J Antimicrob Chemother 2018; 73: 1–11

doi:10.1093/jac/dkx349 Advance Access publication 20 October 2017

Daptomycin
Mohsen Heidary1, Azar Dohkt Khosravi2,3, Saeed Khoshnood3*, Mohammad Javad Nasiri4, Saleh Soleimani5
and Mehdi Goudarzi4

1
Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; 2Infectious and Tropical Diseases
Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 3Department of
Microbiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 4Department of Microbiology, School
of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 5Department of Biology, Payame Noor University, Isfahan, Iran

*Corresponding author. Tel: !98-6113330074; Fax: !98-6113332036; E-mail: saeed.khoshnood22@gmail.com

Daptomycin is a cyclic lipopeptide antibiotic used for the treatment of Gram-positive infections including compli-
cated skin and skin structure infections, right-sided infective endocarditis, bacteraemia, meningitis, sepsis and
urinary tract infections. Daptomycin has distinct mechanisms of action, disrupting multiple aspects of cell
membrane function and inhibiting protein, DNA and RNA synthesis. Although daptomycin resistance in Gram-
positive bacteria is uncommon, there are increasing reports of daptomycin resistance in Staphylococcus aureus,
Enterococcus faecium and Enterococcus faecalis. Such resistance is seen largely in the context of prolonged treat-
ment courses and infections with high bacterial burdens, but may occur in the absence of prior daptomycin expo-
sure. Furthermore, use of inadequate treatment regimens, irregular drug supply and poor drug quality have also
been recognized as other important risk factors for emergence of daptomycin-resistant strains. Antimicrobial
susceptibility testing of Gram-positive bacteria, communication between clinicians and laboratories, establish-
ment of internet-based reporting systems, development of better and more rapid diagnostic methods and
continuous monitoring of drug resistance are urgent priorities.

Introduction Antimicrobial properties

Daptomycin, a novel cyclic lipopeptide antibiotic produced by
supplying decanoic acid to the growth media of Streptomyces
roseosporus during fermentation, was approved by the FDA in
2003 for the treatment of complicated skin and skin structure
infections (cSSSIs), right-sided infective endocarditis and
bacteraemia associated with cSSSIs or right-sided infective
endocarditis.1,2 Daptomycin exhibits in vitro bactericidal activity
(which does not seem to be related to an inoculum effect)
against Gram-positive pathogens including strains for which
there are limited therapeutic alternatives. In addition, dapto-
mycin has been used as a treatment option for paediatric
infections including meningitis, bacteraemia, sepsis, endocardi-
tis and urinary tract infections caused by VRE.3,4 However,
there are increasing reports of daptomycin resistance, in
Staphylococcus aureus, Enterococcus faecium and Enterococcus
faecalis isolates. Such resistance is largely in the context of
prolonged treatment courses and infections with high bacterial
burdens, but it may occur in the absence of prior daptomycin
exposure. It seems that resistance in both staphylococci and
enterococci is mediated by adaptations to cell wall homeostasis
and membrane phospholipid metabolism.5,6
This review aims to summarize the available evidence on dap-
tomycin resistance in Gram-positive pathogens and the clinical
use of this treatment option to provide new insights into this
phenomenon.
Mechanism of action
Daptomycin is structurally and functionally related to cationic anti-
microbial peptides produced by the innate immune system.
The daptomycin molecule consists of a cyclic polypeptide core of
13 amino acids, which 10 C-terminal residues form a ring closed by
an ester bond and a 3-amino acid exocyclic side chain with a ter-
minal tryptophan attached to a fatty acyl residue (decanoic acid).
Several of the amino acid residues that make up daptomycin
are non-standard, including three D-amino acids, ornithine,
3-methyl-glutamic acid and kynurenine (Figure 1).7
The initial binding event between daptomycin and the target
Gram-positive cell membrane (CM) has not yet been defined
but may be via interaction with the bacterial membrane lipid,
phosphatidylglycerol (PG).8 Daptomycin inserts into the CM in a
Ca2!-dependent manner, resulting in membrane depolarization
and subsequent loss of intracellular components, including K!,
Mg2! and ATP.9,10 The antibacterial potency reaches its maximum
at a Ca2! concentration of 1.2 mM, which is the same as the con-
centration of free Ca2! in human extracellular fluid.11 Daptomycin
also caused leakage of K! ions, thus causing dissipation of
the membrane potential in Bacillus megaterium and S. aureus.
