TRIPASS XR تري باس

 

Figure 66-1 Janeway lesions. Extensive ecchymotic embolic lesions in a case of acute bacterial endocarditis.

Figure 66-2 Splinter hemorrhages in the nail bed.

Figure 66-3 Petechialskin lesions in a case of acute staphylococcal endocarditis.

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. Leukocytosis

with a left shift, although not evident in A.G., commonly is seen in those with acute,

fulminant disease such as staphylococcal endocarditis. The ESR nearly always is

elevated in IE, but this finding is nonspecific and can be associated with several

other disease entities. RF (an immunoglobulin M antiglobulin) and circulating

immune complexes can be detected in most patients with long-standing disease, but

both are nonspecific findings.

1

Major embolic episodes and infarction involving the kidney, spleen, lung, and

brain may 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. Alterations 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). Erythrocyte and

leukocyte cast formation also may be present. Renal impairment usually is reversible

with the institution of effective antimicrobial therapy.

1

,

10

Cardiac complications occur most frequently. CHF from infection-induced

valvular damage is the most common cause of death in IE and is the most common

indication for surgery.

1

,

10 As many as two-thirds of patients with endocarditis

develop CHF. Aortic valve infection is more frequently associated with CHF than

mitral valve infection. Other manifestations include paravalvular abscesses,

pulmonary edema, and pericarditis.

10 Mitral valve injury caused by viridans

streptococci generally is better tolerated hemodynamically than aortic valve injury

caused by staphylococci. Although A.G. has no apparent signs of overt heart failure,

he should be monitored closely for the development of hemodynamic instability.

Neurologic complications, most commonly stroke, rank second to cardiac

complications in frequency, but they may be the leading cause of death in patients

with endocarditis.

10 A stroke syndrome in a patient with underlying valvular

abnormalities should prompt the clinician to rule out IE. Other clinical manifestations

include headache, mental status change, transient ischemic attack, seizures, brain

abscess, or intracranial mycotic aneurysms.

1

,

10 Neurologic symptoms associated with

high mortality can be observed in up to 35% of S. aureus endocarditis patients who

are not drug addicts.

11

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 Splenomegaly, although not part of

A.G.’s findings, occurs in 20% to 60% of all cases and is more common in subacute

disease.

Diagnosis

CASE 66-1, QUESTION 2: How was the diagnosis of IE established in A.G.?

BLOOD CULTURES

Although A.G.’s medical history (mitral valve prolapse, recent dental procedure) and

clinical presentation are highly suggestive of IE, blood culture is the single most

important diagnostic workup for IE.

1 Bacteremia (when present) secondary to

endocarditis is continuous and low grade; more than 50% of the cultures show only 1

to 30 bacteria/mL. Despite the low concentration of organisms, at least one of the

first two blood cultures is positive in 95% of cases.

1

In order to achieve a high yield,

at least three sets of blood cultures collected by separate venipunctures should be

obtained during the first 24 hours of presentation.

1 Administration of antibiotics

within the previous 2 weeks may significantly decrease this yield.

12

It is also important to establish the exact microbiologic cause before initiating

antimicrobial therapy. In patients who are acutely ill, empiric therapy should start as

soon as the appropriate cultures are obtained to avoid further valvular damage or

other complications.

1

p. 1387

p. 1388

ECHOCARDIOGRAPHY

Echocardiography is a valuable tool in establishing early diagnosis (e.g., the

presence and size of vegetations), identifying patients at high risk for complications,

and optimizing the timing and mode of surgical intervention by detecting and

monitoring associated pathologic changes such as valvular abscess.

1

,

13

,

14 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. Sensitivity 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 invasive, 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, to help guide future

medical management and timing of intervention.

14

In particular, compared with TTE,

TEE is superior in the diagnosis of pacemaker IE and IE in the elderly. 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.

