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JAC Advance Access originally published online on December 10, 2007
Journal of Antimicrobial Chemotherapy 2008 61(2):382-388; doi:10.1093/jac/dkm467
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection

Raf De Jongh1, Ria Hens1, Violetta Basma2, Johan W. Mouton3, Paul M. Tulkens2,* and Stéphane Carryn2

1 Dienst Voor Intensieve Zorgen, Ziekenhuis Oost-Limburg, B-3600 Genk, Belgium 2 Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, B-1200 Bruxelles, Belgium 3 Afdeling Medische Microbiologie en Infectieziekten, Canisius Whilhemina Ziekenhuis, NL-6500 GS Nijmegen, The Netherlands

* Corresponding author. Tel: +32-2-764-7371; Fax: +32-2-764-7373; E-mail: tulkens{at}facm.ucl.ac.be

Received 28 August 2007; returned 5 October 2007; revised 5 November 2007; accepted 12 November 2007


   Abstract
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Background and aims: Temocillin, a 6{alpha}-methoxy-penicillin stable towards most β-lactamases (including extended-spectrum β-lactamase), is presented as an alternative to carbapenems for susceptible Enterobacteriaceae in microbiological surveys. We aimed at documenting its potential clinical usefulness in intensive care (IC) patients using pharmacokinetic/pharmacodynamic approaches applied to conventional (twice daily) and continuous infusion (CI) modes of administration.

Methods: (i) In vitro evaluation of temocillin stability and compatibility with other drugs under conditions pertinent of CI in IC patients; (ii) pharmacokinetic study in patients treated by CI (4 g/day; n = 6) versus [twice daily (2 g every 12 h); n = 6]; (iii) population pharmacokinetic analysis of twice daily with Monte Carlo simulations to determine 95% probability of target attainment (PTA95) versus MIC (based on time above MIC ≥40% for measured free drug).

Results: Temocillin was stable at 37°C in 8.34% solutions for 24 h and compatible with flucloxacillin and aminoglycosides, but not with several other antibiotic and non-antibiotic drugs. With CI, stable total serum concentrations were 73.5 ± 3.0 mg/L (SEM) and free concentration 29.3 ± 2.8 mg/L. With twice daily, Cmax (total drug) was 147 ± 12.3 mg/L (SEM; free drug: 50.3 ± 15.8 mg/L), lowest trough (total drug) 12.3 mg/L, and PTA95 (free drug) obtained for MIC ≤8 mg/L.

Conclusions: Temocillin (4 g/day) by CI yields stable free serum concentrations above the current breakpoint (16 mg/L), although individual variations may suggest lowering the breakpoint to 8 mg/L (as for twice daily) unless the daily dose or the frequency of administration is increased.

Keywords: HPLC , Monte Carlo simulation , target attainment


   Introduction
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Empirical therapy of nosocomial pneumonia requires careful optimization of antibiotic administration. For β-lactams, the fraction of the dosing interval during which the free serum concentration exceeds the MIC of the offending organism (fT > MIC) is the main parameter determining the treatment outcome.1 Administration of β-lactams by continuous infusion (CI) has, therefore, been advocated for difficult-to-treat situations2 and tested in several indications including nosocomial pneumonia.3–5

Temocillin is a 6{alpha}-methoxy-penicillin active against Enterobacteriaceae and resisting to most β-lactamases6,7 [including extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases8,9 and carbapenemases10]. It is a potential alternative to carbapenems in infections when and where ESBL producers and other cephalosporin-resistant strains have become prevalent as long as Pseudomonas aeruginosa can be excluded,8 but clinical data are still scarce. We have examined the potential of temocillin for administration via CI in nosocomial pneumonia in comparison with its conventional, twice daily mode of administration. On the basis of previous experience of CI with other β-lactams,11–13 we first examined the stability of temocillin and its compatibility with other common medications used in the intensive care (IC) patients. As the number of patients that could be recruited in a reasonable time frame was small, we performed a population pharmacokinetic analysis and a Monte-Carlo simulation14 to calculate target attainment probabilities15,16 and determine pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.


