19/06/2013 1 Preclinical approaches: What is important – synergy or activity of combinations Brian T. Tsuji, Pharm.D. Assistant Professor of Pharmacy School of Pharmacy and Pharmaceutical Sciences University at Buffalo, State University of New York Director, Laboratory for Antimicrobial Pharmacodynamics Rationale for Polymyxin Combinations An increasing body of evidence based on in vitro and clinical studies demonstrate that colistin monotherapy results in emergence of resistance (at increasing bacterial densities) and poor clinical outcomes in patients. Clinical Practice Yesterday (May 2 nd ) Prato Conference: Dr. David Patterson: Polymyxin monotherapy is inferior to combinations against CRE Dr. Mical Paul: Colistin is not as effective as Beta‐lactams Dr. Alexandre Zavascki: Empiric therapy now involves combinations 3 drugs with polymyxin Dr. Helen Giamarellou: Empiric therapy involves carbapenem and colistin Dr. Nation: The difficulty of achieving adequate formed colistin conc. in patients with normal to high CLcr Not to be copied and distributed to others without the permission of the author
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Preclinical approaches: What is of combinations T. Tsuji ......What about the in vivo picture other models G. mellonella, Larvae of wax moth, have been used to study pathogenicity
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19/06/2013
1
Preclinical approaches: What is important – synergy or activity
of combinations
Brian T. Tsuji, Pharm.D.Assistant Professor of Pharmacy
School of Pharmacy and Pharmaceutical Sciences
University at Buffalo, State University of New York
Director, Laboratory for Antimicrobial Pharmacodynamics
Rationale for Polymyxin Combinations
An increasing body of evidence based on in vitro and clinical studies demonstrate that colistin monotherapy results in emergence of resistance (at increasing bacterial densities) and poor clinical outcomes in patients.
Clinical Practice Yesterday (May 2nd) Prato Conference:
Dr. David Patterson: Polymyxin monotherapy is inferior to combinations against CRE
Dr. Mical Paul: Colistin is not as effective as Beta‐lactams
Dr. Alexandre Zavascki: Empiric therapy now involves combinations 3 drugs with polymyxin
Dr. Helen Giamarellou: Empiric therapy involves carbapenem and colistin
Dr. Nation: The difficulty of achieving adequate formed colistin conc. in patients with normal to high CLcr
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Goal of Combination Antibiotic Therapy: Polymyxin and Second Antibiotic
CombinationTherapy
Killing Resistance
Maximize Minimize
Differing Mechanisms of Action & PK/PD
Optimize combination of antibiotics in difficult to treat infections based PK/PD
strategies
Exploit
Toxicity
Minimize
What agents do we have left: Combinations with differing PK/PD and
Mechanisms of Action
AUC/MICPolymyxin
T>MICCarbapenem
Cmax/MICAminoglycosides
Rifampicin
AUC/MICFluoroquinolonesGlycopeptidesTigecycline
MICROBIOLOGICAL SCENARIOS• Susceptible active agents• Intermediate or resistant agents• Agents with no intrinsic activity
CLINICAL SCENARIOS• Empirical at the Beginning of Therapy• Rescue or Salvage Therapy with Colistin• Rescue or Salvage Therapy with 2nd Abx
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Heterogeneous Resistance to Polymyxins
Li et. al. AAC. 2006.Li et. al. CID 2007.
Colistin monotherapyAmplification of colistin‐resistant sub‐population
Colistin‐susceptible population
Colistin‐resistant sub‐population
Colistin
Slide from J. Li & R.L. Nation
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Promising therapeutic optionsColistin + second antibiotic
Colistin‐susceptible population
Colistin‐resistant sub‐population
Colistin 2nd antibiotic
May not be a synergistic effect against a homogeneous population
Rather, different antibiotics tacklingtheir respective susceptible populations
Slide from J. Li & R.L. Nation
0 24 48 72 96 120 144 168 192 216 2400
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4
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10
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Log 1
0(C
FU
/mL)
Time (h)
Total Population 0.5 mg/L colistin1 mg/L colistin2 mg/L colistin3 mg/L colistin4 mg/L colistin6 mg/L colistin8 mg/L colistin10 mg/L colistin
Polymyxin Monotherapy results in Rapid Emergence of Resistance
colistin monotherapy(5mg/L CI) vs. hetero‐resistant P. aeruginosa.
