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Background: The 2023 Duke-International Society of Cardiovascular Infectious Diseases (ISCVID) criteria for infective endocarditis (IE) were introduced to improve classification of IE for research and clinical purposes. External validation studies are required., Methods: We studied consecutive patients with suspected IE referred to the IE team of Amsterdam University Medical Center (from October 2016 to March 2021). An international expert panel independently reviewed case summaries and assigned a final diagnosis of "IE" or "not IE," which served as the reference standard, to which the "definite" Duke-ISCVID classifications were compared. We also evaluated accuracy when excluding cardiac surgical and pathologic data ("clinical" criteria). Finally, we compared the 2023 Duke-ISCVID with the 2000 modified Duke criteria and the 2015 and 2023 European Society of Cardiology (ESC) criteria., Results: A total of 595 consecutive patients with suspected IE were included: 399 (67%) were adjudicated as having IE; 111 (19%) had prosthetic valve IE, and 48 (8%) had a cardiac implantable electronic device IE. The 2023 Duke-ISCVID criteria were more sensitive than either the modified Duke or 2015 ESC criteria (84.2% vs 74.9% and 80%, respectively; P < .001) without significant loss of specificity. The 2023 Duke-ISCVID criteria were similarly sensitive but more specific than the 2023 ESC criteria (94% vs 82%; P < .001). The same pattern was seen for the clinical criteria (excluding surgical/pathologic results). New modifications in the 2023 Duke-ISCVID criteria related to "major microbiological" and "imaging" criteria had the most impact., Conclusions: The 2023 Duke-ISCVID criteria represent a significant advance in the diagnostic classification of patients with suspected IE., Competing Interests: Potential conflicts of interest. L. M. B. reports consulting fees from Boston Scientific and Roivant Sciences; UpToDate royalty payments, paid to the author (authorship duties); and consultant duties, paid to the author, from Botanix Pharmaceuticals. A. S. B. reports research grants from the National Institute of Allergy and Infectious Diseases, Akagera Medicines, ContraFect, and Riovant Pharmaceuticals and payment for expert testimony from Harrison, Skemp & Sleik and Patrick J. Higgins, Law. E. D. M. reports research funding for his institution from MSD, Pfizer, Angelini, Infectopharm, and Advanz Pharma; grants or contracts from Menarini and Shionogi; and personal fees, fees for participation on advisory boards, or speaker honoraria from Roche, Genentech, Pfizer, MSD, Angelini, Advanz Pharma, Bio-Merieux, Shionogi, Menarini, AbbVie, Sanofi-Aventis, Medtronic, Trx, and DiaSorin; and a role as secretary of the International Society for Cardiovascular Infectious Diseases. T. L. H. reports grants or contracts from Karius (adjudication committee) and the National Institutes of Health; royalties or licenses from UpToDate; consulting fees from Aridis, Pfizer, Lysovant, and Affinivax; and participation on a data and safety monitoring board for a platform trial for the SNAP Trial and on an advisory board for Basilea. A. W. K. reports a research grant from Karius (investigator-initiated grant to study plasma cell-free pathogen DNA in patients with endocarditis or infected cardiac implantable electronic device (CIEDs) having the intravascular site of infection removed); honoraria from Pfizer for service on a data and safety monitoring board; personal fees for consulting from Debio Pharma; royalties from UpToDate for chapters on infected CIEDs and prosthetic valve endocarditis; ownership of stock options in Pfizer, AbbVie, and Johnson & Johnson; and payment or honoraria for a chapter on infective endocarditis from McGraw-Hill education. J. M. M. reports consulting honoraria and/or research grants from Angelini, Contrafect, Cubist, Genentech, Gilead Sciences, Jansen, Lysovant, Medtronic, MSD, Novartis, Pfizer, and ViiV Healthcare, outside the submitted work. P. M. reports support for meeting fees and travel as a member of the organizing committee (no direct payment) for the 16th International Society for Cardiovascular Infectious Diseases Symposium in Barcelona, Spain, 18–22 June 2022. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, 374 Achaogen, Affinium, The Medicines Company, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer, grants from the National Institutes of Health, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for service as the associate editor of Clinical Infectious Diseases; a sepsis diagnostics patent pending; and support from Contrafect for presenting phase 2 data at the 2019 European Congress of Clinical Microbiology and Infectious Diseases. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The microbiology, epidemiology, diagnostics, and treatment of infective endocarditis (IE) have changed significantly since the Duke Criteria were published in 1994 and modified in 2000. The International Society for Cardiovascular Infectious Diseases (ISCVID) convened a multidisciplinary Working Group to update the diagnostic criteria for IE. The resulting 2023 Duke-ISCVID IE Criteria propose significant changes, including new microbiology diagnostics (enzyme immunoassay for Bartonella species, polymerase chain reaction, amplicon/metagenomic sequencing, in situ hybridization), imaging (positron emission computed tomography with 18F-fluorodeoxyglucose, cardiac computed tomography), and inclusion of intraoperative inspection as a new Major Clinical Criterion. The list of "typical" microorganisms causing IE was expanded and includes pathogens to be considered as typical only in the presence of intracardiac prostheses. The requirements for timing and separate venipunctures for blood cultures were removed. Last, additional predisposing conditions (transcatheter valve implants, endovascular cardiac implantable electronic devices, prior IE) were clarified. These diagnostic criteria should be updated periodically by making the Duke-ISCVID Criteria available online as a "Living Document.", Competing Interests: Potential conflicts of interest. V. G. F. reports personal consulting fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, and Valanbio; Akagera, Aridis, Roche, and Pfizer (paid to author); grants from the National Institutes of Health, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, and Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for his service as Associate Editor of Clinical Infectious Diseases; travel support from Contrafect to 2019 ECCMID; and a sepsis diagnostics patent pending. D. T. D. reports payment for expert testimony for 2 worker's compensation claims and 1 medico-legal claim (paid to author); membership on the ISCVID Council; stock in Becton Dickinson Company, Moderna, Merck, and Illumina; and stock options in Magnolia Medical, Inc. A. S. B. reports research grants from the National Institute of Allergy and Infectious Diseases, Akagera Medicines, ContraFect Corporation, and Riovant Pharmaceuticals; and payment for expert testimony from Hanson, Skemp & Sleik, La Crosse, Wisconsin. A. D. reports research grant support from the Lundbeck Foundation (unrelated to this work). L. D. reports payment for expert testimony in inferior vena cava filter litigation for Cordis, Braun, and Bard; and stock or stock options from Asensus Surgical (Transenterix). E. D. M. reports research funding for his institution from MSD, Pfizer, Angelini, Infectopharm, Advanz pharma, Menarini, and Shionogi; and personal consulting fees from Genentech, Roche, Angelini, Trx, Medtronic, and Abbvie; fees to participate in advisory boards for Pfizer; role as Secretary of the International Society for Cardiovascular Infectious Diseases; speaker's honoraria from Pfizer, Shionogi, and Advanz pharma; as well as personal fees from Bio-Merieux, Sanofi-Aventis, and DiaSorin. X. D. reports grants or contracts with Pfizer and Sanofi Pasteur (paid to institution). All other authors report no potential conflicts. E. F. reports independent research grants for valvular heart diseases from the Novo Nordisk Foundation. M. M. H. reports payment from Up To Date (paid to author) and participation on an Advisory Board for Takeda Island. A. W. K. reports a research grant from Karius; honoraria from Pfizer, Data Safety Monitoring Board; personal fees consulting from Debio Pharma; royalties from Up To Date; common stock in Pfizer, Abbvie, and Johnson and Johnson; and participation in Winter Course in Infectious Diseases. C. A. M. reports personal fees from Edwards Lifesciences (Clinical Events Committee) and Cytosorbents Corp. S. D. P. reports event payment from Agilent and Cariomyopathy UK (paid to institution); role as councilor for Association for European Cardiovascular Pathology (unpaid). F. V. reports research funding outside the scope of the present study by bioMérieux; 2 patents pending in antimicrobial resistance detection (PCT/EP2022/069857 July 2022; FR 2200268 Jan 2022); and shares in Weezion. J. M. M. reports consulting honoraria and/or research grants from Angelini, Contrafect, Cubist, Genentech, Gilead Sciences, Jansen, Lysovant, Medtronic, MSD, Novartis, Pfizer, and ViiV Healthcare, outside the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mycobacterial infection-related morbidity and mortality in patients following cardiopulmonary bypass surgery is high and there is a growing need for a consensus-based expert opinion to provide international guidance for diagnosing, preventing and treating in these patients. In this document the International Society for Cardiovascular Infectious Diseases (ISCVID) covers aspects of prevention (field of hospital epidemiology), clinical management (infectious disease specialists, cardiac surgeons, ophthalmologists, others), laboratory diagnostics (microbiologists, molecular diagnostics), device management (perfusionists, cardiac surgeons) and public health aspects., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for the prevention of infective endocarditis, which were last published in 1997., Methods: and, Results: A writing group appointed by the AHA for their expertise in prevention and treatment of infective endocarditis (IE) with liaison members representing the American Dental Association, the Infectious Diseases Society of America and the American Academy of Pediatrics. The writing group reviewed input from national and international experts on IE. The recommendations in this document reflect analyses of relevant literature regarding procedure-related bacteremia and IE; in vitro susceptibility data of the most common microorganisms, which cause IE; results of prophylactic studies in animal models of experimental endocarditis; and retrospective and prospective studies of prevention of IE. MEDLINE database searches from 1950 through 2006 were done for English language articles using the following search terms: endocarditis, infective endocarditis, prophylaxis, prevention, antibiotic, antimicrobial, pathogens, organisms, dental, gastrointestinal, genitourinary, streptococcus, enterococcus, staphylococcus, respiratory, dental surgery, pathogenesis, vaccine, immunization and bacteremia. The reference lists of the identified articles were also searched. The writing group also searched the AHA online library. The American College of Cardiology/AHA classification of recommendations and levels of evidence for practice guidelines were used. The article subsequently was reviewed by outside experts not affiliated with the writing group and by the AHA Science Advisory and Coordinating Committee., Conclusions: The major changes in the updated recommendations include the following. (1) The committee concluded that only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100 percent effective. (2) IE prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE. (3) For patients with these underlying cardiac conditions, prophylaxis is recommended for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. (4) Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of IE. (5) Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. These changes are intended to define more clearly when IE prophylaxis is or is not recommended and to provide more uniform and consistent global recommendations.

