Diagnosis and Treatment of Bacterial Endocarditis

Transcription

1 Infectious diseases Board Review Manual Statement of Editorial Purpose The Hospital Physician Infectious Diseases Board Review Manual is a study guide for fellows and practicing physicians preparing for board exam inations in infectious diseases. Each manual reviews a topic essential to current practice in the subspecialty of infectious diseases. Diagnosis and Treatment of Bacterial Endocarditis Series Editor: Varsha Moudgal, MD Infectious Diseases Fellowship Program Director, St. Joseph Mercy Hospital, Ann Arbor, MI; and Assistant Professor of Medicine, Wayne State University School of Medicine, Detroit, MI PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White Senior EDITOR Robert Litchkofski executive vice president Barbara T. White Contributors: Amber M. Vasquez, MD Fellow, Division of Infectious Diseases, The Ohio State University Wexner Medical Center, Columbus, OH Jose A. Bazan, DO Assistant Professor of Clinical Internal Medicine, Division of Infectious Diseases, The Ohio State University Wexner Medical Center, Columbus, OH executive director of operations Jean M. Gaul Table of Contents NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the Introduction... 2 Amer ican Board of Internal Medicine. Case Presentations Board Review Questions References... 18

2 Infectious Diseases Board Review Manual Diagnosis and Treatment of Bacterial Endocarditis Amber M. Vasquez, MD, and Jose A. Bazan, DO INTRODUCTION In the United States and Western Europe, the incidence of community-acquired native valve endocarditis (NVE) has been reported to range from 1.7 to 6.2 cases per 100,000 patient-years. 1,2 While the incidence and clinical characteristics of infective endocarditis (IE) often vary by the predisposing clinical condition (eg, intravenous drug use and structural heart disease) as well as by geographic region, the rise of Staphylococcus aureus as the leading cause of IE in the 21st century has led to a shift toward a more acute illness presentation and an increased risk of secondary complications. Despite improvements in diagnostic criteria and advancements in antimicrobial therapy and surgical repair, there remains an ever high risk of mortality associated with this disease. 3 In this review, we address the diagnosis, clinical characteristics, complications, and treatment of bacterial endocarditis. CASE PRESENTATIONS CASE PATIENT 1 Initial Presentation and History A 55-year-old man with a history of anemia and mitral valve prolapse presents with a 2-month history of progressive shortness of breath on exertion, lower extremity swelling, nonproductive cough, and unintentional weight loss of 20 lb. He received a 5-day course of azithromycin for a presumptive diagnosis of pneumonia approximately 1 month ago. His last dental cleaning was 2 months ago, and he states that he always takes antibiotic prophylaxis. He denies any intravenous drug use. He is a carpenter and cut his hand at work about 3 months ago, but that area healed within a few days. Physical Exam and Diagnostic Testing Examination reveals a temperature of F, heart rate of 77 beats/min, normal blood pressure, and normal oxygen saturation. There is 1+ pitting edema at the ankles. The lung examination is clear. Cardiac exam reveals a faint holosystolic murmur heard at the apex and left sternal border. Two sets of blood cultures are growing viridans group streptococci. Complete blood count as well as renal and hepatic function test results are normal. Transthoracic echocardiogram (TTE) demonstrates a 0.6-cm mobile vegetation on the aortic valve and a 0.8-cm vegetation on the mitral valve with moderate mitral regurgitation. Copyright 2014, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA , All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. 2 Hospital Physician Board Review Manual

3 How is the diagnosis of IE established in this patient? The diagnosis of IE begins with the critical step of blood culture acquisition prior to the initiation of antimicrobial therapy. Echocardiography is performed to evaluate for the presence of intracardiac vegetation or valvular compromise. Electrocardiogram may demonstrate new heart block that telegraphs a recently acquired cardiac abnormality. Chest X-ray (CXR) and cerebral imaging can assist in screening for evidence of embolic phenomenon, as can basic renal and hepatic panels on laboratory work-up. A leukocytosis is often present along with a normocytic, normochromic anemia and elevated inflammatory markers. Physical examination may reveal a new heart murmur and various stigmata of endocarditis, such as splinter hemorrhages, Osler nodes, Janeway lesions, and Roth spots. However, no single diagnostic tool alone can establish or reject the diagnosis of IE. Thus, the Duke criteria were designed as a tool that would better allow clinicians to confirm or eliminate the diagnosis. 4 Established in 1994, the Duke criteria divide the likelihood of IE into 3 primary categories: definite, possible, or rejected (Table). Definite IE can be established pathologically with demonstration of vegetation or microorganisms on intracardiac tissue obtained during open heart surgery or autopsy. It can also be established clinically based on the presence of major or minor criteria: to qualify for clinically definite IE, 2 major, 1 major and 3 minor, or all 5 minor criteria must be present. In the original Duke criteria, weight was given to S. aureus bacteremia when infection was community-acquired and another primary focus was lacking, since endocarditis was felt to be more likely in these situations. 4,5 With the rise of nosocomially acquired S. aureus bacteremia, particularly from indwelling vascular catheters, the modified Duke criteria from 2000 placed S. aureus back in the major criteria, regardless of the presence of a removable focus of infection. 6,7 Possible IE is defined by the presence of 1 major and 1 minor criterion or 3 minor criteria. The diagnosis of IE is rejected if the patient does not meet the criteria for possible IE, there is a firm alternative diagnosis, IE syndrome resolves with less than 4 days of treatment, or the patient fails to demonstrate pathological evidence of IE. 4,7 What organisms are the most likely to cause native valve endocarditis? Staphylococci and streptococci continue to be the leading pathogenic organisms causing both native and prosthetic valve endocarditis, occurring in roughly equal numbers in community-acquired cases, while staphylococci are the leading cause of health-care associated infections. 3 With the rising incidence of infections due to S. aureus over recent decades, it has now become the leading causal organism of IE as well as the most important prognostic indicator of disease outcome. 8,9 NVE patients with S. aureus have higher mortality and an increased risk of embolic phenomenon and central nervous system (CNS) disease. 10 IE was previously categorized as either having an acute (onset of illness <6 weeks) or subacute (6 weeks to 3 months) presentation. While this distinction has largely become a historical practice, the acuity of the presenting illness can still be a helpful clue as to the most likely etiologic organism. Endocarditis due to S. aureus, Streptococcus pyogenes, and Streptococcus pneumoniae is more likely to present with an acute onset of symptoms, whereas viridans group streptococci, enterococci, and fastidious gram-negative organisms are more Infectious Diseases Volume 15, Part 1 3

