P-Grossi

Infectious & Tropical Diseases Unit
Department of Transplantation
Ospedale di Circolo e Fondazione Macchi –
University of Insubria, Varese,Italy
Ruolo di daptomicina nel trattamento di infezioni
gravi da Gram-positivi
Paolo Grossi
XIV CONGRESSO NAZIONALE SIMIT
Catania 8-11 Novembre, 2015
ANTIBIOTIC RESISTANCE IN 2015
• Antibiotic-resistant bacteria, including
methicillin-resistant Staphylococcus aureus
(MRSA), extended-spectrum beta-lactamase
producers, and carbapenem-resistant
Enterobacteriaceae, are increasing in
prevalence worldwide, resulting in infections
that are difficult and expensive to treat.
The greater the volume of
antibiotics used, the greater
the chances that antibioticresistant populations of
bacteria will prevail in the
contest for survival of the
fittest at the bacterial level
Definition of Multidrug Resistant Bacteria
• The most widely accepted definition of MDR includes lack of
susceptibility to one or more agents in three or more
antimicrobial categories active against the isolated bacteria
– In the case of S. aureus, methicillin resistance on its own
defines the strain as MDR, regardless of resistance to other
antimicrobials.
• Extensively-drug resistant (XDR) bacteria is defined as
susceptibility to no more than two classes of active categories
of antimicrobials
• Pan-resistance (PR) is defined as nonsusceptibility to all
licensed, routinely available antibacterials.
van Duin D. & van Delden C. AJT 2013; 13: 31–41
Percentuale di S. aureus resistente alla meticillina (2011-2014)
Source: CDDEP 2015, WHO 2014 and PAHO, forthcoming
Staphylococcus aureus Resistance to Oxacillin/Methicillin
50
Italia
40
30
20
10
20
13
20
12
20
11
20
10
20
09
20
08
20
07
20
06
20
05
0
35,8%
EARS-NET Annual Report 2013
•
•
•
Studio epidemiologico condotto per 3 mesi in 52 centri su 21.873
patogeni
Prevalenza di S. aureus: 11.6% (MRSA, 35.8%)
Il 58.3% dei ceppi di S. aureus avevano MIC per la vancomicina
comprese tra 1 e 2 mg/L
Journal of Global Antimicrobial Resistance 2015 In press
MIC and probability of achieving target
vancomycin serum concentrations
 Trough 9.4 μg/ml: AUC
(±SD) 318±111 μg·h/ml
 Trough 20.4 μg/ml: AUC
(±SD) 418±152 μg·h/ml
 Probability of AUC/MIC of
>400 by Monte Carlo
simulation
□ MIC=0.5: 100%
□ MIC=2.0: 0%
 Mohr et al., 20072
 30% of MRSA blood isolates
have MIC of 2 μg/ml
Jeffres M et al. Chest 2006;130:947–955
Mohr J et al. Clin Infect Dis 2007;44:1536–1542
Probability of achieving an AUC:MIC ratio of >400
LD vancomycin*
1.0
Probability of target
attainment
 Jeffres et al., 20061
HD vancomycin†
0.8
0.6
0.4
0.2
0
0.25
0.5
1.0
Vancomycin MIC, µg/ml
*LD, low-dose vancomycin (trough concentration ≤15 µg/ml)
†HD, high dose vancomycin (trough concentration >15 µg/ml)
2.0
4.0
Vancomycin MIC significantly predicts for
mortality in MRSA
Treatment group
Risk of mortality
(OR [95% CI])
P-value
Vancomycin MIC=1
1
Vancomycin MIC=1.5
2.86 (0.87, 9.35)
0.08
Vancomycin MIC=2
6.39 (1.68, 24.3)
<0.001
Inappropriate therapy*
3.62 (1.20, 10.9)
<0.001
0.5
1
2
5
10
*Inappropriate therapy defined as empirical therapy to which the MRSA strain was resistant
Soriano A et al. Clin Infect Dis 2008;46:193–200
MRSA Bacteremia
 Among the Gram-positive organisms, methicillinresistant Staphylococcus aureus (MRSA) and E. faecium
represent the biggest therapeutic hurdles.
