P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.
664in
LWBK915-63 LWW-KodaKimble-educational
1490 INFECTIVE ENDOCARDITIS
Infective endocarditis (IE) is a microbial infection of the heart
valves or other endocardial tissue, often associated with an under-
lying cardiac defect. IE used to be classified as either acute bac-
terial endocarditis or subacute bacterial endocarditis based on
the clinical presentation and course of the untreated disease.
This classification system is nonspecific, however, and it does
not account for many nonbacterial causes of endocarditis such
as chlamydiae, rickettsiae, and fungi. Hence, the current sys-
tem based on the causative organism is preferred because it pro-
vides information regarding the probable course of the disease,
the likelihood of underlying heart disease, and the appropriate
antimicrobial regimens.1
Pathogenesis
The pathogenesis of endocarditis involves a complex series of
events that ultimately results in the formation of an infected
platelet β-fibrin thrombus on the valve surface.1,2 This thrombus
is called a vegetation.
Section 14
The first step in the formation of the vegetation involves mod-
ification of the endocardial surface, which is normally nonthrom-
bogenic.
For a visual of tissue changes in endocarditis,
Infectious Disease
go to http://thepoint.lww.com/AT10e.
In patients with rheumatic heart disease, endocardial injury
occurs as a result of immune complex deposition or hemody-
namic disturbances. Valvular insufficiency caused by aortic steno-
sis or ventricular septal defects can produce regurgitant blood
flow, high-pressure gradients, or narrow orifices, resulting in tur-
bulence and endocardial damage.
Once the endocardial surface of the valve is traumatized,
small, sterile thrombi consisting of platelets and fibrin are
deposited, forming the lesion called nonbacterial thrombotic
endocarditis (NBTE). NBTE occurs most commonly on the atrial
surfaces of the mitral and tricuspid valves and on the ventricular
surface of the aortic valve.
NBTE serves as a nidus for microbial colonization during
periods of bacteremia. Table 63-1 lists procedures associated
with bacteremia. Organisms such as Streptococcus viridans, En-
terococcus species, Staphylococcus aureus, Staphylococcus epider-
midis, Pseudomonas aeruginosa, and Candida albicans possess adher-
ence factors that facilitate their pathogenicity. In particular,
platelet aggregation has been shown to be an important virulence
factor in experimental streptococcal endocarditis; larger vegeta-
tions and multifocal embolic spread have been associated with
strains that aggregate platelets.3 Once the NBTE lesion becomes
colonized by microorganisms, the surface is rapidly covered with
a sheath of fibrin and platelets. This avascular encasement pro-
vides an environment protected from host defenses and is con-
ducive to further bacterial replication and vegetation growth.
Progression of the infection can be interrupted at any time by
various host defense mechanisms, including blocking antibod-
ies that interfere with bacterial adherence, serum bactericidal
complement activity, hemodynamic forces that dislodge poorly
adherent bacteria, and circulating prophylactic antibiotics.
The vegetation is thought to propagate by continuous reseed-
ing of the thrombus by circulating organisms. As the vegetation
enlarges, it takes on a laminar appearance caused by the alternat-
ing layers of bacteria and platelet fibrin deposits. The bacterial
November 17, 2011 16:49
TA B L E 6 3 - 1
Cardiac Conditions for Which Prophylaxis is Recommended
Cardiac Conditions
Prophylaxis Recommended
s
Prosthetic cardiac valves
s
Previous bacterial endocarditis
s
Congenital heart disease
– Unrepaired cyanotic CHD, including palliative shunts and conduits
– Completely repaired congenital heart defect with prosthetic
material device during the first 6 months after the procedure
– Repaired CHD with residual defects at or adjacent to the site of the
prosthetic device or patch
– Mitral valve prolapse with valvular regurgitation and/or thickened
leaflets
s
Cardiac transplantation recipients who develop cardiac valvulopathy
CHD, congenital heart disease.
Source: Wilson W et al. Prevention of infective endocarditis: guidelines from the
American Heart Association: a guideline from the American Heart Association
Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on
Cardiovascular Disease in the Young, and the Council on Clinical Cardiology,
Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care an
Outcomes Research Interdisciplinary Working Group. American Heart
Association [published correction appears in Circulation. 2007;116:e376].
Circulation. 2007;116:1736.
colony count can be as high as 104 to 105 bacteria per gram of
valvular vegetation.
Endocarditis can result in life-threatening hemodynamic dis-
turbances and embolic episodes. Without antimicrobial therapy
and surgical intervention, IE is virtually 100% fatal. Because of
bacterial proliferation to high densities in the fibrin mesh pro-
tected from normal host defenses, cure of infection requires pro-
longed therapy of 4 to 6 weeks with relapse not uncommon.
Epidemiology
IE accounts for approximately 15,000 to 20,000 new cases per
year in the United States.4 The overall incidence has been stable;
however, health care–associated IE has emerged as a result of
increased use of invasive medical devices and procedures (e.g.,
intravenous [IV] catheters, total parenteral nutrition intravenous
[TPN] lines, pacemakers, dialysis shunts).1 The mean patient age
has shifted from younger than 30 years in the 1920s to older than
55 years today.4,5 This increase in age is likely attributable to (a) a
decline in the incidence of acute rheumatic fever and rheumatic
heart disease counterbalanced by degenerative valvular disease
in an increasing elderly population, (b) the increasing longevity
of the general population, and (c) increased exposure to more
intense and invasive medical procedures in both the overall and
the aging populations. Men are infected more often than women
(roughly 2:1), and the disease remains uncommon in children,
primarily in association with underlying congenital cardiac defect
and nosocomial catheter-related bacteremia.1
Predisposing Factors
In general, any structural cardiac defect that leads to the tur-
bulence of blood flow predisposes to the development of IE.
Rheumatic heart disease was at one time the most common
underlying cardiac defect associated with endocarditis; however,
the proportion of cases related to rheumatic heart disease have
declined to 25% or less in developed countries while remain-
ing the predominant defect in developing countries. Mitral valve
prolapse with thickened leaflets and valvular redundancy is a
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational November 17, 2011 16:49

recognized predisposing risk to IE, with a documented occur- 1491

rence rate of 10%. Clinical presentation is often subtle with lower
associated mortality in these individuals compared with left-sided
IE of other types. In the absence of underlying valvular defects,
degenerative cardiac lesions, such as calcified mitral annulus sec-
ondary to atherosclerotic cardiovascular disease and postmyocar-
dial infarction thrombus, may be a significant risk factor for the
elderly. In one series of native valve endocarditis cases, 50% of
patients 60 years of age or older had degenerative cardiac lesions;
however, the actual contribution of these lesions is unknown.6
Intravenous drug users constitute a unique population at greatest
risk for recurrent and polymicrobial IE. In addition, health care–
related IE occurs with increasing frequency among hospitalized
critically ill patients and others who are subjected to IV access
procedures or invasive medical device placement (hemodialysis
shunts or fistulas, intracardiac prosthesis, central venous pressure FIGURE 63-1 Janeway lesions. Extensive ecchymotic embolic
monitoring lines, TPN lines, defibrillators, permanent cardiac lesions in a case of acute bacterial endocarditis.
pacemakers).1
Hemodialysis dependency (8%), diabetes mellitus (16%), and
congenital heart disease (12%) are the most common demo- affected simultaneously. Some studies have shown that aortic
graphic characteristics associated with IE.7 Up to 25% of all cases valve involvement is increasing in frequency and is associated
are acquired in health care–related settings. Notably, in the United with higher morbidity and mortality.

Chapter 63
States, health care–associated IE is more likely compared with
community acquisition.
STREPTOCOCCUS VIRIDANS
Bacteriology ENDOCARDITIS
Streptococci and staphylococci are the cause of 80% to 90% of

Endocarditis
cases of IE. Historically, viridans streptococci were the predomi- Clinical Presentation
nant causative pathogens in IE, accounting for 60% to 80% of all
cases.1 When comparing epidemiologic studies in the aggregate CASE 63-1
during the past decades, however, staphylococci are increasingly QUESTION 1: A.G., a 57-year-old, 60-kg man with chief
prevalent as a cause of IE. Viridans streptococci remain the pre- complaints of fatigue, a persistent low-grade fever, night
dominant cause of IE in children and in young women with sweats, arthralgias, and a 7-kg unintentional weight loss,
isolated mitral valve involvement.1 is admitted to the hospital for evaluation. Visual inspec-
Staphylococcus aureus is the leading cause of IE.6,7 Acquisition tion reveals a cachectic, ill-appearing man in no acute
of IE in nearly half of these cases was likely health care–related, distress. Physical examination is significant for a grade
supporting a low threshold to evaluate underlying IE in the set- III/IV diastolic murmur with mitral regurgitation (insuffi-
ting of health care–related S. aureus bacteremia. More impor- ciency) increased from pre-existing murmur, a temperature
tantly, methicillin-resistant strains account for up to 40% of IE of 100.5◦ F, petechial skin lesions, subungual splinter hem-
cases involving S. aureus.4,5 orrhages, and Janeway lesions on the soles of both feet
Endocarditis in IV drug users often is caused by S. aureus, (Figs. 63-1, 63-2, and 63-3). Nail clubbing, Roth spots,
whereas prosthetic valve endocarditis is more commonly caused or Osler’s nodes are not evident (Figs. 63-4 and 63-5).
by coagulase-negative staphylococci, such as S. epidermidis.
Gram-negative bacilli and fungi together account for less than
10% of all endocarditis cases, which usually are associated with
IV drug use, valvular prostheses, and hospital IV access proce-
dures. Endocarditis caused by anaerobes and other organisms is
rare. Polymicrobial infective endocarditis (caused by at least two
organisms), although uncommon in the typical patient, is being
recognized more frequently in IV drug users and certain postop-
erative patients. Candida species, S. aureus, P. aeruginosa, Serratia
marcescens, and non-β group D streptococci are the organisms
involved most frequently in these populations.

Site of Involvement
The site of heart valve involvement is determined by the under-
lying cardiac defect and the infecting organism.2,4,5,7 The mitral
valve is affected in more than 85% of cases caused by viridans
streptococci with underlying rheumatic heart disease. The tricus-
pid valve is the common site of involvement in staphylococcal
endocarditis associated with IV drug use. Overall, the distribu-
tion ranges from 28% to 45% for mitral valve, 5% to 36% for
aortic valves, and 0% to 6% for tricuspid valves, and the pul-
monary valve is rarely affected.8 Multiple heart valves may be FIGURE 63-2 Splinter hemorrhages in the nailbed.
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational November 17, 2011 16:49

1492

FIGURE 63-3 Petechial skin lesions in a case of acute

staphylococcal endocarditis.

The remainder of his physical examination is unremarkable.

Section 14

A.G.’s medical history is significant for mitral valve prolapse FIGURE 63-4 Osler nodes on the tip of the index finger in a case of
and, more recently, a dental procedure involving the extrac- endocarditis caused by Staphylococcus aureus.
tion of four wisdom teeth. The history of his present illness
is noteworthy for the development of symptoms 2 weeks
after the dental procedure (about 2 months before admis- afternoon and evening. The temperature rarely exceeds 103◦ F
sion). His only current medication is ibuprofen 600 mg four in subacute disease.1 Fever may be absent or minimal in patients
Infectious Disease

times a day (QID).
Relevant laboratory results include the following:
Hemoglobin (Hgb), 11.4 g/dL (SI units, 114 g/L [normal,
140–180])
Hematocrit (Hct), 34% (SI units, 0.34 [normal, 0.39–0.49])
Reticulocyte count, 0.5% (SI units, 0.005 [normal, 0.001–
0.024])
White blood cell (WBC) count, 85,000/μL with 65% polys
and 1% bands (SI units, 85 × 10/L with 0.65 polys and
0.01 bands [normal, 3.2–9.8 with 0.54–0.62 polys and
0.03–0.05 bands])
Blood urea nitrogen (BUN), 21 mg/dL (SI units, 7.5
mmol/L of urea [normal, 2.9–8.9])
Serum creatinine (SCr), 1.8 mg/dL (SI units, 159 mmol/L
[normal, 53–133])
A urinalysis (UA) reveals 2+ proteinuria and 10 to 20 red
blood cells (RBCs) per high-power field (HPF). The erythro-
cyte sedimentation rate (ESR) is elevated at 66 mm/hour,
and the rheumatoid factor (RF) is positive. Results from a
transthoracic echocardiogram were unrevealing.
Three blood cultures were obtained during 24 hours,
and all cultures obtained on day 1 are growing α -hemolytic
streptococci. While confirmation and speciation of the
organism is being performed, A.G. is started on penicillin
G, 2 million units IV every 4 hours (12 million units/day), and
gentamicin, 120 mg (loading dose) followed by 60 mg every
12 hours. Antimicrobial susceptibility results are pending.
What clinical manifestations and laboratory abnormalities
in A.G. are consistent with IE?
with congestive heart failure (CHF), chronic renal and liver fail-
ure, prior use of antimicrobial agents, or IE caused by less vir-
ulent organisms.1 Musculoskeletal complaints (e.g., arthralgias,
myalgias, and back pain) are common and may mimic rheumatic
disease. Other symptoms can include lethargy, anorexia, malaise,
nausea, and vomiting.1 Because signs and symptoms are nonspe-
cific and subtle, diagnosis is often difficult to make. In addition,
the time from bacteremia to diagnosis is often prolonged because
of the insidious progression of symptoms.1 Delayed diagnosis
occurs more commonly in the elderly. Fever may be absent in
30% to 40% of patients older than 60 years of age, whereas it can
be present in more than 90% of patients younger than 40 years
of age. Elderly patients are less likely to have new or changed
heart murmurs. The most common presenting complaints in
the elderly with endocarditis are confusion, anorexia, fatigue,
and weakness, which may be readily attributable to stroke, heart
failure, or syncope.
The temporal relationship between A.G.’s dental procedure
and the onset of symptoms suggest it was the etiology of bac-
teremia and subsequent endocarditis. Although it is assumed

