methicillin-resistant endocarditis: pathophysiology ... · introduction s taphylococcus aureus...

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Methicillin-Resistant Staphylococcus aureus Prosthetic Valve Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management Alicia Galar, a,b Ana A. Weil, c,d David M. Dudzinski, d,e Patricia Muñoz, a,b,f,g Mark J. Siedner c,d a Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain b Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain c Division of Infectious Diseases, Medicine Department, Massachusetts General Hospital, Boston, Massachusetts, USA d Harvard Medical School, Boston, Massachusetts, USA e Cardiology Division, Medicine Department, Massachusetts General Hospital, Boston, Massachusetts, USA f Department of Medicine, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain g CIBER de Enfermedades Respiratorias-CIBERES (CB06/06/0058), Madrid, Spain SUMMARY ........................................................................................ 1 INTRODUCTION .................................................................................. 2 TIMING, PATHOPHYSIOLOGY, PATHOGENESIS, AND HISTOPATHOLOGY ................ 2 Timing of Infection ............................................................................ 2 Pathophysiology ............................................................................... 2 Pathogenesis ................................................................................... 3 Histopathology ................................................................................. 5 EPIDEMIOLOGY .................................................................................. 5 CLINICAL PRESENTATION, ASSESSMENT, AND DIAGNOSIS ............................... 7 TREATMENT .................................................................................... 13 Vancomycin ................................................................................... 14 Rifampin ...................................................................................... 14 Gentamicin .................................................................................... 15 Alternative Therapies ........................................................................ 16 The “Endocarditis Team” ..................................................................... 18 Choice and Timing of Surgery .............................................................. 18 PROGNOSIS ..................................................................................... 18 PREVENTION .................................................................................... 18 CHALLENGES AND FUTURE PERSPECTIVES ................................................ 18 REFERENCES ..................................................................................... 19 AUTHOR BIOS ................................................................................... 26 SUMMARY Staphylococcus aureus prosthetic valve endocarditis (PVE) remains among the most morbid bacterial infections, with mortality estimates ranging from 40% to 80%. The proportion of PVE cases due to methicillin-resistant Staphylococcus aureus (MRSA) has grown in recent decades, to account for more than 15% of cases of S. aureus PVE and 6% of all cases of PVE. Because no large studies or clinical trials for PVE have been published, most guidelines on the diagnosis and management of MRSA PVE rely upon expert opinion and data from animal models or related conditions (e.g., coagulase- negative Staphylococcus infection). We performed a review of the literature on MRSA PVE to summarize data on pathogenic mechanisms and updates in epidemiology and therapeutic management and to inform diagnostic strategies and priority areas where additional clinical and laboratory data will be particularly useful to guide therapy. Major updates discussed in this review include novel diagnostics, indications for surgical man- agement, the utility of aminoglycosides in medical therapy, and a review of newer anti- staphylococcal agents used for the management of MRSA PVE. KEYWORDS methicillin-resistant Staphylococcus aureus, prosthetic valve endocarditis Citation Galar A, Weil AA, Dudzinski DM, Muñoz P, Siedner MJ. 2019. Methicillin-resistant Staphylococcus aureus prosthetic valve endocarditis: pathophysiology, epidemiology, clinical presentation, diagnosis, and management. Clin Microbiol Rev 32:e00041-18. https://doi.org/10.1128/CMR.00041-18. Copyright © 2019 American Society for Microbiology. All Rights Reserved. Address correspondence to Alicia Galar, [email protected]. Published 13 February 2019 REVIEW crossm April 2019 Volume 32 Issue 2 e00041-18 cmr.asm.org 1 Clinical Microbiology Reviews on July 4, 2020 by guest http://cmr.asm.org/ Downloaded from

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Page 1: Methicillin-Resistant Endocarditis: Pathophysiology ... · INTRODUCTION S taphylococcus aureus prosthetic valve endocarditis (PVE) is a devastating infection. The mortality rate due

Methicillin-Resistant Staphylococcus aureus Prosthetic ValveEndocarditis: Pathophysiology, Epidemiology, ClinicalPresentation, Diagnosis, and Management

Alicia Galar,a,b Ana A. Weil,c,d David M. Dudzinski,d,e Patricia Muñoz,a,b,f,g Mark J. Siednerc,d

aClinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, SpainbInstituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, SpaincDivision of Infectious Diseases, Medicine Department, Massachusetts General Hospital, Boston, Massachusetts, USAdHarvard Medical School, Boston, Massachusetts, USAeCardiology Division, Medicine Department, Massachusetts General Hospital, Boston, Massachusetts, USAfDepartment of Medicine, School of Medicine, Universidad Complutense de Madrid, Madrid, SpaingCIBER de Enfermedades Respiratorias-CIBERES (CB06/06/0058), Madrid, Spain

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2TIMING, PATHOPHYSIOLOGY, PATHOGENESIS, AND HISTOPATHOLOGY . . . . . . . . . . . . . . . . 2

Timing of Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

EPIDEMIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5CLINICAL PRESENTATION, ASSESSMENT, AND DIAGNOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7TREATMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Vancomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Rifampin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Gentamicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Alternative Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16The “Endocarditis Team” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Choice and Timing of Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

PROGNOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18PREVENTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18CHALLENGES AND FUTURE PERSPECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19AUTHOR BIOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

SUMMARY Staphylococcus aureus prosthetic valve endocarditis (PVE) remains amongthe most morbid bacterial infections, with mortality estimates ranging from 40% to 80%.The proportion of PVE cases due to methicillin-resistant Staphylococcus aureus (MRSA)has grown in recent decades, to account for more than 15% of cases of S. aureus PVEand 6% of all cases of PVE. Because no large studies or clinical trials for PVE have beenpublished, most guidelines on the diagnosis and management of MRSA PVE rely uponexpert opinion and data from animal models or related conditions (e.g., coagulase-negative Staphylococcus infection). We performed a review of the literature on MRSAPVE to summarize data on pathogenic mechanisms and updates in epidemiology andtherapeutic management and to inform diagnostic strategies and priority areas whereadditional clinical and laboratory data will be particularly useful to guide therapy. Majorupdates discussed in this review include novel diagnostics, indications for surgical man-agement, the utility of aminoglycosides in medical therapy, and a review of newer anti-staphylococcal agents used for the management of MRSA PVE.

KEYWORDS methicillin-resistant Staphylococcus aureus, prosthetic valve endocarditis

Citation Galar A, Weil AA, Dudzinski DM,Muñoz P, Siedner MJ. 2019. Methicillin-resistantStaphylococcus aureus prosthetic valveendocarditis: pathophysiology, epidemiology,clinical presentation, diagnosis, andmanagement. Clin Microbiol Rev 32:e00041-18.https://doi.org/10.1128/CMR.00041-18.

Copyright © 2019 American Society forMicrobiology. All Rights Reserved.

Address correspondence to Alicia Galar,[email protected].

Published 13 February 2019

REVIEW

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INTRODUCTION

Staphylococcus aureus prosthetic valve endocarditis (PVE) is a devastating infection.The mortality rate due to methicillin-resistant Staphylococcus aureus (MRSA) has

climbed in recent decades, reaching more than 15% of cases of S. aureus PVE (12) and6.6% of cases of PVE (4, 6).

Management for MRSA PVE is complex, and guidelines recommend both a multi-disciplinary team and an individualized approach to care. Given the lack of clinical trialstesting treatments for MRSA PVE, many aspects of management lack an empirical basis.For example, the timing and necessity of valve surgery remain unknown. In somestudies, hospital mortality rates for S. aureus PVE were significantly higher in patientswho had not undergone valve surgery (2, 3, 7, 8, 10, 13–15), prompting some investi-gators to conclude that early valve surgery (EVS) should be considered a standardtreatment for S. aureus PVE, especially in patients with early-onset infection (2, 11).However, recent literature and the experience of the International Collaboration onEndocarditis (ICE) have called into question the value of EVS (1, 11, 16–18). Specifically,work by Hill et al. (16) suggested that uncomplicated S. aureus PVE cases might besuccessfully managed without early valve surgery, and a multicenter study reported in2015 by the ICE found no association between EVS and a reduction of 1-year mortalityrates in patients with S. aureus PVE (11).

Furthermore, although multiple treatment guidelines advocate for incorporating anaminoglycoside into MRSA PVE therapy (19, 20) to promote sustained susceptibility torifampin, these recommendations are largely based on experimental models (21–23)and the use of aminoglycosides for treatment of coagulase-negative Staphylococcus(CoNS) PVE (24). Clinical data on the benefit of aminoglycoside combination therapy inhumans for MRSA PVE are lacking. Furthermore, the use of an aminoglycoside for othercauses of endocarditis, including methicillin-sensitive Staphylococcus aureus (MSSA)native valve endocarditis (NVE) and CoNS PVE, demonstrates either harm or a lack of asurvival benefit (24–27). Although current guidelines discuss this lack of evidence, mostcontinue to recommend the addition of an aminoglycoside based on expert opinion(28–31). Trimethoprim-sulfamethoxazole, clindamycin, ceftaroline, daptomycin, lin-ezolid, telavancin, oritavancin, tigecycline, and combinations that might result insynergy could have a role in treatment but have not yet been thoroughly studied.

