case study 7 infective endocarditis

• Case report
• Open access
• Published: 08 May 2017

Complicated infective endocarditis: a case series

• Joo Seop Kim 1 ,
• Min-Kyung Kang 1 ,
• A. Jin Cho 2 ,
• Yu Bin Seo 3 &
• Kun Il Kim 4  

Journal of Medical Case Reports volume  11 , Article number:  128 ( 2017 ) Cite this article

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Infective endocarditis is associated with not only cardiac complications but also neurologic, renal, musculoskeletal, and systemic complications related to the infection, such as embolization, metastatic infection, and mycotic aneurysm.

Case presentation

We report three cases (the first patient is Chinese and the other two are Koreans) of complicated infective endocarditis; two of the cases were associated with a mycotic aneurysm, and one case was associated with a splenic abscess. One case of a patient with prosthetic valve endocarditis was complicated by intracerebral hemorrhage caused by mycotic aneurysm rupture. A second case of a patient with right-sided valve endocarditis associated with a central catheter was complicated by an abdominal aortic mycotic aneurysm. The third patient had a splenic infarction and abscess associated with infected cardiac thrombi.

Conclusions

Complicated infective endocarditis is rare and is associated with cardiac, neurologic, renal, musculoskeletal, and systemic complications related to infection, such as embolization, metastatic infection, and mycotic aneurysm. Infective endocarditis caused by Staphylococcus aureus is more frequently associated with complications. Because the mortality rate increases when complications develop, aggressive antibiotic therapy and surgery, combined with specific treatments for the complications, are necessary.

Peer Review reports

Infective endocarditis (IE) is associated with not only cardiac complications but also neurologic, renal, musculoskeletal, and systemic complications related to infection, such as embolization, metastatic infection, and mycotic aneurysm (MA) [ 1 ]. We report three cases of patients with complicated IE; two were associated with MA, and one was associated with splenic abscess.

Case presentations

A 57-year-old Chinese woman presented to our hospital with generalized weakness. Her medical history included hypertension and early liver cirrhosis caused by chronic viral hepatitis C (platelet count 104,000/μl). She had undergone mitral valve replacement (MVR) with a Hancock II 27-mm prosthesis (Medtronic, Minneapolis, MN, USA) for mitral valve prolapse 1 month earlier. Her blood pressure was 100/60 mmHg, her breathing rate was 12 breaths/minute, her heart rate was 121 beats/minute, and her body temperature was 36.5 °C. She appeared acutely ill and was dehydrated. The result of an initial chest x-ray was normal, and the patient’s electrocardiogram showed sinus tachycardia. Transthoracic echocardiography (TTE) showed normal prosthetic valve motion without evidence of vegetation or paravalvular leakage, but the patient’s mean diastolic pressure gradient was elevated at 10.3 mmHg (Fig.  1a ) [ 2 ]. She had been discharged on warfarin and other medications after successful MVR without complications. Transesophageal echocardiography (TEE) (Fig.  1b and Additional file 1: Video 1) showed hyperdynamic echogenic material attached to the prosthetic MV. During preparation for redo surgery with administration of appropriate antibiotics, the patient suddenly had a generalized seizure with decreased mentation. Brain computed tomography (CT) and magnetic resonance imaging (Fig.  2a , b ) revealed acute hemorrhage with perilesional edema in the bilateral cerebellum causing obstructive hydrocephalus, suggestive of MA rupture. She was transferred to the intensive care unit with an indwelling external ventricular drain (EVD) for monitoring. We performed a redo MVR with a Hancock II 27-mm prosthesis after resolution of her hemorrhage.

Transthoracic echocardiograms showing an elevated mean diastolic pressure gradient ( a ) of 10.3 mmHg and a hyperdynamic echogenic mass attached to the prosthetic MV ( b ) ( white arrows )

Brain computed tomography ( a ) and magnetic resonance imaging ( b ) revealing acute hemorrhage with perilesional edema in the bilateral cerebellum causing obstructive hydrocephalus, suggestive of mycotic aneurysmal rupture

Additional file 1: TEE showed a hyper-dynamic echogenic mass attached to the prosthetic mitral valve. (WMV 804 kb)

A 70-year-old Korean woman presented with generalized weakness and headache. Her medical history included diabetes mellitus and hypertension. Her physical examination revealed her blood pressure was 163/81 mmHg and her pulse rate was 91 beats/minute. Brain CT revealed a chronic left subdural frontotemporal hemorrhage. After burr hole trephination was performed, generalized edema developed because of acute kidney injury (creatinine level 0.86 → 1.89 mg/dl). A peripherally inserted central catheter (PICC) was placed. The patient developed a fever (38.1 °C) after 3 weeks, without a definite source of infection. TEE revealed a globular, mobile, echogenic mass (1.91 × 1.0 cm) (Fig.  3a, b ) attached to the tricuspid valve. Blood cultures revealed Staphylococcus aureus sensitive to vancomycin. The patient’s fever subsided after treatment with antibiotics, but a vegetation and persistent septicemia were noted after 2 weeks. We performed coronary angiography prior to possible valve surgery and observed no significant coronary obstruction, but a large saccular aneurysm was detected in the infrarenal abdominal aorta (Fig.  4a and Additional file 2: Video 2). CT indicated this was a newly developed abdominal aortic aneurysm (maximum diameter 5.2 cm) (Fig.  4b, c ) that had not been present 2 years previously (Fig.  4d ). The appearance was suggestive of an MA associated with IE. We recommended valve surgery and endovascular stenting or surgical removal of the MA in sequence, but the patient’s guardians refused. The patient was discharged to a private convalescent hospital and was lost to follow-up. We suspect IE developed in association with PICC placement and that persistent septicemia, despite use of proper antibiotics, led to an MA.

a and b Transesophageal echocardiography revealing a globular, mobile, echogenic mass (1.91 × 1.0 cm; arrows ) attached to the tricuspid valve

A large saccular aneurysm was detected in the infrarenal abdominal aorta by aortography ( a , white arrow ) and computed tomography ( b and c , white arrows ). The aneurysm had not been present 2 years previously ( d )

Additional file 2: A large saccular aneurysm was detected in the infrarenal abdominal aorta by aortography. (WMV 2144 kb)

A 76-year-old Korean woman with acute onset of flank pain caused by splenic infarction and abscess was transferred to our hospital with percutaneous drainage (Fig.  5 ). She had been diagnosed with a stroke in our hospital 3 months earlier. Other than fever (38.1 °C), she had stable vital signs. Although splenic infarction or embolism is common, splenic abscess is rare. In every patient diagnosed with splenic infarction, a search for the possible source of emboli should be performed, and IE is the most common cause [ 3 ]. There was no evidence of IE in this patient, but slightly increased mitral regurgitation (grade 1–2) (Additional file 3: Video 3 and Additional file 4: Video 4) was noted by TTE. TEE revealed a thickened, nonhomogeneous area with an echo-dense appearance around the aortic root (Fig.  6a ) and discontinuous endocardial tissue (Fig.  6b ) with flow communication detected by color and pulsed wave Doppler ultrasound (Fig.  6c , d ). This patient needed surgery for locally uncontrolled infection [ 4 ]. A weblike structure with interruption of endocardial tissue continuity was noted (Fig.  7a ), and thrombi were observed within the pocket (Fig.  7b ). The patient recovered fully and was discharged.

Computed tomography shows splenic infarction ( a , white arrow ) and abscess with percutaneous drainage ( b , white arrow )

Transesophageal echocardiography shows a thickened nonhomogeneous area with echo-dense appearance around the aortic root ( a , white arrow ), as well as discontinuous endocardial tissue ( b , white arrow ) with flow communication detected by color and pulsed wave Doppler ultrasound ( c and d )

Intraoperative views show a weblike structure with interruption of endocardial tissue continuity ( a , white arrow ) and that thrombi were present in the pocket ( b , white arrow )

Additional file 3: TTE showed mild mitral regurgitation. (WMV 1254 kb)

Additional file 4: TTE showed increased mitral regurgitation. (WMV 1692 kb)

IE is associated with cardiac, neurologic, renal, and musculoskeletal complications. Predisposing factors include the infecting pathogen, duration of illness prior to therapy, and underlying comorbidities [ 1 ]. IE caused by S. aureus is associated with complications more frequently than other pathogens [ 5 ].

MA can develop in the cerebral or systemic circulation in the setting of IE [ 6 ], and cerebral hemorrhage caused by stroke or a ruptured MA can cause neurologic complications. Direct bacterial inoculation, bacteremic seeding, contiguous infection, and septic emboli are the sources of MA. Intracranial MA usually involves more distal portions of the middle cerebral artery, as in patient 1, and unruptured aneurysms may be managed with antibiotics alone. However, ruptured aneurysms should be managed with a combination of antibiotics and surgery [ 6 ]. Patient 1 developed intracranial hemorrhage and a seizure; we initially attempted conservative treatment with EVD and close monitoring in the intensive care unit, and then we performed a redo MVR after stabilization [ 4 ]. The perioperative mortality rate for infected aortic aneurysms is 15% to 20% [ 7 ]. Survival is better for an infrarenal abdominal aortic aneurysms than for noninfrarenal aneurysms (96% versus 57%, respectively) [ 8 ]. Therefore, we suggest debridement of an infected infrarenal aortic aneurysm, along with extraanatomic reconstruction. The guardians of patient 2 refused all surgery because of the high morbidity and mortality risk.

In contrast to relatively common splenic infarctions in patients with embolic events, splenic abscesses are very rare and fatal complications of IE [ 3 ]. The treatments of choice are antibiotics, splenectomy, and valve replacement surgery. After patient 3 was stabilized with drainage of a splenic abscess, we decided to perform valve replacement surgery and debridement of the perforated intracardiac abscess pocket. The aortic and mitral valves were relatively clean, except for degenerative changes, but infected thrombi were noted in a phlegmon.