Amplification of resistance in the HFIM with colistin monotherapy.
In vitro static time killImipenem, Doripenem, Rifampin
In vitro one compartmentDoripenem, Imipenem, Rifampin
Hollow fiber modelDoripenem, Rifampin
Animal Infection ModelsDoripenem, Rifampin
Translational Approaches for Combinations
Driven by PK/PD
36 Strains, 12 for each species: P. aeruginosa, A. baumanniiK. pneumoniae:1 PolymyxinS
1 PolymyxinHR
1 PolymyxinR
Brian
Colistin (mg/L)
0 1 2 3 4 5 6 7 8 9 10
Lo
g10
CF
U/m
L
2
3
4
5
6
7
8
9
LOQ
Time (h)
0 12 24 36 48 60 72 84 96
Lo
g10
CF
U/m
L
2
3
4
5
6
7
8
9
LOQ
A B
Control Col 0.5 mg/L CICol 2 mg/L CIDori Cmax=2.5 mg/L Dori Cmax=25 mg/L Col 0.5 mg/L CI + Dori Cmax=2.5 mg/LCol 0.5 mg/L CI + Dori Cmax=25 mg/LCol 2 mg/L CI + Dori Cmax=2.5 mg/L Col 2 mg/L CI + Dori Cmax=25 mg/L
Control at baselineControl Col 0.5 mg/L CICol 2 mg/L CI Col 0.5 mg/L CI + Dori 2.5 mg/LCol 0.5 mg/L CI + Dori 25 mg/LCol 2 mg/L CI + Dori 2.5 mg/LCol 2 mg/L CI + Dori 25 mg/L
Colistin and Doripenem Against Colistin Hetero-Resistant P. aeruginosa ATCC
Colistin and Doripenem Against Colistin Hetero-Resistant P. aeruginosa ATCC
MIC: 1 mg/L (Col), 0.25 mg/L(Dori)
Time (h) Colistin (mg/L)
Log 1
0(CFU
/mL)
Baseline
Total Population Count Population Analysis Profile at 240 h
0 24 48 72 96 120 144 168 192 216 2400
2
4
6
8
10
12
0 24 48 72 96 120 144 168 192 216 2400
2
4
6
8
10
12
0 24 48 72 96 120 144 168 192 216 2400
2
4
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8
10
12
0 24 48 72 96 120 144 168 192 216 2400
2
4
6
8
10
12
Col 5 mg/L and Dori
Dori alone
Col 2 mg/L and Dori
Ly N. et. al. ICAAC.2011.
Col 2 mg/LCol 5 mg/L
Col 2 mg/LCol 5 mg/L
COMBOs
0 24 48 72 96 120 144 168 192 216 2400
2
4
6
8
10
12
Colistin (mg/L)
Time (h) Colistin (mg/L)
Colistin and Doripenem Against Colistin Hetero-resistant P. aeruginosa
MIC: 1 mg/L (Col), 1 mg/L(Dori)
Total Population Count Population Analysis Profile at 240 h
0 24 48 72 96 120 144 168 192 216 2400
2
4
6
8
10
12
Col 2 mg/L and DoriCol 5 mg/L and Dori
Log 1
0(CFU
/mL)
Ly N. et. al. ICAAC.2011.
Col 2 mg/LCol 5 mg/L
Dori
COMBOs
Col 5 mg/L
Col 2 mg/L
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Colistin (mg/L)
Log 1
0 (CFU
/mL)
Time (h)
Colistin and Doripenem against Colistin Resistant P. aeruginosa
MIC: >128 mg/L (Col), 1 mg/L(Dori)
Total Population Count Population Analysis Profile at 240 h
0 24 48 72 96 120 144 168 192 216 2400
2
4
6
8
10
12
0 24 48 72 96 120 144 168 192 216 2400
2
4
6
8
10
12
0 24 48 72 96 120 144 168 192 216 2400
2
4
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8
10
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Col 2 mg/L and Dori
Col 5 mg/L and Dori
Ly N. et. al. ICAAC.2011.
Col 2 mg/LCol 5 mg/L
Dori
What about the in vivo picture in mice
Points to consider in animal infection models• Animal Scaling to humanize pharmacokinetics• Clinical relevant doses in mg/kg (e.g. same mg/kg dose as used in patients)
unlikely to have human PK• Confirmation of plasma concentrations