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Daptomycin for endocarditis and/or bacteraemia: a systematicreview of the experimental and clinical evidence
Matthew E. Falagas1,2*, Konstantina P. Giannopoulou1, Fotinie Ntziora1
and Konstantinos Z. Vardakas1
1Alfa 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
Background: Endocarditis and bacteraemia are devastating infections with high mortality. Gram-
positive 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 activeagainst 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.
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 aureusbacteraemia 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 ofpatients 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 develop-
ment 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
Introduction
Endocarditis and bacteraemia are devastating infections associ-
ated with considerable mortality, which reaches 16% to 25% ofthe affected individuals.
14Their microbiology includes both
Gram-positive and Gram-negative bacteria as well as fungi.
Among the Gram-positive microbes, the highly resistant staphy-
lococcal and enterococcal species are of extreme importance
because they are related with more severe disease and higher
mortality.5
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, isa 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
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
*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: [email protected]
Journal of Antimicrobial Chemotherapy (2007) 60, 719
doi:10.1093/jac/dkm137
Advance Access publication 4 June 2007
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
# The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.For Permissions, please e-mail: [email protected]
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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 ofdaptomycin 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 appro-
priate 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.
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 eli-
gible 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 of1 blood sample
that yielded Gram-positive cocci (2 for coagulase-negative staphy-
lococci) and clinical profile compatible with a diagnosis of bacterae-
mia with one of the following findings: fever, chills, leucocytosis
with prominent left shift, changes in vital signs, signs of septicshock (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 dap-
tomycin 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 admin-
istration 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
treatment, adverse events due to the studied medications and mor-
tality 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 infor-
mation provided by the authors of each case report. Treatment
outcome was defined as improvement when there were no signs ofpersistent infection (negative blood cultures, no evidence of persist-
ent 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, symp-
toms and laboratory or imaging findings of infective endocarditis or
bacteraemia despite appropriate antibiotic treatment with daptomy-
cin, relapse of the infection or death due to infective endocarditis or
bacteraemia or their complications.
ResultsIn 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.
Experimental models
A summary of the available evidence regarding the effectiveness
of daptomycin for the treatment of endocarditis in experimentalmodels is shown in Table 1.
1020Eleven 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 vancomycin-
resistant Enterococcus (VRE) and seven strains of vancomycin-
susceptibleEnterococcus].
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 veri-
fied 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
Systematic review
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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 experimen-
tal models are contradictory. In one model, the administration of
daptomycin twice daily (5 mg/kg every 12 h) was more effectivein 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 dapto-
mycin than with vancomycin; on the contrary, antistaphylococ-
cal penicillins were as effective as daptomycin on this issue.
Enterococcus spp. endocarditis models. Enterococcus faecalis
was the infecting organisms in six models.10,14,1720
In all of
them, treatment with daptomycin was as effective as glycopep-tides and penicillins in reducing the bacterial count of aortic
valve vegetations. Daptomycin was more effective than amoxi-
cillin 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 tei-
coplanin 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 signifi-
cant reduction of the bacterial counts of the vegetations as well
as an increased number of sterile valves. Daptomycin was moreeffective than amoxicillin for the treatment of endocarditis due
to VRE faecium, but it was as effective as amoxicillin for VRE
faecalisendocarditis.10
Bacteraemia models. One experimental model with S. aureus
bacteraemia has been conducted, in which daptomycin was com-
pared 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.
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 2.2233
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 1392). 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
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). Vancomycin-
susceptible E. faecalis, coagulase-negative Staphylococcus and
Corynebacterium striatum were the remaining isolates. One of
the blood cultures yielded two microorganisms (MRSA andE. 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, dapto-
mycin 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 sta-
phylococcal 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 ofco-morbidity during the follow-up period and one more due to
relapse of the infection. The general status as well as the labora-
tory 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 hae-
morrhagic 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. Twopatients 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.