IE is associated with cardiac, neurologic, renal, musculoskeletal, and systemic complications related to the infection (embolization, metastatic infection, and MA). Predisposing factors include the infecting pathogen, duration of illness, prior therapy, and underlying comorbidities. Complications can occur before, during, and after completion of therapy. IE caused by S. aureus is associated with complications more frequently. Because the mortality rate increases with complications, aggressive antibiotic therapy combined with surgery and other specific treatments for complications is necessary.

Abbreviations

Computed tomography

External ventricular drain

• Infective endocarditis
• Mycotic aneurysm

Mitral valve replacement

Peripherally inserted central catheter

Transesophageal echocardiography

Transthoracic echocardiography

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All authors contributed to the conception of this case report, the literature review, the analysis and interpretation of the material, and drafting and critical revision of the manuscript; All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.

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Division of Cardiology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea

Joo Seop Kim & Min-Kyung Kang

Division of Nephrology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea

Division of Infection, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea

Division of Cardiothoracic Surgery, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea

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Kim, J.S., Kang, MK., Cho, A.J. et al. Complicated infective endocarditis: a case series. J Med Case Reports 11 , 128 (2017). https://doi.org/10.1186/s13256-017-1274-7

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DOI : https://doi.org/10.1186/s13256-017-1274-7

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McDonald EG , Aggrey G , Tarık Aslan A, et al. Guidelines for Diagnosis and Management of Infective Endocarditis in Adults : A WikiGuidelines Group Consensus Statement . JAMA Netw Open. 2023;6(7):e2326366. doi:10.1001/jamanetworkopen.2023.26366

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Guidelines for Diagnosis and Management of Infective Endocarditis in Adults : A WikiGuidelines Group Consensus Statement

• 1 Division of General Internal Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada
• 2 Montgomery Medical Associates, Rockville, Maryland
• 3 The University of Queensland, Faculty of Medicine, Centre for Clinical Research, Brisbane, Queensland, Australia
• 4 Jersey Shore University Medical Center, Neptune, New Jersey
• 5 Division of Infectious Diseases, University of Nebraska Medical Center, Omaha
• 6 New York Health and Hospitals–Bellevue Hospital, New York
• 7 Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada
• 8 Providence Portland Medical Center, Portland, Oregon
• 9 University of Queensland, Centre for Clinical Research, Brisbane, Queensland, Australia
• 10 Cooper University Healthcare, Camden, New Jersey
• 11 Women’s College Hospital, Toronto, Ontario, Canada
• 12 Departments of Internal Medicine & Community Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
• 13 Division of Infectious Diseases, Allergy and Immunology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
• 14 Infectious Diseases Fellowship, Universidad de Antioquia, Medellín, Colombia
• 15 Division of Infectious Diseases, Department of Medicine, Queen’s University, Kingston, Ontario, Canada
• 16 Louisiana State University, Baton Rouge
• 17 Right to Care, NPC, Centurion, South Africa and London School of Hygiene and Tropical Medicine, London, United Kingdom
• 18 Division of Internal Medicine, Michigan Medicine, Ann Arbor
• 19 Los Angeles County and University of Southern California Medical Center, Los Angeles
• 20 Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Victoria, Australia
• 21 Rush University Medical Center, Chicago, Illinois
• 22 King Abdulaziz Medical City, Jeddah, Saudi Arabia
• 23 Institute for Infectious Diseases and Infection Control, Jena University Hospital–Friedrich Schiller University Jena, Jena, Germany
• 24 Infection Science, North Bristol NHS Trust, Bristol, United Kingdom
• 25 Department of Infectious Diseases, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland
• 26 Division of Infectious Diseases and Geographic Medicine, University of Texas Southwestern, Dallas
• 27 University of Vermont Medical Center, Burlington
• 28 University of Maryland Medical Center, Baltimore
• 29 University of Alabama at Birmingham
• 30 Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong
• 31 Bellevue Hospital Center, New York, New York
• 32 MemorialCare, Fountain Valley, California
• 33 University of Nebraska Medical Center, Children’s Hospital and Medical Center, Omaha
• 34 Hôpital Maisonneuve Rosemont, Montréal, Quebec, Canada
• 35 Section of Infectious Diseases, West Virginia University, Morgantown
• 36 Institut universitaire de cardiologie et de pneumologie de Québec–Université Laval, Québec, Canada
• 37 University of Texas Southwestern Medical Center, Dallas
• 38 University of Kentucky Medical Center, Lexington
• 39 Division of Nephrology, Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada
• 40 Keystone Infectious Diseases, Chambersburg, Pennsylvania
• 41 Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
• 42 Robert Wood Johnson University Hospital, New Brunswick, New Jersey
• 43 Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec, Canada
• Correction Error in Box 1 JAMA Network Open
• Correction Errors in Table and Supplement 1 JAMA Network Open

Question   Using the WikiGuidelines approach to the construct of clinical guidelines, how often can clear recommendations be made in the diagnosis and management of adult bacterial infective endocarditis?

Findings   In this consensus statement, a panel of 51 members found that only 1 of 17 questions had sufficiently high-quality data to allow for a clear recommendation. Oral transitional therapy is at least as effective as intravenous-only therapy for the treatment of infective endocarditis.

Meaning   These findings suggest that a higher quality of evidence needs to be established to guide the diagnosis and management of infective endocarditis.

Importance   Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence.

Objective   To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength.

Evidence Review   This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches.

Findings   A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)–only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions.

Conclusions and Relevance   In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Infective endocarditis (IE) is an ancient illness that can be difficult to diagnose and treat, leading to substantial morbidity and mortality even in the modern era. The literature regarding the management of IE spans decades but features few high-quality randomized clinical trials. This second WikiGuidelines consensus statement addresses the evidence-based management of IE. The guideline was drafted by an independent, international consortium of medical professionals who previously established a collaborative method to construct pragmatic, real-world, clinical practice guidelines. 1 , 2 WikiGuidelines provide clear recommendations when reproducible, high-quality data and/or hypothesis-confirming evidence is available and otherwise provide comprehensive clinical reviews summarizing different clinical approaches. WikiGuidelines offer clinician insights and are not intended to establish care mandates or medicolegal standards of care, nor to replace individual clinician judgment.

The intended end users are clinicians providing patient care across diverse settings (academic, community-based) and socioeconomic statuses (low-, middle-, or high-income countries), with varied experience (generalists or specialists). We incorporate the principles of high-value care (ie, right care, right place, right cost) and health care quality (ie, timely, safe, effective, efficient, equitable, patient-centered). As such, considerations of resource utilization, systems-based practice, reduction in health care waste, and harm reduction are intrinsic.

Feedback is solicited from many licensed practitioners to move away from guidelines constructed by subspecialty member organizations by invitation only. This allows for a more inclusive, broader representation of everyday care practitioners from across the world. We seek to change the traditional guidelines practice of creating care mandates based on expert opinion rather than hypothesis-confirming data, which risks societal-level harm by setting incorrect standards of care. 3 - 6 Following electronic polling of clinicians, we identified the next most preferred topic that could benefit from the WikiGuidelines approach: the diagnosis, prophylaxis, antibiotic therapy, and team-based management of bacterial IE in adults.

This guideline was crafted in accordance with the WikiGuidelines charter and follows the Standards for Quality Improvement Reporting Excellence ( SQUIRE 2.0) reporting guideline. 7 The authorship team included 51 members from 10 countries (listed in eAppendix 1 in Supplement 1 ), including 31 MDs and 16 PharmDs with expertise in internal medicine, hospital medicine, infectious diseases and microbiology, cardiac surgery, cardiology, radiology, nephrology, and pharmacology. The charter specifies the process for selection of members (authors), conflict resolution, and for evidentiary and consensus standards used to review the literature. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system for evaluating the strength of evidence was replaced with a dichotomized approach of providing either clear recommendations or clinical reviews, due to published concerns with GRADE, including risk of bias, poor interrater reliability, and the dissociation between strength of recommendation and quality of evidence. 5 , 8 , 9

High-quality, hypothesis-confirming data enable a clear recommendation and are based on at least 1 properly conducted, adequately powered randomized controlled trial (RCT) and at least 1 other concordant, prospective, controlled clinical study (either a second RCT, a quasi-experimental pre-post study, a pragmatic clinical trial, or a carefully conducted historically controlled study). In the absence of such data, to provide guidance that is permissive rather than proscriptive, WikiGuidelines provides clinical reviews that discuss clinical approaches, comparing risks and benefits. Recognizing the core ethical and clinical principle of first do no harm, consensus on routinely avoiding unsubstantiated care is permitted even in the absence of a clear recommendation.

On April 29, 2022, interested members were asked to submit their top questions on the diagnosis and management of endocarditis. Questions were thematically grouped into topic sections and individual members volunteered to collaboratively author sections of interest. Sections had 1 or 2 team leaders and drafting team members who conducted literature reviews using PubMed or alternatives. There were no restrictions to searches, and all languages and dates were considered for inclusion. Following internal revision by topic group members, initial versions were revised by the first and senior authors and then circulated to all members participating in the guideline for further refinement. Drafting members could post questions electronically (social media or email) to receive open-source feedback on how to construct answers to questions that lacked hypothesis-confirming data. The second open round of revisions led to a final version of each topic, which then underwent a third round of revisions by all members. When feasible, for answers with more than 1 relevant study, meta-analysis was conducted using Stata version 17.0 (StataCorp).

The tables and boxes included here are not intended to serve as recommendations in the traditional sense of guidelines. The information is often based on limited data, extrapolations, or both. Some of the content represents the authors’ attempt to present reasonable clinical options based on their interpretations of imperfect published literature. A nuanced discussion of this information is contained in eAppendix 3 in Supplement 1 .

