REVIEW

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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. Siednerc,d

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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 Citation Galar A, Weil AA, Dudzinski DM,
expert opinion and data from animal models or related conditions (e.g., coagulase- Muñoz P, Siedner MJ. 2019. Methicillin-resistant
Staphylococcus aureus prosthetic valve
negative Staphylococcus infection). We performed a review of the literature on MRSA endocarditis: pathophysiology, epidemiology,
PVE to summarize data on pathogenic mechanisms and updates in epidemiology and clinical presentation, diagnosis, and
therapeutic management and to inform diagnostic strategies and priority areas where management. Clin Microbiol Rev 32:e00041-18.
https://doi.org/10.1128/CMR.00041-18.
additional clinical and laboratory data will be particularly useful to guide therapy. Major
Copyright © 2019 American Society for
updates discussed in this review include novel diagnostics, indications for surgical man- Microbiology. All Rights Reserved.
agement, the utility of aminoglycosides in medical therapy, and a review of newer anti- Address correspondence to Alicia Galar,
staphylococcal agents used for the management of MRSA PVE. alg331@mail.harvard.edu.
Published 13 February 2019
KEYWORDS methicillin-resistant Staphylococcus aureus, prosthetic valve endocarditis

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Galar et al. Clinical Microbiology Reviews

INTRODUCTION

S taphylococcus 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) and
6.6% 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 trials
testing treatments for MRSA PVE, many aspects of management lack an empirical basis.
For example, the timing and necessity of valve surgery remain unknown. In some
studies, hospital mortality rates for S. aureus PVE were significantly higher in patients
who 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 standard
treatment for S. aureus PVE, especially in patients with early-onset infection (2, 11).

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However, recent literature and the experience of the International Collaboration on
Endocarditis (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 be
successfully managed without early valve surgery, and a multicenter study reported in
2015 by the ICE found no association between EVS and a reduction of 1-year mortality
rates in patients with S. aureus PVE (11).
Furthermore, although multiple treatment guidelines advocate for incorporating an
aminoglycoside into MRSA PVE therapy (19, 20) to promote sustained susceptibility to
rifampin, 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 in
humans for MRSA PVE are lacking. Furthermore, the use of an aminoglycoside for other
causes of endocarditis, including methicillin-sensitive Staphylococcus aureus (MSSA)
native valve endocarditis (NVE) and CoNS PVE, demonstrates either harm or a lack of a
survival benefit (24–27). Although current guidelines discuss this lack of evidence, most
continue 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 in
synergy could have a role in treatment but have not yet been thoroughly studied.

TIMING, PATHOPHYSIOLOGY, PATHOGENESIS, AND HISTOPATHOLOGY

Timing 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. These
thresholds have been developed based on the risk of developing PVE and differences
in the microbiology of the disease between periods (33, 34). The risk of PVE is greatest
during the first 3 months after surgery. The risk peaks approximately 15 days after
surgery, 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 patient
days from 150 days to 20 years postoperatively (35–39). The cumulative proportions of
patients developing PVE range from 1 to 3% in the first 365 days after surgery according
to several studies with close follow-up and from 3 to 6% in 5 years (35–39). S. aureus is
a 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 months
from surgery) and 18 to 30% of late cases (6, 41). A large, multicenter, international
study (6) showed that MRSA was the causative microorganism in 18.9% of early cases
of PVE, versus 3.3% of late cases.

Pathophysiology
Early PVE infection is believed to be caused by accidental seeding during surgery or
due to bloodstream dissemination in the first hours to months postoperatively. Early
after surgery, the prosthetic sewing ring and cardiac connection tissue and sutures
have 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 cardiac
structures become fully endothelized, and the pathogenesis of disease more resembles
that of NVE (42).
The location and distribution of PVE also differ by the type of prosthetic valve and
the 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). In
one postmortem study, perivalvular invasion, which is commonly coupled with pros-
thesis dehiscence and paravalvular regurgitation, appeared in approximately 40% of
autopsies performed for patients with PVE, and frank extension into tissue leading to
myocardial abscess was seen in 15% (46). Annular and/or myocardial abscesses were
present in 68% of the 47 patients with PVE in another study (47). Dehiscence of the
prosthesis was described in more than 80% of cases of aortic and mitral prostheses

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examined by Ben Ismail et al. (48), and vegetations were seen in 75% (48). More than
1 year postoperatively, infection related to biological PVE is more commonly found at
the prosthesis leaflets. Complications of late PVE include leaflet rupture and perforation
of an aortic valve prosthesis, which can extend through the intervalvar fibrosa and
annulus to cause pericarditis or, more frequently, can spread into the membranous
portion of the interventricular septum and cause arrhythmia (49–51). Large vegetations
may also keep the prosthesis open, causing malfunction or encroachment on the valve
orifice, 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-platelet
matrices of “nonbacterial thrombotic endocarditis,” such as fibronectin, laminin, and
collagen, and these can also adhere to the normal endothelium or minimally injured
tissue (40, 52, 53). Once the thrombus is colonized by MRSA, this microorganism can
proliferate, creating the characteristic vegetation of infective endocarditis (IE). The
presence of cardiac prostheses introduces an additional variable that favors PVE, since
MRSA can adhere by forming biofilms (Fig. 2 and 3) (40, 53). At initial placement, the
ring-prosthesis interface is not endothelized and favors fibrin-platelet thrombus for-
mation. The suture points where the prostheses are placed constitute a mechanism
whereby MRSA can invade the heart tissue and form abscesses. In addition, the
continuous stress caused by the repetitive movement in the bioprostheses may disrupt
the 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 drug
use, a surgical wound, or pulmonary or urinary tract infection (40, 53, 54). During the
surgical procedure (Fig. 4), the surgical site may be exposed to MRSA from the patient’s
or 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 (ⱖ7 days) and the
evolution of prosthetic valve vegetation propagation (52, 55, 56).
Nonvalvular invasive infection may also cause bioprosthetic valve endocarditis. For
example, annular and myocardial invasion was observed in 38 of 85 patients (45%) in
one study and was more common among cases of bioprosthetic PVE occurring during
the 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 late
bioprosthetic PVE (79% versus 31%) in another series (58).
A large proportion of cases of PVE is nosocomial and correlates with a high
proportion of MRSA infections (6). An international study including 556 patients with
PVE demonstrated that 36.5% of infections were nosocomially acquired or related to
frequent 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 to
perform valve culture and 16S PCR (courtesy of Mercedes Marín, Hospital General Universitario Gregorio Marañón, Madrid, Spain). Shown
are a mechanical valve, a mitral ring, an aortic bioprosthesis, and a mitral bioprosthesis.