TIMING, PATHOPHYSIOLOGY, PATHOGENESIS, AND HISTOPATHOLOGYTiming of Infection

MRSA PVE is often dichotomized based on duration of disease (32) into early,defined as the first year postsurgery, or late, defined as after 1 year postsurgery. Thesethresholds have been developed based on the risk of developing PVE and differencesin the microbiology of the disease between periods (33, 34). The risk of PVE is greatestduring the first 3 months after surgery. The risk peaks approximately 15 days aftersurgery, during which the PVE risk is estimated to be 45 cases/100,000 patient days (35).After this time period, it decreases steadily to approximately 1 case/100,000 patientdays from 150 days to 20 years postoperatively (35–39). The cumulative proportions ofpatients developing PVE range from 1 to 3% in the first 365 days after surgery accordingto several studies with close follow-up and from 3 to 6% in 5 years (35–39). S. aureus isa frequently encountered pathogen in both early and late PVE cases (6, 16, 40, 41),accounting for approximately 12 to 36% of early cases (53 to 69% at the first 2 monthsfrom surgery) and 18 to 30% of late cases (6, 41). A large, multicenter, internationalstudy (6) showed that MRSA was the causative microorganism in 18.9% of early casesof PVE, versus 3.3% of late cases.

Pathophysiology

Early PVE infection is believed to be caused by accidental seeding during surgery ordue to bloodstream dissemination in the first hours to months postoperatively. Earlyafter surgery, the prosthetic sewing ring and cardiac connection tissue and sutureshave not yet endothelized. Fibronectin and fibrinogen coat these areas and are

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believed to be a possible nidus for infection. In late PVE infection, these cardiacstructures become fully endothelized, and the pathogenesis of disease more resemblesthat of NVE (42).

The location and distribution of PVE also differ by the type of prosthetic valve andthe route of infection (Fig. 1). In cases where the infection is introduced via contami-nation around the surgical site, it typically affects the annulus and sewing ring union,causing pseudoaneurysms, dehiscence, fistulas, and abscesses around valves (43–45). Inone postmortem study, perivalvular invasion, which is commonly coupled with pros-thesis dehiscence and paravalvular regurgitation, appeared in approximately 40% ofautopsies performed for patients with PVE, and frank extension into tissue leading tomyocardial abscess was seen in 15% (46). Annular and/or myocardial abscesses werepresent in 68% of the 47 patients with PVE in another study (47). Dehiscence of theprosthesis was described in more than 80% of cases of aortic and mitral prosthesesexamined by Ben Ismail et al. (48), and vegetations were seen in 75% (48). More than1 year postoperatively, infection related to biological PVE is more commonly found atthe prosthesis leaflets. Complications of late PVE include leaflet rupture and perforationof an aortic valve prosthesis, which can extend through the intervalvar fibrosa andannulus to cause pericarditis or, more frequently, can spread into the membranousportion of the interventricular septum and cause arrhythmia (49–51). Large vegetationsmay also keep the prosthesis open, causing malfunction or encroachment on the valveorifice, resulting in functional stenosis or regurgitation via malcoaptation or perforation.

Pathogenesis

Several independent factors are involved in the development of MRSA PVE (Fig. 2).MRSA has microbial surface components recognizing adhesive matrix molecules(MSCRAMMs) that recognize and bind to adhesion molecules of the fibrin-plateletmatrices of “nonbacterial thrombotic endocarditis,” such as fibronectin, laminin, andcollagen, and these can also adhere to the normal endothelium or minimally injuredtissue (40, 52, 53). Once the thrombus is colonized by MRSA, this microorganism canproliferate, creating the characteristic vegetation of infective endocarditis (IE). Thepresence of cardiac prostheses introduces an additional variable that favors PVE, sinceMRSA can adhere by forming biofilms (Fig. 2 and 3) (40, 53). At initial placement, thering-prosthesis interface is not endothelized and favors fibrin-platelet thrombus for-mation. The suture points where the prostheses are placed constitute a mechanismwhereby MRSA can invade the heart tissue and form abscesses. In addition, thecontinuous stress caused by the repetitive movement in the bioprostheses may disruptthe surface of the leaflets and predispose to infection of the fibrin-platelet thrombus.MRSA can reach the prosthesis by contamination of the prosthetic valve during surgery(Fig. 4) or by a hematogenous route via a catheter-related infection, intravenous druguse, a surgical wound, or pulmonary or urinary tract infection (40, 53, 54). During thesurgical procedure (Fig. 4), the surgical site may be exposed to MRSA from the patient’sor health care practitioner’s skin. The ability of S. aureus strains to produce biofilms (Fig.3) in vitro has been linked to clinically persistent MRSA bacteremia (�7 days) and theevolution of prosthetic valve vegetation propagation (52, 55, 56).

Nonvalvular invasive infection may also cause bioprosthetic valve endocarditis. Forexample, annular and myocardial invasion was observed in 38 of 85 patients (45%) inone study and was more common among cases of bioprosthetic PVE occurring duringthe first year after valve placement than in cases presenting later (59 versus 25%) (57).Invasive disease was more frequent in patients with early than in those with latebioprosthetic PVE (79% versus 31%) in another series (58).

A large proportion of cases of PVE is nosocomial and correlates with a highproportion of MRSA infections (6). An international study including 556 patients withPVE demonstrated that 36.5% of infections were nosocomially acquired or related tofrequent health care visits (6). Similarly, the use of transcatheter aortic valve implanta-tion (TAVI) also increased the risk for MRSA PVE (59, 60), as did the use of orotracheal

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FIG 1 Prosthetic valves explanted from patients with MRSA prosthetic valve endocarditis, and received at the microbiology laboratory toperform valve culture and 16S PCR (courtesy of Mercedes Marín, Hospital General Universitario Gregorio Marañón, Madrid, Spain). Shownare a mechanical valve, a mitral ring, an aortic bioprosthesis, and a mitral bioprosthesis.

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intubation and percutaneous self-expandable valves (59). Further studies are needed tobetter establish a relationship between MRSA virulence factors observed experimen-tally in vitro and in animal models (61) and clinical disease in humans.

Histopathology

There is no typical pattern of PVE histological characterization in bioprostheticvalves. As bioprosthetic valves degenerate, they often create noninfective, calcific,vegetative-like lesions with inflammatory infiltrates, which can result in a noninfectiousprocess that can mimic and be misdiagnosed as PVE. A retrospective pathological studyof inflamed bioprosthetic valve tissues from 88 cases of resected bioprosthetic valves(21 for probable endocarditis and 67 for noninfective dysfunction) was performed tobetter define the histological criteria for PVE (62). PVE was histologically characterizedby neutrophil-rich inflammatory infiltrates and the presence of microorganisms. Inflam-matory infiltrates in valve tissue samples from the noninfective control group consistedmainly of lymphocytes and macrophages. In that study, having a neutrophil percentageexceeding 1.5% of the valve surface area was associated with a high specificity (94%)for infectious PVE (62).

EPIDEMIOLOGY

PVE occurs in 1% to 6% of patients after prosthetic valve placement (63), accom-panied by an incidence of 0.3% to 1.2% per patient year (6, 64–66) and accounting for16% to 31% of IE cases in several studies (1, 6, 67–70). The etiology of 146 early-PVEclinical cases and 140 late-PVE cases was summarized from 17 published reports (32).In that study, early S. aureus PVE accounted for 19.2% of the cases, and late compli-cations were less likely with increasing time after surgery, occurring in only 11.4% of thecases. The incidence of both early and late PVE was correlated with increasing under-lying comorbidity at the time of valve placement, surgeon experience, extracorporealcirculation duration, sterility of the heart-lung machine and the operating theater,extracardiac postoperative infection, and the length of time that the patient was

FIG 2 Pathogenesis of MRSA (methicillin-resistant Staphylococcus aureus) PVE. MSCRAMMs, microbial surface components recognizingadhesive matrix molecules.

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FIG 3 An original electron scanning microscope image of a methicillin-resistant Staphylococcus aureusbiofilm on a patient’s mechanical heart prosthesis. The image was prepared at both the ClinicalMicrobiology and Infectious Diseases Department and the Pathology Department of the Hospital GeneralUniversitario Gregorio Marañón and was taken at the National Center of Electron Microscopy (JSM 6400,CNME, Madrid, Spain).

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monitored after surgery (32). MRSA accounted for approximately 6.5% of PVE cases(n � 556) assessed by the ICE Prospective Cohort Study (6). Figure 5 shows a compar-ison of cases of S. aureus (P � 0.003) and MRSA (P � 0.001) involved in PVE acrossgeographic regions. The data provided by Wang et al. (6) are consistent with the globalepidemiology of S. aureus (P � 0.007) and MRSA (P � 0.001) PVE found and also kindlyshared by Murdoch et al. (4).

