Journal of Antimicrobial Chemotherapy (2007) 60, 7 19

doi:10.1093/jac/dkm137
Advance Access publication 4 June 2007

Daptomycin for endocarditis and/or bacteraemia: a systematic

review of the experimental and clinical evidence
Matthew E. Falagas1,2*, Konstantina P. Giannopoulou1, Fotinie Ntziora1
and Konstantinos Z. Vardakas1
1

Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece; 2Department of Medicine, Tufts University School
of Medicine, Boston, MA, USA
Received 8 February 2007; returned 21 March 2007; revised 30 March 2007; accepted 11 April 2007

Methods: We performed a systematic review of the evidence for the effectiveness of daptomycin in the
treatment of patients and animals with endocarditis and/or bacteraemia. We searched PubMed and
Scopus databases for relevant studies. Case reports, case series, controlled trials, randomized
controlled trials and comparative studies using experimental animal models were included.
Results: The most reliable information comes from the single multicentre randomized controlled trial
conducted on this issue, which showed that daptomycin is a promising antibiotic for the treatment of
patients with Staphylococcus aureus bacteraemia and endocarditis. The experimental models indicate
that the combination of daptomycin with rifampicin or gentamicin can improve outcomes further.
Finally, in several of the published relevant case reports daptomycin was administered in patients with
haematological malignancies.
Conclusions: Daptomycin is a promising antibiotic that has been already approved for the treatment of
patients with right-sided endocarditis and bacteraemia. However, the available clinical evidence is
limited and further evaluation of the antibiotic is warranted. The commonly reported de novo development of resistance is a major concern that may limit its use. More controlled trials are needed,
especially for patients infected with multidrug-resistant Gram-positive cocci, comparing daptomycin
with other available treatment options, including glycopeptides and oxazolidinones.
Keywords: lipopeptides, antibiotics, treatment

Antibiotics with bactericidal activity have been considered

the gold standard for the treatment of patients with deep tissue
infections such as endocarditis and bacteraemia. Daptomycin, a
fermentation product produced by Streptomyces roseosporus, is
a cyclic lipopeptide antibiotic with potent bactericidal activity
against most Gram-positive organisms, including multiple
antibiotic-resistant strains.6 The activity of daptomycin depends
on the presence of physiological levels of free calcium.
Daptomycin has a novel mechanism of actioninsertion into
and disruption of the functional integrity of the Gram-positive

Introduction
Endocarditis and bacteraemia are devastating infections associated with considerable mortality, which reaches 16% to 25% of
the affected individuals.1 4 Their microbiology includes both
Gram-positive and Gram-negative bacteria as well as fungi.
Among the Gram-positive microbes, the highly resistant staphylococcal and enterococcal species are of extreme importance
because they are related with more severe disease and higher
mortality.5

.....................................................................................................................................................................................................................................................................................................................................................................................................................................

*Correspondence address. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Greece.
Tel:30-694-611-0000; Fax:30-210-683-9605; E-mail: m.falagas@aibs.gr
.....................................................................................................................................................................................................................................................................................................................................................................................................................................

7
# The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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Background: Endocarditis and bacteraemia are devastating infections with high mortality. Grampositive cocci are the most commonly isolated pathogens. In an era of multidrug-resistant pathogens,
the evaluation of new treatment options is important. Daptomycin is a cyclic lipopeptide that is active
against most of these pathogens. Furthermore, it is a bactericidal antibiotic, a factor that is frequently
considered in the choice of treatment of patients with bacteraemia and endocarditis.

Systematic review
plasma membranewhich results in rapid loss of membrane
potential, cessation of macromolecular synthesis and cell death.7
It has been approved for the treatment of patients with skin and
soft tissues infections. Although it has been recently approved
for the treatment of patients with bacteraemia and right-sided
endocarditis, the available evidence to date for its effectiveness
for the treatment of such patients is limited. Thus, we sought to
review systematically the available evidence, including animal
and human studies, regarding the effectiveness and safety of
daptomycin for the treatment of endocarditis and bacteraemia.

Methods
Literature search
We carried out a systematic review of the current evidence for the
effectiveness of daptomycin in the treatment of patients and animals
with endocarditis and/or bacteraemia. Two authors (K. P. G. and
F. N.) independently searched PubMed (January 1985 to January
2007) and Scopus (19862006) in order to identify articles appropriate for inclusion in the review. They also searched reference lists
of retrieved articles for other relevant papers. Search terms included
daptomycin, endocarditis, heart disease and bacteremia.

Results
In total, 102 potentially relevant articles identified from the
PubMed database; 6 additional articles were identified from the
Scopus database. Thus, 108 articles were examined for potential
inclusion in our review. Seventy-three studies were excluded
from the review because they were not directly relevant to the
focus of our study or because daptomycin administration was
not appropriate. Finally, 35 studies were selected for further
evaluation and are presented in the Tables below.

Study selection and data extraction

Potentially relevant studies were selected according to title and
abstract review of all initially identified articles. Case reports, case
series, controlled trials, randomized controlled trials (RCTs) and
studies using experimental animal models were included, while
review articles were excluded from this review.
Consequently, any study assessing the effectiveness and safety of
daptomycin for the treatment of endocarditis or bacteraemia was eligible for inclusion in the review. Animal studies were eligible for
inclusion in the review only if the studied animals were randomly
assigned to each treatment group. A group of animals receiving no
treatment should have been included in the study. No restriction on
the studied microorganism was set. Decreases in the number of
colony forming units of the vegetations or sterilization of the
resected valves were the primary outcomes in these studies.
In case reports and case series, patients receiving treatment with
daptomycin for endocarditis or bacteraemia were evaluable for the
analysis, if age, gender, medical history, reason for daptomycin
administration and/or outcome of the infection were available. All
patients with endocarditis according to Dukes criteria who received
daptomycin as a monotherapy or as a part of the regimen were
included.8,9 Bacteraemia was defined as culture of 1 blood sample
that yielded Gram-positive cocci (2 for coagulase-negative staphylococci) and clinical profile compatible with a diagnosis of bacteraemia with one of the following findings: fever, chills, leucocytosis
with prominent left shift, changes in vital signs, signs of septic
shock (decreased peripheral perfusion or hypotension) and petechiae
or purpura.
Case reports and case series were excluded if no data regarding
the effectiveness of daptomycin for the treatment of patients with
endocarditis and bacteraemia were available. Reports that used daptomycin for the treatment of infections due to microorganisms that
were not susceptible to this antibiotic were excluded. In addition,
case reports were excluded when the duration of daptomycin administration was not adequate for the treatment of such patients.
All controlled trials and RCTs identified through the search
process were eligible for inclusion in the review. Effectiveness of