 The evolution of MRSA exemplifies the genetic
adaptation of an organism into a first-class multidrugresistant pathogen.
 While glycopeptides such as vancomycin have been the
treatment of choice for MRSA, poor outcomes have
frequently been reported, particularly among isolates
with higher MICs, within the susceptible range
(≤2mg/L).
Treatment options for resistant Gram-positive cocci
alternative to Vancomycin and Teicoplanin
Drug
Approved indications
Daptomycin
ABSSSI, Bacteremia/Endocarditis
Tygecycline
ABSSSI, IAI, CAP (US)
Linezolid
Telavancin
Ceftaroline
Ceftobiprole
ABSSSI, CAP, HAP
cSSTI (US), HAP
ABSSSI, CAP
HAP, CAP
Oritavancin
ABSSSI (US)
Dalbavancin
ABSSSI (US) (EMA approval)
Tedizolid
ABSSSI (US) (EMA approval)
Grossi, November 2015
New therapeutic options for treatment of MDR
Gram-positives
• Despite concerns about vancomycin use in the treatment of multidrugresistant Gram-positives, evidence for better therapeutic outcomes with
alternative antibiotics is lacking.
• Daptomycin, Ceftaroline, Telavancin, Oritavancin and Dalbavancin were
associated with comparable clinical cure rates compared with
vancomycin in the treatment of complicated skin and soft tissue
infections.
• In the treatment of hospital-acquired pneumonia, both Telavancin and
Linezolid resulted in significantly greater clinical cure rates compared
with vancomycin.
• Despite greater clinical cure rates, no difference in overall or infectionrelated mortality was detected.
• Of concern is the appearance of daptomycin and linezolid resistance
following increased use.
Treatment of MRSA Bacteremia
IDSA Guidelines 2011
Uncomplicated
Daptomycin 6
mg/kg iv once
daily AI
Vancomycin AII
Treatment
duration
At least 2
weeks
Complicated
Treatment
duration
Daptomycin 8-10
mg/kg iv once
4-6 weeks
daily BIII
• Addition of gentamycin to vancomycin is not recommeded for
bacteremia or native valve endocarditis
• Addition of rifampin to vancomycin is not recommeded for
bacteremia or native valve endocarditis
Liu C, et al. CID 2011:52:285–292
What is Daptomycin?
• Cyclic lipopeptide natural product
• Approved (IV, 4 mg/kg q24h) for
complicated skin and skin structure
infections, including MRSA
• 6 mg/kg q24h for right-sided infective
endocarditis (RIE) due to Staphylococcus
aureus, and S. aureus Bacteremia, in
cases when associated with RIE or with
complicated skin and soft-tissue
infections (cSSTI)
– US
2003-2006
– Israel
2004
– Argentina
2005
– EU
01/2006-5.9.2007
• Italy AIC cSSTI 12.12.2006
• Italy AIC Bact & RIE 21.11.2007
Relative bacteriostatic and bactericidal
activity of antibiotic agents
Bacteriostatic
Rolinson GN, Geddes AM. Int J Antimicrob Agents 2007;29:3–8
Bactericidal
The present review will present the available evidence on daptomycin
resistance of S. aureus, with particular attention to its development.
In addition to a literature overview, we have compiled the reported cases
of daptomycin non-susceptibility to shed light on possi-ble clinical
mechanisms of resistance.
In the 36 reports describing 62 clinical cases, infections caused by
meticillin-resistant S. aureus (MRSA) strains with a vancomycin minimum
inhibitory concentration (MIC) between 1 mg/L and 2 mg/L often led to
vancomycin treatment failure, which may be associated with the
development of non-susceptibility to daptomycin. Additional evidence
suggests that underdosage of daptomycin is an important clinical aspect
that merits further study.
Early use of daptomycin versus vancomycin for MRSA bacteremia
with vancomycin MIC >1 mg/L: a matched cohort study
Dark gray indicates clinical success; light gray indicates clinical failure
Murray KP, et al. CID 2013; 56(11):1562-9.
How can we increase daptomycin efficacy when
treating complicated SAB or IE?
 Increasing daptomycin dose
 ↑↑ Cmax/MIC - ↑↑ AUC/MIC
 8-10 mg/kg/day
 Higher doses (12 mg/kg/d)?