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

intubation and percutaneous self-expandable valves (59). Further studies are needed to
better 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 bioprosthetic
valves. As bioprosthetic valves degenerate, they often create noninfective, calcific,
vegetative-like lesions with inflammatory infiltrates, which can result in a noninfectious
process that can mimic and be misdiagnosed as PVE. A retrospective pathological study
of inflamed bioprosthetic valve tissues from 88 cases of resected bioprosthetic valves
(21 for probable endocarditis and 67 for noninfective dysfunction) was performed to
better define the histological criteria for PVE (62). PVE was histologically characterized
by neutrophil-rich inflammatory infiltrates and the presence of microorganisms. Inflam-
matory infiltrates in valve tissue samples from the noninfective control group consisted
mainly of lymphocytes and macrophages. In that study, having a neutrophil percentage
exceeding 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 for
16% to 31% of IE cases in several studies (1, 6, 67–70). The etiology of 146 early-PVE
clinical 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 the
cases. The incidence of both early and late PVE was correlated with increasing under-
lying comorbidity at the time of valve placement, surgeon experience, extracorporeal
circulation duration, sterility of the heart-lung machine and the operating theater,
extracardiac postoperative infection, and the length of time that the patient was

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FIG 3 An original electron scanning microscope image of a methicillin-resistant Staphylococcus aureus

biofilm on a patient’s mechanical heart prosthesis. The image was prepared at both the Clinical
Microbiology and Infectious Diseases Department and the Pathology Department of the Hospital General
Universitario Gregorio Marañón and was taken at the National Center of Electron Microscopy (JSM 6400,
CNME, Madrid, Spain).

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

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 across
geographic regions. The data provided by Wang et al. (6) are consistent with the global
epidemiology of S. aureus (P ⫽ 0.007) and MRSA (P ⫽ 0.001) PVE found and also kindly
shared 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 postoperative
S. aureus PVE (71). Unsurprisingly, the incidence of PVE was higher when the valve
replacement occurred in the setting of active or recently treated endocarditis (36, 39,
72, 73). In several observational studies, bioprosthetic valves appear to increase the risk
for infection over mechanical valves after 18 months (37, 72, 73). However, three
randomized trials including 1,418 patients monitored for 8 to 20 years could not
demonstrate a statistically significant difference in PVE occurrence between biological
and mechanical valves (P ⫽ 0.45 [74], P ⫽ 0.71 [75], and P ⫽ 0.70 [76]). Another
observational study that included 38,000 patients ⱖ65 years of age demonstrated a
higher risk of endocarditis after a median of 12 years of follow-up among those with
bioprosthetic valves (2.2% versus 1.4%; unadjusted hazard ratio, 1.69 [95% confidence
interval {CI}, 1.43 to 2.00]) (77). Finally, Calderwood et al. (37) showed a higher risk of
occurrence of PVE among patients (n ⫽ 116 out of 2,608 evaluated) who received
mechanical valves than among those who received bioprosthetic valves at 3 months
postsurgery (P ⫽ 0.02), but in contrast, Grover et al. (73) could not demonstrate any
difference between the valves in 66 patients who developed PVE out of 1,032 observed
during 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 clinical
presentation of MRSA PVE is often nonspecific, especially soon after surgery, when
inflammation 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 individuals
with PVE suffered some combination of worsened or new cardiac failure, a changed or
new cardiac murmur, continuous fever, or irregularities upon electrocardiography
(ECG). These complications were more common in the first year after valve replacement
and in aortic valve prosthesis infections (Table 1). New or changing murmurs, heart
failure, and new electrocardiographic conduction disturbances are noted more often in

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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 valve
endocarditis in 53 sites worldwide (P ⫽ 0.003 for Staphylococcus aureus; P ⫽ 0.001 for MRSA [methicillin-resistant Staphylococcus
aureus]). MSSA, methicillin-sensitive Staphylococcus aureus.

PVE than in NVE cases due to the likelihood of invasive infection. ECG (Fig. 6), chest
radiograph, and blood cultures are considered part of the standard work-up if there is
a clinical suspicion of PVE.
Pulmonary, neurological, kidney, and musculoskeletal complications or complica-