Experimental models
A summary of the available evidence regarding the effectiveness
of daptomycin for the treatment of endocarditis in experimental
models is shown in Table 1.10 20 Eleven reports of experimental
models of aortic valve endocarditis in rats and rabbits comparing
the effectiveness of daptomycin with vancomycin, teicoplanin,
amoxicillin and penicillin G were conducted. Several strains
of potential pathogens were used. The most common
Gram-positive coccus used in these models was Staphylococcus
aureus [six strains of methicillin-susceptible S. aureus (MSSA)
and five strains of methicillin-resistant S. aureus (MRSA)]
followed by Enterococcus spp. [three strains of vancomycinresistant Enterococcus (VRE) and seven strains of vancomycinsusceptible Enterococcus].
MRSA endocarditis models. In all models, the administration of
daptomycin resulted in a significant reduction of the bacterial
counts of the aortic vegetations in comparison with the
no-treatment arm. In addition, two models reported that the
addition of rifampicin in the daptomycin regimen resulted in a
further significant reduction in the counts of vegetations when
compared with daptomycin alone.11,12 The assumption that the
administration of daptomycin twice daily could result in a better
outcome than its administration in a single dose12 was not verified in other models.13 There was no significant difference in the
effectiveness of daptomycin in comparison with vancomycin
and teicoplanin. The number of sterile valves after
8

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treatment, adverse events due to the studied medications and mortality were the outcome measures for the trials.
The treatment outcome was defined as cure when the patient
general status had improved, the blood cultures were negative, and
in the cases of endocarditis the transthoracic echocardiograph (TTE)
or transoesophageal echocardiograph (TEE) revealed no evidence of
persistent vegetations on the infected valve according to the information provided by the authors of each case report. Treatment
outcome was defined as improvement when there were no signs of
persistent infection (negative blood cultures, no evidence of persistent vegetations) but the duration of the treatment period was not
adequate or the infection relapsed after discharge from hospital or
the patient died due to other reasons during the same hospitalization
but there was evidence for resolution of the infection. Duration of
treatment was considered as adequate when it lasted for a week or
more. Treatment failure was defined as persistence of signs, symptoms and laboratory or imaging findings of infective endocarditis or
bacteraemia despite appropriate antibiotic treatment with daptomycin, relapse of the infection or death due to infective endocarditis or
bacteraemia or their complications.

Table 1. Experimental animal models regarding the use of daptomycin for the treatment of endocarditis
Mean + SD
log10 cfu of
vegetation/g in
no treatment

Duration
of therapy

Reference

Bacterial inoculum

Vouillamoz et al. 10

VRE faecium

7.3 + 0.8

2 days

Vouillamoz et al. 10

VRE faecalis

7.6 + 0.8

2 days

Vouillamoz et al. 10

E. faecalis

7.5 + 0.7

2 days

Sakoulas et al. 11

MRSA

10.6 + 0.8 and

10.3 + 0.5

NA

Voorn et al. 12

MSSA

9.6 + 0.4

9.6 + 0.4

5 days

5 days

9
Caron et al. 13

VRE faecium from stool

of a neutropenic
patient

8.0 + 1.0

5 days

No. of
sterilized
valves

iv simulating human
dosage of 6 mg/kg
q24 h
iv simulating human
dosage of 6 mg/kg
q24 h
iv simulating human
dosage of 6 mg/kg
q24 h

2.1 + 0.4

11/12

2.5/20.5

9/11

2.3 + 0.6

10/12

sc 25 mg/kg q24h and

40 mg/kg q24h
sc 40 mg/kg q24,
im rifampicin
25 mg/kg
sc 10 mg/kg q24h or
5 mg/kg q12h

5.5 + 1. 7 and
4.2 + 1.5
2.9 + 0.9

NA
NA

6.8 + 2.5 and

3.9 + 1.8

1/10 or 8/
15

sc 10 mg/kg q24h and

5 mg/kg q12h, im
rifampicin
6 mg/kg
sc 10 mg/kg q24h and
5 mg/kg q12h

3.8 + 1.5

5/11

7.3 + 2.6 and

3.4 + 0.9

sc 10 mg/kg q24h and

5 mg/kg q12h, im
rifampicin 6 mg/kg
sc 10 mg/kg q12h and
12 mg/kg q8h

Comparator 1 dosage

Mean + SD
log10 cfu of
vegetation/g

No. of
sterilized
valves

iv teicoplanin simulating
human dosage of
12 mg/kg q12h
iv vancomycin simulating
human dosage of q12h

3.6 + 1.8

5/9

8.3 + 0.5

0/6

iv vancomycin simulating
human dosage of q12h,
or iv teicoplanin
12 mg/kg q12h
iv vancomycin 150 mg/kg
q24h
iv vancomycin 150 mg/kg
q24h, im rifampicin
25 mg/kg
im vancomycin 100 mg/kg
q12h

3.3 + 1.2, or
4.4 + 2.5

5/9, or 4/9

7.1 + 2.5

NA

3.3 + 1.1

Comparator 2 dosage

Mean + SD
log10 cfu of
vegetation/g

No. of
sterilized
valves

5.2 + 1.0

0/9

2.3 + 0.6

9/11

2.5 + 1.2

8/9

NA

NA

NA

NA

NA

NA

NA

5.6 + 1.8

1/14

8.6 + 0.4 or
6.9 + 2.6

1/13 or
2/16

im vancomycin 100 mg/kg

q12h, im rifampicin
6 g/kg

3.9 + 1.5

3/12

im teicoplanin 30 mg/kg
q24h or 15 mg/kg
q12h
im teicoplanin 30 mg/kg
q24h, im rifampicin
6 g/kg

3.4 + 1.0

4/11

1/10 or 4/
13

im vancomycin 100 mg/kg

q12h

5.2 + 2.0

3/11

7.8 + 2.0 or
6.8 + 2.7

1/12 or
4/22

3.3 + 1.3

7/11

3.5 + 1.8

7/11

3.6 + 1.5

6/12

6.5 + 1.6 and

5.5 + 1.4

0/8 and 0/6

im vancomycin 100 mg/kg

q12h, im rifampicin
6 g/kg
teicoplanin 10 mg/kg q12h
and 40 mg/kg q12h

7.8 + 1.5 and

8.2 + 0.9

0/7 and 0/6

im teicoplanin 30 mg/kg
q24h or 15 mg/kg
q12h
im teicoplanin 30 mg/kg
q24h, im rifampicin
6 g/kg
NA

NA

NA

6.1 + 2.0 and

3.0 + 1.4

1/10 and 5/
9

teicoplanin 40 mg/kg
q12h, gentamicin
6 mg/kg q12h

6.6 + 1.3 and

5.7 + 2.1

0/9 and 1/9

NA

NA

NA

2.1 + 1.4

11/13

iv vancomycin 20 mg/kg
q12h

2.2 + 0.4

9/12

im ampicillin 100 mg/kg

q8h, or im ampicillin
100 mg/kg plus
gentamicin 2.5 mg/kg
q12h
im ampicillin 100 mg/kg
q8h, im gentamicin
2.5 mg/kg q12h
NA

3.5 + 1.7 or
2.2 + 0.4

3/10 or
9/11

7.7 + 1.5

0/15

NA

NA

sc cloxacillin 200 mg/kg

q5h

median ,2
(,2 3.6)

