvu.edu *corresponding author **alternate corresponding author Submitted December 27, 2019, revised February 7, 2020 JC, DH and TL evaluated the patients and directed the diagnostic evaluation. JF and JC prepared the manuscript and literature review. All authors discussed the results, contributed to and approved the final manuscript. The Christ Hospital, Cincinnati, OH USA West Virginia University, Morgantown, WV USA Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Abstract: We report two cases of infective endocarditis in injection drug users due to Brucella infection. While cardiac involvement is a frequent sequela of Brucellosis and endocarditis is often seen with injection drug use, Brucella endocarditis in persons who inject drugs without zoonotic exposure has not been reported to date. Key words: infective endocarditis, Brucella, injection drug use, culture negative endocarditis Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 In the last ten years, the United States has seen a dramatic increase in injection drug use and its associated infectious sequelae. These include HIV, hepatitis B and hepatitis C as well as suppurative complications, including endovascular and musculoskeletal infections. The rate of infective endocarditis, in particular, has risen dramatically, having increased from 6% between 2000 and 2008 to 12% in 2013 (1). Furthermore, endocarditis often serves as a sentinel marker for the introduction of injection drug use in a given area (2). Most cases of infective endocarditis associated with injection drug use are due to Staphylococcus aureus, however streptococci, enterococci, gram negative organisms and Candida spp. are also observed (3). Culture negative disease in this population, while uncommon and typically due to obtaining cultures following administration of antibiotics, has been reported and is most commonly due to infection with Bartonella spp. (4). Here, we present what is to our knowledge the first two cases of culture negative infective endocarditis due to Brucella in injection drug users without identifiable zoonotic exposures. Case 1: A 24-year old woman with a complicated medical history including injection heroin use, tricuspid valve replacement following endocarditis due to Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 methicillin susceptible Staphylococcus aureus and hepatitis C infection was admitted with fever. Multiple blood cultures obtained prior to antibiotic therapy were without growth and transesophageal echocardiography demonstrated a vegetation on the tricuspid prosthesis with associated regurgitation and stenosis. She was evaluated by cardiac surgery and surgical intervention was recommended but was deferred due to injection drug use while hospitalized. She was treated with empiric vancomycin, cefepime and levofloxacin and refused therapy with buprenorphine for opioid use disorder. She left the hospital against medical advice after 11 days. Over the next several months she intermittently presented to multiple facilities with dyspnea and lower extremity edema although repeatedly left against medical advice. Five months after her initial presentation she returned to our institution with ongoing complaints of dyspnea and edema; repeat echocardiogram demonstrated multiple vegetations on the prosthetic tricuspid valve as well as tricuspid stenosis and regurgitation. Cultures of blood obtained on admission for bacterial, fungal and acid-fast pathogens were without growth. Serologic testing for Bartonella henselae, Legionella pneumophilia and Coxiella burnettii were negative while serologic testing for Brucella spp at Quest Diagnostics (San Juan Capistrano, CA) demonstrated a positive IgM, negative IgG, and a positive serum agglutination test (SAT) at 1:640. The SAT was repeated two weeks after the initial test and was again positive with a titer of 1:320. Serologic and nucleic acid testing for HIV were negative while additional testing showed immunity to hepatitis B without evidence of prior infection, positive hepatitis C antibody and undetectable Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 hepatitis C RNA. Testing for Tropheryma whipplei, Histoplasma or Aspergillus was not performed. She reported living in urban areas in the Midwest and repeatedly denied any zoonotic exposures, including cats, dogs, sheep or goats as well as consumption of unpasteurized milk or cheeses. She denied any visits or periods of residence in rural areas or exposures to farm animals. She was unwilling to discuss her source of opioids or injection equipment despite repeated requests. Therapy for brucellosis with rifampin and doxycycline was initiated. She again refused buprenorphine therapy for opioid use disorder and was discharged on oral doxycycline and rifampin, as outpatient parenteral therapy with gentamicin was judged to be unacceptably high risk. She has followed up intermittently with cardiology, cardiac surgery and infectious diseases. At her most recent follow-up visit two months after discharge she reported ongoing adherence to doxycycline and rifampin although she has refused follow-up serologic testing. She has not returned for further visits. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Case 2: Approximately 8 months following the initial presentation of Case 1 and six months after her second admission, a 44-year old man with a history of injection drug use and chronic hepatitis C presented with several months of subjective fevers, malaise, night sweats, back pain, weight loss, and intermittent abdominal pain. Evaluation revealed anemia, thrombocytopenia and hepatosplenomegaly with enlargement of portocaval and porta hepatis lymph nodes. Transesophageal echocardiography demonstrated mitral valve vegetation with associated mitral regurgitation. Multiple sets of blood cultures obtained prior to initiation of antibiotics were negative. Testing for HIV, hepatitis B and syphilis was negative while infection with hepatitis C, genotype 3, was confirmed. Rheumatoid factor was elevated at 58 IU/ml while anti-nuclear antibody testing was negative. He was evaluated by Hematology and started on glucocorticoids for presumed autoimmune hemolytic anemia and thrombocytopenia. Vertebral MRI showed no evidence of osteomyelitis or discitis and CSF analysis revealed normal glucose and protein levels without pleocytosis. Serologic testing for Brucella species was performed at Quest Diagnostics (San Juan Capistrano, CA) and demonstrated positive IgM, negative IgG, and positive serum agglutination titer (SAT) at 1:320. Further testing for culture negative