The reference standard for diagnosis of IE is pathological confirmation. However, such information is virtually never available at the time when empirical therapeutic decisions must be made and, unless the patient undergoes surgical replacement of a valve, remains unavailable to confirm the diagnosis later. Several schemas have been developed over the years to guide clinicians in the diagnosis of IE absent pathological confirmation (eAppendix 2 in Supplement 1 ). Five of the 7 schema are based on the original Duke criteria and an iterative process that has aimed at improving sensitivity. Such schemas typically include clinical, microbiological, and imaging (eg, echocardiography or positron emission tomography [PET]) criteria. Schemas such as the modified Duke criteria (updated in 2023 to the Duke-ISCVID criteria 10 ) are widely used and convenient for clinicians facilitating real-time diagnostic and therapeutic decision-making. However, there are no high-quality studies that definitively determine which diagnostic schema is most accurate, nor have head-to-head studies compared clinical outcomes between schemas. Studies that have reported the diagnostic accuracy have important limitations including retrospective designs, heterogeneous reference standards, and patient populations at variable risk of IE. It is therefore unclear how well schemas extrapolate to diverse care settings. Thus, no recommendation can be made regarding which, if any, are preferred for use. However, a structured approach to the diagnosis of IE is preferrable clinically and essential to guide research. Since most research studies apply the modified Duke criteria, these criteria likely accord with what most clinicians use.

Observational data suggest time-to-positivity (TTP) of blood cultures of less than 12 hours is associated with Staphylococcus aureus IE and independently predicts hospital mortality. 11 A similar study found that a shorter TTP was associated with IE in monomicrobial Enterococcus faecalis bacteremia (odds ratio [OR], 13.0; 95% CI, 4.4-38.0 in multivariate analysis). 12 TTP is likely influenced by the blood culture machine and/or bottles being used and by preexposure to antibiotics. 13

Observational data suggest that with modern culture techniques, a standard 5-day incubation for blood cultures is adequate for almost all causes of IE. 14 , 15 Prolonged incubation could be considered in patients with prosthetic valve endocarditis (PVE) when Cutibacterium acnes is suspected. 14 - 16

Two large observational studies suggest that the maximum yield for recovering a pathogen from blood cultures is achieved with 3 (96% 17 -98% 18 ) to 4 sets (99.8% 18 ) over 24 hours, with each set comprising 2 × 10 mL filled bottles. Where possible, these should be taken prior to antibiotics, as the yield of blood cultures decreases after antibiotics are received. 19 The relationship between the number of positive blood culture sets and the diagnosis of IE requires additional study; however, growth in multiple vs single blood culture bottles is associated with IE in S aureus bacteremia and growth in 3 or more bottles is associated with IE in E faecalis bacteremia. 20 , 21

There are limited published data to inform the accuracy of diagnostic testing for Bartonella IE, and published C Burnetii data have come from 1 center. While it may be reasonable to use an Ig G titer cutoff of at least 1:800 as diagnostic evidence of Bartonella IE, clinicians should be aware that the data set supporting accuracy of this cutoff is limited, 22 patients who do not have IE can have titers as high as 1:800 or higher, and patients can have lower titers but still have Bartonella as an etiology for IE.

The widely used serological cutoff to diagnose Q fever IE is a phase I IgG antibody titer of 1:800. However, validation of this titer cutoff was based on a 20-patient case series, 22 and no high-quality published studies have established its accuracy.

A systematic review and meta-analysis of molecular rapid diagnostic tests suggested improved outcomes in bloodstream infection when guided by antimicrobial stewardship programs 23 ; however, no studies have assessed the impact on outcomes in IE. Where available, some clinicians use 16s rRNA testing of valve tissue in unsolved cases of culture-negative endocarditis, with a wide variability in sensitivity reported between studies. 24 Molecular diagnostic tests require further study before they can be routinely recommended, but they may be useful in select cases.

In most cases of suspected IE, obtaining an echocardiogram represents usual care. Nonetheless, like any test, echocardiography should be ordered when it will inform management decisions.

Both the pretest probability of IE and study quality strongly affect the impact of transthoracic echocardiography (TTE) on patient treatment. A negative TTE may be adequate to rule out native valve endocarditis (NVE) if the initial pretest probability 25 , 26 is low (eg, <10%), or with a high-quality study, even if the pretest probability is moderate (eg, <25%).

Transesophageal echocardiography (TEE) is more sensitive than TTE for the diagnosis of IE. A TEE is most useful in specific scenarios: (1) to reduce the possibility of NVE where an unacceptably high posttest probability remains after a negative TTE (eg, 5%-10%) and where eliminating the diagnosis will change patient treatment; (2) in the evaluation of PVE where TTE has a lower sensitivity; and/or (3) to facilitate surgical planning or to evaluate for specific complications (eg, perivalvular abscess).

Not all centers have timely access to TEE (or TTE). Decisions regarding transfer to obtain an echocardiogram in resource-constrained settings need to be individualized.

Numerous clinical scoring systems have been developed to better identify patients who may benefit from invasive testing with TEE (eAppendix 2 in Supplement 1 ). Many have demonstrated high negative predictive values, which could be useful for resource stewardship. However, clinical prediction scores have important limitations. They have only been evaluated in retrospective studies, in some cases with relatively small numbers of patients with IE due to a single causative pathogen, with varied reference standards. Furthermore, there may be considerable selection bias and included patients may not be generalizable. Clinical prediction scores for IE have never been applied in a prospective study to demonstrate improved clinical outcomes or resource utilization. Scores may also be more complex than clinical criteria commonly used in clinical practice (eg, multiple positive blood cultures, time to clearance of bacteremia, and the presence of IE sequelae). Thus, the data are insufficient to make a clear recommendation.

There are no high-quality data to support repeated or serial echocardiogram in patients with an initial negative study. Observational studies suggest repeated imaging may increase the diagnostic sensitivity but with unclear impact on patient outcomes. 27 If the result will change treatment (eg, alter antibiotic duration, prompt surgical evaluation), a repeated echocardiogram may be of value. Otherwise, routine use of follow-up or end-of-treatment TTE does not appear to provide a benefit to patients.

Numerous observational studies have evaluated the accuracy of 2-[18F]-fluorodeoxyglucose (18-FDG)–PET/computed tomography (CT) for the diagnosis of NVE, PVE, and cardiac device–related IE (CDIE). Meta-analyses have reported the sensitivity of 18F-FDG-PET/CT for NVE as poor, especially compared with PVE and CDIE; however, specificity remains high. Specifically, the pooled sensitivity and specificity of 18F-FDG-PET/CT for NVE was reported as 31% and 82% vs 73% and 80% for PVE and 87% and 94% CDIE. 28 - 30 Given its low sensitivity, a negative 18F-FDG-PET/CT cannot rule out a diagnosis of NVE, even in cases where there is a low pretest probability. It may be reasonable at appropriately resourced centers to use 18F-FDG-PET/CT for strongly suspected cases of PVE or CDIE in the presence of a negative or nondiagnostic TTE or TEE.

The ability of 18F-FDG-PET/CT to affect clinical outcomes has not been assessed for IE specifically, but observational studies have suggested 18F-FDG-PET/CT may increase detection of occult, secondary seeded sites of infection during S aureus bacteremia. 31 18F-FDG-PET/CT is resource-intensive, not routinely available in all centers, and exposes patients to ionizing radiation, and whether use improves outcomes remains unknown.

Multidisciplinary IE teams may be comprised of experts in infectious diseases, pharmacy, cardiology, cardiac surgery, and depending on availability and the clinical presentation, specialists in radiology, neurology, stroke, general or vascular surgery, addiction medicine, and social services. Observational studies suggest the involvement of a multidisciplinary IE team may improve patient outcomes, including time to surgical intervention, and mortality. 32 , 33 However, there are no randomized clinical trials. There is also insufficient evidence to support routine transfer to a specialized referral center for treatment. If transfer is feasible, some clinicians may choose to do so to have more ready access to subspecialized services. Some higher risk complex populations that may benefit from a multidisciplinary team include persons who inject drugs (PWID), PVE, CDIE, presence of hemodynamic instability, acute heart failure or cardiogenic shock, new severe valve regurgitation, perivalvular abscess, stroke, recurrent embolisms, or highly virulent and/or resistant organisms (eg, methicillin-resistant S aureus [MRSA] 34 ).

Antibiotic prophylaxis of endocarditis risks toxic effects and selects for antibiotic resistance, causing societal-level harm. 35 Consequently, WikiGuidelines authors prefer limiting prophylaxis to patients who both are perceived to be at higher risk for IE (prosthetic cardiac valves or retained prosthetic material used for cardiac valve repair; cardiac transplant recipients with valve regurgitation; congenital cyanotic heart diseases unrepaired or with residual shunt; and those with a history of IE 36 ) and who are undergoing dental procedures where there is likely a greater risk of bacteremia (eg, manipulation of the gingival tissue or periapical region around the teeth, or perforation of the oral mucosa). 36 Of note, a 2022 study by Vähäsarja et al 37 found no increased incidence of oral streptococcal IE among high-risk individuals following a recommendation to no longer administer antibiotic prophylaxis in dentistry. More evidence is required to support any recommendation regarding prophylaxis for gastrointestinal, genitourinary, respiratory, or skin and soft tissue procedures. 38 If used, the risks of antimicrobial prophylaxis may be partly mitigated by using a single dose rather than longer courses.

No high-quality data inform relative efficacy of various prophylaxis regimens to prevent IE. Nevertheless, given the known microbiology of procedurally related cases of IE, it is rational to select prophylactic antibiotics that are active against viridans group Streptococci (VGS). Oral administration is preferred, with penicillins and cephalosporins associated with a lower rate of Clostridioides difficile infection when compared with clindamycin. 39 There are no RCTs in support of one agent vs another; however, amoxicillin seems to be the most commonly used and carries the lowest risk of adverse events overall ( Table 1 ). 36 , 40 , 41

Little high-quality evidence is available to guide selection of empirical therapy for known or suspected IE. Observational studies have suggested that IE outcomes may be improved by consulting infectious diseases experts. 42 , 43 Empirical regimens are generally selected to cover the most likely potential causes based on the history and physical examination incorporating risk factors or clues for the source of infection and/or local antimicrobial resistance patterns (which may differ by geographic location). In general, a combination of vancomycin or daptomycin (to cover MRSA, Enterococcus spp , and in the case of prosthetic valve, coagulase-negative staphylococci 44 ) and a β-lactam like ceftriaxone (if suspecting an odontogenic or gastrointestinal focus) or cefazolin (if suspecting methicillin-susceptible S aureus [MSSA]) may be reasonable, although alternative regimens are also possible and there is almost no direct comparative evidence ( Box 1 ; eAppendix 3 in Supplement 1 ). 48 - 50 Absent comparative outcomes studies, some authors prefer a daptomycin dose of 8 to 10 mg/kg if S aureus is suspected 51 and 10 to 12 mg/kg if enterococcus is being targeted. 52 To minimize harm, the aminoglycosides and rifampin are best reserved for definitive therapy, if used at all.