The clinical presentation of IE is highly variable and can

involve almost any organ system.1 A.G. appears pale and
chronically ill and represents the typical patient with subacute
disease (e.g., that caused by viridans streptococci). Nonspecific
complaints consistent with endocarditis in A.G. include fatigue,
weight loss, fever, night sweats, and arthralgias. Fever alone is
present in most (90%) patients with endocarditis. The fever is FIGURE 63-5 Clubbing of the fingers in longstanding subacute
characteristically low grade and remittent, with peaks in the bacterial endocarditis.
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
that prophylactic antibiotics were administered before the pro-
cedure, endocarditis can develop despite receipt of adequate
chemoprophylaxis.9
A.G. has an increase in his pre-existing diastolic murmur with
mitral insufficiency, a finding consistent with endocarditis. Car-
diac murmurs are present in more than 85% of patients with
endocarditis. Murmurs frequently are absent in patients with
acute disease (e.g., staphylococcal endocarditis), right-sided dis-
ease (e.g., endocarditis in IV drug users), or mural infection.1
A.G. exhibits several peripheral manifestations of IE, includ-
ing conjunctival petechiae, Janeway lesions, and splinter hemor-
rhages. Overall, peripheral manifestations are observed in 10%
to 50% of cases, but none of these is pathognomonic for IE.
These manifestations are usually a result of septic embolization
of vegetations to distal sites or immune complex deposition.
Mucocutaneous petechial lesions of the conjunctiva, mouth, or
pharynx are present in 20% to 40% of patients, especially those
with longstanding disease. These lesions generally are small, non-
tender, and hemorrhagic in appearance and occur as a result of
vasculitis or peripheral embolization. Janeway lesions are pain-
less, hemorrhagic, macular plaques most commonly found on
the palms and soles (Fig. 63-1). Splinter hemorrhages are non-
specific findings that appear as red to brown linear streaks in
the proximal portion of the fingers or toenails (Fig. 63-2). Other
findings can include Roth spots (small, flame-shaped retinal hem-
orrhages with pale white centers found near the optic nerve) and
Osler nodes (purplish, nonhemorrhagic, painful nodules that
develop on the subcutaneous pads of the fingers and toes or on
palms and soles) (Fig. 63-4). Clubbing (broadening and thick-
ening) of the nails also may be observed in patients with pro-
longed disease (Fig. 63-5).1,10 Petechial skin lesions also are seen
(Fig. 63-3).
Several laboratory findings are consistent with IE in A.G. A
low Hgb and Hct with normal red cell indices suggest anemia
of chronic disease. Of patients with subacute disease, 70% to
90% will have a normochromic, normocytic anemia. Leukocy-
tosis with a left shift, although not evident in A.G., commonly
is seen in those with acute, fulminant disease such as staphy-
lococcal endocarditis. The ESR nearly always is elevated in IE,
but this finding is nonspecific and can be associated with several
other disease entities. Rheumatoid factor (an immunoglobulin M
antiglobulin) and circulating immune complexes can be detected
in most patients with longstanding disease, but both are nonspe-
cific findings.1
Major embolic episodes and infarction involving the kidney,
spleen, lung, and brain develop as secondary complications in up
to one-third of cases.1 A.G. exhibits some degree of renal damage,
as evidenced by moderate hematuria and proteinuria. Erythro-
cyte and leukocyte cast formation also may be present. Alter-
ations in A.G.’s renal function (increased BUN and creatinine)
probably are a result of immune complex deposition (diffuse
glomerulonephritis) or secondary to renal embolization (focal
glomerulonephritis). Renal impairment usually is reversible with
the institution of effective antimicrobial therapy.1,10
Cardiac complications occur most frequently. CHF, the most
common cause of death in IE, is the most common indica-
tion for surgery. Infection-induced valvular damage is respon-
sible for valvular insufficiency causing heart failure.1,10 As many
as two-thirds of patients with endocarditis develop CHF. Aor-
tic valve infection is more frequently associated with CHF than
mitral valve infection. Other manifestations include paravalvu-
lar abscesses, pulmonary edema, and pericarditis.10 Mitral valve
injury caused by viridans streptococci generally is better tolerated
hemodynamically than aortic valve injury caused by staphylo-
cocci. Although A.G. has no apparent signs of overt heart failure,
he should be monitored closely for the development of hemody-
namic instability.
November 17, 2011 16:49
Neurologic complications rank second to cardiac complica- 1493
tions in frequency, but they may be the leading cause of death in
patients with endocarditis. Stroke is the most common neuro-
logic complication of IE.10 A stroke syndrome in a patient with
underlying valvular abnormalities should prompt the clinician to
rule out IE. Other clinical manifestations include headache, men-
tal status change, stroke or transient ischemic attack, seizures,
brain abscess, or intracranial mycotic aneurysms.1,10 Neurologic
symptoms take place in up to 35% of with S. aureus endocarditis
patients who are not drug addicts. Mortality is significantly more
likely in those with neurologic manifestations compared with
those without.11
Splenomegaly, although not part of A.G.’s findings, occurs
in 20% to 60% of all cases and is more common in subacute
disease. In addition, metastatic abscesses can develop in virtually
any organ secondary to systemic septic embolization. The most
commonly involved metastatic foci are the spleen, kidney, liver,
and iliac and mesenteric arteries.10
Diagnosis
Chapter 63
CASE 63-1, QUESTION 2: How was the diagnosis of IE
established in A.G.?
BLOOD CULTURES
Although A.G.’s medical history (mitral valve prolapse, recent
Endocarditis
dental procedure) and clinical presentation are highly sugges-
tive of IE, blood culture is the single most important diagnostic
workup for IE.1 Bacteremia secondary to endocarditis is contin-
uous and low grade; more than 50% of the cultures have only 1
to 30 bacteria/mL. Despite the low concentration of organisms,
bacteremia (when present) results in at least one of the first two
blood cultures being positive in 95% of cases.1 Administration of
antibiotics within the previous 2 weeks may significantly decrease
this yield.12
At least three sets of blood cultures collected by separate
venipunctures should be obtained during the first 24 hours of
presentation.1 In a “stable” patient such as A.G. who has had
the disease for several weeks or months, it is important to estab-
lish the exact microbiologic cause before initiating antimicrobial
therapy. Patients who are acutely ill should have empiric therapy
started as soon as the appropriate cultures are obtained to avoid
further valvular damage or other complications.1
ECHOCARDIOGRAPHY
Echocardiography is a valuable tool in establishing early diagno-
sis, identifying patients at high risk for complications, and opti-
mizing the timing and mode of surgical intervention by detecting
and monitoring associated pathologic changes such as valvular
abscess, as well as the presence and size of vegetations.1,13,14 With
echocardiography, high-frequency sound waves are applied,
and the reflection by body tissues is processed by a trans-
ducer to create images. The transducer may be placed on the
chest (transthoracic echocardiogram [TTE]) or in the esophagus
(transesophageal echocardiogram [TEE]).14 TTE is a rapid and
noninvasive procedure with 98% specificity for vegetations. Sen-
sitivity for vegetations may be less than 60% to 70%, however,
for adult patients with obesity, hyperinflated lungs caused by
emphysema, or a prosthetic valve. TEE is more costly and inva-
sive, but is significantly more sensitive in detecting vegetations
while maintaining high specificity. All patients with suspected
IE should have echocardiography on admission and repeated
during their course, as necessary.14 Two cost-effective analyses
support the increased use of TEE to define antibiotic therapy
duration for intravascular catheter-related S. aureus bacteremia
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
1494 (2 vs. 4 weeks).15,16 In particular, compared with TTE, TEE is
superior in the diagnosis of pacemaker IE and IE in the elderly,
and should be performed in all patients with a complicated course
in whom paravalvular extension is suspected unless contraindi-
cated by underlying esophageal disease.1 A.G. has a negative
TTE result on admission. Given the high clinical suspicion for
IE in A.G., a follow-up TEE is recommended to rule out a false-
negative TTE result. Documentation of valvular morphology,
the presence and size of vegetations, ventricular function, and
valvular insufficiency is important to establish a baseline and, on
completion of therapy, to guide future medical management and
appropriate timing of intervention.7
In summary, IE should be suspected in any patient who
has a documented fever and heart murmur. Prior cardiac dis-
ease, peripheral manifestations, splenomegaly, various labora-
tory abnormalities, and a positive echocardiogram strengthen
the diagnosis, but microbiologic documentation is the most
important factor in confirming IE. Disease entities with overlap-
ping clinical presentation and laboratory abnormalities should
be excluded using the appropriate tests.1
Standardized criteria (Duke criteria) for the clinical assess-
ment of patients suspected of having IE were proposed by a group
Section 14
at Duke University in 1994.17 Limitations of the Duke criteria,
such as misclassification of culture-negative endocarditis and the
overly broad categorization of “possible” causes as well as the
increasing role of TEE and the relative risk of IE with S. aureus bac-
teremia, were addressed in a modified version.18 Diagnostic cri-
teria for IE are listed in Tables 63-2 and 63-3, which integrate clin-
Infectious Disease
ical, laboratory, microbiologic, and echocardiographic data.7,18
Based on published evidence involving nearly 2,000 patients, the
2005 American Heart Association (AHA) guidelines suggest that
the modified Duke criteria be used as the primary diagnostic
schema to evaluate patients suspected of IE.7
A.G. possesses one major criterion (positive blood cultures)
and three minor criteria (fever, predisposing heart condition, vas-
cular and immunologic phenomena); therefore, he meets the
diagnostic criteria for definite IE.18
TA B L E 6 3 - 2
Definition of Infective Endocarditis (IE) According to the
Modified Duke Criteriaa
Definite Infective Endocarditis
pathologic criteria
Microorganisms: Demonstrated by culture or histology examination
of a vegetation, a vegetation that has embolized, or an intracardiac
abscess specimen, or
Pathologic lesions: Vegetation or intracardiac abscess confirmed by
histologic examination showing active endocarditis
clinical criteria
Using specific definitions listed in Table 63-3; two major criteria or
one major and three minor criteria or five minor criteria
Possible Infective Endocarditis
One major criterion and one minor criterion; or three minor criteria
Rejected
Firm alternative diagnosis explaining evidence of IE; or
Resolution of IE syndrome with antibiotic therapy for <4 days; or
No pathologic evidence of infective endocarditis at surgery or autopsy,
with antibiotic therapy for <4 days; or not meet criteria for possible
IE as above
a
Modifications shown in bold.
Reprinted with permission from Li JS et al. Proposed modifications to the Duke
criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633.
November 17, 2011 16:49
TA B L E 6 3 - 3
Definitions of Terminology Used in the Modified Duke Criteria
for the Diagnosis of Infective Endocarditis (IE)a
Major Criteria
Blood Culture Positive for Infective Endocarditis
s
Typical microorganisms consistent with IE from two separate blood
cultures
1. Viridans streptococci, Streptococcus bovis, HACEK group, or
2. Staphylococcus aureus or community-acquired enterococci in the
absence of a primary focus, or
s
Microorganisms consistent with IE from persistently positive blood
cultures defined as follows:
1. At least two positive blood cultures drawn >12 hours apart, or
2. All of three or a majority of four separate cultures of blood (with
first and last sample drawn at least 1 hour apart)
s
Single positive blood culture for Coxiella burnetii or antiphase
1 IgG antibody titer >1:800
Evidence of Endocardial Involvement
s
Echocardiogram positive for IE (TEE recommended for patients
with prosthetic valves, rated at least “possible IE” by clinical
criteria or complicated IE [paravalvular abscess]; TEE as first test
in other patients) defined as follows:
1. Oscillating intracardiac Masson valve or supporting structures, in
the path of regurgitant jets, or on implanted material in the
absence of an alternative anatomic explanation; or
2. Abscess, or
3. New partial dehiscence of prosthetic valve
s
New valvular regurgitation (worsening or changing of pre-existing
murmur not sufficient)
Minor Criteria
s
Predisposition: Predisposing heart condition or intravenous drug use
s
Fever >38◦ C (100.4◦ F)
s
Vascular Phenomena: Major arterial emboli, septic pulmonary infarcts,
mycotic aneurysm, intracranial hemorrhage, conjunctival
hemorrhages, Janeway lesions
s
Immunologic Phenomena: Glomerulonephritis, Osler nodes, Roth spots,
rheumatoid factor
s
Microbiologic Evidence: Positive blood culture but not meeting major
criterion as noted aboveb or serologic evidence of active infection
with organism consistent with IE
s
Echocardiographic minor criteria eliminated
a
Modifications shown in bold.
b
Excludes single positive cultures for coagulase-negative staphylococci and
organisms that do not cause endocarditis.
HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans,
Cardiobacterium hominis, Eikenella species, and Kingella kingae; TEE,
transesophageal echocardiography.
Reprinted with permission from Li JS et al. Proposed modifications to the Duke
criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633.
Antimicrobial Therapy
GENERAL PRINCIPLES
CASE 63-1, QUESTION 3: What would be a reasonable dura-
tion of antibiotic therapy for A.G.? When is determination of
minimum bactericidal concentration (MBC) useful in treating
bacterial endocarditis?
The avascular nature of the vegetation results in an envi-
ronment that is devoid of normal host defenses (e.g., phago-
cytic cells and complement); this permits uninhibited growth of
bacteria.2 Therefore, to eradicate the causative organism, high
doses of a parenterally administered, bactericidal antibiotic gen-
erally are administered for 4 to 6 weeks.1,19 For some infections,
it may be necessary to use two antibiotics to achieve synergistic
activity against the organism.20 For example, the addition of an
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
aminoglycoside to penicillin results in a more rapid and complete
bactericidal effect against enterococci.21
Once an organism has been identified, its in vitro suscepti-
bility pattern is determined by the minimum inhibitory concen-
tration (MIC) for various antibiotics. Standard Kirby-Bauer disk
diffusion testing is inadequate in the setting of IE to aid in selec-
tion of antibiotics without the quantitative information provided
by the MIC.1 In addition, the MBC may be useful in detect-
ing tolerant strains, particularly in the setting of unexplained
slow response or treatment failure. Routine MBC determina-
tion is not recommended, however.1 Treatment of endocardi-
tis requires antibiotics with bactericidal activity; therefore, the
serum concentration of the antibiotic must greatly exceed the
MBC for the particular organism. For endocarditis caused by
viridans streptococci acquired from the community, this usually
is achieved without much difficulty because most isolates are
sensitive to penicillin at an MIC of less than 0.125 mcg/mL; cor-
responding MBC are, at most, one or two tube dilutions higher.8
The emergence of strains demonstrating resistance to penicillin
and related β-lactams, such as ceftriaxone, is a significant prob-
lem, particularly among bloodstream isolates obtained from the
nosocomial setting and neutropenic cancer patients.8,22–24 The
increasing prevalence of β-lactam–resistant clinical isolates high-
lights the importance of determining the MIC and continued
close monitoring of the antibiotic susceptibility of viridans strep-
tococci. An increasing number of reports have described subopti-
mal response to vancomycin therapy for the treatment of invasive
infection caused by methicillin-resistant S. aureus (MRSA) strains
showing borderline susceptibility (MIC 2 mcg/mL).25 Many such
strains demonstrated tolerance to vancomycin as defined by a
high MBC-to-MIC ratio (≥32).26 Thus, these data support the
need to determine MBC, especially in the setting in which the
treatment option for IE caused by S. aureus is limited to van-
comycin and suboptimal response is observed.26
REGIMEN SELECTION
CASE 63-1, QUESTION 4: What factors must be considered
in selecting a regimen for A.G.? Which regimen should be
used for A.G.?
Patients with endocarditis caused by penicillin-sensitive
strains of viridans streptococci and nonenterococcal group D
streptococci (e.g., Streptococcus bovis; MIC <0.1 mcg/mL) can
be treated with any one of three regimens as outlined in
the 1995 AHA treatment guidelines.19 The suggested regimens
(Table 63-4) are associated with cure rates of up to 98% and
include (a) high-dose parenteral penicillin for 4 weeks; (b) high-
dose parenteral ceftriaxone for 4 weeks; and (c) 2 weeks of
combined therapy with high-dose parenteral penicillin and an
aminoglycoside.19,27–33 Ceftriaxone with an aminoglycoside for
2 weeks appears to be equally effective.34,35
HIGH-DOSE PENICILLIN FOR 4 WEEKS
Ten to 20 million units/day of IV penicillin G for 4 weeks
resulted in a cure rate of 100% for 66 patients with nonenterococ-
cal streptococcal endocarditis.29 Another study using penicillin
monotherapy reported relapse in only 2 of 49 patients; however,
both of these patients received less than 4 weeks of therapy.30
The large range of 12 to 18 million units/day of penicillin is rec-
ommended to allow flexibility in dosing based on the patient’s
renal function and disease severity.
SINGLE DAILY CEFTRIAXONE FOR 4 WEEKS
Ceftriaxone is active against viridans streptococcal strains isolated
from patients with endocarditis. In one study, all 49 strains of viri-
November 17, 2011 16:49
dans streptococci and 11 strains of S. bovis were inhibited at a con- 1495
centration of less than 0.125 mcg/mL of ceftriaxone; one strain of
Streptococcus sanguinis was inhibited at an MIC of 0.25 mcg/mL.36
Although no direct comparative trials have been performed eval-
uating ceftriaxone against high-dose penicillin for the treatment
of streptococcal endocarditis, it appears to be comparable to
high-dose penicillin when treatment is given for 4 weeks.37,38 Of
the 70 assessable patients who received ceftriaxone 2 g as a single
daily dose for 4 weeks, all were cured, except for 1 patient who
had a probable relapse 3 months after completion of therapy.
All strains of viridans streptococci were inhibited by ceftriaxone
at an MIC of 0.25 mcg/mL in both studies. Although the sim-
plicity of single daily treatment with ceftriaxone is attractive for
outpatient use, careful patient selection based on microbiologic,
clinical, and host factors is critical to the success of treatment and
the proper and timely management of potential complications.
(See Case 63-6, Question 1, for a detailed discussion of outpatient
therapy.)
HIGH-DOSE PENICILLIN OR CEFTRIAXONE PLUS AN
AMINOGLYCOSIDE FOR 2 WEEKS
The combination of 2 weeks of streptomycin (or gentamicin)
Chapter 63
with 4 weeks of penicillin is synergistically bactericidal for most
streptococci, including enterococci (see Case 63-4, Question
4).20,33 This in vitro synergy also has been correlated with a
more rapid rate of eradication of viridans streptococci from car-
diac vegetations in the rabbit model.31 A shortened combination
regimen consisting of high-dose penicillin G and streptomycin
Endocarditis
for 2 weeks is an effective alternative to the previously described
regimens. The reported cure rate in 104 patients treated at the
Mayo Clinic with this regimen was 99%.32,33
Although clinical experience with combination therapy has
been primarily with penicillin and streptomycin, in vitro and
animal data support that streptomycin and gentamicin are rea-
sonably interchangeable. Gentamicin is more widely used in
clinical practice, and serum concentrations are more readily
available to monitor efficacy and toxicities. Administration of
gentamicin once daily versus thrice daily when added to peni-
cillin appears equally effective in the treatment of viridans strep-
tococcal endocarditis.28
Combination therapy with ceftriaxone and an aminoglyco-
side for 2 weeks has also been evaluated.30,34 A 2-week course
of ceftriaxone 2 g plus netilmicin (3 mg/kg) (both given once
daily) resulted in a clinical cure of 87%.34 A second open-label
study compared ceftriaxone 2 g alone versus the combination
of ceftriaxone 2 g plus gentamicin (3 mg/kg), both given once
daily, for the treatment of endocarditis caused by penicillin-
susceptible streptococci.35 Patients were randomly assigned to
either regimen; 26 monotherapy recipients and 25 combination
therapy recipients were evaluable. Clinical cure was observed
in 96% of the patients in both groups at completion of ther-
apy and at 3-month follow-up. This study excluded patients with
suspected or documented cardiac or extracardiac abscesses and
those with prosthetic valve endocarditis. Although the amino-
glycoside agent (netilmicin or gentamicin) was administered as
a single daily dose in both studies, all of the patients had measur-
able serum trough levels. Therefore, the efficacy of “extended-
interval dosing” of aminoglycoside (whereby trough levels are
not detectable, allowing a drug-free interval) in short-course
combination therapy remains uncertain.
Based on available data, the 2-week regimen of penicillin
or ceftriaxone plus an aminoglycoside appears to be effica-
cious for uncomplicated cases of penicillin-susceptible viridans
streptococci endocarditis. It is not currently recommended
for patients with extracardiac complications or intracardiac
abscesses. Patients infected with Abiotrophia species (formerly
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational November 17, 2011 16:49

1496
TA B L E 6 3 - 4
Suggested Regimens for Therapy of Native Valve Endocarditis Caused by Streptococcus viridans and Streptococcus bovis

Antibiotic Dosea,b and Route Duration

Penicillin-Susceptible (minimum inhibitory concentration = 0.12 mcg/mL)

Aqueous crystalline penicillin Gc
Ceftriaxone sodiumc
Aqueous crystalline penicillin G
Ceftriaxone sodium
With gentamicin sulfated
Relatively Penicillin G Resistant (minimum inhibitory concentration > 0.1 mcg/mL and < 0.5 mcg/mL)
Adult: 12–18 million units/24 h IV either continuously or in four to six equally divided doses 4 weeks
Pediatric: 200,000 units/kg/24 h IV (max: 20 million units/24 h) either continuously or in four to
six equally divided doses
Adult: 2 g once daily IV or IM 4 weeks
Pediatric: 100 mg/kg once daily IV or IM
Adult: 12–18 million units/24 h IV either continuously or in six equally divided doses 2 weeks
Pediatric: 200,000 units/kg/24 h IV (max: 20 million units/24 h) either continuously or in six
equally divided doses
Adult: 2 g once daily IV or IM
Pediatric: 100 mg/kg once daily IV or IM
Adult: 3 mg/kg once daily IV or IM 2 weeks
Pediatric: 3 mg/kg once daily IV or IM or in three equally divided doses