However, all these observations were made at daptomycin
concentrations several times higher than the MIC; these are prob-
ably not attainable in vivo. At MIC concentrations in the presence

C The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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Figure 1. (a) Structure of daptomycin and (b) proposed mechanism of action. Reproduced with permission from Tran et al.42 This figure appears in
colour in the online version of JAC and in black and white in the print version of JAC.
of Ca2!, daptomycin inhibited regeneration of cells from proto-
plasts in E. faecium.12
The mechanisms that lead to daptomycin-mediated bacterial
cell death remain poorly understood. However, the rapidly depolari-
zation cells of Bacillus spp. and inhibition of the active transport
of amino acids are proposed as the target of this antibiotic.
Furthermore, it has also been suggested that daptomycin’s mode of
action includes inhibition of peptidoglycan and/or lipoteichoic acid
synthesis, through mechanisms that are not fully established.13
Immunomodulating activity
Antibiotics may have bacteriostatic or bactericidal effects but may
also cause immunomodulation. Lipopeptides are known immuno-
modulators that interact with pattern recognition receptors
such as Toll-like receptors (TLRs) in antigen-presenting cells.
Daptomycin is a lipopeptide antibiotic with a lipid moiety and
unique structure that in the presence of divalent ions can directly
interact with lipid membrane phospholipids, the major component
of lipid membranes in immune cells. Daptomycin may also pene-
trate immune cells including neutrophils and macrophages.
However, the possible immunomodulatory effects of daptomycin
remain unknown.14
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Understanding these effects is important to determine whether
this agent can provide protection against infectious challenge
through multiple mechanisms. Preliminary studies suggest that
daptomycin may have minimal effects on cytokine production and
may have synergistic immunomodulatory effects in combination
with other immunomodulators.15
The inhibiting effects of daptomycin on the production of cyto-
kines including IL-1b, IL-6, IL-8, IFN-c, TNF-a and TLRs are variable.
In an experimental model of human endotoxaemia, no effect of
daptomycin on levels of IL-1b, IL-6 and TNF- a was found, probably
due to high affinity of daptomycin for the bacterial CM and its
low potential to penetrate in to human cells.16 Bode and col-
leagues17 showed that both linezolid and vancomycin broadly
upregulate the expression of distinct TLRs. In contrast, daptomycin
downregulates TLR1, TLR2 and TLR6, which are responsible for the
recognition of pathogen-associated molecular patterns from
Gram-positive bacteria.17 The penetration of daptomycin into the
cell’s cytosol and nucleus still remains a prerequisite to exert
immunomodulatory effects on the human DNA.18,19 Therefore, it
is not surprising that those antibiotics that show large volumes of
distribution, such as fosfomycin and macrolides, were shown to be
able to modulate cytokine.20–22 In contrast to daptomycin, the
aforementioned antibiotics are recognized to accumulate intra-
cellularly in human blood and body cells to a varying extent,
 Review
potentially allowing them to interact with DNA and affecting
mRNA and protein synthesis.16
Activity in biofilms
Biofilms are extracellular matrices that protect bacteria from both
host defences and antibiotics allowing bacteria to accumulate at
high density at sites of infection. S. aureus is one of the most fre-
quent pathogens responsible for biofilm-associated infections and
the choice of antibiotics to treat these infections remains a clinical
challenge. Daptomycin is the most effective antibiotic against
Gram-positive bacteria in biofilms, being more active than other
anti-Gram-positive agents (i.e. minocycline, quinupristin/dalfopris-
tin and linezolid).23 In the presence of rifampicin, daptomycin is
present in the vicinity of the bacterial cells allowing prevention of
the emergence of rifampicin-resistant mutants.24 The use of
rifampicin alone is associated with the emergence of rifampicin-
resistant MRSA, making this drug the last-effective drug in decreas-
ing the microbial burden of MRSA colonization in biofilm after
5 days of daily 4 h exposures. However, when rifampicin is used in
combination with daptomycin, the combination expedited the
elimination of MRSA colonization in biofilm.25
Neither linezolid nor high-dose daptomycin alone exhibited
bactericidal activity against MRSA biofilms; however, combination
therapy with daptomycin plus linezolid significantly improved the
bacterial killing effect of both agents against biofilms of MRSA.26
Raad et al.25 evaluated the activity of daptomycin, linezolid, mino-
cycline and quinupristin/dalfopristin against VRE isolates from
patients with catheter-related bacteraemia. Daptomycin was the
most effective antibiotic tested, producing an 97% reduction in
the number of bacteria in biofilms generated from VRE isolates.25
Spectrum of activity
Daptomycin has rapid in vitro bactericidal activity against a wide
spectrum of Gram-positive organisms including VRE, MRSA and
penicillin-resistant streptococci for which there are very few thera-
peutic alternatives,27 and is approved for the treatment of cSSSIs
caused by susceptible strains of S. aureus (methicillin-susceptible and
-resistant), vancomycin-susceptible E. faecalis, Streptococcus pyo-
genes, Streptococcus agalactiae and Streptococcus dysgalactiae.28
The bactericidal effect of daptomycin is rapid with .99.9% of both
MRSA and MSSA bacteria dead in ,1 h. Daptomycin also remains
bactericidal (99.9% kill within 24 h) against stationary-phase cultures
of both MSSA and MRSA present at high density (109 cfu) in a simu-
lated endocardial vegetation model.29,30
Despite lacking FDA approval for VRE infections, daptomycin
has become a first-line agent to treat severe VRE infections.