4 Table. Diagnosis of Infective Endocarditis According to the Modified Duke Criteria Definite IE Pathological criteria Microorganisms demonstrated by culture or histologic examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen; OR Pathological lesions, vegetation, or intracardiac abscess confirmed by results of histologic examination showing active endocarditis Clinical criteria 2 major criteria; OR 1 major criterion and 3 minor criteria; OR 5 minor criteria Possible IE 1 major criterion and 1 minor criterion; OR 3 minor criteria Rejected IE Firm alternative diagnosis explaining evidence of IE; OR Resolution of IE syndrome with antibiotic therapy for 4 days; OR No pathological evidence of IE at time of surgery or autopsy, with antibiotic therapy for 4 days; OR Does not meet criteria for possible IE as above Definition of Terms Used in the Modified Duke Criteria for IE Diagnosis Major criteria Blood culture findings positive for IE Typical microorganisms consistent with IE from 2 separate blood cultures: Viridans streptococci, Streptococcus bovis, bacteria in the HACEK group, or Staphylococcus aureus Community-acquired enterococci, in the absence of a primary focus Microorganisms consistent with IE from persistently positive blood culture findings, defined as: At least 2 positive culture findings of blood samples drawn >12 h apart; OR All 3 or a majority of 4 separate cultures of blood (with first and last sample drawn at least 1 h apart) Single positive blood culture for Coxiella burnetii or antiphase I IgG antibody titer >1:800 Evidence of endocardial involvement Echocardiographic findings positive for IE (TEE recommended in patients with prosthetic valves, rated at least possible IE by clinical criteria or complicated IE [paravalvular abscess]; TTE as first test in other patients), defined as follows: Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; OR Abscess; OR New partial dehiscence of prosthetic valve; New valvular regurgitation (worsening or changing of preexisting murmur not sufficient) Minor criteria Predisposition, predisposing heart condition, or intravenous drug use Fever, temperature >38 C Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor Microbiological evidence: positive blood culture finding but does not meet a major criterion* or serologic evidence of active infection with organism consistent with IE Echocardiographic minor criteria eliminated HACEK = Haemophilus species, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; IE = infective endocarditis; TEE = transesophageal echocardiography; TTE = transthoracic echocardiography. *Excludes single positive culture findings for coagulase-negative staphylococci and organisms that do not cause endocarditis. Adapted from Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30: Hospital Physician Board Review Manual

5 likely to have subacute symptomatology. 11 This patient s insidious, subacute presentation, along with his dental cleaning that occurred around the time of symptom onset, should raise suspicion for the presence of underlying IE due to viridans group streptococci. What is the approach to antimicrobial therapy for patients with IE due to viridans group streptococci? The viridans group streptococci are α-hemolytic gram-positive organisms that exist abundantly as normal flora in the mouth. The group includes such species as S. sanguis, S. mitis, S. mutans, and the S. milleri group (S. anginosus, S. intermedius, and S. constellatus). The vast majority of these species remain highly sensitive to penicillins, but an increasing number of them demonstrate intermediate susceptibility or, more rarely, penicillin resistance. 11 The degree of susceptibility of the organism to penicillin affects the recommended antimicrobial dosing and duration of therapy. Highly susceptible strains, defined as having a penicillin minimum inhibitory concentration (MIC) of 0.12 μg/ml, can be treated with 12 to 18 million units/day of intravenous (IV) aqueous crystalline penicillin-g, either as a continuous infusion or in 4 to 6 equally divided doses for a duration of 4 weeks. In patients unable to tolerate penicillin but lacking an immediatetype hypersensitivity reaction that would risk crossreactivity with another beta-lactam antibiotic, a 4-week course of IV ceftriaxone (2 g every 24 hours) is the preferred alternative therapy, and it has shown cure rates comparable to those seen with treatment with penicillin. 12,13 Patients with these highly susceptible strains who have an uncomplicated bacterial endocarditis may be candidates for synergistic therapy with gentamicin 3 mg/kg IV every 24 hours (administered in 3 equally divided doses). The addition of synergistic gentamicin to either penicillin or ceftriaxone allows for treatment to be shortened to a 2-week duration of combination therapy while maintaining efficacy comparable to beta-lactam therapy alone. 14 Penicillin-intermediate or relatively resistant strains of streptococci (MIC >0.12 μg/ml to 0.5 μg/ml) require 24 million units/day of IV aqueous crystalline penicillin-g for 4 weeks with the addition of synergistic gentamicin for the first 2 weeks of therapy. Vancomycin (30 mg/kg IV every 24 hours in 2 equally divided doses) should be reserved for patients who have an immediate hypersensitivity reaction to penicillin. 11 What would be the preferred treatment if S. aureus were the causative pathogen? A semi-synthetic penicillin, such as nafcillin or oxacillin, at 12 g/day via continuous IV infusion or 4 to 6 equally divided doses is the preferred therapy for NVE caused by methicillin-sensitive S. aureus (MSSA). The majority of MSSA isolates are now resistant to penicillin, but in the rare instance that a highly penicillin-susceptible strain is isolated, then high-dose aqueous crystalline penicillin-g (24 million units/day) can be substituted for nafcillin or oxacillin. In uncomplicated right-sided MSSA IE (absence of renal failure, metastatic infection, leftsided valvular involvement, or meningitis), studies have shown success in treating these patients with 2 weeks of beta-lactam therapy with or without an aminoglycoside There is no clear data as to the most appropriate duration of nafcillin therapy in left-sided MSSA IE. If the infection is uncomplicated, 4 weeks of IV therapy should be sufficient. If the infection is complicated, such as the presence of a perivalvular abscess or meta- Infectious Diseases Volume 15, Part 1 5

