Infections of intracardiac devices.pdf

Infections of intracardiac devices

Adolf W. Karchmer, MDa,b,*,David L. Longworth, MDc,d,e

aDivision of Infectious Diseases, Beth Israel Deaconess Medical Center,

330 Brookline Avenue, Kennedy-6, Boston, MA 02215, USAbHarvard Medical School, 25 Shattuck Street, Boston, MA 02115, USAcDepartment of Infectious Diseases, The Cleveland Clinic Foundation,

Infectious Diseases Section, 9500 Euclid Avenue, Cleveland, OH 44106, USAdCleveland Clinic Foundation Health Sciences Center, The Ohio State University

School of Medicine, Cleveland, OH, USAeSchool of Medicine, Pennsylvania State University, PA, USA

Prosthetic cardiac valves, pacemakers, and implanted defibrillators are

essential to maintain the hemodynamic capacity or electrical integrity of theheart in several cardiac disease states. Severe morbidity and mortality results

when these devices become infected. Treatment of infected cardiac devices is

particularly complex. Eradication of infection involving an implanted for-

eign device often requires removal of the foreign material in conjunction

with antimicrobial therapy. If the device is not essential and if removal does

not entail significant risks, treatment may be simple. Prosthetic valves and

electrophysiologic devices, however, are usually essential for life. Further-

more, removal requires replacement with a functioning device, a procedurethat is associated with morbidity and potential mortality. This article will

address infection of these devices and their treatment.

Prosthetic valve endocarditis

Frequency and risk

The frequency of prosthetic valve endocarditis (PVE) after cardiac sur-

gery is not uniform. The rate is highest during the initial three months aftersurgery, remains high through the sixth month, then declines gradually to a

relatively constant rate of 0.3% to 0.6% at 12 months and thereafter [1–3].

Infect Dis Clin N Am 16 (2002) 477–505

* Corresponding author.

E-mail address: [email protected] (A.W. Karchmer).

0891-5520/02/$ - see front matter � 2002, Elsevier Science (USA). All rights reserved.

PII: S 0 8 9 1 - 5 5 2 0 ( 0 1 ) 0 0 0 0 5 - 8

When valve recipients are followed actively after surgery, the actuarial esti-

mate of the cumulative rate of PVE ranges from 1.0% to 1.4% at 12 months

and from 3.0% to 5.7% at 60 months [1–6] (Table 1). Although conflictingdata have been reported, recent studies have suggested that infection occurs

with similar frequency on valves implanted at the mitral or aortic site [1,3,6].

Additionally, at the end of the initial postoperative year, the rates of infec-

tion involving mechanical valves and bioprosthetic valves (tissue leaflets) are

similar [6–9]. Alternatively, other studies have indicated that the risk of

infection is greater for mechanical valves compared with bioprosthetic

valves during the initial year after valve replacement, but that over time the

risk of infection for bioprosthetic valves increases so that rates are compar-able for the two valve types 5 years after valve surgery [1,3,5,8].

Pathogenesis

The pathogenesis of infective endocarditis is complex. Anatomic and

hemodynamic abnormalities alter endothelial surfaces resulting in the

deposition of platelet–fibrin thrombi. These platelet–fibrin aggregates are

sites at which organisms with unique surface components acting as adhesins

can attach. Some organisms, most notably Staphylococcus aureus, whichuses surface proteins that recognize and bind to adhesive matrix molecules,

can also adhere to apparently normal or minimally traumatized endothelial

surfaces in the absence of preparatory platelet–fibrin thrombi. Adherent

organisms that survive and proliferate in spite of host defenses give rise to

infective endocarditis. The presence of a foreign body (e.g., a prosthetic

heart valve) at the site of infection introduces other major variables. Initi-

ally, the annulus–prosthesis interface is not endothelialized and acts as a for-

mation site for platelet–fibrin thrombi. Exposed sutures anchoring theprosthesis provide pathways whereby organisms can invade cardiac tissue.

Table 1

Estimated cumulative rate of PVE after valve replacement

% patients with PVE

Study (years valves Initial number valve Months after surgery

implanted) recipients 12 24 48 60

Rutledge et al. (1956–81) [6] 1598 1.4 — — 3.2

Ivert et al. (1975–79) [3] 1465 3.0 — 4.1 —

Calderwood et al. (1975–82) [1] 2608 3.1 — 5.4 5.7

Arvay and Lengyel (1981–85) [5] 912 — — — 4.9

Agnihotri et al. (1970–92) [4] 2413a 1.0 1.5 — 3.0

Glower et al. (1975–95) [2] 1119b — — — 3.0

a Aortic position only.b Carpentier-Edwards bioprosthesis only.

Adapted from Karchmer AW. Infections of prosthetic valves and intravascular devices. In:

Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases, 5th

edition. Philadelphia: Churchill Livingstone; 2000. p. 903–17; with permission.

478 A.W. Karchmer, D.L. Longworth / Infect Dis Clin N Am 16 (2002) 477–505

After several years in place, the stress of repetitive motion may alter the sur-

face of leaflets in bioprostheses and allow the deposition of infection-prone

platelet–fibrin thrombi. The foreign material also impairs host defenses in its

immediate microenvironment and alters the behavior of adherent infectingmicroorganisms, rendering them more difficult to eradicate with antimicro-

bial agents. Organisms can reach the prosthesis site either by the hematoge-

neous route (from a remote site) or by direct introduction at the time of

surgery. This grossly oversimplified scenario has been reviewed in detail

[10–12].

The clinical events that contribute to the development of PVE markedly

influence the microbiology, time of symptomatic onset, and, potentially, the

pathology of PVE. Accordingly, understanding and recognizing these eventsis relevant to the management of infected patients. Based on the types

of organisms causing PVE that develop during the first two months after

valve surgery, it appears that many of these episodes are nosocomial. Epide-

miologic and microbiologic studies have linked PVE caused by coagulase-

negative staphylococci—the cause of 31% of PVE cases during the initial

postoperative months—to intra-operative contamination [13–16]. Most

cases of PVE occurring in these clusters became symptomatic within 60 days

after surgery; however, occasional patients presented clinically between 3and 13 months postoperatively. The cases with delayed onset illustrate the

potential for slow evolution from early infection to symptomatic PVE.

Early-onset PVE has been linked to bacteremia arising from invasive mon-

itoring and support devices and surgical wound infections. The frequency of

these events engenders the high rates of PVE noted through the initial six

months after surgery. Furthermore, during these early months after valve

surgery, infection of the prosthesis is more likely to be associated with para-

valvular invasion and hemodynamically significant valve dysfunction[17,18].