 A high once-daily dose (≥ 8 mg/kg) of
daptomycin is often considered for difficult-totreat infections (e.g. involving biofilms) and high
bacterial burden, based on its dose-dependent
anti-bacterial activity.
Is empiric daptomycin effective in reducing mortality in
Staphylococcus aureus bacteraemia? A real-life experience
In hospital mortality
OR
p-value
DAP vs Glycopeptides
DAP vs β-lactams
10.66
4.84
0.009
0.022
• In conclusion, our study suggests that an empiric
antibiotic regimen with high-dose daptomycin may be
more effective than an adequate empiric regimen
with glycopeptides or beta-lactams when a SAB is
suspected, especially in the context of high local
prevalence of MRSA.
Bassetti M, et al. Intensive Care Med (2015) 41:2026–2028
Safety of High-Dose Daptomycin for Gram-Positive
Infections
Kullar R., et al. Pharmacotherapy. 2011 Jun;31(6):527-36
 HD DAP (> 8 mg/kg/day) was well-tolerated in 153 patients
with complicated Gram-positive infections.
 Over 90% of patients had end-of therapy CPK levels < 150
IU/L.
 No direct relationship was found between DAP dose and CPK
levels.
 Concomitant HMG-CoA reductase inhibitor therapy did not
predict CPK elevations.
 HD DAP may prove to be a safe alternative for treatment of
Gram-positive infections.
Use of Daptomycin on Gram-positive pathogens
Personal experience in Varese (N of cases=67, 21% SOT)
Infection
Bacteremia 18 Left-sided IE 14
N, (%)
(27)
(21)
Pathogen
Enterococci
0
7
MRSA
7
1
MSSA
3
1
Others
5
5
3
0
No isolation
Dose (mg/kg)
4
0
0
6
8
3
8
10
10
10
0
1
Success
Clinical
13
14
Microbiological
8
12
A. Tebini, et al. ICAAC Chicago 2011 – Poster # K1413
cSSTI Others 12
23 (34)
(18)
Total
67 (100)
3
7
7
2
4
5
1
1
1
4
15 (22)
16 (24)
12 (18)
13 (19)
11 (17)
3
18
2
0
0
7
5
0
20
10
11
4
3 (5)
36 (54)
27 (40)
1 (1)
*
58 (87)
34 (51)
Dosage and duration of DAP H8 therapy
Patients, n (%)
Most frequently used initial daptomycin dose
≥8 and ≤10 mg/kg/day
>10 mg/kg/day
Median duration of daptomycin therapy
223 (95.3)
11 (4.7)
Days (min─max)
Overall
25 (14─20)
Inpatients
21 (1─110)
Outpatients
21 (3─85)
ICU
7 (1─51)
 The frequency of DAP H8 use increased over the 4 consecutive years
(3%, 8%, 12% and 18%, respectively)
Utili R, et al. ECCMID 2012, P1846
24
Clinical outcomes for DAP H8 for ≥14 days
by infection type
Success
100
Non-evaluable
97.1
93.3
88
Patient population (%)
Failure
86.3
80
74.1
60
40
18.5
20
4.7 7.3
1.3
5.3
11.4
2.3
0
Overall
(n=234)
Endocarditis
(n=75)
Utili R, et al. ECCMID 2012, P1846
Osteomyelitis
(n=44)
0 2.9
SSTI
(n=34)
7.4
Bacteraemia
(n=27)
25
Clinical outcomes for DAP H8 for ≥14 days
by pathogen
Success
Patient population (%)
100
88.9
Failure
88.1
Non-evaluable
92.4
88.3
89.3
80
60
40
20
6.7 4.4
7.1 4.8
7 4.7
10.7
3 4.5
0
All S. aureus
(n=90)
MSSA (n=42)
MRSA (n=43)
CoNS (n=66)
0
Enterococci
(n=28)
CoNS: Staph. epidermidis and other CoNS; Enterococci: E. faecalis, E. faecium and Enterococcus spp.
Utili R, et al. ECCMID 2012, P1846
26
Adverse events
 The overall rates of AEs were independent of the duration of
daptomycin ≥8 mg/kg/day treatment (16.6% for <14 days,
14.9% for ≥14 days and 18.2% for ≥30 days).
