1. 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

2. 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.

3. The greater the volume of antibiotics used, the greater the chances that antibiotic-resistant populations of bacteria will prevail in the contest for survival of the fittest at the bacterial level

4. 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

5. Percentuale di S. aureus resistente alla meticillina (2011-2014)
Source: CDDEP 2015, WHO 2014 and PAHO, forthcoming

6. Staphylococcus aureus Resistance to Oxacillin/Methicillin
35,8%
EARS-NET Annual Report 2013

8. Studio epidemiologico condotto per 3 mesi in 52 centri su 21
Studio epidemiologico condotto per 3 mesi in 52 centri su 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

9. Probability of target attainment
MIC and probability of achieving target vancomycin serum concentrations
Jeffres et al., 20061
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
Probability of achieving an AUC:MIC ratio of >400
LD vancomycin*
1.0
HD vancomycin†
0.8
0.6
Probability of target attainment
0.4
0.2
0.25
0.5
1.0
2.0
4.0
Vancomycin MIC, µg/ml
*LD, low-dose vancomycin (trough concentration ≤15 µg/ml)
†HD, high dose vancomycin (trough concentration >15 µg/ml)
Jeffres M et al. Chest 2006;130:947–955
Mohr J et al. Clin Infect Dis 2007;44:1536–1542

10. 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)
We tested this hypothesis in 414 episodes of mrsa bacteremia consecutively diagnosed in our hospital over 15 years. The most important finding was that mortality within the first 30 days after bacteremia significantly increased with increasing vanco MIC
Vancomycin MIC significantly predicts for mortality in MRSA
In a multivariate regression analysis of 414 episodes of MRSA bacteraemia consecutively diagnosed in a single hospital over 15 years, the risk of death within 30 days of bacteraemia onset significantly increased with increasing vancomycin MIC1
A 0.5 µg/ml increase in MIC, from 1 to 1.5, increased the odds ratio (risk of mortality) by 1.86 (P=0.08), whereas a 1 µg/ml increase, increased the odds ratio by 5.39
Inappropriate empiric therapy was associated with a risk of death similar to that associated with an infection due to MRSA with a vancomycin MIC=2 µg/ml
Reference
Soriano A et al. Clin Infect Dis 2008;46:193–200
*Inappropriate therapy defined as empirical therapy to which the MRSA strain was resistant
Soriano A et al. Clin Infect Dis 2008;46:193–200

11. MRSA Bacteremia
Among the Gram-positive organisms, methicillin-resistant 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 multidrug-resistant 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).

12. 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
ABSSSI, CAP, HAP
Telavancin
cSSTI (US), HAP
Ceftaroline
ABSSSI, CAP
Ceftobiprole
HAP, CAP
Oritavancin
ABSSSI (US)
Dalbavancin
ABSSSI (US) (EMA approval)
Tedizolid
Grossi, November 2015

13. New therapeutic options for treatment of MDR Gram-positives
Despite concerns about vancomycin use in the treatment of multidrug-resistant 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 infection-related mortality was detected.
Of concern is the appearance of daptomycin and linezolid resistance following increased use.

15. Treatment of MRSA Bacteremia IDSA Guidelines 2011
Uncomplicated
Treatment duration
Complicated
Daptomycin 6 mg/kg iv once daily AI
At least 2 weeks
Daptomycin 8-10 mg/kg iv once daily BIII
4-6 weeks
Vancomycin AII
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

16. 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
Israel
Argentina
EU /
Italy AIC cSSTI
Italy AIC Bact & RIE

17. Relative bacteriostatic and bactericidal activity of antibiotic agents
Rolinson GN, Geddes AM. Int J Antimicrob Agents 2007;29:3–8

18. 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.

19. 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):

20. Increasing daptomycin dose ↑↑ Cmax/MIC - ↑↑ AUC/MIC 8-10 mg/kg/day
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-to-treat infections (e.g. involving biofilms) and high bacterial burden, based on its dose-dependent anti-bacterial activity.

21. Is empiric daptomycin effective in reducing mortality in Staphylococcus aureus bacteraemia? A real-life experience
In hospital mortality OR
p-value
DAP vs Glycopeptides
10.66
0.009
DAP vs β-lactams
4.84
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

22. Safety of High-Dose Daptomycin for Gram-Positive Infections Kullar R
Safety of High-Dose Daptomycin for Gram-Positive Infections Kullar R., et al. Pharmacotherapy 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.