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 TABLE 1 Key articles on epidemiology, diagnosis, management, conclusions, and prevention of S. aureus PVE and IEa
Author(s) (yr) (reference)
Béraud et al. (2011) (215)
Bille (1995) (216)
Calderwood et al. (1985) (37)
Cervera et al. (2014) (217)
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Chirouze et al. (2004) (1)
Chirouze et al. (2015) (11)
Cosgrove et al. (2009) (218)
de Feiter et al. (2005) (219)
Del Río et al. (2014) (220)
Fernández Guerrero et al.
(2009) (15)
Fowler et al. (2006) (157)
Hasbun et al. (2003) (221)
Holland et al. (2014) (222)
John et al. (1998) (3)
Kang et al. (2012) (223)
Karchmer et al. (1983) (24)
cmr.asm.org 9
Epidemiology
137 physicians participated in the study
Antimicrobial therapy review
2,642 patients who underwent valve replacement
for the first time were included in the study
Analysis of a study cohort
Evaluation of mortality risk
Impact of early valve surgery on clinical outcome of
S. aureus PVE within the International
Collaboration of Endocarditis
236 patients from 44 hospitals and 4 countries were
prospectively evaluated
Fusidic acid, rifampicin, vancomycin, oxacillin, and
gentamicin treatment failures
Rescue therapy with imipenem ⫹ fosfomycin
Incidence of infective endocarditis, epidemiology,
clinical features, prognosis
Daptomycin vs standard therapy
Prognostic factors
Review on hospital management
Clinical strategies and prognostic factors
6-wk occurrence of embolic events and mortality
Retrospective study of 75 PVE cases
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Diagnosis
Infective endocarditis
Endocarditis due to Staphylococcus
116 patients with PVE (4.4%)
93 cases of S. aureus infective
endocarditis (left sided)
61 cases of S. aureus PVE
747 cases of definite left-sided PVE
S. aureus bacteremia and native
valve infective endocarditis
Patient with Staphylococcus
epidermidis PVE
Complicated bacteremia and
MRSA endocarditis
Definite S. aureus endocarditis
(right sided and left sided)
S. aureus bacteremia and
endocarditis
Left-sided endocarditis (native
valve) with complications
Bacteremia caused by S. aureus
Definite PVE caused by S. aureus
Patients with large vegetations,
severe disease in valves, left-
sided endocarditis due to
infection
Staphylococcus epidermidis PVE
Management
Endocarditis was treated with gentamicin doses of 3 mg/
kg/day by 61% of physicians, 4 mg/kg/day by 22.1%,
and 5 mg/kg/day by 16.9%
A combination of 3 antibiotics (vancomycin or oxacillin ⫹
gentamicin and rifampin) is suggested for PVE during
at least 6 wk
At 12 mo, the risk of PVE was 3.1%, and at 60 mo, the risk
was 5.7%; porcine valves had a significantly lower risk
of PVE during the first 90 days from surgery than
mechanical valves but a significantly higher risk after
12 mo postsurgery
57% had a vancomycin MIC of ⬍1.5 ␮g/ml, and 43% had
an MIC of ⱖ1.5 ␮g/ml
Patients who had their valve replaced early, despite
having heart complications, showed lower mortality
rates (P ⫽ 0.09)
Non-S. aureus PVE caused significantly lower rates of
death after 1 yr than S. aureus PVE; at this time,
patients with S. aureus PVE and EVS also had lower
mortality rates (P ⬍ 0.01); EVS did not diminish
mortality at 1 yr
Vancomycin or an antistaphylococcal penicillin ⫹ low-
dose gentamicin or daptomycin alone was
administered to patients; renal adverse events were
evaluated
Despite the nonapproval for this indication, linezolid was
administered to this patient
Treatment was successful in 69% of cases; the mortality
rate due to MRSA was 1/5 (20%)
NVE was a less common hospital-acquired infection than
PVE; for both types of endocarditis, renal and cardiac
failure and central nervous system complications were
detected
Microbiological failure was more common in the group
treated with daptomycin than in the one with
standard therapy
Factors related to mortality after 6 mo, including
abnormal mental status, bacterial cause, comorbidities,
medical treatment, moderate/severe congestive cardiac
failure
Diagnostic methods and antibiotic treatment strategies
Complications affecting the central nervous system (33%)
and heart (67%) were found; the 3-mo mortality rate
was 42%
Patients were randomized into 2 groups, conventional
treatment or early surgery
The gentamicin susceptibility rate was 78%, and those for
rifampin and vancomycin were 100% for all isolates
tested; dysfunction of valves and tissue progression
were the most common problems, needing surgery in
30 cases
Conclusion(s) and/or prevention strategy
Guidelines were not followed by most of the
physicians for gentamicin dosing in these
patients; instead, they used validated
regimens from published studies
Further studies are needed to incorporate novel
treatment options, especially in patients
affected by MRSA
There were significant differences in the risk of
PVE depending on the type of valve, but no
significant differences between porcine and
mechanical valves were observed in the risk
of having PVE after 5 yr
Percentages of in-hospital death varied
significantly between both groups, at 30 and
53%, respectively
S. aureus PVE is a disease with high morbidity
and mortality rates (28.6–85.7%)
Staphylococcus aureus Prosthetic Valve Endocarditis
Different factors should be taken into account
before deciding on EVS
Low-dose gentamicin should not be used
routinely for S. aureus bacteremia and native
valve infective endocarditis due to the
nephrotoxicity shown
Patient had a favorable outcome with linezolid
Combination therapy was safe and effective as
rescue therapy
Valve replacement significantly improved
outcomes for patients with PVE
A noninferiority rate was observed in the group
treated with daptomycin compared to the
one treated with standard therapy for
bacteremia and right-sided endocarditis
caused by S. aureus
4 groups of patients were identified depending
