Infect Dis Clin N Am 16 (2002) 437452

Special issues in the management

of infective endocarditis caused
by Gram-positive cocci
Bruno Hoen, MD, PhD
Service de Maladies Infectieuses et Tropicales, University of Besancon
Medical Center, F-25030 Besancon Cedex, France

Gram-positive cocci, mainly streptococci and staphylococci, continue to

cause the majority of cases of infective endocarditis. This key fact remains
true at the beginning of the twenty-rst century, more than one hundred
years after the rst comprehensive clinical description of this entity by Sir
William Osler [1]. However, several important changes in the distribution
and antibiotic susceptibility of pathogens within these two families of microorganisms have occurred over the last two decades.
Among the streptococci causing infective endocarditis (IE), the longstanding predominance of oral (viridans group) streptococci has progressively waned, while the number of cases caused by enteric streptococci
(Streptococcus bovis and enterococci) has increased [24]. For example, in
a recent survey of IE conducted in France up to 1999, S. bovis and enterococci accounted for 25% and 7% respectively of the 390 cases collected,
while oral streptococci were responsible for only 17% [5]. This trend is probably related to the increasing median age of patients with endocarditis, with
elderly patients being more prone than younger ones to develop S. bovis
infection.
As for antibiotic susceptibility, while most oral streptococci and S. bovis
strains remain fully sensitive to penicillin [6], nutritionally variant streptococcinow renamed Abiotrophiaand enterococci can exhibit resistance
to penicillin or glycopeptides, which makes endocarditis more dicult to
treat. Among the staphylococci causing endocarditis, the increasing proportion of coagulase-negative and methicillin-resistant strains observed in
recent years has changed the approach of choice to antibiotic therapy. These
two emerging trends are linked to the increasing frequency of nosocomial

E-mail address: bruno.hoen@ufc-chu.univ-fcomte.fr (B. Hoen).

0891-5520/02/$ - see front matter
2002, Elsevier Science (USA). All rights reserved.
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B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

endocarditis, because most cases of IE due to coagulase-negative or methicillin-resistant staphylococci occur in patients with prosthetic valves or other
implanted intracardiac devices.
The purpose of this paper is not to re-visit the well-known therapeutic
recommendations that have been issued in recent years by various expert
panels [710]. These recommendations are broadly similar despite the fact
that they have been issued by independent groups; they are still valid, and
can be used to guide the choice of antibiotic therapy for the majority of
cases of IE. The author will focus instead on some new aspects of the management of antibiotic therapy of IE due to streptococci and staphylococci,
including recent developments such as once-daily aminoglycoside administration in IE and outpatient antibiotic therapy. The author will review
recent advances in the evaluation of new antibiotics for the treatment of
IE in humans and studies in animals, because some new pre-clinical investigational compounds are likely to be used for treatment of IE in humans in
the near future.
Management of resistant and nutritionally
decient variant oral streptococci
Oral streptococci include Streptococcus oralis, Streptococcus sanguis,
Streptococcus parasanguis, Streptococcus gordonii, Streptococcus mitis, Streptococcus mutans, Streptococcus salivarius, and Streptococcus sobrinus. Streptococci belonging to the milleri group (Streptococcus intermedius, Streptococcus
constellatus, and Streptococcus adjacens) are usually regarded as viridans
streptococci as well. Almost all of these streptococci are fully sensitive to
penicillin (dened as MIC 0.125 mg/L) and to glycopeptides, and exhibit
low-level resistance to aminoglycosides. Therefore, IE caused by these streptococci can be cured eectively by a 2-week short course of b-lactam plus
gentamicin combination, provided that all appropriate conditions for shortcourse therapy are fullled (Table 1). Otherwise, the traditional 4-week treatment course (usually 2 weeks of the combination followed by 2 weeks of
b-lactam alone) is recommended. The b-lactam can be selected from the
standard list: penicillin G, amoxicillin, or ceftriaxone. Ceftriaxone was added
recently to the list of recommended b-lactams after several clinical studies
demonstrated its ecacy [1113]. For the aminoglycoside, gentamicin and
Table 1
Criteria favoring use of short course, 2-week b-lactam plus aminoglycoside combination
therapy for penicillin-sensitive streptococcal endocarditis
1.
2.
3.
4.
5.
6.