Aqueous crystalline penicillin Ge Adult: 24 million units/24 h IV either continuously or in four to six equally divided doses 4 weeks
Pediatric: 200,000–300,000 units/kg/24 h IV (max: 20 million units/24 h) either continuously or in
four to six equally divided doses
Section 14

Ceftriaxone sodium Pediatric: 100 mg/kg once daily IV or IM

With gentamicin sulfated Adult: 3 mg/kg once daily IV or IM 2 weeks
Pediatric: 3 mg/kg once daily IV or IM or in three equally divided doses
β -Lactam Allergic Patients

Vancomycin hydrochloride f Adult: 30 mg/kg/24 h IV in two equally divided doses (max: 2 g/24 h unless serum concentrations 4 weeks
are monitored)
Infectious Disease

Pediatric: 40 mg/kg/24 h IV in two or three equally divided doses (max: 2 g/24 h unless serum
concentrations are monitored)
a
Pediatric doses should not exceed that of a normal adult.
b
Antibiotic doses for patients with impaired renal function should be modified appropriately. Vancomycin dosage should be reduced in patients with renal dysfunction;
cephalosporin dosage may need to be reduced in patients with moderate to severe renal dysfunction.
c
Preferred in most patients >65 years of age and in those with impairment of the eighth nerve or renal function.
d
Two-week regimen not intended for patients with known cardiac or extracardiac abscess or for those with creatinine clearance of <20 mL/min, impaired eighth cranial
nerve function or Abiotrophia, Granullicatella, or Gemelia infection. Gentamicin dosage should be adjusted to achieve peak serum concentrations of 3–4 mcg/mL and trough
serum concentrations of <1 mcg/mL when three divided doses are used; nomogram used for single daily dosing. Other potential nephrotoxic drugs should be used with
caution in patients receiving gentamicin therapy.
e
Cefazolin or other first-generation cephalosporins may be substituted for penicillin in patients whose penicillin hypersensitivity is not of the immediate type.
f
Vancomycin dosage should be reduced in patients with impaired renal function. Vancomycin given on a milligram per kilogram basis produces higher serum
concentrations in obese patients than in lean patients. Therefore, in obese patients, dosing should be based on ideal body weight. Each dose of vancomycin should be infused
for at least 1 hour to reduce the risk of the histamine-release red man syndrome. Peak serum concentrations of vancomycin should be obtained 1 hour after completion of the
infusion and should be in the range of 30–45 mg/mL. Trough concentrations should be obtained within half an hour of the next dose and be in the range of 10–15 mcg/mL.
IM, intramuscular; IV, intravenous.
Source: Baddour LM et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from
the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology,
Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;
111:e394.

known as nutritionally variant viridans streptococci) or viri-
dans streptococci who have a penicillin MIC greater than 0.1
mcg/mL or patients who have prosthetic valve infections should
not receive short-course therapy.19
SPECIAL CONSIDERATIONS
The risk of relapse may be higher in patients who have had
symptoms for more than 3 months before the initiation of
treatment.1,19,37 These patients should be treated with 4 to
6 weeks of penicillin combined with an aminoglycoside for the
first 2 weeks.1,19,37
Nutritionally deficient or variant streptococci (NVS) have
been reclassified into a new genus, Abiotrophia, which includes
Abiotrophia defectiva, Abiotrophia adiacens (renamed again as Gran-
ulicatella adiacens), and Abiotrophia elegans. Abiotrophia species
are slow-growing, fastidious organisms that are responsible for
approximately 5% of IE cases. Previously, NVS was the cause of
most of the cases of endocarditis diagnosed as “culture-negative”
initially owing to its requirement for the addition of vitamin B6
(pyridoxal HCl) to the culture media for laboratory growth. Lab-
oratory identification is no longer a significant problem, however,
because of current culture media and laboratory techniques.8
Nutritionally deficient or variant streptococci are less suscep-
tible to penicillin when compared with other streptococci. Many
NVS have a relatively high MIC to penicillin (0.2–2.0 mcg/mL),
and some show high-level resistance to penicillin (MIC >4
mcg/mL).8 In addition, tolerance to penicillin has been described
in many strains.8 An animal model of endocarditis indicates that
a penicillin–aminoglycoside (streptomycin or gentamicin) com-
bination is significantly better than penicillin alone in reducing
bacterial counts.39 High rates of bacteriologic failure and relapse
may be expected in patients despite completion of the treatment
course for strains highly susceptible to penicillin.8 All patients
infected with NVS or Abiotrophia should receive 4 to 6 weeks
of penicillin (or ampicillin) in combination with gentamicin.19
A 6-week course of combination therapy with penicillin and
gentamicin is recommended for patients with symptoms longer
than 3 months in duration and those with prosthetic valve
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
endocarditis caused by these strains.8,19 Patients with endocardi-
tis caused by relatively resistant viridans streptococci with peni-
cillin MIC of greater than 0.5 mcg/mL or enterococci should
receive a similar treatment regimen, as described above.19
Patients allergic to β-lactams should receive vancomycin 30
mg/kg/day divided into two doses for 4 to 6 weeks. In patients
who have had minor reactions to penicillins (e.g., a delayed rash),
a first-generation cephalosporin, such as cefazolin (2 g every
8 hours), may be cautiously substituted. Although the addition of
an aminoglycoside to a cephalosporin or vancomycin enhances
bactericidal activity in vitro, it is unknown whether the addition
of an aminoglycoside confers any additional clinical benefit.19 For
most cases of endocarditis caused by penicillin-sensitive viridans
streptococci (in patients not allergic to penicillin), all three of the
aforementioned regimens are equally acceptable; therefore, the
choice should be based on their relative advantages and disadvan-
tages. The 2-week regimen requires the shortest hospital stay, but
it has the disadvantage of possible ototoxicity and nephrotoxicity
secondary to aminoglycoside administration. Therefore, it may
be prudent to consider the use of penicillin or ceftriaxone alone
for 4 weeks in older persons (>65 years) and those with impaired
renal or vestibular function. For those with uncomplicated viri-
dans streptococci endocarditis who can manage the technical
aspects of outpatient therapy, ceftriaxone monotherapy offers
the convenience of single daily administration. The combined
regimen consisting of penicillin (or ampicillin) and an amino-
glycoside for 4 to 6 weeks can be used for patients infected with
NVS or relatively penicillin-resistant strains, those with prosthetic
valve infections, and those with longstanding disease (symptoms
>3 months).8,19,37
Assuming the viridans streptococci isolated from A.G. is not
resistant to penicillin and he has no other complicating factors,
any of the suggested regimens would be appropriate. Because
no compelling reason exists to use the 4-week regimens, the 2-
week penicillin–aminoglycoside regimen is the optimal choice.
Although A.G. has mild renal impairment, this is most likely
secondary to the endocarditis and should improve once adequate
antimicrobial therapy has been instituted. A.G. was begun on 12
million units/day of penicillin G, which would be reasonable
for his age and mild renal impairment. If nephrotoxicity were a
major concern in A.G., penicillin or ceftriaxone alone for 4 weeks
would be reasonable. If gentamicin is used, A.G.’s dose should
be adjusted appropriately and he should be evaluated frequently
for signs of toxicity. Periodic peak and trough aminoglycoside
concentrations should be monitored.
STAPHYLOCOCCUS EPIDERMIDIS:
PROSTHETIC VALVE ENDOCARDITIS
Etiology
CASE 63-2
QUESTION 1: F.T., a 65-year-old man, presents with chief
complaints of anorexia, fever, chills, and weight loss. His
medical history is significant for replacement of his mitral
and aortic heart valves (both porcine) 1 year ago for aor-
tic stenosis, mitral regurgitation, and mitral stenosis sec-
ondary to rheumatic heart disease. One month later he was
readmitted with fever, a right pleural effusion, a pericar-
dial friction rub, and pericarditis. The impression at that
time was either postpericardiotomy or Dressler syndrome.
F.T. was sent home on anti-inflammatory agents but failed
to improve. After continued complaints of anorexia, nau-
November 17, 2011 16:49
1497
sea, chills, and fever to 101◦ F, he returned to the hospital.
On readmission, his physical examination was noteworthy
for a systolic ejection murmur at the left sternal border
and 3+ pedal edema. Blood cultures were obtained, and
routine laboratory studies were performed. His history and
clinical presentation were strongly suggestive of prosthetic
valve endocarditis (PVE). What are the most likely organisms
responsible for PVE in F.T.?
Prosthetic valve endocarditis is a life-threatening infectious
complication of artificial heart valve implantation that accounts
for 7% to 25% of cases of IE in developed countries.40,41 The
prevalence of complications resulting in death has been as high
as 20% to 40%.41 The risk of PVE after surgery is approximately
1% at 12 months and 2% to 3% at 60 months. PVE is categorized
as early or late, depending on the onset of clinical manifestations
after cardiac surgery.40,41 Early PVE occurs within 2 months after
surgery and is thought to represent infection acquired during
valve placement. It usually is caused by skin organisms that were
implanted into the valve annulus (suture site where the valve
is attached to cardiac muscle) at the time of surgery.40,41 The
Chapter 63
most common organisms cultured from patients such as F.T.
with early PVE are coagulase-negative staphylococci (primarily
S. epidermidis [>30%], most of which are resistant to methicillin),
followed by S. aureus (20%), and gram-negative bacilli (10%–
15%). Miscellaneous organisms, such as diphtheroids and fungi,
account for the remainder.40,41 In contrast, streptococci are a
more common cause of late PVE (>2 months after surgery).40,41
Endocarditis
Nosocomial bacteremia and fungemia in a patient with pros-
thetic heart valves contribute to a significant risk for the devel-
opment of PVE. One study noted that bacteremia caused by
staphylococci and gram-negative bacilli resulted in 55% and 33%
of subsequent PVE cases, respectively.42 Another study observed
the development of PVE in 25% (11 of 44) of patients after noso-
comial candidemia.43
Prophylaxis
CASE 63-2, QUESTION 2: What measures can be taken to
prevent early PVE?
The overall frequency of early PVE, despite antibiotic pro-
phylaxis, is 1% to 4%.44 Complications are severe and include
valve dehiscence, acute heart failure, arrhythmias, and out-
flow obstruction. Although antibiotic prophylaxis before valve
surgery (a “clean” procedure) has not been proved to reduce
the frequency of early PVE, it is indicated nevertheless because
the complications of infection are catastrophic. Animal data indi-
cate that antibiotic prophylaxis reduces the infection rate.44
CEPHALOSPORINS
The antimicrobial regimen used most commonly for cardiac
surgery prophylaxis (see Chapter 61, Antimicrobial Prophy-
laxis for Surgical Procedures) consists of an antistaphylococcal
cephalosporin, such as cefazolin, given in the operating room at
the time of induction of anesthesia or within 60 minutes before
the procedure. Prophylaxis should only be continued for up to
48 hours because there is no evidence that administration of
antibiotics for prolonged duration confers any greater benefit.
The Joint Commission has set standards outlining appropriate
antibiotic selection and timing based on the type of surgery. These
standards are referred to in the focus area, Surgical Care Improve-
ment Project (SCIP).45 Cephalosporins are the agent of choice
because they are active against most strains of S. aureus. The
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
1498 prevalence of methicillin- (and cephalosporin-) resistant strains
is increasing, with rates exceeding 50% in many centers.
Most strains (87%) of coagulase-negative staphylococci are
also methicillin- (and cephalosporin-) resistant.41,46 Resistance is
thought to be caused by an altered penicillin-binding protein
(PBP 2a); thus, cross-resistance to all other β-lactams, except
ceftaroline, is expected.47
VANCOMYCIN
Vancomycin is the prophylactic agent of choice when a first-
generation cephalosporin cannot be used. Vancomycin could be
considered the prophylactic agent of choice for cardiovascular
procedures, including prosthetic valve replacement and implan-
tation of prosthetic grafts, in the presence of any of the follow-
ing: (a) documented penicillin allergy, (b) prior receipt of broad-
spectrum antimicrobial therapy and high likelihood of being
colonized with cephalosporin-resistant staphylococci or entero-
cocci, or (c) performance of the procedure in a center experienc-
ing outbreaks or a high endemic rate of surgical infection with
methicillin-resistant staphylococci.48
Because the frequency of PVE is low, it would be nearly impos-
Section 14
sible to demonstrate a statistically significant decrease in its inci-
dence after the use of vancomycin compared with conventional
agents. Thus, the decision to use vancomycin rests on its supe-
rior in vitro activity for methicillin-resistant staphylococci. Argu-
ments against the routine use of vancomycin in this specific set-
ting include the potential for vancomycin-related hypotension.48
Infectious Disease
More importantly, the emergence of vancomycin-resistant
enterococci (VRE), heterogeneous glycopeptide-intermediate
(hGISA) S. aureus, glycopeptide-intermediate S. aureus (GISA),
and glycopeptide-resistant S. aureus (VRSA) heightens the need
to limit vancomycin use because prior exposure to vancomycin is
a recognized predisposing risk for the development of resistance
to vancomycin.49–52
Of note, ceftaroline, a fifth-generation cephalosporin, is active
against methicillin-resistant S. aureus and S. epidermidis. However,
it is not approved for the treatment or prevention of IE.
In summary, selection of the most appropriate prophylac-
tic antibiotic for valve replacement surgery should take into
account the SCIP antibiotic recommendations and patient- and
institution-specific factors. The choice should be based on drug
allergy history, rates of postoperative wound infection, and asso-
ciated pathogens.
ADVERSE EFFECTS
The most common adverse effect associated with vancomycin
administration is the so-called red man or red neck syndrome,53,54
which most commonly causes erythema of the head and upper
torso, pruritus, urticaria, and in some cases hypotension. It is
mediated in part by histamine release, and the severity of the
reaction is proportional to the quantity released. The total dose
of vancomycin administered and the rate of infusion are major
determinants of the frequency and severity of this reaction. The
reaction can be minimized by administering vancomycin over
at least 1 hour. Cutaneous manifestations of the vancomycin-
induced red man syndrome still can occur with a 1-hour infusion,
but hypotension is uncommon.53,54
Several drugs used perioperatively and in anesthesia also cause
histamine release; therefore, the possibility of additive toxic-
ity with vancomycin is possible. Most of the serious reactions
caused by vancomycin have been associated with perioperative
use. Vancomycin-induced hypotension occurred in 7% of patients
scheduled for cardiothoracic surgery, despite the 1-hour infusion
time.48
November 17, 2011 16:49
ADMINISTRATION
Vancomycin is difficult to administer in the operating room
because it must be administered by infusion for 1 hour and admin-
istration right before the procedure may not provide sufficient
time for the vancomycin infusion to achieve adequate serum and
tissue levels. Therapeutic serum concentrations of vancomycin
can be maintained reliably during surgery if the 15-mg/kg dose
is administered within 2 hours before the initial incision.
ANTIBIOTIC-IMPREGNATED HEART VALVES
PVE after heart valve replacement surgery is rare, but early-onset
infection is associated with a mortality rate of 23% to 41%.40
Systemically administered antibiotic prophylaxis before surgery
does not confer 100% protection. The infectious process typically
begins at the sewing ring and extends to involve the adjacent area
between the prosthesis and the annulus of the heart valve. Hence,
investigators have evaluated the use of antibiotic-impregnated
heart valve sewing rings for the prophylaxis and treatment of
bacterial endocarditis. Various antibiotics, including rifampin,
gentamicin, and clindamycin, have been studied with respect to
their diffusion kinetics and duration of antimicrobial activity both
in vitro and in animal experiments.55–57 It is unknown whether
these antibiotic-impregnated heart valve rings decrease the risk
of postoperative endocarditis.
Antimicrobial Therapy
CASE 63-2, QUESTION 3: What are the treatment options
for F.T.?
As noted earlier, F.T. most likely is infected with coagulase-
negative staphylococci. For those rare coagulase-negative staphy-
lococci that remain sensitive to β-lactams (<20%), a penicillinase-
resistant penicillin (nafcillin or oxacillin) is the drug of choice
(Table 63-5).46 For the treatment of PVE caused by methicillin-
resistant, coagulase-negative staphylococci, vancomycin should
be used.46,58,59 Most staphylococci are sensitive to vancomycin at
concentrations of 2 mcg/mL or less; however, strains of staphy-
lococci with intermediate susceptibility to vancomycin have
emerged.58,59
The AHA currently recommends the use of triple-drug com-
bination therapy for the treatment of PVE caused by methicillin-
resistant, coagulase-negative staphylococci.21 In a retrospective
review of 75 episodes of PVE caused by methicillin-resistant
S. epidermidis (MRSE),60 21 of 26 patients treated with van-
comycin were cured compared with 10 of 20 patients treated with
a β-lactam antibiotic (p = 0.05); however, the addition of either
rifampin or an aminoglycoside to vancomycin was associated
with increased cure (18 of 20 cured) compared with vancomycin
alone (3 of 6 cured; p = 0.06). A subsequent prospective, mul-
ticenter study compared the efficacy of 6 weeks of vancomycin
plus rifampin with and without gentamicin for the first 2 weeks
for the treatment of PVE caused by MRSE.41,46 The emergence
of rifampin-resistant strains during therapy was reduced by the
addition of gentamicin (6 of 15 vs. 0 of 8; p = 0.04). Based on
current data, a three-drug regimen (vancomycin, gentamicin,
and rifampin) should be used for the treatment of PVE caused
by MRSE. When isolates of MRSE are resistant to all available
aminoglycosides, aminoglycoside treatment should be omitted.
A fluoroquinolone active against the isolate may be considered
as substitute for the aminoglycoside in the three-drug regimen.
In addition to medical therapy, most patients also required valve
replacement surgery.40,41,46
Although quinupristin/dalfopristin (Synercid), linezolid
(Zyvox), daptomycin (Cubicin), telavancin, and ceftaroline have
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational November 17, 2011 16:49