 Adverse events (AEs), regardless of relationship to
daptomycin, were reported in 15.8% of patients receiving
daptomycin ≥8 mg/kg/day for ≥14 days, including 3.8% of
patients with creatine phosphokinase (CPK) elevations and
0.4% of patients with musculoskeletal AEs, which is
comparable to patients receiving ≥8 mg/kg/day daptomycin for
<14 days (16.6%) and patients on approved dose of
daptomycin (4 to 6mg/kg/day; 13.2%).
Utili R, et al ECCMID 2012
How can we increase daptomycin efficacy
 Daptomycin combinations
 To look for synergy and greater
bactericidal activity
 To avoid development of resistance
 To decrease individual doses
Distribution of bactericidal concentrations at 4 h with and without the
addition of oxacillin. The distributions of bactericidal activity with and
without oxacillin are statistically significantly different at 4 h (p =0.005) and
at 24 h (p<0.0001) by 2 analysis.
Rand KH & Houck HJ. AAC 2004;48:2871-2875
Daptomycin-Oxacillin Combinations in Treatment of
Experimental Endocarditis Caused by Daptomycin
Nonsusceptible Strains of MRSA
•
•
Collectively, these results suggest that combination therapy
regimens of DAP and OX has enhanced in vivo efficacy relative
to DAP monotherapy in DAPr strains which exhibit the DAP-OX
seesaw phenomenon in vitro.
This combination antibiotic approach may be relevant to
salvaging DAP therapy in patients with evolving increases in
DAP MICs during treatment, especially when OX MICs
decrease in parallel.
Yang S-J. AAC 2010;54:3161–3169
Daptomycin treatment success for S. aureus bacteremia,
stratified by concomitant β-lactam use
p=0.061
Moise P., et al. Antimicrob. Agents Chemother. 2013, 57:1192.
Activities of antimicrobials tested alone and in
combination against MRSA
LaPlante K, et al. AAC 2009;53:3880-3886
Effects of antibiotic treatment on experimental MRSA
prosthetic knee infection in rabbits
Saleh-Mghir A, et al. AAC 2011;55:4589
Daptomycin Plus Fosfomycin Is Synergistic Against MSSA and
MRSA Strains
Miro JM, et al. Antimicrob Agents Chemother. 2012;56:4511-4515
•
In conclusion, the novel combination of DAP plus
TMP/SMX provided rapid bactericidal activity and
provides a therapeutic option for treating DNS MRSA
infections, especially when bactericidal activity is
desired.
Impact of the Combination of Daptomycin and TrimethoprimSulfamethoxazole on Clinical Outcomes in MRSA Infections
 This was a multicenter, retrospective case series of patients treated
with the combination of daptomycin and TMP-SMX for at least 72 h.
 The objective of this study was to describe the safety and
effectiveness of this regimen in clinical practice.
 The most commonly stated reason that TMP-SMX was added to
daptomycin was persistent bacteremia and/or progressive signs and
symptoms of infection.
 After the initiation of combination therapy, the median time to
clearance of bacteremia was 2.5 days.
 Microbiological eradication was demonstrated in 24 out of 28 patients,
and in vitro synergy was demonstrated in 17 of the 17 recovered
isolates.
 Further research with this combination is necessary to describe the
optimal role and its impact on patient outcomes.
Claeys KC, et al. Antimicrob Agents Chemother 2015;59:1969 –1976
 Therapeutic enhancement was observed with
daptomycin plus ceftaroline in both strains and
vancomycin plus ceftaroline against D592.
 Ceftaroline exposure enhanced daptomycin-induced
depolarization (81.7% versus 72.3%; P=0.03) and
killing by cathelicidin LL37 (P<0.01) and reduced cell
wall thickness (P<0.001).
Werth BJ, et al. Antimicrobial Agents and Chemotherapy 2013;57:66–73
Addition of Ceftaroline to Daptomycin after Emergence of DaptomycinNonsusceptible Staphylococcus aureus during Therapy
Improves Antibacterial Activity
DAP
DAP + CPT from day 1
Rose WE, et al. AAC 2012;56:5296-5302
Antimicrobial Salvage Therapy for Persistent Staphylococcal
Bacteremia Using Daptomycin Plus Ceftaroline
 Daptomycin plus ceftaroline was used in 26 cases of staphylococcal
bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 MSSA, 2
methicillin-resistant S epidermidis).