While not universally indicative of endocarditis, nosocomial bacteremia

or fungemia occurring in a patient with a prosthetic valve constitutes a risk

for subsequent PVE. Fang et al. noted PVE in 18 of 115 patients (16%) with

nosocomial bacteremia. Of the bacteremias associated with subsequent

PVE, 61% arose from intravascular catheters or skin and wound infections

[19]. Bacteremia due to staphylococci and gram-negative bacilli resulted in

55% and 33% of subsequent PVE, respectively. Although the experience issmall, PVE developed in 6 of 19 patients (31%) with bacteremia due to Staph-

ylococcus epidermidis, 4 of 23 (17%) with S. aureus bacteremia, and 6 of 58

(10%) with gram-negative rod bacteremia. In 12 of the 18 patients with PVE,

the inciting bacteremia occurred within 60 days of surgery; however, the

published data do not allow assessment of risk for PVE following bactere-

mia in the early months after surgery versus later bacteremia [19]. Nasser et

al. examined the consequences of nosocomial candidemia in 44 patients with

prosthetic heart valves [20]. Eleven patients (25%) developed PVE. In 7patients (16%) with a mean of 8.1 days of fungemia, coincident PVE was

479A.W. Karchmer, D.L. Longworth / Infect Dis Clin N Am 16 (2002) 477–505

evident at the time of presentation (median 149 days, range 8–1240 days

after surgery; only 3 within 60 days postoperatively). These patients gener-

ally lacked an identifiable portal of entry for fungemia, and in retrospect hadnot experienced a complicated recovery after surgery. Among the 37

patients without evident PVE at the time of candidemia, 4 (11%) developed

PVE. Blood cultures had been obtained in these 4 patients between days 4

and 36 postoperatively, but PVE was not noted until days 26, 101, 112, and

690. In contrast to those with PVE on presentation, these 37 patients had

definable portals of entry and had experienced long, complicated recoveries

after surgery. Among these 37 patients, the 4 with subsequent PVE had

more sustained fungemia than those who did not develop endocarditis(mean 14.3 days versus 4.3 days). Patients with prosthetic valves who experi-

ence fungemia are at significant risk of either having (those without an iden-

tifiable portal of entry) or developing PVE. In spite of aggressive antifungal

therapy, patients with nosocomial fungemia remain at risk for the develop-

ment of PVE months or years later.

Microbiology

Many and varied organisms, including Coxiella burnetii, Mycoplasma

hominis, many species of bacteria, Tropheryma whippelii, atypical mycobac-

teria, Legionella dumoffii and Legionella pneumophila, and an array of yeasts

and molds have infected prosthetic heart valves. The vast majority of episo-

des, however, are caused by a relatively small number of organisms

(Table 2). From a microbiological perspective, PVE can be divided into

three periods. The origin of infection among those who become sympto-

matic within 60 days of valve surgery (i.e., those with early PVE) is pre-dominantly nosocomial. Accordingly, the major causes of these infections

are organisms commonly associated with intraoperative contamination and

nosocomial infection. With the exception of an increased frequency of cases

caused by S. epidermidis and other species of coagulase-negative staphylo-

cocci, the organisms causing PVE that presents more than 12 months after

cardiac surgery in generally healthy community-residing patients resemble

the causes of native valve endocarditis; the major pathogens are viridans

streptococci, S. aureus, and enterococci. The HACEK group of organisms(Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardio-

bacterium hominis, Eikenella spp, and Kingella spp) cause a small but signifi-

cant number of these late PVE cases. During the period from 2 months to 12

months after surgery the organisms causing PVE are a blend of those

encountered in early and late PVE cases.

The coagulase-negative staphylococci causing PVE vary significantly in

relation to the time of onset of infection after cardiac surgery. Those causing

infection during the initial year after valve surgery are S. epidermidis, andalmost 85% are methicillin-resistant. The coagulase-negative staphylococci

are roughly equally divided between S. epidermidis and non-epidermidis


species after 12 months have elapsed; additionally, only 30% or less of these

isolates are methicillin resistant [1,17,21]. Although the mechanism of methi-

cillin resistance is the same as that in methicillin-resistant (MR) S. aureus,

coagulase-negative staphylococci commonly exhibit heteroresistance, which

makes detection of the MR phenotype more difficult. When initiatingtherapy for coagulase-negative staphylococcal PVE, the organism should

be assumed to be MR until the microbiology laboratory definitively ex-

cludes MR.

Various diphtheroids or Corynebacterium spp, including isolates consis-

tent with the antibiotic-resistant C. jekiem, have caused PVE. Many

diphtheroids are fastidious and difficult to grow and test for antibiotic sus-

ceptibility; however, most isolates are highly susceptible to vancomycin.

Additionally, strains not resistant to gentamicin are killed synergisticallyby the combination of penicillin and gentamicin [22].

Among 270 cases of fungal endocarditis reported from 1965 through

1995, 135 (50%) occurred on prosthetic valves [23]. Candida albicans, fol-

lowed by non-albicans Candida spp and Aspergillus spp, are the most

common fungi that cause PVE [17,24,25]. Occasional cases have been cau-

sed by Cryptococcus neoformans, Histoplasma capsulatum, and a variety of

molds that are uncommon human pathogens. Blood cultures are commonly

Table 2

Organisms causing prosthetic valve endocarditis

Number of cases (%)

Time of onset after valve surgery

Organism

2 mo

N¼ 161

>2–12 mo

N¼ 31

>12 mo

N¼ 194

Streptococcia 5 (3) 3 (9) 61 (31)

Pneumococci — — —

Enterococci 13 (8) 4 (12) 22 (11)

Staphylococcus aureus 36 (22) 4 (12) 34 (18)

Coagulase-negative staphylococci 51 (32) 11 (32) 22 (11)

Fastidious gram-negative

coccobacilli (HACEK group)b— — 11 (6)

Gram-negative bacilli 19 (11) 1 (3) 11 (6)

Fungi, Candida species 12 (7) 4 (12) 3 (1)

Polymicrobial/miscellaneous 4 (2) 2 (6) 9 (5)

Diphtheroids 9 (5) — 5 (3)

Culture negative 7 (7) 2 (6) 16 (8)

a Includes viridans streptococci, Streptococcus bovis, other non-group A, groupable strepto-

cocci, and Abiotrophia species (nutritionally variant streptococci).b Includes Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium

hominis, Eikenella species, and Kingella kingae.

Data from Karchmer AW. Infections of prosthetic valves and intravascular devices. In:

Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases, 5th

edition. Philadelphia: Churchill Livingstone; 2000. p. 903–17; and Karchmer AW. Infective

endocarditis. In: Braunwald E, editor. A textbook of cardiovascular medicine. Philadelphia:

W.B. Saunders Company; 2000.


positive in patients with PVE caused by Candida spp or C. neoformans,

whereas blood cultures are often negative when PVE is caused by other

fungi. In the latter circumstance, cultures and microscopic examination ofvegetation recovered at cardiac surgery or embolized peripherally may be

needed to establish a microbiologic diagnosis.

Although a rare cause of endocarditis in the United States, C. burnetii is

an important cause of PVE in regions where Q fever is endemic. Among 229

episodes of C. burnetii endocarditis diagnosed between 1985 and 1998, 157

(69%) involved prosthetic valves [26].