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Stability and compatibility studies

Based on the temocillin registered daily dose (4 g) and on practical experience with the preparation of β-lactam solutions for CI in IC units13 (daily dose prepared in a volume of 48 mL), stability was tested at a concentration of 83.4 g/L in water (Milli-Q Academic Ultrapure® Water System, Millipore Corp., Bedford, MA, USA) at temperatures ranging from 20 to 37°C for up to 24 h and under exposure to normal room light. To detect incompatibilities related to the infusion of temocillin with other drugs through a common infusion set,11,13 temocillin and each other drug were mixed at those concentrations susceptible to be observed in a common infusion line (following conventional conditions of administration) and left at 25°C for 1 h before being examined for physical and chemical compatibilities as described previously.11,13

Assay of temocillin

Temocillin was assayed by HPLC with ticarcillin as internal standard and detection of both epimers of the two drugs17 [see Supplementary data available at JAC Online (http://jac.oxfordjournals.org/) for details].

MIC determination

MICs were determined using standard CLSI procedure for Enterobacteriaceae with Escherichia coli ATCC 25922 as control organism.18

Overall design of the clinical study, patient selection and treatment modalities

The study was prospective and randomized but not blinded, and the protocol approved by the ad hoc Ethics Committee (Ziekenhuis Oost-Limburg, Genk, Belgium). Inclusion criteria were (i) a high probability of infection from nosocomial origin [body temperature >38 or <35.5°C not induced by external factors; leucocytosis or leucopenia; one or several suspected infection foci (based on X-ray pathognomonic image, purulent sputum, white blood cells in urine, or other accepted clinical sign)]; and (ii) no suspicion of an infection by Pseudomonas spp. or another temocillin-resistant bacteria. Exclusion criteria were (i) age <18 or >75 years; (ii) patient's weight <50 or >100 kg; (iii) renal insufficiency (estimated clearance <45 mL/min); (iv) haemodialysis; (v) estimated survival <5 days; (vi) documentation of temocillin-resistant organism; (vii) meningitis or other proven infections of the CNS; (viii) IgE-mediated allergy to penicillins; (ix) severe granulocytopenia (<500 polymorphonuclear leucocytes/mm3); (x) pregnancy; (xi) patients having participated in another study <30 days before; and (xii) retrospectively, marked deterioration of the renal function during the study period. No patient was included more than once. All patients were categorized using APACHE II and SOFA scores. Patients received temocillin according to the following schemes: CI, loading dose (2 g) administered in 30 min in 50 mL of pro injectione water followed by infusion [4 g in 48 mL of pro injectione water infused at a rate of 2 mL/min (2.78 mg/min)]; twice daily, 2 g temocillin (in 50 mL of pro injectione water) every 12 h injected over a 30 min period. All patients also received flucloxacillin (six times 1 g/day).

Sample collection and preparation for analysis

Under CI, samples were withdrawn 1, 2, 3, 6, 12, 24, 48, 72, 96 and 120 h after loading dose; twice daily 1, 2, 3, 6 and 12 h after the first administration on day 0 and just before and after the ninth administration on day 4. All samples were taken from arterial catheter or from an infusion-free upper extremity. Serum (obtained by centrifugation after blood clotting) was frozen (–70°C) until analysis. Total antibiotic was extracted by a solid-phase method (OASIS® HLB Extraction Cartridge System, Waters Corp.; typical recovery, 95% to 97%). The free fraction of temocillin was measured on serum ultrafiltrates (Centrifree® devices, Millipore Corp.).

Pharmacokinetic analyses, population pharmacokinetics and calculation of probability target attainment rate

For patients treated twice daily, a one-phase exponential decay function was fitted to the data (GraphPad Prism version 4.03; GraphPad Software, San Diego, CA, USA), and individual AUC0–24 and f T > MIC19 values were determined by graphical intrapolation. For data from patients treated by CI, AUC0–24 was calculated at steady state by intragraphical integration of values obtained >12 h after the initial loading dose. Population pharmacokinetic modelling was performed with WinNonMix® software (Pharsight Corp., Mountain View, CA, USA) using a one-compartment open model. Population pharmacokinetic parameters20 were estimated from patients treated twice daily and used to derive the value of f T > MIC of free drug as a function of the MIC.21 Hereto, a Monte Carlo approach was applied using the full covariance matrix (MICLAB version 2.33 program, Medimatics, Maastricht, The Netherlands) and a log-normal distribution of parameters to simulate 10 000 subjects for each regimen, and the results were used to calculate the median and 95% confidence interval of the fT > MIC over MIC (0.25–128 mg/L).22

Statistical analyses

Stability data were analysed by one-way analysis of variance with the Tukey–Kramer multiple comparisons test for individual differences within groups (GraphPad InStat version 3.01, GraphPad Software), patient data with two-tailed unpaired t-test (with Welsh correction) or with Student's t-test for parametric data (GraphPad Instat), and with Wilcoxon's test for non-parametric data (JMP 5.1, SAS Institute Inc., Cary, NC, USA).