Background: The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for the prevention of infective endocarditis that were last published in 1997., Methods and Results: A writing group was appointed by the AHA for their expertise in prevention and treatment of infective endocarditis, with liaison members representing the American Dental Association, the Infectious Diseases Society of America, and the American Academy of Pediatrics. The writing group reviewed input from national and international experts on infective endocarditis. The recommendations in this document reflect analyses of relevant literature regarding procedure-related bacteremia and infective endocarditis, in vitro susceptibility data of the most common microorganisms that cause infective endocarditis, results of prophylactic studies in animal models of experimental endocarditis, and retrospective and prospective studies of prevention of infective endocarditis. MEDLINE database searches from 1950 to 2006 were done for English-language papers using the following search terms: endocarditis, infective endocarditis, prophylaxis, prevention, antibiotic, antimicrobial, pathogens, organisms, dental, gastrointestinal, genitourinary, streptococcus, enterococcus, staphylococcus, respiratory, dental surgery, pathogenesis, vaccine, immunization, and bacteremia. The reference lists of the identified papers were also searched. We also searched the AHA online library. The American College of Cardiology/AHA classification of recommendations and levels of evidence for practice guidelines were used. The paper was subsequently reviewed by outside experts not affiliated with the writing group and by the AHA Science Advisory and Coordinating Committee., Conclusions: The major changes in the updated recommendations include the following: (1) The Committee concluded that only an extremely small number of cases of infective endocarditis might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100% effective. (2) Infective endocarditis prophylaxis for dental procedures is reasonable only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis. (3) For patients with these underlying cardiac conditions, prophylaxis is reasonable for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. (4) Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of infective endocarditis. (5) Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. These changes are intended to define more clearly when infective endocarditis prophylaxis is or is not recommended and to provide more uniform and consistent global recommendations.