25/27

Ramos et al. 14

E. raffinosus
(penicillin-resistant)

7.2 + 0 1.8

5 days

sc 10 mg/kg q12h and

12 mg/kg q8h, im
gentamicin 6 mg/kg
q12h
im 20 mg/kg q12h

Ramos et al. 14

9.1 + 0.3

5 days

im 20 mg/kg q12h

4.0 + 1.5

0/13

iv vancomycin 20 mg/kg
q12h

5.9 + 1.2

0/12

Cantoni et al. 15

E. faecalis (penicillinand aminoglycosideresistant)

MRSA

median 8.5
(6.59.5)

6 days

sc 10 mg/kg q12h, or
10 mg/kg q24h, or
5 mg/kg q12h

10/17, or
6/8, or
5/17

sc vancomycin 30 mg/kg
q6h

median ,2
(,2
10.1)

8/15

Cantoni et al. 15

MSSA

median 5.8
(,2 8.6)

3 days

sc 10 mg/kg q12h

median ,2
(,2 9.5),
or ,2
(,2
10.3) or
7.1 (,2
10.0)
median ,2
(2 4.4)

10/11

sc vancomycin 30 mg/kg
q12h

median ,2
(2 9.8)

12/18

iv amoxicillin simulating
human dosage of 2 g
q6h
iv amoxicillin simulating
human dosage of 2 g
q6h
iv amoxicillin simulating
human dosage of 2 g
q6h

Continued

Systematic review

Voorn et al. 12

MRSA

Daptomycin dosage

Mean + SD
log10 cfu of
vegetation/g

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Table 1. Continued
Mean + SD
log10 cfu of
vegetation/g in
no treatment

Duration
of therapy

sc 10 mg/kg q12h, or
10 mg/kg q24h, or
5 mg/kg q12h, or
5 mg/kg q24h

Kaatz et al. 16

9.0 + 0.7

4 days

iv 8 mg/kg q8h

Kaatz et al. 16

MSSA with reduced

susceptibility to
teicoplanin
MSSA

median ,2
(,2 4.4),
or ,2
(,2 10),
or 2.6
(,2 10),
or 8.3
(5.29.8)
4.1 + 1.1

9.7 + 0.5

4 days

iv 8 mg/kg q8h

3.3 + 1.9

11/16

Kaatz et al. 16

MRSA

8.8 + 0.9

4 days

iv 8 mg/kg q8h

2.4 + 0.3

17/17

E. faecalis

8.8 + 2.2

5 days

iv 50 and 25 mg/kg/day

2.9 + 0.2 and

2.9 + 0.2

9/21 and
6/19

6/16

4.6 + 2.4 or
7.1 + 3.3

6/16 or 1/6

iv vancomycin 17.5 mg/kg

q6h

5.2 + 2.2

2/14

4.3 + 1.5 or
5.8 + 2.7

5/16 or 1/9

iv vancomycin 17.5 mg/kg

q6h
iv imipenem
300 mg/kg/day

3.0 + 1.6

14/18

2.9 + 0.9

12/15

3.3 + 0.3

4/12

3.1 + 0.3

12/20

4.0 + 0.3

5/19

3.9 + 0.4

8/19

2.6 + 2.8

NA

iv teicoplanin 40 mg/kg
q12h or 12.5 mg/kg
q12h
iv teicoplanin 40 mg/kg
q12h or 12.5 mg/kg
q12h
iv teicoplanin 40 mg/kg
q12h
iv ampicillin/sulbactam
400/100 mg/kg/day
plus iv gentamicin
30 mg/kg/day
iv ampicillin/sulbactam
400/100 mg/kg/day
NA

NA

2 days

iv 10 mg/kg q24h

1.8 + 1.9

NA

NA

NA

MSSA

NA

4 days

iv 10 mg/kg q24h

0.7 + 0.9

NA

2.7 + 2.3

NA

NA

NA

NA

MRSA

NA

4 days

iv 10 mg/kg q24h

3.9 + 2.4

NA

3.5 + 1.8

NA

NA

NA

NA

E. faecalis Cordero

NA

3 days

iv 10 mg/kg q24h

2.1 + 2.1

NA

2.9 + 2.0

NA

NA

NA

NA

S. sanguis Poise

NA

2 days

iv 10 mg/kg q24 h

6.6 + 2.2

NA

2.0 + 1.5

NA

NA

NA

NA

E. faecalis from
bacteraemic patient

9.0 + 0.1

3 days

sc 10 mg/kg q12h

7.4 + 0.3

0/10

6.0 + 0.2

0/9

5.6 + 0.2

0/8

3.2 + 0.1

0/9

3.7 + 0.1

1/9

5.8 + 1.6

2/19

im penicillin G 1.2 mU
q12h
im penicillin G 1.2 mU
q12h, gentamicin
5 mg/kg q12h
NA

4.4 + 0.5

0/10

5 days

sc 10 mg/kg q12h, im
gentamicin 5 mg/kg
q12h
iv 100 mg/kg q24 h

4.7 + 2.0

2/17

NA

NA

Comparator 1 dosage

iv vancomycin
200 mg/kg/day
iv vancomycin 25 mg/kg
q12h
im nafcillin 100 mg/kg
q8h
iv vancomycin 25 mg/kg
q12h
im penicillin 600 000 U
q24h
im penicillin 600 000 U
q24h
im vancomycin 75 mg/kg
q12h
im vancomycin 75 mg/kg
q12h, im gentamicin
5 mg/kg q12h
iv vancomycin 50 mg/kg
q24h

No. of
sterilized
valves

No. of
sterilized
valves

NA, not available/applicable; iv, intravenously; sc, subcutaneously; im, intramuscularly; MSSA, methicillin-susceptible S. aureus; MRSA, methicillin-resistant S. aureus; VRE, vancomycin-resistant
Enterococcus; q8h, every 8 h; q12h, every 12 h; q24h, every 24 h.

Systematic review

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10

MRSE

8.0 + 1.7

4.6 + 2.4

iv vancomycin 17.5 mg/kg

q6h

6 days

E. faecalis

3/7

3/16

median 9.1
(6.410.3)

Eliopoulos et al. 20

median 3.5
(,2 5.1)

median 7.8
(,2 9.5),
or 3.4
(,2 9.6)

MSSA

Kennedy and
Chambers18
Kennedy and
Chambers18
Kennedy and
Chambers18
Kennedy and
Chambers18
Kennedy and
Chambers18
Bush et al. 19

sc cloxacillin 200 mg/kg

q5h

sc vancomycin 30 mg/kg
q12h, or 30 mg/kg q6h

Cantoni et al. 15

Hindes et al.