Pathology

Infection involving prosthetic valves commonly invades paravalvular tis-

sue, resulting in abscess formation or valve dehiscence, and occasionally

affects the valve orifice directly, resulting in either regurgitation or stenosis

[17,27–31]. Extension of infection through the aortic valve annulus maycause pericarditis, and invasion of the membranous portion of the interven-

tricular septum may disrupt the conduction system and cause various forms

of heart block [27,28,31,32]. Annulus invasion and myocardial abscess were

noted at surgery or autopsy in 42% and 14%, respectively, of 85 patients

with mechanical valve endocarditis [15,30]. Ismail et al. noted annulus inva-

sion and valve dehiscence in 82% of 41 patients with mechanical valve infec-

tion [29]. With bioprosthetic valve infection, especially that occurring within

the initial postoperative year, invasion into and beyond the annulus hasbeen reported in 36% to 54% of cases [17,33,34]. Among patients with PVE

treated surgically, Lytle et al. noted that infection invaded paravalvular tis-

sue in 43 of 54 (79%) mechanical valves and 37 of 90 (41%) bioprosthetic

valve infections [18]. In addition, Lytle et al. reported that invasion was

common among patients with mechanical valve endocarditis regardless of

time of onset, whereas among patients with bioprosthetic valve infection

invasive disease was more common among those with onset during the initi-

al year after valve replacement (15 of 18, 83%) versus those with later onsetinfection (22 of 71, 31%) [18]. Infection involving the leaflets of bioprosthetic

valves can result in perforation and tears with regurgitation, bulky vegeta-

tions can cause stenosis, and after infection has been cured, delayed leaflet

stiffening also can result in stenosis [34,35].

Clinical and laboratory manifestations

The clinical and laboratory features of PVE are similar to those encoun-

tered in patients with native valve endocarditis [36]. When PVE presents dur-

ing the early postoperative period, the subtle and time-dependent signs of

endocarditis may be absent or masked by complications of surgery. The high

frequency of paravalvular invasion infection in patients with PVE, especiallyin those with aortic valve infection during the initial postoperative year,

results in a higher frequency of new or changing regurgitant murmurs,


congestive heart failure, persistent fever in spite of optimal antimicrobial

therapy, and new electrocardiographic conduction disturbances than is

encountered with native valve endocarditis [17,37]. Almost 40% of patients

experience clinically apparent systemic emboli; 20% to 40% experience stroke,central nervous system hemorrhage, or neurologic complications [29,38,39].

Unless antibiotics have been administered recently, blood cultures will be

positive in 90% of patients with PVE, and multiple cultures obtained inde-

pendently over time will be positive (persistent bacteremia). When dealing

with blood cultures yielding coagulase-negative staphylococci or diphther-

oids (organisms that often contaminate cultures), persistent bacteremia

helps to distinguish patients with PVE. Although polyclonal coagulase-

negative staphylococcal endocarditis has been reported, this is unusual, andusing molecular techniques to demonstrate clonality among sporadic coagu-

lase-negative staphylococci in blood cultures obtained from patients with

prosthetic valves is also suggestive of PVE rather than contamination [40,41].

Occasionally, patients with PVE who have not received antibiotics re-

cently will have persistently negative blood cultures. These cases are cau-

sed by fastidious microorganisms, for example, Legionella spp, C. burnetii,

M. hominis, Bartonella spp, atypical mycobacteria, and fungi other than

Candida spp (particularly molds). Special blood culture, techniques, serologictests (antigen or antibody detection), and, when possible, culture, micro-

scopic, andmolecular analysis of vegetationmay facilitate making a diagnosis

in these cases [42].

Transthoracic echocardiography (TTE) and transesophageal echocardio-

graphy (TEE) using biplane or multiplanar transducers that allow continu-

ous wave, pulse-wave Doppler, and color-flow imaging are essential for the

diagnosis and management of PVE [43,44]. Together the two approaches

provide optimal imaging of prostheses in the aortic, mitral, and tricuspidpositions. TEE is superior to TTE when imaging a mitral valve prosthesis.

Although TTE and TEE are complimentary, TEE is more sensitive without

loss of specificity for the diagnosis of PVE than is TTE (82% to 96% versus

17% to 36%) regardless of prosthesis type or anatomic position (Table 3)

[43–47]. Additionally, TEE is also superior to TTE for detecting paravalvu-

lar abscesses, fistulae, and paraprosthetic leaks—intracardiac complications

that have a major impact on management strategy [48]. The negative predic-

tive value of a single TEE in a patient with suspected PVE is 86% to 94%[46,49]. However, if PVE is strongly suspected in a patient with negative

TEE, the study should be repeated. Although a repeat TEE may provide

diagnostic evidence of PVE, a second negative study does not exclude PVE

in the face of strong clinical evidence [49].

Diagnosis

The diagnosis of PVE requires a high index of suspicion, knowledge ofthe subtle signs of endocarditis, obtaining 3 or 4 blood cultures prior to the


administration of antibiotics, and full echocardiographic assessment. The

Duke criteria for the diagnosis of endocarditis provide a systematic

approach to evaluating patients with suspected PVE [50]. In three studies

of pathologically confirmed PVE, retrospective application of the Duke cri-

teria classified 76% to 79% of patients as definite and 21% to 24% as possibleendocarditis [51–53]. Although a significant number of patients were not

assessed by TEE, the diagnosis of PVE was erroneously rejected in only 1

of 118 patients. The importance of TEE evaluation in the diagnosis of PVE

was examined by Roe et al. [54]. Among 34 patients with prosthetic heart

valves and suspected endocarditis, the classification of 13 (38%) was changed

when the assessment included TEE data versus when only TTE findings were

used; 11 were reclassified from possible to definite and 2 from rejected to

possible. The positive predictive value of a TEE for PVE was 89%. The TEEcan be negative in patients with PVE; in the diagnosis of PVE a negative

TEE should never override strong clinical evidence of endocarditis [49,54].

Antimicrobial treatment

Effective therapy for PVE requires identification of the microbial cause,

determination of a bactericidal regimen of proven efficacy, an understanding

of the intracardiac pathology of PVE and its implications for valve replace-

ment, and effective management of extracardiac complications. The com-

plexity of evaluation and treatment suggests that patients should be

hospitalized in centers with experience in treating PVE. It is essential to iso-

late the causative organism. When evaluating patients who present withindolent disease and are hemodynamically stable, antibiotic therapy should

be delayed for 2 or 3 days awaiting the results of blood cultures. This is par-

ticularly important if antibiotics have been administered recently, because if

initial cultures are negative, it allows one to obtain additional cultures with-

out further confounding. Patients who present with fulminant PVE or who

are hemodynamically unstable and may require urgent replacement of the

Table 3

Echocardiography in the diagnosis of PVEa

Number of valves (%)

Prosthesis type and position Transthoracic Transesophageal

(number studied) Non-diagnostic Diagnostic Non-diagnostic Diagnostic

Aortic position (34) 16 18 (53) 5 29 (85)

Bioprosthesis (12) 6 6 (50) 1 11 (92)

Mechanical valve (22) 10 12 (55) 4 18 (82)

Mitral position (37) 32 5 (14) 4 33 (89)

Bioprosthesis (10) 8 2 (25) 2 8 (80)

Mechanical valve (27) 24 3 (11) 2 25 (93)

a Patients had pathoanatomic or clinically confirmed (Von Reyn criteria) PVE.