Background: Optimal resource allocation for antiretroviral treatment (ART) in developing countries requires assessment of different strategies for drug treatment and laboratory monitoring., Objectives: To compare costs and outcomes for 10 000 simulated HIV-infected patients followed every 6 months for 10 years in a limited-resource setting., Method: Five nested strategies, with and without the availability of a second-line treatment regimen, were simulated: (a) no ART (NO ART); (b) with ART but without any laboratory markers of HIV other than positive serology (ART ONLY); (c) ART plus total lymphocyte count (TLC); (d) ART plus CD4 cell counts (CD4); and (e) ART plus CD4 cell count plus viral load measurement (VL). Baseline prices of CD4 cell count and viral load measurements were $5.00 and $25.00 per test, respectively., Results: With no second-line treatment available, treating 10 000 patients with ART ONLY compared with NO ART would cost $14.49 million [95% confidence interval (CI), 14.45-14.52] and would generate an additional 23 060 quality-adjusted life years (QALYS) (95% CI, 22 770-23 360) for a median incremental cost effectiveness ratio (ICER) of $628/QALY. Median ICER values per QALY for CD4 and VL strategies are $238 and $16 139, respectively, when second-line treatment is unavailable. With second-line ART available, the corresponding median ICER values are $8636, and $14 670., Conclusions: In the absence of second-line ART, the CD4 strategy is a more cost-effective laboratory testing strategy for managing HIV infection than either TLC or VL. Availability of second-line ART plus CD4 cell count and/or viral load measurement would save additional lives, but at high incremental cost.