1499
TA B L E 6 3 - 5
Treatment of Staphylococcal Endocarditis

Antibiotic Dosage and Route Duration

Without Prosthetic Materiala

Oxacillin-Susceptible Staphylococci
Nonpenicillin-Allergic Patients
Nafcillin
or Adult: 2 g IV every 4 hours 4–6 weeks
Pediatric: 150–200 mg/kg/24 h IV (max: 12 g/24 h) in four to six equally divided doses
Adult: 2 g IV every 4 hours
Oxacillin Pediatric: 200 mg/kg/24 h IV (max: 12 g/24 h) in four to six equally divided doses 4–6 weeks
With optional addition of Adult: 3 mg/kg IV or IM in two or three equally divided doses 3–5 days
gentamicinb ,c Pediatric: 3 mg/kg IV or IM in three equally divided doses
Penicillin-Allergic Patients
1. Cefazolind Adult: 2 g IV every 8 hours 4–6 weeks
Pediatric: 100 mg/kg/24 h IV (max: 6 g/24 h) in equally divided doses every 8 hours
With optional addition of Adult: See Nonpenicillin-allergic patient
gentamicinb Pediatric: See Nonpenicillin-allergic patient
2. Vancomycinb ,e , f Adult: 30 mg/kg/24 h IV in two or four equally divided doses (max: 2 g/24 h unless serum levels 4–6 weeks
monitored)
Pediatric: 40 mg/kg/24 h IV in two or four equally divided doses (max: 2 g/24 h unless serum levels

Chapter 63
monitored)
Methicillin-Resistant Staphylococci
Vancomycinb ,e , f Adult: 30 mg/kg/24 h IV in two or four equally divided doses (max: 2 g/24 h unless serum levels 4–6 weeks
monitored)
Pediatric: 40 mg/kg/24 h IV in two or four equally divided doses (max: 2 g/24 h unless serum levels
monitored)
With Prosthetic Valve or Other Prosthetic Materialg

Endocarditis
Methicillin-Resistant Staphylococci
Vancomycinb ,e ,g Adult: 30 mg/kg/24 h IV in two or three equally divided doses (max: 2 g/24 h unless serum levels ≥6 weeks
monitored)
Pediatric: 40 mg/kg/24 h IV in two or four equally divided doses (max: 2 g/24 h unless serum levels
monitored)
With rifampinh Adult: 300 mg IV/PO every 8 hours ≥6 weeks
and Pediatric: 20 mg/kg/24 h PO (max: 900 mg/24 h) in two equally divided doses
With gentamicinb ,g ,i, j Adult: 3 mg/kg IV or IM in two or three equally divided doses 2 weeks
Pediatric: 3 mg/kg IV or IM in three equally divided doses
Methicillin-Susceptible Staphylococci
Nafcillin or oxacillink Adult: 2 g IV every 4 hours ≥6 weeks
Pediatric: 150–200 mg/kg/24 h (max: 12 g/24 h) in four to six equally divided doses
With rifampinh Adult: 300 mg IV/PO every 8 hours ≥6 weeks
and Pediatric: 20 mg/kg/24 h PO (max: 900 mg/24 h) in three equally divided doses
With gentamicinb ,g ,i, j Adult: 3 mg/kg IV or IM in two or three equally divided doses 2 weeks
Pediatric: 3 mg/kg IV or IM in three equally divided doses

