Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients

Quinton, M.-C.; Bodeau, Sandra; Kontar, Loay; Zerbib, Yoann; Maizel, Julien; Slama, Michel; Masmoudi, Kamel; Lemaire-Hurtel, Anne-Sophie; Bennis, Youssef

doi:10.1128/aac.00654-17

Cited by 73 publications

(52 citation statements)

References 15 publications

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“…To achieve the target of 100% f T > 1×MIC, the applied dose needs to be increased many-fold irrespective of the licensed regimen or EI, as illustrated in Figure 5, leading to high peak concentration and exposure, with potential toxicity issues 40 . The target of 50% f T > 4×MIC is achieved at doses of 40–80 mg/kg for an MIC of 4.0 mg/L by administering piperacillin as a 3 h EI q8h, i.e.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen

Thorsted

Kristoffersson

Maarbjerg

et al. 2019

Journal of Antimicrobial Chemotherapy

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BackgroundThe β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target.ObjectivesTo guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights.MethodsForty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights.ResultsA two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT > 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2–3 (q6h) or 3–4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT > 1×MIC due to the rapid piperacillin elimination.ConclusionsThe licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT>MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT > 1×MIC) or prolonged infusions (50% fT > 4×MIC).

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen

Thorsted

Kristoffersson

Maarbjerg

et al. 2019

Journal of Antimicrobial Chemotherapy

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“…Exposure to higher than defined SCs was associated with significantly higher With regard to adverse effects, Imani et al [37] demonstrated neuro-and nephrotoxicity during bolus application of PIP. Quinton et al [38] predicted neurotoxicity following continuous application of PIP at around a threshold concentration of 157 mg/L with a sensitivity of 52% which implies that neurotoxicity might well happen above and below 157 mg/L that concentration. Noticeably, patients with neurotoxic symptoms showed a significantly lower eGFR (18 mL/min) as compared to those without neurotoxicity (50 mL/min).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience

Richter

Frey²,

Röhr³

et al. 2019

Infection

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Purpose Standard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with β-lactams in critically ill patients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically ill patients. Methods This is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2-4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)]. Results PK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CL PIP ): no RRT CL PIP 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CL PIP 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CL PIP 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m 2 significantly increased CL PIP 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33-64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]). Conclusion TDM-guided CI of PIP is safe in critically ill patients and improves PK-target attainment. Exposure to defined PK-targets impacts patient mortality while lower and higher than intended SCs may influence the outcome of critically ill patients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.

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“…Overexposure to these agents is a primary risk factor for neurotoxicity . Piperacillin was also associated with neurotoxicity in cases of overexposure . Even in the context of ARC, empirical dose escalation beyond doses approved by the Food and Drug Administration (FDA) may not be appropriate given the risk of toxicity and the relative lack of data linking ARC to lower β‐lactam CNS concentrations.…”

Section: Identifying Patients At Risk For Arcmentioning

confidence: 99%

Augmented Renal Clearance

2019

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Augmented renal clearance (ARC) is a phenomenon in critically ill patients characterized by increased creatinine clearance and elimination of renally eliminated medications. Patients with severe neurologic injury, sepsis, trauma, and burns have been consistently identified as at risk of ARC, with mean creatinine clearances ranging from 170 ml/minute to more than 300 ml/minute. Several potential mechanisms may contribute to the occurrence of ARC including endogenous responses to increased metabolism and solute production, alterations in neurohormonal balance, and therapeutic maneuvers such as fluid resuscitation. Augmented renal clearance is associated with suboptimal exposure to critical medications, including β‐lactams and vancomycin, increasing the risk of treatment failure. Although definitive screening tools are not yet known, critical care pharmacists must be vigilant in recognizing when ARC may be a contributing factor affecting expected treatment outcomes in individual patients. Optimizing dosing strategies in critically ill patients with ARC remains a goal of continued research. The current review discusses the clinical characteristics and methods of identifying patients at risk of ARC, potential mechanisms for ARC, and describes pharmacotherapy dosing considerations in patients with ARC.

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Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients

Cited by 73 publications

References 15 publications

Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen

Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen

Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience

Augmented Renal Clearance

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