Introduction (1) - Bad bugs, no drugs

18/03/2014
How to dose colistin?
Isabel Spriet, UZ Leuven
BAPCOC National Study Day 22 03 2014
Introduction (1) - Bad bugs, no drugs
- 3 ‘superbugs’ on IDSA hit list:
- P. aeruginosa
- A. baumanii (USA, Asia, MidEast)
- K. pneumonia
- Increase in ESBL/CPE (India, UK, …)
- No new antimicrobials in the pipeline
POLYMYXINS (colistin and polymyxin B)
50yr old antibiotics… no official drug development
requirements, no detailed insight in PK….
Introduction (2) - Polymyxins throughout the world
Polymyxins – group of 5 antibiotics (A, B, C, D, E)
Polymyxin B: used in Singapore, Brasil, some parts of USA only
Polymyxin E (= colistin): worldwide use
1
18/03/2014
Introduction (3) - ‘Redevelopment’ of colistin
•
•
•
Launched in 1959
Disappeared in ‘80s due to fatal nephrotoxicity and availability of less toxic
alternatives
Re-used since 2003-2005, triggered by MDR Gram– Predominantly in CF and ICU patients
– Predominantly for VAP/sepsis
– Intravenously/nebulisation
 Use in UZ Leuven: ± 70 ICU patients/yr treated with IV colistin
 Lots of effort and financial support (NIH, NIAID) for redevelopment
– Roger Nation - Jian Li (Monash University) - preclinical/clinical studies
– Lena Friberg (Uppsala) – popPK
– William Couet (Poitiers) - clinical studies
Introduction (3) - ‘Redevelopment’ of colistin
Consensusmeeting:
- Recent research
presented by experts
- Consensus in:
-
-
Dosing/Loading dose
Clinical use (combinations)
TDM
Susceptibility testing
Nephrotoxicity
Future research needs
Consensus ‘guidelines’
will be published soon
CMS vs. colistin (1) – what is administered?
– Colistin is administered as prodrug, i.e. CMS
– CMS is less acutely toxic
– CMS = colistin methanesulphonate=colistimethate=colistinsulphomethate=
sulphomethylcolistin
– 5 amines are sulphomethylated = penta-methanesulphonate
– CMS = poly-anion at pH 7,4
2
18/03/2014
CMS vs. colistin (1) – what is administered?
– Conversion of CMS to colistin via spontaneous hydrolysis in aqueous
environment
– Occurs in water, plasma, blood, urine, BAL (also in samples and growth
media)
– Occurs slowly, sulphomethylgroups hydrolyse one by one: circulation of CMS,
colistin and intermediates (= in toto 25 possibilities = 32 circulating
derivatives!)
– Implications:
•
•
•
•
Conversion to active colistin is critical for efficacy
PK/PD studies: correct sample handling!
Susceptibility testing: use active colistin instead of CMS
Publications: should clearly state if doses/levels are expressed in CMS vs. colistin
1 MIU = 80 mg CMS Na = 30 mg CBA or 12500 IU/mg CMS
Pharmacodynamics
•
•
Excellent in vitro activity
Spp.
MIC90
CLSI
breakpoints
susceptibility
CLSI
breakpoints
resistance
Acinetobacter
spp.
2
2
2
K. pneumoniae
2
2
2
E. coli
1
2
2
P. aeruginosa
2
2
8
PK/PD Target
– Based on dose fractionnationstudies in neutropenic murine
models (infected thigh models)
– AUC/MIC is best correlating PK/PD parameter, no PAE
– Sustaining sufficient antibiotic exposure is important
AUC/MIC between 25-50 – corresponding to Cavg
2 mg/L for isolates with a MIC ≤ 1 mg/L
Dudhani et al AAC 2010
Bergen et al., Curr Opin Pharmacol 2011
Bergen et al., Curr Opin Infect Dis 2012
Bergen et al., Diagn Microbiol Infect. Dis 2012
Pharmacokinetics (1) – quantification assay and reliability of
data
•
•
•
Before 2003-2005: plasma concentration analysis via microbiological assay
– Long duration of incubation at 37°C
– Important dilution
– Conversion of CMS colistin continues during assay
– Overestimation of colistin concentration
PK results based on micro assay (including package insert information) not reliable
Since 2005: validation of HPLC-UV and LC-MS/MS with reliable separation of
CMS / colistine, and quick results
Until 2009 – case reports and small studies
2009 – 3 studies studying colistin dosing, followed by popPK and simulation
• Plachouras (AAC 2009) – 18 pts, CrCl 41-116 mL/min
• Garonzik (AAC 2011) – 105 pts, CrCl 3 en 169 ml/min, 16 on RRT
• NIH funded study (not yet published) – 228 pts with CrCl 6-171 mL/min, 66
pts on RRT
3
18/03/2014
Pharmacokinetics (2) – partial elucidation of clearance
70%
20%
10%
<1%
‘Other clearance’
unclear!