3/10, or
5/15

17/21, or
6/10, or
9/18, or
0/10

Bacterial inoculum

17

Comparator 2 dosage

Mean + SD
log10 cfu of
vegetation/g

No. of
sterilized
valves

Reference

Daptomycin dosage

Mean + SD
log10 cfu of
vegetation/g

Mean + SD
log10 cfu of
vegetation/g

Systematic review
administration of daptomycin varied between models (range
10% to 100%), but there was no difference between daptomycin
and glycopeptides in the individual models. None of the models
compared daptomycin with linezolid or quinupristin
dalfopristin.
MSSA endocarditis models. The available data from experimental models are contradictory. In one model, the administration of
daptomycin twice daily (5 mg/kg every 12 h) was more effective
in reducing bacterial counts of vegetations than 10 mg/kg of
daptomycin once daily and vancomycin twice daily.12 In two
other models, daptomycin in adequate dosage was either more
effective than or at least as effective as vancomycin, depending
on the strain used for infection.15,16 Finally, daptomycin was as
effective as antistaphylococcal penicillins in reducing bacterial
counts of aortic valve vegetations.15,18 Accordingly, more
excised valves were sterilized after the administration of daptomycin than with vancomycin; on the contrary, antistaphylococcal penicillins were as effective as daptomycin on this issue.
Enterococcus spp. endocarditis models. Enterococcus faecalis
was the infecting organisms in six models.10,14,17 20 In all of
them, treatment with daptomycin was as effective as glycopeptides and penicillins in reducing the bacterial count of aortic
valve vegetations. Daptomycin was more effective than amoxicillin or ampicillin alone when penicillin-resistant isolates were
used, but this difference was eliminated when the combination
of amoxicillin with gentamicin or ampicillin with sulbactam was
used.
VRE endocarditis models. Two models used VRE faecium as
the offending organism10,13 Daptomycin was as effective as teicoplanin for the reduction of bacterial counts of aortic valve
vegetations. The combination of daptomycin with gentamicin
was the single most effective regimen that resulted in a significant reduction of the bacterial counts of the vegetations as well
as an increased number of sterile valves. Daptomycin was more
effective than amoxicillin for the treatment of endocarditis due
to VRE faecium, but it was as effective as amoxicillin for VRE
faecalis endocarditis.10
Bacteraemia models. One experimental model with S. aureus
bacteraemia has been conducted, in which daptomycin was compared with vancomycin.21 Two different dosage regimens were
used for each antibiotic. There was no significant difference in
survival in any of the four treatment groups.

Bacteraemia. A summary of the evidence from published case

reports and case series to date with use of daptomycin for the treatment of patients with bacteraemia is shown in Table 3.28,34 44
A total of 41 cases was retrieved. Information regarding the demographics, clinical data, type of heart valve and other variables
were not reported in a few cases, thus the denominator varies in
the following proportions of cases; 58.5% (24/41) of the affected
individuals were men. The median age of patients was 58 years
(range 1887). Sixteen patients had haematological diseases
(including acute myeloid leukaemia) and nine of them had undergone bone marrow transplantation, four patients had chronic renal
failure, four had bone and joint infections, two had liver cirrhosis
and two had pyelonephritis. No history was available for 12 of the
included patients.
Blood cultures were performed and proved positive for all
but one of the reviewed patients. VRE (24/47 isolates, 51.1%)
was the predominant isolated pathogen followed by S. aureus
[12 isolates of MRSA (25.5%) and 2 isolates of MSSA (4.3%)].

Case reports and case series

Endocarditis. A summary of the evidence from published case
reports and case series to date with use of daptomycin for the
treatment of patients with bacterial endocarditis is shown in
Table 2.22 33 A total of 19 cases were retrieved. Information
regarding the demographics, clinical data, type of heart valve
and other variables were not reported in a few cases, thus the
denominator varies in the following proportions of cases; 47.3%
(9/19) of the affected individuals were men. The median age of
patients was 60.5 years (range 13 92). Prosthetic valve infective
endocarditis accounted for 10.5% (2/19) of cases. Three patients
had undergone bone marrow transplantation, three patients had
chronic renal failure, two had coronary artery disease and two
11

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had systemic lupus erythematosus. No history was available for

seven of the included patients.
Blood cultures were performed and proved positive for all
but one of the reviewed patients. S. aureus was the predominant
isolated pathogen (seven isolates of MRSA and five isolates of
MSSA) followed by VRE (four isolates). Vancomycinsusceptible E. faecalis, coagulase-negative Staphylococcus and
Corynebacterium striatum were the remaining isolates. One of
the blood cultures yielded two microorganisms (MRSA and
E. faecalis).
In most cases, the reason for administration of daptomycin
was treatment failure with other antibiotics (mainly vancomycin
15/19, 79%) or combinations of antibiotics. In one case, daptomycin was administered because there was increased possibility
for adverse effects from linezolid administration to a patient
with splenectomy and bone marrow transplantation. In another
patient, daptomycin was administered empirically because a staphylococcal infection was presumed. Finally, no reason was
reported for one case.
The median duration of daptomycin administration was 28
days (range 8 91). The outcome at the end of treatment was
good for the majority of patients with endocarditis treated with
daptomycin (11/19 cases, 57.8%). One of these patients died of
co-morbidity during the follow-up period and one more due to
relapse of the infection. The general status as well as the laboratory and/or imaging findings of three (15.8%) additional patients
improved after the administration of daptomycin; one of these
patients died after withdrawal of life support due to severe haemorrhagic pancreatitis and acute respiratory distress syndrome.
Failure of treatment with daptomycin was seen in five cases
(26.3%); four of these patients died. The overall mortality of the
reviewed case reports was 38.9% (7/18).
Information regarding the possible adverse effects associated
with daptomycin administration was available in 10 cases. Adverse
effects developed in five patients (50). Increase in the levels of
creatine kinase (CK) was reported in four of them; the remaining
patient developed mild deterioration of renal function. Two
patients discontinued treatment with daptomycin. One of
these patients required intubation after the development of
eosinophilic pneumonia that was attributed to the daptomycin
administration. None of the treated isolates developed resistance
or decreased susceptibility to daptomycin.

Table 2. Case reports and case series regarding the use of daptomycin for the treatment of patients with endocarditis

Reference

Sex/age

Akins et al. 22

M/13

Carlyn et al. 23

M/70

Cunha et al. 24

M/65

Reason for
daptomycin
administration
treatment failure,
co-morbidity

Site of infection

aplastic anaemia, BMT,

haemorrhagic pancreatitis,
perforated colon, ARDS
RA, DM, AF, AV and MV disease,
CRF, neuropathy, resected
adenocarcinoma of the rectum,
right TKP infection,
bacteraemia

aortic arch segment

vegetation, TV

VRE faecium

AV, epidural
abscess,
C3 C6
vertebral
osteomyelitis

1st MSSA 2nd

MSSA,
MRSA
SCV

arrhythmias, CAD, CA stent

placement, pacemaker insertion

MV, bacteraemia

MSSA

vancomycin/
meropenem/
gentamicin
1st oxacillin (42),
cefazolin (7) 2nd
vancomycin (54)/
rifampicin (21),
linezolid (14),
vancomycin (12)/
rifampicin (10)/
minocycline (4)/
gentamicin (7)
none

previous MSSA endocarditis

AV, bacteraemia

MSSA

none

history of
cephalosporin
sensitivity

vegetation on the
pacemaker
wire,
bacteraemia
MV, bacteraemia

MRSA

vancomycin (25)

MRSA

Development of
daptomycin
resistance during
treatment

Follow-up
duration
(months)

Outcome

Adverse effects

6 mg/kg/day (2)
8 mg/kg/day
(6)
6 mg/kg every 2
days
daptomycin/
rifampicin/
minocycline
(74)/gentamicin
(5)