6 static infection, treatment should include 6 weeks of nafcillin. 11 A 1982 randomized prospective trial evaluated the addition of synergistic gentamicin to nafcillin during the first 2 weeks of therapy for the treatment of S. aureus IE. The study demonstrated a reduction in the duration of bacteremia in both intravenous drug users and non intravenous drug users, including both right- and left-sided IE. However, no benefit to morbidity or mortality was seen, and in the non intravenous drug users who received synergistic gentamicin therapy, there was a higher incidence of aminoglycoside-induced nephrotoxicity. 18 More recent data has further highlighted the nephrotoxic risks associated with the use of synergistic gentamicin therapy, along with its lack of clinical benefit in the treatment of left-sided IE due to S. aureus. Therefore, its use is no longer routinely recommended. 19 In those unable to tolerate nafcillin or oxacillin due to side effects or non immediate-type hypersensitivity reactions, cefazolin 2 g IV every 8 hours is an accepted alternative. Though cefazolin has shown equal efficacy to cloxacillin, there is evidence that the use of other cephalosporins (eg, ceftriaxone or cefuroxime) is associated with a significantly higher 30-day mortality than cefazolin or cloxacillin. 20 Vancomycin is reserved for patients with immediate-type hypersensitivity reactions to beta-lactams or derivatives, but such situations present a treatment dilemma since vancomycin has demonstrated suboptimal outcomes when compared to beta-lactam therapy. 21 Desensitization to nafcillin or oxacillin for the duration of treatment can be considered over vancomycin. If vancomycin is used, the duration of treatment for right-sided IE due to MSSA is 4 weeks, while for left-sided IE the treatment duration is 6 weeks. 11 Finally, daptomycin has been shown to be noninferior to standard therapy in the treatment of right-sided IE due to S. aureus, but prospective studies are still limited as to its efficacy in left-sided or complicated IE caused by MSSA. 22 In cases of methicillin-resistant S. aureus (MRSA) IE, 6 weeks of vancomycin is the preferred first-line therapy. Daptomycin is an acceptable alternative to vancomycin and is recommended at a dosage of 6 mg/kg IV every 24 hours, though some experts recommend a dose of 8 to 10 mg/kg every 24 hours. 22,23 Increasingly, MRSA isolates are demonstrating higher MICs to vancomycin that can lead to treatment failure. This has led to newer recommendations that failure to respond to vancomycin (eg, microbiologic failure with persistent bacteremia for 7 days) should prompt a switch to daptomycin therapy. 24,25 Newer evidence suggests that patients may have better clinical outcomes when treated with daptomycin compared to vancomycin when the MRSA isolate has a vancomycin MIC >1 μg/ml. 25 Ceftaroline, a fifthgeneration cephalosporin and one of the newest anti-mrsa antibiotics, is currently only approved by the Food and Drug Administration for complicated bacterial skin and soft tissue infections and community-acquired bacterial pneumonia. However, there has been some promising data demonstrating clinical success with its use as salvage therapy for MRSA endocarditis. 26 CASE PATIENT 2 Initial Presentation and History A 67-year-old man with end-stage renal disease and a history of mechanical aortic valve replacement for severe aortic stenosis 2 years prior presents following his hemodialysis session with a fever of 102 F. He reports feeling intermittently feverish for the last 3 weeks. Blood cultures drawn at dialysis grew Enterococcus faecalis. Despite removal of his dialysis catheter 6 Hospital Physician Board Review Manual

