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Increased dosing regimens of piperacillin-tazobactam are needed to avoid subtherapeutic exposure in critically ill patients with augmented renal clearance

Dear Editor,

In intensive care settings, augmented renal clearance (ARC) is recognized as a leading cause of subtherapeutic antibiotic exposure, and piperacillin-tazobactam (PTZ) has been the most frequently studied antibiotic in this context [1,2,3,4,5] (Table 1). We, like others, previously suggested that higher than licensed dosing regimens should be necessary for empirical treatment in patients with ARC [4, 5]. We thus aimed to determine the efficacy and tolerability of such a strategy.

Table 1 Documented rates of pharmacodynamic target non-attainment for various piperacillin dosing regimens in ARC patients

For this purpose, we performed a retrospective analysis of our local database over a 10-month period (February to November 2018). Ethical approval confirmed the observational design of the study (IRB number: CERAR 00010254-2018-074). Over the study period, every patient with a 24-h measured creatinine clearance (CLCr) ≥ 150 mL/min received increased dosing regimens of PTZ (20/2.5 g daily after a loading dose of 4/0.5 g over 60 min) [4]. Subsequent dose adjustments were guided by therapeutic drug monitoring performed between 24 and 72 h of antimicrobial therapy. As previously described, observed concentrations were corrected for protein binding (30% for piperacillin) to estimate unbound fraction [1].

As MIC data are often not available to the clinician prescribing an empirical antimicrobial regimen, piperacillin underdosing was defined by an unbound concentration under 16 mg/L, representing the highest MIC for Pseudomonas as per the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [4]. Empirical underdosing for tazobactam was defined by an unbound concentration under 2 mg/L, representing the highest MIC for high-level β-lactamase-producing strains [4]. Excessive dosing was defined as a free drug concentration above 150 mg/L [4].

The final dataset consisted of 36 PTZ samples collected from 35 patients. The main characteristics and outcomes of these patients are resumed in Table 2. Except for one tazobactam sample, all samples were in the therapeutic range (Fig. 1). No patient experienced excessive dosing above the supposed toxic cutoff ≥ 150 mg/L. Three of them (9%) experienced therapeutic failure or relapse [4], all related to secondary acquisition of antimicrobial resistance.

Table 2 Characteristics of the population
Fig. 1
figure1

Unbound steady-state concentrations (mg/L) of piperacillin (a) and tazobactam (b) using higher than licensed dosing regimens (20 g/day [160 mg/mL, 10-h infusion] after a loading dose of 4 g) in critically ill patients with ARC (ClCr ≥ 150 mL/min the first day of antimicrobial therapy). The dotted line indicates underdosing threshold for piperacillin (fixed at 16 mg/L) and tazobactam (fixed at 2 mg/L) [4]. The black circles indicate samples from patients who experienced therapeutic failure [4]

When targeting a theoretical MIC at the upper limit of the susceptibility range, higher than licensed doses of PTZ allowed achieving the pharmacodynamic target in all patients with CLCr ≥ 150 mL/min, without excessive dosing. Further studies are warranted to confirm if such a strategy improves the rate of therapeutic success.

Abbreviations

%fT > 16 mg/L :

Fraction of time spent with an unbound concentration > 16 mg/L (representing the highest MIC for Pseudomonas as per the European Committee on Antimicrobial Susceptibility Testing)

ARC:

Augmented renal clearance

ClCr :

Creatinine clearance

eClCr :

Estimated creatinine clearance (Cockcroft and Gault)

FTA:

Fractional target attainment

mClCr :

Measured creatinine clearance

MIC:

Minimum inhibitory concentration

PIP:

Piperacillin

PTZ:

Piperacillin-Tazobactam

References

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    Udy AA, Lipman J, Jarrett P, Klein K, Wallis SC, Patel K, Kirkpatrick CM, Kruger PS, Paterson DL, Roberts MS, Roberts JA. Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance? Crit Care. 2015;19:28.

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    Carlier M, Carrette S, Roberts JA, Stove V, Verstraete A, Hoste E, Depuydt P, Decruyenaere J, Lipman J, Wallis SC, De Waele JJ. Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? Crit Care. 2013;17(3):R84.

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    Carrié C, Legeron R, Petit L, Ollivier J, Cottenceau V, d'Houdain N, Boyer P, Lafitte M, Xuereb F, Sztark F, Breilh D, Biais M. Higher than standard dosing regimen are needed to achieve optimal antibiotic exposure in critically ill patients with augmented renal clearance receiving piperacillin-tazobactam administered by continuous infusion. J Crit Care. 2018;48:66–71.

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Acknowledgements

The authors thank members of the Department of Laboratory Medicine at Paris Saint Joseph University Hospital for their contribution for samples storage, preparation and quantification.

Funding

Only departmental funds were used for this study. No external funds were obtained.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author information

CC and LP designed the study. TB recruited the patients and collected the data. CC and TB wrote the manuscript. CC, LP, and MB have personally reviewed the data and confirmed that the methods are clearly described and that they are a fair way to report the results. All authors read and approved the final manuscript.

Correspondence to Cédric Carrié.

Ethics declarations

Ethics approval and consent to participate

Ethical approval was obtained from the Ethics Committee of the French Society of Anesthesiology and Intensive Care (IRB number: CERAR 00010254-2018-074). Our local database was declared to the French Data Protection Authority (declaration number 2166637v0). The patients and/or next of kin were informed about the inclusion of their anonymized health data in the database, and none declined participation.

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Not applicable

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The authors declare that they have no competing interests.

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Keywords

  • Augmented renal clearance
  • Piperacillin
  • Critical care