Table 1.  In Vitro Susceptibility Testing of Several Multi-Drug Resistant and Susceptible Gram-Positive Organisms Against Daptomycin.  The MIC 90 and MIC Range in the Respective Studies are Seen Below. 

 

Organism

No.

MIC90

MIC range       

Reference

 Enterococcus faecalis

 

 

 

 

    Vancomycin – Susceptible

220

1.0-2.0

0-.015-4.0

(12,28,72)

    Vancomycin – Resistant           

231

0.5-4.0

0.25-8.0

(39,53,81)

    Enterococcus faecium

 

 

 

 

    Vancomycin – Susceptible

358

1.0-4.0

0.5-8.0

(28,72)

    Vancomycin – Resistant           

249

1.0-4.0

0.25-4

(12,28,39,53,72)

    Listeria monocytogenes

25

4.0

2.0-8.0

(39)

Staphylococcus aureus

 

 

 

 

   Glycopeptide - Intermediate

22

4

0.5-16

(3,39,66)

   Methicillin – Resistant

711

0.25-1

0.06-2.0

(12,28,39,40,41,53,66,72,90)

   Methicillin – Susceptible

1473

0.5-1.0

0.015-2.0

(12,28,39,40,41,53,66,72,90)

   Vancomycin – Intermediate

47

1

0.0625-2.0

(72,86)

   Vancomycin – Resistant

1

n/a

0.25

(24)

Staphylococcus coagulase negative

 

 

 

 

   Methicillin - Resistant

954

0.5-1.0

0.004-1.0

(12,28,39,41)

   Methicillin - Susceptible

728

0.25-2.0

0.03-0.5

(12,28,39)

   Staphylococcus epidermidis

 

 

 

 

   Methicillin – Resistant

65

0.25-0.5

0.12-1.0

(39,72)

   Methicillin – Susceptible

66

0.25

0.06-1.0

(39,72)

Staphylococcus species

 

 

 

 

   S. haemolyticus

56

0.25-0.5

0.03-1.0

39,40,41,53)

   S. saprophyticus

30

0.5

0.25-1.0

(90)

Streptococci species

 

 

 

 

   Group G Streptococci

10

0.06

0.015-0.06

(90)

   Streptococcus milleri 

30

1.0

0.25-1.0

(90)

   Streptococcus pyogenes

340

0.06

0.015-0.5

(12,39,40,53)

   Viridans Streptococci

126

1.0-2.0

0.016-8.0

(12,39,40,53)

   Streptococcus agalactiae

81

0.25

0.12-.025

(53)

   Streptococcus pneumoniae

50

0.25

0.06-0.25

(53)

   Penicillin Intermediate

389

0.25-1.0

0.008-1.0

(12,28,39,81)

   Penicillin Resistant

267

0.25-1.0

0.015-1.0

(12,28,39,81)

   Penicillin Susceptible

1166

0.25-0.5

0.015-0.5

(12,28,39,81)

 

MIC90 = minimum inhibitory concentration for 90% of strains tested in mg/L.

 
 

Table 2.  Susceptibility Breakpoints.  The Following Susceptibility Interpretive Criteria Breakpoints are Approved by the Food and Drug Administration (FDA) and are Based Upon Several in vitro and in vivo Activity Studies.

TENTATIVE SUSCEPTIBILITY BREAKPOINTS

 

Minimum Inhibitory Concentration

 

 

Susceptible

Intermediate

Resistant

Enterococcus sp.

< 4

N/A

N/A

Staphylococcus sp.

< 1

N/A

N/A

Streptococcus sp.

(other than Streptococcus pneumoniae)

< 1

N/A

N/A

Disk Diffusion for above organisms

(except Enterococcus sp.)

> 16mm

N/A

N/A

Disk Diffusion for Enterococcus sp.

> 11mm

N/A

N/A

 

 

 

Table 3.  Comparative Inhibitory Activity of Daptomycin, Linezolid, Quinupristin/Dalfopristin and Vancomycin against Selected Gram-Positive Organisms.                    