In one observational study, the prophylactic use of penicillinase-resistant penicillins(methicillin and oxacillin) during the perioperative periods reduced early postoperativeS. aureus PVE (71). Unsurprisingly, the incidence of PVE was higher when the valvereplacement occurred in the setting of active or recently treated endocarditis (36, 39,72, 73). In several observational studies, bioprosthetic valves appear to increase the riskfor infection over mechanical valves after 18 months (37, 72, 73). However, threerandomized trials including 1,418 patients monitored for 8 to 20 years could notdemonstrate a statistically significant difference in PVE occurrence between biologicaland mechanical valves (P � 0.45 [74], P � 0.71 [75], and P � 0.70 [76]). Anotherobservational study that included 38,000 patients �65 years of age demonstrated ahigher risk of endocarditis after a median of 12 years of follow-up among those withbioprosthetic valves (2.2% versus 1.4%; unadjusted hazard ratio, 1.69 [95% confidenceinterval {CI}, 1.43 to 2.00]) (77). Finally, Calderwood et al. (37) showed a higher risk ofoccurrence of PVE among patients (n � 116 out of 2,608 evaluated) who receivedmechanical valves than among those who received bioprosthetic valves at 3 monthspostsurgery (P � 0.02), but in contrast, Grover et al. (73) could not demonstrate anydifference between the valves in 66 patients who developed PVE out of 1,032 observedduring a mean length of follow-up of 7.7 years.

CLINICAL PRESENTATION, ASSESSMENT, AND DIAGNOSIS

PVE signs and symptoms are similar to those of native valve disease. Yet the clinicalpresentation of MRSA PVE is often nonspecific, especially soon after surgery, wheninflammation and fever might occur for other reasons. Due to the intracardiac compli-cations described above, clinical manifestations of PVE frequently include hemolysis,heart failure, valvular dysfunction, and/or new arrhythmia (13, 78, 79). Calderwood et al.(78) studied the outcomes of 116 patients with PVE and found that 64% of individualswith PVE suffered some combination of worsened or new cardiac failure, a changed ornew cardiac murmur, continuous fever, or irregularities upon electrocardiography(ECG). These complications were more common in the first year after valve replacementand in aortic valve prosthesis infections (Table 1). New or changing murmurs, heartfailure, and new electrocardiographic conduction disturbances are noted more often in

FIG 4 Surgery image (courtesy of Gregorio Cuerpo, Cardiac Surgery, Hospital General UniversitarioGregorio Marañón, Madrid). Shown is mitral prosthetic valve endocarditis caused by S. aureus.

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PVE than in NVE cases due to the likelihood of invasive infection. ECG (Fig. 6), chestradiograph, and blood cultures are considered part of the standard work-up if there isa clinical suspicion of PVE.

Pulmonary, neurological, kidney, and musculoskeletal complications or complica-

FIG 5 Global epidemiology of MRSA involved in prosthetic valve endocarditis (PVE). The causative agents of PVE differ geographically(4, 6). Data from Wang et al. (6) were collected between June 2000 and August 2005 from 556 patients with infective prosthetic valveendocarditis in 53 sites worldwide (P � 0.003 for Staphylococcus aureus; P � 0.001 for MRSA [methicillin-resistant Staphylococcusaureus]). MSSA, methicillin-sensitive Staphylococcus aureus.

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pat

ient

s;in

stea

d,th

eyus

edva

lidat

edre

gim

ens

from

pub

lishe

dst

udie

sBi

lle(1

995)

(216

)A

ntim

icro

bia

lth

erap

yre

view

Endo

card

itis

due

toSt

aphy

loco

ccus

Aco

mb

inat

ion

of3

antib

iotic

s(v

anco

myc

inor

oxac

illin

�ge

ntam

icin

and

rifam

pin

)is

sugg

este

dfo

rPV

Edu

ring

atle

ast

6w

k

Furt

her

stud

ies

are

need

edto

inco

rpor

ate

nove

ltr

eatm

ent

optio

ns,e

spec

ially

inp

atie

nts

affe

cted

by

MRS

AC

alde

rwoo

det

al.(

1985

)(3

7)2,

642

pat

ient

sw

houn

derw

ent

valv

ere

pla

cem

ent

for

the

first

time

wer

ein

clud

edin

the

stud

y11

6p

atie

nts

with

PVE

(4.4

%)

At

12m

o,th

eris

kof

PVE

was

3.1%

,and

at60

mo,

the

risk

was

5.7%

;por

cine

valv

esha

da

sign

ifica

ntly

low

erris

kof

PVE

durin

gth

efir

st90

days

from

surg

ery

than

mec

hani

cal

valv

esb

uta

sign

ifica

ntly

high

erris

kaf

ter

12m

op

osts

urge

ry

Ther

ew

ere

sign

ifica

ntdi

ffer

ence

sin

the

risk

ofPV

Ede

pen

ding

onth

ety

pe

ofva

lve,

but

nosi

gnifi

cant

diff

eren

ces

bet

wee

np

orci

nean

dm

echa

nica

lva

lves

wer

eob

serv

edin

the

risk

ofha

ving

PVE

afte

r5

yrC

erve

raet

al.(

2014

)(2

17)

Ana

lysi

sof

ast

udy

coho

rt93

case

sof

S.au

reus

infe

ctiv

een

doca

rditi

s(le

ftsi

ded)

57%

had

ava

ncom

ycin

MIC

of�

1.5

�g/

ml,

and

43%

had

anM

ICof

�1.

5�

g/m

lPe

rcen

tage

sof

in-h

osp

ital

deat

hva

ried

sign

ifica

ntly

bet

wee

nb

oth

grou

ps,

at30

and

53%

,res

pec

tivel

yC

hiro

uze

etal

.(20

04)

(1)

Eval

uatio

nof

mor

talit

yris

k61

case

sof

S.au

reus

PVE

Patie

nts

who

had

thei

rva

lve

rep

lace

dea

rly,d

esp

iteha

ving

hear

tco

mp

licat

ions

,sho

wed

low

erm

orta

lity

rate

s(P

�0.

09)

S.au

reus

PVE

isa

dise

ase

with

high

mor

bid

ityan

dm

orta

lity

rate

s(2

8.6–

85.7

%)

Chi

rouz

eet

al.(

2015

)(1

1)Im

pac

tof

early

valv

esu

rger

yon

clin

ical

outc

ome

ofS.

aure

usPV

Ew

ithin

the

Inte

rnat

iona

lC

olla

bor

atio

nof

Endo

card

itis

747

case

sof

defin

itele

ft-s

ided

PVE

Non

-S.a

ureu

sPV

Eca

used

sign

ifica

ntly

low

erra

tes

ofde

ath

afte

r1

yrth

anS.

aure

usPV

E;at

this

time,

pat

ient

sw

ithS.

aure

usPV

Ean

dEV

Sal

soha

dlo

wer

mor

talit

yra

tes

(P�

0.01

);EV

Sdi

dno

tdi

min

ish

mor

talit

yat

1yr

Diff

eren

tfa

ctor

ssh

ould

be

take

nin

toac

coun

tb

efor

ede

cidi

ngon

EVS

Cos

grov

eet

al.(

2009

)( 2

18)

236

pat

ient

sfr

om44

hosp

itals

and

4co

untr

ies

wer

ep

rosp

ectiv

ely

eval

uate

dS.

aure

usb

acte

rem

iaan

dna

tive

valv

ein

fect

ive

endo

card

itis

Vanc

omyc

inor

anan

tista

phy

loco

ccal

pen

icill

in�

low

-do

sege

ntam

icin

orda

pto

myc

inal

one

was

adm

inis

tere

dto

pat

ient

s;re

nal

adve

rse

even

tsw

ere

eval

uate

d

Low

-dos

ege

ntam

icin

shou

ldno

tb

eus

edro

utin

ely

for

S.au

reus

bac

tere

mia

and

nativ

eva

lve

infe

ctiv

een

doca

rditi

sdu

eto

the

nep

hrot

oxic

itysh

own

deFe

iter

etal

.(20

05)

(219

)Fu

sidi

cac

id,r

ifam

pic

in,v

anco

myc

in,o

xaci

llin,

and

gent

amic

intr

eatm

ent

failu

res

Patie

ntw

ithSt

aphy

loco

ccus

epid

erm

idis

PVE

Des

pite

the

nona

pp

rova

lfo

rth

isin

dica

tion,

linez

olid

was

adm

inis

tere

dto

this

pat

ient

Patie

ntha

da

favo

rab

leou

tcom

ew

ithlin

ezol

id

Del

Río

etal

.(20

14)

(220

)Re

scue

ther

apy

with

imip

enem

�fo

sfom

ycin

Com

plic

ated

bac

tere

mia

and

MRS

Aen

doca

rditi

sTr

eatm

ent

was

succ

essf

ulin

69%

ofca

ses;

the

mor

talit

yra

tedu

eto

MRS

Aw

as1/

5(2

0%)

Com

bin

atio

nth

erap

yw

assa

fean

def

fect

ive

asre

scue

ther

apy

Fern

ánde

zG

uerr

ero

etal

.(2

009)

(15)