Although robust clinical evidence for the use of daptomycin for this
indication is lacking, its in vitro profile and perceived clinical success
has made daptomycin attractive for clinicians.31 However, the use
of daptomycin for these infections has several caveats, including
emergence of resistance during therapy, presence of mutations
associated with daptomycin resistance in isolates and optimal
daptomycin dosing for VRE infections having not been established,
with some in vitro data suggesting that doses of 10–12 mg/kg
should be used to prevent development of resistance.32 This anti-
microbial agent is not used to treat pneumonia, because the mole-
cule is inactivated by pulmonary surfactant.33,34
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Intracellular bactericidal activity
There is some evidence for intracellular accumulation of daptomy-
cin particularly in osteoblasts. In a survey to determine whether
daptomycin is applicable for the clinical use in prophylaxis and
treatment of osteomyelitis and implant-associated infections, its
intracellular activity and the feasibility of mixing daptomycin in
polymethylmetacrylate (PMMA) were analysed. The compressive
and tensile strength testing of daptomycin-laden PMMA was
carried out. Then the microstructure of the antibiotic-laden PMMA
was determined by scanning electron microscopy and intracellular
activity of daptomycin was evaluated in a human osteoblast infec-
tion model. Elution kinetics of the antibiotic-laden bone cement
was measured by using a continuous flow chamber setup.
The results showed that there was no significant negative effect of
adding 1.2% and 7.5% per weight of daptomycin to PMMA. Elution
of daptomycin from PMMA was detected within the first-hour
initial peak values of 15–20 mg/L. Daptomycin admixed to PMMA
remains bactericidal and does not significantly impair structural
characteristics of the PMMA.35,36
In another study, intracellular antibacterial effects of daptomy-
cin, vancomycin and oxacillin were determined against intracellu-
lar MRSA and MSSA in human monocyte-derived macrophages.
The degree of antimicrobial activity was concentration, time and
strain dependent. Daptomycin caused the greatest and most rapid
decrease in bacterial viability at 2 and 4 h, followed by oxacillin
(P , 0.01). At lower concentrations (0.5% and 1% MIC), there was
regrowth to the same cell density as the control for daptomycin
and vancomycin, while oxacillin demonstrated continued antibac-
terial activity for 24 h with either stable suppression or continued
net decline in the number of viable bacteria (P , 0.01).18
Mechanisms of resistance
Intrinsic resistance
A novel mechanism of intrinsic resistance to daptomycin among
low GC% Gram-positive bacteria (such as Staphylococcus,
Micrococcus, Streptococcus and Lactobacillus) is inactivation by
hydrolytic cleavage of the ester bond between the threonine and
kynurenine residues, resulting in ring-opening inactivation.
Whether the ‘ancient’ development of daptomycin resistance in
the absence of exposure to this ‘modern’ agent results from natu-
ral production of daptomycin-like molecules by part of this
archaic microbiome remains to be determined.37
Acquired resistance
The types of mechanisms usually seen in acquired resistance are
drug target modification, drug inactivation and drug efflux.
Development of daptomycin resistance during therapy seems to
be an important problem affecting the clinical efficacy of dapto-
mycin. The exact mechanisms of daptomycin resistance remain to
be elucidated, but current knowledge suggests that they are com-
plex, diverse and multifactorial, arising from mutational changes.