7 and treatment with daptomycin, his blood cultures have remained positive for the past 4 days. Aside from chills and some vague lower abdominal pain, he reports no other symptoms. He takes warfarin for anticoagulation of his mechanical heart valve. Physical Exam and Diagnostic Testing Examination reveals an appropriate mechanical valve click on cardiac examination and normal lung and abdominal exam. He has a new temporary hemodialysis catheter in his right groin, and his prior dialysis catheter site shows no signs of drainage or erythema. Vitals signs are normal. The white blood cell count is 18,500 cells/μl; hemoglobin, 9.1 g/dl; and platelets, 75,000 cells/μl. TTE reveals the presence of his known mechanical mitral valve that is functioning normally without evidence of valvular vegetation. Given his high-grade bacteremia and high suspicion for IE, transesophageal echocardiogram (TEE) is performed and demonstrates a mitral valve vegetation with perivalvular abscess. What is the role of echocardiography in diagnosing IE? Echocardiography is an essential tool not only for the diagnosis of IE, but also for assessing potential complications of IE and risk of embolism. The choice of whether to order a TTE or TEE is based on the clinical index of suspicion for IE and underlying medical conditions affecting the sensitivity of the test. For the diagnosis of right-sided IE, TTE has been shown to have sensitivity and specificity equal to those of TEE. 27 However, TEE has shown markedly higher sensitivity over TTE in numerous studies, particularly with regard to the diagnosis of left-sided IE and prosthetic valve endocarditis (PVE), with TTE having a 62% sensitivity as compared to 92% with TEE TEE is also better at detecting perivalvular complications, such as abscesses. 31 Obesity and underlying chronic obstructive pulmonary disease can limit the clarity of images by TTE, and TTE is often unable to adequately view the perivalvulvar area, where many cases of PVE begin. 32,33 The patient presented in this case study emphasizes the limitations of TTE in the setting of PVE and also stresses the need to pursue more sensitive testing if clinical suspicion is high for IE but TTE is negative. Pretest probability and the clinical characteristics of the patient should be taken into account when considering whether to choose TTE or TEE as the initial imaging modality. If the suspicion for IE is low or there is an expectation of good image quality, then it is reasonable to begin the imaging evaluation with a TTE. If there is a high clinical suspicion for IE or the presence of medical conditions that would preclude good image quality by TTE, then TEE is the preferred and most cost-effective initial exam. 34,35 However, prompt diagnosis is paramount in guiding many treatment decisions, such as the need for early surgical intervention to prevent complications. Both TTE and TEE have demonstrated the increased risk of embolization with increasing size of the vegetation. 29,36 If the suspicion for IE is high but TEE is not readily available, then a TTE should be obtained as soon as possible and TEE performed in those at high risk for valve perforation, perivalvular abscess, or pyogenic complication that would be less likely to be detected on TTE While a negative TEE makes the diagnosis of IE unlikely, there is still the possibility of a falsenegative result if vegetations are small or have embolized, or if TEE is obtained early in the disease course before an abscess or fistula has had time to develop. 38 TEE can be repeated after 7 to 10 days in those with a negative initial study but high index Infectious Diseases Volume 15, Part 1 7

8 of suspicion for IE and in those at risk for fistula or abscess formation. 40 A false-positive result is also possible if nonspecific changes are present in a patient with a history of prior IE or other valvular abnormality. 11 Comparison to prior echocardiography should be attempted, when available. What is the role of surgical repair in treating IE? The 2006 American College of Cardiology/ American Heart Association (ACC/AHA) guidelines on the management of valvular heart disease include recommendations for surgery in patients with either NVE or PVE. For NVE, there is consensus agreement that moderate to severe heart failure due to valvular dysfunction is an indication for surgery. 41 The presence of significant heart failure caused by IE portends a grave prognosis with high mortality when treated with medical therapy alone as compared to surgical correction. 42 Surgery should be sought as soon as symptoms of heart failure arise since higher mortality has been noted in patients for whom surgical correction is delayed while waiting for improvement on medical therapy alone. 43 While there is some preference for blood culture sterilization prior to valve replacement due to the risk of prosthetic valve re-infection, the risk remains low at 2% to 3% as compared to the risk of mortality associated with heart failure due to IE. 44,45 Other indications for surgery include severe aortic or mitral valve regurgitation leading to hemodynamic instability, IE caused by fungal or multidrug-resistant organisms that are extremely difficult to cure with medical therapy alone, and infection complicated by perivalvular abscess, fistula formation, or mitral valve perforation. 42 The presence of a new heart block may portend the presence of periannular abscess and should also prompt surgical consideration. 46 In patients with PVE, the ACC/AHA guidelines include valve dysfunction, valve dehiscence, worsening valvular regurgitation, or complications (eg, abscess formation) as strong indications for surgery. 41 Increased mortality has been seen in PVE complicated by severe heart failure and disease caused by S. aureus infection. 47 On the other hand, success has been seen with medical therapy alone when PVE patients have no evidence of heart failure or valvular dysfunction, lack invasive or metastatic infection, or are infected with a less virulent organism such as enterococci, viridans group streptococci, or some of the fastidious gramnegative organisms that cause culture-negative IE. 47,48 There are other clinical scenarios that may warrant careful evaluation of the risks versus benefits of surgical intervention, such as persistent bacteremia for more than 7 days despite appropriate antibiotics. 11,49 An increase in vegetation size despite appropriate antibiotic therapy may prompt surgical consideration as well. 40 Vegetations greater than 1 cm on the anterior mitral leaflet have the highest risk of embolization, 50 and while not an absolute indication for surgery, the ACC/AHA guidelines include any mobile vegetations greater than 1 cm as a less well established reason to seek surgical correction. Recurrent embolic phenomenon, particularly within the first 2 weeks of antimicrobial therapy, also confers the need for surgical consideration. 11 How would you manage this patient s antimicrobial therapy? Enterococcal endocarditis requires susceptibility to and treatment with a cell-wall active agent in conjunction with an aminoglycoside. Aqueous crystalline penicillin-g, ampicillin, and vancomycin 8 Hospital Physician Board Review Manual