Data from Refs. [36,45,46].


infected prosthetic valve should be treated empirically immediately after

obtaining blood cultures.

Although administered for a longer duration, the antimicrobial therapy

recommended for the treatment of PVE caused by specific organisms, withthe exception of staphylococci, is similar to that used to treat native valve

endocarditis (Table 4). Detailed comments regarding these regimens can

be found elsewhere [17,36,55]. If streptomycin or gentamicin is to be com-

bined with a cell wall active antibiotic to achieve synergistic killing of strep-

tococci or enterococci, the organism must not exhibit high-level resistance to

the selected aminoglycoside (i.e., unable to grow in the presence of 500 lg/mL of gentamicin or 1000 lg/mL of streptomycin). The presence of high-

level resistance precludes a synergistic effect from the respective aminoglyco-side. Gentamicin high-level resistance also generally precludes a synergistic

effect from netilmicin, kanamycin, tobramycin, and amikacin. Optimal ther-

apy for PVE caused by vancomycin-resistant Enterococcus faecium (VREF)

that are also resistant to penicillin and ampicillin and highly resistant to

streptomycin and gentamicin has not been established. Although linezolid

and quinupristin–dalfopristin are often active against VREF, these agents

have not been proven to be effective therapy for PVE. Surgical intervention

during suppressive antimicrobial therapy should be considered for thesepatients.

For optimal treatment of staphylococcal PVE, a multi-drug regimen is

recommended. In vitro data, evidence from animal models, and clinical

experience indicate that rifampin has a unique ability to kill staphylococci

adherent to foreign material and is an important component of regimens

used to treat staphylococcal PVE [17,21,56–60]. Staphylococci have a rela-

tively high intrinsic mutation rate for the gene controlling the site of rifam-

pin action; thus when relatively large populations of staphylococci areexposed to rifampin, selection of rifampin-resistant organisms is common.

To prevent the emergence of rifampin-resistant organisms, the regimens

selected for the treatment of staphylococcal PVE should contain two anti-

biotics that are known to be active against the staphylococcal isolate in

addition to rifampin. All three antimicrobials can be started at the same

time. If two additional anti-staphylococcal agents have not been identified,

treatment with a single anti-staphylococcal agent should be administered for

3 to 5 days before beginning rifampin. This approach may reduce the totalnumber of staphylococci and thus diminish the probability that a rifampin-

resistant subpopulation will emerge.

The regimens recommended for the treatment of staphylococcal PVE are

not based on the species of the isolate—S. aureus or coagulase-negative

staphylococci—but rather upon susceptibility of the isolate to methicillin.

For isolates that are susceptible to gentamicin, it is an effective second

anti-staphylococcal antimicrobial. For strains resistant to gentamicin and

other aminoglycosides, a fluoroquinolone to which the strain is highly sus-ceptible should be considered [57,60].


Table

4

Recommended

antibiotictherapyforpatients

withPVE

Infectingorganism

Antibiotic

Dose

androute

a

Duration

(wk)

Comments

1.Penicillin-susceptible

viridansstreptococci,

Streptococcusbovis,

andother

streptococci

(penicillinMIC

£0.1

lg/m

L)

A.PenicillinG

plus

gentamicin

18–24millionunitsIV

dailyin

divided

dosesq4h

1mg/kgIM

orIV

q8h

6 2

Mayomitaminoglycoside

when

potentialfornephrotoxicity

isincreased

B.Ceftriaxoneplus

gentamicin

2gIV

orIM

daily

assingle

dose

1mg/kgIM

orIV

q8h

6 2

Canbeusedin

patients

withnon-immediate

penicillinallergy.

Intramuscularceftriaxoneispainful.

Cephapirin

2gIV

q4hcanbe

substitutedforceftriaxone.

C.Vancomycinb

15mg/kgIV

q12h

6Use

forpatients

withim

mediate

orseverepenicillinorcephalosporinallergy.

Infuse

dosesover

1hourto

avoid

histaminerelease

reaction(redmansyndrome).

2.Relativelypenicillin-resistant

streptococci(penicillinMIC

>0.2

lg/m

L)

A.PenicillinG

plus


dailyin

divided

dosesq4h

6Preferred

fornutritionallyvariant

(pridoxal-orcysteine-requiring)

streptococci(A

biotrophia

spp).

gentamicin

1mg/kgIM

orIV

q8h

4

3.Enterococci(invitro

evaluationforMIC

topenicillinandvancomycin,

b-lactamase

production,

andhigh-level

resistance

togentamicin

and

streptomycinrequired)

A.PenicillinG

plus

gentamicin


dailyin

divided

dosesq4h

1mg/kgIV

orIM

q8h

6 6

Streptomycincanbeusedinstead

ofgentamicin

ifstreptomycinhigh-level

resistance

isnotpresent.If

high-level

resistance

togentamicin

butnotto

streptomycinisdetected,streptomycin

ispreferred.


B.Ampicillinplus

gentamicin

2gIV

q4h

6

Samedose

asnotedabove

6

C.Vancomycinbplus

gentamicin

15mg/kgIV

q12h

Samedose

asnotedabove

6 6

Use

forpatients

withpenicillinallergy.

Donotuse

cephalosporins.

4.Staphylococci

methicillin-susceptible

(assumepenicillinresistance)

A.Nafcillinoroxacillin

plusgentamicin

plusrifampin

c

2gIV

q4h

1mg/kgIV

orIM

q8h

300mgpoq8h

6–8

2 6–8

Penicillin18–24millionunitsdailyin

divided

dosesq4hcanbeusedinsteadofnafcillin

oroxacillin

ifstrainsdonotproduce

b-lactamase

andpenicillinMIC

is£0

.1lg

/mL.

Cephapirin

2gm

IVq4hcanbeused

inlieu

ofnafcillin/oxacillin

forpatients

withnon-immediate

allergyto

penicillins.

Use

gentamicin

duringinitialtw

oweeks.

See

textforalternatesforgentamicin.

Forpatients

withim

mediate

penicillinallergy,

use

regim

en5.

5.Staphylococci

methicillin-resistant

A.Vancomycinbplus

gentamicin

plusrifampin

c

15mg/kgIV

q12h

1mg/kgIV

orIM

q8h

300mgpoq8h

6–8

2 6–8

Use

gentamicin

duringtheinitialtw

o

weeksoftherapy.See

textforalternatives

togentamicin.Donotsubstitute

acephalosporinorim

ipenem

forvancomycin.

6.HACEK

organismsd

A.Ceftriaxone

2gIV

orIM

daily

asasingle

dose

6Cefotaxim

eorother

thirdgeneration

cephalosporinin

comparable

doses

maybeused.

B.Ampicillinplus

gentamicin

2gIV

dailyin

divided

dosesq4h

1mg/kgIV

orIM

q8h

6 4

Testorganism

forb-lactamase

production.