23. Use of Daptomycin on Gram-positive pathogens Personal experience in Varese (N of cases=67, 21% SOT)
Infection
N, (%)
Bacteremia 18 (27)
Left-sided IE 14 (21)
cSSTI
23 (34)
Others 12 (18)
Total
67 (100)
Pathogen
Enterococci 7 3 5
15 (22)
MRSA 1
16 (24)
MSSA
12 (18)
Others 2
13 (19)
No isolation 4
11 (17)
Dose (mg/kg)
3 (5) 6 8 18
36 (54) 10
27 (40)
1 (1)
Success *
Clinical 13 14 20 11
58 (87)
Microbiological 12
34 (51)
Execellent Outcome; 1 case of MSSA cSSTI failure (selection of Daptomycin non-susceptible strain after 10 days of 4 mg/kg/day
Excellent safety profile (1 patient developed reversible CPK elevation)
* Documented at follow-up
A. Tebini, et al. ICAAC Chicago 2011 – Poster # K1413

24. Dosage and duration of DAP H8 therapy
Patients, n (%)
Most frequently used initial daptomycin dose
≥8 and ≤10 mg/kg/day
223 (95.3)
>10 mg/kg/day
11 (4.7)
Median duration of daptomycin therapy
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

25. Clinical outcomes for DAP H8 for ≥14 days by infection type
Utili R, et al. ECCMID 2012, P1846

26. Clinical outcomes for DAP H8 for ≥14 days by pathogen
CoNS: Staph. epidermidis and other CoNS; Enterococci: E. faecalis, E. faecium and Enterococcus spp.
Utili R, et al. ECCMID 2012, P1846

27. 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

28. 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

29. 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:

30. 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

31. Daptomycin treatment success for S
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.

32. Treatment of experimental endocarditis caused by MRSA-572
Addition of Gentamicin or Rifampin Does Not Enhance the Effectiveness of Daptomycin in Treatment of Experimental Endocarditis Due to MRSA
Treatment of experimental endocarditis caused by MRSA-572
Miró JM, et al. AAC, 2009;53:4172–4177

33. Activities of antimicrobials tested alone and in combination against MRSA
LaPlante K, et al. AAC 2009;53:

34. Effects of antibiotic treatment on experimental MRSA prosthetic knee infection in rabbits
Saleh-Mghir A, et al. AAC 2011;55:4589

35. Outcomes in Evaluable Patients by Infection Type
CLINICAL EXPERIENCE WITH DAPTOMYCIN (DAP) AND CONCOMITANT (CON) RIFAMPIN (RIF)
Outcomes in Evaluable Patients by Infection Type
CONCLUSIONS
These data suggest that concomitant therapy with daptomycin and rifampin appear to be reasonable therapeutic option.
Further study is needed to explore the role of concomitant therapy with daptomycin and rifampin, particularly in patients with foreign body infections.
Ghosh M., et al. ICAAC 2009

37. Daptomycin Plus Fosfomycin Is Synergistic Against MSSA and MRSA Strains
Miro JM, et al. Antimicrob Agents Chemother. 2012;56:

38. 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.

40. Impact of the Combination of Daptomycin and Trimethoprim- Sulfamethoxazole 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

41. 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

42. Addition of Ceftaroline to Daptomycin after Emergence of Daptomycin-Nonsusceptible Staphylococcus aureus during Therapy Improves Antibacterial Activity
DAP
Antibiotic activity in the in vitro PK/PD model of daptomycin alone and in combination with ceftaroline in the initial daptomycin-susceptible clinical isolate W3148. (A) Single antibiotic exposure. black circles, growth control; black squares, daptomycin at 6 mg/kg every 48 h; white circles, ceftaroline at 200 mg every 12 h. (B) Combination antibiotic exposure results. Black circles, growth control; black triangles, DAP treatment every 48 h with CPT added on day 3; white diamonds, initial therapy with DAP every 48 h combined with CPT on day 1.
DAP + CPT from day 1
Rose WE, et al. AAC 2012;56:

43. 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:

45. Enterococcus faecalis
Enterococcus faecalis. Percentage (%) of invasive isolates with high-level resistance to aminoglycosides, by country, EU/EEA countries, 2013

46. Enterococci from Blood Cultures - Varese Hospital
N. Of isolates

47. 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:
Kelesidis T et al. Clin Infect Dis 2011; 52:

48. Daptomycin MIC, mg/L: no. isolates (%)
Daptomycin MIC distribution against enterococci collected during 2006 in Europe
Daptomycin MIC, mg/L: no. isolates (%)
0.12
0.25
0.5 1 2 4 8
Enterococcus spp.* (n=1169) 15
(1.3) 53
(4.5)
395 (33.8)
534 (45.7)
167 (14.3) 5
(0.4)
(0.0)
E. faecalis* (n=741)
(0.7) 43
(5.8)
344
(46.4)
334
(45.1)
(2.0)
E. faecalis van-S (n=737) 41
(5.6)
343
(46.5)
333
(45.2)
E. faecalis van-NS† (n=4)
(50.0)
(25.0)
E. faecium* (n=376) 3
(0.8)
(0.5) 40
(10.6)
188
138
(36.7)
E. faecium van-S (n=279) 27
(9.7)
128
(45.9)
116
(41.6)
(1.8)
E. faecium van-NS† (n=97)
(1.0) 13
(13.4) 60
(61.9) 22
(22.7)
The MIC90 is highlighted. *All isolates regardless of susceptibility to vancomycin. †Vancomycin non-susceptible, i.e. resistant (≥32 mg/l) and intermediate (8–16 mg/l) combined.
JMI European Surveillance Report 2007