Inci

denc

eof

infe

ctiv

een

doca

rditi

s,ep

idem

iolo

gy,

clin

ical

feat

ures

,pro

gnos

isD

efini

teS.

aure

usen

doca

rditi

s(r

ight

side

dan

dle

ftsi

ded)

NVE

was

ale

ssco

mm

onho

spita

l-acq

uire

din

fect

ion

than

PVE;

for

bot

hty

pes

ofen

doca

rditi

s,re

nal

and

card

iac

failu

rean

dce

ntra

lne

rvou

ssy

stem

com

plic

atio

nsw

ere

dete

cted

Valv

ere

pla

cem

ent

sign

ifica

ntly

imp

rove

dou

tcom

esfo

rp

atie

nts

with

PVE

Fow

ler

etal

.(20

06)

(157

)D

apto

myc

invs

stan

dard

ther

apy

S.au

reus

bac

tere

mia

and

endo

card

itis

Mic

rob

iolo

gica

lfa

ilure

was

mor

eco

mm

onin

the

grou

ptr

eate

dw

ithda

pto

myc

inth

anin

the

one

with

stan

dard

ther

apy

Ano

ninf

erio

rity

rate

was

obse

rved

inth

egr

oup

trea

ted

with

dap

tom

ycin

com

par

edto

the

one

trea

ted

with

stan

dard

ther

apy

for

bac

tere

mia

and

right

-sid

eden

doca

rditi

sca

used

by

S.au

reus

Has

bun

etal

.(20

03)

(221

)Pr

ogno

stic

fact

ors

Left

-sid

eden

doca

rditi

s(n

ativ

eva

lve)

with

com

plic

atio

nsFa

ctor

sre

late

dto

mor

talit

yaf

ter

6m

o,in

clud

ing

abno

rmal

men

tal

stat

us,b

acte

rial

caus

e,co

mor

bid

ities

,m

edic

altr

eatm

ent,

mod

erat

e/se

vere

cong

estiv

eca

rdia

cfa

ilure

4gr

oup

sof

pat

ient

sw

ere

iden

tified

dep

endi

ngon

the

mor

talit

yris

k6

mo

afte

rb

asel

ine

Hol

land

etal

.(20

14)

(222

)Re

view

onho

spita

lm

anag

emen

tBa

cter

emia

caus

edb

yS.

aure

usD

iagn

ostic

met

hods

and

antib

iotic

trea

tmen

tst

rate

gies

Ther

ear

egr

oup

sof

pat

ient

sw

hodo

not

need

TEE

John

etal

.(19

98)

(3)

Clin

ical

stra

tegi

esan

dp

rogn

ostic

fact

ors

Defi

nite

PVE

caus

edb

yS.

aure

usC

omp

licat

ions

affe

ctin

gth

ece

ntra

lne

rvou

ssy

stem

(33%

)an

dhe

art

(67%

)w

ere

foun

d;th

e3-

mo

mor

talit

yra

tew

as42

%

Mor

ep

atie

nts

died

due

tohe

art

pro

ble

ms

than

due

top

rob

lem

saf

fect

ing

the

cent

ral

nerv

ous

syst

em,b

utth

ism

orta

lity

was

dim

inis

hed

whe

nth

ere

was

surg

ery

for

valv

ere

pla

cem

ent

durin

gan

tibio

tictr

eatm

ent

Kang

etal

.(20

12)

(223

)6-

wk

occu

rren

ceof

emb

olic

even

tsan

dm

orta

lity

Patie

nts

with

larg

eve

geta

tions

,se

vere

dise

ase

inva

lves

,lef

t-si

ded

endo

card

itis

due

toin

fect

ion

Patie

nts

wer

era

ndom

ized

into

2gr

oup

s,co

nven

tiona

ltr

eatm

ent

orea

rlysu

rger

yRa

tes

ofem

bol

icev

ents

and

mor

talit

ysi

gnifi

cant

lyde

crea

sed

inth

egr

oup

with

early

surg

ery

com

par

edto

the

grou

pof

pat

ient

str

eate

dco

nven

tiona

llyKa

rchm

eret

al.(

1983

)(2

4)Re

tros

pec

tive

stud

yof

75PV

Eca

ses

Stap

hylo

cocc

usep

ider

mid

isPV

ETh

ege

ntam

icin

susc

eptib

ility

rate

was

78%

,and

thos

efo

rrif

amp

inan

dva

ncom

ycin

wer

e10

0%fo

ral

lis

olat

este

sted

;dys

func

tion

ofva

lves

and

tissu

ep

rogr

essi

onw

ere

the

mos

tco

mm

onp

rob

lem

s,ne

edin

gsu

rger

yin

30ca

ses

Ant

ibio

ticth

erap

yin

clud

ing

vanc

omyc

in�

rifam

pin

oran

amin

ogly

cosi

dein

crea

sed

favo

rab

leou

tcom

era

tes;

surg

ical

trea

tmen

tw

asal

soim

por

tant (C

ontin

ued

onne

xtp

age)

Staphylococcus aureus Prosthetic Valve Endocarditis Clinical Microbiology Reviews

April 2019 Volume 32 Issue 2 e00041-18 cmr.asm.org 9

on July 4, 2020 by guesthttp://cm

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nloaded from

Page 10: Methicillin-Resistant Endocarditis: Pathophysiology ... · INTRODUCTION S taphylococcus aureus prosthetic valve endocarditis (PVE) is a devastating infection. The mortality rate due

TAB

LE1

(Con

tinue

d)

Aut

hor

(s)

(yr)

(ref

eren

ce)

Epid

emio

log

yD

iag

nos

isM

anag

emen

tC

oncl

usio

n(s

)an

d/o

rp

reve

nti

onst

rate

gy

Karc

hmer

(199

1)(2

24)

Infe

ctio

nco

ntro

lPV

ED

urin

ga

year

pos

tsur

gery

,the

noso

com

ial

risk

ofPV

Ew

as1.

4–3.

0%;t

hem

ost

com

mon

reas

onfo

rho

spita

l-ac

quire

dPV

Ew

asm

ethi

cilli

n-re

sist

ant

coag

ulas

e-ne

gativ

eSt

aphy

loco

ccus

Furt

her

stud

ies

are

need

edto

dete

ctp

osts

urgi

cal

caus

esof

hosp

ital-a

cqui

red

PVE

and

dim

inis

hth

em

Lean

dBa

yer

(200

3)(2

25)

Revi

ewon

antib

iotic

trea

tmen

tfo

ren

doca

rditi

sca

used

by

freq

uent

lyde

tect

edm

icro

orga

nism

sFe

wst

rate

gies

for

invi

tro,

exp

erim

enta

l,an

dcl

inic

alev

alua

tion

ofen

tero

cocc

alen

doca

rditi

sha

veb

een

show

n

Hum

ancl

inic

alda

taar

esc

arce

onco

mb

inat

ion

antib

iotic

trea

tmen

tfo

rin

fect

ive

endo

card

itis

due

toS.

aure

usM

ayer

and

Scho

enb

aum

(198

2)(2

26)

Revi

ewan

dap

pro

ach

PVE

Hig

her

rate

sof

mor

bid

ityan

dm

orta

lity

wer

ede

tect

edin

early

than

inla

tePV

Eca

ses;

the

etio

logy

ofte

nin

clud

edfu

ngi,

stap

hylo

cocc

i,an

dG

ram

-neg

ativ

ero

dsin

early

PVE

and

stre

pto

cocc

iin

late

PVE

Fact

ors

rela

ted

top

oor

outc

ome

wer

eea

rlyPV

E,p

arav

alvu

lar

leak

age,

emb

oli,

per

sist

ent

feve

r,no

nstr

epto

cocc

alm

icro

orga

nism

s,no

nhet

erog

raft

aort

icva

lve,

cong

estiv

eca

rdia

cfa

ilure

Muñ

ozet

al.(

2015

)(1

2)Ep

idem

iolo

gy,c

linic

alfe

atur

es,p

rogn

ostic

fact

ors

Infe

ctiv

een

doca

rditi

s(1

,804

case

s)Pr

evio

usca

rdia

csu

rger

y,at

rial

fibril

latio

n,ca

rdia

cco

mp

licat

ions

and

failu

re,s

eptic

shoc

k,ag

e,ce

reb

rova

scul

arco

mp

licat

ions

,or

Cand

ida

orSt

aphy

loco

ccus

caus

ew

asre

late

dto

in-h

osp

ital

deat

hs(2

8.9%

);af

ter

1yr

,ass

ocia

tion

was

foun

dfo

rca

ncer

,ca

rdia

cfa

ilure

,age

,and

rena

lin

suffi

cien

cy(1

1.2%

)

The

rate

sof

in-h

osp

ital

and

1-yr

deat

hsw

ere

elev

ated

,and

surg

ery

was

the

only

pro

tect

ive

fact

or

Mur

doch

etal

.(20

09)

( 4)

Glo

bal

infe

ctiv

eca

uses

and

clin

ical

feat

ures

Infe

ctiv

een

doca

rditi

sIn

fect

ions

ofm

itral

and

aort

icva

lves

due

toS.