In summary, IE should be suspected in any patient who has a documented fever and

heart murmur and a preceding risk of bacteremia. Prior cardiac disease, peripheral

manifestations, splenomegaly, various laboratory abnormalities, and a positive

echocardiogram strengthen the diagnosis, but microbiologic documentation is the

most important factor in confirming IE. Disease entities with overlapping clinical

presentation and laboratory abnormalities should be excluded using the appropriate

tests.

1

Diagnostic criteria for IE which integrate clinical, laboratory, microbiologic, and

echocardiographic data are listed in Tables 66-1 and 66-2.

7

,

15 Based on published

evidence involving nearly 2,000 patients, the 2015 AHA guidelines suggest that the

modified Duke criteria be used as the primary diagnostic schema to evaluate patients

suspected of IE.

7

Table 66-1

Definition of Infective Endocarditis (IE) According to the Modified Duke

Criteria

Definite IE

a

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 66-2; two major criteria or one major and three minor criteria or five

1.

2.

1.

2.

1.

2.

3.

minor criteria

Possible IE

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 IE at surgery or autopsy, with antibiotic therapy for <4 days; or not meet criteria for

possible IE as above

aModifications 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.

Table 66-2

Definitions of Terminology Used in the Modified Duke Criteria for the Diagnosis

of Infective Endocarditis (IE)

Major Criteria

a

BLOOD CULTURE POSITIVE FOR IE

Typical microorganisms consistent with IE from two separate blood cultures:

Viridans streptococci, Streptococcus bovis, HACEK group; or

Staphylococcus aureus or community-acquired enterococci in the absence of a primary focus; or

Microorganisms consistent with IE from persistently positive blood cultures defined as follows:

At least two positive blood cultures drawn >12 hours apart; or

All of three or a majority of four separate cultures of blood (with first and last sample drawn at least 1

hour apart)

Single positive blood culture for Coxiella burnetii or antiphase 1 IgG antibody titer >1:800

EVIDENCE OF ENDOCARDIAL INVOLVEMENT

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:

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

Abscess; or

New partial dehiscence of prosthetic valve

New valvular regurgitation (worsening or changing of preexisting murmur not sufficient)

Minor Criteria

Predisposition: Predisposing heart condition or IV drug use

Fever >38°C (100.4°F)

Vascular Phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial

hemorrhage, conjunctival hemorrhages, Janeway lesions

Immunologic Phenomena: glomerulonephritis, Osler nodes, Roth spots, RF

Microbiologic Evidence: positive blood culture but not meeting major criterion as noted above

b or serologic

evidence of active infection with organism consistent with IE

Echocardiographic minor criteria eliminated

aModifications shown in bold.

bExcludes 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.

A.G. possesses one major criterion (positive blood cultures) and three minor

criteria (fever, predisposing heart condition, vascular and immunologic phenomena);

therefore, he meets the diagnostic criteria for definite IE.

15

p. 1388

p. 1389

Antimicrobial Therapy

GENERAL PRINCIPLES

CASE 66-1, QUESTION 3: What would be a reasonable duration 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 environment that is devoid of

normal host defenses (e.g., phagocytic cells and complement); this permits

uninhibited growth of bacteria.

2 Therefore, to eradicate the causative organism, high

doses of an IV bactericidal antibiotic generally are administered for 4 to 6 weeks.

1

,

7

For some infections, it may be necessary to use two antibiotics to achieve synergistic

activity against the organism. Once an organism has been identified, its in vitro

susceptibility pattern is determined by the minimum inhibitory concentration (MIC)

for various antibiotics. Standard Kirby-Bauer disk diffusion testing is inadequate in

the setting of IE to aid in selection of antibiotics without the quantitative information

provided by the MIC.

1

In addition, the MBC may be useful in detecting tolerant

strains, particularly in the setting of unexplained slow response or treatment failure.

Routine MBC determination is not recommended, however.

1 Treatment of

endocarditis 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 0.12 mcg/mL

7

; corresponding MBCs

are, at most, one or two tube dilutions higher.

9 The emergence of strains

demonstrating resistance to penicillin and related β-lactams, such as ceftriaxone, is a

significant problem, particularly among bloodstream isolates obtained from the

nosocomial setting and neutropenic cancer patients.