Materials

Temocillin and ticarcillin were obtained as NEGABAN® (Eumedica s.a., Brussels, Belgium) and TIMENTIN® (GlaxoSmithKline Belgium, Rixensart, Belgium), respectively. All other drugs were procured as described previously.11,13 Products for chromatography were of HPLC grade and obtained from Sigma-Aldrich Corp. (St Louis, MO, USA) or E. Merck AG (Darmstadt, Germany).


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Laboratory studies

Stability studies. Temocillin solutions maintained at temperatures up to 37°C showed <2% loss in total drug content with only minor (13%) change in the R to S epimer ratio [see Supplementary data available at JAC Online (http://jac.oxfordjournals.org/)].

Compatibility studies. Table 1 shows the results of the compatibility studies. Among antibiotics, flucloxacillin, cefuroxime, aminoglycosides (gentamicin, tobramycin and amikacin), erythromycin and moxifloxacin were compatible. All other β-lactams tested caused a >10% loss of temocillin. Vancomycin, clarithromycin and clindamycin were physically incompatible, and iprofloxacin was chemically incompatible. Fluconazole was compatible. All sedatives, anticonvulsants and analgesics tested were compatible, except propofol, midazolam and piritramide. Among the other drugs tested, only nicardipine, milrinone, ranitidine and vitamin K were incompatible.


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  		Table 1. Temocillin compatibility with other drugs under conditions mimicking their co-administration through the same line of infusiona

 
Clinical study

Demography and clinical outcomes. The twice daily and CI groups were similar in terms of demographic and disease- and treatment-related characteristics and drop-outs unrelated to the treatment (Table 2). The clinical outcome of all patients was favourable with no temocillin-related adverse effect (including drug incompatibility or neurotoxicity).


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  		Table 2. Characteristics of patients and microbiological, pharmacokinetic and PD/PK parameters

 
Pharmacokinetic and microbiological studies. The temocillin serum concentrations (free and total drug) from patients treated twice daily or by CI are shown in Figure 1, with MIC and key pharmacokinetic parameters presented in Table 2. For the twice daily group, these parameters were consistent with previously reported values for patients with normal renal function.23 For CI, the total concentration levels stabilized after ~12 h (the first peak being due to the administration of a loading dose of 2 g) to a mean total drug value of 73.5 ± 3.0 mg/L [SEM; see Supplementary data available at JAC Online (http://jac.oxfordjournals.org/) for values of individual patients]. The percentage of free drug was 23.7 ± 6.15 (SD) for patients treated twice daily and 29.3 ± 2.8 (SD) for patients treated by CI (P = 0.022; 95% confidence interval of the difference: 0.96–10.28).


Figure 1
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  		Figure 1. Serum concentrations (total and free) of temocillin in patients receiving temocillin. Upper panel: patients received 2 g every 12 h (discontinuous administration) with samples taken after the first administration (0–12 h) and 1 h before and after the ninth administration (95–108 h). Lower panel: patients received a loading dose of 2 g followed by a CI at a rate of 4 g per 24 h (CI). All values are means ± SD (n = 6 for each treatment group).

 
PK/PD modelling and calculation of probability of target attainment. For patients treated twice daily, a one-compartment model best fitted to the data (total drug), with estimates of 14.3 ± 0.87 L for the volume of distribution (V) and 0.172 ± 0.059 L/h for the elimination constant (kel; corresponding to a mean half-life of 4.03 h), with good correlation between predicted and observed concentrations [see Supplementary data available at JAC Online (http://jac.oxfordjournals.org/)]. These parameter estimates and the actual data on free drug percentages were used to predict the free concentrations during CI (at steady state), which was 19.5 versus 21.5 mg/L measured (mean).

A Monte Carlo simulation for target attainment (fT > MIC) for the twice daily group was then performed using 25% average free drug. Figure 2 shows that an fT > MIC of 40% or more will be reached with 95% probability for an MIC slightly above 8 mg/L [to move this value to 4 mg/L (one dilution), the actual free fraction of temocillin should have been as low as 15%]. Simulating 2 g every 24 h (less than recommended) or 2 g every 8 h (off-label but often used by clinicians) gave an fT > MIC >40% for isolates, with MICs of 4 and 16 mg/L, respectively, for the mean values of the population [see Supplementary data available at JAC Online (http://jac.oxfordjournals.org/)].