9 demonstrate only inhibitory activity against enterococci when used as single-agent therapy. To enact bactericidal killing, these agents require the addition of synergistic gentamicin (3 mg/kg IV per day in 3 equally divided doses) or streptomycin (15 mg/kg per day in 2 equally divided doses). PVE requires 6 weeks of this combination therapy. 11 For enterococcal NVE, treatment duration is dependent upon the duration of symptoms. If infectious symptoms have been present for less than 3 months, the duration may be decreased to 4 weeks for penicillin-susceptible strains of enterococci. 51 IE in which symptoms have been present for more than 3 months requires 6 weeks of therapy similar to PVE. Penicillin-resistant strains also require a full 6 weeks of therapy with vancomycin and synergistic gentamicin due to decreased activity of vancomycin as compared to penicillin. 52 Streptomycin can be substituted for gentamicin in gentamicin-resistant strains. 11 If full aminoglycoside resistance is detected, the British Society for Antimicrobial Chemotherapy currently recommends treatment for 6 weeks with a monotherapy penicillin agent in susceptible strains. 53 However, based on recent evidence that the combination of ampicillin 2 g IV every 4 hours plus ceftriaxone 2 g IV every 12 hours for 6 weeks is as effective for treating E. faecalis endocarditis as the combination of ampicillin and gentamicin, many authorities would recommend dual beta-lactam therapy for high-level aminoglycoside-resistant strains. 54 Infection with vancomycin-resistant enterococci (VRE) presents a treatment dilemma. E. faecium is the organism most likely to demonstrate vancomycin resistance, but data is limited with regard to the best method of treatment. Linezolid (600 mg every 12 hours) and quinupristin/dalfopristin (22.5 mg/kg IV per day in 3 equally divided doses) for at least 8 weeks are currently recommended by the AHA guidelines, and case reports have been published demonstrating good results with daptomycin therapy. 11,55 Nevertheless, optimal therapy is yet to be established, and surgical intervention may be necessary for treatment success. As with NVE, S. aureus and streptococci remain common causes of PVE. MSSA strains are treated with nafcillin or oxacillin for 6 weeks plus synergistic gentamicin for the first 2 weeks of therapy. Rifampin 300 mg every 8 hours is added as a third agent for the full 6-week duration based on in vitro studies and clinical observations establishing its ability to help eradicate S. aureus from prosthetic material. 11,56 In methicillin-resistant strains, vancomycin is substituted for the beta-lactam, but the addition and duration of gentamicin and rifampin remains the same. 11 Viridans group streptococci and Streptococcus bovis are treated with 6 weeks of aqueous crystalline penicillin-g or ceftriaxone if the strain is highly susceptible (MIC 0.12 µg/ml) and synergistic gentamicin may be added for the first 2 weeks. If the MIC is elevated ( 0.12 to 0.5 µg/ml), then synergistic gentamicin is added to the beta-lactam therapy for the full 6-week course. 11 Coagulase-negative staphylococci (CoNS) are also common etiologies of PVE. 57 While most CoNS are indolent due to low virulence of the organisms, Staphylococcus lugdunensis is a notable exception due to its higher virulence, which increases complications such as perivalvular extension and disseminated infection. 58 Similar to S. aureus PVE, CoNS endocarditis is treated with either nafcillin/oxacillin or vancomycin depending on the methicillin susceptibility of the organism. Rifampin and synergy gentamicin are also added, the latter having been demonstrated in animal models of IE to improve eradication of CoNS from prosthetic valves. 11,59 Infectious Diseases Volume 15, Part 1 9

10 What should be done regarding this patient s anticoagulation? The risk of systemic embolization is of particular concern when addressing the role of anticoagulation in the setting of IE. The majority of embolic events involve the CNS, 60 and the first 2 weeks of IE treatment involve the highest risk of embolism. 61 To date, there remains no clear evidence of the benefit of anticoagulation in NVE. On the other hand, there is little in the way of general consensus in regard to mechanical valve IE. 62 The necessity of anticoagulation for thrombotic prevention in patients with a mechanical heart valve places them at risk for hemorrhagic conversion should the patient suffer a CNS embolic event from IE. While some experts recommend continuation of anticoagulation throughout the entire treatment course of mechanical valve IE, there is some consensus that anticoagulation should be discontinued for at least the first 2 weeks of therapy in patients who have experienced a recent CNS embolic event or stroke. 63 CASE PATIENT 3 Initial Presentation and History An 86-year-old man with a history of hypertension, diabetes mellitus, and atrial fibrillation requiring a permanent pacemaker presents with oozing from the site of his pacemaker device. The pacemaker was initially placed 4 years ago for sick sinus syndrome and was upgraded 10 days ago. Within a few of days of the procedure, the surgical site became red, swollen, and painful to palpation. A small opening at the incision site began draining serosanguinous fluid. He denies any fevers, chills, or rigors. He was given a prescription for oral amoxicillin/clavulanic acid 875/125 twice daily, which he has been taking for the past 6 days without improvement. Physical Exam and Diagnostic Testing Physical examination reveals a temperature of F, a heart rate of 67 beats/min, and normal respiratory rate and oxygen saturation. Cardiac rhythm is irregularly irregular and breath sounds are clear. The left anterior chest wall pacemaker site is red, swollen, warm, and tender to palpation with a small amount of serosanguinous drainage from an opening on the left end of the surgical incision site. Two sets of blood cultures drawn 2 hours apart are growing methicillin-resistant Staphylococcus epidermidis. TEE shows a 1.4-cm vegetation on the right atrial lead pacer wire and a 0.8-cm vegetation on the tricuspid valve. What is the recommended treatment for patients with cardiovascular implantable electronic device related IE? The incidence of cardiovascular implantable electronic device (CIED) related IE has been increasing over the years as patients are increasingly being treated with implantation of these devices. 64,65 Staphylococci account for the majority of CIED infections. If a CIED infection is suspected, at least 2 sets of blood cultures should be drawn prior to the initiation of antibiotics. TEE should be performed in any patient suspected of having a CIED infection in the setting of a positive blood culture or administration of antibiotics prior to blood culture procurement. TEE may demonstrate lead-associated vegetations and/or valvular vegetation. Even if a TTE demonstrates the presence of a lead vegetation, a TEE should be performed in order to evaluate for left-sided IE since this could potentially change antimicrobial or surgical management. 66 Any CIED infection or CIED-related IE should then prompt complete removal of the hardware as relapse rates are high 10 Hospital Physician Board Review Manual