9

,

16

,

17 The increasing prevalence

o f β-lactam-resistant clinical isolates highlights the importance of determining the

MIC and continued close monitoring of the antibiotic susceptibility of viridans

streptococci. An increasing number of reports have described suboptimal response to

vancomycin therapy for the treatment of invasive infection caused by methicillinresistant S. aureus (MRSA) strains showing borderline susceptibility (MIC 2

mcg/mL).

18

,

19 Many such strains demonstrated tolerance to vancomycin as defined by

a high MBC-to-MIC ratio (≥32).

20 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 vancomycin and suboptimal response is observed.

20

REGIMEN SELECTION

CASE 66-1, 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

gallolyticus; MIC <0.1 mcg/mL) can be treated with any one of three regimens as

outlined in the 2015 AHA treatment guidelines.

7 The suggested regimens (Table 66-

3) 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.

7

,

21–27 Ceftriaxone with an aminoglycoside for 2 weeks appears to be

equally effective.

28

,

29

p. 1389

p. 1390

Table 66-3

Suggested Regimens for Therapy of Native Valve Endocarditis Caused by

Streptococcus viridans group and Streptococcus gallolyticus

Antibiotic Dose

a

,

b and Route Duration

Penicillin-Susceptible [minimum inhibitory concentration (MIC) ≤0.12 mcg/mL]

Aqueous crystalline

penicillin G

c

Adult: 12–18 million units/24 hour IV either continuously or in four to six

equally divided doses

4 weeks

Pediatric: 200,000 units/kg/24 hour IV (max: 20 million units/24 hour) either

continuously or in four to six equally divided doses

Ceftriaxone sodium

c Adult: 2 g once daily IV or IM 4 weeks

Pediatric: 100 mg/kg once daily IV or IM

Aqueous crystalline

penicillin G

See penicillin-susceptible dosing for penicillin above 2 weeks

CWeftriaxone sodium See penicillin-susceptible dosing for ceftriaxone above 2 weeks

ith gentamicin

sulfate

d

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

Relatively Penicillin G Resistant (MIC >0.12 mcg/mL and <0.5 mcg/mL)

Aqueous crystalline

penicillin G

Adult: 24 million units/24 hour IV either continuously or in four to six equally

divided doses

4 weeks

Pediatric: 200,000–300,000 units/kg/24 hour IV (max: 20 million units/24 hour)

either continuously or in four to six equally divided doses

With gentamicin

sulfate

d

Adult: 3 mg/kg once daily IV or IM

Pediatric: 3 mg/kg once daily IV or IM or in three equally divided doses

2 weeks

Ceftriaxone sodium Adult: 2 g once daily IV or IM

Pediatric: 100 mg/kg once daily IV or IM

4 weeks

β-Lactam Allergic Patients

Vancomycin

hydrochloride

e

Adult: 30 mg/kg/24 hour IV in two equally divided doses (max: 2 g/24 hour

unless serum concentrations are monitored)

4 weeks

Pediatric: 40 mg/kg/24 hour IV in two or three equally divided doses (max: 2

g/24 hour unless serum concentrations are monitored)

aPediatric doses should not exceed that of a normal adult.

bAntibiotic doses for patients with impaired renal function should be modified appropriately.

cPreferred in most patients >65 years of age and in those with impairment of the eighth nerve or renal function.

dTwo-week regimen not intended for patients with known cardiac or extracardiac abscess or for those with

creatinine clearance of <20 mL/minute, impaired eighth cranial nerve function or Abiotrophia, Granulicatella, or

Gemella infection. Gentamicin nomogram should be used for preferred single daily dosing; when three divided

doses are used, dosage should be adjusted to achieve peak serum concentrations of 3–4 mcg/mL and trough

serum concentrations of <1 mcg/mL. Other potential nephrotoxic drugs should be used with caution in patients

receiving gentamicin therapy.

eVancomycin 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 adjusted 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. 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 in adults: diagnosis, antimicrobial therapy, and management of

complications. A Scientific Statement for Healthcare Professionals from the American Heart Association (AHA);

on behalf of the AHA Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on

Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and

Anesthesia, and Stroke Council: Endorsed by the Infectious Diseases Society of America. Circulation.