on the mortality risk 6 mo after baseline
There are groups of patients who do not need
TEE
More patients died due to heart problems than
due to problems affecting the central
nervous system, but this mortality was
diminished when there was surgery for valve
replacement during antibiotic treatment
Rates of embolic events and mortality
significantly decreased in the group with
early surgery compared to the group of
patients treated conventionally
Antibiotic therapy including vancomycin ⫹
rifampin or an aminoglycoside increased
favorable outcome rates; surgical treatment
was also important
(Continued on next page)
Clinical Microbiology Reviews
 TABLE 1 (Continued)
Author(s) (yr) (reference)
Karchmer (1991) (224)
Le and Bayer (2003) (225)
Mayer and Schoenbaum
(1982) (226)
Muñoz et al. (2015) (12)
April 2019 Volume 32 Issue 2 e00041-18
Murdoch et al. (2009) (4)
Rajashekaraiah et al. (1980)
(26)
Ribera et al. (1996) (27)
Sohail et al. (2006) (17)
Wang et al. (2007) (6)
Wareham et al. (2005) (227)
Watanakunakorn (1979) (32)
Wilson et al. (1995) (228)
Yaw et al. (2014) (229)
aASA, American Society of Anesthesiologists; EVS, early valve surgery; MBC, minimal bactericidal concentration; MRSA, methicillin-resistant Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; NVE,
native valve endocarditis; PVE, prosthetic valve endocarditis; TEE, transesophageal echocardiography; VRE, vancomycin-resistant Enterococcus; ICU, intensive care unit; HACEK group, a group of Gram-negative bacilli
consisting of Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella spp.
cmr.asm.org 10
Epidemiology
Infection control
Review on antibiotic treatment for endocarditis
caused by frequently detected microorganisms
Review and approach
Epidemiology, clinical features, prognostic factors
Global infective causes and clinical features
Evaluation of tolerance (MBC/MIC ⬎ 16)
Cloxacillin vs cloxacillin ⫹ gentamicin during 2 wk
Mortality rates in patients who received medical vs
surgical treatment
Global infective causes and clinical features
Cases treated with linezolid
Treatment with penicillin vs penicillin ⫹ gentamicin
Treatment efficacy experience
Clinical outcome evaluation
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Diagnosis
PVE
PVE
Infective endocarditis (1,804 cases)
Infective endocarditis
S. aureus bacteremia and
endocarditis
S. aureus endocarditis (right sided)
S. aureus PVE
PVE
MRSE and VRE endocarditis
S. aureus endocarditis
Endocarditis caused by
enterococci, staphylococci,
streptococci, and members of
the HACEK group
MRSA and MSSA bacteremia
Management
During a year postsurgery, the nosocomial risk of PVE
was 1.4–3.0%; the most common reason for hospital-
acquired PVE was methicillin-resistant coagulase-
negative Staphylococcus
Few strategies for in vitro, experimental, and clinical
evaluation of enterococcal endocarditis have been
shown
Higher rates of morbidity and mortality were detected in
early than in late PVE cases; the etiology often
included fungi, staphylococci, and Gram-negative rods
in early PVE and streptococci in late PVE
Previous cardiac surgery, atrial fibrillation, cardiac
complications and failure, septic shock, age,
cerebrovascular complications, or Candida or
Staphylococcus cause was related to in-hospital deaths
(28.9%); after 1 yr, association was found for cancer,
cardiac failure, age, and renal insufficiency (11.2%)
Infections of mitral and aortic valves due to S. aureus
were the most frequent presentation, also complicated
with heart failure, stroke, and other emboli and
abscess in the heart
Tolerant microorganisms were accompanied by more
deaths, complications, hospitalization in ICU,
prolongation of fever
Mortality occurred 1 and 2 cases, respectively
Mortality rates of 48% and 28%, respectively
The most frequent microorganism was S. aureus; 36.5% of
cases were related to health care; the of in-hospital
death rate was 22.8% and was related to health care,
age, persistent bloodstream infection, S. aureus cause,
and cardiac and CNS problems
In vitro study of Staphylococcus epidermidis and
Enterococcus faecalis infections treated with linezolid ⫹
gentamicin or vancomycin
The death rate was 40% in both groups of patients
Recommendations of treatment based on previously
reported studies
Rehospitalization rates associated with infection were
similar in both groups of patients
Conclusion(s) and/or prevention strategy
Further studies are needed to detect
Galar et al.
postsurgical causes of hospital-acquired PVE
and diminish them
Human clinical data are scarce on combination
antibiotic treatment for infective endocarditis
due to S. aureus
Factors related to poor outcome were early
PVE, paravalvular leakage, emboli, persistent
fever, nonstreptococcal microorganisms,
nonheterograft aortic valve, congestive
cardiac failure
The rates of in-hospital and 1-yr deaths were
elevated, and surgery was the only
protective factor
Risk factors for in-hospital mortality were lung
edema, age, prosthetic infection, S. aureus or
coagulase-negative staphylococcal cause,
mitral vegetation, and valve problems
Poor outcomes of endocarditis were more
common in cases caused by tolerant
microorganisms than in cases caused by
sensitive ones
Combination treatment was not more effective
than the single one
The no. of deaths was lower in the surgical
group; bioprosthetic valves and ASA class IV
were prognostic factors
S. aureus is globally the main cause of PVE, and
the presence of complications is an
important prognostic factor
Outcome was favorable in both cases
There is no clinically demonstrated advantage
of the use of combination therapy with
gentamicin
Literature is scarce
MSSA bacteremia outcomes were more
favorable than MRSA bacteremia ones;
patients colonized with MRSA should be
treated carefully
Clinical Microbiology Reviews
Staphylococcus aureus Prosthetic Valve Endocarditis Clinical Microbiology Reviews

