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J Antimicrob Chemother
doi:10.1093/jac/dkaa248
Monte Carlo simulation of temocillin
6 g daily administered by continuous
infusion or intermittent dosage
Athanasios Tsakris1*, Vasiliki Koumaki1,
Aristides Dokoumetzidis2 and Indran Balakrishnan3
1
Department of Microbiology, Medical School, University of
Athens, Athens, Greece; 2Faculty of Pharmacy, University of
Athens, Athens, Greece; 3Department of Medical Microbiology,
Royal Free London NHS Foundation Trust, London, UK
*Corresponding author. E-mail: atsakris@med.uoa.gr
Sir,
Temocillin has been reintroduced in England and other countries
as an alternative therapy for infections caused by ESBL-, de-
repressed AmpC- or KPC-producing Enterobacteriaceae.1,2 This
has renewed interest regarding appropriate dosage regimens for
the drug.3 In that respect a randomized study has shown that a
6 g daily dose of temocillin given to critically ill patients in three
divided doses provides coverage against infections caused by
Enterobacteriaceae with MICs up to 16 mg/L.4 However, the Monte
Carlo simulation performed showed that 6 g administered in three
divided doses provides a 95% PTA of 50% fT>MIC for MICs only
slightly over 8 mg/L.4 It has also been suggested that continuous
infusion might improve outcomes when treating pathogens with
higher MICs but, to the best of our knowledge, no Monte Carlo
simulation using continuous infusion regimens has been pub-
lished. Here we report the results of Monte Carlo simulations
performed using 6 g daily administered both by continuous infu-
sion and by intermittent dosage as 2 g q8h.
Monte Carlo simulation was carried out using the population
pharmacokinetic model previously used by Laterre et al.4 in order
to calculate the PTA of temocillin 2 g q8h dosage by 30 min infu-
sion and 6 g daily dosage by continuous infusion. The pharmacoki-
netic profiles of 10 000 subjects were simulated for 5 days and for
each of these the % fT>MIC on the fifth day was calculated. A range
of MICs was considered from 1 to 256 mg/L. Each subject was con-
sidered to have achieved the target when the % fT>MIC was at least
40% and 100% for the intermittent and continuous dosage regi-
mens, respectively.5 The percentage of subjects who achieved the
target was the PTA; dosage efficacy was taken as a PTA of 90%.
The parameter values used for the model were clearance of
3.69 L/h [inter-individual variability (IIV) of 36%], central volume of
C The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
V
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distribution of 14 L (IIV of 58%), inter-compartmental clearance of
4.45 L/h and peripheral volume of distribution of 21.7 L. Protein
binding was taken as 59%.4
Our results have shown that for an MIC of 16 mg/L, a 6 g daily
dose administered as 2 g q8h has a PTA of 86.6%, marginally
below the threshold of 90%, while the same daily dose adminis-
tered by continuous infusion achieves a PTA that is clearly above
this threshold, at 93.3% (Figure 1).
We are aware that, especially for continuous infusion, more
demanding pharmacokinetic/pharmacodynamic targets have
been proposed (Css > 4 % MIC), on the basis that this maximizes
bacterial killing and minimizes the risk of drug resistance.5,6
However, in order to achieve Css > 4 % MIC a 24 g daily dose would
be required, which is not currently licensed.
To date, three different breakpoint values have been used (8,
16 and 32 mg/L) in different countries for different infections.7
BSAC has issued temocillin breakpoints for Enterobacterales (sus-
ceptible at MIC 8 mg/L for systemic infections and 32 mg/L for
urinary tract infections). It has already been suggested in animal
models that temocillin at 2 g q12h could be efficacious for the
treatment of non-severe pyelonephritis due to Escherichia coli for
strains with MICs up to 16 mg/L.7 This is supported by British experi-
ence, which has shown high clinical and microbiological cure
rates in less severely ill patients and in urinary tract infections for
strains with these MICs.8 Recent epidemiological data have
shown MIC90 of 16 mg/L against MDR ESBL- or AmpC-producing
Enterobacteriaceae.1,3 Our data provide evidence by Monte Carlo
simulation that a temocillin susceptibility breakpoint of 16 mg/L
could be applied for a dosage regimen of 6 g per day administered
by continuous infusion, achieving a PTA that is clearly above the
threshold of 90%.
100
80
60
PTA (%)
40
20
2 g q8 h
6 g/day continuous infusion
0
1 2 4 8 16 32 64 128 256
MIC (mg/L)
Figure 1. PTA of a 6 g daily dose administered as 2 g q8h or as a continu-
ous infusion for an MIC of 16 mg/L after a Monte Carlo simulation of
10 000 AUC values. This figure appears in colour in the online version of
JAC and in black in white in the print version of JAC.
1 of 2
Research letter
Funding
This study was conducted as part of our routine work.
Transparency declarations
None to declare.
References
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