It has been postulated that the mechanism of daptomycin
resistance in S. aureus is mediated by electrostatic repulsion of the
daptomycin–calcium complex from the cell surface, mainly by
increasing the positive charge of the bacterial surface (Figure 2).38
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Figure 2. Proposed mechanisms of action and resistance to daptomycin in Gram-positive organisms. Reproduced with permission from Tran et al.42
Daptomycin–calcium complex interacts with the cell membrane mainly at septal areas in daptomycin-susceptible Gram-positive bacteria (a). Two
main mechanisms of resistance have been postulated. The first is diversion (Enterococcus faecalis only) of the antibiotic from the preferential binding
site of daptomycin at the septum (black arrow), in a process associated with redistribution of anionic phospholipid microdomains (e.g. cardiolipin)
away from the septal plane, resulting in ineffective binding of daptomycin (b). Second mechanism, seen in Bacillus subtilis, Staphylococcus aureus
and Enterococcus faecium, is electrostatic repulsion of the positively charged daptomycin–calcium complex from the CM in a process associated with
increase in the net positive charge of the cell envelope (not all strains) (c). This figure appears in colour in the online version of JAC and in black and
white in the print version of JAC.

The most common gene implicated in daptomycin resistance is
mprF, which encodes a bifunctional enzyme (MprF) that incorpo-
rates the positive charged amino acid lysine to PG. Several mprF
mutations have been associated with daptomycin resistance,
most frequently producing a ‘gain of function’ phenotype. The
increased positive charge of the cell envelope is thought to impair
the binding of daptomycin to the CM target. Other determinants
implicated in daptomycin resistance include genes encoding
enzymes involved in phospholipid metabolism, such PG and cardi-
olipin synthetases (pgsA and cls, respectively).39
Mutations in mprF (which encodes lysylphosphatidylglycerol
synthetase), yycG (which encodes sensor histidine kinase) and
rpoB and rpoC (which encode the b and b0 subunits, respectively, of
RNA polymerase) have been found in S. aureus isolates with dapto-
mycin MICs greater than the susceptible range. Mutations in mprF
appear to occur early in the selection process, whereas mutations
in rpoB and rpoC occur later. Given that these mutations are not
present in several daptomycin-non-susceptible clinical S. aureus
strains, more work is needed to define the mechanism by which
these and perhaps other mutations lead to decreased microbio-
logical activity of daptomycin.
Acquired resistance among Enterococcus spp. is mediated by
transferable transposons or plasmids encoding resistance cas-
settes. Thus, a possible mechanism of resistance in daptomycin-
non-susceptible Enterococcus (DNSE) cases could be the
co-transfer of resistance.40 The in vivo acquisition of daptomycin
resistance in S. aureus has rarely been reported, and previous van-
comycin exposure is mainly associated with the emergence of
such daptomycin-resistant strains.41,42 Further understanding of
decreased daptomycin susceptibility should enhance understand-
ing of the mechanism of interaction between daptomycin and the
bacterial CM.43
Heteroresistance
‘Heteroresistance’ describes a phenomenon where subpopulations
of seemingly isogenic bacteria exhibit a range of susceptibilities to
a particular antibiotic. Unfortunately, a lack of standard methods
to determine heteroresistance has led to inappropriate use of this
term. ‘Heterogeneous resistance’, ‘population-wide variation of
resistance’ and ‘heterogeneity of response to antibiotics’ are also
used to describe this phenomenon. Initial treatment with glyco-
peptides led to the development of heterogeneous glycopeptide
resistance, which transformed to full resistance following dapto-
mycin treatment.44
Recently, it is reported the establishment of a laboratory MRSA
strain 10*3d1 having dual heteroresistance to daptomycin and
vancomycin by serial daptomycin selection. Despite its selection by
daptomycin alone, this strain expressed raised resistance to both
daptomycin and vancomycin, a thickened cell wall and a partially
overlapped transcription profile with that of hetero-vancomycin-
intermediate S. aureus (h-VISA). By using WGS and gene replace-
ment experiments, it was proved that a non-synonymous muta-
tion in rpoB, the gene that codes for the b subunit of the bacterial
DNA-dependent RNA polymerase, was responsible for the pheno-
typic conversion. This experiment also confirmed that the rpoB