 Bacteremia persisted for a median of 10 days (range,3–23 days) on
previous antimicrobial therapy.
 After daptomycin plus ceftaroline was started, the median time to
bacteremia clearance was 2 days (range, 1–6 days).
 In vitro studies showed ceftaroline synergy against MRSA and
enhanced MRSA killing by cathelicidin LL-37 and neutrophils.
Ceftaroline also induced daptomycin binding in MSSA and MRSA to a
comparable degree as nafcillin.
Sakoulas G, et al. Clinical Therapeutics. 2014;36:1317-1333
Enterococcus faecalis. Percentage (%) of invasive isolates with high-level
resistance to aminoglycosides, by country, EU/EEA countries, 2013
Enterococci from Blood Cultures - Varese Hospital
350
300
N. Of isolates
250
HLAR
200
Enterococci
150
100
50
0
2003-2005
2006-2008
2009-2011
HLAR – Enterococcal Infections
• HLAR is an acquired mechanism of resistance that
impaires the synergism between ampicillin or
glycopeptide and aminoglycoside
• Some options are needed to treat this emerging
resistant pathogens
• Ampicillin + Ceftriaxone for E. faecalis
• Ampicillin + Daptomycin for E. faecalis and E.
faecium
Gavalda J et al. Ann Intern Med 2007; 146: 574-579
Kelesidis T et al. Clin Infect Dis 2011; 52: 228-234
Time kill curves against VRE with Daptomycin (D) and
Ampicillin (A) at the specified concentrations in
Mueller-Hinton Broth
Sakoulas G, et al. AAC 2012;56:838-44
8 infezioni difficili da Enterococcus spp trattate con
l’associazione Ampicillina - Daptomicina
ID ETA’
INFEZIONE
ISOLATO
MIC
V/D
Dapto
(mg/Kg/die)
GG
AMPI
GG
DAPTO
1
61
EI
E. faecalis
1 /1
8
49
42
2
59
EI
E. Faecalis HLAR
≤ 0.5 / ?
8
42
28
3
49
EI
E. Faecium HLAR
≤ 0.5 / 4
8
42
42
4
49
EI
E. Faecalis HLAR
?/?
8
42
42
5
76
EI
E. Faecalis
≤0.5 / 2
8
56
56
6
49
BATTERIEMIA
E. Faecium
≤0.5 / 4
8
12
12
7
53
cSSTI
E. Faecalis HLAR
1/1
6
20
30
8
53
cSSTI
E. Faecalis HLAR
1/1
6
30
35
Grossi P. et al. 2012 Unpublished
Daptomycin – Ampicillin Combination in
enterococcal infectious endocarditis
ID Age
1
2
3
4
5
61
59
49
49
76
Strain
HLAR
Valve
E. faecalis
E. faecalis
E. faecium
E. faecalis
E. faecalis
/
Yes
Yes
Yes
/
PROSTHETIC AORTA
NATIVE AORTIC
NATIVE MITRAL
PROSTHETIC MITRAL
PROSTHETIC AORTA
Tebini A, et al. ECCMID 2012, O346
Surgery Outcome
YES
YES
NO
NO
YES
Cured
Cured
Cured
Cured
Cured
University of Insubria, Varese, Italy - phone +390332393075; e-mail [email protected]
L-1739
Treatment of Enterococcus spp infections with Ampicillin (AMP) plus Daptomycin (DAP) Combination
P. A. Grossia, S. Caputoa, S. Stefanib
aUniversity of Insubria, Varese, Italy, bUniversity of Catania, Catania, Italy
ABSTRACT
Background: DAP is a cyclic lipopeptide antibiotic, active against Gram positive
bacteria including Enterococcus spp. DAP binds calcium to form a cationic
complex in bacterial membranes causing depolarization and rapid bacterial cell
death. In vitro studies have shown synergy between AMP and DAP against
Enterococcus spp: AMP reduces the net positive bacterial surface charge
increasing the bactericidal effect of DAP.