Donotuse

thisregim

en

ifb-lactamase

isproduced.

(continued

onnextpage)


Table

4

(continued

)

InfectingOrganism

Antibiotic

Dose

andRoute

a

Duration

(wk)

Comments

7.Diphtheroids

A.PenicillinG

plus


dailyin

divided

dosesq4h

6Bactericidalsynergyresultsifisolate

isnotresistantto

gentamicin

(MIC

‡4lg/m

L).

gentamicin

1mg/kgIM

orIV

q8h

6

B.Vancomycin

15mg/kgIV

q12h

6Use

iforganism

resistant

togentamicin,

highly

resistantto

penicillin,

orpatientisallergic

topenicillin.

aRecommended

dosesare

foradultswithnorm

alrenalandhepaticfunction.Dosesofgentamicin,streptomycin,andvancomycinmust

beadjusted

in

patientswithrenaldysfunction.Use

idealbodyweightto

calculate

doses(m

en¼50kg+2.3

kgper

inover

5ft;women

¼45.5

kgplus2.3

kgper

inover

5ft).

Donotuse

aminoglycosides

assingle

dailydoses.

bPeaklevelsobtained

1hourafter

completionoftheinfusionshould

be30–45lg

/mLtroughlevel

10–20lg

/mL.

cRifampin

increasesthedose

ofwarfarinordicumarolrequired

foreffectiveanticoagulation.

dHACEK

organismsincludeHaem

ophilusparainfluenzae,

Haem

ophilusaphrophilus,

Actinobacillusactinomycetemcomitans,

Cardiobacterium

hominis,

Eikenella

corrodens,andKingella

kingii.

Adaptedfrom

Karchmer

AW.Infectionsofprosthetic

valves

andintravasculardevices.In:MandellGL,BennettJE

,DolinR,editors.Principlesand

practiceofinfectiousdiseases,5th

edition.Philadelphia:ChurchillLivingstone;

2000.p.903–17;withpermission.


For fungal PVE, amphotericin B (0.7 to 1.0 mg/kg/d) is recommended;

larger doses (1.0 to 1.5 mg/kg/d) are recommended for treatment of PVE

caused by molds (e.g., Aspergillus spp). A synergistic effect is often sought

by combining amphotericin B with 5-fluorocytosine (150 mg/kg/d dividedinto 4 doses with adjustments for renal dysfunction). The role of liposomal

formulations of amphotericin B or caspofugin in the treatment of PVE has

not been established. Early surgical intervention is considered a standard

element of treating fungal PVE [23–25]. As a result of the high rate of

relapse of candida PVE, initial therapy is often followed by long-term or

indefinite suppressive therapy with fluconazole (200 to 400 mg orally per

day) [24,25,61].

Surgical management

Murmurs suggesting valve dysfunction, moderate to severe congestive

heart failure due to valve dysfunction, fever for 10 or more days in spite

of appropriate antibiotic therapy, new onset electrocardiographic conduc-

tion abnormalities, or selected findings on echocardiogram identifies compli-

cated PVE with extension of infection into paravalvular tissue or valve

dysfunction. PVE with one or more of these features is not likely to respondto antibiotic therapy alone [37,62,63]. Complicated PVE is more common

with infection of aortic valve prostheses and with infection during the initial

year after valve surgery [37]. Antibiotic therapy combined with valve repla-

cement and cardiac reconstruction results in higher survival rates and fewer

relapses, rehospitalizations for valve surgery, and late endocarditis-related

mortality than does treatment with antibiotics alone in patients with compli-

cated PVE [37,63–65].

Indications for surgical treatment of PVE have been developed step-wiseas the pathology of PVE was defined, surgical techniques were refined, and

the presumed inevitability of recurrent PVE involving the newly implanted

prosthesis was disproven. The indications (see box on following page) are

not absolute and must be implemented with a careful risk–benefit analysis.

Notably, patients with late-onset PVE caused by viridans streptococci,

HACEK, or enterococci and without evidence of paravalvular invasion or

valve dysfunction can be treated successfully with antibiotics alone [17].

Survival rates among PVE patients with moderate to severe congestiveheart failure due to valve dysfunction are dramatically improved if these

patients are treated surgically. Only occasional patients in this group will

survive if treated with antibiotics alone. In contrast, 44% to 64% survive

when treated with antimicrobials plus valve replacement [17,63,66]. If out-

come is to be optimal, surgical intervention to correct valve dysfunction

must be performed before intractable heart failure ensures. There is no

evidence that delaying surgery in the face of progressive hemodynamic

deterioration in order to administer additional antibiotics improves out-come or reduces the frequency of recurrent endocarditis [33,67]. In fact,


postoperative mortality is proportional to the severity of hemodynamic

impairment at the time of surgery [33,68]. Occasionally, patients with PVE

who have responded to antibiotics develop valve dysfunction but remain

hemodynamically compensated. Surgery can be delayed until late in the

course of antimicrobial therapy in these patients.

Even in the absence of heart failure, mortality rates are high for patients

with paravalvular invasion when they are treated with antibiotics alone. Incontrast, complex reconstructive surgery in these patients has been associa-

ted with survival rates of 80% [64,69,70]. Relapse of PVE after optimal anti-

microbial therapy commonly reflects unrecognized invasive disease. These

patients should be treated with antibiotics plus surgery [37,62].

The outcome of S. aureus PVE is improved by aggressive surgical inter-

vention. When treated with antibiotics alone, 70% of patients with S. aureus

PVE die [71–73]. Intracardiac complications in patients with S. aureus PVE

are associated with a 13.7-fold increase in mortality; however, mortality isreduced 20-fold (OR 0.05, 95% CI: 0.005–0.42; P¼ 0.004) by surgical inter-

vention during antimicrobial therapy [51]. In fact, improved survival with

Indications for cardiac surgery in patients with PVEa

• Moderate to severe congestive heart failure due to valvedysfunction (regurgitant or stenotic)

• Unstable prosthesis• Paravalvular extension of infection, especially with abscessformation or fistula

• Uncontrolled infection (persistent bacteremia) on optimalantimicrobial therapy

• PVE caused by selected microorganisms�fungi�P. aeruginosa�S. aureus�enterococci in the absence of available bactericidaltherapy

�other gram-negative bacilli and microorganisms thatusually require surgery when infecting native valves(e.g., Brucella spp, Coxiella burnetii)

Relapse after optimal therapyLarge (>10 mm) hypermobile vegetationsCulture negative PVE with unexplained persistent (‡10 days)

fever

a Not all indications are absolute (see text)Adapted from Karchmer AW. Infections of prosthetic valves and intravascular

devices. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice ofinfectious diseases. New York: Churchill Livingstone; in press.


antibiotics plus surgical treatment versus antibiotics alone was noted among

both those with and without intracardiac complication. Multiple studies

have suggested that PVE caused by S. aureus is treated most effectively with

antibiotics plus aggressive cardiac surgery [63,72–74].The role of surgical intervention to prevent systemic emboli is unclear.