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FIG 6 Electrocardiogram at 25 mm/s of a patient with aortic MRSA PVE with nonspecific findings, including tachycardia (heart rate of approximately 125 beats
per 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).

tions associated with systemic infections might also occur, at the same time, in some
PVE cases (80–87). Of note, S. aureus is the pathogen most commonly related to IE
complications compared to others (88). Lung complications are more frequently seen
in patients with right-sided endocarditis, in several cases presenting manifestations
such 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%, with
overt arterial emboli being noted for 40% of patients with PVE (48, 89–91). Similar rates
of embolic stroke (18%) and ischemic stroke (20%) among patients with PVE were
reported by Davenport and Hart (92) and Keyser et al. (89), respectively. Fernández
Guerrero et al. (15) observed that, compared to NVE, S. aureus PVE clinical manifesta-
tions were characterized by less-frequent cardiac murmurs and a shorter symptomatic
prodrome.
In PVE patients with no prior antibiotic therapy, blood cultures are positive in at least
90% of cases (63). Molecular techniques, such as DNA examination by pulsed-field gel
electrophoresis or 16S rRNA sequencing, can be used when standard blood or tissue
cultures 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 or
multiplane transducer that allows continuous-wave and pulsed-wave Doppler and
color flow imaging can increase the accuracy of diagnosis of PVE (96). TEE is considered
the method of choice for diagnosis of PVE (97), because although transthoracic
echocardiography (TTE) may lead to a diagnosis in some cases, TEE has a higher
sensitivity for PVE (98, 99) (Fig. 7A). This increase in sensitivity is not accompanied by
a loss of specificity and is independent of the valve type or position (98–101). For
suspected PVE, TEE sensitivity and specificity have been estimated at 77 to 90% and
90%, respectively, compared to TTE, with a specificity and sensitivity estimated at 40 to
70% and 90%, respectively (102). Nonetheless, TTE has value for the assessment of
ventricular size and function and severe hemodynamic lesions in valves and can often

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FIG 7 Imaging modalities for MRSA prosthetic valve endocarditis diagnosis. (A) Transesophageal echocardiography demonstrating a 1.4- by
1.2-cm highly mobile echodensity at the ventricular side of the bioprosthetic aortic valve (indicated by the arrow), without significant valvular
dysfunction. (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 well
visualized, 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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Staphylococcus aureus Prosthetic Valve Endocarditis Clinical Microbiology Reviews

detect anterior aortic prosthetic valve abscesses (103) (Fig. 7B). Typically, the ventricular
surfaces of prostheses in the mitral, tricuspid, and aortic positions are better viewed by
TTE, whereas TEE has additional value for viewing the aortic valve surfaces, tricuspid
and mitral valves, and the exit of the prosthesis in the aorta; fistula and abscess
detection; detection of paraprosthetic leaks; and visualization of a mitral valve pros-
thesis (104, 105). However, TEE will miss some cases of prosthetic valve dehiscence. In
a study of 26 patients with PVE, there were 14 (56%) cases of aortic valve dehiscence
intraoperatively, 4 (29%) of which were not detected upon TEE (106). One prospective
study that compared the paired use of TTE with TEE in 114 episodes of clinically
suspected IE (34 PVE and 80 NVE) found that the results of the two tests were
concordant in only 55% of cases (107). TEE prompted reclassification for 34% of patients
with prosthetic valves, compared with 11% of patients with native valves.
The Duke criteria have been described as being less useful for the diagnosis of PVE

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because 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 testing
and clinical scores, other techniques have been assessed. Magnetic resonance imaging
(MRI) and multislice computed tomography (MS-CT) might improve the detection of an
intra- or pericardiac anatomical complication (112). The value of ECG-gated multide-
tector CT angiography (MDCTA) was addressed by three studies (113–115), which
demonstrated a ⬎90% sensitivity for the diagnosis of PVE (113), which was improved
to a sensitivity and a specificity of 100% and 83%, respectively, after completion of
routine 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 diagnostic
criterion 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 infection
process (120). For suspected PVE, [18F]FDG PET/CT demonstrated a 67 to 100% positive
predictive value, a 50 to 100% negative predictive value, 73 to 100% sensitivity, and 71
to 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 cases
that do not meet criteria for endocarditis by the modified Duke criteria but remain
under high clinical suspicion. The sensitivity of the modified Duke criteria significantly
increased 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 consequence
of 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 scintigraphy
with single-photon emission tomography/computed tomography (SPECT/CT) for the
detection of PVE (119, 124, 125). Probable (125) or definite (119, 124) IE cases were
included. Globally leukocyte scintigraphy showed an 85 to 100% positive predictive
value, 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 for
better 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 advances
in 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/CT
image 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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Galar et al. Clinical Microbiology Reviews

TABLE 2 International guidelines for therapy of MRSA PVEa

AHA guidelines
ESC guidelines for adults Pediatric Adult
Vancomycin at 30–60 mg/kg Q24h i.v., BID or TID Vancomycin at 40 mg/kg Q24h i.v. (maximum dose, 2 g Q24h), Vancomycin at 30 mg/kg Q24h i.v., BID
during ⱖ6 wk BID or TID during ⱖ6 wk during ⱖ6 wk
Rifampin at 900–1,200 mg Q24h i.v./orally, BID or Rifampin at 20 mg/kg Q24h i.v. (maximum dose, 900 mg Rifampin at 900 mg Q24h i.v./orally, TID
TID during ⱖ6 wk Q24h), TID during ⱖ6 wk during ⱖ6 wk
Gentamicin at 3 mg/kg Q24h i.v./i.m., once a day Gentamicin at 3 to 6 mg/kg Q24h i.v./i.m., TID during the first Gentamicin at 3 mg/kg Q24h i.v./i.m., BID
or BID during the first 2 wk 2 wk or TID during the first 2 wk
aThedoses 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.

counterpart, the European Society for Cardiology (ESC), suggest a triple-drug regimen
(class I; level of evidence C) with vancomycin and rifampin for ⱖ6 weeks and genta-

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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, IE
experiments, and retrospective clinical series (57, 127–130). A single retrospective study
of valve cultures from 61 patients with staphylococcal PVE (29 due to S. aureus and 32
due to CoNS) treated surgically showed that those receiving combination therapy were
5.9 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 six
patients treated with a triple-drug regimen including rifampin prior to surgery had
negative valve cultures. Regarding surgical indication, all of the groups of therapy
evaluated 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 those
with S. aureus PVE were reported.
Antibiotic recommendations for treatment of MRSA PVE are also partially based on
ex vivo and animal studies of Staphylococcus epidermidis PVE. A retrospective evaluation
of 23 cases of methicillin-resistant S. epidermidis (MRSE) PVE (129) showed an increase
in 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 of
S. epidermidis from vegetations compared to beta-lactam antibiotics alone (131, 132).
Another study (130) found that when rifampin was added to the combination of
vancomycin and gentamicin in broth, there was an enhanced bactericidal effect in
rabbits despite antagonism of the bactericidal rate. Notably, similar data for these
relationships on MRSA are lacking.