Bacteraemia. A summary of the evidence from published case
reports and case series to date with use of daptomycin for the treat-
ment of patients with bacteraemia is shown in Table 3.28,3444
A total of 41 cases was retrieved. Information regarding the demo-
graphics, 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 18 87). Sixteen patients had haematological diseases
(including acute myeloid leukaemia) and nine of them had under-
gone 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%)].
Systematic review
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Mohanet al.30 M/75 right knee replacement, DM, CAD,
CHF, CABG, AV replacement,
non-ST elevation MI
prostheti c AV MRSA vancomyci n (9),
linezolid (2)
treatment failure,
patient refused
surgery
6 mg/kg/day (11) no
Shah and Murillo31 F/46 haemodialysis-dependent CRF,
removal of infected femoral
graft used to repair a
pseudoaneurysm
TV C. striatum linezolid, vancomycin treatment failure,
allergy to
vancomycin
6 mg/kg/every 2
days (42)
daptomycin/
rifampicin
no
Stevens and
Edmond32F/25 SLE, ESRD, MV regurgitation,
haemolytic anaemia, MV
replacement
prostheti c MV VR Efaecium l in ez ol id ( 10 ) n ot a ca nd id at e f or
surgery,
possible
treatment failure
8 mg/kg/day
(14, 77)
daptomycin/
gentamicin/
rifampicin
no
Veligandlaet al.33 F/26 splenectomy, autologous BMT,
ITP, SLE, disc herniation
MV MRSA,
E. faecalis
quinupristin/dalfopristin
(18), linezolid/tobrarmycin/
rifampicin (10)
high risk for
adverse effectsrelated to
linezolid
6 mg/kg/day (15) NA
AE, adverse effects; AF, atrial fibrillation; AV, aortic valve; CA, coronary artery; CK, creatine kinase; iv, intravenous; MV, mitral valve; NA, not availablTV, tricuspid valve.Co-morbidities: AML, acute myelogenous leukaemia; ARDS, acute respiratory distress syndrome; BMT, bone marrow transplantation; CABG, coronary artCHF, congestive heart failure; CML, chronic myelogenous leukaemia; CRF, chronic renal failure; DM, diabetes mellitus; ESRD, end stage renal disease; IE-tive endocarditis with unknown valvular involvement; ITP, idiopathic thrombocytopenic purpura; MI, myocardial infarction; MOF, multiple organ failurRA, 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, methicresistant Enterococcus.aPatient developed complications (5 mm mobile density on the aortic valve verified by transoesophageal echocardiography, C3C6 osteomyelitis, a posteriosplenic infarct and progressive renal failure) while being treated for bacteraemia that necessitated cardiac and neurosurgical interventions.b
Patient was discharged and readmitted.13
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Table 3. Case reports and case series regarding the use of daptomycin for the treatment of patients with bacteraemia
Referen ce Sex/age Co -morbidity Site of in fection Isolated path ogens
Previous
antibiotic
treatment
(duration, days)
Reason for
daptomycin
administration
Dosage and
duration of
daptomycin
treatment (days)
Development
of daptomycin
resistance
during
treatment
Burns34 M/54 morbid obesity, chronic
right hip arthroplasty
infection
bacteraemia MRSA levofloxacin,
vancomycin
(3),vancomycin/
gentamicin (4)
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)
no
Greenet al.35 F/62 myelofibrosis, allogenic
bone marrow transplant,
acute-on-chronic RF,
haemodialysis
bacteraemia P. aeruginosa,
K. pneumoniae,
Enterococcus
spp., E. durans
cefazolin,
levofloxacin
treatment failure
and known
history of
VRE
6 mg/kg/every 2
days (20)
yes
Kvirikadze
et al.36
M/74 CAD, HT, DM, AML bacteraemia VRE faecium ceftazidime treatment failure 4 mg/kg/day (14) no
F/58 Endometrial Ca, total
hysterectomy, bilateral
salpingo-oophorectomy,
chemotherapy, acute
cholecystitis,
percutaneous
cholecystectomy
bacteraemia methicillin-resistant
Staphylococcus
lugdunensis,
VRE faecium
vancomycin/
piperacillin/
tazobactam/
tobramycin
treatment failure 4 mg/kg/day (26) no
Martyet al.37 M/61 AML, non-myeloablative
allogeneic HscT,
GVHD
bacteraemia,
osteomyelitis,
discitis
MRSA linezolid (4),
vancomycin/
gentamicin (3)
treatment failure 6 mg/kg/day
daptomycin/
gentamicin
(21,6)
yes
Papadopoulos
et al.38
F/45 refractory AML,
chemotherapy
bacteraemia VRE faecium linezolid (14),
linezolid/
aztreonam/
levofloxacin/
aciclovir/
amphotericin/
azithromycin
treatment failure daptomycin/
meropenem/
caspofungin/
metronidazole/
levofloxacin/
aciclovir 6 mg/
kg/day (10)
NA
Poutsiakaet al.