2015;132:1435–1486.

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 nonenterococcal streptococcal endocarditis.

23 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.

24 The large

range of 12 to 18 million units/day of penicillin is recommended to allow flexibility

in dosing based on the patient’s renal function and disease severity. Ampicillin 2 g

every four hours is a reasonable alternative.

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 viridans streptococci and 11 strains

o f S. bovis were inhibited at <0.125 mcg/mL of ceftriaxone; one strain of

Streptococcus sanguinis was inhibited at an MIC of 0.25 mcg/mL.

30 Although no

direct comparative trials have been performed evaluating ceftriaxone against highdose penicillin for the treatment of streptococcal endocarditis, it appears to be

comparable to high-dose penicillin when treatment is given for 4 weeks.

31

,

32 Of the

70 assessable patients who received ceftriaxone 2 g as a single daily dose for 4

weeks, all were cured, except for one 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 simplicity 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 66-6, 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) with 4 weeks of

penicillin is synergistically bactericidal for most streptococci, including enterococci

(see Case 66-4, Question 4).

27

,

33 This in vitro synergy also has been correlated with a

more rapid rate of eradication of viridans streptococci from cardiac vegetations in

the rabbit model.

25 A shortened combination regimen consisting of high-dose

penicillin G and streptomycin 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%.

26

,

27

Although clinical experience with combination therapy has been primarily with

penicillin and streptomycin, in vitro and animal data support that streptomycin and

gentamicin are reasonably interchangeable. Administration of gentamicin once daily

versus thrice daily when added to penicillin appears equally effective in the

treatment of viridans streptococcal endocarditis.

21

Combination therapy with ceftriaxone and aminoglycoside for 2 weeks has also

been evaluated.

24

,

28 Clinical cure rates of 87% to 96% were observed in patients

infected with penicillin-susceptible streptococci when given once daily ceftriaxone 2

g plus netilmicin or gentamicin at 3 mg/kg. This study excluded patients with

suspected or documented cardiac or extracardiac abscesses and those with PVE.

Although the aminoglycoside agent (netilmicin or gentamicin) was administered as a

single daily dose in both studies, all of the patients had measurable serum trough

levels. Therefore, the efficacy of “extended-interval dosing” of aminoglycoside

(whereby trough levels are not detectable, allowing a drug-free interval) in shortcourse combination therapy remains uncertain.

Based on available data, the 2-week regimen of penicillin or ceftriaxone plus an

aminoglycoside appears to be efficacious for uncomplicated cases of penicillinsusceptible viridans streptococci endocarditis. It is not currently recommended for

patients with extracardiac complications or intracardiac abscesses. Patients infected

w i t h Abiotrophia species (formerly known as nutritionally variant viridans

streptococci) or viridans streptococci with a penicillin MIC greater than 0.1 mcg/mL

or patients who have prosthetic valve infections should not receive short-course

therapy.

7

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

,

7

,

31 These patients should be treated with 4

to 6 weeks of penicillin combined with an aminoglycoside for the first 2 weeks.

1

,

7

,

31

p. 1390

p. 1391

Nutritionally deficient or variant streptococci (NVS) have been reclassified into a

new genus, Abiotrophia, which includes Abiotrophia defectiva, Abiotrophia

adiacens (renamed again as Granulicatella adiacens), and Abiotrophia elegans.

Abiotrophia species are slow-growing, fastidious organisms that are responsible for

approximately 5% of IE cases.

34 Previously, NVS were 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. Laboratory identification is no longer a significant problem, however,

because of current culture media and laboratory techniques.

9

NVS are less susceptible 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).

9

In addition, tolerance to

penicillin has been described in many strains.

9 An animal model of endocarditis

indicates that a penicillin–aminoglycoside (streptomycin or gentamicin) combination

is significantly better than penicillin alone in reducing bacterial counts.