Vancomycin
Vancomycin remains the mainstay of therapy for MRSA PVE (29, 30). Vancomycin
dosing should be based on actual body weight and adjusted to achieve troughs of 15
to 20 ␮g/ml (29). Vancomycin binds the terminal D-alanyl-D-alanine moieties of
N-acetylmuramic acid (NAM)/N-acetylglucosamine (NAG) peptides in the bacterial cell
wall and thus prevents the addition of the NAM/NAG peptide subunits into the
peptidoglycan 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 and
nephrotoxicity when used concomitantly with aminoglycosides (134). Significant
weight 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 synthesis
through the inhibition of the bacterial DNA-dependent RNA polymerase. Rifampin is
believed to bind to a pocket of the RNA polymerase ␤-subunit within the DNA/RNA
channel. This noncompetitive inhibitor prevents RNA synthesis by directly blocking RNA
elongation and thus preventing the synthesis of host bacterial proteins (136). Hepatic
and immunoallergic toxicities are the most common rifampin adverse effects. Hepato-

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toxicity usually affects patients with previous liver damage and is associated with the
dose administered. Adverse immunoallergic events might be minor or major and are
predominantly 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 rpoB
gene, encoding the rifampin-binding site. When large numbers of S. aureus bacteria are
exposed to rifampin alone or in combination with ineffective antimicrobials, single
mutations 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 to
rifampin. Similarly, many have recommended waiting until vancomycin and gentamicin
have been administered for 3 to 5 days, bacteremia has resolved, and undrained

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abscesses or collections have been debrided prior to initiation of rifampin (30). This
approach is supported by the in vitro antagonism demonstrated when rifampin is
exposed to replicating bacteria in combination with other antimicrobials (141) and the
synergism detected when bacteria are instead in a latent state (142). This effect can be
seen in biofilm-mediated foreign-body infections, such as those associated with ortho-
pedic hardware, prostheses, or vascular grafts (143). Lowy et al. (131) prevented the
development of rifampin-resistant S. epidermidis by adding either vancomycin or
gentamicin in a rabbit endocarditis model, but these observations have unclear clinical
utility in treating PVE in humans.
Rifampin is recommended for a minimum of 6 weeks, at a dosing regimen of 300 mg
every 8 h, in combination with gentamicin for the first 2 weeks and vancomycin for the
full 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 another
antistaphylococcal 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 eradication
of serious S. aureus and S. epidermidis infections, others have reported both in vitro
synergy and antagonism for rifampin in combination with beta-lactam agents, vanco-
mycin, or gentamicin against S. aureus (149, 150). Another study concluded that there
was no synergy or antagonism against MRSE regarding the concomitant use of other
antibiotics (cephalothin, nafcillin, vancomycin, or gentamicin) with rifampin (127).
MRSE isolates harboring rifampin mutations appeared to be as virulent as their
rifampin-sensitive antecedents in rabbit endocarditis models, although a similar effect
was not seen in rifampin-resistant S. aureus isolates in a mouse model (151). The
mechanism of decreased virulence may be due to decreased production of toxins by
rifampin-resistant S. aureus (127). The emergence of rifampin resistance was not
prevented 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 in
vitro when there was a prevention of emergent rifampin-resistant mutants by a
beta-lactam antibiotic.

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

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Galar et al. Clinical Microbiology Reviews

highly hydrophilic. Therefore, corrected body weight should be used for dosing calcu-
lations for obese patients, rather than ideal body weight. The gentamicin mechanism
of action is based on irreversible binding to specific proteins on the 30S subunit of the
MRSA ribosome and the decoding site of the 16S rRNA. This leads to a misreading of
the mRNA, the addition of incorrect amino acids in the growing peptide chain, and the
interruption of MRSA protein synthesis (154).
Ototoxicity and nephrotoxicity are important adverse events limiting gentamicin
clinical use. Both side effects are associated with the dose administered and might not
appear until the end of treatment. Kidney damage, in contrast to inner ear damage, is
usually reversible but can be fatal (155, 156). Gentamicin trough and peak values lower
than 1 ␮g/ml and 3 to 4 ␮g/ml, respectively, are recommended when gentamicin is
administered every 8 h. When gentamicin is dosed daily, serum troughs should be
lower than 1 ␮g/ml. ESC guidelines recommend that peaks be assessed once after