Rational Choices of Empirical Antimicrobial Therapy Based on Likely Microbiology

This box lists reasonable options based largely on historical practice and in vitro susceptibility, with little clinical data to validate relative efficacies for most regimens. It is best practice to select regimens based on specific clinical situations and patient/local epidemiology. Please see the eAppendix 3 in Supplement 1 .

Native Valve

Principal agent.

Vancomycin: the principal agent most authors use is vancomycin, as it has the most evidence and will cover Staphylococcus aureus , streptococci, and most enterococci. Note that none of the principal agents may be required in native valve endocarditis if there is minimal clinical concern for MRSA or coagulase-negative staphylococci or enterococci since monotherapy with cefazolin or ceftriaxone may suffice.

Daptomycin: daptomycin may offer some advantages in terms of pharmacokinetics and the local net financial and clinical resources required with a similar spectrum of activity. Most authors prefer a dose of 8 to 10 mg/kg if S aureus is being targeted or 10 to 12 mg/kg if enterococcus is being targeted.

Alternative, linezolid: linezolid can be an alternative for patients where there are challenges in obtaining or maintaining intravenous access, where there is reasonable concern for vancomycin-resistant organisms, or where both vancomycin and daptomycin are precluded (eg, vancomycin allergy and pneumonia).

Second Agent

Ceftriaxone: ceftriaxone is preferred by some WikiGuidelines authors as a second agent since it has superior coverage for streptococcal species and HACEK organisms. Yet, there are times when S aureus is more likely clinically.

Cefazolin: The combination of vancomycin or daptomycin and cefazolin is synergistic for MRSA in vivo without evidence of increased nephrotoxicity. 45 For MSSA, there is observational evidence that beta-lactam therapy is superior to vancomycin therapy, and for this reason many authors prefer to include a beta-lactam with good S. aureus activity. Most WikiGuidelines authors prefer cefazolin over anti-staphylococcal penicillins in this context due to decreased toxicity, with similar clinical efficacy described in recent observational studies. 46 , 47

Prosthetic Valve

Daptomycin: Most authors prefer a dose of 8 to 10 mg/kg if S aureus is being targeted or 10 to 12 mg/kg if enterococcus is being targeted.

Alternative, linezolid

Early (<3 mo)

For early prosthetic valve infection, choice of the second agent is driven primarily by the local microbiology of gram-negative bacterial infections. It may be desirable to avoid carbapenem therapy due to the need to preserve them for more resistant cases, although in some regions, empirical use may be necessary depending on local microbiology. For early prosthetic valve disease, ceftriaxone could have inferior nosocomial gram-negative coverage, depending on local microbiology.

Piperacillin-tazobactam

Ceftriaxone

Later (>3 months):

Amoxicillin-clavulanate (IV)

Ampicillin-sulbactam

Abbreviations: IV, intravenous; MRSA, methicillin-resistant S aureus ; MSSA, methicillin-susceptible S aureus.

Definitive antibiotic therapy recommended for IE depends on the etiologic organism, its susceptibility, patient factors (eg, comorbidity, allergy), and whether the infection is of a native or prosthetic valve. This treatment regimen complexity has limited the availability of high-quality comparative outcomes studies. In general, the addition of adjunctive agents (eg, β-lactam, aminoglycosides, rifampin) requires a careful consideration of the risks and benefits and an acknowledgment of the limitations of the evidence. 53 Most WikiGuidelines authors suggest against routine use of adjunctive aminoglycosides because of a lack of evidence of benefit with a demonstrable risk of harm (discussed in eAppendix 3 in Supplement 1 ). Options for definitive intravenous therapy by organism are presented in Table 2 , with nuanced discussions in eAppendix 3 in Supplement 1 . 54 - 60

We can provide a clear recommendation for this question. Three randomized clinical trials have established that transition from initial intravenous therapy to oral therapy is at least as effective as intravenous-only therapy for the treatment of IE. 55 , 61 , 62 These results are also supported by pharmacologic data demonstrating that many oral antibiotics achieve adequate levels in blood to exceed the minimum inhibitory concentrations (MICs) of target pathogens, as well as numerous observational studies of oral therapy for IE demonstrating favorable outcomes. 63 Importantly, intravenous-only therapy has never been established to be superior to modern oral antimicrobial therapy in any clinical trial or observational study of patients with IE. Therefore, after factoring in considerations presented in eAppendix 3 in Supplement 1 , transition to oral therapy from initial intravenous therapy is a reasonable option for treating patients with IE.

Not all oral antimicrobial agents are likely candidates for treatment of IE. Historical experience suggests that older sulfonamides, tetracyclines, and macrolides may lead to poor outcomes perhaps related to low achievable blood levels relative to target MICs. 64 - 66 Trimethoprim-sulfamethoxazole was inferior as a lead-in option for the treatment of staphylococcal IE in 2 RCTs. 45 , 67 If oral therapy is used, it is rational to select antibiotics demonstrated to have efficacy in published studies ( Table 3 and Box 2 ). 46 , 47 , 55 , 61 , 62 , 68 - 71 , 73 - 77 It is unclear whether dual regimens, such as those used in the POET study, 55 are required, as other data have demonstrated favorable outcomes with certain monotherapy regimens ( Table 2 ; eAppendix 3 in Supplement 1 ). It is also unclear to what extent intravenous lead-in therapy is needed prior to transitioning to oral therapy, as studies have used a wide range of intravenous lead-in prior to oral therapy, including 1 RCT with no intravenous lead-in. 62 Reasonable patient selection criteria for oral therapy may include (1) clinical stability with no immediate indication for procedural source control or cardiac surgery; and (2) bacteremia has cleared or is clearing without the need for source control; and (3) an oral antibiotic regimen is available to which the etiologic organism is susceptible in vitro and which is supported by published clinical data; and (4) the patient is likely to absorb the antibiotic from the gastrointestinal tract; and (5) there are no socioeconomic determinants of health or inequities rendering intravenous therapy the preferred route.

Summary of Oral Step-Down Antibiotics by Organism a

Streptococci: penicillin-sensitive (mic ≤0.12 μg/ml).

Amoxicillin 1 g 4 times daily, only for native valve infection b

Amoxicillin 1 g 4 times daily with rifampin 600 mg once daily

Linezolid 600 mg twice daily alone or with rifampin 600 mg once daily

Moxifloxacin 400 mg once daily with rifampin 600 mg once daily or linezolid 600 mg twice daily

Streptococci: penicillin-intermediate (MIC 0.25-1.00 μg/mL) or Enterococcus

Amoxicillin 1 g 4 times daily with rifampin 600 mg once daily or linezolid 600 mg twice daily

Moxifloxacin 400 mg once daily with rifampin 600 mg once daily

Streptococci: penicillin-resistant (MIC ≥2 μg/mL) or amoxicillin-resistant Enterococcus

Linezolid 600 mg twice daily alone or with (rifampin 600 mg once daily)

Staphylococcus spp

Levofloxacin 750 mg once daily with rifampin 600 mg once daily or linezolid 600 mg twice daily

Linezolid 600 mg twice daily alone or in combination with rifampin 600 mg once daily (rifampin lowers linezolid blood levels, so whether monotherapy or combination therapy is preferred remains unclear)

TMP-SMX 960 mg or 4800 mg daily in divided doses c

Dicloxacillin 1 g 4 times daily plus rifampin 600 mg once daily (only for methicillin-sensitive strains)

Abbreviations: MIC, minimum inhibitory concentration; TMP-SMX, trimethoprim-sulfamethoxazole.

a Combination regimens were used in the largest randomized clinical trial; other published regimens have included either monotherapy or combination therapy regimens. 3

b Amoxicillin monotherapy was studied in a 30-patient randomized clinical trial with excellent outcomes, 1 whereas dual therapy was used in a substantially larger randomized clinical trial. 3 Thus, it is not clear that rifampin is needed for sensitive streptococci, but there are more data for the combination.

c If used for transitioning from intravenous to oral therapy, the dosing of TMP-SMX is uncertain. The quasi-experimental study used a very high dose equivalent to 3 double-strength tablets twice daily, which had a relatively high rate of intolerance. 46 Many WikiGuidelines authors prefer to use lower doses, such as 2 double-strength tablets twice daily; 1 double-strength tablet twice daily may be conceivably sufficient, but there are currently no published data demonstrating efficacy of such a dose.

Evidence to support durations of treatment for IE are almost entirely observational, and most durations are based on historical practice. One RCT 78 established that penicillin-susceptible streptococcal endocarditis treated with 2 weeks of combination therapy with ceftriaxone and gentamicin resulted in similar outcomes as 4 weeks of ceftriaxone monotherapy. 78 Whether combination therapy is necessary is addressed in eAppendix 3 in Supplement 1 .

For other pathogens, and in absence of data, the historical practice has been to treat staphylococcal and enterococcal left-sided endocarditis for 6 weeks and Haemophilus, Aggregatibacter , Cardiobacterium , Eikenella , and Kingella (HACEK) endocarditis for 4 weeks. Recommendations to treat PVE for 6 weeks are also based on opinion rather than high-quality data. Ongoing RCTs SATIE 79 and POET II 80 should help to establish optimal durations.