Methods: Clinical and microbiological outcomes of 23 cases of enterococcal
infections successfully treated with AMP plus DAP were retrospectively reviewed.
All strains were tested for their antibiotic susceptibilities by broth microdilution
methods, following international guidelines (CLSI, EUCAST). Bactericidal activity
and synergistic effect of AMP and DAP (1xMIC, 2xMIC) - alone and in combination
- were evaluated by time-kill curves, following standard procedures.
Results: AMP plus DAP combination was used in 23 patients (M:F=15:8; median
age 60 years) with infectious endocarditis (IE) (n=12), bacteremia (BSI)(n=6),
urinary tract infection (UTI)(n=3)or complicated skin-soft tissue infections
(cSSTI)(n=2). Infection was caused by E. faecalis in 20/23 cases and E. faecium in
3/23. High level gentamycin resistance (HLGR) was documented in 11/23 strains.
In vitro data demonstrated the good synergistic interaction of DAP in
combination with AMP among E. faecalis (12/20 strains), higher in E. faecium (3/3
strains), including HLGR strains. DAP was administered at 6 mg/kg q24h in UTIs
and cSSTIs and 8 mg/kg q24h in BSIs and IEs. AMP was administered at 2g q4h in
all patients. Surgery was performed in cSSTIs and in 7 IEs. Clinical and
microbiological responses occurred within a median of 3 days after the start of
therapy. DAP plus AMP combination treatment was stopped because of end of
treatment (n.12) or its simplification (n.11) Median length of treatment was 49
day in IEs, 11 days in BSIs, 8 days in UTIs and 23 days in cSSTIs, with AMP plus DAP
administration respectively for 29, 10, 8 and 23 days. No adverse event was
observed. All patients were cured, with no relapse at median 174 days after
treatment withdrawal.
Conclusions: Despite published clinical data are very limited, we have observed
that AMP plus DAP is a reasonable and effective option for treatment of
enterococcal infections, even if caused by HLGR strains.
BACKGROUND
DAP is a cyclic lipopeptide antibiotic, active against Gram
positive bacteria including Enterococcus spp. DAP binds
calcium to form a cationic complex in bacterial
membranes causing depolarization and rapid bacterial
cell death1. Higher doses and combination therapy
strategies have been investigated in some difficult-totreat infections in order to: enhance clinical success
rates; treat pathogens that may be non-susceptible to
standard doses; and minimise the risk of resistance
development2. In vitro studies have shown synergy
between AMP and DAP against Enterococcus spp: AMP
reduces the net positive bacterial surface charge
increasing the bactericidal effect of DAP3,4.
METHODS
Clinical and microbiological outcomes of 23 cases of
enterococcal infections successfully treated with AMP plus
DAP were retrospectively reviewed. All strains were tested
for their antibiotic susceptibilities by broth microdilution
methods, following international guidelines (CLSI, EUCAST).
Bactericidal activity and synergistic effect of AMP and DAP
(1xMIC, 2xMIC) - alone and in combination - were evaluated
by time-kill curves, following standard procedures.
RESULTS
AMP plus DAP combination was used in 23 patients
(M:F=15:8; median age 60 years) with infectious endocarditis
(IE) (n=12), bacteremia (BSI)(n=6), urinary tract infection
(UTI)(n=3)or complicated skin-soft tissue infections
(cSSTI)(n=2). Infection was caused by E. faecalis in 20/23 cases
and E. faecium in 3/23. High level gentamycin resistance
(HLGR) was documented in 11/23 strains. In vitro data
demonstrated the good synergistic interaction of DAP in
combination with AMP among E. faecalis (12/20 strains),
higher in E. faecium (3/3 strains), including HLRG strains. DAP
was administered at 6 mg/kg q24h in UTIs and cSSTIs and 8
mg/kg q24h in BSIs and IEs. AMP was administered at 2g q4h
in all patients. Surgery was performed in cSSTIs and in 7 IEs.