aure

usw

ere

the

mos

tfr

eque

ntp

rese

ntat

ion,

also

com

plic

ated

with

hear

tfa

ilure

,str

oke,

and

othe

rem

bol

ian

dab

sces

sin

the

hear

t

Risk

fact

ors

for

in-h

osp

ital

mor

talit

yw

ere

lung

edem

a,ag

e,p

rost

hetic

infe

ctio

n,S.

aure

usor

coag

ulas

e-ne

gativ

est

aphy

loco

ccal

caus

e,m

itral

vege

tatio

n,an

dva

lve

pro

ble

ms

Raja

shek

arai

ahet

al.(

1980

)(2

6)Ev

alua

tion

ofto

lera

nce

(MBC

/MIC

�16

)S.

aure

usb

acte

rem

iaan

den

doca

rditi

sTo

lera

ntm

icro

orga

nism

sw

ere

acco

mp

anie

db

ym

ore

deat

hs,c

omp

licat

ions

,hos

pita

lizat

ion

inIC

U,

pro

long

atio

nof

feve

r

Poor

outc

omes

ofen

doca

rditi

sw

ere

mor

eco

mm

onin

case

sca

used

by

tole

rant

mic

roor

gani

sms

than

inca

ses

caus

edb

yse

nsiti

veon

esRi

ber

aet

al.(

1996

)(2

7)C

loxa

cilli

nvs

clox

acill

in�

gent

amic

indu

ring

2w

kS.

aure

usen

doca

rditi

s(r

ight

side

d)M

orta

lity

occu

rred

1an

d2

case

s,re

spec

tivel

yC

omb

inat

ion

trea

tmen

tw

asno

tm

ore

effe

ctiv

eth

anth

esi

ngle

one

Soha

ilet

al.(

2006

)(1

7)M

orta

lity

rate

sin

pat

ient

sw

hore

ceiv

edm

edic

alvs

surg

ical

trea

tmen

tS.

aure

usPV

EM

orta

lity

rate

sof

48%

and

28%

,res

pec

tivel

yTh

eno

.of

deat

hsw

aslo

wer

inth

esu

rgic

algr

oup

;bio

pro

sthe

ticva

lves

and

ASA

clas

sIV

wer

ep

rogn

ostic

fact

ors

Wan

get

al.(

2007

)(6

)G

lob

alin

fect

ive

caus

esan

dcl

inic

alfe

atur

esPV

ETh

em

ost

freq

uent

mic

roor

gani

smw

asS.

aure

us;3

6.5%

ofca

ses

wer

ere

late

dto

heal

thca

re;t

heof

in-h

osp

ital

deat

hra

tew

as22

.8%

and

was

rela

ted

tohe

alth

care

,ag

e,p

ersi

sten

tb

lood

stre

amin

fect

ion,

S.au

reus

caus

e,an

dca

rdia

can

dC

NS

pro

ble

ms

S.au

reus

isgl

obal

lyth

em

ain

caus

eof

PVE,

and

the

pre

senc

eof

com

plic

atio

nsis

anim

por

tant

pro

gnos

ticfa

ctor

War

eham

etal

.(20

05)

(227

)C

ases

trea

ted

with

linez

olid

MRS

Ean

dVR

Een

doca

rditi

sIn

vitr

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tions associated with systemic infections might also occur, at the same time, in somePVE cases (80–87). Of note, S. aureus is the pathogen most commonly related to IEcomplications compared to others (88). Lung complications are more frequently seenin patients with right-sided endocarditis, in several cases presenting manifestationssuch as pneumonia, abscesses, pleural effusion, and/or atelectasis.

Central nervous system (CNS) complications, primarily embolic infarcts or hemor-rhage, are also more common in PVE than in NVE cases, ranging from 20 to 40%, withovert arterial emboli being noted for 40% of patients with PVE (48, 89–91). Similar ratesof embolic stroke (18%) and ischemic stroke (20%) among patients with PVE werereported by Davenport and Hart (92) and Keyser et al. (89), respectively. FernándezGuerrero et al. (15) observed that, compared to NVE, S. aureus PVE clinical manifesta-tions were characterized by less-frequent cardiac murmurs and a shorter symptomaticprodrome.

In PVE patients with no prior antibiotic therapy, blood cultures are positive in at least90% of cases (63). Molecular techniques, such as DNA examination by pulsed-field gelelectrophoresis or 16S rRNA sequencing, can be used when standard blood or tissuecultures have not revealed a pathogen (93, 94).

Transesophageal echocardiography (TEE) has poorer diagnostic validity for PVE(including MRSA PVE) than for NVE (95). However, TEE with a high-resolution biplane ormultiplane transducer that allows continuous-wave and pulsed-wave Doppler andcolor flow imaging can increase the accuracy of diagnosis of PVE (96). TEE is consideredthe method of choice for diagnosis of PVE (97), because although transthoracicechocardiography (TTE) may lead to a diagnosis in some cases, TEE has a highersensitivity for PVE (98, 99) (Fig. 7A). This increase in sensitivity is not accompanied bya loss of specificity and is independent of the valve type or position (98–101). Forsuspected PVE, TEE sensitivity and specificity have been estimated at 77 to 90% and90%, respectively, compared to TTE, with a specificity and sensitivity estimated at 40 to70% and 90%, respectively (102). Nonetheless, TTE has value for the assessment ofventricular size and function and severe hemodynamic lesions in valves and can often

FIG 6 Electrocardiogram at 25 mm/s of a patient with aortic MRSA PVE with nonspecific findings, including tachycardia (heart rate of approximately 125 beatsper minute), a first-degree block with a PR interval exceeding a duration of 0.2 s (indicated by the arrow), and ST segment changes (indicated by the circle).

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FIG 7 Imaging modalities for MRSA prosthetic valve endocarditis diagnosis. (A) Transesophageal echocardiography demonstrating a 1.4- by1.2-cm highly mobile echodensity at the ventricular side of the bioprosthetic aortic valve (indicated by the arrow), without significant valvulardysfunction. (B) Transthoracic echocardiogram image showing a parasternal view with the prosthetic aortic valve, right ventricular outflow tract,and aorta on the top; the left atrium and mitral valve at the bottom; and the left ventricle on the left. The prosthetic aortic valve is not wellvisualized, but there is a vegetation on the ventricular side (indicated by the circle) and anterior aortic root thickening (indicated by the arrow),

(Continued on next page)

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detect anterior aortic prosthetic valve abscesses (103) (Fig. 7B). Typically, the ventricularsurfaces of prostheses in the mitral, tricuspid, and aortic positions are better viewed byTTE, whereas TEE has additional value for viewing the aortic valve surfaces, tricuspidand mitral valves, and the exit of the prosthesis in the aorta; fistula and abscessdetection; detection of paraprosthetic leaks; and visualization of a mitral valve pros-thesis (104, 105). However, TEE will miss some cases of prosthetic valve dehiscence. Ina study of 26 patients with PVE, there were 14 (56%) cases of aortic valve dehiscenceintraoperatively, 4 (29%) of which were not detected upon TEE (106). One prospectivestudy that compared the paired use of TTE with TEE in 114 episodes of clinicallysuspected IE (34 PVE and 80 NVE) found that the results of the two tests wereconcordant in only 55% of cases (107). TEE prompted reclassification for 34% of patientswith prosthetic valves, compared with 11% of patients with native valves.

The Duke criteria have been described as being less useful for the diagnosis of PVEbecause of low sensitivity (108, 109) compared to the sensitivity of 70 to 80% (110, 111)in the diagnosis of NVE. Because of diagnostic challenges in PVE with standard testingand clinical scores, other techniques have been assessed. Magnetic resonance imaging(MRI) and multislice computed tomography (MS-CT) might improve the detection of anintra- or pericardiac anatomical complication (112). The value of ECG-gated multide-tector CT angiography (MDCTA) was addressed by three studies (113–115), whichdemonstrated a �90% sensitivity for the diagnosis of PVE (113), which was improvedto a sensitivity and a specificity of 100% and 83%, respectively, after completion ofroutine testing for endocarditis and resulted in modification of therapy in 25% of cases(115) (Fig. 7C).

Recently, nuclear imaging has shown promise for improving diagnostics. [18F]fluo-rodeoxyglucose positron emission tomography electrocardiogram-gated computer to-mography ([18F]FDG PET/CT) scans have shown utility as an additional diagnosticcriterion for PVE in cases where a diagnosis cannot be made with standard echocar-diography (116–119) (Fig. 7D). FDG PET/CT detects inflammation early in the infectionprocess (120). For suspected PVE, [18F]FDG PET/CT demonstrated a 67 to 100% positivepredictive value, a 50 to 100% negative predictive value, 73 to 100% sensitivity, and 71to 100% specificity (116–119, 121–123). As such, an algorithm reported by Saby et al.(116) shows that PET/CT is useful to assess probable PVE cases. This algorithm incor-porates the PET/CT 2013 modified Duke criteria for the diagnosis of possible PVE casesthat do not meet criteria for endocarditis by the modified Duke criteria but remainunder high clinical suspicion. The sensitivity of the modified Duke criteria significantlyincreased with the addition of PET imaging to the scoring system, from 70% (95% CI,52% to 83%) to 97% (95% CI, 83% to 99%) (P � 0.008). This result was the consequenceof a significant reduction (P � 0.0001) in the number of possible PVE cases from 56%to 32% (116).