11 in the setting of retained hardware If valvular endocarditis is seen on TEE, the patient should be treated for IE based on the AHA guidelines. 11 If a lead vegetation is present without evidence of valvular vegetation, treatment varies between 2 to 6 weeks depending on the clinical scenario. Complicated lead infections, such as those involving osteomyelitis or septic thrombophlebitis, should be treated with 4 to 6 weeks of therapy. Uncomplicated lead infections vary in duration based on the organism isolated. S. aureus should be treated for 2 to 4 weeks, whereas other organisms can be treated for only a 2-week duration. 66 The patient presented in this case study has evidence of bacteremia and vegetation on the atrial lead pacer wire and the mitral valve. Management would include removal of all the pacemaker hardware and treatment with vancomycin for 6 weeks. What are the recommendations for CIED reimplantation? One third to one half of patients may not require placement of a new CIED, and so careful consideration of the necessity of reimplantation should be undertaken after removal of an infected device. New device implantation should take place on the contralateral side and preferably occur after complete treatment and resolution of the underlying infection. However, patients who are pacemakerdependent may require earlier reimplantation, for which the optimal timing is not known. The 2010 AHA guidelines on the management of CIED infections recommend that in the setting of bacteremia and vegetations that are present only on device leads, reimplantation of a new CIED can be performed once blood cultures remain negative at 72 hours following complete removal of infected device. The time until reimplantation should be extended to 14 days from the date of the first negative blood culture after complete device removal if there is evidence of valvular vegetations, which would be the case in the patient presented here. 66 CASE PATIENT 4 Initial Presentation and History A 32-year-old women with a history of intravenous drug use and hepatitis C presents with symptoms of fever, headache, altered mental status, nausea, and vomiting. Her husband states that she had been feeling poorly for a couple of days but became progressively confused that morning, prompting presentation to the hospital. She continues to use intravenous drugs on a daily basis, including heroin and bath salts, via a clean needle program. She has no other relevant past medical history. Physical Exam and Diagnostic Testing Examination shows a thin, agitated woman who does not answer questions or follow commands. The temperature is F; heart rate, 120 beats/min; and oxygen saturation, 92% on 6 L via nasal cannula. Lung exam reveals diminished breath sounds in both bases and diffuse crackles. There is bilateral lower extremity swelling to the knees and 2 splinter hemorrhages are seen in the nailbeds of her right hand. The white blood cell count is 21,000 cells/μl with normal renal and hepatic function. Blood cultures are growing MSSA in 2 sets of blood culture bottles, and TEE shows a 1.8-cm vegetation on the anterior mitral valve with valve perforation and a 1.2- cm vegetation on the tricuspid valve. What are the most common organisms isolated in intravenous drug users with IE? While right-sided endocarditis is relatively uncommon in the general population, intravenous 12 Hospital Physician Board Review Manual