a
Antibiotic doses should be modified appropriately for patients with impaired renal function. Shorter antibiotic courses have been effective in some drug addicts with
right-sided endocarditis caused by S. aureus. (See text for comments on the use of daptomycin and rifampin.)
b
Dosing of aminoglycosides and vancomycin on a milligram per kilogram basis will give higher serum concentrations in obese than in lean patients.
c
The benefit of additional aminoglycoside has not been established. The risk of toxic reactions because of these agents is increased in patients >65 years of age or those with
renal or eighth nerve impairment.
d
There is potential cross-allergenicity between penicillins and cephalosporins. Cephalosporins should be avoided in patients with immediate-type hypersensitivity to
penicillin.
e
Peak serum concentrations of vancomycin should be obtained 1 hour after infusion and should be in the range of 30–45 mcg/mL for twice daily dosing and 20–30 mcg/mL
for four times a day dosing. Trough serum concentrations should be obtained within half an hour of the next dose and should be in the range of 10–15 mcg/mL. (See text for
detailed discussion on the need for high trough target of 15–20 mcg/mL for strains with reduced susceptibility to vancomycin. Each vancomycin dose should be infused for
1 hour.)
f
See text for consideration of optional addition of gentamicin.
g
Vancomycin and gentamicin doses must be modified appropriately in patients with renal failure.
h
Rifampin is recommended therapy for infections caused by coagulase-negative staphylococci. Its use in coagulase-positive staphylococcal infections is controversial.
Rifampin increases the amount of warfarin sodium required for antithrombotic therapy.
i
Serum concentration of gentamicin should be monitored and the dose should be adjusted to obtain a peak level of approximately 3 mcg/mL.
j
Use during initial 2 weeks. (See text on alternative aminoglycoside therapy for organisms resistant to gentamicin.)
k
First-generation cephalosporins or vancomycin should be used in penicillin-allergic patients. Cephalosporins should be avoided in patients with immediate-type
hypersensitivity to penicillin and those infected with methicillin-resistant staphylococci.
IM, intramuscular; IV, intravenous; PO, orally.
Source: Baddour LM et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the
Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and
Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394.
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
1500 potent in vitro activity against coagulase-negative staphylococci,
clinical experience in the treatment of IE caused by these strains
is lacking.46,61,62
STAPHYLOCOCCUS AUREUS
ENDOCARDITIS
Intravenous Drug User Versus Nonuser
CASE 63-3
QUESTION 1: T.J., a 36-year-old human immunodeficiency
virus (HIV)-seropositive man with a long history of IV drug
abuse, was admitted to the hospital 4 months after being
released from the state prison. His chief complaints included
fever, night sweats, pleuritic chest pain, shortness of breath,
dyspnea on exertion, and fatigue. Physical examination was
remarkable for a temperature of 101.2◦ F, splenomegaly,
and a pansystolic ejection murmur at the left sternal bor-
der, best heard during inspiration. The chest radiograph
Section 14
revealed diffuse nodular infiltrates. TTE was positive for a
small vegetation on the tricuspid valve leaflet. Significant
laboratory results included the following:
WBC count, 14,000/μL with 65% polys and 5% bands
(SI units, 14 × 10/L with 0.65 polys and 0.05 bands
Infectious Disease
[normal, 3.2–9.8 with 0.54–0.62 polys and 0.03–0.05
bands])
CD4 cell count, 350/μL
Hgb, 13.1 g/dL (SI units, 131 g/L [normal, 140–180])
Hct, 39% (SI units, 0.39 [normal, 0.39–0.49])
ESR, 55 mm/hour (Westergren)
IE was suspected. Blood cultures were obtained, and
all six samples were positive for coagulase-positive,
gram-positive cocci, later identified as methicillin-sensitive
S. aureus (MSSA). How do the clinical presentation and
prognosis of endocarditis in the IV drug user differ from
that of the nonuser? What impact does HIV infection have
on the risk and outcomes of endocarditis in the IV drug user?
The annual incidence of endocarditis among IV drug users
is estimated at 1% to 5%; parenteral cocaine addicts have the
highest risk.63 The presentation, pathophysiology, and progno-
sis of endocarditis in those who acquire the disease secondary
to IV drug use differ from those in nonusers.1,63,64 S. aureus is
tenfold more likely than other pathogens to cause infection in
this population.7 S. aureus is part of the normal skin flora and
is introduced when the illicit drug is injected. It is hypothesized
that insoluble agents used to “cut” the drug damage the normal
heart valve, preparing the surface for bacterial adherence and
growth.1
The following are differences between addicts and nonaddicts
with S. aureus endocarditis: addicts are significantly younger; they
have fewer underlying diseases and more right-sided (tricuspid)
involvement (in contrast to the predominance of left-sided dis-
ease in nonaddicts); they are less likely to have heart failure or
central nervous system complications; and they exhibit fewer
signs of peripheral involvement and have a lower incidence of
death.64 Among patients without history of IV drug use, MRSA
was involved in one-third of a cohort of 424 patients with def-
inite S. aureus IE. Clinical features that characterized MRSA IE
were persistent bacteremia, chronic immunosuppressive ther-
apy, health care–associated infection, a presumed intravascular
device source, and diabetes mellitus.5
November 17, 2011 16:49
The prevalence of HIV seropositivity is 40% to 90% among IV
drug users with IE.63,65 HIV-related immunosuppression may be
an independent risk factor for the development of endocarditis.66
Antimicrobial Therapy
METHICILLIN-SENSITIVE STAPHYLOCOCCUS AUREUS
CASE 63-3, QUESTION 2: What are the therapeutic options
for treating S. aureus endocarditis in T.J.?
The susceptibility of S. aureus to methicillin is the major deter-
minant of which antibiotic is selected to treat T.J.’s endocarditis.
T.J. is infected with MSSA. Therapy of choice for methicillin-
sensitive strains is a penicillinase-resistant penicillin, such as naf-
cillin or oxacillin19 (Table 63-5). Penicillin G rarely is appropri-
ate because nearly all isolates of S. aureus produce penicillinase.
Methicillin is no longer used because it is associated with a high
incidence of interstitial nephritis.
A 4- to 6-week course of therapy with high-dose (12 g/day)
nafcillin is the therapy of choice.67,68 Vancomycin may be less
efficacious than nafcillin as an antistaphylococcal agent.19,67 IV
drug addicts, for the reasons previously identified, have a higher
response rate to appropriate therapy compared with nonaddicts,
and 4 weeks of therapy is probably adequate. In one study, 31
addicts were successfully treated with 16 days of parenteral ther-
apy followed by 26 days of oral dicloxacillin.69
Addicts with uncomplicated right-sided endocarditis caused
by MSSA can be treated successfully with a 2-week course of
combination therapy with a penicillinase-resistant penicillin and
an aminoglycoside.70–72 In one study, 47 of 50 patients (94%) were
cured after treatment with the combination of IV nafcillin (1.5
g every 4 hours) and tobramycin (1 mg/kg every 8 hours) for a
total of 2 weeks. Notably, 2 of 3 patients treated with vancomycin
relapsed, resulting in early termination of this arm of study. Thus,
vancomycin should not be used to substitute for nafcillin in this
regimen. In another study, 71 patients who completed the 2-
week course of treatment with cloxacillin (2 g IV every 4 hours)
plus amikacin (7.5 mg/kg IV every 12 hours) had a cure rate of
94%.72 Of the four patients who failed, the 2-week treatment
period had to be extended to achieve cure. In contrast to the
prior study, most (72%) patients had definite endocarditis with
echocardiographic vegetations. Overall, none of the patients who
responded promptly to treatment relapsed. In addition, amino-
glycoside nephrotoxicity was minimal in this selected patient
population. Alternatively, Ribera et al. demonstrated in a study
that cloxacillin alone was as effective as combination therapy
of cloxacillin plus gentamicin for the treatment of right-sided
MSSA endocarditis; the treatment response exceeded 90% in
the cloxacillin monotherapy arm.73 Gentamicin administered at
1 mg/kg every 8 hours for 7 days in the combination group did
not improve treatment response.
An abbreviated course of treatment can be used in a defined
group of IV drug users with right-sided endocarditis. These
patients should have the following characteristics: (a) clinical and
bacteriologic response within 96 hours of initiation of therapy;
(b) no evidence of hemodynamic compromise, metastatic infec-
tion, or neurologic or systemic embolic complications either at
the initiation or completion of 2 weeks of therapy; (c) no echocar-
diographically demonstrable vegetations larger than 2 cm3 ; (d)
not infected with MRSA; and (e) not receiving antibiotics other
than penicillinase-resistant penicillins, such as first-generation
cephalosporins and glycopeptides.19,71 HIV-seropositive patients
(CD4 counts >300 × 106 cells) with tricuspid involvement
included in the above studies also responded favorably to these
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
short-course regimens; thus, a short-course regimen is an option
for T.J.73
Some studies suggest that the addition of an aminoglycoside
to the treatment regimen does not improve overall response
for patients who meet the above criteria for short-course ther-
apy. Thus, all patients receiving this regimen should be carefully
evaluated for evidence of continuing infection or complications
before discontinuing therapy at the end of the 2-week treatment
course; extension of therapy with a β-lactam agent to at least
4 weeks’ duration is recommended with any evidence of active
disease or complications. Although response to antibiotic ther-
apy has been shown to be similar between asymptomatic HIV-
seropositive and HIV-seronegative IV drug users, short-course
therapy should be avoided in more immunosuppressed individ-
uals (CD4 cell counts <200 μL) until more definitive outcome
data are available in this subgroup.63
ORAL REGIMEN
An oral treatment regimen consisting of ciprofloxacin (750 mg
every 12 hours) plus rifampin (300 mg every 12 hours) has also
been evaluated in addicts with uncomplicated right-sided endo-
carditis. In one small, noncomparative study, 10 addicts were
successfully treated with the combination of ciprofloxacin and
rifampin for 4 weeks.74 Ciprofloxacin was given IV (300 mg every
12 hours) for the first 7 days, followed by oral administration (750
mg every 12 hours) for the remaining 21 days of therapy. Another
study prospectively compared the oral regimen with standard
parenteral therapy for this subgroup.75 Patients were randomly
assigned to receive 28 days of therapy with oral ciprofloxacin plus
rifampin or oxacillin (2 g IV every 4 hours) plus gentamicin (2
mg/kg IV every 8 hours). Vancomycin (1 g IV every 12 hours) was
substituted for oxacillin in the penicillin-allergic patients. One of
19 patients in the oral group versus 3 of 25 in the IV group failed
treatment; however, approximately half of the study patients in
either group had possible endocarditis. Given the small number
of patients who completed treatment, therapeutic equivalency
between the oral and parenteral regimens will need to be con-
firmed in larger trials. In addition, emerging quinolone resistance
in S. aureus and the compliance and monitoring required of this
regimen when administered in the outpatient setting are of con-
cern. Nonetheless, it appears that a 4-week oral regimen with
ciprofloxacin and rifampin may be a useful alternative treatment
option in addicts with uncomplicated right-sided endocarditis.
PENICILLIN-ALLERGIC PATIENTS
Treatment of penicillin-allergic patients with S. aureus endocardi-
tis is somewhat controversial. First-generation cephalosporins
have been used with some success for the treatment of patients
with mild penicillin allergy, but treatment failures with cefazolin
are difficult to explain.76 The stability of cefazolin when exposed
to staphylococcal β-lactamase has been proposed as a mecha-
nism for these failures.77 Notably, staphylococci are capable of
producing four penicillinase subtypes, to which the stability of
cefazolin varies. These susceptibility differences are apparent on
MIC testing only if a larger-than-usual inoculum is used (i.e.,
>106 organisms).77 It is possible that treatment failures with
cefazolin may be caused by a combination of the recalcitrant
nature of the infection and the instability of cefazolin against a
particular subtype of penicillinase produced by the staphylococ-
cal strain, which is not readily detectable via routine MIC test-
ing. For patients with endocarditis caused by S. aureus who have
immediate-type hypersensitivity to penicillin, vancomycin or
daptomycin may be used. Other treatment options include line-
zolid and quinupristin/dalfopristin.78 Selection of agent depends
on organism susceptibility, potential of drug–drug interactions,
and host predisposition for development of adverse effects.
November 17, 2011 16:49
COMBINATION THERAPY 1501
An enhanced response to combination therapy in the experimen-
tal animal model of MSSA endocarditis has prompted clinical
trials to evaluate whether the addition of gentamicin to nafcillin
confers any additional benefit. The combination of nafcillin and
gentamicin resulted in more rapid clearing of organisms from
the blood, but the response rates were similar to patients treated
with nafcillin alone.67 As expected, the group receiving genta-
micin had a higher incidence of nephrotoxicity. Thus, for the rou-
tine management of endocarditis caused by MSSA, the addition
of a second drug does not appear to offer additional benefit when
a penicillinase-resistant penicillin is used unless an abbreviated
treatment course in a select patient group is desired (see Case
63-3, Question 2, previous discussion). For patients who remain
bacteremic or who fail to improve clinically (usually nonaddicts),
imaging studies are often performed to identify metastatic sites
of infection (i.e., occult abscess) with possible need for surgical
intervention.
METHICILLIN-RESISTANT STAPHYLOCOCCUS
AUREUS: VANCOMYCIN
Chapter 63
CASE 63-3, QUESTION 3: How would T.J.’s therapy differ if
he were infected with MRSA?
Staphylococcus aureus IE involving methicillin-resistant strains
has become increasingly common and accounts for up to 40%
of cases.4,5 MRSA-infected patients have more chronic comor-
Endocarditis
bid conditions (e.g., diabetes mellitus, hemodialysis dependency)
and are more likely to have health care–associated infection (76%
vs. 37%) and an indwelling intravascular catheter or hemodial-
ysis fistula as the presumed source of infection (60% vs. 31%)
when compared with patients infected with MSSA.4,5 Persistent
bacteremia was more common with MRSA IE, occurring in 43%
versus 9% of patients infected with MSSA. Of interest, in this
study, patients with S. aureus IE from the United States were
significantly more likely to be infected with MRSA, to receive
vancomycin therapy, and to develop persistent bacteremia.79
In 20% of patients with MRSA IE, identifiable health care con-
tact was absent. MRSA infection is traditionally associated with
health care contact in the nosocomial setting, but is now becom-
ing more prevalent in the community (CA-MRSA).5 Young and
otherwise healthy individuals without the traditional risk factors
are infected in the community.80 CA-MRSA strains are distinct
from health care–associated strains in that most possess a dis-
tinct virulence gene encoding for the Panton-Valentine leuko-
cidin [PVL]. Expression of this pore-forming toxin that causes
severe necrosis in polymorphonuclear neutrophil cells in a rabbit
model has been implicated to cause invasive infections, including
necrotizing pneumonia and skin abscesses.81–87 Specifically, CA-
MRSA PVL-producing strains causing IE have been reported.88
TREATMENT OPTIONS
Vancomycin has been the accepted standard of treatment for
MRSA endocarditis. Response to treatment, however, is slower
than with semisynthetic penicillins (e.g., nafcillin) for MSSA
endocarditis. The mean duration of bacteremia in patients with
MSSA endocarditis has been reported to be 3.4 days for naf-
cillin alone and 2.9 days for the combination of nafcillin and
gentamicin.70 In contrast, the median duration of bacteremia for
MRSA endocarditis was 7 days for vancomycin alone. Failure
rates of up to 40% have been documented in patients even with
right-sided involvement. Of great concern is the emergence of
resistant strains of S. aureus after repeated and prolonged expo-
sure to vancomycin therapy.58,89
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
1502 Either vancomycin or daptomycin at 6 mg/kg IV once daily
(up to 10 mg/kg/day) may be used to treat patients with MRSA
endocarditis.90 Vancomycin 30 mg/kg/day in two divided doses
for a total of 4 to 6 weeks is recommended for adults with
normal renal function. Ideal body weight should be used to
dose vancomycin on a milligram per kilogram basis in obese
patients. Dosage adjustment for renal dysfunction is necessary.
Vancomycin peak levels are not recommended. Dosage adjust-
ment of vancomycin therapy based on measured trough levels
is more reliable. Given the emergence of MRSA strains with
reduced susceptibility to vancomycin, published guidelines from
the Infectious Diseases Society of America recommend a tar-
get trough of 15 to 20 mcg/mL7,91,92 in an attempt to overcome
increasing MIC of clinical strains and limited tissue penetration.
Measurement of trough serum vancomycin concentrations is
typically within 30 minutes of the fourth dose for patients receiv-
ing a dosing interval of every 12 hours. A dosage regimen of
vancomycin aimed to achieve an area under the curve-to-MIC
ratio of 400 or an unbound trough at four to five times MIC of
the infected strain has been proposed as the optimal pharmaco-
dynamic target.90,93,94
Section 14
PERSISTENT BACTEREMIA
CASE 63-3, QUESTION 4: T.J. has been treated with van-
comycin 1 g IV every 12 hours for 5 days for his MRSA endo-
carditis, but does not seem to be clinically improving. His
blood cultures are still positive, and his WBC count remains
Infectious Disease
elevated at 12,500/μL with 55% polys and 7% bands. He
continues to have a low-grade fever since starting van-
comycin. His vancomycin trough level on the second day
of therapy was 17 mcg/mL. The infected MRSA strain had a
vancomycin MIC of 1.5 mcg/mL as determined by Epsilome-
ter test. What factors may be contributing to T.J.’s poor
response to treatment? What other therapeutic options are
available for T.J.?
In a large multinational study of nearly 1,800 patients with def-
inite IE, persistent bacteremia, receipt of vancomycin, and health
care contact were significantly more common in patients with
MRSA IE from the United States compared with those from other
geographic regions.5 The authors speculated that the higher rates
of persistent bacteremia in US patients may be attributable in part
to the receipt of vancomycin therapy.
Vancomycin MICs against S. aureus have been increasing over
the years. At one university medical center, vancomycin MICs
were determined by broth microdilution for 6,000 nosocomial
MRSA isolates collected during a 5-year period. In the year 2000,
80% of the strains had vancomycin MIC of 0.5 mcg/mL; however,
by 2004, 70% of isolates had MICs of 2 mcg/mL.52 In response
to increasing reports of vancomycin failures caused by strains
that are in the susceptible range, the vancomycin breakpoint for
susceptibility was reduced from 4 to 2 mcg/mL for S. aureus in
2005 per the Clinical and Laboratory Standards Institute.95,96
Widespread use of vancomycin has led to the emergence of
GISA or hGISA strains.58 Reduced susceptibility to glycopep-
tides results from an increase in the production of peptidoglycan
precursors leading to a thickened cell wall and decreased pene-
tration of glycopeptides into the bacterial cell membrane.97 In
the absence of vancomycin, hGISA strains may revert to gly-
copeptide susceptibility, making it difficult to detect these strains
in vitro. As such, several investigators have found that hGISA
strains have an MIC range that overlaps with the currently defined
susceptible range and that the prevalence among hospitalized
patients is increasing.98–100 Routine susceptibility testing meth-
ods performed in the clinical laboratory are unreliable in detect-
November 17, 2011 16:49
ing MRSA strains with hGISA phenotype.101 MIC determined by
Epsilometer test (Etest) best predicts treatment outcome with
vancomycin.26,79,102,103
Experts have recommended a target vancomycin trough con-
centration of 15 to 20 mcg/mL to overcome increasing MIC when
treating pneumonia or endocarditis caused by MRSA.79,103 A pub-
lished study of adult infections with MRSA reported that 54% (51
of 95) of clinical isolates had vancomycin MIC of 2 mcg/mL.25
Notably, invasive infections, such as bacteremia and pneumonia,
were linked to higher MIC. Infections caused by those strains
were associated with lower end of treatment responses (62%
vs. 85%) and increased mortality (24% vs. 10%) compared with
strains with MIC of 1 mcg/mL or less irrespective of attaining
a goal trough of 15 to 20 mcg/mL (achieving the goal of four
to five times greater than MIC of an infected strain that has an
MIC of 2 mcg/mL). Borderline susceptibility (MIC 2 mcg/mL)
and severity of underlying disease were independent predictors
of poor treatment response. Many strains demonstrated toler-
ance to vancomycin as defined by the MBC-to-MIC ratio of 32,
and up to 10% exhibited heterogeneous vancomycin intermedi-
ate resistance phenotype (hVISA).26,104 Vancomycin monother-
apy of hVISA was associated with treatment failure, whereas
combination therapy responded favorably. Combination regi-
mens included vancomycin plus rifampin, linezolid, or dapto-
mycin. These findings suggest a role for combination therapy
or alternative agents when treating invasive infections caused
by MRSA strains with borderline susceptibility. However, the
above study was not designed to compare the efficacy of van-
comycin monotherapy versus combination therapy for the treat-
ment of MRSA infections, and the sample size of patients infected
with hVISA in this study was small. Therefore, the role of van-
comycin as the treatment of choice for MRSA IE will need to be
re-evaluated against other available treatment options.
Despite attaining a pharmacodynamic goal of unbound van-
comycin trough level of at least four times MIC of the infected
strain, T.J. fails to clinically improve and has persistent bac-
teremia. It is possible that T.J. is infected with an hVISA strain;
thus, a change in therapy is warranted.
Trimethoprim-sulfamethoxazole has been used successfully
in a limited number of patients with right-sided native valve
endocarditis caused by susceptible strains of S. aureus and may
be an alternative to vancomycin.105 A study of experimen-
tal staphylococcal endocarditis, however, found trimethoprim-
sulfamethoxazole to be inferior to cloxacillin, vancomycin, and
teicoplanin. Alternatively, minocycline has been shown to be a
potential treatment alternative to vancomycin in experimental
endocarditis caused by MRSA. Although both drugs are equally
effective in decreasing the bacterial density of cardiac vegetations,
the penetration of minocycline into vegetation was twice that of
vancomycin.106
Other agents showing promise for the treatment of MRSA IE
based on their in vitro activity include quinupristin/dalfopristin,
linezolid, daptomycin, telavancin, and ceftaroline. A limited
number of patients with MRSA endocarditis have been suc-
cessfully treated with quinupristin/dalfopristin.107,108 A cure
rate of 56% was reported for patients treated with quin-
upristin/dalfopristin for MRSA endocarditis in an international
open trial in patients intolerant of or failed prior therapy.107,108
Additional data are needed before quinupristin/dalfopristin can
be recommended for therapy.
Linezolid (Zyvox), an oxazolidinone, is not US Food and
Drug Administration (FDA)-approved for the treatment of endo-
carditis, but has been used in cases of treatment failures, intol-
erability to standard therapy, or in infections with multidrug-
resistant gram-positive cocci.109 In a review article that included
33 case reports of endocarditis treated with linezolid, 63.6% of
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
patients had successful outcomes at the end of the follow-up
period.110 MRSA and vancomycin intermediate S. aureus were the
most common pathogens, accounting for 24% and 30% of cases,
respectively. Failure with linezolid treatment was documented
in seven cases, including four deaths attributed to endocarditis
and three owing to persistent positive blood cultures. Throm-
bocytopenia was the most common adverse effect, occurring in
eight of nine patients. In a compassionate use program, linezolid
achieved 50% clinical and microbiologic cure rates at 6-month
follow-up in 32 patients with definite IE; MRSA was the causative
agent in 7 of those patients. The most common adverse events
reported in this group were gastrointestinal system effects and
thrombocytopenia, each occurring in 15% of patients.111 The
degree of thrombocytopenia associated with linezolid correlates
with the extent of drug exposure, as measured by area under
the concentration curve and duration of treatment.112 Of note,
treatment failure with linezolid for MRSA endocarditis caused
by persistent bacteremia has been described in two patients and
in one patient with relapse of infection.109,113 Thus, additional
efficacy data are needed before linezolid can be recommended
for the treatment of IE caused by MRSA.
Daptomycin (Cubicin) is a cyclic lipopeptide that has been
approved for treatment of S. aureus bacteremia and right-sided
endocarditis. In vivo, it has a wide spectrum of activity against
gram-positive bacteria, including S. aureus (including MRSA),
Enterococcus faecalis, Enterococcus faecium, streptococci, and most
other species of aerobic and anaerobic gram-positive bacteria.
It was approved for the treatment of S. aureus bacteremia and
endocarditis in a noninferiority study in patients receiving dap-
tomycin or standard therapy consisting of an antistaphylococcal
penicillin or vancomycin in addition to low-dose gentamicin.114
Successful outcome was seen in 46% (41 of 90) of patients who
had presumed or definite endocarditis at their baseline diagno-
sis. Of those, MRSA endocarditis was successfully treated in 42%
(15 of 36) of cases. In patients with confirmed uncomplicated
and complicated right-sided endocarditis, treatment success was
similar between the daptomycin group (8 of 18) and the group
receiving standard therapy (7 of 16) at 44%. Microbiologic failure
occurred in seven patients in the daptomycin group and in five
patients receiving standard therapy. Overall, the most common
cause of daptomycin failure was persistent or relapsing infections,
accounting for 16% of failures. In contrast, failure of standard
therapy was more often the result of treatment-limiting adverse
events, accounting for 15% of failures. Increase in the MIC of
the infected strain was observed more often in the daptomycin
group compared with standard treatment (six in the daptomycin
group vs. one patient in the standard therapy group). The use of
daptomycin for treatment of left-sided endocarditis is not estab-
lished because only nine patients were treated and only one had
treatment success.
Daptomycin at 6 mg/kg/day for a total duration of 6 weeks
should be used for the treatment of endocarditis. Considering
its concentration-dependent effects, some recommended higher
doses of 8 to 10 mg/kg/day, which appear to be safe.92 Fre-
quency of administration should be increased to every 48 hours
for patients with a clearance of creatinine of 30 mL/minute or
less. Daptomycin should be dosed based on total body weight
because obese patients have a larger volume of distribution
as well as increased clearance compared with the nonobese
population.115 Creatinine kinase elevations were more com-
monly seen in the daptomycin group (6.7%) compared with
the standard therapy group (0.9%).114 Creatinine kinase lev-
els should be obtained at baseline and weekly to monitor for
elevations, and more frequently in patients who may be at
risk for developing skeletal-muscle dysfunction (e.g., concomi-
tant therapy with hydroxymethylglutaryl-coenzyme A reduc-
November 17, 2011 16:49
tase inhibitors). In addition, 9% of patients experienced periph- 1503
eral nervous system–related adverse events (e.g., paresthesia
and peripheral neuropathies), which resolved during continued
treatment.115
High-dose daptomycin at 10 mg/kg daily90 should be con-
sidered as alternative therapy in T.J. Emergence of cross-
resistance to daptomycin after vancomycin exposure has been
documented.51,116 Similar to a thickened cell wall contributing
to decreased susceptibility to vancomycin, the same mechanism
is thought to contribute to daptomycin resistance in S. aureus.117
Therefore, it is important to confirm MRSA susceptibility to
daptomycin when used in a patient who had prior vancomycin
exposure. Either gentamicin (at 1 mg/kg every 8 hours or 5 mg/kg
daily) or rifampin 300 to 450 mg orally (PO) twice daily or both
may be used in combination with daptomycin as in vitro syn-
ergy has been demonstrated for the combinations.79 Alterna-
tively, daptomycin 10 mg/kg/dose IV once daily118 plus linezolid
600 mg PO twice daily may be used, particularly with concomi-
tant pneumonia. Linezolid is a potential treatment option for T.J.
if his infected MRSA strain demonstrates reduced susceptibility
to daptomycin; however, clinical experience is limited to case
reports and compassionate use.
Chapter 63
Once daptomycin therapy is initiated, continued monitoring
of clinical response and organism susceptibility to daptomycin
is warranted because resistance development has been reported
during prolonged therapy.119–122 Daptomycin MIC increase dur-
ing therapy for S. aureus endocarditis was demonstrated in six
patients.115 Baseline MIC increased from 0.25 to 2 mcg/mL in
Endocarditis
five isolates and from 0.5 to 4 mcg/mL in one isolate. Five of
those six isolates were MRSA.
ENTEROCOCCAL ENDOCARDITIS
Antimicrobial Therapy
ANTIBIOTIC SYNERGY
CASE 63-4
QUESTION 1: G.S., a 35-year-old woman, has been com-
plaining of anorexia, weight loss, and fever for the past
2 months. Her medical history is significant for an aortic
aneurysm with insufficiency that resulted in an aortic valve
replacement (porcine) 3 years before admission. Approx-
imately 2 months before admission, G.S. had a cesarean
section followed by a tubal ligation. She did not receive
antibiotic prophylaxis for either procedure. Physical exam-
ination revealed a thin woman (5 foot 0 inches, 48 kg) in
no acute distress with evidence of a systolic heart murmur,
splinter hemorrhages, and petechiae on her soft palate. Her
temperature was 100.2◦ F. Her WBC count was 14,000/μL
(SI unit, 14 × 10/L) with a slight left shift; all other labo-
ratory results were within normal limits. She was not tak-
ing any medications, and she has a documented allergy to
penicillin (rash, urticaria, and wheezing). The working clin-
ical diagnosis was probable bacterial endocarditis, which
was confirmed when four sets of blood cultures grew gram-
positive cocci. Biochemical testing subsequently identified
the organism as E. faecalis, highly resistant to streptomycin
(MIC > 2,000 mcg/mL). Antibiotic therapy with gentamicin
(50 mg IV every 8 hours) and vancomycin (1,000 mg IV every
12 hours) was begun. Why were two antibiotics prescribed
for the treatment of enterococcal endocarditis in G.S.?
Enterococci, unlike streptococci, are inhibited but not
killed by penicillin or vancomycin alone.20,123 The synergistic
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational November 17, 2011 16:49

1504
TA B L E 6 3 - 6
Therapy for Endocarditis Caused by Enterococci (or Streptococci viridans with an MIC ≥0.5 mcg/mL)a,b

Antibiotic Dose and Route Duration

Nonpenicillin-Allergic Patient

1. Penicillin G Adult: 18–30 million units/24 h IV given continuously or in six equally divided doses 4–6 weeks
Pediatric: 300,000 units/kg/24 h IV (max: 30 million units/24 h) given continuously or in four to six equally 4–6 weeks
divided doses
With gentamicinc ,d ,e Adult: 1 mg/kg IM or IV every 8 hours 4–6 weeks
or Pediatric: 1 mg/kg IM or IV every 8 hours 4–6 weeks
2. Ampicillin Adult: 12 g/24 h IV given continuously or in six equally divided doses 4–6 weeks
Pediatric: 300 mg/kg/24 h IV (max: 12 g/24 h) in four to six equally divided doses 4–6 weeks
With gentamicinc ,d ,e Adult: 1 mg/kg IM or IV every 8 hours 4–6 weeks
Pediatric: 1 mg/kg IM or IV every 8 hours 4–6 weeks
Penicillin-Allergic Patientsf

Vancomycine Adult: 30 mg/kg/24 h IV in two equally divided doses (max: 2 g/24 h unless serum levels monitored) 6 weeks
Pediatric: 40 mg/kg/24 h IV in two to three equally divided doses (max: 2 g/24 h unless serum levels 6 weeks
monitored)
With gentamicinc ,d Adult: 1 mg/kg IM or IV (max: 80 mg) every 8 hours 6 weeks
Pediatric: 1 mg/kg IM or IV (max: 80 mg) every 8 hours 6 weeks
Section 14

a
Antibiotic doses should be modified appropriately in patients with impaired renal function.
b
Enterococci should be tested for high-level resistance (gentamicin: MIC ≥500 mcg/mL).
c
Serum concentration of gentamicin should be monitored and dosage adjusted to obtain a peak level of approximately 3 mcg/mL. (For shorter course gentamicin therapy
for enterococcal endocarditis see comment in text.)
d
Dosing of aminoglycosides and vancomycin on a mg/kg basis gives higher serum concentrations in obese than in lean patients.
e
Peak serum concentrations of vancomycin should be obtained 1 hours after infusion and should be in the range of 30–45 mcg/mL for twice daily dosing and 20–30 mcg/mL
for four times a day dosing. Trough serum concentrations should be obtained within half an hours of the next dose and should be in the range of 10–15 mcg/mL. Each dose
should be infused over 1 hours; 6 weeks of vancomycin therapy recommended because of decreased activity against enterococci.
Infectious Disease

f
Desensitization should be considered; cephalosporins are not satisfactory alternatives.
IM, intramuscular; IV, intravenous; MIC, minimum inhibitory concentration.
Source: Baddour LM et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the
Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and
Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394.