NA

improvement,
died

NA

none

NA

improvement

3 months,
relapse,
patient died
due to
MOF

none

no

cure

28 days after
end of
daptomycin
treatment,
no relapse

none

no

failure

NA

eosinophilic
pneumonia

treatment failure

6 mg/kg/day (9),
then 12 mg/kg/
day (41)
daptomycin/
linezolid (9),
daptomycin/
gentamicin (8)
daptomycin
treatment was
discontinued
after 14 days
7 mg/kg/day (29)

yes, within a
single strain
of MRSA

failure, died

NA

NA

treatment failure

6 mg/kg/day (8)

yes

died

no

NA

treatment failure

6 mg/kg/day (8)

NA

cure

NA

treatment failurea

empirical treatment
with
daptomycin for
a presumed
staphylococcal
infection

Hirschwerk et al. 26

F/92

permanent pacemaker, history of

MRSA bacteraemia,
endophthalmitis

Paez et al. 27

F/37

Segreti et al. 28

M/50

CML, chemotherapy, AML,

allogenic bone marrow
transplantation
NA

IE-L, bacteraemia

MRSA

vancomycin,
imipenem/cilastatin,
clindamycin
vancomycin

F/89

NA

IE-U, bacteraemia

MRSA

vancomycin

treatment failure

6 mg/kg/day (22)

NA

cure

NA

F/57
F/64

NA
haemodialysis, prosthetic MV,
history of MSSA endocarditis

IE-L, bacteraemia
IE-L, bacteraemia

MRSA
VRE

vancomycin
none

treatment failure
NA

6 mg/kg/day (43)
6 mg/kg/day (7,
15b)

NA
NA

cure
died

NA
NA

F/70

NA

IE-L, bacteraemia

MSSA

vancomycin

treatment failure

6 mg/kg/day (37)

NA

NA

M/78

NA

IE-L

negative

treatment failure

NA

NA

NA
NA
PICC line for iv hyperalimentation
due to hyperemesis gravidum
(third trimester of pregnancy)

IE-L, bacteraemia
IE-L, bacteraemia
TV

CoNS
VRE
MSSA

6 mg/kg/day
(35, 25b)
6 mg/kg/day (6, 3b)
6 mg/kg/day (27)
6 mg/kg/day (49)

NA

M/75
M/51
F/33

vancomycin,
gentamicin
vancomycin
vancomycin
piperacillin/tazobactam,
vancomycin,
cefazolin (28)

cure (patients
condition
resolved
with
cefazolin)
cure

CK elevation
.10-fold
versus baseline
CK elevation
.10-fold
versus baseline
NA
CK elevation
.10-fold
versus baseline
(from 28 to
281 U/L)
NA

NA
NA
no

cure
died
cure

NA
NA
fifth week of
daptomycin
therapy
TTE, no
TV
vegetation

NA
NA
NA

Cunha et al. 29

treatment failure
treatment failure
treatment failure

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12

Co-morbidity

Dosage and
duration of
daptomycin
treatment (days)

Systematic review

Hayes et al. 25

Isolated
pathogens

Previous antibiotic
treatment (duration,
days)

Mohan et al. 30

M/75

Shah and Murillo31

F/46

Stevens and
Edmond32

F/25

Veligandla et al. 33

F/26

right knee replacement, DM, CAD,

CHF, CABG, AV replacement,
non-ST elevation MI
haemodialysis-dependent CRF,
removal of infected femoral
graft used to repair a
pseudoaneurysm
SLE, ESRD, MV regurgitation,
haemolytic anaemia, MV
replacement

prosthetic AV

MRSA

vancomycin (9),
linezolid (2)

TV

C. striatum

linezolid, vancomycin

prosthetic MV

VRE faecium

linezolid (10)

not a candidate for

surgery,
possible
treatment failure

splenectomy, autologous BMT,

ITP, SLE, disc herniation

MV

MRSA,
E. faecalis

quinupristin/dalfopristin
(18), linezolid/
tobrarmycin/
rifampicin (10)

high risk for

adverse effects
related to
linezolid

treatment failure,
patient refused
surgery
treatment failure,
allergy to
vancomycin

6 mg/kg/day (11)

no

cure

NA

6 mg/kg/every 2
days (42)
daptomycin/
rifampicin
8 mg/kg/day
(14, 77)
daptomycin/
gentamicin/
rifampicin
6 mg/kg/day (15)

no

cure

no

cure

3 months, no
recurrence
of
endocarditis
4 months, died
of unknown
cause

NA

improvement,
discontinued
due to AE

6 weeks, TEE,
marked
decrease of
vegetation
size

slow deterioration
of renal
function
none

NA

severe muscle
aches, CK
increase from
2 to 492 U/L
on 15th day of
daptomycin
therapy

Systematic review

Downloaded from http://jac.oxfordjournals.org/ by guest on December 13, 2015

13

AE, adverse effects; AF, atrial fibrillation; AV, aortic valve; CA, coronary artery; CK, creatine kinase; iv, intravenous; MV, mitral valve; NA, not available data; TEE, transoesophageal echocardiogram;
TV, tricuspid valve.
Co-morbidities: AML, acute myelogenous leukaemia; ARDS, acute respiratory distress syndrome; BMT, bone marrow transplantation; CABG, coronary artery bypass graft; CAD, coronary artery disease;
CHF, congestive heart failure; CML, chronic myelogenous leukaemia; CRF, chronic renal failure; DM, diabetes mellitus; ESRD, end stage renal disease; IE-L, left-sided infective endocarditis; IE-U, infective endocarditis with unknown valvular involvement; ITP, idiopathic thrombocytopenic purpura; MI, myocardial infarction; MOF, multiple organ failure; PICC, peripherally inserted central catheter;
RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TKP, total knee prosthesis.
Responsible pathogens: CoNS, coagulase negative Staphylococcus; MRSA (SCV), methicillin-resistant S. aureus (small colony variant); MSSA, methicillin-susceptible S. aureus; VRE, vancomycinresistant Enterococcus.
a
Patient developed complications (5 mm mobile density on the aortic valve verified by transoesophageal echocardiography, C3 C6 osteomyelitis, a posterior epidural abscess verified by MRI, an embolic
splenic infarct and progressive renal failure) while being treated for bacteraemia that necessitated cardiac and neurosurgical interventions.
b
Patient was discharged and readmitted.

