Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an
            <i>In Vitro</i>
            Infection Model

Nicasio, Anthony M.; VanScoy, Brian; Mendes, Rodrigo E.; Castanheira, Mariana; Bulik, Catharine C.; Okusanya, Ólanrewaju O.; Bhavnani, Sujata M.; Forrest, Alan; Jones, Ronald N.; Friedrich, Lawrence V.; Steenbergen, Judith N.; Ambrose, Paul G.

doi:10.1128/aac.02747-15

Cited by 46 publications

(45 citation statements)

References 11 publications

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“…The choice was based on the only properly designed in vitro study in which the pharmacodynamics of tazobactam was characterised in combination with piperacillin. 5 Further studies are required to confirm the appropriate target. Our analysis should be interpreted with caution, but it does provide insight into how differences in exposure may affect antimicrobial response.…”

Section: Discussionmentioning

confidence: 99%

“…Threshold concentration targets were thought to depend on β-lactamase transcription level, with upper limits of 4 mg/L used. 5,6 Piperacillin and tazobactam are predominantly excreted in unchanged form by glomerular filtration and tubular secretion (piperacillin: 46 to 73%; tazobactam: 65 to 80%). 7 In addition, saturable renal elimination has been identified previously in adults.…”

Section: Introductionmentioning

confidence: 99%

“…3 Recent studies reported the PK/PD efficacy index for the β-lactamase inhibitor (BLI) tazobactam to be the percentage of time during which the unbound concentration remains above a threshold concentration (fT>CT). 4,5 fT>CT targets ranged from 35 to 85% of the dosing interval, depending on the antibiotic-BLI combination and stability of the β-lactamase. Threshold concentration targets were thought to depend on β-lactamase transcription level, with upper limits of 4 mg/L used.…”

Section: Introductionmentioning

confidence: 99%

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Dose optimization of piperacillin/tazobactam in critically ill children

Cock¹,

Dijkman

Jaeger

et al. 2017

Journal of Antimicrobial Chemotherapy

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Running title: Paediatric piperacillin/tazobactam dose rationale SynopsisObjectives. The aim of this study was to characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.Patients and Methods. This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg q6h based on piperacillin). Piperacillin/tazobactam concentrations were measured by a liquid chromatography-tandem mass spectrometry method. Pharmacokinetic data was analysed using nonlinear mixed effects modelling.Results. Piperacillin and tazobactam blood samples were collected from 47 patients (median age: 2.83 years; range: 2 months -15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model which included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 L/h and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) q4h over 2 hours, 100 mg/kg q4h given over 1 hour or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24h were minimally required to achieve the therapeutic targets for piperacillin (60 % fT>MIC>16 mg/L). Conclusion. Standard intermittent dosing regimens do not ensure optimalpiperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dose optimization of piperacillin/tazobactam in critically ill children

Cock¹,

Dijkman

Jaeger

et al. 2017

Journal of Antimicrobial Chemotherapy

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“…Optimal drug doses were defined as the smallest practical daily dose resulting in at least 90% of the 5,000 virtual patients attaining a predetermined pharmacodynamic target of a free ceftolozane serum concentration above the minimum inhibitory concentration (MIC) of 4 mg/L (fT/MIC) for ≥60% of the dosing interval versus Pseudomonas aeruginosa during the initial 48 h of treatment [24,25]. Given that tazobactam has no activity against Pseudomonas aeruginosa , the target of a free tazobactam serum concentration above an MIC of 2 mg/L for ≥50% of the dosing interval for Enterobacteriaceae was used [25,26,27,28,29]. This >50% fT/MIC threshold is based on in vitro infection models that indicated good correlation between fT/MIC for 50% of a dosing interval and reduction in colony forming units over 24 h [29].…”

Section: Methodsmentioning

confidence: 99%

Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy

et al. 2017

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Background/Aims: To determine ceftolozane/tazobactam transmembrane clearances (CL_TM) in continuous hemofiltration (CHF) and continuous hemodialysis (CHD) and to determine optimal ceftolozane/tazobactam dosing regimens for patients receiving continuous renal replacement therapy (CRRT). Method: Validated, ex vivo CHF and CHD bovine blood models using polysulfone (HF1400) and AN69 (Multiflow 150-M) hemofilters were used to evaluate adsorption and CL_TM at different effluent flow rates. Monte Carlo simulations (MCS) using pharmacokinetic parameters from published studies and CL_TM from this study were used to generate ceftolozane/tazobactam dosing for patients receiving CRRT. Results: CHF and CHD CL_TM did not differ at equivalent effluent rates. CL_TM approximated effluent flow rates. No adsorption of ceftolozane/tazobactam occurred for either hemofilter. Effluent flow was the most important determinant of MCS-derived doses. Conclusion: CRRT clearances of ceftolozane/tazobactam depended on effluent flow rates but not hemofilter types. MCS-derived ceftolozane/tazobactam doses of 750 (500/250)-1,500 (1,000/500) mg every 8 h met pharmacodynamic targets for virtual patients receiving CRRT at contemporary effluent rates.

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“…Previously, we identified the %TimeϾthreshold as the tazobactam PK-PD index most closely associated with efficacy in combination with ceftolo- zane, piperacillin, or cefepime (18,23,24), while herein we identified the AUC 0 -24 as the exposure measure most associated with efficacy for CB-618 when used in combination with meropenem. The basis for this observation is unknown.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in an In Vitro Infection Model

VanScoy

Trang

McCauley

et al. 2016

Antimicrob Agents Chemother

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cThe usefulness of ␤-lactam antimicrobial agents is threatened as never before by ␤-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum ␤-lactamase inhibitors. Herein we describe the results of dose fractionation and dose-ranging studies carried out using a one-compartment in vitro infection model to determine the exposure measure for CB-618, a novel ␤-lactamase inhibitor, most predictive of the efficacy when given in combination with meropenem. The challenge panel included Enterobacteriaceae clinical isolates, which collectively produced a wide range of ␤-lactamase enzymes (KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and TEM-1). Human concentration-time profiles were simulated for each drug, and samples were collected for drug concentration and bacterial density determinations. Using data from dose fractionation studies and a challenge Klebsiella pneumoniae isolate (CB-618-potentiated meropenem MIC ‫؍‬ 1 mg/ liter), relationships between change from baseline in log 10 CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC 0 -24 ), maximum concentration (C max ), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold were evaluated in combination with meropenem at 2 g every 8 h (q8h). The exposure measures most closely associated with CB-618 efficacy in combination with meropenem were the CB-618 AUC 0 -24 (r 2 ‫؍‬ 0.835) and C max (r 2 ‫؍‬ 0.826). Using the CB-618 AUC 0 -24 indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log 10 CFU/ml at 24 h and CB-618 AUC 0 -24 /MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC 0 -24 /MIC ratio associated with net bacterial stasis and the 1-and 2-log 10 CFU/ml reductions from baseline at 24 h were 27.3, 86.1, and 444.8, respectively. These data provide a pharmacokinetics-pharmacodynamics (PK-PD) basis for evaluating potential CB-618 dosing regimens in combination with meropenem in future studies.

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Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model

Cited by 46 publications

References 11 publications

Dose optimization of piperacillin/tazobactam in critically ill children

Dose optimization of piperacillin/tazobactam in critically ill children

Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy

Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in an In Vitro Infection Model

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