Pencillin-sensitive oral (viridans group) streptococcus or S. bovis (MIC 0.125 mg/L)

Native valve endocarditis
No heart failure; no aortic insuciency; no conduction abnormalities
No evidence of extracardiac metastatic septic foci
Vegetation size 10 mm diameter
Favorable clinical response within 7 days, including resolution of fever

B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

439

netilmicin are equally eective. In patients allergic to penicillin, a glycopeptide should be used instead of a b-lactam. For this application, vancomycin
is most commonly used in the United States, but teicoplanin has proven to
be even more eective in vitro than vancomycin against such strains of streptococci [14] and is more convenient to use in vivo.
Recent studies have reported the emergence of strains of viridans streptococci with decreased susceptibility to certain antibiotics, notably b-lactams.
In Taiwan, among a collection of 207 isolates of viridans streptococci isolated from blood cultures, high-level resistance to penicillin, dened as MIC
4 mg/L, was found in 35% of S. oralis, 16% of S. mitis, 6% of S. salivarius,
and 3% of S. sanguis [15]. In Spain, high-level resistance to penicillin was
also reported in 16%, 6%, and 3% of S. mitis, S. salivarius, and S. sanguis,
respectively, among 410 strains of viridans streptococci [16]. Finally, in the
United States, 13.4% of 252 blood culture isolates of viridans streptococci
exhibited high-level resistance to penicillin. Furthermore, 17% of these
strains were resistant to ceftriaxone, dened as MIC >2 mg/L [17]. Three
case reports of IE due to S. mitis with high-level resistance to penicillin and
third-generation cephalosporins have been published recently [1820]. In
two of these cases the patients were HIV-positive. Although the optimal
antibiotic treatment of IE due to resistant streptococci such as these is not
known, high doses of penicillin or a cephalosporin appeared to be ineective; a cure was achieved only after a prolonged course of a glycopeptide.
Nutritionally decient variant streptococci have been taxonomically
grouped into a new genus, Abiotrophia, which includes Abiotrophia defectiva
and Abiotrophia adjacens (the latter has been even more recently re-classied
as Granulicatella adjacens). Another member of this genus, Abiotrophia elegans, was described recently as a new causative agent of IE [21]. Abiotrophia
spp usually show reduced sensitivity to penicillin, while amoxicillin, thirdgeneration cephalosporins, and carbapenems are more active [22]. Abiotrophia spp are also dicult to identify using conventional culture techniques;
use of molecular techniques, when available, may provide more rapid and
accurate identication of these fastidious bacteria, thus allowing clinicians
to implement adequate therapy earlier [23,24].
Furthermore, even penicillin-susceptible strains are often tolerant to the
bactericidal eect of b-lactams. Although the clinical signicance of tolerance remains uncertain, it may be prudent to treat IE caused by these strains
for at least 4 weeks until better data are available. The same comment
applies to strains of S. durans, of which a high proportion are tolerant to
penicillin.
Management of enterococcal IE
Enterococci are far less sensitive to penicillins than other streptococci.
MICs to b-lactams are 10 to 100 fold higher for enterococci than for streptococci. This is even more pronounced for Enterococcus faecium than for

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B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