Despite the decline in rheumatic heart disease worldwide and the use of antibiotic prophylaxis, there is no evidence that the incidence of infective endocarditis is decreasing. In fact, some data suggest it may be increasing. The classical fever of unknown origin presentation represents a minority of infective endocarditis cases today; thus, clinicians need to be vigilant about keeping infective endocarditis in mind with some of these more unusual presentations. This article focuses on the various presentations of infective endocarditis, which are organized into three groups of presenting symptoms and signs: nonspecific, cardiac, and embolic.

The culture of viable microorganisms from the blood or from cardiac tissue is currently the most important test for diagnosis of IE. This is followed by phenotypic identification methods used for taxonomic positioning of isolates. However, in those cases where the invading microorganism is difficult or impossible to culture (including instances of prior antimicrobial treatment), molecular methods provide the best means for detection. Molecular identification methods, either nucleic acid target or signal amplification alone or in combination with sequence analysis can offer a more specific and in some cases a more rapid alternative to the phenotypic methods. We propose revised Duke criteria of IE, including positive identification of an organism by molecular biology methods.

Infective endocarditis (IE) often presents diagnostic and therapeutic challenges and continues to cause high morbidity and mortality. Confirmation of the diagnosis of IE is important for the purposes of epidemiologic and clinical studies and is crucial for patient management. Despite recent advances in diagnostic techniques, about 10% of IE cases remain culture-negative. Because pathological examination of cardiac valves to demonstrate vegetations and valvular inflammation remains the gold standard for the diagnosis of IE, the role of the pathologist is often decisive, especially when bacteriologists fail to isolate a microorganism or when a microorganism that has been isolated may be a contaminant. Furthermore, the pathologist may play an important role in identification of previously unknown infectious agents.

Background: Previous studies have generated inconsistent results when attempting to define predictors of stroke and death in patients with endocarditis. We sought to examine the relationship between vegetation 2-dimensional size and stroke in those with infective endocarditis (IE) and to identify differences between aortic valve (AV) and mitral valve (MV) IE with regard to clinical characteristics, echocardiographic findings, stroke, and death., Methods: We used the Duke Endocarditis Database to examine 145 episodes of definite IE involving the AV, n = 62, or MV, n = 83. A logistic regression model was developed to analyze important variables in predicting stroke, and a Cox proportional hazards model was used in predicting mortality., Results: The mitral valve was infected in 57% of the cases. Vegetations were more commonly detected in patients with MV IE (92.8% vs 66.1%, P =.001) and these MV vegetations were significantly larger (P <.05). Thirty-four of 145 episodes (23.4%) were complicated by stroke. MV IE was associated with a greater stroke rate, 32.5% versus 11.3% (P =.003). Strokes tended to occur early in the course of illness, particularly in MV IE. In the multivariable model, the independent predictors of stroke were MV IE (P =.04) and vegetation length (P =.03). Independent predictors of 1-year mortality were age (P =.02) and vegetation area (P =.048)., Conclusion: Stroke is more common in patients with MV IE. Vegetation 2-dimensional size and characteristics are important predictors of stroke and mortality. These findings may lead to predictive models that allow physicians to identify high-risk patients who need aggressive treatment strategies to prevent long-term morbidity and mortality.

Bacteremia originating from the oral cavity is common, but the role of bacteremia in the genesis of infective endocarditis and other distant site infections is unclear. Only a small percentage of oral flora have been associated with distant site infection. Important issues remain unresolved concerning the identification of patients at risk, the relative risk from invasive dental procedures versus naturally occurring bacteremia, and the impact of prophylactic antibiotics on the incidence, nature, magnitude, and duration of bacteremia from the oral cavity. This article addresses the controversies in infection management in patients at risk for distant site infection.

This randomized, multicenter, open-label study compared the efficacy and safety of monotherapy with 2 g of intravenous ceftriaxone once daily for 4 weeks with those of combination therapy with 2 g of intravenous ceftriaxone and 3 mg of intravenous gentamicin/kg once daily for 2 weeks as therapy for endocarditis due to penicillin-susceptible streptococci. Sixty-one patients were enrolled in the study. Clinical cure was observed for 51 evaluable patients both at termination of therapy and at the 3-month follow-up: 25 (96.2%) of 26 monotherapy recipients and 24 (96%) of 25 combination therapy recipients. Of the 23 patients in each treatment group who were microbiologically evaluable, 22 (95.7%) in each group were considered cured. No patient had evidence of relapse. Fourteen patients (27.5%) required cardiac surgery after initiation of treatment, including five monotherapy recipients and nine combination therapy recipients. Adverse effects were minimal in both treatment groups. We conclude that 2 g of ceftriaxone once daily for 4 weeks and 2 g of ceftriaxone in combination with 3 mg of gentamicin/kg once daily for 2 weeks are both effective and safe for the treatment of streptococcal endocarditis.