For uncomplicated right-sided IE caused by MSSA (defined as lacking intracardiac or systemic complications of infection), prospective observational studies and 1 RCT conducted in the PWID population 81 suggest that 2 weeks of combination antibiotic therapy might result in similar cure rates as longer courses. However, both 2-week treatment groups in the only RCT 81 had a lower-than-expected combined treatment success in the intention-to-treat population (mean, 72% [95% CI, 63%-81%]), and the observational studies all had major limitations. Optimal durations of therapy for uncomplicated right-sided IE outside of the PWID population and/or caused by other pathogens are unknown. In the absence of evidence, WikiGuidelines authors feel it may be reasonable in carefully selected cases (eAppendix 3 in Supplement 1 ) to use a similar duration of therapy for other pathogens as for MSSA. For patients with complicated right-sided IE, no data are available to guide duration of therapy, and longer courses are often used without any supporting evidence.

IE is associated with high morbidity and mortality. Despite extensive literature discussing the management of IE, we found that most aspects of diagnosis and management are based on historical practice and small, outdated, observational studies. High-quality studies can inform only 1 clear recommendation: oral transitional antibiotics for the treatment of IE. This paucity of high-quality evidence will change with the arrival of results of several much-needed ongoing RCTs.

This study has limitations, primarily the lack of high-quality studies. The entire area of treatment in terms of antibiotic prophylaxis, empirical therapy, selection of optimal antibiotic classes, and almost all permutations of durations of therapy are based on case series or small observational studies. Again, very few (or no) head-to-head trials of different therapeutic options exist. It was striking to observe how much of the management of IE is currently based on historical practice or expert opinion. Although oral antibiotics to complete treatment of IE have the strongest evidence, this approach still lags in clinical practice. Much of the observational evidence also has very important limitations with respect to the diagnosis of IE as the criterion standard varies between studies, there is obvious selection and immortal time bias present, and few studies use pathologically confirmed IE.

This consensus statement highlights the lack of high-quality evidence that supports most of the modern practices in diagnosis and management of bacterial IE in adults. This study represents data available as of June 1, 2023. Clinicians who believe other evidence should be considered are encouraged to contact the authors to propose revisions to the online living version of this guideline. As previously stated, no clinical trial or knowledge synthesis can extrapolate to all possible patient care scenarios; hence, this guideline is not intended to establish medicolegal standards of care or replace clinician judgment for individual patients.

Accepted for Publication: June 14, 2023.

Published: July 31, 2023. doi:10.1001/jamanetworkopen.2023.26366

Correction: This article was corrected on August 24, 2023, to fix an error in Box 1, and on October 19, 2023, to fix errors in the unit of penicillin in Table 2 and eTable 3 in Supplement 1.

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 McDonald EG et al. JAMA Network Open .

Corresponding Authors: Emily G. McDonald, MD, MSc, Centre for Outcomes Research and Evaluation, 5252 De Maisonneuve Blvd, Office 3E.03, Montréal, QC H4A 3S9, Canada ( [email protected] ); Todd C. Lee, MD, MPH, McGill University Health Centre, 1001 Decarie E5-1820, Montreal, QC H4A 3J1, Canada ( [email protected] ).

Author Contributions: Drs McDonald and T. C. Lee had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Spellberg and T. C. Lee made equal contributions for the purposes of authorship.

Concept and design: McDonald, Aggrey, Tarık Aslan, Cortes-Penfield, Dong, Maximos, Caceres, Clark, Forrest, Ghanem, Lahey, Ryder, Sanders, Tirupathi, Tong, Yassin, Spellberg, T. C. Lee.

Acquisition, analysis, or interpretation of data: McDonald, Aggrey, Tarık Aslan, Casias, Cortes-Penfield, Dong, Egbert, Footer, Isler, King, Maximos, Wuerz, Abdul Azim, Alza-Arcila, Bai, Blyth, Boyles, Caceres, Clark, Davar, Denholm, Ghanem, Hagel, Hanretty, Hamilton, Jent, Kang, Kludjian, Lapin, R. Lee, Li, Mehta, Moore, Mowrer, Ouellet, Reece, Ryder, Sanctuaire, Sanders, Stoner, So, Tessier, Tong, Wald-Dickler, Yassin, Yen, Spellberg, T. C. Lee.

Drafting of the manuscript: McDonald, Aggrey, Tarık Aslan, Casias, Cortes-Penfield, Dong, Egbert, Footer, Isler, Maximos, Wuerz, Abdul Azim, Alza-Arcila, Bai, Blyth, Caceres, Clark, Denholm, Forrest, Ghanem, Hanretty, Hamilton, Kang, Kludjian, Lahey, Lapin, R. Lee, Mehta, Moore, Mowrer, Reece, Ryder, Sanctuaire, Sanders, Stoner, So, Tirupathi, Tong, Wald-Dickler, Yassin, Yen, Spellberg, T. C. Lee.

Critical review of the manuscript for important intellectual content: McDonald, Tarık Aslan, Casias, Cortes-Penfield, Dong, Egbert, Footer, Isler, King, Wuerz, Abdul Azim, Alza-Arcila, Bai, Blyth, Boyles, Clark, Davar, Forrest, Hagel, Hanretty, Jent, Kang, Lahey, R. Lee, Li, Mowrer, Ouellet, Reece, Ryder, Sanctuaire, Sanders, Stoner, Tessier, Tong, Yen, Spellberg, T. C. Lee.

Statistical analysis: McDonald, Cortes-Penfield, T. C. Lee.

Obtained funding: Spellberg.

Administrative, technical, or material support: McDonald, Tarık Aslan, Cortes-Penfield, Dong, Egbert, Footer, Maximos, Abdul Azim, Alza-Arcila, Blyth, Kang, Lapin, Moore, Sanctuaire, Sanders, Yen, Spellberg, T. C. Lee.

Supervision: McDonald, Aggrey, Casias, Egbert, Footer, Maximos, Wuerz, Alza-Arcila, Denholm, Ghanem, Spellberg, T. C. Lee.

Conflict of Interest Disclosures: Dr McDonald reported being a member of the board of WikiGuidelines, a not-for-profit organization. Dr Maximos reported receiving honoraria from SPOR Evidence Alliance, University of Waterloo School of Pharmacy, and the Canadian Society of Hospital Pharmacists; receiving travel funding from Fresenius Kabi; working with Firstline (formerly Spectrum) as a knowledge mobilization expert; receiving previous study funding from MedBuy and the London Health Sciences Centre Foundation; receiving current funding for unrelated graduate school work through Ontario Graduate Scholarship and the President’s Graduate Scholarship. Dr Forrest reported receiving grants from the Antibiotic Resistance Leadership Group outside the submitted work. Dr Sanders reported receiving grants from Merck and Shionogi outside the submitted work. Dr Tessier reported receiving personal fees from Pfizer, AstraZeneca, Otsuka, AVIR Pharma, and Gilead outside the submitted work. Dr Tong reported receiving grants from the National Health and Medical Research Council and personal fees from Roivant Sciences outside the submitted work. Dr T. C. Lee reported receiving salary support from Fonds de Recherche du Quebec–Sante Research outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We also wish to thank Gabriel Vilchez, MD, for providing critical insights to the crafting of this WikiGuideline. They were not compensated for their time.

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11:  Infective Endocarditis

Rachel A. Foster; P. Brandon Bookstaver

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Patient presentation.

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Chief Complaint

Headache, fevers, and chills

History of Present Illness

GR is a 68-year-old woman with a notable past medical history of rheumatoid arthritis on infliximab and a prosthetic aortic valve, who was brought to the emergency department (ED) after her family found her extremely lethargic and confused at home. She had been complaining of fevers, chills, headache, and neck pain for 2 days prior to presentation, and as per the patient’s family had steadily become less and less communicative. Otherwise the patient has had no major medical issues in the last year since her aortic valve replacement.

Past Medical History

CAD, depression, type II DM, eczema, HTN, fibromyalgia, severe aortic stenosis with valve replacement

Surgical History

Bioprosthetic aortic valve replacement (10 months ago), S2–S4 diskectomy (4 years ago), tubal ligation (>15 years ago), cholecystectomy (>15 years ago)

Family History

Father passed away from HF; mother has type II DM, HTN, and h/o stroke; sister has type II DM, COPD, and HTN

Social History

Widowed, lives by herself, never used alcohol, former smoker (quit 10 years ago)

Hydrocodone/acetaminophen (vomiting)

Home Medications

Aspirin DR tablet 81 mg PO daily

Atorvastatin 20 mg PO daily

Fluoxetine 40 mg PO daily

Glimepiride 4 mg PO daily

Infliximab 3 mg/kg IV every 2 months

Lisinopril 10 mg PO daily

Pregabalin 75 mg PO BID

Triamcinolone 0.1% lotion topical BID

Vitamin D3 5,000 IU PO daily

Physical Examination

Vital signs.

Temp 102.1°F (tympanic), HR 112 bpm, RR 19 breaths per minute, BP 91/52 mm Hg, SpO 2 97% (on room air), Ht 165 cm, Wt 91 kg, BMI 33.4 kg/m 2

Lethargic, acutely ill appearing, appears stated age

Normocephalic, atraumatic, PERRLA, EOMI, faint conjunctival hemorrhage, non-icteric sclera, poor dentition, no erythema or swelling in the oropharynx

No nuchal rigidity, tenderness to palpation on lower lumbar region

Clear to auscultation bilaterally, no wheezes or crackles

Cardiovascular

Regular rate and rhythm, faint systolic murmur over the right base

Soft, non-distended, no masses, no focal rebound or guarding, tenderness in the epigastric region to palpation

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A 58-year-old man presents with intermittent fever for three weeks. The fever was 100˚F on average. He felt fatigued and listless during this time. No other symptoms were present. His medical and surgical histories are unremarkable. He is not on any medications or supplements. There is no history of recreational drug abuse. His family history is unremarkable. A chest x-ray and urinalysis are both normal.

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Atypical Presentation of Infective Endocarditis: A Case Report

Arian bethencourt.