Enterococcus faecalis, with MIC50 to penicillin of 8 and 1 mg/L and to

amoxicillin of 4 and 0.5 mg/L, respectively. In addition, E. faecium strains
are almost always penicillin tolerant. b-lactamase-producing strains of
E. faecalis have been described in the United States, but not yet in Europe.
Regarding aminoglycosides, high-level resistance is found in E. faecalis in
about 10% of endocarditis strains, a gure lower than that observed among
strains isolated from nosocomial bacteremias. For management of endocarditis, enterococcal isolates must be checked routinely for high-level resistance to avoid the use of aminoglycosides when no synergism with either
b-lactams or glycopeptides can be expected. In addition, gentamicin should
always be preferred over netilmicin for the treatment of IE due to E. faecium
because this species possesses a constitutive AAC60 enzyme that inactivates
netilmicin.
Glycopeptide-resistant enterococci were rst described in the late 1980s
[25]. Most often these strains exhibit high-level resistance to both vancomycin, dened as MIC >64 mg/L, and to teicoplanin, dened as MIC >16 mg/L.
This resistance prole, indicating the Van A phenotype, is plasmid-mediated,
and therefore potentially transferable from one strain to another. Occasionally (mostly in Europe) teicoplanin sensitivity is preserved despite the presence of high-level resistance to vancomycin; this is the Van B phenotype.
Optimal antibiotic prescribing for enterococcal IE requires that MICs of
penicillin, amoxicillin, aminoglycosides, and glycopeptides for the infecting
strain be determined. When the isolate exhibits only low-level resistance to
aminoglycosides, the recommended therapy is a combination of high-dose
b-lactam at 30 to 40 million units/d for penicillin, or 200 mg/kg/d for amoxicillin, plus an aminoglycoside for 4 to 6 weeks. The aminoglycoside component should be administered twice daily; this recommendation is based on
results of experimental studies [26].
In the case of high-level resistance to gentamicin, cross-resistance may be
expected with all other aminoglycosides, except sometimes streptomycin. If
the strain shows only low-level resistance to streptomycin, the latter can be
used in combination with high doses of a cell wall active agent, either a
b-lactam or a glycopeptide. If the strain shows high-level resistance to streptomycin as well, the best treatment option is probably monotherapy with
amoxicillin or a glycopeptide, given at high dose for at least 8 weeks. Even
with such prolonged therapy, antibiotic therapy often fails, and surgical
therapy is likely to be required.
Glycopeptide-resistant enterococci are often multi-drug resistant, also
exhibiting high MICs to b-lactams and high levels of resistance to aminoglycosides. No consensus has been reached regarding the treatment of enterococcal endocarditis caused by such strains. In vitro studies have shown that
combinations of cell wall active antibiotics might be synergistic without an
added aminoglycoside. This is particularly evidenced in the teicoplanin plus
imipenem combination [27]. In vivo experimental studies have conrmed
this fact. Teicoplanin plus imipenem is superior to teicoplanin aloneand

B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

441

to teicoplanin plus ceftriaxonein the treatment of experimental endocarditis caused by a high-level aminoglycoside-resistant strain of E. faecalis [28].
An ampicillinceftriaxone combination has proven to be as eective as an
ampicillingentamicin combinationand more eective than ampicillin
alonein reducing the bacterial density in vegetations infected with a
low-level aminoglycoside-resistant E. faecalis strain in rabbits [29]. A triple
combination of penicillin, vancomycin, and gentamicin has been eective in
the treatment of experimental endocarditis caused by penicillin- and glycopeptide-resistant isolates of E. faecium [30,31]. A ceftriaxone, vancomycin,
and gentamicin combination was unexpectedly found to be more eective
than a penicillin, vancomycin, and gentamicin regimen. However, even this
regimen failed to prevent the emergence of resistant bacteria, which
occurred in 10% to 20% of the animals [32].
Newer antibiotics that show some promise for treatment of multidrug
resistant enterococcal endocarditis include quinupristindalfopristin, linezolid, LY333328, and evernimicin (SCH 27899), either alone or in combination with other antibiotics (see below and Table 2).

Pneumococcal IE
Since the introduction of penicillin, the proportion of endocarditis cases
caused by pneumococci has dramatically decreased, from approximately
15% to less than 1%. A recent study collected 197 cases published in Englishlanguage literature over the course of 30 years (19661996) [33]. Another
study retrospectively collected 30 cases that had occurred between 1991 and
1996 [34]. In both studies, alcoholism was the most frequent underlying condition. Age greater than 65 years and presence of septic shock were predictive
of death, while early valve replacement surgery appeared to be protective [34].
The course of the disease was often complicated with meningitis, congestive
heart failure, arterial emboli, and focal abscess formation.
It is still unclear whether or not the addition of an aminoglycoside to the
basic b-lactam regimen confers any benet for the treatment of pneumococcal IE. In contrast, it appears that valve replacement is often necessary,
and seems to improve outcomes [34]. The impact of emerging Streptococcus
Table 2
Suggested regimens for new antibiotics in the treatment of endocarditis due to resistant
staphylococci or enterococci in humans
Drug

Administration regimen

Quinupristindalfopristin

7.5 mg/kg tid IV by way of a central venous line

Note: not active against E. faecalis
600 mg bid IV possibly followed by oral treatment
3 mg/kg bid IV
Phase 2 trials ongoing