With use of new Duke criteria, 405 episodes of suspected endocarditis were previously classified as "definite," "possible," or "rejected" endocarditis. To determine the negative predictive value of the Duke clinical criteria for the classification of suspected endocarditis, chart review and follow-up were performed for the 52 episodes in which the diagnosis of endocarditis was rejected. Three of 52 episodes were reclassified to possible endocarditis; 49 episodes in 48 patients met the criteria for rejected endocarditis. Of these 49 episodes, 31 (63%) had a firm alternate diagnosis other than endocarditis, 17 (35%) had resolution of the clinical syndrome leading to the suspicion of endocarditis with < or = 4 days of antibiotics, and 1 patient had no evidence of endocarditis at surgery. Echocardiograms recorded in 3 patients with rejected endocarditis had evidence of oscillating valvular masses, and blood cultures were positive in 13 episodes; none of these patients had evidence of endocarditis at follow-up. Follow-up or outcome information was available in all 49 episodes. Excluding the 5 in-hospital deaths, mean duration (+/- SD) of follow-up was 39.9 +/- 28.8 months (range 0.5 to 108.0); in living patients, mean time to final follow-up was 56.2 +/- 25.2 months (range 25.0 to 108.0). One patient had possible infective endocarditis at autopsy. No patient in our series whose diagnosis of endocarditis had been rejected had proven endocarditis. Therefore, the negative predictive value of the Duke clinical criteria for endocarditis is at least 92%.

Objective: To provide guidelines for the treatment of endocarditis in adults caused by the following microorganisms: viridans streptococci and other streptococci, enterococci, staphylococci, and fastidious gram-negative bacilli of the HACEK group., Participants: An ad hoc writing group appointed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young., Evidence: Published studies of the treatment of patients with endocarditis and the collective clinical experience of this group of experts., Consensus Process: The recommendations were formulated during meetings of the working group and were prepared by a writing committee after the group had agreed on the specific therapeutic regimens. The consensus statement was subsequently reviewed by standing committees of the American Heart Association and by a group of experts not affiliated with the working group., Conclusions: Sufficient evidence has been published that recommendations regarding treatment of the most common microbiological causes of endocarditis (viridans streptococci, enterococci, Streptococcus bovis, staphylococci, and the HACEK organisms) are justified. There are insufficient published data to make a strong statement regarding the efficacy of specific therapeutic regimens for cases of endocarditis due to microorganisms that uncommonly cause endocarditis. As a useful aid to the practicing clinician, the writing group developed a consensus opinion regarding management of endocarditis caused by the most commonly encountered microorganisms and regarding those cases due to infrequent causes of endocarditis.

When infective endocarditis is a diagnostic possibility, echocardiography permits noninvasive imaging of cardiac structures. As involvement of the endocardium is a sine qua non of endocarditis, echocardiography may assist in its diagnosis by demonstrating such involvement. The ability of echocardiography to detect the intracardiac manifestations of infective endocarditis has continued to improve, especially with the introduction of transesophageal imaging. This article will discuss some of the echocardiographic findings in endocarditis and elucidate the incorporation of these findings in the new Duke criteria for the diagnosis of endocarditis.

Objective: To evaluate the impact of the Duke University Medicine Residency International Health Program (IHP) on program participants and to evaluate the relationship of the IHP to the residency program., Subjects and Methods: The Duke University Medicine Residency Program classes of 1988 to 1996 participated in a questionnaire-based survey. All program participants (n = 59), a group of nonparticipants (n = 138), and residents who had not yet had an opportunity to participate (preparticipants; n = 106)., Results: The overall response rate to the questionnaire was 93%. Participation exceeded expectations and had a strongly positive impact on personal and professional lives of the majority of the participants. Participants reported a significant positive impact on their training in internal medicine and their knowledge of tropical medicine. A minority of nonparticipants identified a positive effect in these areas due to conferences and interactions with their participating colleagues. Participants who changes career plans during residency tended to move toward areas of general internal medicine or public health, in contrast to nonparticipants who tended to change areas of subspecialty or chose private practice. The IHP was identified as a significant factor for selection of the Duke Medicine Residency by 42% of the preparticipant group. Nearly all of the respondents (99%) indicated that the IHP should be continued., Conclusion: The IHP has a measurable positive impact on the participants, as well as on the Medicine Residency Program.