2 Internal Medicine Department, Kendall Hospital, USA

Daylin Rodriguez

1 College of Medicine, University of Science, Arts and Technology, Montserrat, British West Indies

Dalie Ortet

3 Clinica Biblical Hospital, Costa Rica

Tony L Brown

4 Harvard University, USA

Nicholas A. Kerna

5 Department of Internal Medicine, Suriwongse Medical Center, Thailand

Joseph Reimon

6 Internal Medicine, Kendall Regional Hospital

Robert Hernandez

7 Transitional Year Director, Kendall Regional Hospital

The American Heart Association defines Infective Endocarditis (IE) or bacterial endocarditis as an infection caused by bacteria that enter the bloodstream and settle in the heart lining, heart valve, or blood vessel [ 1 ].

IE is considered the fourth most common life-threatening infection syndrome after sepsis, pneumonia, and intra-abdominal abscess. In 2010, IE was associated with 1.58 million disability-adjusted life years, or years of healthy life lost, as a result of death and nonfatal illness and impairment [ 2 , 3 ].

The variability in clinical presentation of IE and the importance of early diagnosis require a diagnostic strategy that is prompt for disease detection and specific for its exclusion across all forms of the disease [ 2 ].

Introduction

The objectives of this case report are to increase awareness of the atypical presentations of IE, to emphasize the complications of IE, to avoid unnecessary invasive treatment for patients with septic emboli secondary to IE, and to promote timely diagnosis and treatment of patients with similar clinical presentations.

Case Presentation

We present a 68-year-old Caucasian male who reported left leg weakness during his intake interview at a local hospital. The patient had been experiencing leg weakness for one week. He was admitted to the hospital due to his complaint of leg weakness and fever.

After three days, he was discharged from the hospital with the impression of a viral infection. Subsequently, the patient’s symptoms worsened. He returned to the hospital one week later and was readmitted due to his inability to walk and left side and left arm weakness.

The patient is married and living with his wife. He is a former ETOH abuser and former tobacco user (20 packs/year), and stated that he is currently a nondrinker and nonsmoker. The patient has worked for several years as a tugboat operator. The patient did not report any family medical history or known drug allergies.

Medical History

The patient reported a history of Hepatitis C, diabetes mellitus type 2, gastroesophageal reflux, aortic stenosis, and primary liver cancer metastasized to the right suprarenal gland. The patient had an aortic valve replacement one year ago, adrenalectomy (right), and chemoembolization about two years ago.

Physical Examination Findings

General appearance:.

The patient was alert, awake, and oriented times 3 to person, place, and time. The patient did not display signs of acute distress.

Vital Signs:

Temperature: 36.9 o C; blood pressure: 139/58 mmHg; heart rate: 83 bpm; respiratory rate: 19 rpm; O2 saturation 98%.

Normocephalic atraumatic; mucous membranes moist; extraocular muscles intact; pupils equally round and reactive to light, with accommodation bilaterally; no jugular venous distention.

Clear to auscultation.

S1/ S2, holosystolic murmur at apex radiating to the axilla 3/6; no rubs, gallops.

Soft, nontender, nondistended.

Extremities:

No edema; pedal pulses +; + Janeway lesions on the right palm.

Musculoskeletal:

No joint swelling or deformity.

Venous stasis changes.

Neurological:

AAOx3; Hand dominance: right.

Short term/long term: intact.

Cranial nerves:

2 to 12 intact.

Sensory Exam:

Normal: light touch, pin prick, position, vibration, temperature.

Motor testing 1:

Normal: bulk, tone.

Motor Testing 2:

The patient showed no asterixis, no dystonia, no fasciculation, no myoclonus, no tremor.

2/5, UE Right: 5/5

1/5, LE Right: 5/5

Cerebellar Test:

Absent nystagmus.

Doll’s eyes, corneal reflex, gag reflex.

Tendon Reflexes:

1+ B/L UE and LE

Plantar Reflexes:

No response (right, left).

The patient exhibited focal weakness, gait disorder. The patient denied bladder incontinence, bowel incontinence, change in LOC, confusion, dizziness, headache, lightheaded, numbness, seizure, slurred speech, spinning sensation, fainting, unable to speak, vision change, and generalized weakness.

Laboratory Findings

White count 14 mg/dl, H and H 11 mg/dl, 35 mg/dl, platelet count 61 mg/dl.

Creatinine 1.16mg/dl, potassium 3.7Eq/l, alk phos 143U/I, Mg 2.3 mEq/dl, Ca 8.2mE/dl, Pho 1.9 mE/dl.

Coagulation:

PT/INR: 17/1.6 sec; PTT: 31.5 sec.

Total bilirubin 2.1 mg/dl H; total protein 5.7 mg/dl; AST 39 U/L, ALT 39 U/L.

Diagnostic Imaging

Carotid doppler:.

Intracranial hemorrhage, not aneurysm.

CT head without contrast (below):

2.8 × 3 cm right parietal parenchymal hemorrhage; right parietal and left parietal subarachnoid hemorrhage.

Technique throughout the carotid arterial system bilaterally showed calcified plaque at the carotid bulbs with no flow-limiting stenosis.

RUQ US (below):

Mildly echogenic liver (possibly secondary to fatty infiltration); prominent portal vein.

(This raised the consideration of early portal hypertension. It was suggested to correlate further with clinical findings.)

Transesophageal echocardiography (below)

(Note. Image of mitral valve vegetation as shown on TEE from najms.org .)

Assessment and Diagnosis

The initial findings led to an impression of metastatic disease. After further evaluation and testing (including blood and urine cultures), the patient was given a definitive diagnosis of infective endocarditis.

It is important to note that the subsequent testing revealed two significant findings that suggested infective endocarditis by Duke criteria. (Major Duke criteria: positive blood culture tested two times, Gram-positive cocci in pairs as Streptococcus, and vegetation on the mitral valve noted on the 2D echo 10 mm; Minor Duke criteria: Murmur, systolic murmur on the apex MR, and hemorrhagic stroke [ 4 ].) The patient suffered acute hemorrhagic CVA secondary to septic cardioembolism.

Management and Treatment

• Administration of vancomycin empirically [ 5 ].
• Blood culture taken twice.
• Picc line for long-term IV ABX, 6 weeks.
• Reevaluate for possible mitral valve surgery.

Case Discussion

Preliminary impression for the patient was a large intraparenchymal hemorrhage likely secondary to metastatic disease since the patient had a history of hepatic cancer versus coagulopathy thrombocytopenia.

During day 1 and 2 of treatment, the patient’s MRI showed sizeable dominant hemorrhage in the right posterior parietal lobe demonstrating peripheral enhancement–which can be seen in metastatic disease but can also be due to the subacute phase of hemorrhage/ischemia. The findings showed large intraparenchymal hemorrhage, likely secondary to septic emboli. These findings contributed to the impression of metastatic disease, but other conditions were considered possible.

The care providers discussed differential diagnoses for amyloidosis (less likely because the bleeding area), an aneurysm, AV malformation, and Traumatic Brain Injury (TBI); however, the patient did not report any trauma. Approximately day 4, the care providers suspected IE.

On day 4 of treatment, an echocardiogram was ordered. An annular calcification in the mitral valve was observed as was mild thickening and normal leaflet separation and possible, mobile vegetation measuring 10 mm x 26 mm. The transmitral velocity was within normal range. There was moderate regurgitation and no evidence of stenosis.

After reviewing the additional findings, an Infectious Disease (ID) inter-consult was completed. Blood and urine cultures were taken. The blood culture was positive for Gram-positive cocci (Enterococcus faecalis). TTE and TEE confirmed mitral valve vegetation. The definitive diagnosis was determined as bacterial endocarditis (2 major Duke criteria) with septic embolic and hemorrhagic bleeding.

The management of the condition was focused on continuing patient treatment with vancomycin, ceftriaxone, and ampicillin/ sulbactam (Unasyn); IV for 6 weeks.

The patient was discharged from the facility with close follow-up by the ID internist (infection disease specialist), a cardiologist, and a cardiothoracic surgeon. Mitral valve replacement was not needed. However, it was recommended to continue monitoring the bacteremia to assess the need for possible heart surgery and removal of the prosthetic valve.

Considerations Regarding IE

Complications of IE include cardiac, neurologic, renal, musculoskeletal; and complications related to systemic infection, such as embolization, metastatic infection, and mycotic aneurysm. These complications can co-occur and can be considered based on pathogenesis; such as cerebral infarct (embolic), heart valve destruction (the local spread of infection), vertebral osteomyelitis (metastatic infection), and glomerulonephritis (immune-mediated damage).

It has been researched and described that IE should be considered a possible etiology if the patient displays symptoms of systemic arterial embolization. The likelihood of IE is increased in patients with cerebral and systemic arterial embolization [ 6 , 7 ].

Echocardiography is central to the diagnosis and management of patients with IE. Evidence of an oscillating intracardiac mass or vegetation, an annular abscess, prosthetic valve partial dehiscence, and new valvular regurgitation are significant criteria in the diagnosis of IE [ 1 ]. Definitive diagnosis of IE can be made based on clinical manifestations, blood cultures, and echocardiography. Additional evaluations for patients with suspected IE include electrocardiography, chest radiography, and other radiographic imaging targeting clinical manifestations [ 8 ].

Suggested Guidelines for the Timely Assessment and Treatment of IE

During an intake interview, it is essential to assess a patient with a prosthetic heart device, a history of surgeries, or recent dental procedures. It is imperative to highlight cerebral and systemic arterial embolization as related complications of IE.

Echocardiography should be performed directly in patients suspected of IE (Class I; Level of Evidence A) [ 1 ].

At least three sets of blood cultures obtained from different venipuncture sites should be obtained, with the first and last samples drawn at least one hour apart. (Class I; Level of Evidence A) [ 1 ].

TEE should be performed if initial TTE images are negative, or inadequate in patients for whom there is an ongoing suspicion for IE, or when there is a concern for intracardiac complications in patients with an initial positive TTE (Class I; Level of Evidence B) [ 1 ].

If there is high suspicion of IE despite initial negative TEE, then repeat TEE is recommended in 3 to 5 days, or sooner if clinical findings change (Class I; Level of Evidence B) [ 1 ].

Repeat TEE after initial positive TEE if clinical features suggest a new development of intracardiac complications (Class I; Level of Evidence B) [ 1 ].