(A621E) mutation alone is responsible for the dual heteroresist-
ance to vancomycin and daptomycin.45

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Recent studies described three sets of clinical MRSA isolates
(each set of isolates being collected from a separate patient) in
which glycopeptide-intermediate S. aureus (GISA) or hetero-GISA
(h-GISA) phenotypes arose during vancomycin therapy and
demonstrated increases in daptomycin MICs and daptomycin het-
eroresistance. While the emergence of daptomycin resistance
associated with amino acid substitutions in MprF occurred in the
context of daptomycin exposure, none of the GISA or h-GISA iso-
lates associated with daptomycin resistance had been collected
from patients treated with daptomycin. h-VISA strains have
vancomycin MICs in the susceptible range (4 mg/L) but have been
suggested to be an origin of treatment failure due to resistant
subpopulations.46
Synergism
Antimicrobial agents have increasingly been used in combinations
to provide a wide-spectrum effect or delay and inhibit the emer-
gence of resistant pathogenic bacteria during the treatment. As
daptomycin has a distinct mode of action, there is no cross-
resistance to other antibiotics, making it a useful choice in the
treatment of serious infections caused by VRE or MRSA. The inter-
action of daptomycin with other antimicrobial agents could be
promising in treatment and its clinical benefits have been investi-
gated for years.47
Daptomycin synergy with rifampicin and ampicillin
against VRE
Daptomycin can open the channels for the hydrophobic antibiotic
as rifampicin and promote the entry of rifampicin into a bacterial
cell. Therefore, the combination of daptomycin with rifampicin
may be an alternative in the treatment of VRE infections. In addi-
tion, daptomycin is able to reverse rifampicin resistance in some
strains of VRE, but the mechanism could not be explained by the
effect of daptomycin on entry of rifampicin into or transport out of
the cell, by inactivation of rifampicin or by mutation involving the
rifampicin-binding site.48 Rand et al.48 performed a study in which
rifampicin MICs were determined for a strain of VRE using Etests
performed on agar containing 0, 0.125 and 0.25 mg/L daptomycin.
There was a marked decrease in Etest MICs (as well as an increase
in zone size around rifampicin discs) indicating synergy between
daptomycin and rifampicin. When there was no daptomycin in the
agar, growth was observed all the way up to the disc and rifampi-
cin MICs were .32 mg/L. At 0.125 mg/L daptomycin the rifampicin
MIC was 0.25 mg/L and the disc zone was 21 mm, and at
0.25 mg/L daptomycin the rifampicin MIC was 0.047 mg/L and the
disc zone was 28 mm.49 In terms of the effect of ampicillin upon
daptomycin-induced killing, ampicillin (in a dose-dependent man-
ner) can substantially decrease the net positive surface charge on
VRE isolates. Furthermore, ampicillin increases susceptibility to kill-
ing by a number of other cationic peptides, including those of
diverse structures, charges, sources and mechanism of action.
Sakoulas et al.50 showed that VRE grown in the presence of ampi-
cillin, compared with VRE grown in medium without ampicillin had
significantly increased binding to labelled daptomycin. Their obser-
vations strongly suggest a charge-based mechanism for the
impact of ampicillin on daptomycin-mediated killing of VRE
isolates.50
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Daptomycin synergy with rifampicin and gentamicin
against MRSA
It is unknown whether daptomycin’s activity against MRSA may be
improved by combining it with one or more additional antibiotics
to produce a potentially additive or synergistic effect. Gentamicin
has been shown to augment daptomycin’s activity against strains
of MRSA in vitro. The combination of daptomycin plus rifampicin
has demonstrated enhanced activity against MRSA in vitro and
in vivo.51,52 Tsuji and Rybak53 have reported that a single dose of
gentamicin (5 mg/kg) in combination with daptomycin may be
used to maximize synergistic and bactericidal activity and mini-
mize toxicity, in an in vitro pharmacodynamic model. In contrast, a
recent study by DeRyke et al.54 showed that the coadministration
of gentamicin did not alter daptomycin pharmacokinetics. The
other study showed that enhanced killing of MRSA was observed
when gentamicin was combined with daptomycin, most com-
monly with daptomycin concentrations below the peak serum
free-drug concentrations achieved with standard dosing.
Combination therapy also prevented the emergence of resistance.