Clinical and microbiological responses occurred within a
median of 3 days after the start of therapy. DAP plus AMP
combination treatment was stopped because of end of
treatment (n.12) or its simplification (n.11). Median length of
treatment was 49 day in IEs, 11 days in BSIs, 8 days in UTIs
and 23 days in cSSTIs, with AMP plus DAP administration
respectively for 29, 10, 8 and 23 days. No adverse event was
observed. All patients were cured, with no relapse at median
CONCLUSIONS
174 days after treatment withdrawal. (Table 1).
Despite published clinical data are very limited5, we have
observed that AMP plus DAP is a reasonable and effective
option for treatment of enterococcal infections, even when
caused by HLGR strains. Randomized controlled trials are
needed to confirm these findings.
Table 1: Enterococcal infections treated with AMP plus DAP
Sex,
age
Strain
Diagnosis
M,59
E. faecalis
IE
F,49
E. faecalis
IE
M,53
E. faecalis
cSSTI
M,60
F,53
F,54
E. faecium
E. faecium
E. faecalis
IE
IVU
IVU
M,62
E. faecalis
IE
M,49
E. faecium
BSI
F,76
E. faecalis
IE
M,41
M,79
E. faecalis
E. faecalis
BSI
IE
M,80
E. faecalis
IE
M,60
E. faecalis
BSI
M,92
E. faecalis
IE
F,94
E. faecalis
IE
F,80
E. faecalis
IE
M,40
M,64
M,73
F,50
E. faecalis
E. faecalis
E. faecalis
E. faecalis
IE
BSI
BSI
IVU
F,70
E. faecalis
BSI
M,82
M,54
E. faecalis
E. faecalis
IE
cSSTI
Treatment (Duration)
AMP + G (9 days), then DAP + AMP (28 days),
then AMX/CLV (21 days)
VA (6 days), then DAP + AMP (43 days)
DAP (1 day), then DAP+AMP (32 days), then
DAP+PIP/TZB (3 days), then PIP/TZB (12 days)
DAP + AMP (9 days), then Teicoplanin (28 days)
DAP (6 days), then DAP + AMP (8 days)
DAP + AMP (8 days)
AMP + G (10 days), then DAP + AMP (31 days),
then AMX (36 days)
DAP + AMP (13 days)
PIP/TZB (9 days), then DAP + MER (2 days), then
DAP + AMP (54 days)
DAP + AMP (10 days), then AMX/CLV (5 days)
PIP/TZB (14 days), then DAP + AMP (56 days)
AMP (21 days), then DAP + AMP (11 days), then
DAP (45 days)
DAP + AMP (13 days)
DAP + AMP (17 days), then AMP (11 days), then
AMX/CLV (28 days)
PIP/TZB (7 days), then DAP + AMP (17 days),
then AMP + CRO (18 days)
CRO (4 days), then DAP + AMP (19 days), then
AMP + CRO (23 days)
AMP + G (5 days), then DAP + AMP (42 days)
DAP + AMP (9 days), then AMX (1 day)
PIP/TZB (32 days), then DAP + AMP (4 days)
DAP + AMP (8 days), then AMX/CLV (6 days)
DAP (2 days), then DAP + AMP (5 days), then
PIP/TZB (7 days)
CRO (15 days), then DAP + AMP (56 days)
DAP + AMP (12 days)
DAP dose
(mg/Kg)
Outcome
6 q24h
Cured
8 q24h
Cured
6 q48h
Cured
8 q24h
6 q48h
6 q24h
Cured
Cured
Cured
8 q24h
Cured
8 q24h
Cured
8 q24h
Cured
8 q24h
8 q24h
Cured
Cured
8 q48h
Cured
8 q24h
Cured
8 q24h
Cured
8 q48h
Cured
6 q24h
Cured
8 q24h
8 q24h
8 q24h
8 q24h
Cured
Cured
Cured
Cured
8 q24h
Cured
8 q24h
8 q24h
Cured
Cured
DAP: Daptomycin; AMP: Ampicillin; AMX/CLV: Amoxicillin/Clavulanate; VA: vancomycin; PIP/TZB: Piperacillin/Tazobactam; G:
Gentamicin; MER: Meropenem; CRO: Ceftriaxone
REFERENCES
1. Micklefield J. Daptomycin structure and mechanism of action revealed. Chem Biol 2004;11:887,888.
2. Gould IM, Miró JM, Rybak MJ. Daptomycin: the role of high-dose and combination therapy for Grampositive infections. Int J Antimicrob Agents. 2013;42:202-10.