Figure 2
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  		Figure 2. Probabilities of target attainment of temocillin (as obtained with the Monte Carlo simulation: solid line, median value; dotted lines, 95% confidence interval) for the currently registered treatment (2 g every 12 h), using the pharmacokinetic data of the six patients treated according to this dosage and schedule in this study (twice daily group). The abscissa shows the MIC range used for the simulations and the ordinate the fraction of time (as a percentage) during which free serum levels remain above the corresponding MIC. The horizontal dotted line indicates the 40% f T > MIC limit achieving a bacteriostatic effect and survival for penicillins in animal models with Gram-negative bacteria.1 The highest MIC at which this target will be obtained is shown by the vertical arrows (arrow with solid line, median; arrow with dotted line, 95% probability).

 

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The present study is a first approach to better delineate the potential usefulness of temocillin in IC patients based on a PK/PD approach and examining its use by both discontinuous infusion and CI. The data were also used to rationally define potential breakpoints for temocillin.

In discontinuous administration, the value of the fT > MIC parameter ensuring in vitro bacteriostatic effect and animal survival was found to be between 29% and 34% for penicillins against a variety of target organisms.1 In the absence of experimental data for temocillin, we used a cut-off value of 40% as a precaution (this value has also been shown to be sufficient for ceftazidime against P. aeruginosa,24 a drug–bacteria combination requiring an optimal antibiotic administration at least as effective as the temocillin/Enterobacteriaceae combination). We also know that the value of f T > MIC parameter is not influenced by the presence of resistance mechanisms such as ESBL (of importance for temocillin) as the MIC includes that information.25 On this basis, the Monte-Carlo simulations for temocillin, given at 2 g every 12 h, suggest a clinical breakpoint at an MIC of 16 mg/L (originally proposed as epidemiological cut-off)26 if using the median values, but at 8 mg/L to cover the 95% confidence interval. An ongoing survey of MIC distributions of temocillin towards Enterobacteriaceae based on data published over the last 25 years (data on file, available upon request) shows that about 90% of all isolates have MIC ≤8 mg/L (confirmed by two recent independent surveys of ESBL-producing clinical isolates9,27).

The interest of administering β-lactams by CI has been repeatedly advocated,1 but still needs support from both laboratory and clinical studies, which are presented here for temocillin.

We first show that the stability of temocillin largely exceeds the requirements of the European Pharmacopeia28 even if stored at 37°C, which is in contrast to ceftazidime (>10% degradation in 8 h with the release of pyridine if stored above 25°C),11,12 cefepime (>10% degradation in 8 h at temperatures >25°C, with appearance of so far unidentified coloured products if using commercial preparations),13 or imipenem and meropenem (>10% loss in 3–5 h).12 The change in R/S epimer ratio, although significant, is probably unimportant as it remains in a range within which activity is not affected.29 We, however, document several incompatibilities with drugs often required for patients hospitalized in IC units. As drug incompatibilities are difficult to predict (and may vary among β-lactams),11,13 clinicians need to seek specific information on all drugs they wish to use in combination with temocillin (beyond what is recorded here), if administration through a common line is envisaged. Secondly, we show that stable levels can be obtained and used to assess the potential efficacy of temocillin. Although in vitro studies suggest that the free serum concentration at steady state (Css) must be greater than or equal to four times the MIC for maximal bactericidal effect,30,31 a static effect (obtained by definition at one times the MIC) may be sufficient in vivo if the patients are not immunocompromised. This would set a susceptibility breakpoint for temocillin (4 g/day) slightly above 16 mg/L. Because of inter-individual variabilities in serum levels, however, a more conservative limit of 8 mg/L seems appropriate. These variabilities are, actually, quite puzzling, as the observed mean value at equilibrium (73 mg/L) was close to the predicted one [64 mg/L; based on the temocillin average clearance (~40 mL/min)20,23 and the rate of infusion used]. Similar inter-individual variabilities in serum levels have been observed for ceftazidime32,33 and are not specific to CI (as variations in Cmax in twice daily patients are quite as large). Thus, serum monitoring of β-lactams may be more necessary than originally thought, especially with isolates having MICs close to PK/PD breakpoints. CI makes it easy to perform because sampling time is not critical (if disregarding the post-loading dose period).