Linezolid
Daptomycin
LY333328

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B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

pneumoniae resistance to penicillin on clinical manifestations and outcome

of pneumococcal IE has not yet been evaluated adequately. In a French retrospective study, 5 patients (16.7%) were infected with community-acquired
strains of S. pneumoniae that had decreased sensitivity or were intermediately resistant to penicillin [34]. In this series, one patient who was infected
with a penicillin-resistant strain of S. pneumoniae was cured with amoxicillin
given for one month, combined with vancomycin for the rst four days.
Various other antibiotic regimens were used in 4 cases of IE caused by penicillin-resistant strains of S. pneumoniae, published as single case reports [35
38]. No denitive recommendation can be derived from these anecdotal
observations. One can only suggestbased on experimental data [39]that
penicillin at a dose high enough to maintain serum concentrations above the
MIC of the strain should be eective. Ceftriaxone, vancomycin, teicoplanin,
and quinupristin-dalfopristin might also be eective [39,40].
b-hemolytic streptococci
Infective endocarditis caused by b-hemolytic streptococci is uncommon.
However, in a recent French survey, b-hemolytic streptococci accounted for
22 of 390 cases (6%) of IE. Sixteen of these cases (73%) were caused by the
group B streptococcus Streptococcus agalactiae [5]. In another recent study,
31 cases of b-hemolytic streptococcal endocarditis were reported between
January 1994 and December 1996. Group B b-hemolytic streptococci again
accounted for over two-thirds of isolates [41]. The mortality rate of 12.9%
among patients in this survey was remarkably low. Sixty-one percent (19
of 31) were treated with penicillin G, either as monotherapy or in combination with gentamicin. Twenty-ve patients (80.7%) developed complications
of infective endocarditis, and 15 (48.4%) underwent surgical intervention for
valvular repair or excision.

Staphylococcal IE
Treatment regimens for methicillin-susceptible staphylococcal endocarditis are well established. Regimens rely upon a combination of cloxacillin or
ucloxacillin 200 mg/kg/d for 4 weeks in combination with gentamicin 3 mg/
kg/d for the rst week [7,8,10]. The most common causative pathogen is
Staphylococcus aureus, which most often infects native valves.
In recent years, the incidence of endocarditis caused by methicillin-resistant staphylococci (both S. aureus and coagulase-negative staphylococci) has
risen, especially in intravenous drug users (IDUs) and in patients who have
prosthetic valves. For IDUs, rst-line treatment of staphylococcal IE should
include vancomycin until the susceptibilities of the strain have been determined. An early switch to an oral combination of ciprooxacin and rifampin
after a few days of parenteral therapy has proven to be eective in one study

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443

[42]. However convenient such oral treatment regimens may be, physicians
and patients should be aware that sub-optimal compliance could lead to
treatment failure, and is likely to select for resistant mutants [43]. Nevertheless, a randomized trial demonstrated that oral ciprooxacin and rifampin
given as initial treatment for right-sided S. aureus IE in IDUs was as eective
asand better tolerated thanparenteral cloxacillin or vancomycin in combination with gentamicin [44]. Two trials also demonstrated that short-term
therapy with two weeks of cloxacillin with or without aminoglycoside could
achieve high cure rates in IDUs infected with methicillin-susceptible S. aureus
IE [45,46]. In one of these trials, combination with gentamicin provided no
signicant advantage compared to cloxacillin alone [45].
Prosthetic-valve methicillin-resistant staphylococcal IE should be treated
with a triple combination of vancomycin, rifampin, and gentamicin, provided
that the strain is sensitive to rifampin and gentamicin [10]. However,
although vancomycin is universally regarded as the drug of choice for this
indication, its bactericidal activity against staphylococci is slow, resulting
in delayed responses to therapy [47]. In this study, 42 patients with MRSA
endocarditis were treated with either vancomycin or vancomycin plus rifampin for 28 days. A delayed clinical response was common, with median durations of fever and bacteremia of 7 days and 9 days, respectively. Despite this,
no unusual complications were seen in either treatment group, and most
patients responded to continued antibiotic therapy. These data make it clear
that vancomycin should be reserved for the treatment of MRSA endocarditis,
while b-lactams remain the best choice for MSSA endocarditis.
Currently, physicians must contend with the emergence of strains of staphylococci with reduced susceptibility to vancomycin. Two options must be
explored: (1) development, evaluation and deployment of new compounds
active against these resistant strains, and (2) optimization of currently available combinations. The rst option will be further discussed below. The second option has been addressed in a recent in vitro study of synergistic eects
of various double and triple combinations of b-lactams, vancomycin, and
aminoglycosides [48]. Among the eight aminoglycosides tested in this study,
netilmicin was found to be the best agent for combination with vancomycin,
showing a benecial bacteriostatic eect. A favorable bacteriostatic eect
was also demonstrated with imipenem plus vancomycin or cefazolin plus
vancomycin combinations. Furthermore, addition of netilmicin to these
combinations enhanced their bactericidal eect. The fact that the benecial
bacteriostatic eect of b-lactam-vancomycin combinations was observed
only with cefazolin, imipenem, and ampicillin-sulbactam might be related
to the binding anities of these three b-lactams for penicillin-binding protein 2a of MRSA, which are stronger than that of methicillin [48].
Teicoplanin, which is more convenient to use and less toxic than vancomycin, may constitute an eective alternative to vancomycin in the treatment of
MRSA endocarditis, provided that it is administered at sucient dosages.
The initially recommended dose of 6 mg/kg/d was too low, resulting in

