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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

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

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# 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

Systematic review

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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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