Transcript The Relationship between Daptomycin (DAP) Free drug AUC/MIC

The Relationship between Daptomycin (DAP) Free drug AUC/MIC, Antibacterial effect (ABE)
and Emergence of Resistance (EoR) in S.aureus.
49th ICAAC Meeting
San Francisco, CA
September 12-15, 2009
KE Bowker, AR Noel, AP MacGowan
BCARE, Department of Microbiology, North Bristol NHS Trust, Bristol, UK
Introduction
Results
 Animal studies indicate that for daptomycin (DAP) AUC/MIC is
the main pharmacodynamic index for S. aureus, S. pneumoniae
and Enterococcus spp.
 Extrapolated animal data has shown that a free drug
(f)AUC/MIC between 12 and 62 is required for a static effect.
DAP is 92% protein bound. The DAP EUCAST/CLSI breakpoint
for staphylococci (1mg/L) based on 4mg/kg dosing confers a
mean target AUC/MIC of 438 equating to fAUC/MIC of 35.
 The relationship between DAP fAUC/MIC and log reduction in
count at 24h for the individual strains and the meaned data is
shown on Table 1.
 The combined DAP fAUC/MIC ratios for the six strains were
plotted against log change in viable count at 24h using a sigmoid
Emax model (r2 =0.80) (Figure1).
 A static effect, 1 log and 3 log reduction in count were achieved
at ratios of 37.2  16.5, 40.6 17.8 and 49.8  19.2 respectively.
 A good correlation was also demonstrated for the six strains
between AUC/MIC and AUBKC24 (r2 =0.78) (Figure 2).
 The EoR assessed by growth on plates containing x2 and x4
DAP MIC, associated with fAUC/MIC ratio is shown on Table 2.
 The relative risk of EoR increased from 17% at fAUC/MIC>40, to
67 (x2MIC) or 73% (x4MIC) at fAUC/MIC <10.
 The objectives of this study were: determine the DAP
fAUC/MIC ratio required for a static, 1, 2 and 3 log reduction in
viable count against UKEMRSA15, UKEMRSA16 strains and a
VISA strain with raised DAP MIC and, to relate these targets to
the DAP clinical breakpoint and the relative risk of emergence of
resistance (EoR).
Corresponding author
[email protected]
Results cont’d
Figure1) Relationship between fAUC/MIC and d24 (all strains)
4
d24 (logCFU/mL)
A1-1271
2
0
-2
-4
0
1
2
3
4
AUC/MIC
Figure 2) Relationship between fAUC/MIC and AUBKC (all strains)
Table 1 Relationship between DAP fAUC/MIC and ABE
 An in vitro pharmacokinetic (pK) model was used to perform
DAP dose ranging studies simulating free drug pK concentrations
based on DAP 6 mg/kg 24 hrly: Cmax 6.4 mg/L, T1/2 8h for 48h.
 Five strains UKEMRSA-15 (SMH15841 & SMH40289) and 16
(SMH40275, SMH33922 & SMH33024) a VRSA (SMH19898)
from the collection of BCARE were used.
 10% Mueller Hinton broth supplemented with 50 mg/L calcium,
inoculum of 106 cfu/mL were used and aliquots taken throughout
the simulations were plated onto nutrient agar plates for viable
count determination.
 Antibacterial effect (ABE) was assessed by area-under-the
bacterial kill curve 0–24 h (AUBKC24) and 0–48 (AUBKC48; log
CFU/ml.h); and log reduction in viable count at 24 and 48 h (d24)
(48h data not shown)
 Dose ranging A sigmoid dose-response variable slope Emax
model was used to relate ABE to fAUC/MIC.
 EoR was determined by plating aliquots of the bacterial
suspensions onto nutrient agar plates containing x2, x4 and x8
the DAP MIC. The risk of EoR as measured by growth on x2MIC
and x4MIC plates was related to fAUC/MIC.
fAUC/MIC (DAP MIC mg/L)
ABE at 24h
SMH15841
(0.12)
52.48
SMH40289
(0.25)
36.3
SMH19898
(1.0)
22.9
SMH40275
(0.06)
63.1
SMH33922
(0.19)
33.9
SMH33024
(0.25)
14.45
meaned data
1 log drop
56.23
38.0
23.44
70.79
35.5
19.9
40.6 ± 17.8
2 log drop
63.1
42.6
24.0
75.86
38.0
26.3
45.0 ± 18.8
3 log drop
74.1
49.0
25.1
75.86
39.8
34.67
49.8 ± 19.2
40.8 ± 17.3
Static Effect
EC50
54.11
39.15
23.68
70.47
37.08
20.26
2
0.9376
0.9845
0.9933
0.9982
0.9583
0.9845
r
37.2 ± 16.5
AUBKC0-24 ( logCFU/mL.h
Materials and methods
150
125
100
75
50
25
0
0
1
2
3
4
AUC/MIC
Conclusions
Table 2 Relationship between fAUC/MIC and EoR
fAUC/MIC
no. of
exps
x2 MIC
no of plates
count
counts>2log
(logcfu/mL)
no. of
exps
x4 MIC
no. of plates
count
counts >2log
(logcfu/mL)
0.5-10
9
6(67)
6.23+/-1.25
11
8(73)
4.29+/- 1.26
>11-30
8
5(63)
4.50+/-0.37
5
3(60)
3.93+/-0.76
>30-40
3
2(75)
4.93
3
2(67)
3.58
>40-80
6
1(17)
4.32
6
1(17)
4.74
 The EoR data in this study validates the existing AUC/MIC targets:
DAP fAUC/MICs of >40 are associated with 1-3 log drop in MRSA
bacterial counts and a minimum risk of EoR, fAUC/MICs of <30 have
an increased risk of emergence of resistance.
 Dose ranging experiments indicate that the fAUC/MIC associated
with a 24h bacteriostatic to 1 log reduction in count is compatible with
a clinical breakpoint of 0.5-1mg/L for a DAP dose of 6mg/kg.