Daptomycin and gentamicin combination therapy may provide
the synergy required to prevent emergence of resistance in com-
plicated infections.55 There is very little information on the rifampi-
cin/daptomycin combination against MRSA, with most in vitro
studies, animal studies and case reports showing controversial
data. In another study, daptomycin and rifampicin were synergis-
tic and the combinations of daptomycin plus rifampicin, enhanced
the bactericidal activity against MRSA isolates.56
Daptomycin synergy with oxacillin and other b-lactams
against MRSA
Anti-staphylococcal b-lactams have emerged as an additional tool
to enhance daptomycin activity in eradicating persistent bacterae-
mia due to MRSA. The b-lactams deployed off label in combination
for this scenario include nafcillin, oxacillin and ceftaroline.57 The
key synergic event is likely the capacity of the b-lactams of interest
to block PBP1.58 This synergic event with daptomycin occurs
whether the PBP1 blockade is promiscuous or occurs in a more
PBP1-specific manner.59 The enhanced binding of daptomycin to
the divisome, its principal site of action, and augmentation of the
functional activity of daptomycin without increasing binding are
two main theories about the mechanism(s) of this synergy
between cationic peptides (e.g. calcium daptomycin) and PBP1-
targeting b-lactams.60 In a study performed by Rand and Houck,61
the increases in zone size for oxacillin, cloxacillin, ampicillin/sulbac-
tam, piperacillin/tazobactam and ticarcillin/clavulanate were com-
pared by using Kirby–Bauer discs. A daptomycin disc was included
as a control for additivity. When the daptomycin concentration in
the agar was raised from one-quarter to one-half the MIC, there
were increases in average zone sizes of 7.3 mm for oxacillin and
10.3 mm for ampicillin/sulbactam. In contrast, a daptomycin disc
showed only a 4.8 mm increase in zone size after the daptomycin
concentration in the agar was increased from one-quarter to one-
half the MIC. By this method, daptomycin with ampicillin/sulbac-
tam, ticarcillin/clavulanate or piperacillin/tazobactam showed
synergy comparable to or greater than daptomycin with oxacillin.
For seven of the eight strains tested, time–kill studies confirmed
synergy between daptomycin and ampicillin/sulbactam with
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ampicillin in the range of 2–8 mg/L. The combination of daptomy-
cin and b-lactams may be useful for the treatment of MRSA infec-
tion, but further studies are needed to elucidate the mechanisms
and to determine the in vivo efficacy of the combination.61–63
Pharmacokinetics and pharmacodynamics
The pharmacokinetics and pharmacodynamics of daptomycin
have been extensively explored in a host of in vitro models, mul-
tiple different patient populations and clinical studies.
Evaluation of pharmacokinetics of daptomycin in the adult pop-
ulation showed several parameters including patient character-
istics, particularly renal function, body temperature and sex
may affect clearance of daptomycin. Body temperature
.37.2  C (99  F) increased the clearance of daptomycin in a
small number of patients. The pharmacokinetics of daptomycin
in critically ill paediatric patients may be considerably different
from that in adults, including a faster elimination rate, shorter
half-life and increased clearance. However, the volume of
distribution appears to be similar to that in adults.64 In vitro
pharmacodynamic studies indicate that daptomycin exhibits
dose-dependent bactericidal activity and that efficacy is best
correlated with the maximum plasma concentration to MIC
(Cmax/MIC) ratio and the area under the plasma concentration–
time curve to MIC (AUC/MIC) ratio. The strong experimental
evidence suggests that higher doses (e.g. 8–10 mg/kg) of dapto-
mycin are more effective and equally safe and should be used
for MRSA and enterococcal infections in critically ill patients as
well as in bacteraemia and endocarditis.
Because patients with cancer often have low levels of serum
proteins and significant shifts of fluid between body compart-
ments, the optimal daptomycin dosing strategy is uncertain, as
the pharmacokinetics of daptomycin in these patients vary from
those in healthy subjects. Daptomycin is predominantly cleared
renally (52% of unchanged drug in urine) and it has the following
physicochemical characteristics that limit its distribution to the
plasma compartment: high polarity, low lipid solubility, high
molecular mass and a high degree of plasma protein binding.65
Daptomycin is excreted mainly in urine (78%), with 50% of
the active drug being recovered unchanged from urine within 24 h.
A small proportion (6%) of this drug is also recovered in faeces.