endocarditis, including Bartonella, Coxiella, Aspergillus, Histoplasma, Legionella or Tropheryma whipplei, was not performed. He reported living in urban areas in the Midwest and repeatedly denied any zoonotic exposures, including cats, dogs, sheep or goats. He denied any Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 visits or periods of residence in rural areas or exposures to farm animals as well as consumption of unpasteurized milk or cheeses. He was unwilling to discuss the source of his opioids or injection equipment despite repeated requests. Therapy with doxycycline, rifampin and gentamicin was initiated, however he left against medical advice after 10 days of antibiotic treatment. He was not considered a candidate for outpatient parenteral antibiotic therapy or cardiac surgery due to his poor compliance and ongoing injection drug use. He subsequently returned to the hospital after approximately 24 hours and was restarted on doxycycline, rifampin and gentamicin to complete an additional 7 days of aminoglycoside therapy. He was discharged to complete six weeks of doxycycline and rifampin as well as a prednisone taper and has since been lost to follow-up. Discussion Brucellosis is the most common zoonotic infection worldwide and is acquired by ingestion of contaminated food or contact with infected tissues (5). It is endemic in Western Europe, North and sub-Saharan Africa, Central and South America and the United States (6), with approximately 2.5 billion people living in regions where Brucella is endemic and a worldwide burden of disease of approximately 500,000 cases annually (7). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Brucellosis typically presents with non-specific symptoms, including fevers, malaise, arthralgia and night sweats. After this initial prodrome, focal disease with osteoarticular, genitourinary, neurologic or cardiovascular involvement develops in 30% to 90% of infected individuals (5). Endocarditis is a rare complication of systemic Brucella infection, occurring in 2-3% of cases, with fewer than 400 cases reported in the literature since 1966 (8), and no reported cases in which injection drug use was the sole risk factor for endovascular infection. Despite its rarity, infective endocarditis is responsible for 80% of the deaths due to brucellosis (9). To date, infective endocarditis due to Brucella has been exclusively reported in individuals with a clear history of exposure to animal sources. Definitive diagnosis requires isolation of Brucella species in culture of blood, body fluid or tissue samples or a four-fold increase in antibody titer, obtained two or more weeks apart while a presumptive diagnosis is made by isolation of Brucella DNA in a tissue sample or a SAT  1:160 in a symptomatic individual (10). The preferred treatment of brucellosis is six weeks of doxycycline with either three weeks of streptomycin, one week of gentamicin, or six weeks of rifampin. The treatment of Brucella infective endocarditis is complex and, due to the limited number of cases, poorly defined. In general, a combination of medical and surgical therapy is required for cure (11), although management via successful medical therapy alone has been reported (12). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 We believe these are the first cases of Brucella infective endocarditis associated with injection drug use without identifiable zoonotic risk factor. Although the possibility of false positive serologic testing or unidentified zoonotic exposure exists, we were unable to identify any zoonotic risk factor despite repeated inquiry. While attempts to determine the source of the drugs and/or injection equipment were unavailing, it is possible that there was a zoonotic source for these infections that occurred in the same area and during a narrow timeframe and that may have been connected to the source of the drugs and/or injection equipment. Given these cases, we suggest consideration of brucellosis when evaluating culture-negative infective endocarditis in persons who inject drugs. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 5U54GM104942-04 (Co-Investigator Feinberg) and the National Institute on Drug Abuse Award Number DA 2UG3DA044825-02 (P.I. Feinberg). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 References 1. Wurcel AG, Anderson JE, Chui KK, Skinner S, Knox TA, Snydman DR, et al. Increasing Infectious Endocarditis Admissions Among Young People Who Inject Drugs. Open Forum Infect Dis. 2016;3(3):ofw157. 2. Keeshin SW, Feinberg J. Endocarditis as a Marker for New Epidemics of Injection Drug Use. Am J Med Sci. 2016;352(6):609-14. 3. Mathew J, Addai T, Anand A, Morrobel A, Maheshwari P, Freels S. Clinical features, site of involvement, bacteriologic findings, and outcome of infective endocarditis in intravenous drug users. Arch Intern Med. 1995;155(15):1641-8. 4. Moss R, Munt B. Injection drug use and right sided endocarditis. Heart. 2003;89(5):577-81. 5. Pappas G, Akritidis N, Bosilkovski M, Tsianos E. Brucellosis. N Engl J Med. 2005;352(22):2325-36. 6. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis. 2006;6(2):91-9. 7. Jennings GJ, Hajjeh RA, Girgis FY, Fadeel MA, Maksoud MA, Wasfy MO, et al. Brucellosis as a cause of acute febrile illness in Egypt. Trans R Soc Trop Med Hyg. 2007;101(7):707-13. 8. Keshtkar-Jahromi M, Razavi SM, Gholamin S, Keshtkar-Jahromi M, Hossain M, Sajadi MM. Medical versus medical and surgical treatment for brucella endocarditis. Ann Thorac Surg. 2012;94(6):2141-6. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa063/5739769 by guest on 05 March 2020 9. Colmenero JD, Reguera JM, Martos F, Sanchez-De-Mora D, Delgado M, Causse M, et al. Complications associated with Brucella melitensis infection: a study of 530 cases. Medicine (Baltimore). 1996;75(4):195-211. 10. Prevention CfDCa. Brucellosis Reference Guide: Exposures, Testing and Prevention 2017 [Available from: https://www.cdc.gov/brucellosis/pdf/brucellosi-reference-guide.pdf. 11. Mert A, Kocak F, Ozaras R, Tabak F, Bilir M, Kucukuglu S, et al. The role of antibiotic treatment alone for the management of Brucella endocarditis in adults: a case report and literature review. Ann Thorac Cardiovasc Surg. 2002;8(6):381-5. 12. Fonseca JP, Pereiro T, Dos Santos DP, Correia JM, Capelo J, Carragoso A. Successful Management of Prosthetic Valve Brucella Endocarditis with Antibiotherapy Alone. Eur J Case Rep Intern Med. 2018;5(4):000808. Accepted Manuscript

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Published: Apr 1, 2020

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