Table 3. Case reports and case series regarding the use of daptomycin for the treatment of patients with bacteraemia

Site of infection

Burns34

M/54

morbid obesity, chronic

right hip arthroplasty
infection

bacteraemia

MRSA

levofloxacin,
vancomycin
(3),
vancomycin/
gentamicin (4)

treatment failure

Green et al. 35

F/62

bacteraemia

M/74

P. aeruginosa,
K. pneumoniae,
Enterococcus
spp., E. durans
VRE faecium

cefazolin,
levofloxacin

Kvirikadze
et al. 36

myelofibrosis, allogenic
bone marrow transplant,
acute-on-chronic RF,
haemodialysis
CAD, HT, DM, AML

ceftazidime

Dosage and
duration of
daptomycin
treatment (days)

Development
of daptomycin
resistance
during
treatment

Outcome

Follow-up
duration
(months)

Adverse effects

no

cure

15 days after
end of
treatment,
no relapse

increase in serum
Cr levels
(2.3 mg/dL)

treatment failure
and known
history of
VRE
treatment failure

6 mg/kg/day
daptomycin/
rifampicin/
vancomycin/
gentamicin (4),
6 mg/kg/every 2
days
daptomycin/
rifampicin (38),
6 mg/kg/day
daptomycin/
rifampicin (14)
6 mg/kg/every 2
days (20)

yes

cure with
linezolid
administration

NA

NA

4 mg/kg/day (14)

no

cure

NA

none

14

Endometrial Ca, total

hysterectomy, bilateral
salpingo-oophorectomy,
chemotherapy, acute
cholecystitis,
percutaneous
cholecystectomy
AML, non-myeloablative
allogeneic HscT,
GVHD

bacteraemia

methicillin-resistant
Staphylococcus
lugdunensis,
VRE faecium

vancomycin/
piperacillin/
tazobactam/
tobramycin

treatment failure

4 mg/kg/day (26)

no

cure

NA

none

bacteraemia,
osteomyelitis,
discitis

MRSA

linezolid (4),
vancomycin/
gentamicin (3)

treatment failure

6 mg/kg/day
daptomycin/
gentamicin
(21,6)

yes

improvement

none

treatment failure

daptomycin/
meropenem/
caspofungin/
metronidazole/
levofloxacin/
aciclovir 6 mg/
kg/day (10)
6 mg/kg/day (1),
then 3 mg/kg/
every 12 days
(15)
1st 6 mg/kg/day
(1), then
2.25 mg/kg/
every 18 h (13)
2nd 6 mg/kg/
day (1), then
2.25 mg/kg/
every 18 h, then
4 mg/kg/day
(14)

NA

failure

12 days after
discharge,
MRSA in
blood
cultures
died on
hospital day
36

NA

cure

30, survived

NA

failure

30, survived

Marty et al. 37

M/61

Papadopoulos
et al. 38

F/45

refractory AML,
chemotherapy

bacteraemia

VRE faecium

Poutsiaka
et al. 39

M/49

AML, allogenic HscT

bacteraemia

VRE faecium

linezolid (14),
linezolid/
aztreonam/
levofloxacin/
aciclovir/
amphotericin/
azithromycin
none

M/70

AML

bacteraemia

VRE faecium

none

according to
protocol (B)a

according to
protocol (B)a

increased CPK
(996 U/L)f,
urine
myoglobin
(30 890 ng/
mL), Cr levels
(1.9 mg/dL)
NA

Cr clearance
20 mL/min

Systematic review

Sex/age

bacteraemia

Isolated pathogens

Reason for
daptomycin
administration

Reference

F/58

Co-morbidity

Previous
antibiotic
treatment
(duration, days)

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Segreti
et al. 28

AML, allogenic HscT

bacteraemia

VRE faecium

none

according to
protocol (B)a

M/66

AML

bacteraemia

VRE faecium

none

M/61

MDS progressed to AML

bacteraemia

VRE faecium

none

M/25

AML, allogenic HscT

bacteraemia

VRE faecium

none

F/58

AML, allogenic HscT

bacteraemia

VRE faecium

none

according to
protocol (B)a
according to
protocol (A)a
according to
protocol (A)a
according to
protocol (B)a

M/38

AML, autologous HscT

bacteraemia

VRE faecalis

none

M/59

lymphoma, CLL, allogenic

HscT

bacteraemia

VRE faecium

none

F/69

bacteraemia

VRE

none

NA

M/55
F/47
M/59
M/41

DM, COPD, ChHF,

haemodialysis
NA
NA
NA
septic joint

bacteraemia
bacteraemia
bacteraemia
bacteraemia

MRSA
VRE
VRE
MSSA

vancomycin
linezolid
vancomycin
none

treatment failure
treatment failure
treatment failure
NA

F/87

septic arthritis

bacteraemia

MRSA

treatment failure

F/48

NA

bacteraemia

VRE

vancomycin,
gentamicin
none

M/45
M/30
M/55
M/68
F/63
F/60
M/59
M/53
M/87

NA
NA
NA
pulmonary aspergillosis
NA
NA
NA
NA
NA

bacteraemia
bacteraemia
bacteraemia
bacteraemia
bacteraemia
bacteraemia
bacteraemia
bacteraemia
bacteraemia

MSSA
MRSA
MRSA
VRE
VRE
VRE
MRSA
VRE
MRSA

F/37

UTI, pyelonephritis,
nephrolithiasis
infected decubitus
osteomyelitis, septic
arthritis

bacteraemia

VRE

bacteraemia
bacteraemia

MRSA
MRSA

F/79
F/58

Mangili
et al. 40

M/54

alcohol-related cirrhosis,
ESLD, spontaneous
bacterial peritonitis,
hepatic encephalopathy,
variceal bleeding

bacteraemia

MRSA

Munoz-Price
et al. 41

F/64

cryptogenic cirrhosis,
haemodialysis,
penicillin allergy

bacteraemia

VRE faecalis

according to
protocol (B)a
according to
protocol (B)a

6 mg/kg/day (1),
then 4.5 mg/kg/
every 36 h (9)
6 mg/kg/day (14)

NA

failure

30, died

Cr clearance
32 mL/min

NA

cure

30, survived

NA

4 mg/kg/day (14)

NA

cure

30, survived

NA

4 mg/kg/day (10)

NA

cure

30, survived

NA

6 mg/kg/day (1),
then 3 mg/kg/
every 12 h (8)
4 mg/kg/day (3)

NA

failure

30, died

NA

NA

failure

NA

NA

failure

NA

Cr clearance
,10 mL/min
Cr clearance
56 mL/min

NA

failure

NA

NA

NA
NA
NA
NA

cure
cure
died
cure

NA
NA
NA
NA

NA
NA
NA
NA

NA

cure

NA

NA

NA

cure

NA

NA

NA
NA
NA
NA
NA
NA
NA
NA
NA

cure
cure
cure
died
died
cure
cure
cure
cure

NA
NA
NA
NA
NA
NA
NA
NA
NA

NA
NA
NA
NA
NA
NA
NA
NA
NA

6 mg/kg/day (1),
then 4.5 mg/kg/
every 36 h (2)
6 mg/kg/day (3)

vancomycin
vancomycin
none
none
none
linezolid
vancomycin
vancomycin
vancomycin,
quinupristin/
dalfopristin
linezolid

treatment failure
treatment failure
NA
NA
NA
treatment failure
treatment failure
treatment failure
treatment failure

6 mg/kg/day (6)
6 mg/kg/day (13)
6 mg/kg/day (10)
6 mg/kg/day (9,
23b)
6 mg/kg/day (22,
2b)
4, 6 mg/kg/dayc,
(3, 3b)
6 mg/kg/day (14)
6 mg/kg/day (14)
6 mg/kg/day (10)
6 mg/kg/day (13)
6 mg/kg/day (12)
6 mg/kg/day (9)
4 mg/kg/day (36)
6 mg/kg/day (8)
6 mg/kg/day (28)

treatment failure

6 mg/kg/day (20)

