Thrice-Weekly Temocillin Administered After Each Dialysis Session Is Appropriate for the Treatment of Serious Gram-Negative Infections in Haemodialysis Patients

Thrice-Weekly Temocillin Administered After Each Dialysis Session Is Appropriate for the Treatment of Serious Gram-Negative Infections in Haemodialysis Patients

International Journal of Antimicrobial Agents 46 (2015) 660–665 Contents lists available at ScienceDirect International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag Thrice-weekly temocillin administered after each dialysis session is appropriate for the treatment of serious Gram-negative infections in haemodialysis patients Stefaan J. Vandecasteele a,1, Ana C. Miranda Bastos b,c,d,1, Arnaud Capron e,f, Anne Spinewine d, Paul M. Tulkens b,c, Franc¸ oise Van Bambeke b,c,∗ a Nephrology and Infectious Diseases Department, AZ Sint-Jan Brugge-Oostende AV, AV Ruddershove 10, 8000 Brugge, Belgium b Pharmacologie cellulaire et moléculaire (LDRI/FACM), Av. E. Mounier 73, bte B1.73.05, B-1200 Brussels, Belgium c Center for Clinical Pharmacy, Université catholique de Louvain, Av. E. Mounier 73, bte B1.73.05, B-1200 Brussels, Belgium d Clinical Pharmacy Research Group (LDRI/CLIP), Av. E Mounier 72, bte 01.72.02, B-1200 Brussels, Belgium e Clinical Chemistry Department, Cliniques Universitaires St Luc, Av. Hippocrate 10, B-1200 Brussels, Belgium f Louvain Center for Toxicology and Applied Pharmacology, Université catholique de Louvain, Av. E. Mounier 53, Box B1-52-12, B-1200 Brussels, Belgium article info abstract Article history: In patients with end-stage renal disease (ESRD) treated with intermittent haemodialysis, a limited Received 17 July 2015 number of antibiotics have been studied for their suitability for parenteral administration after dialy- Accepted 8 September 2015 sis sessions only in a thrice-weekly regimen. Temocillin is a ␤-lactam antibiotic with a long half-live and enhanced activity against most Gram-negative bacteria, including extended-spectrum ␤-lactamase- Keywords: producers, thus making it an ideal candidate for use in this setting. This study aimed to evaluate the ESRD reliability of thrice-weekly parenteral temocillin in haemodialysis patients by characterising the phar- Gram-negative infection macokinetics of total and free temocillin. Free and total temocillin concentrations were determined with Intermittent haemodialysis Pharmacodynamics a validated HPLC method in 448 samples derived from 48 administration cycles in 16 patients with ESRD Pharmacokinetics treated with intermittent haemodialysis and temocillin. Pharmacokinetics were non-linear partly due to Temocillin saturation in protein binding. Median clearance and half-life for the free drug during intradialysis and interdialysis periods were 113 mL/min vs. 26 mL/min and 3.6 h vs. 24 h, respectively, with dialysis extract- ing approximately one-half of the residual concentration. The free temocillin concentration remained >16 mg/L (MIC90 threshold for most Enterobacteriaceae) during 48%, 67% and 71% of the dosing interval for patients receiving 1 g q24h, 2 g q48h and 3 g q72h, respectively, suggesting appropriate exposure for the two latter therapeutic schemes. Temocillin administered on dialysis days only in a dosing schedule of 2 g q48h and 3 g q72h is appropriate for the treatment of serious and/or resistant Gram-negative infec- tions in patients with ESRD undergoing intermittent haemodialysis. These doses are higher than those previously recommended. © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. 1. Introduction septicaemia and pulmonary infections, are the second leading cause of death in this population [2]. Historically, Gram-positive Patients with end-stage renal disease (ESRD) suffer signifi- infections were predominant in the haemodialysis population [3]. cantly higher mortality than the general population, with values However, in the past few years a concerning rise in infections 48 times higher in the 20- to 44-year-old age group and 7 times caused by Gram-negative pathogens with increasing rates of drug higher in the over 75 years age group [1]. Infections, especially resistance in dialysis patients has fuelled a renewed interest in this field [3–5]. Parenteral antibiotics that permit thrice-weekly dosing after each dialysis session are preferable because they can reduce hospitalisation duration and costs as well as enhance quality of life ∗ Corresponding author. Present address: Pharmacologie cellulaire et moléculaire, [1]. Whilst this common practice is supported by strong clinical Université catholique de Louvain, Avenue E. Mounier 73, B1.73.05, B-1200 Brussels, data for the treatment of Gram-positive infections with cefazolin Belgium. Tel.: +32 2 764 7378. E-mail address: [email protected] (F. Van Bambeke). [6] or vancomycin [7], the antibiotics most frequently administered 1 These authors contributed equally to this work. on dialysis days only for the treatment of Gram-negative infections http://dx.doi.org/10.1016/j.ijantimicag.2015.09.005 0924-8579/© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. S.J. Vandecasteele et al. / International Journal of Antimicrobial Agents 46 (2015) 660–665 661 Fig. 1. Study design. Temocillin was administered by