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B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

unacceptably high treatment failure rates. It has now been shown that teicoplanin trough serum concentrations provide the best predictor of treatment
success [49]. Trough serum levels <5 mg/L are associated with 20% success
rate, while trough serum levels >25 mg/L are associated with 90% success rate.
It is now recommended that teicoplanin therapy be started at the dose of 6
mg/kg twice a day for 3 to 4 days, until a trough serum concentration of 20
to 30 mg/L is reached. Thenceforward, the trough concentration must be
maintained for the remainder of the treatment period; this can usually be
achieved with once daily administration of about 10 mg/kg/d teicoplanin [50].
Once-daily aminoglycoside (ODA) administration in the management of IE
Once-daily aminoglycoside administration is the method in which the
total daily dose is administered in a single dose instead of two to three doses
per day, as previously recommended. Many clinical trials and meta-analyses
have demonstrated that ODA is at least as eective as, and less toxic than,
conventional dosing. However, only a few trials have specically addressed
the question of ODA in IE. As a rule, the use of ODA has not been recommended in IE, mainly because of unfavorable results of experimental studies
in enterococcal endocarditis performed in the early 1980s [26]. Since then,
several other studies using animal models of IE caused by a variety of pathogens have shown that ODA performs as well as conventional dosing [51]. In
another animal study, a combination of teicoplanin plus gentamicin given
once daily was as eective as ampicillin plus gentamicin three times daily
in an animal model of sensitive E. faecalis endocardits [52]. A clinical and
bacteriological cure was reported recently in a patient with right-sided sensitive E. faecalis endocarditis who was given once-daily gentamicin [53].
Clinical trials in humans are limited to those already mentioned, which
evaluated once-daily gentamicin or netilmicin in combination with ceftriaxone for the treatment of penicillin-susceptible IE on native valves [12,13].
Based on these results, one can now recommend such regimens in the same
situations as those in which they were evaluated (i.e., uncomplicated native
valve endocarditis caused by fully sensitive streptococci viridans streptococci and S. bovis). For other situations, such recommendations cannot
be made at present. However, sucient information has been gathered in
the last few years to warrant the continuation of experimental and clinical
studies of the treatment of enterococcal and staphylococcal IE with oncedaily dosing of aminoglycoside.

Outpatient antibiotic therapy for IE

Simplication of endocarditis treatment regimens as described above,
namely by ODA administration, teicoplanin administered once daily after
initial loading, and shortened duration of therapy, could facilitate increased

B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

445

use of outpatient antibiotic therapy (OPAT) in IE. To date, however, no

randomized prospective study has compared inpatient to OPAT for the
treatment of IE. Conversely, there is no prospective evidence that inpatient
therapy improves outcomes or decreases the risk of complications such as
stroke, emboli, or rupture of mycotic aneurysms compared with OPAT.
Extensive reviews of indications, limitations, and pragmatic aspects of
OPAT in IE have been published recently [54,55]. Therefore, the author will
not review this new aspect of IE treatment in depth. Table 3 summarizes the
most important factors that must be addressed for an adequate selection of
patients eligible for OPAT. Options for parenteral antibiotic delivery are
displayed in Table 4. It should also be emphasized to both patients and physicians that OPAT has not yet become the standard therapy for IE, even
though it is increasingly used in the United States, where it has succeeded
in reducing the duration of in-hospital treatment.
In addition to simplication of therapy and improved convenience for the
patient, it has been pointed out that OPAT may be of particular value in
countries with limited health care resources [54].