3. Sakoulas G, Bayer AS, Pogliano J, Tsuji BT, Yang SJ, Mishra NN, et al. Ampicillin enhances daptomycinand cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant
Enterococcus faecium. Antimicrob Agents Chemother 2012;56:838–44
4. Rand KH, Houck H. Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant
enterococci. J Antimicrob Chemother 2004; 53: 530–2.
5. Sierra-Hoffman M, Iznaola O, Goodwin M, Mohr J. Combination therapy with ampicillin and
daptomycin for treatment of Enterococcus faecalis endocarditis. Antimicrob Agents Chemother.
2012;56:6064.
Daptomicina nelle Infezioni Enterococciche Gravi
• Efficace e ben tollerata in infezioni enterococciche gravi incluse EI di
cuore sinistro e su valvola protesica
• Evidenze di successo nelle batteriemie ed EI enterococciche
soprattutto ad elevate dosi (> 8 mg/kg)
• Sinergismo con ampicillina promettente in vivo nei confronti di
enterococchi multiresistenti
• Ipotizzabile un ruolo di daptomicina in HLAR o insufficienza renale
come alternativa ad aminoglicoside; suggerito anche possibile uso
short term nelle IVU complicate
• Bias di studi osservazionali non controllati - non comparativi o signoli
case reports con elevate comorbosità.
• Necessari studi prospettici controllati per corretta valutazione
dell’outcome
Combination therapy with ampicillin and daptomycin for the
treatment of Enterococcus faecalis endocarditis
 We report a case of a 89-year old Caucasian female in good
health, but with a history of chronic hypertension and stage 4
chronic kidney disease (estimated baseline GFR of 25 ml/min),
admitted for mitral valve endocarditis.
 Ampicillin (1 gram q 6 hrs) plus daptomycin (6 mg/kg q 48 hrs)
were initiated with a goal of 6 weeks of therapy. CPK was
measured routinely throughout the 6 weeks with no significant
elevation noted.
 At week 6, blood cultures were negative, antibiotics were
stopped and repeat blood cultures 2 weeks later were also
negative. Twelve months later, the patient was alive and had no
clinical signs of endocarditis or active infection.
M. Sierra-Hoffman, et al. AAC 2012; doi:10.1128/AAC.01760-12
Treatment of High-Level Gentamicin-Resistant
Enterococcus faecalis Endocarditis with Daptomycin
plus Ceftaroline
Sakoulas G, et al. AAC 2013;57:4042–4045
Enterococcus faecium. Percentage (%) of invasive isolates resistant to
vancomycin, by country, EU/EEA countries, 2013
Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in
Vancomycin-Resistant Enterococcal Bloodstream Infection: A National
Cohort Study of Veterans Affairs Patients
• Treatment with linezolid for VRE-BSI resulted in significantly higher
treatment failure in comparison to daptomycin.
• Linezolid treatment was also associated with greater 30-day all-cause
mortality and microbiologic failure in this cohort.
Britt NS, et al. Clinical Infectious Diseases® 2015;61(6):871–8
Ampicillin + Daptomycin
• This drug association seems promising according to some
in vitro study, also to treat Vancomycin-resistant E.
faecium infections
• Ampicillin enhance daptomycin killing also against VRE
modifying bacterial surface charge
• Ampicillin seems to avoid selections of DNS-strains,
expecially where the bacterial inoculum is high
Entenza JM et al. Int. J. Antimicrob. Agents 2010; 35:451– 456
Sakoulas G et al. Antimicrob Agents Chemother. 2012 Feb;56(2):838-44
Conclusions
• Few molecules are currently available for the treatment
of severe infections due to MDR Gram-positives and
some of them are already loosing their efficacy
• The use of Daptomycin at high dose or in combination
with beta-lactams, rifampin, fosfomycin, cotrimoxazole or
ceftaroline has been shown to prevent the development
of non-susceptible strains and to treat severe infections.
However, most of the currently available data come from
small case series or in vitro studies
• An optimized use of Daptomycin might help in preserving
its activity
• Large randomized clinical trials are needed