Daptomycin exhibits 92% binding to plasma proteins,
particularly albumin. However, its binding to plasma proteins
appears to be weaker than the irreversible bond it forms with the
bacterial membrane, resulting in daptomycin being significantly
more bioavailable than this level of protein binding would
suggest.62
Daptomycin has a relatively long half-life of 8–9 h, thereby
making it suitable for once-daily dosing. It exhibits consistent and
predictable kinetics for doses of 4, 6 and 8 mg/kg per day (Cmax of
58, 99 and 133 mg/L and 24 h AUC of 494, 747 and 1130 mgh/L,
respectively). Its low volume of distribution (0.1 L/kg) indicates
that it remains primarily within plasma and interstitial fluid.66
Clinical treatment
Daptomycin is indicated for the treatment of cSSSIs caused by sus-
ceptible strains of MRSA, S. pyogenes, S. agalactiae, S. dysgalactiae
subsp. equisimilis and E. faecalis. Combination therapy may be
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clinically indicated if the documented or presumed pathogens
include Gram-negative or anaerobic organisms.67 In clinical prac-
tice, patients with prosthetic joint infections due to Gram-positive
cocci are often treated with vancomycin although heteroresist-
ance to vancomycin, high failure rates in MRSA infections and its
poor bone penetration are limitations to successful therapy with
this drug.68 Daptomycin is an alternative to vancomycin for the
treatment of MRSA/methicillin-resistant CoNS infections and an
attractive option for antibiotic-resistant Gram-positive prosthetic
joint infections. Another advantage of daptomycin is its relatively
long half-life, which makes it particularly suitable for outpatient
administration.5
Daptomycin is found to be effective even in some clinical condi-
tions where comparator antibiotics had failed. There is a successful
use of both intravenous and intracatheter lock therapy for
catheter-related bloodstream infection due to CoNS or enterococci
in six of eight patients who were unsuccessfully treated with van-
comycin or cefazolin.
Daptomycin appeared safer than vancomycin, even when
administered for long periods or at high doses and is a promising
therapeutic option for the treatment of paediatric diseases due to
MDR Gram-positive bacilli. However, further studies aimed at
establishing the adequate dosage for different paediatric ages are
needed before daptomycin can be licensed for use in newborns
and children. The data collected in adults can only be transferred
to children .12 years. For younger patients, the information avail-
able does not seem adequate to define the dosage that will assure
the highest antimicrobial efficacy and only a marginal risk of
adverse events. Some studies specifically planned to solve these
problems are ongoing in toddlers and school-age subjects.69
Epidemiology of daptomycin resistance
Little is known about the frequency of the emergence of
daptomycin-non-susceptible Gram-positive bacteria. Knowledge
of daptomycin clinical resistance is mostly obtained from case
reports, letters and short communications from diverse geo-
graphic locations, including the USA, Europe and Asia (Table 1).
In 2010, six cases of daptomycin-non-susceptible S. aureus
bacteraemia were reported, all in patients previously treated with
vancomycin. These are also daptomycin-non-susceptible S. aureus
cases identified in local hospitals within a year of the launch
of the antibiotic in Singapore. They provide in vivo corroboration
of in vitro results linking the development of daptomycin
resistance with vancomycin exposure. It is striking that all post-
vancomycin-, pre-daptomycin-exposed isolates remained
susceptible to daptomycin with little or no increase in the
daptomycin MICs compared with initial isolates.70 In European
studies there are significance differences in the numbers of
resistant isolates collected from the various countries that were
used to profile the activity of daptomycin. There is little or no
variation in the activity of daptomycin (based on MIC ranges)
regardless of phenotype, national origin of isolates or varying
numbers of resistant isolates per country.71
Less than 2% of enterococcal isolates are daptomycin non-
susceptible, with MICs .4 mg/L. The prevalence of resistance of
VRE isolates to daptomycin may be overestimated due to the
spread of clonally related isolates in healthcare settings. In the
international daptomycin surveillance programmes for Europe,
 Review JAC
Table 1. Prevalence of daptomycin resistance worldwide

Location/ No. of Resistance