It is fundamental to obtain at least two sets of blood cultures every 24 to 48 hours until the bloodstream infection has cleared (Class IIa; Level of Evidence C) [ 1 ].

If operative tissue cultures are positive, then an entire antimicrobial course is indicated after valve surgery (Class IIa; Level of Evidence B) [ 1 ].

The risk of embolization in the setting of native valve endocarditis is 13 to 44 percent, and in many cases embolization occurs before a diagnosis of IE has been established. Among patients with IE, risk factors for embolization include vegetation size >10 mm; vegetation mobility; vegetation location on the anterior mitral leaflet; prior embolization; and infection with Staphylococcus aureus, Streptococcus bovis, or fungus.

In a multicenter study of 384 patients with definitive IE (75 percent with native valve endocarditis), S. aureus and S. bovis were predictors of total embolic events, while vegetation length >10 mm and severe vegetation mobility were significant predictors of embolic events after initiation of antibiotic therapy. It is clear that the incidence of septic emboli in the setting of infected endocarditis depends on the size of the vegetation and the type of infective microorganism [ 9 ].

Considerations for Early Valve Surgery

Early valve surgery in left-sided NVE (during initial hospitalization and before completion of a full course of antibiotics) is indicated in patients with IE who present with valve dysfunction resulting in symptoms or signs of heart failure (Class I; Level of Evidence B) [ 1 ].

Early surgery should be considered, particularly in patients with IE caused by fungi or highly-resistant organisms; such as vancomycin-resistant Enterococcus or multidrug-resistant Gramnegative bacilli (Class I; Level of Evidence B) [ 1 ].

Early surgery is indicated in patients with IE complicated by heart block, annular or aortic abscess, or destructive penetrating lesions (Class I; Level of Evidence B) [ 1 ].

Early surgery is indicated with evidence of persistent infection after the start of appropriate antimicrobial therapy (Class I; Level of Evidence B) [ 1 ].

Early surgery is reasonable in patients who present with recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy (Class IIa; Level of Evidence B) [ 1 ].

Early surgery is rational in patients with severe valve regurgitation and mobile vegetations >10 mm (Class IIa; Level of Evidence B) [ 1 ].

Early surgery may be considered in patients with mobile vegetations >10 mm, particularly when involving the anterior leaflet of the mitral valve and other relative indications for surgery (Class IIb; Level of Evidence C) [ 1 ].

Valve surgery may be considered without delay in IE patients with stroke or subclinical cerebral emboli and residual vegetation if imaging studies have excluded intracranial hemorrhage and if neurological damage is not severe (Class IIb; Level of Evidence B) [ 1 ].

In patients with major ischemic stroke or intracranial hemorrhage, it is recommended to delay valve surgery for at least four weeks (Class IIa; Level of Evidence B) [ 1 ].

Many complications are commonly observed in patients with infective endocarditis. Even though cardiac complications are the most common, neurologic and septic complications are the leading cause of death in patients with infective endocarditis [ 5 ]. The advantages of timely diagnosis and treatment for this patient–and patients with similar histories and presentations-include avoiding unnecessary and invasive interventions, and possible death. By presenting this case report, it is proposed that care providers can more readily recognize infective endocarditis and its atypical presentation in similar settings and circumstances.

Abbreviations

Conflict of Interest Statement

The authors declare that this paper was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Volume 27, Number 11—November 2021

Bordetella hinzii Pneumonia and Bacteremia in a Patient with SARS-CoV-2 Infection

Cite This Article

Patients with severe acute respiratory syndrome coronavirus 2 infection may have bacterial co-infections, including pneumonia and bacteremia. Bordetella hinzii infections are rare, may be associated with exposure to poultry, and have been reported mostly among immunocompromised patients. We describe B. hinzii pneumonia and bacteremia in a severe acute respiratory syndrome coronavirus 2 patient.

Since the December 2019 beginning of the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), there have been >180 million cases and >3.9 million deaths worldwide ( 1 ). Severe bacterial and fungal co-infections are a major concern with COVID-19 and increase disease mortality ( 2 ).

The genus Bordetella comprises >10 known species of small, gram-negative coccobacilli, the most common of which is Bordetella pertussis ( 3 ). Bordetella hinzii was first identified as a cause of respiratory infection in poultry and more rarely in rodents ( 4 ). It was first reported as a human infection in a patient with HIV infection in 1994 as a cause of bacteremia ( 5 ) and has subsequently been identified as a cause of soft tissue infections, pneumonia, cholangitis, urinary tract infections, bacteremia, and endocarditis, most often in immunocompromised patients ( 4 – 15 ; Appendix references 16,17 ). We report a case of B. hinzii pneumonia and bacteremia in a patient with SARS-CoV-2 infection.

A 77-year-old man with medical history notable for uncontrolled type 1 diabetes mellitus and coronary artery disease and who was receiving hemodialysis for end-stage renal disease sought treatment with worsening shortness of breath and 3 days of chest pain. He also reported cough, nausea, fever, and back pain. He lived at a nursing home and had no known poultry or pet exposure. At initial examination, he was afebrile; had a blood pressure of 165/83 mm Hg; heart rate of 92 beats/min, and respiratory rate of 18 breaths/min; was severely hypoxic with oxygen saturation of 50% on room air, requiring a nonrebreather mask; and had decreased breath sounds on chest auscultation. Blood test results (reference ranges) showed hemoglobin, 10 g/dL (12–16 g/dL); leukocytes, 4,300 cells/mm 3 (4,000–11,000 cells/mm 3 ), 78% neutrophils; platelets, 238,000/mm 3 (140,000–440,000/mm 3 ); serum creatinine level, 4.3 mg/dL (0.5–1.1 mg/dL); procalcitonin, 3.3 ng/mL (0.00–0.30 ng/mL); lactate dehydrogenase, 169 U/L (100–230 U/L); C-reactive protein, 213 mg/L (0.0–3.0 mg/L); and ferritin, 2,492 ng/mL (22.0–322.0 ng/mL). A SARS-CoV-2 nasopharyngeal swab sample test was positive by PCR. A computed tomography scan of his chest revealed multiple rib fractures, a large right-side pleural effusion, and right upper-lobe pulmonary infiltrate.

We started the patient on dexamethasone. We considered remdesivir therapy but did not start it because of his renal disease. We also empirically initiated treatment with piperacillin/tazobactam and levofloxacin for bacterial pneumonia. We performed right-side thoracentesis and drained 725 mL of transudative fluid; fluid culture was negative for growth of bacteria. He was intubated on day 7 after admission because of worsening hypoxemia but subsequently extubated on day 9. On day 13, acute respiratory failure (oxygen saturation ≈70%) and bradycardia (heart rate ≈40 beats/min) developed, and he was hypotensive with agonal breathing. He was emergently reintubated and given atropine, which improved his heart rate. We initiated broad-spectrum antimicrobial treatment with intravenous vancomycin and cefepime.

Figure . Computed tomography image of the chest showing bilateral dense consolidations and right-sided pleural effusion in 77-year-old man with severe acute respiratory syndrome coronavirus 2 who was later found to be...

Blood cultures drawn on day 13 after admission grew gram-negative rods in routine blood, chocolate, and MacConkey agar media. A computed tomography scan of the chest revealed bilateral patchy ground glass opacities, dense consolidations in both lung bases, and a small right pleural effusion ( Figure ). The patient underwent a bronchoalveolar lavage (BAL) on day 14; the BAL fluid grew >100,000 CFUs of the same gram-negative bacilli, which we had not yet identified, along with 20,000–50,000 CFUs of Klebsiella pneumoniae . Gram stain of the BAL fluid showed many leukocytes and few gram-negative rods. We continued treatment with vancomycin and cefepime. On day 17, we extubated then reintubated him the same day because of ongoing hypotension and poor mentation. Because of worsening hemodynamic status, continued poor mentation, and overall poor prognosis, we changed goals of care to comfort measures only, and the patient died soon after.

On day 18 after the patient’s admission, we identified the gram-negative rod in the blood culture and BAL fluid as Bordetella hinzii on the basis of an excellent score (2.43) in matrix-assisted laser desorption/ionization-time of flight mass spectrometry testing. We measured antimicrobial sensitivities by broth microdilution using the Vitek 2 system (bioMérieux; https://www.biomerieux.com ) and MIC, interpreting breakpoints using Clinical and Laboratory Standards Institute ( https://clsi.org ) guidelines. The isolate was sensitive only to meropenem, levofloxacin, amikacin, and gentamicin and showed high MICs of 32 μg/mL to ceftazidime and 64 μg/mL to cefepime ( Table 1 ).

Conclusions

B. hinzii is a strictly aerobic gram-negative bacillus that was first identified as a cause of respiratory illnesses, mostly rhinotracheitis, in poultry ( 3 ). Manifestations from reported human cases include skin infection, urinary tract infection, pneumonia, and infective endocarditis, with or without bacteremia ( 4 – 15 ; Appendix references 16,17 ) ( Table 2 ). Human infection with B. hinzii is very uncommon; the 18 cases thus far reported suggest that B. hinzii behaves like an opportunistic pathogen in humans. Underlying conditions in patients from those cases included HIV, malignancy, liver disease, ulcerative colitis, diabetes, and liver transplantation; 3 of the patients had no underlying medical conditions. There was often known poultry exposure, unlike in this case. It is possible that this pathogen colonizes the respiratory tract then is activated to cause infection later when the host becomes immunocompromised ( 7 ; Appendix reference 16 ). B. hinzii was isolated from wild rodents in Southeast Asia, raising the possibility that they might serve as reservoirs that could transmit the pathogen to humans or pets (Appendix reference 18 ). Most patients recovered when treated with appropriate antimicrobial drugs, but this infection can lead to death, especially in severely immunocompromised patients ( 10 , 13 ).