combination of penicillin (or ampicillin, piperacillin, or van-
comycin) and an aminoglycoside are required to produce the
desired bactericidal effect.20,124 One definition of synergy is when
a combination of antibiotics lowers the MIC to at least one-
fourth the MIC of either drug alone.125 The mechanism of syn-
ergy against enterococci is caused by an increased cellular uptake
of the aminoglycoside with agents that inhibit cell wall synthe-
sis (e.g., β-lactams and vancomycin).126 Because G.S. is allergic
to penicillin, vancomycin was prescribed with an aminoglyco-
side. Relapse rates are unacceptably high if penicillin is used
alone for the treatment of enterococcal endocarditis.19,21,125,126
The addition of an aminoglycoside to penicillin therapy signif-
icantly increases the sterilization rate of vegetations in animal
studies.125,126 Numerous clinical studies have confirmed the in
vitro synergy for penicillin in combination with streptomycin or
gentamicin for enterococcal endocarditis.20
STREPTOMYCIN RESISTANCE
As many as 55% of all enterococcal blood isolates are highly
resistant to streptomycin (MIC >2,000 mcg/mL), and the com-
bination of streptomycin with penicillin is not synergistic for
those isolates. In contrast, gentamicin in combination with
penicillin, ampicillin, or vancomycin is synergistic for most
blood isolates of enterococci, regardless of their susceptibil-
ity to streptomycin.1,21,127 In addition, ototoxicity in the form
of vestibular dysfunction secondary to streptomycin therapy
occurs in nearly 30% of patients in the treatment of ente-
rococcal endocarditis and is most often irreversible. High
peak concentrations and prolonged drug therapy have been
associated with ototoxicity, but laboratory assays for strepto-
mycin levels are not readily available. For these reasons, genta-
micin in combination with penicillin (or ampicillin) or van-
comycin is recommended by most authorities for the treatment
of aminoglycoside-susceptible and, in particular, streptomycin-
resistant enterococcal endocarditis, as it was for G.S.19 Of note,
other aminoglycosides cannot be used to substitute for gen-
tamicin or streptomycin because of the uncertain correlation
between in vitro synergy and in vivo efficacy.19 Table 63-6
lists the suggested regimens for the treatment of enterococcal
endocarditis.
GENTAMICIN RESISTANCE
Of the aminoglycosides, gentamicin and streptomycin are often
tested with penicillin (or ampicillin) for synergistic bactericidal
activity. About 10% to 25% of the clinical isolates of E. faecalis
and up to 50% of E. faecium are resistant to gentamicin.127,128
Without conclusive data, some groups favor long-term (8–12
weeks) therapy with high-dose penicillin (20–40 million units/day
IV in divided doses) or ampicillin (2–3 g IV every 4 hours)
for treatment of multiply resistant enterococci. Ampicillin plus
the β-lactamase inhibitor sulbactam (Unasyn) would be substi-
tuted for β-lactamase–producing, high-level gentamicin-resistant
enterococci. In light of the increasing prevalence of enterococci
with high-level aminoglycoside resistance, the potential syner-
gistic interaction between ampicillin or amoxicillin and a third-
generation cephalosporin was explored in vitro and in exper-
imental models of IE.129 A bactericidal synergistic effect was
shown between amoxicillin and cefotaxime against 50 strains of
E. faecalis. Amoxicillin MIC decreased from 0.25 to 1 mcg/mL
to 0.01 to 0.25 mcg/mL for 48 of 50 strains tested.130 Addi-
tionally, Brandt et al.131 demonstrated a synergistic bacterici-
dal effect for amoxicillin in combination with imipenem against
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
vancomycin-aminoglycoside–resistant E. faecium strains. The
authors speculated that saturation of different penicillin-binding
proteins by different β-lactam agents may be the underlying
mechanism for the synergy observed. Limited clinical data on 13
endocarditis cases caused by high-level aminoglycoside-resistant
E. faecalis treated with the combination of high-dose ceftriax-
one (4 g/day) and ampicillin appear to confirm the above syn-
ergistic interaction. All 16 evaluable patients were cured by
1 month of double β-lactam therapy with no evidence of relapse
during a 3-month follow-up period. Of note, two patients expe-
rienced reversible neutropenia and were withdrawn from the
study.132 Double β-lactam therapy appears promising for infec-
tions caused by aminoglycoside-resistant E. faecalis strains as well
as an aminoglycoside-sparing regimen for patients with renal
insufficiency, but the above preliminary results need to be con-
firmed with a larger number of patients.
GENTAMICIN
DOSING
CASE 63-4, QUESTION 2: What is the optimal dosage of
gentamicin for G.S.?
Because patients with enterococcal endocarditis require pro-
longed therapy with aminoglycosides, the optimal serum con-
centration should minimize toxicity without jeopardizing clinical
cure. Early in vitro data indicated that the bactericidal activity
of gentamicin against enterococci was not significantly differ-
ent between peak concentrations of 5 mcg/mL and 3 mcg/L;
however, the differences between 3 mcg/mL and 1 mcg/mL
were significant.129 In the rat model of endocarditis, the bac-
terial counts in vegetations at 5 and 10 days were compared
between those treated with low-dose (1 mg/kg intramuscularly
twice daily) and those treated with high-dose (5 mg/kg intra-
muscularly twice daily) gentamicin with penicillin.133 Bacterial
counts did not differ at 5 days, but at 10 days they were sig-
nificantly lower in the rats receiving the high-dose regimen. In
contrast, results in the rabbit model showed no difference in the
amount of bacteria per gram of vegetation in high- and low-dose
gentamicin treatment groups.134 Multiple daily dosing is more
effective in reducing bacterial titers in vegetations than single
daily dosing in experimental enterococcal endocarditits.135–137 In
contrast, viridans streptococci endocarditis can be managed with
single daily dosing33 (see Case 63-1, Question 4). Thus, extended-
interval dosing of aminoglycosides cannot be recommended for
the treatment of enterococcal endocarditis at this time.
The only study comparing high-dose (>3 mg/kg/day) and
low-dose (<3 mg/kg/day) gentamicin with penicillin in humans
with enterococcal endocarditis evaluated 56 patients during a
12-year period (36 with streptomycin-susceptible and 20 with
streptomycin-resistant infections).138 The relapse rate of patients
infected with streptomycin-resistant organisms (n = 20) was not
significantly different between the high- and low-dose treatment
groups (n = 10 each). Furthermore, patients who received the
higher doses of gentamicin experienced a greater prevalence of
nephrotoxicity (10 of 10 vs. 2 of 10; p <0.001). Mean peak and
trough concentrations of gentamicin in the patients who received
the high doses were 5 mcg/mL and 2.1 mcg/mL, respectively;
corresponding levels for patients receiving the low-dose regimen
were 3.1 mcg/mL and 1 mcg/mL.
Given the available data, it would be reasonable to start G.S.
on a gentamicin dosage of 1 mg/kg every 8 hours (assuming
her renal function is normal) and to maintain peak concentra-
tions of 3 to 5 mcg/mL and trough concentrations of less than
1 mcg/mL.
November 17, 2011 16:49
IN COMBINATION WITH VANCOMYCIN 1505
CASE 63-4, QUESTION 3: Why was vancomycin used in com-
bination with gentamicin in G.S.? Is this combination effec-
tive against enterococci?
G.S. has a history of penicillin allergy. Most clinicians favor
a combination of vancomycin and gentamicin for penicillin-
allergic patients with enterococcal endocarditis, although van-
comycin plus streptomycin is a suitable alternative.19,21,138 The
combination of vancomycin and gentamicin demonstrates bacte-
ricidal synergy for about 95% of enterococci strains. In contrast,
the vancomycin and streptomycin combination demonstrates
bactericidal synergy for about 65% of enterococci. Because G.S.
has PVE, she should receive approximately 30 mg/kg/day, or
roughly 1.5 g/day (750 mg every 12 hours), of vancomycin in
combination with gentamicin (3 mg/kg/day). Serum levels of
vancomycin and gentamicin should be monitored as previously
discussed.
DURATION OF THERAPY
Chapter 63
CASE 63-4, QUESTION 4: How long should G.S. be treated?
Historically, enterococcal endocarditis has been treated with
penicillin plus an aminoglycoside for 6 weeks; the overall cure
rate with this regimen is about 85%.19 Four weeks of ther-
Endocarditis
apy is probably adequate for most patients with enterococcal
endocarditis.19,138,139 One study evaluated the efficacy of a treat-
ment regimen involving shorter-course aminoglycoside therapy
(median of 15 days) in combination with a cell wall–active agent
for a median of 42 days in patients with PVE and native valve
enterococcal endocarditis.140 Clinical cure was observed in 75 of
93 (81%) patients overall, 78% of patients with PVE and 82%
of patients with native valves. Among those who had a clinical
cure, 52% received a β-lactam, 12% received vancomycin, and
36% received a combination of both. Ampicillin was given in
88% of patients receiving a β-lactam. The causative organism
was E. faecalis in 78 patients and E. faecium in 5 patients. Clinical
success was also achieved in all eight patients with native valve
IE who received either vancomycin (50%), ampicillin (25%), or
combination of both (25%) without synergistic aminoglycoside
therapy.
Patients with complicated courses should receive 6 weeks of
therapy, including patients infected with streptomycin-resistant
organisms (such as G.S.), those who have had symptoms for more
than 3 months before the initiation of antibiotics, and patients
with PVE (such as G.S.).12,19 Some clinicians recommend 6 weeks
of therapy for all patients in whom the duration of illness cannot
be firmly established; this accounts for many patients who present
with subacute disease.
INCREASED NEPHROTOXICITY WITH VANCOMYCIN
COMBINATION THERAPY
CASE 63-4, QUESTION 5: Is the combination of vancomycin
and an aminoglycoside more nephrotoxic than either drug
alone?
The incidence of nephrotoxicity associated with vancomycin
administration in humans is thought to be minimal or
nonexistent.141 In a three-arm study involving more than 200
patients, nephrotoxicity was found in 5% of patients who received
vancomycin alone, 22% of those receiving vancomycin with an
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
1506 aminoglycoside, and 11% of those receiving an aminoglycoside
alone.142 The study was well designed in that an aminoglycoside
control group was included for comparison of the incidence of
nephrotoxicity. Patients in whom increases in the serum creati-
nine concentration may have been a result of clinical conditions
and patients who received drugs known to alter renal function
were excluded in the analysis of this study. Serial serum van-
comycin and aminoglycoside concentrations, as well as duration
of therapy, were reported and analyzed. The authors concluded
that vancomycin trough concentrations of more than 10 mcg/mL
and concurrent therapy with an aminoglycoside were risk factors
associated with an increased incidence of nephrotoxicity.
Another study specifically evaluated the risk of nephrotoxic-
ity in patients receiving high-dose vancomycin therapy achieving
trough concentrations of 15 to 20 mcg/mL for MRSA infections.28
Nephrotoxicity occurred in 12% (11 of 95) of patients, signifi-
cantly predicted by concomitant therapy with other nephrotoxic
agents. An incremental increase in the risk of nephrotoxicity was
associated with duration of therapy at high trough levels (15–20
mcg/mL): 6.3% for 7 days or less, 21.1% for 8 to 14 days, and 30%
for more than 14 days. In a subanalysis that included only patients
without receipt of concomitant nephrotoxic agents, nephrotox-
Section 14
icity occurred in only 1 (2%) of 44 high-trough versus 0 of 24
low-trough (<15 mcg/mL) patients. A review of the published
literature confirms that an increased incidence of nephrotoxicity
is likely when vancomycin and another nephrotoxic agent (i.e., an
aminoglycoside, nonsteroidal anti-inflammatory drug) are given
concomitantly, especially when vancomycin is dosed targeting
Infectious Disease
trough concentration of 15 to 20 mcg/mL and administered for
prolonged duration (>1 week).141
GLYCOPEPTIDE RESISTANCE IN ENTEROCOCCI
CASE 63-4, QUESTION 6: How do enterococci develop
resistance to vancomycin? What are the therapeutic impli-
cations if G.S. is infected with glycopeptide-resistant ente-
rococci?
VRE, particularly E. faecium, have emerged in the United
States since 1987.140,142 The increased use of vancomycin since
the mid-1980s has coincided with the increased resistance to this
class of compounds. Between 1989 and 1993, the percentage of
nosocomial enterococci reported as resistant to vancomycin in
the United States rose more than 20-fold, from 0.3% to 7.9%.143
Enterococcal isolates from intensive care units increased even
more dramatically, from 0.4% to 13.6%, during that time. Data
from the Centers for Disease Control and Prevention National
Nosocomial Infections Surveillance (NNIS) system indicate that
the rate of increase has slowed down from 31% in 2000 to 12%
in 2003.144,145 A 12% increase was found in VRE infections in
intensive care units between 2003 and the prior 5-year period
(1998–2002). Nonetheless, epidemiologic studies conducted by
the NNIS system, as well as others, have shown that VRE bac-
teremia is associated with significantly increased morbidity and
mortality.144,145
Although E. faecalis is responsible for 80% to 90% of infec-
tions caused by enterococci, E. faecium is more likely to exhibit
resistance to glycopeptides compared with E. faecalis; more than
95% of VRE recovered in the United States are E. faecium.
Glycopeptide-resistant enterococci synthesize abnormal pepti-
doglycan precursors that lower the binding affinity of glycopep-
tides to peptidoglycans.140 VRE can be broadly classified into
three separate phenotypes (A, B, and C) based on three struc-
turally different genes and gene products (e.g., altered ligases).140
Most (approximately 70%) of resistant enterococci are of the
VanA phenotype, which are resistant to high levels of both
November 17, 2011 16:49
vancomycin (MIC >256 mcg/mL) and teicoplanin (MIC >16
mcg/mL). Expression of resistance is inducible, usually plasmid
mediated, and transferable to other organisms via conjugation.
The VanB strains exhibit moderate vancomycin resistance (MIC
16–64 mcg/mL), but remain susceptible to teicoplanin (MIC
≤2 mcg/mL). Overall, the VanC isolates are the least resistant
(vancomycin MIC 8–16 mcg/mL; teicoplanin MIC ≤2 mcg/mL)
because of chromosomal-mediated constitutive expression (i.e.,
not inducible as are VanA and VanB); however, VanC isolates
usually are associated with the much less common Enterococcus
gallinarum and Enterococcus casseliflavus infections.
Vancomycin, as well as extended-spectrum cephalosporins
and drugs with potent antianaerobic activity, are risk factors for
VRE.140
Few therapeutic alternatives exist for VRE, and synergistic
combinations are required for bactericidal activity and clinical
cure in endocarditis. Consequently, the treatment of choice is
unknown. As a result, practitioners must make decisions using
the available data from in vitro synergy studies, experimental
models of endocarditis, and scattered case reports. Of additional
concern, glycopeptide-resistant isolates often exhibit concomi-
tant high-level resistance to aminoglycosides and β-lactams (e.g.,
ampicillin, penicillin) secondary to either β-lactamase produc-
tion or alteration in the target penicillin-binding proteins.
Several antibiotic combinations appear promising in vitro
and in preliminary animal models of endocarditis, but few data
are currently available in humans. Those combinations include
high-dose ampicillin (20 g/day) or ampicillin/sulbactam plus an
aminoglycoside; vancomycin, penicillin or ceftriaxone and gen-
tamicin; ampicillin and imipenem; ciprofloxacin and ampicillin;
ciprofloxacin, rifampin, and gentamicin; and teicoplanin and gen-
tamicin (teicoplanin is not available in the United States).140
STREPTOGRAMIN AND OXAZOLIDINONE
Quinupristin/dalfopristin (Synercid) and linezolid (Zyvox) are
two agents with activity and proven efficacy against some infec-
tions caused by VRE approved for use by the FDA in the United
States. Quinupristin/dalfopristin, available as a fixed 70:30 combi-
nation, is the first drug in the streptogramin class made available
in the United States for human use. It belongs to the antibiotic
family of macrolides/lincosamides/streptogramins. The agent
received accelerated approval by the FDA in late 1999 specifically
for the treatment of vancomycin-resistant E. faecium bacteremia.
The combination is synergistic for glycopeptide-resistant entero-
cocci with an MIC90 of 2 mcg/mL. The fixed product is generally
bactericidal against susceptible streptococci and staphylococci
(including methicillin-resistant strains), but it is bacteriostatic
against E. faecium. Specifically, E. faecalis is not susceptible to the
agent because of the presence of an efflux146 pump conferring
resistance to dalfopristin. Emergence of resistance during ther-
apy has been reported on rare occasions.146 The recommended
dosage is 7.5 mg/kg every 8 to 12 hours (depending on the severity
of infection).147,148
Arthralgias or myalgias were the most frequently reported
events (10%) and also most frequently resulted in drug
discontinuation.147,148 A higher incidence of arthralgias or myal-
gias has been reported by others (up to 50%); those patients
had significant comorbidities.149 All cases were reversible on ces-
sation of therapy. Significant venous irritation occurred (46%)
when the drug was administered via a peripheral vein. Each
dose can be diluted in 250 to 750 mL of dextrose (lower concen-
trations may decrease vein irritation) and infused for 1 hour.62
The drug is not compatible with saline solutions. Laboratory
abnormalities most frequently observed were increases in total
and conjugated bilirubin in up to 34% of patients. As a result,
liver function tests should be obtained once a week during
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
therapy. Because quinupristin/dalfopristin is a potent inhibitor
of the cytochrome P-450 3A4 enzyme system, coadministration
of drugs (e.g., cyclosporine) metabolized by the same enzyme
system should be avoided, if possible, or done only with close
monitoring of therapeutic levels.147
Linezolid has bacteriostatic activity against enterococci,
including vancomycin-resistant E. faecium and E. faecalis. It is
also active against other gram-positive cocci, including Strep-
tococcus pneumoniae and methicillin-resistant staphylococci.147
Vancomycin-resistant E. faecium isolates resistant to linezolid have
been isolated.150,151 Treatment experience with linezolid under
the compassionate use protocol reported clinical and microbio-
logic cure rates of 50% at 6-month follow-up for patients with
endocarditis. Vancomycin-resistant E. faecium was the causative
organism for 19 of the 32 patients treated.111 Common adverse
effects associated with linezolid include nausea, headache, diar-
rhea, rash, and altered taste. Of greater concern is its poten-
tial to cause myelosuppression. Thrombocytopenia, leukope-
nia, anemia, and pancytopenia have all been reported. Up to
30% of patients treated experience thrombocytopenia (platelet
counts <100,000 platelets/μL).147 In addition, linezolid is a weak
monoamine oxidase inhibitor, which may potentiate the adren-
ergic effects of sympathomimetic agents (i.e., pseudoephedrine)
and precipitate serotonergic syndrome when used concomitantly
with selective serotonin reuptake inhibitors. Patients should be
advised to avoid tyramine-containing foods (i.e., aged cheese,
sausages, sauerkraut, wine) during therapy as well. Linezolid is
available both orally and parenterally. Linezolid given orally or
via enteral feedings is completely bioavailable.152 A dosage of
600 mg twice daily is recommended for adults. Persistent MRSA
bacteremia caused by suboptimal serum concentrations of line-
zolid has been described.109
DAPTOMYCIN
Daptomycin is active against enterococci in vitro with an MIC
range of 0.25 to 4 mcg/mL and MIC90 of 4 mcg/mL for 219 vanco-
mycin-resistant E. faecium isolates from the United States. For
40 vancomycin-resistant E. faecalis isolates, the MIC range is
0.015 to 2 mcg/mL, with a MIC90 of 2 mcg/mL.153 When tested
against 20 vancomycin-resistant E. faecium strains, daptomycin
had MIC50 of 2 mcg/mL versus 0.5 mcg/mL and 4 mcg/mL for
quinupristin/dalfopristin and linezolid, respectively.153 Of con-
cern is the emergence of daptomycin resistance during ther-
apy for VRE infections.154,155 In a case report of a patient with
vancomycin-resistant E. faecium pyelonephritis, the initial isolate
had an MIC of 2 mcg/mL; however, after 17 days of treatment, a
blood culture yielded growth of vancomycin-resistant E. faecium
with an MIC increase to 32 mcg/mL.156 Clinical experience with
daptomycin for vancomycin-resistant E. faecium endocarditis is
limited, and treatment failure has been reported.157 Thus, the
role of daptomycin in treating VRE endocarditis is uncertain at
this point.
FUNGAL ENDOCARDITIS CAUSED
BY CANDIDA ALBICANS
Prognosis and Treatment
CASE 63-5
QUESTION 1: B.G., a 35-year-old male heroin addict, was
admitted to the hospital with chief complaints of pleuritic
chest pain and dyspnea on exertion. Physical examination
revealed a cachectic man with a temperature of 104◦ F, a
November 17, 2011 16:49
1507
diastolic regurgitant heart murmur heard loudest during
inspiration, splenomegaly, and pharyngeal petechiae. Fun-
duscopic examination was noncontributory. On the chest
radiograph, several pulmonary infiltrates with cavitation
were evident. UA was significant for microscopic hema-
turia and RBC casts. A transesophageal echocardiogram
demonstrated vegetations on both the tricuspid and aortic
heart valves. B.G. had evidence of moderate heart failure,
although his hemodynamic status at that time was “stable.”
Six sets of blood cultures were drawn over the course of
2 days, and broad-spectrum empiric coverage consisting of
vancomycin, gentamicin, and ceftazidime was initiated. Two
days later, two of the cultures grew Candida albicans, and
a diagnosis of fungal endocarditis was established. What is
B.G.’s prognosis, and how should his fungal endocarditis be
treated?
Fungal endocarditis is a rare but life-threatening infection that
is difficult to diagnose and even more difficult to treat.1 Most cases
are caused by Candida and Aspergillus species. Fungal endocarditis
occurs primarily in IV drug users, patients with prosthetic heart
Chapter 63
valves, immunocompromised patients, those with IV catheters,
or patients receiving broad-spectrum antibiotics.158–161
Management of fungal endocarditis generally requires early
valve replacement and aggressive fungicidal therapy with
amphotericin deoxycholate B 0.6 to 1 mg/kg/day with or without
5-flucytosine (5-FC) 25 mg/kg orally QID. If B.G. had poor renal
Endocarditis
function, liposomal formulations of amphotericin B 3 to 5 mg/kg
daily can be used as an alternative.162
These antifungal agents should be prescribed for B.G., and his
broad-spectrum antibiotic coverage with vancomycin, gentam-
icin, and ceftazidime should be discontinued.
B.G.’s clinical presentation and chest radiograph indicate that
fragments of vegetation have already embolized to his lungs and
possibly to other vital organs (e.g., spleen, kidneys). Because of
the morbidity and mortality associated with major emboli and
valvular insufficiency, B.G. should undergo surgery within 48 to
72 hours after antifungal therapy has been initiated. The prog-
nosis for B.G. is dismal even with proper medical and surgical
treatment. In a series analyzing 270 cases of fungal IE occurring
during a 30-year period, mortality for those who received com-
bined medical and surgical management was 45%, compared
with 64% for those who received antifungal therapy alone.158
Despite initial response to treatment, the rate of relapse is high
(30%–40%), and relapse can occur up to 9 years after the initial
episode of infection.158–161 Most deaths in IV drug users with
endocarditis are secondary to heart failure, a finding already evi-
dent in B.G.1 In addition, replacement of a heart valve for fungal
endocarditis in a heroin addict carries a significant risk of late
morbidity and mortality.158
COMBINATION THERAPY WITH 5-FLUCYTOSINE
AND AMPHOTERICIN B
CASE 63-5, QUESTION 2: Why is it important to treat B.G.’s
fungal endocarditis with the combination of 5-FC and con-
ventional or lipid-based amphotericin B? What is the opti-
mal duration of therapy?
The importance of adding 5-FC (Ancobon) to amphotericin B
(Fungizone) therapy has not been adequately studied; however,
the poor prognosis associated with fungal endocarditis warrants
the administration of 5-FC, despite its potential for causing bone
marrow suppression and hepatotoxicity.158 The vegetations from
his tricuspid or aortic heart valves already have broken off and
caused pulmonary cavitation and possibly splenomegaly. His
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
1508 clinical presentation is consistent with a potentially fatal out-
come; therefore, his blood isolates should be tested for in vitro
susceptibility to amphotericin, 5-FC, and azoles. Fungi resistant
to 5-FC alone may still be susceptible to the synergistic effect
of the 5-FC–amphotericin B combination.163 If the organism is
resistant to 5-FC, in vitro synergy between these two antifungals
should be performed or therapy with an echinocandin should be
considered.
The optimal dose and duration of antifungal therapy for fun-
gal endocarditis have not been determined by clinical studies;
however, postoperative treatment with amphotericin B and 5-FC
(if it has in vitro activity) for a minimum of 6 weeks (total dose,
1.5–3 g of amphotericin B) is recommended and is supported by
the poor penetration of amphotericin B into heart valve tissue.164
In patients with fungal PVE, some experts advocate secondary
prophylaxis for a minimum of 2 years or lifelong suppressive treat-
ment with an oral antifungal agent for nonsurgical candidates in
light of the high rates of relapse.1,158,160,163–166
Nephrotoxicity caused by amphotericin is often a seri-
ous dose-limiting factor to completion of therapy, particu-
larly in patients who require a prolonged treatment course.
Renal dysfunction secondary to the conventional formulation
Section 14
of amphotericin B may stabilize or improve with the switch
to lipid-formulated amphotericin B products (i.e., Abelcet,
AmBisome).167 The efficacy of the new formulations in the treat-
ment of endocarditis has been demonstrated only in anecdotal
reports.158,160,163,164,168 Alternative antifungal agents, including
echinocandins and azole, are potential options in patients who
Infectious Disease
experience significant renal toxicities.
ALTERNATIVE ANTIFUNGALS
CASE 63-5, QUESTION 3: If B.G. experiences significant
toxicities because of prolonged combination treatment with
amphotericin and 5-FC, what alternative antifungal agent(s)
can be used to treat his fungal endocarditis?
Fluconazole (Diflucan) is a triazole compound active against
Candida species, particularly C. albicans and Candida parapsilosis. It
also has a favorable toxicity profile compared with amphotericin
and 5-FC.169 Prolonged combination treatment with ampho-
tericin products and 5-FC often is limited by nephrotoxicity, bone
marrow suppression, and hepatic damage. Limited experimental
and clinical experience exists using fluconazole in the treatment
of candidal endocarditis.
Fluconazole was effective in eradicating cardiac fungal veg-
etations caused by C. albicans and C. parapsilosis in a rabbit
model.170 Successful experience with fluconazole treatment of
fungal endocarditis in humans has been described in only a few
case reports.171–175 Patients with various Candida species (i.e.,
C. albicans, C. parapsilosis, and Candida tropicalis) were treated
with 200 to 600 mg of fluconazole daily for 45 days to 6 months or
until death. Fluconazole therapy reduced or completely removed
all cardiac vegetations and resolved clinical symptoms. Because
of the lack of adequate clinical experience, however, the use of
fluconazole in treating fungal endocarditis cannot be advocated
except in patients who require lifelong therapy because of the
following situations: (a) the patient is a poor surgical candidate,
(b) the patient has relapsed at least once since the initial infection
episode, or (c) the patient has PVE.
Another potential alternative is caspofungin, which is a first-
line agent in the echinocandin class.176 Caspofungin is approved
for the treatment of invasive candidiasis (primarily bloodstream
infections and peritonitis). Caspofungin inhibits fungal cell wall
synthesis by inhibiting β-1,3-glucan synthesis. It is fungicidal
against most Candida species (including C. albicans), and with
minimal toxicity. Case reports describe successful outcomes with
November 17, 2011 16:49
caspofungin in the treatment of IE.177–179 In a patient with Can-
dida glabrata mitral valve endocarditis without surgical interven-
tion, caspofungin was used successfully as induction therapy in
combination with amphotericin B and continued as maintenance
therapy for 12 weeks.180 In a second case report of a patient with
PVE caused by C. glabrata and Candida krusei, resolution of vege-
tation was achieved after 6 weeks of caspofungin therapy alone
without valvular replacement. Both patients were deemed to be
poor surgical candidates and received medical therapy only.179
Micafungin and anidulafungin are other potential echinocandin
options; however, clinical experience in the treatment of endo-
carditis is currently lacking.
GRAM-NEGATIVE BACILLARY
ENDOCARDITIS CAUSED BY
PSEUDOMONAS AERUGINOSA
Prevalence
CASE 63-5, QUESTION 4: Fourteen months after complet-
ing his course of antifungal therapy, B.G. was readmitted to
the hospital with a 48-hour history of fever, shaking chills,
rigors, and night sweats. His vital signs at that time were
blood pressure, 100/60 mm Hg; pulse, 120 beats/minute;
respirations, 24/minute; and temperature, 103.7◦ F. A new-
onset systolic murmur was noted on auscultation. Two-
dimensional echocardiography revealed two small vegeta-
tions on the prosthetic valve. Empiric therapy consisting of
amphotericin B, 5-FC, vancomycin, and gentamicin was ini-
tiated. Three blood cultures drawn on the day of admission
were positive for P. aeruginosa with the following antibi-
otic susceptibilities85 : gentamicin (8 mcg/mL), tobramycin
(2 mcg/mL), piperacillin-tazobactam (64 mcg/mL), and cef-
tazidime (2 mcg/mL). A presumptive diagnosis of PVE
caused by P. aeruginosa was made. Why was the finding
of Pseudomonas expected in B.G.?
The prevalence of endocarditis caused by gram-negative
organisms has increased significantly over the years, especially
in IV drug users such as B.G. and patients with prosthetic
heart valves. Gram-negative organisms are responsible for about
15% to 20% of endocarditis cases in these populations.181 Most
gram-negative endocarditis cases are caused by Pseudomonas
species, S. marcescens, and Enterobacter species, although numer-
ous other gram-negative organisms have been known to cause
endocarditis.181–186 Geographic clustering of certain organisms
causing endocarditis in narcotic addicts has been shown in the
past, such as the association of P. aeruginosa with the Detroit
area and S. marcescens with San Francisco.183,187–189 These past
epidemiologic findings are not necessarily true today. In narcotic
addicts with gram-negative endocarditis, the tricuspid, aortic,
and mitral valves are involved in 50%, 45%, and 40% of cases,
respectively.186
Antimicrobial Therapy
CASE 63-5, QUESTION 5: How should B.G.’s gram-negative
endocarditis be treated and monitored?
The previous empirical antimicrobials should be discontin-
ued because P. aeruginosa has been cultured from B.G.’s blood.
A bactericidal combination of antibiotics usually is required to
provide in vivo synergy and to prevent resistant subpopulations
from emerging during therapy.1,190 B.G., therefore, should be
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
treated with ceftazidime (2 g IV every 8 hours) with concurrent
high-dose tobramycin (3 mg/kg IV every 8 hours). The duration
of therapy is not well defined, but most authorities recommend
4 to 6 weeks.1,182,187,189 Because B.G. should be receiving both
ceftazidime and tobramycin on the same schedule (every
8 hours), the trough titer should be drawn just before dose admin-
istration. Finally, the infected valve should be surgically excised
for the reasons previously discussed.
Endocarditis caused by P. aeruginosa (as in B.G.) should be
treated for at least 6 weeks with a combination of an aminoglyco-
side and an antipseudomonal penicillin (piperacillin-tazobactam)
or cephalosporin (ceftazidime).1,191 The combination of an
antipseudomonal penicillin and an aminoglycoside is synergistic
in vitro and in the rabbit model of P. aeruginosa endocarditis,191,192
and clinical experience has confirmed this finding in IV drug
users. Combination therapy with high dosages of tobramycin or
gentamicin (8 mg/kg/day) has been associated with a significantly
higher cure rate and lower mortality rate compared with an older,
low-dose regimen (2.5–5 mg/kg/day).181,182,189 Aminoglycosides
(tobramycin or gentamicin) should be dosed to produce peak and
trough serum concentrations of 15 to 20 mcg/mL and less than 2
mcg/mL, respectively, to ensure maximum efficacy1 ; therefore,
high-dose tobramycin should be selected for B.G.
Of note, the use of extended-interval dosing of aminogly-
coside has not been evaluated for the treatment of endocardi-
tis caused by gram-negative organisms; therefore, this dosing
approach cannot be recommended at this time. The choice of
aminoglycoside should be based on the in vitro activity of the
organism (i.e., MIC), relative toxicity potential, and cost. In B.G.’s
case, tobramycin should be selected over gentamicin because the
isolated organism was resistant to gentamicin. Generally, P. aerug-
inosa is more susceptible to tobramycin than to gentamicin. Thus,
it is not at all surprising that the P. aeruginosa in B.G.’s blood cul-
tures had an MIC of 2 mcg/mL for tobramycin compared with
MIC of 8 mcg/mL for gentamicin. Ceftazidime is preferred over
piperacillin-tazobactam for B.G. on the basis of its narrower spec-
trum of activity.193
Several compounds such as imipenem (Primaxin),
meropenem (Merrem), aztreonam (Azactam), cefepime
(Maxipime), and ciprofloxacin (Cipro) are active against many
of the gram-negative organisms causing endocarditis. Clinical
data regarding their use in the treatment of endocarditis are
very limited, however.194–197
CULTURE-NEGATIVE ENDOCARDITIS
CASE 63-5, QUESTION 6: B.G.’s history, clinical presenta-
tion, and imaging studies are strongly suggestive of infec-
tive endocarditis. If his blood cultures had been negative
after 48 hours of incubation, the working diagnosis would
have been culture-negative endocarditis. What are the pos-
sible reasons for culture-negative endocarditis, and what
measures should be taken to establish a microbiologic eti-
ology?
The proportion of patients with culture-negative endocarditis
has diminished considerably, presumably as a result of improved
microbiologic culture techniques. Negative blood cultures are
present in only 5% to 7% of patients who meet strict cri-
teria for the diagnosis of IE and have not recently received
antibiotics.198
The prior administration of antimicrobials is thought to
account for most cases of culture-negative endocarditis.199 B.G.’s
blood cultures may remain negative for several days to weeks if
he has taken antibiotics recently. The use of antibiotic absorbance
November 17, 2011 16:49
resins or the addition of β-lactamases to the blood sample may 1509
remove or inactivate some antibiotics.200
Slow-growing and fastidious organisms, such as gram-
negative bacilli in the Haemophilus-Actinobacillus-Cardiobacterium-
Eikenella-Kingella group (HACEK), Brucella, Coxiella, chlamydiae,
strict anaerobes, and fungi, should be pursued in culture-negative
patients. This usually is accomplished by the use of special culture
media or by obtaining appropriate serologic acute and convales-
cent titers. Blood cultures should be saved for at least 3 weeks to
detect slow-growing organisms.199 The use of polymerase chain
reaction to identify nonculturable organisms in excised valvular
specimens or septic emboli has been helpful in some cases.201 Of
note, previously NVS has been the cause of most of the cases of
endocarditis diagnosed as culture-negative, initially because of its
requirement for the addition of vitamin B6 (pyridoxal HCl) to the
culture media for laboratory growth; however, laboratory iden-
tification is no longer a significant problem with current culture
media and laboratory techniques.8
Empiric Therapy
Chapter 63
CASE 63-5, QUESTION 7: The causative organism remains
unidentified. Recommend an antimicrobial regimen for
the empiric treatment of B.G.’s presumed culture-negative
endocarditis.
In the hemodynamically stable patient, antibiotic therapy
should be withheld until positive blood cultures are obtained.1
Endocarditis
Based on B.G.’s clinical presentation and echocardiographic find-
ings, empiric antibiotics should be initiated as soon as necessary
cultures have been collected. Because staphylococci and gram-
negative bacilli account for most cases of endocarditis in the nar-
cotic addict with a prosthetic heart valve, B.G. should be started
on a four-drug regimen: vancomycin targeting trough of 15 to 20
mcg/mL, gentamicin targeting peak of 3 to 4 mcg/mL, cefepime
2 g IV every 8 hours, and rifampin 300 mg IV/PO every 8 hours.7
Because B.G. may be experiencing a relapse caused by C. albicans,
the addition of amphotericin B and 5-FC would be appropriate.
If B.G. is from an area where methicillin-resistant staphylococci
are prevalent, vancomycin should be substituted for nafcillin. A
third-generation cephalosporin (ceftriaxone or ceftazidime) or
piperacillin-tazobactam could be used, depending on the gram-
negative pathogens common to the region and their anticipated
susceptibilities. This regimen, which contains an aminoglyco-
side and piperacillin-tazobactam, also will provide coverage for
enterococci.
B.G.’s clinical status and the positive echocardiogram indi-
cate that early surgical valve excision and replacement are
necessary.202 Cultures obtained from the excised valve may allow
for identification of the causative organism. His antimicrobial
regimen may need to be altered if and when subsequent culture
information becomes available. Other noninfective conditions,
such as atrial myxoma, marasmic endocarditis, and rheumatic
fever, can mimic culture-negative endocarditis and should be
excluded from the differential diagnosis with the appropriate
tests.1
PROPHYLACTIC THERAPY
Rationale and Recommendations
CASE 63-6
QUESTION 1: B.B., a 74-year-old man with poor dentition,
is scheduled to have all of his remaining teeth extracted for
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational November 17, 2011 16:49