intravenous bolus immediately after the haemodialysis (HD) session. This figure represents a typical end-stage renal disease patient who undergoes HD thrice weekly, on Mondays, Wednesdays and Fridays. The study protocol foresaw the administration of 1, 2 or 3 g for a dosing interval of 24 h, 48 h or 72 h, respectively. The 24-h interdialytic period is not represented in this figure. have been shown to lead to inadequate exposure (ceftazidime) [8] conditions; (iii) pregnancy; (iv) IgE-mediated allergy to penicillins; or unacceptable toxicity (aminoglycosides) [9]. or (v) patients not giving informed consent. The attending physician In this setting, temocillin (an intravenous ␤-lactam antibi- determined the indication for temocillin use as well as its duration. otic with a long half-life [10]) constitutes a valuable candidate The dialysis schedule was according to clinical state of the art of as an anti-Gram-negative agent in settings where Pseudomonas the study site and was not altered for the purpose of the study. aeruginosa can be excluded [11]. Moreover, the remarkable sta- Urea clearance (Kt/V) was >1.2; blood flow rates were set as high as bility of temocillin against most ␤-lactamases, including AmpC, possible with a maximum of 400 mL/min and pre-pump pressures extended-spectrum ␤-lactamases and most carbapenemases, not lower than −250 mmHg, unless there was a confirmed disequi- fuelled a recent interest in this antibiotic as a carbapenem-sparing librium syndrome. Blood flow rate, dialysate flow rate, time and agent [12]. For time-dependent antibiotics such as ␤-lactams, the other components of the dialysis prescription were determined probability of therapeutic success is related to the proportion of the according to the clinical need by the attending physician. The dial- dosing interval during which their free concentration exceeds the ysers used were FX80 and FX10 (Fresenius Medical Care AG & Co., minimum inhibitory concentration (MIC) of the offending organism Bad Homburg, Germany). [13]. Therefore, their elimination rate will be a critical determi- nant in their overall efficacy and will dictate the frequency of their administration. 2.2. Temocillin Little is known, however, about temocillin pharmacokine- tics/pharmacodynamics in ESRD patients as well as its dialysability Temocillin (Eumedica SA, Brussels, Belgium) was used through- with contemporary high-flux haemodialysers [11,14]. Its primar- out the study period. Temocillin (1–3 g) was dissolved in 25–75 mL ily renal elimination (mainly by glomerular filtration in unchanged of water for injection and was administered intravenously over a 5- ␤ form) and long serum half-life compared with other -lactams [10] min period directly after dialysis. In analogy with what is done with render it suitable to be administered on haemodialysis days only. cefazolin [15], a fixed temocillin dosing schedule of 1 g for a 24-h This study aimed: (i) to characterise the pharmacokinetics and dia- (1-day) dosing interval, of 2 g for a 48-h (2-day) dosing interval and lytic clearance of temocillin in patients undergoing intermittent of 3 g for a 72-h (3-day) dosing interval was used (Fig. 1). haemodialysis; (ii) to determine the fraction of the dosage interval during which the free concentration exceeds the MIC of target orga- nisms if administered after each haemodialysis session; and (iii) to 2.3. Sample collection propose and validate a dosing schedule on dialysis days only. Blood samples were drawn: (i) just before and at 0.5, 3, 6, 12, 2. Methods 20 (before dialysis) and 24 h (at the end of dialysis) after temocillin administration when patients were dialysed with a 1-day interval; 2.1. Study design and population (ii) just before and at 0.5, 3, 6, 12, 24, 36, 44 (before dialysis) and 48 h (at the end of dialysis) after temocillin administration when This prospective, single-centre (tertiary-care renal unit in patients were dialysed with a 2-day interval; or (iii) just before and Belgium), open-label, non-randomised clinical study characterised at 0.5, 3, 6, 12, 24, 36, 48, 68 (before dialysis) and 72 h (at the end of the pharmacokinetics of temocillin administered on dialysis days dialysis) after temocillin administration when patients were dial- only using a 1-, 2- or 3-day dosing interval. Patients undergo- ysed with a 3-day interval. Additional blood samples were taken 1, ing intermittent haemodialysis for ESRD for whom treatment with 2, 3 and 4 h after the start of dialysis. All samples were taken from temocillin was indicated according to the attending physician were an arterial or venous catheter. Serum samples obtained by centrifu- ◦ eligible for the study. Exclusion criteria were: (i) age <18 years; gation after blood clotting were frozen at −80 C immediately after (ii) estimated life expectancy of <24 h due to major co-morbid sampling. 662 S.J. Vandecasteele et al. / International Journal of Antimicrobial Agents 46 (2015) 660–665 2.4. Temocillin assays Table 1 Patient characteristics (n = 16). Temocillin total serum concentrations were assayed by high- Characteristic Median Range performance liquid chromatography (HPLC) with ultraviolet Age (years) 68.5 24–91 detection [16].

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