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infusion, with a goal range of 10 to 12 ␮g/ml (per AHA/IDSA guidelines, there is no role
for 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 had
improved 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 the
heart vegetation than nafcillin in monotherapy (22).
Nonetheless, clinical data in support of gentamicin use in this setting are lacking. In
a recent study comparing daptomycin therapy with an antistaphylococcal penicillin or
vancomycin in combination with gentamicin for MSSA or MRSA bacteremia and/or
right-sided endocarditis (157), significantly more patients who received standard ther-
apy with gentamicin suffered nephrotoxicity (18.1% versus 6.7% with renal tubular
necrosis and 46.8% versus 19.8% with worsening creatinine clearance), without an
improvement in clinical outcomes for those who received gentamicin (157). Whether
these results pertain to MRSA PVE is unknown, but this topic warrants urgent study
given the ongoing guideline recommendations for the use of gentamicin in the
treatment 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, a
three-drug regimen for the entire course of treatment is preferred. In cases of resistance
to aminoglycosides and fluoroquinolones, ceftaroline, trimethoprim-sulfamethoxazole,
or linezolid (158) has been proposed as the third agent during the first 2 weeks of
treatment, 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 is
daptomycin susceptible), linezolid, telavancin, ceftaroline, and daptomycin combined
with ceftaroline, nafcillin, or fosfomycin, combinations that might result in synergy
(159–165). Yet reported clinical experience with these treatments and combination
therapies 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 of
innate immunity, but the precise molecular mechanism is unknown (139). Dhand et
al. (166) reported a series of seven cases with rapid clearance of persistent MRSA
bacteremia when high-dose nafcillin was added to high-dose daptomycin. Other
experts (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). In
one case report, the efficacy and tolerability of ceftaroline were demonstrated in one
patient with osteomyelitis and endocarditis caused by an MRSA strain that was not
susceptible to daptomycin (170). A patient with MRSA aortic PVE was also cured with
prolonged high-dose daptomycin plus ceftaroline after other therapeutic failures (169).
Ceftaroline fosamil was the most active bactericidal drug in a rabbit model of MRSA
endocarditis (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 mg
twice daily), daptomycin at a dose comparable to 6 mg/kg/24 h in humans, or a
tigecycline 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 vegetation
reduction rates (⬎5 log10 CFU/g), whereas tigecycline did not show bactericidal effi-

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cacy, and MRSA vegetation reduction rates were ⬍2 log10 CFU/g in comparison to
controls. However, the MRSA vegetation sterilization rate by ceftaroline was 100%, in
contrast to the rate of 57% reached by daptomycin, with resistant mutants being seen
only in the daptomycin therapy group. Recent clinical data also demonstrate ceftaroline
as an alternative for MRSA bacteremia salvage treatment (170, 172–177). Two obser-
vational studies also suggest that ceftaroline therapy alone (178) or in combination
with trimethoprim-sulfamethoxazole (179) can be used to treat invasive MRSA infec-
tion, although more experience and, if possible, adequately designed clinical studies
are needed before there is widespread recommendation for its use.
Linezolid is an alternate treatment in cases of MRSA PVE complicated by drug allergy
or intolerance, although its use is limited by a relative scarcity of data and side effects
of prolonged use. Among 33 cases of endocarditis treated with linezolid, 21 (63.6%) had
a favorable outcome. PVE accounted for 25% of the reviewed cases, and MRSA
accounted for 24.2% (1 case of MRSA PVE among 8 PVE cases [12.5%]). The one patient
with MRSA PVE treated with linezolid had a favorable outcome. Additional efficacy and
tolerability 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 could
be as effective as vancomycin in the treatment of endocarditis caused by glycopeptide-
intermediate S. aureus (GISA). Other experimental IE models also showed telavancin
bactericidal 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-sided
MRSA endocarditis. The drug has gained attention for its single intravenous dosing
schedule at 1,200 mg over 3 h, which allows treatment of complicated MRSA infections
without the need for indwelling central venous catheters, a particular concern for
patients with recent or active injection drug use, and has shown promise in other
refractory and drug-resistant cases of PVE (187, 188). A left-sided MRSA endocarditis
rabbit model suggested that oritavancin was superior to vancomycin in resolving
bacteremia and reducing bacterial counts in vegetations and tissues (189). Those
investigators concluded that oritavancin was microbiologically effective and might be
an 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 failed
treatment. Although oritavancin is currently indicated only for acute bacterial skin and
skin structure infections, it has the potential to play an increasing role as an agent
against MRSA PVE, particularly in light of the ongoing international opioid epidemic
(191, 192).
Tigecycline has activity against MRSA; however, it has been demonstrated to have
a lower efficacy than vancomycin against MRSA strains (193), and its peak serum
concentrations do not exceed 1 ␮g/ml (194, 195). As such, tigecycline is not typically
recommended as an agent for MRSA bacteremia or endocarditis. Similarly, although

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Galar et al. Clinical Microbiology Reviews

clindamycin and trimethoprim-sulfamethoxazole are theoretically alternative options

for MRSA PVE, experience with these agents for this condition is limited, and they are
typically considered only in the case of severe drug intolerance or as considerations in
synergistic 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 reductions
in 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 valvular

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failures complicated by heart failure, abscess formation, or fistulas and those not
responding to maximally effective antimicrobial therapy (30). The timing of surgery for
PVE is a topic of ongoing debate (2, 7, 16, 17, 201–203) and is a decision based on
surgeon- and patient-specific factors, including complications of disease, such as CNS
emboli and hemorrhage, and overall surgical risk. A recent study of 4,166 cases of
infective PVE and NVE in patients with heart failure found decreases in both hospital
and 1-year deaths with early surgery (during the index hospitalization) (65). More
recently, two prospective cohort studies, reported by Chirouze et al. (11) and Lalani
et al. (204), found a crude reduction in 1-year mortality rates with early versus delayed
surgery but similar rates after consideration of confounding and survivor bias. Thus, the
decision on the timing of therapy continues to largely depend on surgical risk and input
from multidisciplinary teams.

