Optimisation of Optimisation of combination therapy for combination therapy for

treatment of treatment of Pseudomonas Pseudomonas

aeruginosaaeruginosa

Alex CochraneAlex CochraneBristol Centre for Antimicrobial Research and Evaluation

University of Bristol

Why use combination Why use combination therapy?therapy?

Monotherapy or Combination Therapy?The Pseudomonas aeruginosa Conundrum

Kristi Traugott, Pharmacotherapy 2011

► Medline search 1950 to 2010Medline search 1950 to 2010 P. aeruginosaP. aeruginosa bacteraemia and pneumonia bacteraemia and pneumonia

► ConclusionsConclusions Is there clinically significant synergy?Is there clinically significant synergy?

► UnknownUnknown Is there clinically significant reduction in Is there clinically significant reduction in

resistance?resistance?► UnknownUnknown

Initial StudyInitial Study► AntimicrobialsAntimicrobials

Piperacillin TazobactamPiperacillin Tazobactam GentamicinGentamicin

► OrganismOrganism Bloodculture isolate of Bloodculture isolate of Pseudomonas aeruginosaPseudomonas aeruginosa MIC gentamicin = 2 (sensitive)MIC gentamicin = 2 (sensitive) MIC piperacillin tazobactam = 8 (sensitive)MIC piperacillin tazobactam = 8 (sensitive)

► MethodologyMethodology Kill curveKill curve Sampled at 0, 1,3,6,12,24,36 and 48 hours.Sampled at 0, 1,3,6,12,24,36 and 48 hours. Antibiotic concentrations chosen to reflect Antibiotic concentrations chosen to reflect

concentrations that would be found in serum concentrations that would be found in serum during a standard dosing regimenduring a standard dosing regimen

Antibiotic concentrations Antibiotic concentrations usedused

Gentamicin ConcentrationGentamicin Concentration15mg/l15mg/l 4.5mg/l4.5mg/l 0.5mg/l0.5mg/l 0.1250.125

mg/lmg/lnilnil

P/T

P/T

co

nce

ntra

tion

con

cen

tratio

n

196mg196mg/l/l

AA BB CC DD EE

28mg/l28mg/l FF GG HH II JJ

1mg/l1mg/l KK LL MM NN OO

nilnil PP QQ RR SS Growth Growth controlcontrol

ResultsResults

MonotherapyMonotherapy

Piperacillin tazobactam alone

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

Growth ControlPipTazo 196 Gentamicin 0PipTazo 28 Gentamicin 0PipTazo 1 Gentamicin 0

time (h)

log

cfu

/mL

Gentamicin alone

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 0 Gentamicin 15PipTazo 0 Gentamicin 4.5PipTazo 0 Gentamicin 0.5PipTazo 0 Gentamicin 0.125Growth Control

time (h)

log

cfu

/mL

ResultsResults

Combination therapyCombination therapy

Synergy: low concentration gentamicin and high concentration P/T

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 196 Gentamicin 0.5PipTazo 196 Gentamicin 0PipTazo 0 Gentamicin 0.5Growth Control

time (h)

log

cfu

/mL

Synergy: low concentration gentamicin and high concentration P/T

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 196 Gentamicin 0.5PipTazo 196 Gentamicin 0PipTazo 0 Gentamicin 0.5Growth Control

time (h)

log

cfu

/mL

Synergy average concentration PT with low concentration Gentamicin

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 28 Gentamicin 0.5PipTazo 28 Gentamicin 0PipTazo 0 Gentamicin 0.5Growth Control

time (h)

log

cfu

/mL

Synergy average concentration PT with low concentration Gentamicin

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 28 Gentamicin 0.5PipTazo 28 Gentamicin 0PipTazo 0 Gentamicin 0.5Growth Control

time (h)

log

cfu

/mL

Synergy low concentration P/T, low concentration Gentamicin

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 1 Gentamicin 0.5PipTazo 1 Gentamicin 0PipTazo 0 Gentamicin 0.5Growth Control

time (h)

log

cfu

/mL

Synergy: High concentration P/T and very low concentration Gentamicin

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 196 Gentamicin 0.125PipTazo 196 Gentamicin 0PipTazo 0 Gentamicin 0.125Growth Control

time (h)

log

cfu

/mL

Combinations for reduction of Combinations for reduction of development of resistance: 24 development of resistance: 24

hourshoursGentamicin ConcentrationGentamicin Concentration

15mg/l15mg/l 4.5mg/l4.5mg/l 0.5mg/l0.5mg/l 0.125m0.125mg/lg/l

nilnil

P/T

P/T

co

nce

ntra

tion

con

cen

tratio

n

196mg/196mg/ll

28mg/l28mg/l

1mg/l1mg/l

nilnil Growth Growth controlcontrol

Resistance at 4 X MIC Resistance at 32 X MIC

Resistance - SummaryResistance - Summary

►High level resistance to High level resistance to Piperacillin/Tazobactam developed Piperacillin/Tazobactam developed within 48 hours only in the absence of within 48 hours only in the absence of gentamicin.gentamicin.

► High level resistance to gentamicin High level resistance to gentamicin developed within 48 hours only in the developed within 48 hours only in the absence of Piperacillin/Tazobactamabsence of Piperacillin/Tazobactam

Next stepNext step

►Compare standard dosing and Compare standard dosing and continuous infusion schedules of P/T continuous infusion schedules of P/T alone or in combination with 24hrly alone or in combination with 24hrly and 8hrly dosing of gentamicin in an and 8hrly dosing of gentamicin in an in in vitrovitro dynamic model. dynamic model.

AcknowledgementsAcknowledgements

Alan Noel

Karen Bowker

Alasdair MacGowan

All staff at Bristol Centre for Antimicrobial Research and Evaluation

University of Bristol

Synergy average P/T, very low gentamicin

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 28 Gentamicin 0.125PipTazo 28 Gentamicin 0PipTazo 0 Gentamicin 0.125Growth Control

time (h)

log

cfu

/mL

Synergy low concentration PT, very low concentration Gentamicin

0 6 12 18 24 30 36 42 4810

100

1000

10000

100000

1000000

1.0×1007

1.0×1008

1.0×1009

1.0×1010

1.0×1011

PipTazo 1 Gentamicin 0.125PipTazo 1 Gentamicin 0PipTazo 0 Gentamicin 0.125Growth Control

time (h)

log

cfu

/mL

Combinations for reduction of Combinations for reduction of development of resistance: 48 development of resistance: 48

hourshoursGentamicin ConcentrationGentamicin Concentration

15mg/l15mg/l 4.5mg/l4.5mg/l 0.5mg/l0.5mg/l 0.125m0.125mg/lg/l

nilnil

P/T

P/T

co

nce

ntra

tion

con

cen

tratio

n

196mg/196mg/ll

28mg/l28mg/l

1mg/l1mg/l

nilnil Growth Growth controlcontrol

Resistance at 4 X MIC Resistance at 32 X MIC

Combinations for reduction of Combinations for reduction of development of resistance: 24 development of resistance: 24

hourshoursGentamicin ConcentrationGentamicin Concentration

15mg/l15mg/l 4.5mg/l4.5mg/l 0.5mg/l0.5mg/l 0.125m0.125mg/lg/l

nilnil

P/T

P/T

co

nce

ntra

tion

con

cen

tratio

n

196mg/196mg/ll

28mg/l28mg/l

1mg/l1mg/l

nilnil Growth Growth controlcontrol

Resistance at 4 X MIC Resistance at 32 X MIC