Three retrospective studies have addressed the value of technetium-99m-hexamethylpropylene amine oxime (99mTc-HMPAO)-labeled leukocyte scintigraphywith single-photon emission tomography/computed tomography (SPECT/CT) for thedetection of PVE (119, 124, 125). Probable (125) or definite (119, 124) IE cases wereincluded. Globally leukocyte scintigraphy showed an 85 to 100% positive predictivevalue, a 47 to 81% negative predictive value, 64 to 90% sensitivity, and 36 to 100%specificity (126). Further evaluations with increased sample sizes will be helpful forbetter defining a role and optimal scenario of nuclear imaging in the diagnosis of PVE.

TREATMENT

The S. aureus PVE mortality rate remains high (25 to 42%) (3, 54) despite advancesin antibiotic treatment (1). Both the American Heart Association (AHA) and its European

FIG 7 Legend (Continued)suggestive of an aortic root abscess. There is also mild prosthetic aortic valve regurgitation, but it cannot be appreciated in the still image. (C)Electrocardiogram-gated multidetector CT angiography demonstrating a 4- by 8-mm vegetation on the bioprosthetic aortic valve. (D) PET/CTimage at the posterior prosthetic aortic valve, after 16.29 mCi [18F]fluorodeoxyglucose uptake. The arrow notes an area of hyperintensity,suggesting a focus of inflammation or infection consistent with prosthetic valve endocarditis.

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counterpart, the European Society for Cardiology (ESC), suggest a triple-drug regimen(class I; level of evidence C) with vancomycin and rifampin for �6 weeks and genta-micin during the first 2 weeks for the management of MRSA PVE (Table 2) (29, 30).

These recommendations are based on CoNS PVE therapeutic regimen activity, IEexperiments, and retrospective clinical series (57, 127–130). A single retrospective studyof valve cultures from 61 patients with staphylococcal PVE (29 due to S. aureus and 32due to CoNS) treated surgically showed that those receiving combination therapy were5.9 times more likely to have culture-negative valves than patients receiving mono-therapy (adjusted by the length of therapy prior to surgery) (128). In this study, the sixpatients treated with a triple-drug regimen including rifampin prior to surgery hadnegative valve cultures. Regarding surgical indication, all of the groups of therapyevaluated for S. aureus NVE and any staphylococcal NVE or PVE were similar (P � 0.53,P � 0.51, and P � 0.66, respectively). No data on clinical outcomes restricted to thosewith S. aureus PVE were reported.

Antibiotic recommendations for treatment of MRSA PVE are also partially based onex vivo and animal studies of Staphylococcus epidermidis PVE. A retrospective evaluationof 23 cases of methicillin-resistant S. epidermidis (MRSE) PVE (129) showed an increasein serum bactericidal activity when rifampin was added to vancomycin regimens (129).Studies regarding MRSE endocarditis in rabbit models also demonstrated that genta-micin, rifampin, and vancomycin in combination increased the efficacy of eradication ofS. epidermidis from vegetations compared to beta-lactam antibiotics alone (131, 132).Another study (130) found that when rifampin was added to the combination ofvancomycin and gentamicin in broth, there was an enhanced bactericidal effect inrabbits despite antagonism of the bactericidal rate. Notably, similar data for theserelationships on MRSA are lacking.

Vancomycin

Vancomycin remains the mainstay of therapy for MRSA PVE (29, 30). Vancomycindosing should be based on actual body weight and adjusted to achieve troughs of 15to 20 �g/ml (29). Vancomycin binds the terminal D-alanyl-D-alanine moieties ofN-acetylmuramic acid (NAM)/N-acetylglucosamine (NAG) peptides in the bacterial cellwall and thus prevents the addition of the NAM/NAG peptide subunits into thepeptidoglycan matrix of MRSA. It also acts by altering bacterial cell membrane perme-ability and RNA synthesis (133). Common vancomycin toxicities include hypersensitivity(“red man syndrome,” related to the infusion rate) after intravenous administration andnephrotoxicity when used concomitantly with aminoglycosides (134). Significantweight gain can also occur during prolonged treatment, particularly in older men (135).

Rifampin

The rifampin mechanism of action is based on the suppression of RNA synthesisthrough the inhibition of the bacterial DNA-dependent RNA polymerase. Rifampin isbelieved to bind to a pocket of the RNA polymerase �-subunit within the DNA/RNAchannel. This noncompetitive inhibitor prevents RNA synthesis by directly blocking RNAelongation and thus preventing the synthesis of host bacterial proteins (136). Hepaticand immunoallergic toxicities are the most common rifampin adverse effects. Hepato-

TABLE 2 International guidelines for therapy of MRSA PVEa

ESC guidelines for adults

AHA guidelines

Pediatric Adult

Vancomycin at 30–60 mg/kg Q24h i.v., BID or TIDduring �6 wk

Vancomycin at 40 mg/kg Q24h i.v. (maximum dose, 2 g Q24h),BID or TID during �6 wk

Vancomycin at 30 mg/kg Q24h i.v., BIDduring �6 wk

Rifampin at 900–1,200 mg Q24h i.v./orally, BID orTID during �6 wk

Rifampin at 20 mg/kg Q24h i.v. (maximum dose, 900 mgQ24h), TID during �6 wk

Rifampin at 900 mg Q24h i.v./orally, TIDduring �6 wk

Gentamicin at 3 mg/kg Q24h i.v./i.m., once a dayor BID during the first 2 wk

Gentamicin at 3 to 6 mg/kg Q24h i.v./i.m., TID during the first2 wk

Gentamicin at 3 mg/kg Q24h i.v./i.m., BIDor TID during the first 2 wk

aThe doses of these drugs must be adjusted in the setting of renal insufficiency. The intravenous (i.v.) route is preferred, particularly in infants and children. Q24h,every 24 h; BID, twice a day; TID, three times a day; i.m., intramuscular.

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toxicity usually affects patients with previous liver damage and is associated with thedose administered. Adverse immunoallergic events might be minor or major and arepredominantly observed after prolonged or intermittent treatment (137).

Animal model experiments, in vitro data, and clinical observations have each dem-onstrated an outsized beneficial effect of rifampin on foreign-material infections (24, 57,127, 130, 138–140). Nevertheless, S. aureus has a high intrinsic mutation rate at the rpoBgene, encoding the rifampin-binding site. When large numbers of S. aureus bacteria areexposed to rifampin alone or in combination with ineffective antimicrobials, singlemutations in this region allow the rapid selection of a rifampin-resistant subpopulation(57, 138). Consequently, recommended regimens support the selection of two addi-tional antimicrobials with rifampin, to protect against the development of resistance torifampin. Similarly, many have recommended waiting until vancomycin and gentamicinhave been administered for 3 to 5 days, bacteremia has resolved, and undrainedabscesses or collections have been debrided prior to initiation of rifampin (30). Thisapproach is supported by the in vitro antagonism demonstrated when rifampin isexposed to replicating bacteria in combination with other antimicrobials (141) and thesynergism detected when bacteria are instead in a latent state (142). This effect can beseen in biofilm-mediated foreign-body infections, such as those associated with ortho-pedic hardware, prostheses, or vascular grafts (143). Lowy et al. (131) prevented thedevelopment of rifampin-resistant S. epidermidis by adding either vancomycin orgentamicin in a rabbit endocarditis model, but these observations have unclear clinicalutility in treating PVE in humans.

Rifampin is recommended for a minimum of 6 weeks, at a dosing regimen of 300 mgevery 8 h, in combination with gentamicin for the first 2 weeks and vancomycin for thefull treatment course of 6 weeks (29, 31). Notably, some authors alternatively recom-mend rifampin at 600 mg once daily or 300 to 450 mg every 12 h with anotherantistaphylococcal antibiotic for S. aureus infections (31).

The data on synergy between rifampin and other antimicrobials are conflicting (144,145). Although several studies (146–148) have demonstrated that incorporating rifam-pin into failing therapies can increase bactericidal rates and the chances of eradicationof serious S. aureus and S. epidermidis infections, others have reported both in vitrosynergy and antagonism for rifampin in combination with beta-lactam agents, vanco-mycin, or gentamicin against S. aureus (149, 150). Another study concluded that therewas no synergy or antagonism against MRSE regarding the concomitant use of otherantibiotics (cephalothin, nafcillin, vancomycin, or gentamicin) with rifampin (127).

MRSE isolates harboring rifampin mutations appeared to be as virulent as theirrifampin-sensitive antecedents in rabbit endocarditis models, although a similar effectwas not seen in rifampin-resistant S. aureus isolates in a mouse model (151). Themechanism of decreased virulence may be due to decreased production of toxins byrifampin-resistant S. aureus (127). The emergence of rifampin resistance was notprevented in vivo by the combination of rifampin with a beta-lactam antibiotic,although it was prevented in vitro. There was no decrease in virulence of rifampin-resistant methicillin-resistant S. epidermidis in comparison to rifampin-sensitive ante-cedent strains (127). The MRSE study showed good bactericidal efficacy of rifampin invitro when there was a prevention of emergent rifampin-resistant mutants by abeta-lactam antibiotic.