Role of the liver?
Enzymatic breakdown?
Potential for DDI?
Slide from R. Nation
Pharmacokinetics (3) – Importance of loading dose
LD avoids underdosing
during 48-72 hr
LD avoids induction of
resistance during 48-72 jr
• oplaad
LD dependent on Vd,
correlates well with ABW
Plachouras, AAC 2009
Long t1/2
Frequency of
dosing is not
that important
Cfr: PK/PD
target =
AUC/MIC
Slide from R. Nation
4
18/03/2014
Slide from R. Nation
Slide from R. Nation
Slide from R. Nation
5
18/03/2014
Pharmacokinetics (4): Dosing recommendations UZ Leuven
CrCl (ml/min)
Dag 1 (= eerste 24u)
Vanaf dag 2
> 50 ml/min
Ladingdosis: 9 MIU (< 50 kg: 6 MIU)
Vanaf +12h: 4 x 2 MIU
Ladingsdosis: 9 MIU (< 50 kg: 6 MIU)
Vanaf +12h: 3 x 2 MIU
Ladingsdosis: 9 MIU (< 50 kg: 6 MIU)
Vanaf +12h: 2 x 2 MIU
Ladingsdosis: 9 MIU (< 50 kg: 6 MIU)
Vanaf +12h: 1 x 2 MIU
4 x 2 MIU
30-50 ml/min
10-30 ml/min
< 10 ml/min
3 x 2 MIU
2 x 2 MIU
1 x 2 MIU
CrCl (ml/min)
Dag 1 (= eerste 24u)
Vanaf dag 2
IHD
Ladingdosis: 9 MIU (<50 kg: 6 MIU)
Vanaf 12h: 1 x 2 MIU
1 x 2 MIU (non-IHD)
1 x 3 MIU (IHD)
CVVH
Ladingsdosis: 9 MIU (<50 kg: 6 MIU)
Vanaf 12h: 4 x 2 MIU
4 x 2 MIU tot 12 MIU/dag
> 120 ml/min
Ladingdosis: 9 MIU (<50 kg: 6 MIU)
Vanaf 12h: 4 x 2 MIU
4 x 2 MIU tot 12 MIU/dag
Therapeutic drug monitoring?
•
PRO TDM
–
–
–
–
–
–
•
•
Target concentration more or less known (2mg/L)
Wide variability (Garonzik, NIH)
Unknown causes for variability (non-renal clearance?)
Narrow TT range: toxicity reported at levels > 6 mg/L
Used as last line in vulnerable populations
Dosing in burns, obesity, CVVH, capillary leak, ARC, … not well
known
CONTRA TDM
–
–
–
Benefit TDM on efficacy/toxicity
not yet established
High cost
Critical sample handling
PRECAUTIONS
•
•
•
•
Quick centrifugation and storage of samples (conversion!)
Freezing at -80 °C: stability 4 months – freezing at -20 °C: stability 1 month
Colistin is amphipilic (polycation, fatty acid): sticks to glass and labmaterial – Tween 80 or albumin
should be added to aqueous samples
Analysis only by validated non microbiological assays
Couet W et al. CMI 2011
Dhudani et al. JAC 2010
Note on preparation and administration
Lyofilised powder
Dissolved with 2 mL WFI
Stability of 7 days at 4 and 25°C
Conversion dependent of concentration and temperature
!! Quick conversion at room temp and when diluted
Diluted in 100 mL NaCl 0,9% or
Glu 5%
Quick conversion at room temp.
Recommended to administer
immediately, if not possible: store
at 4°C
6
18/03/2014
Colistin….how to dose
•
•
•
•
•
Preparation just before administration
Dissoluted vials should be discarded
Adequate loading dose
Adequate (high) maintenance dose
Potential role for TDM in ‘difficult’ cases
– Correct sampling and storage
– Only by validated non-microbiological assays
• Future research needed in special subsets of patients
• Hepatobiliary disposition to be elucidated
7

Download Report