We used a modified commercial ELISA kit to test for antibodies to avian leukosis/sarcoma and reticuloendotheliosis viral antigens in the sera of 45 poultry workers and their matched controls. We found that 42% of sera from poultry workers had anti-avian leukosis Sarcoma viruses (anti-ALSV) and 20% had anti-reticuloendotheliosis viruses (anti-REV), antibody titers that were higher than the highest titer recorded in control subjects, and hence were regarded as positive. To determine the specificity of these reactions, selected sera were absorbed with ALSV or REV antigens alone, or with chick embryo fibroblasts (CEF) alone, or with both CEF and ALSV/REV, and then retested. In each case, absorption resulted in a statistically significant reduction in absorbance, which was greatest for the combined CEF and ALSV/REV absorption, thus suggesting that the reactions involved viral as well as chicken antigens. However, definitive tests such as Western Blot analyses are needed to confirm whether indeed antibodies to these viruses were specifically elicited in human sera.

Endocarditis continues to be a popular subject among medical authors. A steady stream of new papers describes evolving aspects of epidemiology, clinical manifestations, natural history, and management. Significant developments include refinements in echocardiography and diagnostic criteria, and the introduction of improved surgical techniques for dealing with the complications of endocarditis. Here we review recent publications that present useful or interesting observations.

Purpose: This study was designed to develop improved criteria for the diagnosis of infective endocarditis and to compare these criteria with currently accepted criteria in a large series of cases., Patients and Methods: A total of 405 consecutive cases of suspected infective endocarditis in 353 patients evaluated in a tertiary care hospital from 1985 to 1992 were analyzed using new diagnostic criteria for endocarditis. We defined two "major criteria" (typical blood culture and positive echocardiogram) and six "minor criteria" (predisposition, fever, vascular phenomena, immunologic phenomena, suggestive echocardiogram, and suggestive microbiologic findings). We also defined three diagnostic categories: (1) "definite" by pathologic or clinical criteria, (2) "possible," and (3) "rejected." Each suspected case of endocarditis was classified using both old and new criteria. Sixty-nine pathologically proven cases were reclassified after exclusion of the surgical or autopsy findings, enabling comparison of clinical diagnostic criteria in proven cases., Results: Fifty-five (80%) of the 69 pathologically confirmed cases were classified as clinically definite endocarditis. The older criteria classified only 35 (51%) of the 69 pathologically confirmed cases into the analogous probable category (p < 0.0001). Twelve (17%) pathologically confirmed cases were rejected by older clinical criteria, but none were rejected by the new criteria. Seventy-one (21%) of the remaining 336 cases that were not proven pathologically were probable by older criteria, whereas the new criteria almost doubled the number of definite cases, to 135 (40%, p < 0.01). Of the 150 cases rejected by older criteria, 11 were definite, 87 were possible, and 52 were rejected by the new criteria., Conclusion: Application of the proposed new criteria increases the number of definite diagnoses. This should be useful for more accurate diagnosis and classification of patients with suspected endocarditis and provide better entry criteria for epidemiologic studies and clinical trials.

Ethical behavior is an essential component of professional life. Developments in medical science continually test society's concepts of right and wrong, of virtue and morality. Ethical conflicts will be played out in public with greater frequency and intensity. Physicians will be challenged to maintain high standards of ethical conduct despite the pressures that personal preference, society, and government may exert. We do not present neat solutions to ethical conflicts, but we describe a framework for understanding models of physician behavior and outline an approach to the analysis of problems.

Disseminated infection with the rapidly growing mycobacteria Mycobacterium chelonae and Mycobacterium fortuitum is uncommon. Only eight cases were diagnosed at Duke University Medical Center (Durham, NC) over the last 14 years. We identified 46 other cases by review of the medical literature since 1960. We categorized these 54 cases into three groups according to underlying disease and outcome. Group 1 comprised patients with no identified immune defect, a kidney transplant, collagen vascular disease, or chronic renal failure; these patients usually presented with skin involvement and responded well to antimicrobial therapy (survival rate, 90%). Group 2 comprised patients with cell-mediated immune deficiency, lymphoma, or leukemia; they presented with widespread, multiorgan involvement and severe illness. The survival rate in this group was only 10%. Patients in group 3 (who had other underlying diseases) had intermediately severe illnesses and intermediate responses to therapy. These groups provide the basis for an understanding of disseminated infection secondary to rapidly growing mycobacteria and of the profound effect that unresolved immunosuppression has on survival.