Gentamicin

European and U.S. guidelines suggest intramuscular or intravenous gentamicin at adose of 3 mg/kg of body weight every 24 h, once daily or in 2 or 3 divided doses, forthe treatment of MRSA PVE. Gentamicin serum levels and renal function should beassessed at least once weekly, and more-frequent measurements are suggested incases of renal insufficiency. Gentamicin doses as high as 4 mg/kg/day have beendemonstrated to be successful in MRSA PVE treatment without additional toxicity inboth human and animal studies (152, 153). In nonobese adults, the gentamicin dose isbased on ideal body weight. Gentamicin is not distributed into adipose tissue, as it is

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highly hydrophilic. Therefore, corrected body weight should be used for dosing calcu-lations for obese patients, rather than ideal body weight. The gentamicin mechanismof action is based on irreversible binding to specific proteins on the 30S subunit of theMRSA ribosome and the decoding site of the 16S rRNA. This leads to a misreading ofthe mRNA, the addition of incorrect amino acids in the growing peptide chain, and theinterruption of MRSA protein synthesis (154).

Ototoxicity and nephrotoxicity are important adverse events limiting gentamicinclinical use. Both side effects are associated with the dose administered and might notappear until the end of treatment. Kidney damage, in contrast to inner ear damage, isusually reversible but can be fatal (155, 156). Gentamicin trough and peak values lowerthan 1 �g/ml and 3 to 4 �g/ml, respectively, are recommended when gentamicin isadministered every 8 h. When gentamicin is dosed daily, serum troughs should belower than 1 �g/ml. ESC guidelines recommend that peaks be assessed once afterinfusion, with a goal range of 10 to 12 �g/ml (per AHA/IDSA guidelines, there is no rolefor measuring peak gentamicin concentrations following single daily dosing).

The risk-to-benefit ratio of gentamicin therapy for MRSA PVE remains controversial.In a study of 35 ex vivo strains of S. aureus isolated from blood cultures of septic patients(23), vancomycin or nafcillin combined with tobramycin, gentamicin, or kanamycin hadimproved activity against most of the strains. In a rabbit model of S. aureus endocarditis,nafcillin and gentamicin altogether achieved a faster eradication of S. aureus at theheart vegetation than nafcillin in monotherapy (22).

Nonetheless, clinical data in support of gentamicin use in this setting are lacking. Ina recent study comparing daptomycin therapy with an antistaphylococcal penicillin orvancomycin in combination with gentamicin for MSSA or MRSA bacteremia and/orright-sided endocarditis (157), significantly more patients who received standard ther-apy with gentamicin suffered nephrotoxicity (18.1% versus 6.7% with renal tubularnecrosis and 46.8% versus 19.8% with worsening creatinine clearance), without animprovement in clinical outcomes for those who received gentamicin (157). Whetherthese results pertain to MRSA PVE is unknown, but this topic warrants urgent studygiven the ongoing guideline recommendations for the use of gentamicin in thetreatment of MRSA PVE.

Alternative Therapies

If an isolate is resistant to gentamicin and all available aminoglycosides, a fluoro-quinolone to which the strain is highly susceptible has been recommended (138–140).If the patient is treated with a fluoroquinolone instead of an aminoglycoside, athree-drug regimen for the entire course of treatment is preferred. In cases of resistanceto aminoglycosides and fluoroquinolones, ceftaroline, trimethoprim-sulfamethoxazole,or linezolid (158) has been proposed as the third agent during the first 2 weeks oftreatment, if the isolate is susceptible in vitro.

For cases of MRSA PVE with reduced vancomycin susceptibility (MIC � 1.0 �g/ml),substantial toxicity, or failure of vancomycin, the optimal treatment is not established.Options include high-dose daptomycin (8 to 10 mg/kg once per day, if the isolate isdaptomycin susceptible), linezolid, telavancin, ceftaroline, and daptomycin combinedwith ceftaroline, nafcillin, or fosfomycin, combinations that might result in synergy(159–165). Yet reported clinical experience with these treatments and combinationtherapies in MRSA PVE is limited. Daptomycin combination with rifampin and genta-micin has been recommended in these cases as a second-line therapy for MRSA PVE(30). Synergy between �-lactams and daptomycin is associated with several character-istics, including increased daptomycin binding and �-lactam-mediated potentiation ofinnate immunity, but the precise molecular mechanism is unknown (139). Dhand etal. (166) reported a series of seven cases with rapid clearance of persistent MRSAbacteremia when high-dose nafcillin was added to high-dose daptomycin. Otherexperts (167) suggested the use of high-dose daptomycin combined with fosfomy-cin for MRSA PVE.

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There are several case reports of ceftaroline being used to successfully treat refrac-tory or drug-resistant MRSA PVE, either alone (168) or in combination therapy (169). Inone case report, the efficacy and tolerability of ceftaroline were demonstrated in onepatient with osteomyelitis and endocarditis caused by an MRSA strain that was notsusceptible to daptomycin (170). A patient with MRSA aortic PVE was also cured withprolonged high-dose daptomycin plus ceftaroline after other therapeutic failures (169).

Ceftaroline fosamil was the most active bactericidal drug in a rabbit model of MRSAendocarditis (171). For each MRSA strain, rabbits were randomized to no therapy(controls), a ceftaroline fosamil dose equivalent to 10 mg/kg/12 h in humans (600 mgtwice daily), daptomycin at a dose comparable to 6 mg/kg/24 h in humans, or atigecycline dose equivalent to 100 mg/24 h in humans plus 50 mg/12 h. Both ceftaro-line and daptomycin exhibited high bactericidal efficacy based on MRSA vegetationreduction rates (�5 log10 CFU/g), whereas tigecycline did not show bactericidal effi-cacy, and MRSA vegetation reduction rates were �2 log10 CFU/g in comparison tocontrols. However, the MRSA vegetation sterilization rate by ceftaroline was 100%, incontrast to the rate of 57% reached by daptomycin, with resistant mutants being seenonly in the daptomycin therapy group. Recent clinical data also demonstrate ceftarolineas an alternative for MRSA bacteremia salvage treatment (170, 172–177). Two obser-vational studies also suggest that ceftaroline therapy alone (178) or in combinationwith trimethoprim-sulfamethoxazole (179) can be used to treat invasive MRSA infec-tion, although more experience and, if possible, adequately designed clinical studiesare needed before there is widespread recommendation for its use.

Linezolid is an alternate treatment in cases of MRSA PVE complicated by drug allergyor intolerance, although its use is limited by a relative scarcity of data and side effectsof prolonged use. Among 33 cases of endocarditis treated with linezolid, 21 (63.6%) hada favorable outcome. PVE accounted for 25% of the reviewed cases, and MRSAaccounted for 24.2% (1 case of MRSA PVE among 8 PVE cases [12.5%]). The one patientwith MRSA PVE treated with linezolid had a favorable outcome. Additional efficacy andtolerability data are required to better support the use of linezolid for PVE (180).

In an experimental rabbit model, Miró et al. (181) suggested that telavancin couldbe as effective as vancomycin in the treatment of endocarditis caused by glycopeptide-intermediate S. aureus (GISA). Other experimental IE models also showed telavancinbactericidal activity against different MRSA strains, including daptomycin-resistant S.aureus, vancomycin-intermediate S. aureus (VISA), and GISA (182–184). Telavancin (185)and also quinupristin-dalfopristin (186) have been reported as favorable rescue thera-pies in MRSA IE patients after vancomycin clinical failure.

The efficacy of oritavancin was also recently assessed in animal models of left-sidedMRSA endocarditis. The drug has gained attention for its single intravenous dosingschedule at 1,200 mg over 3 h, which allows treatment of complicated MRSA infectionswithout the need for indwelling central venous catheters, a particular concern forpatients with recent or active injection drug use, and has shown promise in otherrefractory and drug-resistant cases of PVE (187, 188). A left-sided MRSA endocarditisrabbit model suggested that oritavancin was superior to vancomycin in resolvingbacteremia and reducing bacterial counts in vegetations and tissues (189). Thoseinvestigators concluded that oritavancin was microbiologically effective and might bean alternative to vancomycin in treating similar infections in humans (189). Of note,Stewart et al. (190) reported a case series of 10 patients treated with oritavancin,including 1 patient with NVE due to group B Streptococcus, who unfortunately failedtreatment. Although oritavancin is currently indicated only for acute bacterial skin andskin structure infections, it has the potential to play an increasing role as an agentagainst MRSA PVE, particularly in light of the ongoing international opioid epidemic(191, 192).