NA

cure

NA

NA

cefazolin
vancomycin,
linezolid,
quinupristin/
dalfopristin
ceftriaxone (1),
vancomycin
(10), linezolid
(7)

treatment failure
treatment failure

6 mg/kg/day (28)
6 mg/kg/day (42)

NA
NA

cure
cure

NA
NA

NA
NA

treatment failure

4 mg/kg/day (4)
6 mg/kg/day
(23)

yes

failure

NA

linezolid,
ciprofloxacin

treatment failure

400 mg/every 2
daysd
daptomycin/
amikacin

yes

improvement

4 days, resolution of
bacteraemia
after switch
to linezolid,
vancomycin/
gentamicin
15 days after discharge VRE
faecalis in
blood
cultures,
died

NA

Systematic review

15

F/50

NA

Continued

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Table 3. Continued

Co-morbidity

Site of infection

Lewis et al. 42

M/22

Hodgkins lymphoma,
AML, NSTC, focal
pyelonephritis

bacteraemia

1st VRE faecium

2nd Escherichia
coli, VRE

Golan et al. 43

F/18

Hodgkins lymphoma,
allogenic BMT, GVHD

bacteraemia

Leuconostoc
mesenteroides

M/35

AML, allogeneic BMT,

renal insufficiency,
penicillin allergy

bacteraemia

M/51

multiple fractures and

internal injuries
secondary to a 50 ft fall

bacteraemia

Leuconostoc
mesenteroides,
Staphylococcus
epidermidis
(CSF culture)
S. pneumoniae

F/58

right parietal haemorrhage,

MV replacement,
warfarin therapy

bacteraemia

S. aureus

Garrison
et al. 44

Isolated pathogens

1st chemotherapy
doxycycline/
cefepime/
metronidazole/
vancomycin
2nd
chemotherapy
meropenem
ciprofloxacin/
trimethoprim/
sulfamethoxazole/
aciclovir,
imipenem/
vancomycin,
vancomycin/
cefepime/
amphotericin
cefepime/
penicillin/
vancomycin

Reason for
daptomycin
administration

Dosage and
duration of
daptomycin
treatment (days)

Development
of daptomycin
resistance
during
treatment

Outcome

Follow-up
duration
(months)

Adverse effects

treatment failure

6 mg/kg/day
daptomycin/
cefepime/
metronidazole
(17)

yes

failure

resolution of
bacteraemia
after switch
to linezolid/
doxycycline

NA

treatment failure

loading dose:
400 mg, 4.5 mg/
kg every 1.5
day (8), 6 mg/
kg/day (15)

no

cure

4 days after
end of
treatment
remained
afebrile

NA

treatment failure

6 mg/kg/day
daptomycin/
cefepime (3,23)

no

cure

none

none

according to a
therapeutic
protocole

2 mg/kg/day (3)

NA

failure

none

according to a
therapeutic
protocole

2 mg/kg/day (3)

NA

failure, died

died 1 month
later due to
complications of
leukaemia
resolution of
bacteraemia
after switch
to
ampicillin
blood culture
obtained
before
autopsy
revealed
S. aureus

NA

NA

AV, aortic valve; Cr, creatinine; CSF, cerebrospinal fluid; MV, mitral valve; NA, not available; MOF, multiple organ failure.
Co-morbidities: AML, acute myelogenous leukaemia; AF, atrial fibrillation; BMT, bone marrow transplantation; Ca, carcinoma; CAD, coronary artery disease; ChHF, chronic heart failure; CLL, chronic
lymphocytic leukaemia; CM, cardiomyopathy; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ESLD, end stage liver disease; GVHD, graft-versus-host disease; HscT, haematopoietic
stem-cell transplantation; HT, hypertension; MDS, myelodysplastic syndrome; NSTC, non-seminomatous testicular carcinoma; RA, rheumatoid arthritis; RF, renal failure; TKR, total knee replacement; UTI,
urinary tract infection.
Responsible pathogens: MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; VRE, vancomycin-resistant Enterococcus.
a
All patients that participated in this open label emergency use trial were given daptomycin (one of the two dosing regimens) according to the protocol A (4 mg/kg iv every 24 h) or B (initial loading dose
6 mg/kg iv, and then 3 mg/kg iv every 12 h or 6 mg/kg iv every 24 h). Doses were adjusted for renal insufficiency.
b
Patient was discharged and readmitted.
c
Patient initially received 4 mg/kg for 2 days, and then was switched to 6 mg/kg.
d
The time interval between patients admissions and discharges was few days to 2 weeks. Patient discharged with a prescribed regimen of daptomycin 400 mg every 48 h and amikacin during
haemodialysis.
e
The patient was enrolled in a multicentre randomized study to evaluate the safety and efficacy of DAP as compared with conventional therapy in the treatment of Gram-positive infections.
f
A diagnosis of rhabdomyolysis was made based on the increases in CPK level (from 108 U/L at baseline to 996 U/L) and urine myoglobin level (to 30 890 ng/mL) in a patient with acute renal failure.

Systematic review

Sex/age

16

Reference

Previous
antibiotic
treatment
(duration, days)

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Systematic review

Randomized controlled trials

Only one open-label RCT45 was conducted comparing daptomycin with antistaphylococcal penicillins or vancomycin (standard
therapy), in combination with gentamicin for the treatment of
patients with endocarditis or bacteraemia due to methicillinsusceptible and methicillin-resistant S. aureus. Patients were randomly assigned with the use of a centralized computer-generated
block randomization schedule that was designed to achieve a 1:1
ratio of patients. All data were reviewed regularly by an independent committee. Of the 246 randomized patients, 235 were eligible for the analysis of effectiveness. Overall, daptomycin and
standard therapy were equally effective for the treatment of
patients with endocarditis and bacteraemia (61% versus 60.9%
at the end of treatment and 44.2% versus 41.7% at the
test-of-cure visit 42 days after the end of treatment). Success
rates favoured daptomycin over vancomycin among patients
who were infected with MRSA (44.4% for daptomycin versus
31.8% for standard therapy, P 0.28), but were higher among
patients receiving standard therapy for MSSA infection (44.6%
for daptomycin versus 48.6% for standard therapy, P 0.74).
The authors did not distinguish between patients with definite
endocarditis and bacteraemia on this issue. In patients with baseline diagnosis of definite and possible MRSA endocarditis, daptomycin was also more effective than standard therapy, but
without statistical significance (41.7% versus 28.9%).
Daptomycin was as effective as standard therapy for the treatment of patients with staphylococcal (both MRSA and MSSA)
definite endocarditis (32.1% versus 36.0%) and bacteraemia
(47.8% versus 43.3%). Patients with MRSA bacteraemia and
right-sided endocarditis showed similar success rates when
treated with either daptomycin or vancomycin, suggesting that
daptomycin may be considered an alternative to vancomycin in
the management of these infections.
Elevated CK levels were reported in more patients treated
with daptomycin (6.7% versus 0.9%, P 0.04), while more