Our study could not be powered to provide direct information about the clinical outcomes of the administration of temocillin by CI versus twice daily treatment. With Temocillin being a niche product, conventional, large-scale clinical studies are indeed ethically and economically difficult to perform in a reasonable time frame. The Monte Carlo simulation approach, however, allows one to draw a general conclusion out of a limited patient sample and to predict target attainment rate values that integrate interpatient variability in drug exposure, drug potency and in vitro susceptibility data.34 This study may, therefore, provide guidance for a prudent use of temocillin by CI based on its PK/PD properties if the susceptibility profile of the target organisms is carefully assessed.


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S. C. is supported by a First-Entreprise grant awarded by the Direction Générale de la Recherche et des Technologies of the Région Wallonne. This work was supported by the Belgian Fonds de la Recherche Scientifique Médicale (grant numbers 3.4549.00 and 3.4542.02) and by a grant-in-aid from Eumedica s.a., Brussels, Belgium to R. D. J.


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S. C. is working under contract with Eumedica s.a., Brussels, Belgium, and R. D. J. and P. M. T. are unpaid advisors to Eumedica s.a., Brussels, Belgium. The rest of the authors do not have any conflicts to declare.


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Supplementary data are available at JAC Online (http://jac.oxfordjournals.org/).


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1 Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am (2003) 17:479–501.[CrossRef][Web of Science][Medline]

2 Craig WA, SC Ebert. Continuous infusion of β-lactam antibiotics. Antimicrob Agents Chemother (1992) 36:2577–83.[Free Full Text]

3 Nicolau DP, McNabb J, Lacy M, et al. Pharmacokinetics and pharmacodynamics of continuous and intermittent ceftazidime during the treatment of nosocomial pneumonia. Clin Drug Invest (1999) 18:133–9.[CrossRef]

4 Nicolau DP, McNabb J, Lacy MK, et al. Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia. Int J Antimicrob Agents (2001) 17:497–504.[CrossRef][Web of Science][Medline]

5 Boselli E, Breilh D, Rimmele T, et al. Plasma and lung concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia. Intensive Care Med (2004) 30:989–91.[CrossRef][Web of Science][Medline]

6 Slocombe B, Basker MJ, Bentley PH, et al. BRL 17421, a novel β-lactam antibiotic, highly resistant to β-lactamases, giving high and prolonged serum levels in humans. Antimicrob Agents Chemother (1981) 20:38–46.[Abstract/Free Full Text]

7 Matagne A, Lamotte-Brasseur J, Dive G, et al. Interactions between active-site-serine β-lactamases and compounds bearing a methoxy side chain on the {alpha}-face of the β-lactam ring: kinetic and molecular modelling studies. Biochem J (1993) 293:607–11.[Web of Science][Medline]

8 Livermore DM, Hope R, Fagan E, et al. Activity of temocillin versus prevalent ESBL- and AmpC-producing Enterobacteriaceae from south-east England. J Antimicrob Chemother (2006) 57:1012–4.[Free Full Text]

9 Rodriguez-Villalobos H, Malaviolle V, Frankard J, et al. In vitro activity of temocillin against extended spectrum β-lactamase-producing Escherichia coli. J Antimicrob Chemother (2006) 57:771–4.[Abstract/Free Full Text]

10 Docquier JD, Riccio ML, Mugnaioli C, et al. IMP-12, a new plasmid-encoded metallo-β-lactamase from a Pseudomonas putida clinical isolate. Antimicrob Agents Chemother (2003) 47:1522–8.[Abstract/Free Full Text]

11 Servais H, Tulkens PM. Stability and compatibility of ceftazidime administered by continuous infusion to intensive care patients. Antimicrob Agents Chemother (2001) 45:2643–7.[Abstract/Free Full Text]

12 Viaene E, Chanteux H, Servais H, et al. Comparative stability studies of antipseudomonal β-lactams for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob Agents Chemother (2002) 46:2327–32.[Abstract/Free Full Text]

13 Baririan N, Chanteux H, Viaene E, et al. Stability and compatibility study of cefepime in comparison with ceftazidime for potential administration by continuous infusion under conditions pertinent to ambulatory treatment of cystic fibrosis patients and to administration in intensive care units. J Antimicrob Chemother (2003) 51:651–8.[Abstract/Free Full Text]