Tigecycline has activity against MRSA; however, it has been demonstrated to havea lower efficacy than vancomycin against MRSA strains (193), and its peak serumconcentrations do not exceed 1 �g/ml (194, 195). As such, tigecycline is not typicallyrecommended as an agent for MRSA bacteremia or endocarditis. Similarly, although

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clindamycin and trimethoprim-sulfamethoxazole are theoretically alternative optionsfor MRSA PVE, experience with these agents for this condition is limited, and they aretypically considered only in the case of severe drug intolerance or as considerations insynergistic regimens (196).

The “Endocarditis Team”

A multidisciplinary team including specialists from different clinical fields (neurology,microbiology, infectious diseases, cardiology, imaging, surgery, and congenital heart dis-ease) (30) has been recommended for the management of PVE (197, 198). Early involve-ment of all team members is crucial to this strategy. Some studies have reported reductionsin 1-year mortality rates of PVE with the implementation of such teams (199, 200).

Choice and Timing of Surgery

Surgery is recommended for high-risk patients, particularly those with valvularfailures complicated by heart failure, abscess formation, or fistulas and those notresponding to maximally effective antimicrobial therapy (30). The timing of surgery forPVE is a topic of ongoing debate (2, 7, 16, 17, 201–203) and is a decision based onsurgeon- and patient-specific factors, including complications of disease, such as CNSemboli and hemorrhage, and overall surgical risk. A recent study of 4,166 cases ofinfective PVE and NVE in patients with heart failure found decreases in both hospitaland 1-year deaths with early surgery (during the index hospitalization) (65). Morerecently, two prospective cohort studies, reported by Chirouze et al. (11) and Lalaniet al. (204), found a crude reduction in 1-year mortality rates with early versus delayedsurgery but similar rates after consideration of confounding and survivor bias. Thus, thedecision on the timing of therapy continues to largely depend on surgical risk and inputfrom multidisciplinary teams.

PROGNOSIS

The PVE mortality rate remains high in the current era, ranging from 30 to 80% forearly PVE and 20 to 40% for late PVE (54, 63). The identification of high-risk subgroupsis critical to establishing more-effective treatment strategies (9). Health care-associateddisease, staphylococcal or fungal etiologies, older age, diabetes mellitus, early PVE,heart failure, CNS embolic disease, and intracardiac abscess are predictive of worseclinical outcomes (1, 3, 8, 13, 65, 205). Among these, staphylococcal infection (5) andcomplicated PVE (78) are the strongest indicators of poor outcomes. Patients withcomplications require aggressive management, including antibiotic therapy and, often,early surgery (30).

PREVENTION

The utility of antimicrobial prophylaxis for prevention of bacteremia and IE inhumans remains unclear (30, 206). Since the relaxation of antibiotic prophylaxis afterthe 2007 guideline revisions, no incremental increase in the IE incidence was observed(207, 208), with the exception of a recent ecological study showing increased rates ofStreptococcus but not staphylococcal IE cases since the guideline change (209). Accord-ing to current guidelines, antimicrobial prophylaxis is recommended for high-riskpatients (30, 33, 71, 210–213) undergoing high-risk procedures (30), including thosewith prosthetic heart valves. Probably as important as antibiotic prophylaxis is carefulattention to skin and dental hygiene. Moreover, procedures affecting gastrointestinal,respiratory, musculoskeletal, genitourinary, and dermatological systems do not typicallyrequire antimicrobial prophylaxis unless they are invasive (30).

CHALLENGES AND FUTURE PERSPECTIVES

MRSA is an increasingly common cause of PVE and continues to be among the mostmorbid infections in the modern era. Recent data have changed our approach to thisdisease. Multidisciplinary teams can improve outcomes (200, 214), and specializedcenters are an important aspect of optimizing care. Moreover, both nuclear imagingmodalities and molecular techniques that show promise in improving PVE diagnostic

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sensitivity are emerging. Finally, a number of newer agents that are active againstMRSA have recently been approved and have shown early efficacy in the managementof this condition. However, because prospective and randomized clinical data on themanagement of MRSA PVE remain scarce, recently updated international practiceguidelines for IE from the ESC and the American College of Cardiology (30) continue torely largely on nonhuman data and expert opinion. As such, important priorities for thefield include (i) validating newer diagnostic modalities, such as advanced cardiacimaging, that may increase the sensitivity and specificity of PVE diagnosis; (ii) clarifyingthe role and optimal timing of valve replacement; (iii) performing comparative effec-tiveness studies to assess newer alternatives to vancomycin with gentamicin andrifampin as the mainstays of therapy; and (iv) clarifying the role of aminoglycosides inMRSA PVE therapy.

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Alicia Galar, Pharm.D., Ph.D., studied Phar-macy at the University of Navarra and didboth her residency in Clinical Microbiologyand Parasitology and Ph.D. at the ClínicaUniversidad de Navarra. She was a Postdoc-toral Clinical Research Fellow/Specialist atBrigham and Women’s Hospital and HarvardMedical School. Dr. Galar worked at theWorld Health Organization (WHO) Collabo-rating Centre for Surveillance of Antimicro-bial Resistance and joined the Transplantand Oncology Team at the Infectious Diseases Division of Brigham andWomen’s Hospital/Dana-Farber Cancer Institute/Massachusetts GeneralHospital. She completed her education with several courses at theHarvard School of Public Health, Massachusetts General Hospital, andHarvard University. She is currently working at the Department ofClinical Microbiology and Infectious Diseases of the Hospital GeneralUniversitario Gregorio Marañón in Madrid. Dr. Galar’s main researchinterests include antimicrobial resistance, therapeutic drug monitoring,pharmacokinetic/pharmacodynamic (PK/PD) strategies, antimicrobialstewardship, vaccines, prosthetic-device-related infections, infective en-docarditis, and infections in patients with heart diseases.

Ana A. Weil holds an M.P.H. from the JohnsHopkins School of Public Health and an M.D.at Tufts University. She trained in internalmedicine and infectious diseases at Massa-chusetts General Hospital (MGH), where shealso served as a chief resident. Dr. Weil iscurrently a physician-scientist in the Infec-tious Diseases Division at MGH. The Weillaboratory is focused on understanding theinfluence of the gut microbiome in suscep-tibility to enteric infections and pathogen-gut microbe interactions at the mucosal surface, including identifyinggut species that may protect against infection and relationships be-tween gut microbial species and mucosal immune responses. Dr. Weilalso treats general medicine and infectious disease patients at MGH andhas held several leadership positions in medical education, including asa faculty advisor for an elective course at Harvard Medical School.

David M. Dudzinski studied Medicine atHarvard Medical School and trained at Mas-sachusetts General Hospital, where he was achief resident. He is board certified in inter-nal medicine, cardiovascular diseases, nu-clear cardiology, adult comprehensive echo-cardiography, and critical care medicine. Dr.Dudzinski is a cardiologist, cardiac intensiv-ist, and echocardiographer at Harvard Med-ical School and Massachusetts General Hos-pital and serves as a staff cardiac intensivistin the cardiac and cardiac surgical intensive care units, with a clinicalexpertise centered on the nascent field of critical care cardiology. Dr.Dudzinski’s academic interests are in pulmonary embolism, right ven-tricle function, procedural echocardiography, aortic disease, qualityimprovement, medical education, resuscitation science and emergencycardiovascular care, and critical care cardiology. Dr. Dudzinski is also anattorney with expertise in the scientific and legal aspects of the regu-lation of protein-based therapeutics, and he serves on the AmericanCollege of Cardiology’s national medical professional liability workinggroup.

Patricia Muñoz, M.D., Ph.D., studied Medi-cine at the Complutense University of Ma-drid (UCM) and trained at the HospitalClínico San Carlos. She was deputy editor ofClinical Microbiology and Infection and wasawarded the Young Investigator Award ofthe European Society of Clinical Microbiol-ogy and Infectious Diseases. She is currentlyProfessor in Medicine in Clinical Microbiol-ogy at UCM and Head of the Section ofClinical Microbiology and Infectious Diseasesat the Hospital General Universitario Gregorio Marañón (HGUGM). Dr.Muñoz’s research interests include fungal infections; infective endocar-ditis; infections in solid-organ transplant recipients, immunocompro-mised hosts, and heart surgery patients; and nosocomially acquiredinfectious diseases. She is an active member of the European StudyGroups for Nosocomial Infections and Infection in Compromised Hostand the Spanish Network of Infection in Transplantation. She is theSecretary of the Group for the Management of Infective Endocarditis atHGUGM and has been President of the Spanish Society for Cardiovas-cular Infections.

Mark J. Siedner is an Associate Professor ofMedicine at Harvard Medical School andholds an M.D. from the Johns Hopkins Uni-versity School of Medicine and an M.P.H.from the Johns Hopkins Bloomberg Schoolof Public Health. He trained in internal med-icine at Columbia University Medical Centerand in infectious diseases at MassachusettsGeneral Hospital (MGH). His clinical work fo-cuses on clinical infectious disease both atMGH and as an HIV care provider in south-western Uganda and Kwazulu-Natal, South Africa. He leads a researchprogram in Uganda and South Africa in partnership with MGH and theAfrica Health Research Institute, aimed at mitigating the causes ofmorbidity and mortality among people living with HIV in low-incomecountries.

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