Patients with native valve endocarditis who have vegetations >10 mm in dia-

meter experience a higher rate of embolic complications than do patients

with smaller vegetations [75]. Although data are not available correlating

vegetation size with arterial emboli in patients with PVE, the overall rates

of embolic events are similar in patients with infection of native and prosthe-

tic heart valves. Furthermore, these rates decrease rapidly with effective anti-

biotic therapy. While it is desirable to prevent emboli to vital organs, it isnot clear that mortality and morbidity are reduced by cardiac surgery in

PVE patients simply because vegetations >10 mm in diameter are detected.

The decision to operate in this situation must be made in the context of an

overall clinical evaluation and integrated plan for therapy rather than on

vegetation size alone.

An optimal outcome for patients with PVE often requires complex recon-

struction of the aortic or mitral valve and the supporting or adjacent tissue.

With appropriate antibiotic therapy and surgical intervention by experi-enced cardiac surgeons, survival rates for patients with complicated PVE

range from 70% to 90% [18,64,69,70,76–79]. These remarkable results sup-

port the concept that—when possible—patients with PVE complicated by

extensive invasion and tissue disruption should undergo surgery in centers

with extensive experience.

The long-term results of surgical treatment of PVE are also encouraging.

Recurrent PVE is noted in only 6% to 15% of patients, and repeat cardiac

surgery for either recrudescent PVE or dysfunction of the newly implantedvalve is required in 18% to 26% [18,33,37,64,70,77,79]. Survival rates 5 years

after surgery for PVE have ranged from 54% to 87% [18,33,70,76,77].

Anticoagulant therapy

The use and specific type (heparin versus warfarin) of anticoagulant ther-

apy in patients with active PVE is controversial [80–84]. Cerebrovascular

accidents were reported in 16 of 133 patients (12%) with mechanical valveinfection who were effectively anticoagulated versus 32 of 76 patients (42%)

who were not anticoagulated. Additionally, hemorrhagic complications

were not increased among those who were anticoagulated [80]. Accordingly,

carefully monitored anticoagulant therapy is recommended for patients with

infected mechanical or bioprosthetic valves when this therapy would be used

routinely in the absence of infection. The authors prefer warfarin and

suggest the International Normalized Ratio (INR) be maintained between

2.5 and 3.0. If intracerebral hemorrhage or another contraindication toanticoagulant therapy is noted, anticoagulation should be reversed. Because


rifampin accelerates the hepatic clearance of warfarin, patients being treated

for PVE with rifampin require major adjustments in daily warfarin doses

during and following rifampin therapy.

Infections involving implantable electrophysiologic cardiac devices

Cardiac pacemakers and implantable cardioverter defibrillators haverevolutionized the treatment of patients with rhythm disorders, and their use

has become increasingly common in clinical practice. It is estimated that, as

of April 1999, there are approximately 180,000 functioning implantable car-

diac defibrillators and 3.25 million permanent pacemakers presently in use

worldwide [85]. The rates of infectious complications involving these devices

have decreased in recent years with improvements in surgical techniques and

with the development of transvenous devices. Nevertheless, infection rates

remain in the range of 1% to 7% [85–89]. With the burgeoning number ofdevices implanted, infections involving them are increasingly encountered

in clinical practice.

Anatomy, pathogenesis, and classification

Most permanent pacemakers and cardiac defibrillator devices presently

in use are transvenous devices. They consist of a generator or defibrillator

implanted in the subcutaneous tissue of the chest wall or abdomen, and elec-

trodes which traverse the soft tissue, enter the subclavian vein, pass through

the right heart, and terminate in the right atrial and ventricular endocar-

dium. Depending on the type of device, some patients with transvenous car-

diac defibrillators may have a mesh defibrillator patch positioned in thesubcutaneous tissue in the left mid or posterior axilllary area. In over 98%

of patients, the current cardioverter–defibrillator systems are completely

transvenous. In the early years of cardiac pacing and cardiodefibrillator

technology, electrodes and mesh defibrillator patches were placed by way

of thoractomy or sternotomy directly onto the epicardial surface of the

heart. Some patients still have these devices in place. The development of

transvenous devices—especially cardioverter defibrillators and combination

devices that serve both pacing and defibrillating functions—represents animportant advance in the field, given the reduced morbidity associated with

their implantation.

Infections involving these devices have traditionally been classified ana-

tomically and by time of onset following implantation. Infection may

involve the generator or debrillator pocket (Fig. 1), the electrodes as they

traverse the soft tissue and venous system or track to the epicardium in older

devices, mesh patches in the subcutaneous tissue or on the surface of the

heart, and valvular or nonvalvular endocardium. Deep endovascular infec-tion may involve the tricuspid valve, the insertion site of the lead tip in the

right atrium or ventricle and, on occasion, thrombi that form around the


electrodes in the venous system or right atrium (Fig. 2) [90]. Myocardial

abscesses are rare but have been described [90]. Early infection is classified

as infection developing in the first month following implantation; late infec-

tion presents beyond the first month [85,91]. Some studies have further clas-

sified this latter group into those presenting from months 1 to 12 afterimplantation (‘‘late infection’’) versus those presenting beyond one year

(‘‘delayed infection’’) [85].

Several pathogenetic mechanisms contribute to the development of infec-

tion involving these devices. Early infection most often arises from intrao-

perative contamination at the time of device implantation or generator

exchange and is attributable to direct microbial seeding of the device or

pocket. Late infection occasionally develops from primary mechanical ero-

sion of the generator or defibrillator through the skin, with resultant seedingof the pocket. In other cases, chronic smoldering infection in the pocket pro-

duces a thinning of the overlying tissue and ultimately device erosion.

Whichever mechanism occurs, infection may spread from the pocket to

involve the electrodes and ultimately the endocardial surfaces of the heart.

Hematogenous seeding of the device from distant sites of infection has been

reported, but with the exception of S. aureus bacteremia appears to be rela-

tively rare [90,92,93]. In one study of 21 patients with S. aureus bacteremia

occurring a year or more after device placement, 29% developed a subse-quent device infection [94].

Fig. 1. ‘‘Pocket infection’’: Erythematous discoloration of the skin overlying an infected pocket

in a patient’s left chest wall, containing an implantable cardioverter–defibrillator. (Courtesy of

Bruce Wilkoff, MD.)


Epidemiology and risk factors

A number of studies have examined risk factors associated with the devel-

opment of infections involving these devices. Underlying conditions that

predispose patients to pacemaker-related infections include malnutrition,malignancy, diabetes mellitus, skin disorders, and the use of corticosteroids,

other immunosuppressive agents, or anticoagulants [92,95,96]. Prolonged

operation, re-operation, generator replacement, catheter-related bacteremia,

sternal wound infections, and diabetes mellitus are risk factors associated

with the development of cardiodefibrillator-associated infections [97,98].

In the largest recent review of infections associated with these devices in

123 patients treated at the Cleveland Clinic Foundation, comorbid condi-

tions were common and included coronary artery disease in 64%, coronaryartery bypass surgery in 32%, diabetes mellitus in 26%, anticoagulation

in 19%, atrial fibrillation in 19%, malignancy in 6%, corticosteroid use in

5%, and hemodialysis in 2% [85].