                                                                       

 

 

Daptomycin

MIC90 range

Linezolid

MIC90 range

Quinupristin/ Dalfopristin

MIC90 range

Vancomycin

MIC90 range

Enterococcus faecalis

(12,19,27,28,35-37,40,44,47,49,53,62,72,81,88,95)

Vancomycin – Susceptible

1-2

1-4

8-32

1-4

Vancomycin – Resistant

0.5-4

2-4

16-32

R

Enterococcus faecium

(12,19,27,28,35-37,40,44,48,49,53,72,81,95)

Vancomycin – Susceptible

1-4

2-4

0.5-4

1.5-2

Vancomycin – Resistant

1-4

2-4

0.5-16

R

Staphylococcus aureus

(1,3,4,6,7,10,12,19,26,28,36,37,41,44,46, 47,49,53,65,66,71,72,82,86,88,95)

Methicillin – Susceptible

0.5-1

2-4

0.25-2

0.5-1

Methicillin – Resistant

0.25-1

1-4

1.00.2-2

0.5-2

Vancomycin–Intermediate

0.5-1

1-2

0.25

I

Vancomycin – Resistant*

1

2

<1

R

Coagulase-negative Staphylococci

(65,71,82,88,95)

Methicillin-Susceptible

0.25-2

2

0.1-1

1-2

Methicillin-Resistant

0.5-1

1-2

0.25-1

1-2

Streptococcus pneumoniae

(11,12,19,28,38,41,48,49,81,83,88,93,95)

Penicillin Susceptible

0.25-0.5

1.5-2

0.39-1

0.25-0.5

Penicillin Intermediate

0.25-1

1

0.5-2

0.25-1

Penicillin Resistant

0.25-1

1

0.5-2

0.5-1

Anaerobic Organisms (43)

Actinomyces group

4

0.5

0.25

1

Clostridium difficile

1

16

16

2

Clostridium perfringens

0.5

2

1

0.5

Lactobacillus sp.

16

8

2

32

Peptostreptococcus sp.

0.06-1

1-2

1-2

0.25-1

Propionibacterium sp.

2

1

0.25

0.5

Gram positive bacilli Organisms (43)

Corynebacterium jeikeium

0.25

0.5

0.25

0.5

Corynebacterium sp.

1

1

1

0.5

MIC90 = minimum inhibitory concentration for 90% of strains tested        

* based upon 2 isolates in Michigan and Pennsylvania

                                   

       

Table 4.  Mean Pharmacokinetic Parameters of Daptomycin in Healthy Volunteers After 30 Minute Intravenous Infusions.  

Parameter

Daptomycin

Dose

4mg/kg

Cmax (mg/L)

77.5

t1/2 (h)

8

t1/2 renal failure* (h)

28

% serum protein binding

90

Vd (L)

7

AUC0-24 (mg • hr/L)

468

Systemic clearance (ml/h/kg)

8.2

Urinary excretion (%)

60

* Patients with renal failure

 

Table 5.  Reported Adverse Events in a Large Scale Clinical Trial Evaluating Daptomycin Vs. A Comparator of Vancomycin or a Semi-Synthetic Penicillin in a Complicated Skin and Soft Tissue Phase III Randomized Clinical Trial (8,9). 

Adverse Event

Daptomycin (n=534)

Comparator (n=558)

Constipation

6.2%

6.8%

Nausea

5.8%

9.5%

Injection site reaction

5.8%

7.7%

Headache

5.4%

5.4%

Diarrhea

5.2%

4.3%

Insomnia

4.5%

5.4%

Rash

4.3%

3.8%

Vomiting

3.2%

3.8%

Abnormal liver function tests

3.0%

1.6%

Pruritus

2.8%

3.8%

Elevated CPK

2.8%

1.8%

Fungal Infections

2.6%

3.2%

Hypotension

2.4%

1.4%

Urinary Track Infections

2.4%

0.5%

Renal Failure

2.2%

2.7%

Dizziness

2.2%

2.0%

Anemia

2.1%

2.3%

Dyspenia

2.1%

1.6%

Fever

1.9%

2.5%

Limb pain

1.9%

2.0%

Hypertension

1.1%

2.0%

Dyspepsia

0.9%

2.5%

Arthralgias

0.9%

2.2%

 

Table 6. Dosing During Continuous Renal Replacement Therapy

 

CVVH (Continuous venovenous hemofiltration): 4 or 6mg/kg IV q48h

CVVHD (Continuous venovenous hemodialysis): 4 or 6mg/kg IV q48h

CVVHDF (Continuous venovenous hemodiafiltration) 4 or 6mg/kg IV q48h

 

Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD or CVVHDF which

combine dialysis with fluid removal.

 

Figure 1.  Structure. Daptomycin is a novel 13-member amino acid cyclic lipopeptide compound that contains a water-soluble hydrophilic core with a lipophilic tail. The lipophilic tail exerts itself into the cytoplasmic membrane of the gram-positive cell wall. 

 

 

                                                                                  Daptomycin

 

 

Figure 2. Daptomycin’s Mechanism of Action. Step 1: Calcium-dependent binding/insertion of the lipophillic tail into gram-positive cyotplasmic membrane.  Step 2: Oligomerization/channel formation occur.  Step 3: Ion leakage and collapse of organism leading to cell death.