12 drug users are more likely to have right-sided IE, usually of the tricuspid valve. 11 S. aureus is the most likely cause of right-sided IE in intravenous drug users, 70 while left-sided IE is equally likely to be caused by staphylococci or viridans group streptococci. 71 Intravenous drug users are at particular risk for community-acquired strains of MRSA that have been reported to be especially aggressive, with severe septic shock and multiple pulmonary and cerebral abscesses. 72 They are also at risk for infection with enterococci, aerobic gram-negative bacilli, polymicrobial infections, group B streptococci, and Streptococcus mitis. 70,71 Intravenous drug users, prosthetic valve recipients, and cirrhotic patients are at highest risk for IE due to aerobic gram-negative bacilli. 73 The vast majority of patients with Pseudomonas aeruginosa IE are intravenous drug users 74 and are at high risk for complications such as embolic phenomenon, neurologic complications, ring and annular abscesses, rapid progression to congestive heart failure, and bacteremic relapse. 75 Early surgery is often necessary, 74,76 particularly in the setting of left-sided IE. 77 However, medical therapy alone has been shown to be curative in some patients. 78 Preferred medical therapy consists of an anti-pseudomonal penicillin or cephalosporin in combination with high-dose tobramycin (8 mg/kg IV once daily) for a minimum of 6 weeks. 11 The activity of these beta-lactams on the bacterial cell wall is felt to enhance uptake of the aminoglycoside into the bacteria, where it then exerts its activity in disruption of protein synthesis. 79 Figure. Computed tomography scan image of patient presented in case study 4 showing consolidations and cavitary lesions (arrows). CASE 4 CONTINUED On further workup, magnetic resonance imaging (MRI) of the brain demonstrates multiple bilateral rim-enhancing lesions with diffuse leptomeningeal enhancement. Computed tomography (CT) scan of the chest shows pulmonary edema, dense consolidations, and scattered cavitary lesions (Figure). The patient is subsequently intubated for respiratory failure and altered mental status. What are some other complications of rightand left-sided IE? Heart failure is the IE complication with by far the greatest impact on prognosis. 80,81 It can occur acutely due to valve perforation, valve dehiscence, or large vegetations, and it can also present more insidiously despite appropriate medical therapy. Periannular extension of infection, such as abscess and fistula formation, is difficult to diagnose based on symptomatology alone. It can present as a new heart block or heart failure, persistent bacteremia or fever, new murmur, or recurrent embolic phenomenon. 46,82 A handful of patients with small abscesses measuring less than 1 cm and lacking complicated valvular dysfunction can be treated without surgical intervention, but these patients should be followed with serial TEEs to monitor for worsening disease. 83,84 Infectious Diseases Volume 15, Part 1 13

13 Splenic infarct is a relatively common complication of left-sided IE, although only a small subset of patients progress to splenic abscess. 85,86 Evidence of persistent fever or persistent bacteremia should raise suspicion for splenic involvement and prompt evaluation by abdominal CT or MRI. While splenectomy is the definitive therapy for a splenic abscess, percutaneous drainage or aspiration has been performed with successful outcomes. 87 Mycotic aneurysms can be a potentially devastating complication of IE. Intracranial mycotic aneurysms have a variable presentation that often includes a severe headache and focal neurological deficits. A sterile meningitis with evidence of red blood cells in the cerebrospinal fluid should prompt consideration of an intracranial mycotic aneurysm. Many of these aneurysms resolve on their own with appropriate antibiotic therapy. Patients can be monitored symptomatically and with serial imaging. CT angiography and magnetic resonance angiography are comparable screening tests for aneurysms, but definitive diagnosis is made by conventional angiography. Any new or worsening symptoms or increase in size of the mycotic aneurysm should prompt urgent surgical evaluation. 11 What complicating factors should be considered in intravenous drug users with IE? While intravenous drug users primarily present with right-sided IE and nearly three quarters of them have involvement of the tricuspid valve, 70 there is often multivalvular involvement and the incidence of left-sided IE in intravenous drug users may be increasing. 11 The preponderance of tricuspid valve involvement in intravenous drug users means that many of them may present with acute symptoms in the absence of a heart murmur. However, they usually have positive blood cultures as long as cultures are obtained prior to initiation of antimicrobial therapy. 88 Right-sided IE also places them at particularly high risk for septic pulmonary embolization, 70 and in the setting of S. aureus endocarditis, intravenous drug users have a markedly elevated risk of metastatic deep infection, with up to 85% of cases showing evidence of extracardiac infection. 89 The preference to treat IE with an extended duration of IV antibiotics is also complicated in intravenous drug users due to the inherent risk of discharging these patients with an indwelling venous catheter. A very specialized subset of patients who meet strict criteria for uncomplicated MSSA rightsided IE (lack of any left-sided involvement, metastatic infection, heart failure, or CNS disease) can be treated with 2 weeks of IV beta-lactam therapy plus synergy gentamicin. 15,17 Combination vancomycin plus synergy gentamicin showed a lower efficacy when compared to combination beta-lactam plus synergy gentamicin therapy. 16 In very rare instances where IV therapy is impossible or refused by the patient, 2 studies have demonstrated the effectiveness of oral ciprofloxacin plus rifampin for 4 weeks, assuming the criteria for uncomplicated right-sided IE are met and the S. aureus strain is susceptible to both antibiotics. 90,91 Despite any treatment measures, the risk of recidivism remains high in intravenous drug users, and many present with reinfection of a native or prosthetic valve, complicating their long-term treatment plan and prognosis. It is necessary that the treatment plan upon discharge include outpatient drug rehabilitation and counseling to minimize the risk of relapse. CASE PATIENT 5 Initial Presentation and History A 48-year-old woman with no significant past medical history presents with 3 months of subjective low-grade fevers, generalized malaise, increas- 14 Hospital Physician Board Review Manual