reference Period Bacteria Patients resistant bacteria MIC (mg/L) mechanism Study
74
USA 2004 S. aureus adult – – ND case report
USA75 2005 MRSA adult – 0.5–4 ND case report
North 2005 S. aureus both 2 – ND short communication
America76 CoNS 2
E. faecalis 0
E. faecium 0
b-haemolytic streptococci 0
USA77 2005 MRSA adult – 0.25–4 ND case report
USA78 2005 MRSA adult – – ND case report
Europe76 2005 S. aureus both 0 ND short communication
CoNS 1
E. faecalis 0
E. faecium 0
b-haemolytic streptococci 0
USA79 2006 MRSA adult – 0.5–8 ND case report
USA3 2006 MRSA adult 4 0.25–4 lower bactericidal case report
activity
USA80 2006 MRSA adult – 1–4 ND case report
USA81 2006 MRSA adult 5 0.75–2 ND case report
USA82 2007 VISA adult 29 1–8 MprF I420N mutation case report
USA83 2008 daptomycin-non- adult 10 0.125–4 ND original article
susceptible S. aureus
VISA
MRSA
Taiwan84 2008 MRSA adult 11 1–4 ND case report
USA85 2008 MSSA NS 4 0.125–2 ND original article
USA86 2008 MRSA adult 5 0.5–4 ND case report
USA87 2008 MRSA adult 4 1–4 MprF T345A case report
mutation
Taiwan88 2008 MRSA adult 12 0.5–2 ND case report
UK89 2009 MRSA adult 6 0.25–4 ND case report
USA90 2009 MRSA adult 4 – ND case report
USA91 2009 MRSA adult 2 0.5–2 ND case report
Taiwan92 2009 MRSA adult 10 0.5–2 ND case report
Italy93 2010 MRSA adult – – ND case report
Singapore70 2010 daptomycin-non- adult 6 0.19–4 ND case report
susceptible S. aureus
Taiwan94 2010 MRSA adult – 0.5–4 ND case report
UK95 2011 group G Streptococcus adult – 0.19–4 ND case report
MRSA
Australia96 2011 vancomycin- adult 8 0.25–2 ND case report
unresponsive S. aureus
Taiwan97 2011 daptomycin-non- adult 7 0.25–1 ND case report
susceptible S. aureus
USA98 2012 MRSA adult 6 0.25–1.5 and 8 ND case report
Australia99 2012 MRSA adult 3 – ND case report
Canada100 2012 MRSA adult 3 1 to .4 ND case report
USA101 2013 MRSA adult 3 0.38–3 ND case report
USA102 2013 MRSA both 10 2–4 ND original article
MSSA
France40 2013 MRSA adult 3 0.25–2 ND case report
Spain103 2014 MRSA adult 7 ,0.5–2 ND letter to editor

ND, not determined; NS, not stated.

7
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 Review
Latin America and selected Asia-Pacific nations, a total of 7948
consecutive Gram-positive organisms of clinical significance were
collected in 2011 and tested against daptomycin and various com-
parator agents. The test medium was adjusted to contain physio-
logical levels of calcium (50 mg/L) when testing daptomycin.
Daptomycin exhibited potent activity against MSSA and MRSA
overall and for each region, with susceptibility rates of 100% in
Latin America, Australia/New Zealand and India, and 99.9% in
Europe. The daptomycin MIC50/90 for CoNS was 0.25–0.5/0.5 mg/L
and only one isolate was considered non-susceptible with an
MIC value at 2 mg/L. Daptomycin was also highly active against
E. faecalis (MIC50/90, 1/1–2 mg/L) and E. faecium (MIC50/90,
2/2 mg/L for both vancomycin-susceptible and -resistant isolates).
That organism was a bloodstream Staphylococcus epidermidis iso-
late from a patient in Kiel, Germany. Other agents to which CoNS
exhibited a high level of susceptibility were vancomycin (CLSI
criteria) and tigecycline (EUCAST criteria) with 100.0% susceptibil-
ity in all regions.72
Although in vitro studies suggest that daptomycin resistance is
unlikely to develop in vitro, case reports of DNSE suggest this is an
emerging clinical problem. Among studies reporting DNSE, the
overall prevalence of Enterococcus species with MIC .4 mg/L is
low. This prevalence likely overestimates the true prevalence of
daptomycin resistance among enterococci because of reporting
bias and possible transmission of clonally related isolates in single
institution reports. However, there is a lack of data on DNSE isolates
from the WHO Antimicrobial Resistance Information Bank, and
from international and national programmes such as The
Surveillance Network (TSN) database.73
Discussion
Owing to low (,2%) daptomycin resistance in Gram-positive
pathogens, this antibiotic can be considered a valuable antimicro-
bial agent. However, as there are increasing reports of daptomycin
resistance among MRSA, vancomycin-resistant S. aureus and VRE
isolates, antimicrobial susceptibility testing of Gram-positive iso-
lates, communication between clinicians and laboratories, establish-
ment of internet-based reporting systems, development of better
and more rapid diagnostic methods and continuous monitoring of
drug resistance are urgent priorities.
Transparency declarations
None to declare.
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