The timing, route, and location of implantable cardiodefibrillator place-

ment have been associated with the risk of subsequent infection. In one

recent study, infectious complications fell from 16.7% to zero coincident

with an increase in transvenous device placement and with the elimination

of two staged procedures in which electrophysiologic studies performed inthe cardiac catheterization laboratories were followed within hours to days

by the placement of defibrillator devices in the operating room by cardiac

Fig. 2. Implantable cardioverter–defibrillator lead with a large, attached, infected vegetation.

Adjacent to the lead is a large, infected embolus that was removed from the pulmonary artery of

the patient from whom this infected device was extracted. (Courtesy of Bruce Wilkoff, MD.)


surgeons [88]. In recent years, electrophysiologic studies have been followed

immediately by pacemaker or defibrillator placement in the cardiac catheter-

ization laboratory or in the operating room for patients requiring these

devices.

Microbiology

Numerous studies have examined the microbiology of these infections[85,87,89,91,93,99–105]. In nearly all series, the majority of infections are

caused by staphylococci, including S. aureus and coagulase-negative staphy-

lococci. Some studies have suggested that infections occurring within the

first month following implantation are more likely due to S. aureus, and late

infections are more commonly caused by coagulase-negative staphylococci.

This is likely attributable to the fact that many late infections arise from

mechanical erosion of the device through the skin, resulting in contamina-

tion of the pocket with skin flora. Less common isolates include enterococci,Peptostreptococcus spp, Propionibacterium acnes, micrococcus, and gram-

negative bacilli such as E. coli, and Enterobacter, Serratia, Pseudomonas,

and Klebsiella species. Mycobacterium avium-intracellulare and fungal

pathogens such as Candida spp, Torulopsis glabrata and Aspergillus spp have

been implicated on rare occasion [106–108].

In the most recent series from the Cleveland Clinic, which evaluated 123

patients with infected pacemakers (87) or cardioverter defibrillators (36), the

most common pathogens were coagulase-negative staphylococci (68%),S. aureus (24%), and enteric gram-negative bacilli (17%). Thirteen percent

of infections were polymicrobial. The distribution of pathogens was similar

between infected pacemakers and cardioverter–defibrillators.

Clinical presentation

The clinical presentation of these infections is highly variable, both with

regard to time of onset and clinical severity. In the series by Chua et al., 25%

of infections occurred within the first month, 33% presented late (days

29–364), and 42% were delayed, presenting beyond 1 year [28]. Clinical man-

ifestations in patients from this series are summarized in Table 5 in descend-

ing order of frequency and are consistent with earlier reports [87,98].

Several points merit emphasis. Eighty-five patients (69%) presented withsymptoms localized to the device pocket, including erythema (55%), pain

(55%), a draining sinus (42%), erosion (32%), and warmth (23%). Twenty-

five patients (20%) presented with a combination of local and systemic

symptoms, and thirteen (11%) presented with systemic complaints alone.

Overall, a history of fever was present in only 29%, and was documented

in only 19%. The frequent absence of fever in patients with these infections

has been emphasized by other researchers [98]. Despite the absence of

documented fever in over 80% of patients in the Cleveland Clinic series, bac-teremia was surprisingly common and occurred in one-third of patients.


Among the 40 patients with bacteremia, fever and systemic symptoms were

absent in 16 (40%). Clinicians must therefore have a high index of suspicion

for bacteremia, even in patients who lack fever and systemic signs of infec-

tion. Blood cultures are indicated in all patients with suspected or proveninfections of these devices. The possibility of cryptic device infection, includ-

ing infection limited to the generator pocket, must be considered in patients

with staphylococcal bacteremia. Additionally, occurrence of pulmonary

emboli (Fig. 2) can provide a clue that an intracardiac lead has become

infected, especially if a chest radiography shows multiple focal infiltrates,

indicating the likelihood of septic emboli.

Some studies confined to the analysis of patients with pacemaker endo-

carditis have reported fever in up to 86% to 91% of patients and chills inup to 75% [99,101]. In a review of 44 cases from Israel, a new or changing

murmur was present in 13%, leukocytosis exceeding 10 · 109/L in 66%, sple-nomegaly in 11%, anemia in 39%, and microscopic hematuria in 59% [99].

Several studies have examined the role of echocardiography in the diag-

nosis of implantable cardiac device infections. In the Cleveland Clinic study,

64 of 123 patients had transthoracic (45), transesophageal (8), or both (11)

echocardiographic procedures performed. Vegetations involving the device

leads or a valve were present in 13 patients, 12 with a pacemaker, and 1 witha cardioverter–defibrillator. In three other studies confined to patients with

proven pacemaker endocarditis, the sensitivity of transthoracic echocardio-

Table 5

Clinical manifestations in 123 patients with infections involving implantable electrophysiologic

cardiac devicesa

Manifestation Number Percent

Pocket pain 68 55

Pocket erythema 68 55

Draining sinus from pocket 52 42

Pocket swelling 44 36

Bacteremia 40 33

Pocket erosion 39 32

History of fever 35 29

Pocket warmth 28 23

Purulent drainage from pocket to sinus 28 23

Chills 27 22

Malaise 26 21

Bacteremia accompanied by systemic symptoms 24 20

Fever on examination 23 19

Anorexia 14 12

Sepsis (fever and tachycardia) 14 12

Tachycardia (>100 beats/min) 10 8

Nausea 10 8

a Includes pacemakers (87) and cardioverter defibrillators (36).

Modified from Chua JD, Wilkoff BL, Lee I, Juratli N, Longworth DL, Gordon SM.

Diagnosis and management of infections involving implantable electrophysiologic cardiac

devices. Ann Int Med 2000;133:604–8, with permission.


graphy in demonstrating valvular or lead vegetations was 23% to 30%, com-

pared with 91% to 96% with transesophageal echocardiography [100,101,

105]. The authors believe that echocardiography is indicated in all patients

with bacteremic implantable device-related infections and in those whoseclinical findings that suggest the possibility of endovascular infection. Trans-

esophageal echocardiography is superior in sensitivity to the transthoracic

approach.

Management

The optimal management of implantable device-related infections has

been debated in the literature, especially regarding the necessity for deviceremoval. Some authors have advocated a conservative approach consisting

of antibiotic therapy with hardware in place. Pursuit of this strategy has been

motivated by the desire to avoid invasive surgical procedures, especially in

debilitated individuals and in those with epicardial devices. Turkisher et al.

described a single patient in whom a cardiodefibrillator infection was suc-

cessfully managed with a 3-month course of oral fusidic acid and rifampin

[109]. Lee et al. reported successful treatment of 4 patients with implantable

cardiodefibrillator infections with wide debridement of the device pocketfollowed by placement of a closed irrigation system and continuous irriga-

tion with polymyxin, bacitracin, and neomycin solution, along with culture-

directed antimicrobial therapy [110]. In general, reports of success without

removing the entire device have been based on small numbers of patients

or patients with infections limited to the generator pocket [102].