35 High rates

of bacteriologic failure and relapse may be expected in patients despite completion

of the treatment course for strains highly susceptible to penicillin.

9 All patients

infected with NVS or Abiotrophia should receive 4 to 6 weeks of high-dose

penicillin (or ampicillin) in combination with gentamicin.

7 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 PVE caused by these

strains.

7

,

9 Patients with endocarditis caused by relatively resistant viridans

streptococci with penicillin MIC of greater than 0.5 mcg/mL or enterococci should

receive a similar treatment regimen, as described above.

7

Patients allergic to β-lactams should receive vancomycin 30 mg/kg/day divided

into two doses for 4 to 6 weeks. Although the addition of an aminoglycoside to

vancomycin enhances bactericidal activity in vitro, it is unknown whether the

addition of an aminoglycoside confers any additional clinical benefit.

7 Assuming the

viridans streptococci isolated from A.G. are 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 could be 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 is reasonable. If gentamicin is used, A.G.’s renal

function should be monitored and the dose should be adjusted appropriately if not

using a single daily regimen. Multiple aminoglycoside dosing requires frequent

monitoring for signs of toxicity by taking periodic peak and trough aminoglycoside

concentrations.

STAPHYLOCOCCUS EPIDERMIDIS:

PROSTHETIC VALVE ENDOCARDITIS

Etiology

CASE 66-2

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

month ago for aortic stenosis, mitral regurgitation, and mitral stenosis secondary to rheumatic heart disease.

Two weeks later he was readmitted with fever, a right pleural effusion, a pericardial 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, nausea, 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

PVE. What are the most likely organisms responsible for PVE in F.T.?

PVE is a life-threatening infectious complication of artificial heart valve

implantation that accounts for 7% to 25% of cases of IE in developed countries.

36

,

37

The prevalence of complications resulting in death has been as high as 20% to

40%.

37 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.

36

,

37 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.

36

,

37

The 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. In contrast, streptococci are a more common cause of late PVE (>2

months after surgery).

36

,

37

Nosocomial bacteremia and fungemia in a patient with prosthetic heart valves

contribute to a significant risk for the development of PVE. One study noted that

bacteremia caused by staphylococci and gram-negative bacilli resulted in 55% and

33% of subsequent PVE cases, respectively.

38 Another study observed the

development of PVE in 25% (11 of 44) of patients after nosocomial candidemia.

39

Prophylaxis

CASE 66-2, QUESTION 2: What measures can be taken to prevent early PVE?

The overall frequency of early PVE, despite antibiotic prophylaxis, is 1% to 4%.

40

Complications are severe and include valve dehiscence, acute heart failure,

arrhythmias, and outflow 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. The antimicrobial regimen used most commonly for cardiac surgery

prophylaxis (see Chapter 63, Antimicrobial Prophylaxis 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. Vancomycin could be considered the prophylactic agent of choice for

cardiovascular procedures, including prosthetic valve replacement and implantation

of prosthetic grafts, in the presence of any of the following: (a) documented penicillin

allergy, (b) prior receipt of broad-spectrum antimicrobial therapy and high

likelihood of being colonized with cephalosporin-resistant staphylococci or

p. 1391

p. 1392

enterococci, or (c) performance of the procedure in a center experiencing

outbreaks or a high endemic rate of surgical infection with methicillin-resistant

staphylococci.

41

Antimicrobial Therapy

CASE 66-2, 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 staphylococci that remain sensitive

to β-lactams (<20%), a penicillinase-resistant penicillin (nafcillin or oxacillin) is the

drug of choice (Table 66-4).

42 For the treatment of PVE caused by methicillinresistant, coagulase-negative staphylococci, vancomycin should be used.

42 Most

staphylococci are sensitive to vancomycin at concentrations of 2 mcg/mL or less;

however, strains of staphylococci with intermediate susceptibility to vancomycin

have emerged.

43

,

44 Refer to the IDSA guidelines for vancomycin dosing and drug

level monitoring.