Itraconazole is a broad-spectrum potent triazole antifungal agent. Its efficacy in treatment cannot always be explained by body fluid drug levels. In this study, itraconazole was shown to accumulate into host cells. Its intracellular accumulation in cells is greater than that of the antibacterial agent clindamycin, which is known for intracellular localization, and the uptake process does not appear to be active. This ability to reach high concentrations intracellularly may be an important property for the in vivo efficacy of itraconazole.

A transformation scheme for Cryptococcus neoformans to yield high-frequency, integrative events was developed. Adenine auxotrophs from a clinical isolate of C. neoformans serotype A were complemented by the cryptococcal phosphoribosylaminoimidazole carboxylase gene (ade2) with a biolistic DNA delivery system. Comparison of two DNA delivery systems (electroporation versus a biolistic system) showed notable differences. The biolistic system did not require linear vectors and transformed each auxotrophic strain at similar frequencies. Examination of randomly selected transformants by biolistics showed that 15 to 40% were stable, depending on the recipient auxotroph, with integrative events identified in all stable transformants by DNA analysis. Although the ade2 cDNA copy transformed at a low frequency, DNA analysis found homologous recombination in each of these transformants. DNA analysis of stable transformants receiving genomic ade2 revealed ectopic integration in a majority of cases, but approximately a quarter of the transformants showed homologous recombination with vector integration or gene replacement. This system has the potential for targeted gene disruption, and its efficiency will also allow for screening of DNA libraries within C. neoformans. Further molecular strategies to study the pathobiology of this pathogenic yeast are now possible with this transformation system.

The diagnosis of IE is often difficult to establish with certainty. Current diagnostic criteria have several weaknesses, the most important being failure to utilize the results of echocardiography. This seems inconsistent with modern practice. In reality, the results of modern echocardiography, including appropriate use of transesophageal echocardiography, are critically important for diagnosis of infective endocarditis. New criteria are in the process of development which should prove more sensitive and more specific for disease classification, epidemiologic studies, and clinical trials.

Objective: To determine whether specific intestinal parasites are associated with HIV infection in Tanzanian children with chronic diarrhea., Design: A prospective, cross-sectional study., Setting: Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania., Subjects: All children aged 15 months to 5 years admitted with chronic diarrhea, and age-matched controls., Methods: Standardized history, physical examination, HIV serology, and stool parasitology were evaluated for all subjects. We compared three groups: HIV-infected and non-HIV-infected children with chronic diarrhea and controls without diarrhea., Main Outcome Measures: Fecal parasites and nutritional status., Results: Chronic diarrhea accounted for one-quarter of all cases of diarrheal disease in the defined age range, and children with chronic diarrhea were severely malnourished. Forty per cent of subjects with chronic diarrhea were HIV-seropositive. Although intestinal parasites were detected in approximately 50% of all three groups, diarrheagenic parasites were detected in up to 40% of children with chronic diarrhea. Blastocystis hominis was detected only in HIV-infected patients., Conclusions: HIV infection was common in children with chronic diarrhea, and parasitic agents of diarrhea may be important in children with chronic diarrhea both with and without HIV infection in this setting. B. hominis was more frequent in HIV-infected children. The immunocompromising effects of severe malnutrition may have diminished the difference between HIV-infected and non-HIV-infected children.

Rhodococcus equi is a gram-positive pleomorphic bacillus that has been identified as a life-threatening pulmonary pathogen in the immunocompromised host. Infection with R equi may go unrecognized by physicians unacquainted with its presentation and unaware of the organism's ability to mimic diphtheroids and to stain weakly positive with an acid-fast stain.

The role of antibody in protection against infection with Cryptococcus neoformans is undefined. In this paper we describe the development of opsonic activity in the cerebrospinal fluid (CSF) of rabbits in response to cryptococcal meningitis. The opsonin appeared to be immunoglobulin G (IgG); the activity was heat stable, copurified with the IgG fraction during protein A separation, and could be absorbed by encapsulated cryptococci. Immunosuppression with cyclosporine could be administered to prevent or allow in vivo deposition of IgG on the polysaccharide capsule of yeast in the CSF. Both early and late cyclosporine regimens resulted in prolonged, severe meningeal infections corresponding to the complete absence of in vitro opsonic activity in the CSF. While the production of opsonic antibody is part of the successful host response against C. neoformans in the central nervous system of rabbits, the presence of specific immunoglobulin by itself is insufficient for complete protection.