49. 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

50. 8 infezioni difficili da Enterococcus spp trattate con l’associazione Ampicillina - Daptomicina
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
E. Faecalis HLAR
≤ 0.5 / ? 28 3
E. Faecium HLAR
≤ 0.5 / 4 4
? / ? 5 76
E. Faecalis
≤0.5 / 2 56 6
BATTERIEMIA
E. Faecium
≤0.5 / 4 12 7 53
cSSTI
1 / 1 20 30 35
Grossi P. et al Unpublished

51. Daptomycin – Ampicillin Combination in enterococcal infectious endocarditisID
Age
Strain
HLAR
Valve
Surgery
Outcome 1 61
E. faecalis /
PROSTHETIC AORTA
YES
Cured 2 59
Yes
NATIVE AORTIC 3 49
E. faecium
NATIVE MITRAL NO 4
PROSTHETIC MITRAL 5 76
Tebini A, et al. ECCMID 2012, O346

52. L-1739
University of Insubria, Varese, Italy - phone ;
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
Table 1: Enterococcal infections treated with AMP plus 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.
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.
Sex, age
Strain
Diagnosis
Treatment (Duration)
DAP dose
(mg/Kg)
Outcome
M,59
E. faecalis IE
AMP + G (9 days), then DAP + AMP (28 days), then AMX/CLV (21 days)
6 q24h
Cured
F,49
VA (6 days), then DAP + AMP (43 days)
8 q24h
M,53
cSSTI
DAP (1 day), then DAP+AMP (32 days), then DAP+PIP/TZB (3 days), then PIP/TZB (12 days)
6 q48h
M,60
E. faecium
DAP + AMP (9 days), then Teicoplanin (28 days)
F,53
IVU
DAP (6 days), then DAP + AMP (8 days)
F,54
DAP + AMP (8 days)
M,62
AMP + G (10 days), then DAP + AMP (31 days), then AMX (36 days)
M,49
BSI
DAP + AMP (13 days)
F,76
PIP/TZB (9 days), then DAP + MER (2 days), then DAP + AMP (54 days)
M,41
DAP + AMP (10 days), then AMX/CLV (5 days)
M,79
PIP/TZB (14 days), then DAP + AMP (56 days)
M,80
AMP (21 days), then DAP + AMP (11 days), then DAP (45 days)
8 q48h
M,92
DAP + AMP (17 days), then AMP (11 days), then AMX/CLV (28 days)
F,94
PIP/TZB (7 days), then DAP + AMP (17 days), then AMP + CRO (18 days)
F,80
CRO (4 days), then DAP + AMP (19 days), then AMP + CRO (23 days)
M,40
AMP + G (5 days), then DAP + AMP (42 days)
M,64
DAP + AMP (9 days), then AMX (1 day)
M,73
PIP/TZB (32 days), then DAP + AMP (4 days)
F,50
DAP + AMP (8 days), then AMX/CLV (6 days)
F,70
DAP (2 days), then DAP + AMP (5 days), then PIP/TZB (7 days)
M,82
CRO (15 days), then DAP + AMP (56 days)
M,54
DAP + AMP (12 days)
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 174 days after treatment withdrawal. (Table 1).
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-to-treat 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.
DAP: Daptomycin; AMP: Ampicillin; AMX/CLV: Amoxicillin/Clavulanate; VA: vancomycin; PIP/TZB: Piperacillin/Tazobactam; G: Gentamicin; MER: Meropenem; CRO: Ceftriaxone
REFERENCES
Micklefield J. Daptomycin structure and mechanism of action revealed. Chem Biol 2004;11:887,888.
Gould IM, Miró JM, Rybak MJ. Daptomycin: the role of high-dose and combination therapy for Gram-positive infections. Int J Antimicrob Agents. 2013;42:
Sakoulas G, Bayer AS, Pogliano J, Tsuji BT, Yang SJ, Mishra NN, et al. Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother 2012;56:838–44
Rand KH, Houck H. Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant enterococci. J Antimicrob Chemother 2004; 53: 530–2.
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.
CONCLUSIONS
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. 52

53. 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

54. 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: /AAC

55. Treatment of High-Level Gentamicin-Resistant Enterococcus faecalis Endocarditis with Daptomycin plus Ceftaroline
Sakoulas G, et al. AAC 2013;57:4042–4045

56. Enterococcus faecium. Percentage (%) of invasive isolates resistant to vancomycin, by country, EU/EEA countries, 2013

57. 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

58. 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 Feb;56(2):838-44 58

59. 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