Discussion
The available evidence regarding the treatment of patients with
endocarditis and bacteraemia due to Gram-positive cocci with
daptomycin is limited. The most reliable information comes
from the single multicentre RCT conducted on this issue, which
had some important limitations. The most important of these
limitations was the small number of enrolled patients with final
diagnosis of endocarditis and especially those with left-sided
endocarditis. However, this RCT provides valuable information
regarding patients with bacteraemia. Daptomycin seems to be an
equal alternative to vancomycin and antistaphylococcal penicillins for the treatment of patients with S. aureus bacteraemia.
In the majority of the relevant case reports, daptomycin was
administered when treatment of patients with endocarditis or
bacteraemia with other potentially effective antibiotics (including glycopeptides and linezolid) had failed. Thus far, vancomycin and, in patients who can not tolerate vancomycin or
treatment had failed, linezolid are the recommended antibiotics
for the treatment of patients with endocarditis due to
multidrug-resistant Gram-positive cocci according to the
American Heart Association.46,47 The available data suggest that
daptomycin could also be considered for the treatment of
patients with endocarditis due to Gram-positive cocci, but more
data are necessary.
In the published case reports, several patients receiving treatment with daptomycin for bacteraemia or endocarditis had a
17

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patients receiving standard therapy had renal impairment (18.1%

versus 6.7%, P 0.009). The number of patients treated with
gentamicin was higher in the standard therapy group (93%
versus 0.8%). The MIC for seven isolates increased from baseline values in patients treated with daptomycin, but none of
these isolates developed resistance to daptomycin; however, six
of these seven patients had microbiological failure. Increase in
the MIC of vancomycin was also noticed in four isolates.
Finally, mortality was similar between the compared regimens
(15% versus 16%).
Several limitations of this RCT should be taken into account.
First, the number of enrolled patients with left-sided S. aureus
endocarditis was very small and the treatment success in this
group of patients was very low (11.1% versus 22.2% for daptomycin and standard therapy, respectively). Second, although not
statistically significant, treatment failure due to persistent or
relapsing S. aureus infection was more common in the daptomycin than the standard therapy group (15.8% versus 9.6%, P
0.17). On the other hand, treatment failure due to discontinuation of antibiotic administration because of adverse effects
(mainly impairment of renal function) was more common in the
standard therapy than the daptomycin group (14.8% versus
6.7%, P 0.06); gentamicin was administered to more patients
in the standard therapy group. Third, the criteria for treatment
success were very strict and consequently, the reported clinical
success was very low. The authors considered as treatment
failure all patients that did not have a blood culture drawn at the
test-of-cure visit 42 days after the end of treatment, regardless of
their clinical status. Similarly, all patients who discontinued
treatment due to adverse effects associated with study antibiotics
were considered as treatment failures. Finally, only patients with
S. aureus infections were enrolled in this RCT.

Gram-negative bacteria (three isolates), coagulase-negative

Staphylococcus
(two
isolates),
vancomycin-resistant
Leuconostoc mesenteroides (two isolates), vancomycinsusceptible Enterococcus durans (one isolate) and Streptococcus
pneumoniae (one isolate) were the remaining isolates.
In most cases, the reason for administration of daptomycin
was treatment failure with another antibiotic [mainly vancomycin (16/33, 48.5%) and linezolid (8/33, 24.2%)] or a combination
of antibiotics. In 11 cases, daptomycin was administered according to a therapeutic protocol. No reason was reported for five
cases.
The median duration of daptomycin administration was 14
days (range 3 56). The outcome at the end of treatment was
good for the majority of patients with bacteraemia treated with
daptomycin (27/41 cases, 65.9%). One of these patients died of
co-morbidity during the follow-up period. Failure of treatment
with daptomycin was seen in 14 cases (34.1%); 10 of these
patients died. The overall mortality of the reviewed case reports
was 26.8% (11/41). Adverse effects developed in six patients for
whom data on this issue were available. Increase in the levels of
creatinine kinase (CK) was reported in one of them; the other
patients developed renal failure. Five of the treated isolates
developed resistance to daptomycin during the treatment period.
However, no data were available for 32 patients.

Systematic review
reported de novo development of resistance is a major concern
that may limit its use for the treatment of life-threatening infections. The combination of daptomycin with other antibiotics
active against multi-antibiotic resistant strains could result in
better outcomes and fewer cases of daptomycin-resistant
Gram-positive cocci. However, there are no clinical data supporting this issue. Accordingly, daptomycin should be used with
caution and preferably when standard treatments have failed, in
order to preserve this potentially effective drug for future use.

history of acute leukaemia or had received haemopoietic stemcell transplantation. These patients are at higher risk for development of infections and increased mortality. Daptomycin seems
to be an alternative choice for the treatment of such patients,
especially when treatment with vancomycin has failed.
Although linezolid can also be effective, its administration for a
long period is associated with haematological adverse effects
that may prohibit its use in patients with haematological
abnormalities.
The available experimental models suggested that the combination of daptomycin with rifampicin or gentamicin could
enhance its activity in vivo against MRSA and VRE. However,
in the single RCT conducted on the issue, daptomycin was
barely ever combined with any other antibiotic. On the contrary,
gentamicin was added in 93% of the patients treated with vancomycin or antistaphylococcal penicillins. Whether this could
explain the non-significant more treatment failures reported for
daptomycin in patients with persistent S. aureus infections
enrolled in the RCT should be an issue of further research. Data
from animal studies can be used as a guide for future research,
but should never be considered as strong evidence for treatment
options in humans.
The main adverse effect noted in the studied patients was
myopathy associated with an increase in CK serum levels.
Animal studies have demonstrated that myopathy was specific to
skeletal muscles. The skeletal myopathy was associated with
minimal degeneration that was associated with inflammation at
high doses; the inflammation did not further contribute to
muscle damage, and there was regeneration without fibrosis.48 In
one of the case reports, the authors stated that rhabdomyolysis
also occurred. Others also reported cases of renal damage
associated with the use of daptomycin. It should be noted that
increased caution is required in treating patients with renal dysfunction because prolonged exposure to higher serum levels of
daptomycin may elicit myopathy, which in turn may deteriorate
renal function.
Development of resistance is among the most important
issues regarding antibiotic use. There are several reports of
increase in the minimal inhibitory concentration or de novo
development of resistance during treatment with daptomycin. In
many of these reports, these phenomena were associated with
treatment failures or even death. It is noteworthy that in these
reports the duration of daptomycin administration was relatively
short (range 14 27 days). Future studies should try to evaluate
whether the combination of daptomycin with other antibiotics
effective against Gram-positive bacteria would reduce the
resistance rates reported to date for daptomycin.
Further research is needed regarding the most appropriate
regimen for the treatment of patients with endocarditis due to
resistant Gram-positive cocci like MRSA, methicillin-resistant
coagulase-negative staphylococci and VRE. The currently available antibiotics (vancomycin, teicoplanin, linezolid, daptomycin,
tigecycline and dalbavancin) are promising, but RCTs comparing these agents are lacking while treatment failure and mortality remain high. Therefore, more data are also needed
regarding the effectiveness of combination therapy with rifampicin and/or aminoglycosides.
In conclusion, although daptomycin has already been
approved for the treatment of patients with right-sided endocarditis and bacteraemia, the available evidence is limited and
further evaluation of the antibiotic is warranted. The commonly

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