19

The AHA currently recommends the use of triple-drug combination (vancomycin,

gentamicin, and rifampin) therapy for the treatment of PVE caused by methicillinresistant, coagulase-negative staphylococci (MRSE).

7 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.

36

,

37

,

42

p. 1392

p. 1393

Table 66-4

Treatment of Staphylococcal Endocarditis

Antibiotic Dosage and Route Duration

Without Prosthetic Material

a

OXACILLIN/METHICILLIN–SUSCEPTIBLE STAPHYLOCOCCI

NONPENICILLIN-ALLERGIC PATIENTS

Nafcillin or oxacillin Adult: 2 g IV every 4 hours 6 weeks

Pediatric: 150–200 mg/kg/24 hour IV (max: 12 g/24

hour) in four to six equally divided doses

PENICILLIN-ALLERGIC PATIENTS

Cefazolin

d Adult: 2 g IV every 8 hours 6 weeks

Pediatric: 100 mg/kg/24 hour IV (max: 6 g/24 hour) in

equally divided doses every 8 hours

Vancomycin

b

,

e

,

f Adult: 30 mg/kg/24 hour IV in two or four equally

divided doses

(max: 2 g/24 hour unless serum levels monitored)

6 weeks

Pediatric: 40 mg/kg/24 hour IV in two or four equally

divided doses

(max: 2 g/24 hour unless serum levels monitored)

OXACILLIN/METHICILLIN–RESISTANT STAPHYLOCOCCI

Vancomycin

b

,

e

,

f Adult: 30 mg/kg/24 hour IV in two or four equally

divided doses

(max: 2 g/24 hour unless serum levels monitored)

Pediatric: 40 mg/kg/24 hour IV in two or four equally

divided doses

(max: 2 g/24 hour unless serum levels monitored)

6 weeks

With Prosthetic Valve or Other Prosthetic Material

g

OXACILLIN/METHICILLIN–RESISTANT STAPHYLOCOCCI

Vancomycin

b

,

e

,

g Adult: 30 mg/kg/24 hour IV in two or four equally

divided doses

(max: 2 g/24 hour unless serum levels monitored)

Pediatric: 40 mg/kg/24 h IV in two or four equally

divided doses

(max: 2 g/24 h unless serum levels monitored)

≥6 weeks

With rifampin

h Adult: 300 mg IV/PO every 8 hours ≥6 weeks

Pediatric: 20 mg/kg/24 hour PO (max: 900 mg/24 hour)

in three equally divided doses

With gentamicin

b

,

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

OXACILLIN/METHICILLIN–SUSCEPTIBLE STAPHYLOCOCCI

Nafcillin or oxacillin

k Adult: 2 g IV every 4 hours ≥6 weeks

Pediatric: 150–200 mg/kg/24 hour IV (max: 12 g/24

hour) in four to six equally divided doses

With rifampin

h See prosthetic valve dosing for rifampin above ≥6 weeks

With gentamicin

b

,

g

,

i

,

j See prosthetic valve dosing for gentamicin above 2 weeks

aAntibiotic 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.)

bDosing of aminoglycosides and vancomycin on a milligram per kilogram basis will give higher serum

concentrations in obese than in lean patients.

cThe 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.

dThere is potential cross-allergenicity between penicillins and cephalosporins. Cephalosporins should be avoided in

patients with immediate-type hypersensitivity to penicillin.

eTrough serum concentrations should be obtained within half an hour prior to the next dose and should be in the

range of 10 to 15 mcg/mL. (See text for detailed discussion on the need for high trough target of 15 to 20 mcg/mL

for strains with reduced susceptibility to vancomycin. Each vancomycin dose should be infused for 1 hour.)

fVancomycin and gentamicin doses must be modified appropriately in patients with renal failure.

gRifampin 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.

hSerum concentration of gentamicin should be monitored, and the dose should be adjusted to obtain a peak level of

approximately 3 mcg/mL.

iUse during initial 2 weeks. (See text on alternative aminoglycoside therapy for organisms resistant to gentamicin.)

jFirst-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 oxacillin-resistant

staphylococci.