Other authors have recommended complete explantation of infected

devices, but have commented that in rare cases patients may be successfully

treated with partial device removal [91,98,102]. Partial removal is likely tobe sufficient only when infection is clearly limited to the removed compo-

nent, usually the generator unit and immediately adjacent leads. In the

recent large study involving 123 patients at the Cleveland Clinic, complete

removal of the device and all lead material was successful in 117 patients

(95%) [85]. One hundred nineteen received antimicrobial therapy after hard-

ware removal; specific therapy was guided by culture results but was not

standardized with regard to route or duration. Seventy-one patients received

intravenous therapy for a median of 28 days. Forty-three received intrave-nous antibiotics (median 7 days) followed by oral therapy (median 16 days).

Five patients received oral therapy alone for a median of 24 days. Among

the 117 patients who had complete device removal, relapse occurred in only

one. By contrast, among the remaining six patients in whom device removal

was incomplete, relapse occurred in three. Chua et al. concluded that com-

plete explantation of all hardware combined with antibiotic therapy is the

optimal method of management of implantable device-related infections.

Data from several recent studies of pacemaker endocarditis strongly supportremoval of the entire system as the preferred therapy [93,99,100–102].


Among 190 patients with pacemaker endocarditis, 12 of 29 patients (41%)

treated with antibiotics alone died as contrasted with 30 of the 161 patients

(19%) treated with antibiotics plus removal of the entire system [100].Older studies have emphasized the morbidity and potential mortality

associated with device removal, especially in those requiring sternotomy

or thoracotomy [99]. Older traction techniques to remove transvenous

devices were sometimes associated with complications such as tricuspid

valve tear, rupture of the right atrial or ventricular wall, tearing of the

cephalic or subclavian veins, or rupture of the chordae tendineae [86]. In

recent years, the availability of laser sheath technology for extraction of

pacing leads has facilitated nonoperative removal of transvenous devices[111]. In one recent study, use of the Excimer laser sheath to extract pacing

leads was successful in 94% of cases versus 64% using standard non-laser

technology; in patients who failed non-laser standard extractions, 88% were

successfully treated utilizing the laser tool. Life-threatening complications

occurred in 3% of patients treated with standard non-laser extraction, com-

pared with 0% in those treated with the laser Excimer sheath [111]. Patients

with suspected infection of an implanted defibrillator with epicardial patches

are particularly vexing because removal of the entire device requires a thor-acotomy. Bacteremia, fever, and signs of septic pericarditis are clues that

point to epicardial lead infection. Additionally, computed tomography and

a gallium or labeled white blood cell scan can be used to evaluate for infec-

tion involving the deep leads and patches. If infection appears limited to the

generator pocket (i.e., there are neither clinical clues or patch abnormalities

by computed tomography or isotope scan) removal of only the generator

and adjacent lead wires, in combination with antibiotic therapy, may—on

occasion—be sufficient to eradicate infection [102]. Success rates with partialdevice removal are low because the entire device is typically infected.

Few studies have examined the optimal route or duration of antibiotic

treatment for infected electrophysiologic devices. Experience suggests that

those patients with bacteremia and definite or probable endocarditis or peri-

carditis will require long courses of parenteral therapy as advocated for

endocarditis. Patients with infection limited to the generator unit pocket and

no bacteremia can be treated with less intensive regimens (parenteral ther-

apy followed by oral therapy) and wound care for the pocket from whichthe device has been explanted [36].

At the Cleveland Clinic, all patients with suspected infections involving

cardiac devices have at least 2 sets of blood cultures collected. At the time

of device removal, cultures are obtained from the device pocket and from

all lead tips and mesh. Patients with endocarditis receive at least 4 weeks

of culture-directed intravenous antibiotic therapy. Those with infection con-

fined to the device pocket are treated with parenteral therapy with or with-

out subsequent oral therapy; the duration of therapy depends on thepresence or absence of bacteremia and on the clinical response. The optimal

duration of therapy remains controversial and has not been well defined for


those individuals who lack bacteremia, fever, and echocardiographic evi-

dence of endocarditis but who nevertheless have positive lead tip cultures.

Because of the concern about focal infection at the right atrial or ventricular

lead tip site in those with positive lead tip cultures, most patients receive 4weeks of parenteral therapy. The optimal antibiotic management of patients

with these infections requires further study.

The timing of device reimplanation has been an area of ongoing contro-

versy. Some authors have recommended reimplanation as early as 36 hours

following explantation in those with infection confined to the device pocket

[112]. Because blood cultures may take longer than 36 hours to become

positive, others have advocated waiting at least several days [85]. In the

Cleveland Clinic study, the median interval from device explantation to re-implantation was 5 days (range 0–68 days). Among the thirteen patients

with endocarditis, reimplantation was successfully performed in those who

required it at a median of 7 days following explantation (range 5–25 days).

Before replacing an intracardiac device in a patient with device-associated

endocarditis, it is prudent to provide sufficient antibiotic therapy to eradi-

cate bacteremia and to sufficiently suppress or eradicate endothelial infec-

tion so that the probability of reinfection of the new device is minimized.

It is important to emphasize that not all patients with electrophysiolo-gic cardiac device-related infections require new devices. In the Cleveland

Clinic study, 18% of patients did not require further device therapy after

re-evaluation of their cardiac status.

Infections of left ventricular assist devices and artificial hearts

As an increasing number of left ventricular assist devices (LVAD) areimplanted, it has become clear that they are subject to serious risk of infec-

tion. In a controlled study of 68 patients followed for up to 2.5 years after

implantation of LVADs for severe heart failure, approximately one-third of

the devices became infected within three months [113]. Infections of the

drive-line tract or pocket occurred at a rate of 0.41 per patient year, and

infection of the pump’s interior or inflow/outflow tracts at a rate of 0.23 per

patient year. This resulted in an overall sepsis rate of 0.6 per patient year.

Moreover, sepsis was the most common cause of death. Sepsis caused41% of the 41 deaths in the LVAD group, but only one (2%) of 54 deaths

among the controls [113]. It is evident that until more effective means to

reduce the high rate and high mortality of infections of LVADs and similar

devices such as artificial hearts are found, their long-term value will be

limited.

As to treatment, removal of the device offers the best chance for cure. De

Jonge et al. [114] reported recently an apparent cure of a case of ‘‘endocar-

ditis’’ in an LVAD by ‘‘valve replacement’’—that is, removal and replace-ment of the mechanical inflow and outflow valves of the device. For various


reasons, removal of the device may not be practicable, so many of these

patients have been treated empirically with antibiotics. Data are so far inade-

quate to assess the likelihood of successful long-term suppression—or evenpossibly cure—of such infections by means of antibiotic treatment alone.

However, extensive previous experience with infections of other prosthetic

devices indicates that cure with antibiotics alone is unlikely. Thus, amore pro-

ductive strategy may be suppression of infection and early cardiac transplan-

tation with eradicative therapy administered after heart transplantation.

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