New drugs for treatment of IE caused by Gram-positive cocci

Quinupristindalfopristin
Quinupristindalfopristin (Q/D; Synercid) is a new parenteral streptogramin combination that is potent against most gram-positive pathogens, including methicillin-resistant staphylococci and multidrug-resistant
E. faecium, with the notable exception of E. faecalis.
In S. aureus infections, the impact of resistance to either quinupristin or
dalfopristin on the in vivo activity of Q/D has been studied recently in
an animal model of endocarditis [56]. Cross-resistance of S. aureus to

Table 3
Criteria favoring selection of patients with IE who are suitable for outpatient antibiotic therapy
(OPAT) (data from [54] and [55])
Medical issues
Physical ability to carry out activities of daily living
Willingness, understanding, and compliance with treatment
No major co-morbidities such as renal or cardiac failure
Other medical conditions are stable
No immediate indication for surgery
Reliable venous access site available
General issues
Adequate home/family situation and family support
Excellent collaboration with patients general practitioner for monitoring
Ready access to hospital
Well-dened telephone contact procedures

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B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

Table 4
OPAT options for parenteral antibiotic delivery (data from [54])
Setting
Infusion center
Outpatient clinic
General practitioners oce
Visiting nurse
Self-administration
Venous access options
Direct intravenous or intramuscular administration
Intermittent infusions with a metal buttery needle, replaced daily
Peripheral or central catheter in place
Implanted port, if above mentioned options are not available
Infusion pump

macrolides, lincosamines, and streptogramin B-type antibiotics (MLSB)

results from methylation of the ribosomal target. In S. aureus, the expression of this resistance may be inducible or constitutive. When inducible,
quinupristin remains active because it is not an inducer of the methylase,
whereas quinupristin is inactive and the bactericidal activity of quinupristindalfopristin is altered when resistance is constitutive. Zarrouk et al.
showed that the combination of Q/D plus rifampin was highly bactericidal
and synergistic against strains susceptible to quinupristin, whereas the combination was neither synergistic nor bactericidal against the quinupristinresistant strain, and moreover did not prevent the emergence of mutants
resistant to rifampin [56]. They concluded that the absence of resistance to
quinupristin is a good predictor of treatment success in S. aureus endocarditis. The susceptibility pattern should probably be conrmed before starting
therapy with Q/D.
Q/D has reportedly been eective in a few cases of staphylococcal endocarditis in humans [57,58]. However, in the large international open trial
that evaluated Q/D in the treatment of methicillin-resistant S. aureus infections in patients intolerant to or failing prior therapy, the cure rate of endocarditis was only 54%, which was lower than the mean cure rate of 71%
observed in other situations, such as skin or osteoarticular infections [59].
Further studies are needed to better evaluate the place of Q/D in the treatment of staphylococcal endocarditis in humans.
In multidrug-resistant E. faecium endocarditis, Q/D in combination with
doxycycline was eective in an animal model [60]. The administration of Q/D
as a high-dose continuous infusion might be useful to prevent the development of resistance. Matsumura and Simor [61] reported a case of vancomycin-resistant E. faecium endocarditis in a 76-year-old man that was cured
by a combination of Q/D, doxycycline, and rifampin. They also demonstrated the synergistic eect of this combination [61]. Researchers are awaiting the results of ongoing evaluations of Q/D in combination with other
agents.