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

PREVENTION
The utility of antimicrobial prophylaxis for prevention of bacteremia and IE in
humans remains unclear (30, 206). Since the relaxation of antibiotic prophylaxis after
the 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 of
Streptococcus but not staphylococcal IE cases since the guideline change (209). Accord-
ing to current guidelines, antimicrobial prophylaxis is recommended for high-risk
patients (30, 33, 71, 210–213) undergoing high-risk procedures (30), including those
with prosthetic heart valves. Probably as important as antibiotic prophylaxis is careful
attention to skin and dental hygiene. Moreover, procedures affecting gastrointestinal,
respiratory, musculoskeletal, genitourinary, and dermatological systems do not typically
require 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 most
morbid infections in the modern era. Recent data have changed our approach to this
disease. Multidisciplinary teams can improve outcomes (200, 214), and specialized
centers are an important aspect of optimizing care. Moreover, both nuclear imaging
modalities and molecular techniques that show promise in improving PVE diagnostic

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

Staphylococcus aureus Prosthetic Valve Endocarditis
sensitivity are emerging. Finally, a number of newer agents that are active against
MRSA have recently been approved and have shown early efficacy in the management
of this condition. However, because prospective and randomized clinical data on the
management of MRSA PVE remain scarce, recently updated international practice
guidelines for IE from the ESC and the American College of Cardiology (30) continue to
rely largely on nonhuman data and expert opinion. As such, important priorities for the
field include (i) validating newer diagnostic modalities, such as advanced cardiac
imaging, that may increase the sensitivity and specificity of PVE diagnosis; (ii) clarifying
the role and optimal timing of valve replacement; (iii) performing comparative effec-
tiveness studies to assess newer alternatives to vancomycin with gentamicin and
rifampin as the mainstays of therapy; and (iv) clarifying the role of aminoglycosides in
MRSA PVE therapy.
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cmr.asm.org 25
Galar et al.
Alicia Galar, Pharm.D., Ph.D., studied Phar-
macy at the University of Navarra and did
both her residency in Clinical Microbiology
and Parasitology and Ph.D. at the Clínica
Universidad de Navarra. She was a Postdoc-
toral Clinical Research Fellow/Specialist at
Brigham and Women’s Hospital and Harvard
Medical School. Dr. Galar worked at the
World Health Organization (WHO) Collabo-
rating Centre for Surveillance of Antimicro-
bial Resistance and joined the Transplant
and Oncology Team at the Infectious Diseases Division of Brigham and
Women’s Hospital/Dana-Farber Cancer Institute/Massachusetts General
Hospital. She completed her education with several courses at the
Harvard School of Public Health, Massachusetts General Hospital, and
Harvard University. She is currently working at the Department of
Clinical Microbiology and Infectious Diseases of the Hospital General
Universitario Gregorio Marañón in Madrid. Dr. Galar’s main research
interests include antimicrobial resistance, therapeutic drug monitoring,
pharmacokinetic/pharmacodynamic (PK/PD) strategies, antimicrobial
stewardship, 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 Johns
Hopkins School of Public Health and an M.D.
at Tufts University. She trained in internal
medicine and infectious diseases at Massa-
chusetts General Hospital (MGH), where she
also served as a chief resident. Dr. Weil is
currently a physician-scientist in the Infec-
tious Diseases Division at MGH. The Weil
laboratory is focused on understanding the
influence of the gut microbiome in suscep-
tibility to enteric infections and pathogen-
gut microbe interactions at the mucosal surface, including identifying
gut species that may protect against infection and relationships be-
tween gut microbial species and mucosal immune responses. Dr. Weil
also treats general medicine and infectious disease patients at MGH and
has held several leadership positions in medical education, including as
a faculty advisor for an elective course at Harvard Medical School.
David M. Dudzinski studied Medicine at
Harvard Medical School and trained at Mas-
sachusetts General Hospital, where he was a
chief 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 intensivist
in the cardiac and cardiac surgical intensive care units, with a clinical
expertise 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, quality
improvement, medical education, resuscitation science and emergency
cardiovascular care, and critical care cardiology. Dr. Dudzinski is also an
attorney with expertise in the scientific and legal aspects of the regu-
lation of protein-based therapeutics, and he serves on the American
College of Cardiology’s national medical professional liability working
group.
April 2019 Volume 32 Issue 2 e00041-18
Clinical Microbiology Reviews
Patricia Muñoz, M.D., Ph.D., studied Medi-
cine at the Complutense University of Ma-
drid (UCM) and trained at the Hospital
Clínico San Carlos. She was deputy editor of
Clinical Microbiology and Infection and was
awarded the Young Investigator Award of
the European Society of Clinical Microbiol-
ogy and Infectious Diseases. She is currently
Professor in Medicine in Clinical Microbiol-
ogy at UCM and Head of the Section of
Clinical Microbiology and Infectious Diseases
at 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 acquired
infectious diseases. She is an active member of the European Study
Downloaded from http://cmr.asm.org/ on May 6, 2020 by guest
Groups for Nosocomial Infections and Infection in Compromised Host
and the Spanish Network of Infection in Transplantation. She is the
Secretary of the Group for the Management of Infective Endocarditis at
HGUGM and has been President of the Spanish Society for Cardiovas-
cular Infections.
Mark J. Siedner is an Associate Professor of
Medicine at Harvard Medical School and
holds an M.D. from the Johns Hopkins Uni-
versity School of Medicine and an M.P.H.
from the Johns Hopkins Bloomberg School
of Public Health. He trained in internal med-
icine at Columbia University Medical Center
and in infectious diseases at Massachusetts
General Hospital (MGH). His clinical work fo-
cuses on clinical infectious disease both at
MGH and as an HIV care provider in south-
western Uganda and Kwazulu-Natal, South Africa. He leads a research
program in Uganda and South Africa in partnership with MGH and the
Africa Health Research Institute, aimed at mitigating the causes of
morbidity and mortality among people living with HIV in low-income
countries.
cmr.asm.org 26