14 Kalos MA, Withlock PA. Monte Carlo Methods (1986) John Wiley & Sons, Inc. ISBN: 0-471-89839-2. Hoboken, NJ.

15 Lodise TP Jr, Lomaestro B, Rodvold KA, et al. Pharmacodynamic profiling of piperacillin in the presence of tazobactam in patients through the use of population pharmacokinetic models and Monte Carlo simulation. Antimicrob Agents Chemother (2004) 48:4718–24.[Abstract/Free Full Text]

16 Mouton JW, Schmitt-Hoffmann A, Shapiro S, et al. Use of Monte Carlo simulations to select therapeutic doses and provisional breakpoints of BAL9141. Antimicrob Agents Chemother (2004) 48:1713–8.[Abstract/Free Full Text]

17 Shull VH, Dick JD. Determination of ticarcillin levels in serum by high-pressure liquid chromatography. Antimicrob Agents Chemother (1985) 28:597–600.[Abstract/Free Full Text]

18 Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically: Approved Standard M7-A7 (2006) Wayne, PA, USA: CLSI.

19 Mouton JW, Dudley MN, Cars O, et al. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. J Antimicrob Chemother (2005) 55:601–7.[Abstract/Free Full Text]

20 Overbosch D, van Gulpen C, Mattie H. Renal clearance of temocillin in volunteers. Drugs (1985) 29(Suppl_5):128–34.[Web of Science][Medline]

21 Mouton JW, Punt N. Use of the t>MIC to choose between different dosing regimens of β-lactam antibiotics. J Antimicrob Chemother (2001) 47:500–1.[Free Full Text]

22 Mouton JW, Punt N, Vinks AA. A retrospective analysis using Monte Carlo simulation to evaluate recommended ceftazidime dosing regimens in healthy volunteers, patients with cystic fibrosis, and patients in the intensive care unit. Clin Ther (2005) 27:762–72.[CrossRef][Web of Science][Medline]

23 Hoffler D, Koeppe P. Temocillin pharmacokinetics in normal and impaired renal function. Drugs (1985) 29(Suppl 5):135–9.[Web of Science][Medline]

24 Mouton JW, Punt N, Vinks AA. Concentration–effect relationship of ceftazidime explains why the time above the MIC is 40 percent for a static effect in vivo. Antimicrob Agents Chemother (2007) 51:3449–51.[Abstract/Free Full Text]

25 Andes D, Craig WA. Treatment of infections with ESBL-producing organisms: pharmacokinetic and pharmacodynamic considerations. Clin Microbiol Infect (2005) 11(Suppl 6):10–7.[CrossRef][Web of Science][Medline]

26 Fuchs PC, Barry AL, Thornsberry C, et al. Interpretive criteria for temocillin disk diffusion susceptibility testing. Eur J Clin Microbiol (1985) 4:30–3.[CrossRef][Web of Science][Medline]

27 Glupczynski Y, Huang TD, Berhin C, et al. In vitro activity of temocillin against prevalent extended-spectrum β-lactamases producing Enterobacteriaceae from Belgian intensive care units. Eur J Clin Microbiol Infect Dis (2007) 26:777–83.[CrossRef][Web of Science][Medline]

28 Anonymous. Ceftazidime. Pharmacopée Européenne (2000) 2909–11.

29 White AR, Cooper CE, Griffin KE, et al. Antibacterial activity of resolved temocillin epimers. J Antimicrob Chemother (1986) 18:335–43.[Abstract/Free Full Text]

30 Vogelman B, Craig WA. Kinetics of antimicrobial activity. J Pediatr (1986) 108:835–40.[CrossRef][Web of Science][Medline]

31 Mouton JW, Vinks AA, Punt NC. Pharmacokinetic–pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion. Antimicrob Agents Chemother (1997) 41:733–8.[Abstract]

32 Byl B, Baran D, Jacobs F, et al. Serum pharmacokinetics and sputum penetration of amikacin 30 mg/kg once daily and of ceftazidime 200 mg/kg/day as a continuous infusion in cystic fibrosis patients. J Antimicrob Chemother (2001) 48:325–7.[Free Full Text]

33 Benko AS, Cappelletty DM, Kruse JA, et al. Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected Gram-negative infections. Antimicrob Agents Chemother (1996) 40:691–5.[Abstract]

34 Ambrose PG. Monte Carlo simulation in the evaluation of susceptibility breakpoints: predicting the future: insights from the society of infectious diseases pharmacists. Pharmacotherapy (2006) 26:129–34.[CrossRef][Web of Science][Medline]


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