Transcript Population Pharmacokinetics of Temocillin in ICU patients and

P-807
Population Pharmacokinetics of Temocillin in ICU patients and
Monte Carlo Simulations to Evaluate Resistance Breakpoints
A.E. Muller1, P.F. Laterre3, T. Dugernier3, X. Wittebole3, N. Couwenbergh3, P.M. Tulkens3, S. Carryn3, J.W.Mouton2,4
1Erasmus
Medical Centre Rotterdam, 2Radboud University Nijmegen Medical Centre, 4Canisius Wilhelmina Hospital, Nijmegen, The Netherlands, 3Université catholique de Louvain, Bruxelles, Belgium
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Methods:
Blood samples were taken from ICU patients after (t=0.5, 1, 2, 8 h) a 30 m infusion of 2 g
TMO (n=11) and afterwards cooled, centrifuged and stored at -70°C until analysis by
HPLC. Protein binding was determined using an ultrafiltration method. Results were used
to estimate population pharmacokinetic parameters by NONMEM (version VI, ICON
development solutions, USA) and Miclab2.36 was used to perform MCS (10000 cycles)
and obtain PTAs for the unbound fraction including 95% confidence intervals (CI) for the
target concentrations. fT>MIC was chosen as the PDI because of the pharmacodynamic
properties of TMO.
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Figure 1. predicted concentrations versus measured concentrations
of temocillin. The dotted line represents the line of identity.
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Temocillin (TMO) is a narrow spectrum penicillin with good
activity against Gram negative micro-organisms including
ESBL and AmpC producers. Little pharmacokinetic data are
available however. Previous studies indicated that the
commonly used dose of 2gr every 12 hours could be too low
to cover the WildType distributions of Enterobacteriaceae if
variation of pharmacokinetics in a patient population was
taken into account. Data from a pharmacokinetic study in 11
ICU patients receiving TMO 2g q8h were used to establish a
population model and perform Monte Carlo Simulations
(MCS) to determine Probabilities of Target Attainment (PTAs)
for pharmacodynamic indices (PDI) in order to evaluate and
suggest clinical resistance breakpoints.
Discussion:
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Figure 2. individual plots of the final model
Results:
Mean protein binding was 59%. A two-compartment model
best fitted to the data, with estimates (se) of V1 =14.0 (2.5) L,
CL = 3.69 (0.46) L/h, V2 = 21.7 (4.5) L and Q = 8.45 (1.06)
L/h, and omega’s for V1 and CL of 0.34 and 0.13
respectively. The individual plots are shown in figure 2.
Figure 1 shows the model individual predicted concentrations
versus measured concentrations, indicating a good model fit.
Subsequently, the parameter estimates were used to predict
the concentrations of temocillin to determine the breakpoint.
The breakpoint MIC for a mean fT>MIC of 50% was 32 mg/L.
However, MCS -taking the variation in the population into
account – and a 95% CI at 50% fT>MIC indicated a clinical
breakpoint of 16 mg/L.
Temocillin showed a relatively low plasma clearance
compared to other broad-spectrum penicillins such as
piperacillin and ticarcillin. This is probably partly due to the
relatively high protein binding, resulting in a lower renal
clearance.
Monte Carlo simulations indicate a susceptibility breakpoint of
< 16 mg/L, provided administration of a 2000 mg q8h dosing
regimen. This is based on pharmacokinetics of ICU patients
rather than volunteers, and there is therefore no leeway. It is
often assumed that MCS using data from volunteers yield a
conservative breakpoint estimate. On the other hand, results
from this and other pharmacokinetic studies indicate a much
larger interindividual variation in patients than in volunteers
and the conclusions are therefore less biased.
Conclusions:
• A two compartment population model fitted
well to the data, taking into account the
high protein binding of temocillin
Figure 3. Left panel : mean fT>MIC as a function of MIC for three
different dosing regimens. Right panel : mean fT>MIC and 95% and
99% CI as a function of MIC for 2g q8h. The CI represent PTAs of 95
and 99%, respectively.
• The Monte Carlo Simulations suggest a
clinical susceptible breakpoint of < 16 mg/L
based on a dosing regimen of 2000 mg q8h
Radboud University Nijmegen Medical Centre , Nijmegen, The Netherlands.
Contact: Johan W. Mouton, [email protected] Tel.: +31 (0)24 3614356 Fax: +31 (0)24 365 86 71