IM, intramuscular; IV, intravenous; PO, orally.

Source: Baddour LM et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of

complications. A Scientific Statement for Healthcare Professionals from the American Heart Association (AHA);

on behalf of the AHA Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on

Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and

Anesthesia, and Stroke Council: Endorsed by the Infectious Diseases Society of America. Circulation.

2015;132:1435–1486.

Although alternative agents such as quinupristin/dalfopristin, linezolid,

daptomycin, telavancin, ceftaroline, dalbavancin, and oritavancin have shown potent

in vitro activity against coagulase-negative staphylococci, clinical experience in the

treatment of IE caused by these strains is lacking.

42

,

45

,

46

STAPHYLOCOCCUS AUREUS ENDOCARDITIS

Intravenous Drug User Versus Nonuser

CASE 66-3

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 border, best heard during inspiration. The chest radiograph 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

[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) [normal, ≤30 mm/minute]

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.

47 The presentation,

pathophysiology, and prognosis of endocarditis in those who acquire the disease

secondary to IV drug use differ from those in nonusers.

1

,

47

,

48 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. 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 leftsided disease 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.

48 Among patients without history

of IV drug use, MRSA was involved in one-third of a cohort of 424 patients with

definite S. aureus IE. Clinical features that characterized MRSA IE were persistent

bacteremia, chronic immunosuppressive therapy, health-care-associated infection, a

presumed intravascular device source, and diabetes mellitus.

6

The prevalence of HIV seropositivity is 40% to 90% among IV drug users with

IE.

47

,

49 HIV-related immunosuppression may be an independent risk factor for the

development of endocarditis.

50

p. 1393

p. 1394

Antimicrobial Therapy

METHICILLIN-SENSITIVE STAPHYLOCOCCUS AUREUS

CASE 66-3, 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 determinant 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 nafcillin or oxacillin.

7

(Table 66-4). Penicillin G rarely is

appropriate because nearly all isolates of S. aureus produce penicillinase. A 6-week

course of therapy with high-dose (12 g/day) nafcillin is the therapy of choice.

51

,

52

Vancomycin may be less efficacious than nafcillin as an antistaphylococcal agent.

7

,

51

IV drug addicts, for the reasons previously identified, have a higher response rate to

appropriate therapy compared with nonaddicts. In one study, 31 addicts were

successfully treated with 16 days of parenteral therapy followed by 26 days of oral

dicloxacillin.

53

Addicts with uncomplicated right-sided endocarditis caused by MSSA have been

treated successfully with a 2-week course of combination therapy with a

penicillinase-resistant penicillin and an aminoglycoside.

54–56

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. 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 infection, or neurologic or systemic embolic complications at either the

initiation or completion of 2 weeks of therapy; (c) no echocardiographically

demonstrable vegetations larger than 2 cm3

; (d) not infected with MRSA; and (e) not

receiving antibiotics other than penicillinase-resistant penicillins, such as firstgeneration cephalosporins and glycopeptides.

7

,

55 HIV-seropositive patients (CD4

counts >300 × 10

6 cells) with tricuspid involvement included in the above studies

also responded favorably to these short-course regimens; thus, a short-course

regimen is an option for T.J.

55

Recent 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 therapy and is associated with increased toxicity. Therefore, the

AHA guidelines do not favor the antibiotic combination anymore. Also, all patients

receiving the short 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 a 4 to 6-week

duration is recommended with any evidence of active disease or complications.

Although response to antibiotic therapy 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 individuals (CD4 cell counts

<200 μL) until more definitive outcome data are available in this subgroup.

47

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 endocarditis. In one small, noncomparative study, 10

addicts were successfully treated with the combination of ciprofloxacin and rifampin

for 4 weeks.

57

,

58 Ciprofloxacin was given IV (400 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.

58

,

59 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

confirmed 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 concern. 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 endocarditis 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.

60 The stability of cefazolin when exposed to

staphylococcal β-lactamase has been proposed as a mechanism for these failures.

61

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., >10

6 organisms).

61