14 ing fatigue, shortness of breath, and decreased exercise tolerance. Her appetite has been poor and she states she has lost about 10 lb. Symptoms began after a flu-like illness 3 months ago, but she has not felt well since that time. She has had a course of amoxicillin and a course of trimethoprim/sulfamethoxazole during this time without any relief in symptoms. Her last antibiotic course was over 2 weeks ago. She works at a bank and lives with her husband in the city. She has no pets, animal exposures, sick contacts, or recent travel. Physical Exam and Diagnostic Testing Physical examination is within normal limits. Laboratory studies reveal hemoglobin of 8.9 g/dl and normal white blood cell count with normal kidney and liver function. C-reactive protein is elevated at 58 g/dl. Chest X-ray is normal. A TTE reveals two 0.8-cm vegetations on the aortic valve. Three sets of blood cultures are obtained over the next 2 days and are subsequently finalized as no growth. What are the causes of culture-negative infective endocarditis? Culture-negative endocarditis (CNE) is defined by the presence of endocarditis without microbiological diagnosis after 3 sets of blood cultures have been incubated for 7 days without growth. 92 In some cases, this may be due to a noninfectious cause of endocarditis, such as nonbacterial thrombotic endocarditis (NBTE) or Libman-Sacks endocarditis, which includes the presence of sterile vegetations. In infection-related CNE, blood cultures are negative for 3 primary reasons: administration of antimicrobial therapy prior to obtaining blood cultures, inadequate microbiological technique, and infection with a fastidious bacteria or nonbacterial pathogen. The first of these 3 factors is of critical importance because of how common this practice is and, likewise, how preventable. Administration of antibiotics prior to blood culture procurement may decrease the organism recovery rate by as much as 35% to 40% Isolation of the pathologic organism is necessary to determine appropriately targeted antimicrobial therapy and duration of treatment. 95 The absence of this information can lead to broader empiric treatment that results in increased costs and potentially avoidable antibiotic-related side effects. 11 What are the HACEK and fastidious gramnegative organisms that cause CNE? The gram-negative organisms that cause CNE are most likely to occur as community-acquired NVE in non intravenous drug users. 96 Traditionally, the HACEK organisms (Haemophilus species, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) were thought to be the most common causes of CNE, and recommendations included prolonging the blood culture incubation period to 14 days to promote growth. A 2006 retrospective multicenter trial evaluated the ability to culture these HACEK organisms and found most of them were able to be isolated within the typical 5-day incubation period and that none of the blood cultures incubated for 10 to 14 days grew any of the HACEK organisms. 97 A study from southern France published in 2005 showed the 2 leading causes of CNE to be Coxiella burnetii (Q fever) and Bartonella species. 98 While the local prevalence of C. burnetii is much higher in Europe than in the United States, this study led to C. burnetii serologies being added as a major criterion to the modified Duke criteria. These etiologies Infectious Diseases Volume 15, Part 1 15

15 should be considered on the differential diagnosis of CNE, in addition to the HACEK organisms, if there is a history of potential exposure. 7 Patients at high risk for acquisition of Q fever include those in contact with farm animals and those with a potential occupational exposure. 99,100 Q fever endocarditis primarily develops as a complication in patients at risk due to previous valvular heart disease or immunocompromised state. 101 Bartonella quintana endocarditis has been associated with homelessness, alcoholism, and body lice infestation, whereas previous valvular heart disease and contact with cats are the major risk factors for Bartonella henselae endocarditis. 101,102 The microbiology laboratory should be alerted when these organisms are suspected so that special culturing techniques and prolonged incubation can be implemented due to their fastidious nature and so that, in the cases of C. burnetii and Bartonella species, laboratory personnel can take precautions to avoid exposure during incubation. However, a minority of patients with IE due to these organisms will have positive blood cultures. 103 Diagnosis is more likely to be made by exposure history and serologic testing or by histological examination and polymerase chain reaction testing of explanted intracardiac tissue. A recent Q fever infection is suggested by an antiphase II IgG titer 1:200 or IgM titer 1:50, while an antiphase I IgG titer >1:800 is indicative of chronic infection. The latter is considered diagnostic for Q fever IE (when paired with other Duke criteria) since it is a chronic illness. The vast majority of Bartonella species IE will have an antibody titer 1: How should this patient be treated? If one of the HACEK organisms is isolated or Coxiella or Bartonella species IE diagnosis is proven, therapy should be targeted appropriately. The HACEK organisms are now routinely considered to be resistant to ampicillin due to a high incidence of beta-lactamase production. Thus, ceftriaxone 2 g IV every 24 hours is considered the treatment of choice. Given the method of resistance by beta-lactamase production, ampicillin/ sulbactam 3 g IV every 6 hours is an alternative to ceftriaxone therapy, although ceftriaxone is often preferred due to the ease of once-daily infusion. 104 Ciprofloxacin 500 mg orally or 400 mg IV every 12 hours is another alternative option in patients who are unable to tolerate ceftriaxone or ampicillin. Patients with NVE should be treated for 4 weeks, while those with PVE are treated for 6 weeks. 11 Q fever endocarditis is preferably treated with the combination of doxycycline 100 mg twice daily and hydroxychloroquine 600 mg daily for a minimum of 18 months. 105,106 Bartonella species IE is treated with 6 weeks of doxycycline 100 mg twice a day with gentamicin 1 mg/kg every 8 hours added to the first 2 weeks of therapy. If gentamicin cannot be given, rifampin 300 mg every 8 hours can be substituted for it in the treatment regimen. 11,107 For patients with CNE in whom no etiologic organism is confirmed, the acuity of presentation can help guide antibiotic therapy based on the most likely organisms if it is presumed that the patient did not have a positive blood culture due to administration of antibiotics prior to obtaining cultures or due to improper microbiologic technique. Acute CNE of a native valve should include coverage of MSSA, while a subacute presentation should include viridans group streptococci and enterococci coverage. However, regardless of timing of presentation, treatment for NVE is the same and consists of 4 to 6 weeks of ampicillin/sulbactam 3 g IV every 6 hours plus synergy gentamicin 1 mg/kg every 8 hours. If the patient is unable to tolerate beta-lactam therapy, an alternative regi- 16 Hospital Physician Board Review Manual