Thrice-weekly temocillin administered after each dialysis session is appropriate for the treatment of serious Gram-negative infections in haemodialysis patients

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Highlights

Abstract

In patients with end-stage renal disease (ESRD) treated with intermittent haemodialysis, a limited number of antibiotics have been studied for their suitability for parenteral administration after dialysis sessions only in a thrice-weekly regimen. Temocillin is a β-lactam antibiotic with a long half-live and enhanced activity against most Gram-negative bacteria, including extended-spectrum β-lactamase-producers, thus making it an ideal candidate for use in this setting. This study aimed to evaluate the reliability of thrice-weekly parenteral temocillin in haemodialysis patients by characterising the pharmacokinetics of total and free temocillin. Free and total temocillin concentrations were determined with a validated HPLC method in 448 samples derived from 48 administration cycles in 16 patients with ESRD treated with intermittent haemodialysis and temocillin. Pharmacokinetics were non-linear partly due to 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 extracting 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 infections in patients with ESRD undergoing intermittent haemodialysis. These doses are higher than those previously recommended.

Introduction

Patients with end-stage renal disease (ESRD) suffer significantly higher mortality than the general population, with values 48 times higher in the 20- to 44-year-old age group and 7 times higher in the over 75 years age group [1]. Infections, especially septicaemia and pulmonary infections, are the second leading cause of death in this population [2]. Historically, Gram-positive infections were predominant in the haemodialysis population [3]. However, in the past few years a concerning rise in infections caused by Gram-negative pathogens with increasing rates of drug resistance in dialysis patients has fuelled a renewed interest in this field [3], [4], [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 [1]. Whilst this common practice is supported by strong clinical data for the treatment of Gram-positive infections with cefazolin [6] or vancomycin [7], the antibiotics most frequently administered on dialysis days only for the treatment of Gram-negative infections have been shown to lead to inadequate exposure (ceftazidime) [8] or unacceptable toxicity (aminoglycosides) [9].

In this setting, temocillin (an intravenous β-lactam antibiotic with a long half-life [10]) constitutes a valuable candidate as an anti-Gram-negative agent in settings where Pseudomonas aeruginosa can be excluded [11]. Moreover, the remarkable stability of temocillin against most β-lactamases, including AmpC, extended-spectrum β-lactamases and most carbapenemases, fuelled a recent interest in this antibiotic as a carbapenem-sparing agent [12]. For time-dependent antibiotics such as β-lactams, the probability of therapeutic success is related to the proportion of the dosing interval during which their free concentration exceeds the minimum inhibitory concentration (MIC) of the offending organism [13]. Therefore, their elimination rate will be a critical determinant in their overall efficacy and will dictate the frequency of their administration.

Little is known, however, about temocillin pharmacokinetics/pharmacodynamics in ESRD patients as well as its dialysability with contemporary high-flux haemodialysers [11], [14]. Its primarily renal elimination (mainly by glomerular filtration in unchanged form) and long serum half-life compared with other β-lactams [10] render it suitable to be administered on haemodialysis days only. This study aimed: (i) to characterise the pharmacokinetics and dialytic clearance of temocillin in patients undergoing intermittent haemodialysis; (ii) to determine the fraction of the dosage interval during which the free concentration exceeds the MIC of target organisms if administered after each haemodialysis session; and (iii) to propose and validate a dosing schedule on dialysis days only.

Section snippets

Study design and population

This prospective, single-centre (tertiary-care renal unit in Belgium), open-label, non-randomised clinical study characterised the pharmacokinetics of temocillin administered on dialysis days only using a 1-, 2- or 3-day dosing interval. Patients undergoing intermittent haemodialysis for ESRD for whom treatment with temocillin was indicated according to the attending physician were eligible for the study. Exclusion criteria were: (i) age <18 years; (ii) estimated life expectancy of <24 h due to

Patients and treatment

Sixteen patients were included in the study, including 14 males and 2 females. Their underlying kidney diseases were diabetes (n = 5) and/or nephroangiosclerosis (n = 7), chronic glomerulonephritis (n = 2), interstitial nephritis (n = 1), polycystic kidney disease (n = 1), congenital reflux or hypoplasia (n = 2) and acute tubular necrosis (n = 2). All patients were given temocillin as part of regular medical therapy for suspected or documented Gram-negative infection. Sepsis was observed in 44% of patients,

Discussion

This study is the first to substantiate with robust PK data that temocillin is a reliable option to treat serious Gram-negative infections in ESRD patients when administered thrice weekly on dialysis days only. Previous research on temocillin during haemodialysis was limited to two studies conducted in the 1980s with a small number (n = 5–7) of patients and using older and less efficient low-flux dialysers. The performance of these dialysers in eliminating temocillin is inferior to that of

Conclusion

This study demonstrates that temocillin is a safe, effective, strategically interesting, and easy-to-use therapeutic option in ESRD patients undergoing intermittent haemodialysis provided close attention is given to its proper dosing. The approach followed in this study could also be used to assess the reliability of other β-lactams for the treatment of ESRD patients undergoing intermittent haemodialysis. For the three dosing schedules studied, temocillin trough levels before dialysis were

Acknowledgments

The authors are grateful to patients and the on-site nursing/medical team for their participation. The authors especially thank Mirjan Demesmaecker for collecting all samples. FVB is a Senior Research Associate of the Fonds de la Recherche Scientifique (F.R.S.-FNRS).

Funding: This work was supported in part by the Région Wallonne [project TEMOEX-PAND 1217668].

Competing interests: PMT is an unpaid advisor to Eumedica, the registration holder of temocillin. All other authors declare no competing

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    These authors contributed equally to this work.

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