39 M/49 AML, allogenic HscT bacteraemia VRE faecium none according toprotocol (B)a6 mg/kg/day (1),
then 3 mg/kg/
every 12 days
(15)
NA
M/70 AML bacteraemia VRE faecium none according to
protocol (B)a
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
14
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Gram-negative bacteria (three isolates), coagulase-negative
Staphylococcus (two isolates), vancomycin-resistant
Leuconostoc mesenteroides (two isolates), vancomycin-
susceptibleEnterococcus 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 vancomy-
cin (16/33, 48.5%) and linezolid (8/33, 24.2%)] or a combination
of antibiotics. In 11 cases, daptomycin was administered accord-ing 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.
Randomized controlled trials
Only one open-label RCT45
was conducted comparing daptomy-
cin with antistaphylococcal penicillins or vancomycin (standard
therapy), in combination with gentamicin for the treatment of
patients with endocarditis or bacteraemia due to methicillin-
susceptible and methicillin-resistant S. aureus. Patients were ran-
domly 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 indepen-
dent committee. Of the 246 randomized patients, 235 were eli-
gible for the analysis of effectiveness. Overall, daptomycin andstandard 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 base-
line diagnosis of definite and possible MRSA endocarditis, dap-
tomycin 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 treat-
ment 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
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 base-
line 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 dapto-
mycin and standard therapy, respectively). Second, although not
statistically significant, treatment failure due to persistent or
relapsingS. aureus infection was more common in the daptomy-
cin than the standard therapy group (15.8% versus 9.6%, P
0.17). On the other hand, treatment failure due to discontinu-
ation 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 patientsin 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. aureusinfections were enrolled in this RCT.
Discussion
The available evidence regarding the treatment of patients withendocarditis 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 penicil-
lins 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 (includ-
ing glycopeptides and linezolid) had failed. Thus far, vancomy-
cin 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 treat-
ment with daptomycin for bacteraemia or endocarditis had a
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history of acute leukaemia or had received haemopoietic stem-
cell transplantation. These patients are at higher risk for develop-
ment 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 combi-
nation 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 vanco-
mycin 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 wasmyopathy 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 dys-
function 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 importantissues 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 avail-
able antibiotics (vancomycin, teicoplanin, linezolid, daptomycin,
tigecycline and dalbavancin) are promising, but RCTs compar-
ing these agents are lacking while treatment failure and mor-
tality remain high. Therefore, more data are also needed
regarding the effectiveness of combination therapy with rifampi-
cin and/or aminoglycosides.
In conclusion, although daptomycin has already been
approved for the treatment of patients with right-sided endocar-
ditis and bacteraemia, the available 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 for the treatment of life-threatening infec-
tions. 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 support-
ing 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.
Funding
None.
Transparency declarations
None to declare.
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