L-arginine is required for the fungistatic action of murine macrophages in vitro. To further investigate this requirement, L-arginine metabolism by macrophages was measured under conditions where fungistasis either succeeded or failed. Macrophage fungistasis correlated with metabolism of L-arginine to citrulline, nitrite, and nitrate. The metabolic rate was dependent on extracellular L-arginine concentration, reaching a maximum of 67 nmol nitrite/h per mg protein. It accounted for one-third of arginine consumed by fungistatic macrophages. Equimolar amounts of citrulline and total nitrite plus nitrate accumulated in medium. This was consistent with the hypothesis that one of the equivalent guanidino nitrogens of L-arginine was oxidized to both nitrite and nitrate leaving L-citrulline as the amino acid reaction product. The analogue, NG-mono-methyl-L-arginine, selectively inhibited nitrogen oxidation and it was shown previously that it inhibited fungistatic capability. Resident macrophages were not fungistatic and their nitrogen oxidation was low. Once macrophages began producing nitrite/nitrate, protein synthesis was not required during the next 8 h for either fungistasis or nitrogen oxidation. Two-thirds of L-arginine consumption was due to macrophage arginase yielding L-ornithine and urea, which accumulated in medium. This activity was dissociated from macrophage fungistasis. Nitrogen oxidation metabolism by macrophages is linked to a mechanism that inhibits proliferation of fungi. This may involve synthesis of an intermediate compound(s) that has antimicrobial properties.

Activated macrophages inhibit replication of murine lymphoblastic leukemia L1210 cells without lysis. This inhibition of replication is associated with abnormalities of mitochondrial electron transport at the level of NADH dehydrogenase (NADH-DH) and succinate dehydrogenase (SDH). The mechanism of inhibition is unknown, although it has been demonstrated that as NADH-DH and SDH activity is lost, iron is released from cells. Because both NADH-DH and SDH contain numerous iron-sulfur clusters, damage to these structures may be one result of injury by activated macrophages. L1210 cells were labeled with 55Fe and co-cultivated with activated murine peritoneal macrophages (injured L1210 cells). At 48 h, injured L1210 cells had released 83 +/- 8% (mean +/- SEM of 55Fe activity into the media, compared with 25 +/- 4% release from control and 37 +/- 7% from nondividing mitomycin C-treated control cells. All cells were greater than 90% viable. These differences were also reflected in the iron content of the cells. Mitochondria were then separated by centrifugation after cell disruption and 55Fe activity was found to be similarly decreased in both mitochondrial and nonmitochondrial fractions of injured L1210 cells. To further characterize the changes in mitochondrial iron content, mitochondrial proteins from injured and control L1210 cells were separated by IEF and 55Fe activity of gel slices was determined. There was selective loss of 55Fe activity in the area of the gel corresponding to SDH and NADH-DH, suggesting that iron loss from iron-sulfur clusters may occur in L1210 cells injured by activated macrophages. Iron uptake into L1210 cells after removal from macrophages showed a rapid large influx of radioactive iron. L1210 cells in contact with macrophages appear to develop an iron-depleted state, which is dependent on the continued presence of macrophages.

Previous reports have emphasized that cryptococcemia is almost uniformly fatal. To define the clinical course and prognostic and therapeutic implications of cryptococcemia, we studied 15 patients treated at this medical center over the past 7 years. Cryptococcemia was strongly associated with corticosteroid therapy, especially when the dosage had recently been increased. Meningitis was common (but not invariably present) in these patients, characteristically with a large burden of organisms in the cerebrospinal fluid. Cryptococcemia developed during hospitalization in one-third of our patients; this high rate of nosocomial infection emphasizes that C. neoformans infection should be considered in febrile, immunocompromised patients even when the initial work-up is negative. Most of these patients were treated with amphotericin B plus 5-fluorocytosine. Although the one-year survival rate of 4/15 (29%) was dismal, no patient died from uncontrolled cryptococcal infection. Other infections, which developed before, during or after cryptococcemia was diagnosed, were the major immediate cause of morbidity and mortality. The progress of underlying diseases and the outcome of concomitant infections in these patients were more important determinants of survival than was cryptococcemia itself.

Intravenous acyclovir was evaluated in the treatment of 97 immunocompromised patients with mucocutaneous herpes simplex virus infection in a randomized, double-blind, placebo-controlled trial. Acyclovir recipients had significantly shorter periods of virus shedding (p less than 0.0002) and lesion pain (p less than 0.01), and more rapid lesion scabbing (p less than 0.004) and lesion healing (p less than 0.04). The most common adverse reaction was a low incidence of peripheral vein irritation; no serious toxicity could be definitely attributed to acyclovir treatment even in these seriously ill patients. Intravenous acyclovir offers both safe and effective treatment for mucocutaneous herpes simplex virus infection in the immunocompromised host.