1510
subsequent fitting of dentures. His medical history is sig- TA B L E 6 3 - 7
nificant for numerous infections of the oral cavity and pros- Endocarditis Prophylaxis Regimen Indicated for Patients With
thetic valve replacement 2 years ago. His only current medi- Cardiac Conditionsa
cations are digoxin (Lanoxin) 0.125 mg/day and furosemide Drug Dose
(Lasix) 40 mg every morning. What is the rationale for antibi-
otic prophylaxis? Dental or upper respiratory tract Single dose 30 to 60 minutes
procedures before procedure
Because IE is associated with significant mortality and Standard Regimen
long-term morbidity, prevention in susceptible patients is of Amoxicillin Adult: 2 g
paramount importance.1 Estimates are, however, that less than Pediatric: 50 mg/kg
10% of all cases are theoretically preventable.9,203 The incidence Allergic to penicillin or ampicillin
of endocarditis in patients undergoing procedures known to Clindamycin Adult: 600 mg
cause significant bacteremia, even without antibiotic prophylaxis, or Pediatric: 20 mg/kg
Cephalexinb ,c Adult: 2 g
is low. In addition, endocarditis may develop after the adminis-
or Pediatric: 50 mg/kg
tration of seemingly appropriate chemoprophylaxis. Therefore, Azithromycin or clarithromycin Adult: 500 mg
it is not surprising that the efficacy of prophylaxis has never been Pediatric: 15 mg/kg
established through placebo-controlled clinical trials. Approxi-
Unable to Take Oral Medications
mately 6,000 patients would be necessary to demonstrate a sta- Ampicillin Adult: 2 g IM or IV
tistical difference (if one exists) between untreated controls and Pediatric: 50 mg/kg IM or IV
a group receiving prophylaxis.203,204
Allergic to Penicillin or Ampicillin
Without conclusive clinical data from prospective trials, Clindamycin Adult: 600 mg
Section 14