B. hinzii is frequently resistant to many antimicrobial drugs, including β-lactams, cephalosporins, and quinolones. Reported isolates have been susceptible to piperacillin/tazobactam, ceftazidime, tigecycline, and meropenem ( 4 – 11 ). The interpretation of antimicrobial sensitivity testing is not established. Choice of antimicrobial drugs and treatment duration are also not standardized. The cases of bacteremia and endocarditis identified were treated with ceftazidime and ticarcillin/clavulanate. The patient we describe had received only a short course of vancomycin and cefepime before we identified B. hinzii in cultures from samples he provided. The isolate of B. hinzii identified had a high MIC to cefepime, 64 μg/mL, suggesting inadequate antimicrobial coverage before his death. This high MIC to third- and fourth-generation cephalosporins had been reported in only 1 previous case ( 11 ).

The cause of death in this case was likely multifactorial and included respiratory infection with SARS-COV-2 and the hemodynamic compromise that ensued. The role of Klebsiella isolated from BAL fluid seems unclear, but this bacterium was found only in very small quantities from the respiratory tract and was treated with appropriate antimicrobial drugs.

In summary, B. hinzii has multiple clinical manifestations and outcomes in both immunocompetent and immunocompromised patients. Reports of patients with B. hinzii infections seem to be increasing in recent years, which may be because of the availability of better identification methods, such as matrix-assisted laser desorption/ionization-time of flight mass spectrometry and gene sequencing, as well as an increase in the number of immunocompromised persons who have underlying conditions such as HIV, malignancy, or transplantation or who are taking immunosuppressive agents. Our patient likely had untreated lung B. hinzii infection that led to bacteremia. He had uncontrolled diabetes and received dexamethasone as part of his treatment, which may have resulted in dissemination through bacteremia. In addition, SARS-CoV-2 co-infection rendered him more susceptible to infection. Our findings add to the growing knowledge of emerging secondary infectious complications, including from opportunistic pathogens, concurrent with or after SARS-CoV-2 infection. The increasing case reports of invasive B. hinzii may indicate its emergence as a pathogen in humans.

Dr. Maison-Fomotar is a graduating second-year infectious diseases fellow at the University of California San Francisco, Fresno, California. Her primary interests are HIV, central nervous system infections, and infectious disease issues in underserved populations.

Dr. Sivasubramanian is an assistant professor of infectious diseases at University of California San Francisco, Fresno, California. Her primary interests are fungal infections and infections in critically ill patients.

• WHO . COVID-19 dashboard [ cited 2021 Jun 28 ]. https://covid19.who.int
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• Hristov  AC , Auwaerter  PG , Romagnoli  M , Carroll  KC . Bordetella hinzii septicemia in association with Epstein-Barr virus viremia and an Epstein-Barr virus-associated diffuse large B-cell lymphoma. Diagn Microbiol Infect Dis . 2008 ; 61 : 484 – 6 . DOI PubMed Google Scholar
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• González  MM , Romano  MPC , de Guzmán García Monge  MT , Martín  BB , García  AS . Bordetella hinzii endocarditis, a clinical case not previously described. Eur J Case Rep Intern Med . 2019 ; 6 : 000994 . PubMed Google Scholar
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• Figure . Computed tomography image of the chest showing bilateral dense consolidations and right-sided pleural effusion in 77-year-old man with severe acute respiratory syndrome coronavirus 2 who was later found to...
• Table 1 . Antimicrobial susceptibility of Bordetella hinzii isolate by broth dilution
• Table 2 . Characteristics of previously reported Bordetella hinzii infections

DOI: 10.3201/eid2711.211468

Original Publication Date: August 13, 2021

Table of Contents – Volume 27, Number 11—November 2021

Please use the form below to submit correspondence to the authors or contact them at the following address:

Geetha Sivasubramanian, Division of Infectious Diseases, Department of Internal Medicine, UCSF Fresno, 155 N Fresno St, Ste 307, Fresno, CA 93701, USA

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Study Pinpoints Oral Antibiotics Associated With Serious Skin Reactions

Kate Johnson

August 12, 2024

Potentially life-threatening cutaneous adverse drug reactions (cADRs) are associated with commonly prescribed oral antibiotics, according to a large, population-based, nested case-control study of older adults, spanning two decades.

The findings, published online in JAMA on August 8, "underscore the importance of judicious prescribing, with preferential use of antibiotics associated with a lower risk when clinically appropriate," noted senior author David Juurlink, MD, PhD , professor of medicine; pediatrics; and health policy, management and evaluation at the University of Toronto, and head of the Clinical Pharmacology and Toxicology Division at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, and coauthors.

"We hope our study raises awareness about the importance of drug allergy and gains support for future studies to improve drug allergy care," lead author Erika Lee, MD, clinical immunology and allergy lecturer at the University of Toronto's Drug Allergy Clinic, Sunnybrook Health Sciences Centre, told Medscape Medical News . "It is important to recognize symptoms and signs of a severe drug rash and promptly stop culprit drugs to prevent worsening reaction."

Serious cADRs are "a group of rare but potentially life-threatening drug hypersensitivity reactions involving the skin and, frequently, internal organs," the authors wrote. "Typically delayed in onset, these reactions include drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) — the most severe cADR, which has a reported mortality of 20%-40%," they noted.

Speculation Without Data

Although it has been speculated that some oral antibiotics are more likely than others to be associated with serious cADRs, there have been no population-based studies examining this, they added.

The study included adults aged 66 years or older and used administrative health databases in Ontario, Canada, spanning April 1, 2002, through March 31, 2022. Data on antibiotic use were taken from the Ontario Drug Benefit database. The Canadian Institute for Health Information (CIHI) National Ambulatory Care Reporting System was used to obtain data on emergency department (ED) visits for cADRs, while the CIHI Discharge Abstract Database was used to identify hospitalizations for cADRs. Finally, demographic information and outpatient healthcare utilization data were obtained from the Registered Persons Database and the Ontario Health Insurance Plan database, respectively.

A cohort of 21,758 older adults (median age, 75 years; 64.1% women) who had an ED visit or hospitalization for serious cADRs within 60 days of receiving antibiotic therapy was matched by age and sex with 87,025 antibiotic-treated controls who did not have a cutaneous reaction.

The median duration of antibiotic prescription was 7 days among cases and controls, and among the cases, the median latency period between antibiotic prescriptions and hospital visits for cADRs was 14 days. Most of the case patients went to the ED only (86.9%), and the rest were hospitalized.

The most commonly prescribed antibiotic class was penicillins (28.9%), followed by cephalosporins (18.2%), fluoroquinolones (16.5%), macrolides (14.8%), nitrofurantoin (8.6%), and sulfonamides (6.2%). Less commonly used antibiotics ("other" antibiotics) accounted for 6.9%.

Macrolide antibiotics were used as the reference because they are rarely associated with serious cADRs, noted the authors, and the multivariable analysis, adjusted for risk factors associated with serious cADRs, including malignancy, chronic liver disease, chronic kidney disease, and HIV.

After multivariable adjustment, relative to macrolides, sulfonamides were most strongly associated with serious cADRs (adjusted odds ratio [aOR], 2.9) but so were all other antibiotic classes, including cephalosporins (aOR, 2.6), "other" antibiotics (aOR, 2.3), nitrofurantoin (aOR, 2.2), penicillins (aOR, 1.4), and fluoroquinolones (aOR, 1.3).

In the secondary analysis, the crude rate of ED visits or hospitalizations for cADRs was highest for cephalosporins (4.92 per 1000 prescriptions), followed by sulfonamides (3.22 per 1000 prescriptions). Among hospitalized patients, the median length of stay was 6 days, with 9.6% requiring transfer to a critical care unit and 5.3% dying in the hospital.

Hospitalizations, ED Visits Not Studied Previously

"Notably, the rate of antibiotic-associated serious cADRs leading to an ED visit or hospitalization has not been previously studied," noted the authors. "We found that at least two hospital encounters for serious cADRs ensued for every 1000 antibiotic prescriptions. This rate is considerably higher than suggested by studies that examine only SJS/TEN and drug reaction with eosinophilia and systemic symptoms."

Lee also emphasized the previously unreported findings about nitrofurantoin. "It is surprising to find that nitrofurantoin, a commonly prescribed antibiotic for urinary tract infection, is also associated with an increased risk of severe drug rash," she told Medscape Medical News . "This finding highlights a potential novel risk at a population-based level and should be further explored in other populations to verify this association," the authors wrote.

Amesh Adalja, MD , a senior scholar at the Johns Hopkins Center for Health Security and a spokesperson for the Infectious Diseases Society of America , who was not involved in the study, agreed that the nitrofurantoin finding was surprising, but he was not surprised that sulfonamides were high on the list.

"The study reinforces that antibiotics are not benign medications to be dispensed injudiciously," he told Medscape Medical News . "Antibiotics have risks, including serious skin reactions, as well as the fostering of antibiotic resistance. Clinicians should always first ask themselves if their patient actually merits an antibiotic and then assess what is the safest antibiotic for the purpose, bearing in mind that certain antibiotics are more likely to result in adverse reactions than others."

The study was supported by the Canadian Institutes of Health Research. The study was conducted at ICES, which is funded in part by an annual grant from the Ontario Ministry of Health and Long-Term Care. One coauthor (Drucker) reported receiving compensation from the  British Journal of Dermatology as reviewer and section editor, the  American Academy of Dermatology as guidelines writer,  Canadian Dermatology Today as manuscript writer, and the National Eczema Association and the Canadian Agency for Drugs and Technologies in Health as consultant; he reported receiving research grants to his institution from the National Eczema Association, Eczema Society of Canada, Canadian Dermatology Foundation, Canadian Institutes of Health Research, US National Institutes of Health, and PSI Foundation. Another coauthor (Piguet) reported receiving grants from AbbVie, Bausch Health, Celgene, Lilly, Incyte, Janssen, LEO Pharma, L'Oréal, Novartis, Organon, Pfizer, Sandoz, Amgen, and Boehringer Ingelheim; receiving payment or honoraria for speaking from Sanofi China; participating on advisory boards for LEO Pharma, Novartis, Sanofi, and Union Therapeutics; and receiving equipment donation from L'Oréal. No other disclosures were reported. Adalja reported no relevant disclosures.

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