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447

Linezolid
Linezolid is the rst licensed representative of the oxazolidinones, a new
class of antibiotics that act by inhibition of protein synthesis; they are chemically distinct from all commercially available antibiotics. Linezolid has
signicant activity against multi-resistant gram-positive pathogens such as
methicillin-resistant staphylococci, vancomycin-resistant enterococci, and
penicillin-resistant pneumococci. It has favorable pharmacokinetics, with
equal bioavailability when given by either oral or intravenous routes, and
there is no need for dose adjustment in patients with renal impairment. Linezolid has a good safety prole at least for short-term use.
Although linezolid has proven to be eective in various conditions such as
community-acquired and nosocomial pneumonia and severe skin and softtissue infections [62,63], only a few studies have evaluated this compound
in the treatment of IE. In a rabbit model of S. aureus endocarditis, treatment
with oral linezolid was compared with IV vancomycin. Linezolid at 75 and 50
mg/kg (but not at 25 mg/kg), and vancomycin signicantly reduced S. aureus
in aortic valve vegetations compared with the controls. The ecacy of 75 and
50 mg/kg linezolid was related to maintenance of plasma drug levels near or
above the linezolid MIC for the strain studied (2 mg/L) [64].
Administered intraperitoneally at a dose of 25 mg/kg of body weight every
8 hours, linezolid was compared with vancomycin at a dose of 25 mg/kg, administered intraperitoneally every 8 hours in a rat model of Van A vancomycinresistant E. faecium endocarditis. Linezolid treatment was found to be more
active than vancomycin, which was no better than no treatment at all [65].
Finally, in a human case of vancomycin-resistant E. faecium endocarditis
that failed to respond to sequential monotherapy with chloramphenicol and
quinupristindalfopristin, oral linezolid successfully cured the patient [66].
Further studies are needed to conrm the potential value of this new drug
for staphylococcal or enterococcal endocarditis. Furthermore, clinicians
should be aware that resistance to linezolid can develop during treatment;
therefore, susceptibility testing should be always performed before starting
therapy with linezolid [67].
Newer glycopeptides, lipopeptides, and oligosaccharides
LY333328 is a semi-synthetic, carbohydrate-modied glycopeptide derivative that interacts with cell wall biosynthesis. It was investigated alone and
combined with gentamicin, both in vitro and in a rabbit model of experimental endocarditis, against a susceptible strain of E. faecalis and two
glycopeptide-resistant transconjugants. In vitro, LY333328 alone was bactericidal at 24 hours against the susceptible strain at a concentration of 2 lg/mL
and against the resistant strains at a concentration of 30 lg/mL. The combination of LY333328 and gentamicin was synergistic and bactericidal. In vivo,
intravenous treatment with LY333328 alone was ineective; furthermore, this

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B. Hoen / Infect Dis Clin N Am 16 (2002) 437452

treatment selected mutants resistant to LY333328 in half of the rabbits

infected with the Van A strain. However, the LY333328gentamicin combination was active against the three strains and prevented the emergence of
mutants resistant to either component of the combination. Therefore, the
LY333328gentamicin combination might be of interest for the treatment
of enterococcal infections, particularly against Van A strains [68].
Daptomycin is a lipopeptide with a bactericidal activity against a wide
range of gram-positive pathogens. Its mechanism of action is unique, causing
interference with cell membrane transport. Its bactericidal activity was evaluated against glycopeptide-intermediate susceptible S. aureus (GISA), vancomycin-resistant E. faecium (VREF), and methicillin-resistant S. aureus
(MRSA) in an in vitro infection model with simulated endocardial vegetations. Daptomycin at 6 mg/kg/d and 10 mg/kg/day reduced the bacterial count
of GISA by 5 and 6 log10 CFU/g, VREF by 3.4 and 5 log10 CFU, and MRSA
strains by 6.4 and 6.5 log10 CFU/g in 8 hours. A concentration-dependent killing eect was noted, with daptomycin demonstrating more rapid and stronger
bactericidal activity at 10 mg/kg/d than at 6 mg/kg/d [69]. Further evaluation
of this promising compound, including a multicenter trial in humans, is
ongoing. This drug is likely to be licensed in the United States in 2003.
Evernimicin (SCH 27899) is a novel oligosaccharide antibiotic that
belongs to the everninomicin family. Its antimicrobial activity results from
interference with protein synthesis. In an experimental model of methicillin-resistant S. aureus endocarditis, evernimicin was not signicantly more
eective than vancomycin [70]. The activity of evernimicin was also modest
in a model of enterococcal endocarditis caused by strains that were either
susceptible or resistant to vancomycin [71]. Whether or not this new compound will enlarge the arsenal of drugs active against gram-positive cocci,
especially resistant strains, is still uncertain.

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