recommendations for antibiotic prophylaxis have been based or Pediatric: 20 mg/kg IV

largely on in vitro susceptibility data, evaluation of antibiotic Cefazolinb Adult: 1 g IM or IV
regimens using animal models of endocarditis, and anecdotal Pediatric: 50 mg/kg IM or IV
experiences.203,204
a
Prophylactic antibiotics are thought to provide protection by b
See Table 63-1.
decreasing the number of organisms reaching the damaged heart Cephalosporins should not be used in individuals with immediate-type
hypersensitivity reaction (e.g., urticaria, angioedema, or anaphylaxis) to
Infectious Disease

valve from a primary source. Thus, antibiotics theoretically pre-
vent bacterial multiplication on the valve and interfere with bac-
terial adherence to the cardiac lesion.203,204
The 2007 AHA recommendations for antibiotic prophy-
laxis before common medical procedures are outlined in Table
63-7.204 Compared with the previous (1997) guideline,204 the cur-
rent guidelines only recommend the use of prophylaxis in patients
with specific cardiac conditions who are undergoing only den-
tal or respiratory tract procedures. The use of prophylaxis for
patients undergoing genitourinary or gastrointestinal procedures
is not recommended because of a continuing lack of evidence to
support efficacy.
penicillins or ampicillin.
c
Other first- or second-generation oral cephalosporins in equivalent adult or
pediatric dose.
IM, intramuscular; IV, intravenous.
Source: Wilson W et al. Prevention of infective endocarditis: guidelines from the
American Heart Association: a guideline from the American Heart Association
Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on
Cardiovascular Disease in the Young, and the Council on Clinical Cardiology,
Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care an
Outcomes Research Interdisciplinary Working Group. American Heart
Association [published correction appears in Circulation. 2007;116:e376].
Circulation. 2007;116:1736.

DENTAL AND UPPER RESPIRATORY
TRACT PROCEDURES
The current guidelines only recommend prophylaxis in individ-
uals with cardiac conditions associated with the highest risk of
adverse outcomes from endocarditis (Table 63-1). Previous 1997
AHA guidelines listed a substantial number of procedures in
which prophylaxis is either indicated or not recommended. Anal-
ysis of published data shows that viridans streptococci bacteremia
can result from any procedure that involves the manipulation of
the gingival tissue or the periapical region of the teeth or perfo-
ration of the oral mucosa. Placement or removal of prosthodon-
tic or orthodontic appliances, adjustment of orthodontic appli-
ances, taking dental radiographs, bleeding from trauma to the lips
or oral mucosa, and instantaneous shedding of deciduous teeth
do not require chemoprophylaxis. Endotracheal intubation also
does not require prophylactic therapy.
Antimicrobial prophylaxis should be directed against the viri-
dans group of streptococci because these organisms are the most
common cause of endocarditis after dental procedures. Inva-
sive surgical procedures involving the upper respiratory tract,
such as incision or biopsy of the respiratory mucosa (e.g., tonsil-
lectomy, adenoidectomy), can cause transient bacteremia with
organisms that have similar antibiotic susceptibilities to those
that occur after dental procedures; therefore, the same regimens
are suggested. Prophylaxis is not recommended for broncho-
scopies unless the procedure involves incision of the respiratory
mucosa. Amoxicillin is currently recommended for oral prophy-
laxis in susceptible persons having dental or upper respiratory
tract surgery. Oral clindamycin, clarithromycin, or azithromycin
is recommended for patients with immediate-type hypersensi-
tivity reaction to penicillins. Only patients with outlined cardiac
conditions should receive prophylactic antibiotics.
Most cases of endocarditis that are caused by bacterial flora
from the mouth do not follow dental procedures but rather are
the result of poor oral hygiene. The cumulative exposure to ran-
dom bacteremias from daily oral activities is estimated to be
5,730 minutes during a 1-month period compared with only 6 to
30 minutes for a dental procedure. Furthermore, it is estimated
that the cumulative exposure to bacteremia from routine daily
activities may be as high as 5.6 million times greater than a sin-
gle tooth extraction.203 Based on the study results, concerns for
antimicrobial resistance, and cost, changes to restrict the use of
antibiotic prophylaxis to the highest-risk patients before dental
procedures may be expected with future guidelines issued by the
AHA.
Indications and Choice of Agent
CASE 63-6, QUESTION 2: Is prophylactic antibiotic therapy
indicated for B.B.? If so, which antibiotic(s) should be used?
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
Based on the current recommendations, B.B. is a candidate
for antibiotic prophylaxis. Presence of a prosthetic aortic valve
while undergoing multiple tooth extractions places him at risk
for experiencing endocarditis. He also is scheduled to have all
of his remaining teeth extracted, a procedure likely to result in
bacteremia. According to Table 63-7, B.B. should receive a single
2-g oral dose of amoxicillin 1 hour before the procedure.
HOME INTRAVENOUS
ANTIBIOTIC THERAPY
CASE 63-7
QUESTION 1: T.M., a 48-year-old woman, developed viri-
dans streptococci endocarditis after a dental procedure. Her
medical history is significant for rheumatic heart disease and
chronic renal insufficiency (measured creatinine clearance,
50 mL/minute). She is hemodynamically stable and has no
evidence of vegetation. She is currently on day 7 of ther-
apy with penicillin G, 2 million units IV every 4 hours. The
plan is to continue penicillin therapy for a total of 4 weeks.
What are the considerations for using home IV therapy for
the treatment of infective endocarditis? Is T.M. a candidate
for home antibiotic therapy?
The successful use of home IV antibiotic therapy for the
patient with endocarditis has been described, although the num-
ber of patients treated is relatively small compared with those
treated for osteomyelitis.205–206 The advantages of home ther-
apy include economic benefits to the hospital for early dis-
charge (the diagnosis-related-group allocation for endocarditis
is 18.4 days, which is shorter than the usual recommended dura-
tion of therapy) and the potential for greater acceptance by the
patient.
Home treatment of endocarditis is not without risk,
however.206 Patients must be hemodynamically stable before dis-
charge and free from the risk of sudden valve rupture. The drug
abuser is obviously not a candidate for home treatment, nor is
the patient receiving frequent doses of medication. The success-
ful management of any infection amenable to home treatment
requires careful patient evaluation for suitability and coordina-
tion of the health care provided by key personnel.
T.M. represents the typical patient with uncomplicated strep-
tococcal endocarditis. If the sole reason for continued hospital-
ization is to administer IV antibiotics, she is a potential candidate
for home therapy.
Ceftriaxone is an attractive option for outpatient therapy
of uncomplicated endocarditis caused by penicillin-susceptible
streptococci. The excellent in vitro activity of ceftriaxone and
its long half-life of 6 to 9 hours allow once-a-day administration.
The feasibility of intramuscular administration of ceftriaxone
also obviates the need for IV access, thus avoiding any potential
line-related complications when administered in the outpatient
setting.
Clinical experience with the use of ceftriaxone in the treat-
ment of patients with penicillin-susceptible streptococcal endo-
carditis was described in four open-label studies.38–41 Two of
the studies evaluated ceftriaxone monotherapy for 4 weeks; the
other two evaluated combination therapy with ceftriaxone and
an aminoglycoside for a 2-week duration. All infecting strains of
streptococci in the first two studies were inhibited by ceftriaxone
at an MIC of less than 0.25 mcg/mL. In one study, ceftriaxone
was given at a dosage of 2 g once daily for 4 weeks to most
patients, with 15 receiving ceftriaxone for 2 weeks followed by
amoxicillin 1 g four times daily for 2 weeks. Most of the patients
received therapy predominantly as outpatients. All 30 patients
November 17, 2011 16:49
reported in this study responded favorably to treatment with cef- 1511
triaxone or ceftriaxone followed by amoxicillin.38 Patients with
cardiovascular risk factors, such as heart failure, severe aortic
insufficiency, or evidence of recurrent thromboembolic events,
were excluded from the study. Only one probable relapse was
noted at 3 months after therapy with presentation of febrile syn-
drome, elevated sedimentation rate, and negative bacterial blood
culture. An uncontrolled study extended the favorable results
of the aforementioned study.34 Treatment was completed in 55
of 59 patients. Patients were followed for 4 months to up to
5 years after the end of treatment with no clinical signs or labo-
ratory evidence of relapse. Of patients, 71% completed therapy
without complications; however, 10 required valve replacement
secondary to hemodynamic deterioration or recurrent emboli,
whereas 4 required a change in therapy because of drug allergy.
Adverse side effects were minor, but 3 patients had neutropenia
that resolved after cessation of therapy.
Because of the lack of controlled trials comparing the efficacy
of ceftriaxone against penicillin with or without an aminoglyco-
side in the treatment of penicillin-susceptible streptococcal endo-
carditis, ceftriaxone should be considered primarily in patients
such as T.M. for whom home antibiotic therapy is a treatment
Chapter 63
option and those who are hemodynamically stable with no evi-
dence of vegetation.
The feasibility of home therapy depends on the following
additional factors: (a) patient willingness, (b) adequate venous
access, (c) psychosocial stability, (d) access to medical care if
an emergency occurs, (e) ability to train T.M. (proper asep-
Endocarditis
tic technique, catheter site care, antibiotic preparation, recog-
nition of untoward effects of the antibiotic, and recognition of
symptoms associated with worsening infection), and (f ) insur-
ance coverage for home IV therapy. These conditions can be
accomplished only with the multidisciplinary involvement of
the infectious disease physician, a social worker, a pharmacist,
a specialty nurse, and the patient. Home care, outpatient care,
and other options will be used increasingly because health care
reform mandates the decreased use of tertiary care facilities when
possible.
KEY REFERENCES
A full list of references for this chapter can be found at http://
thepoint.lww.com/AT10e. Below are the key references for this
chapter, with the corresponding reference number in this chapter
found in parentheses after the reference.
Key References
Archer GL et al. Staphylococcus epidermidis and other coagulase-
negative staphylococci. In: Mandell GL et al, ed. Mandell, Douglas,
and Bennett’s Principles and Practice of Infectious Diseases. 7th ed.
Philadelphia, PA: Elsevier Churchill Livingstone; 2009: Chapter
116;2545. (46)
Baddour LM et al. Infective endocarditis: diagnosis, antimicro-
bial therapy, and management of complications: a statement
for healthcare professionals from the Committee on Rheumatic
Fever, Endocarditis, and Kawasaki Disease, Council on Cardio-
vascular Disease in the Young, and the Councils on Clinical
Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia,
American Heart Association: endorsed by the Infectious Diseases
Society of America. Circulation. 2005;111:e394. (7)
Fowler VG Jr et al. Daptomycin versus standard therapy for bac-
teremia and endocarditis caused by Staphylococcus aureus. N Engl
J Med. 2006;355:653. (114)
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-63 LWW-KodaKimble-educational
1512 Fowler VJ Jr et al. Endocarditis and intravascular infections. In:
Mandell GL et al, eds. Mandell, Douglas, and Bennett’s Principles
and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Elsevier
Churchill Livingston; 2009: Chapter 77. (1)
Fowler VG Jr et al. Staphylococcus aureus endocarditis: a conse-
quence of medical progress [published correction appears in
JAMA. 2005;294:900]. JAMA. 2005;293:3012. (5)
Howden BP et al. Reduced vancomycin susceptibility in Staphylo-
coccus aureus, including vancomycin-intermediate and heteroge-
neous vancomycin-intermediate strains: resistance mechanisms,
laboratory detection, and clinical implications. Clin Microbiol Rev.
2010;23:99. (58)
Karchmer AW. Prosthetic valve endocarditis. In: Mandell GL
et al, ed. Mandell, Douglas, and Bennett’s Principles and Practice
of Infectious Diseases. 7th ed. Philadelphia, PA: Elsevier Churchill
Livingstone; 2009: Chapter 78;1113. (41)
Le T, Bayer AS. Combination antibiotic therapy for infective
endocarditis. Clin Infect Dis. 2003;36:615. (20)
Li JS et al. Proposed modifications to the Duke criteria for the
diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633.
Section 14
(18)
Infectious Disease
November 17, 2011 16:49
Liu C et al. Clinical practice guidelines by the Infectious Dis-
eases Society of America for the treatment of methicillin-resistant
Staphylococcus aureus infections in adults and children. Clin Infect
Dis. 2011;52:e18. (79)
Pappas PG et al. Clinical practice guidelines for the management
of candidiasis: 2009 update by the Infectious Diseases Society of
America. Clin Infect Dis. 2009;48:503. (162)
Sexton DJ et al. Ceftriaxone once daily for four weeks compared
with ceftriaxone plus gentamicin once daily for two weeks for
treatment of endocarditis due to penicillin-susceptible strepto-
cocci. Endocarditis Treatment Consortium Group. Clin Infect Dis.
1998;27:1470. (35)
Wilson W et al. Prevention of infective endocarditis: guide-
lines from the American Heart Association: a guideline from
the American Heart Association Rheumatic Fever, Endocardi-
tis, and Kawasaki Disease Committee, Council on Cardiovascu-
lar Disease in the Young, and the Council on Clinical Cardiol-
ogy, Council on Cardiovascular Surgery and Anesthesia, and the
Quality of Care an Outcomes Research Interdisciplinary Work-
ing Group. American Heart Association [published correction
appears in Circulation. 2007;116:e376]. Circulation. 2007;116:1736.
(204)