Pharmacokinetic evaluation of piperacillin-tazobactam

Hayashi, Yoshihiko; Roberts, Jason A.; Paterson, David L.; Lipman, Jeffrey

doi:10.1517/17425255.2010.506187

Cited by 74 publications

(67 citation statements)

References 89 publications

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“…29 ) was noticed in renal clearance estimation. Values of the median Cl tot,me and that of Cl tot,pip were higher than that estimated in healthy volunteers 30 , and compatible with patients´data 31 in the septic patients > 60 year old, Cl ren,me reached only 44.5% of Cl tot,me and indicated the augmented extrarenal clearance in critically ill older patients also reported by others 25 . This outcome is considered a consequence of increased exposure to dehydropeptidase 1, causing nonspecific hydrolysis in tissue to an inactive metabolite 27 .…”

Section: Discussionsupporting

confidence: 85%

“…5,22 ) and failure of antibiotic therapy as shown in patients treated with conventional dosing of piperacillin. Reduced Cl cr and consequent low antibiotic Cl ren can result in drug accumulation 22,30 and elevated %f T. Unfortunately, Cl cr was shown to be a covariate not predictive of variations in drug PK/PD target attainment in such setting 33 . Is CFB next covariate that should be taken into consideration as the predictor of the first (loading) doses and that presented by Cl cr as the predictor of next dosing adaptation?…”

Section: Discussionmentioning

confidence: 99%

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Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

Kaška¹,

Havel²,

Selke-Krulichova³

et al. 2018

BIOMED PAP

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Aims. Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble timedependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates -creatinine clearance (Cl cr ) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/ tazobactam (PIP/TZB). Methods. In this prospective observational pharmacokinetic (PK) study, 18 critically ill patients admitted to a surgical Intensive Care Unit (ICU) were enrolled. The primary PK/PD target was free antibiotic concentrations above MIC at 100% of the dosing interval (100%fT>MIC) to obtain maximum bactericidal activity. Drug concentration was measured using liquid chromatography-tandem mass spectrometry. Results. The treatment of both 8 septic patients with IV extended ME dosing 2 g/3 h q8 h and 10 polytraumatized patients with IV intermittent PIP/TZB dosing 4.0/0.5 g q8 h was monitored. 8/18 patients (44%) manifested augmented renal clearence (ARC) where Cl cr ≥130 mL/min/1.73m 2 . Maximum changes were reported on days 2-3: the median positive CFB followed by the large median volume of distribution: Vd me =70.3 L (41.9-101.5), Vd pip = 46.8 L (39.7-60.0). 100%fT me >MIC was achieved in all patients on ME (aged ≥60 years), and only in two patients (non-ARC, aged ≥65 years) out of 10 on PIP/TZB. A mixed model analysis revealed positive relationship of CFB pip with Vd pip (P=0.021). Conclusion. Assuming that the positive correlation between CFB and Vd exists for piperacillin in the setting of the pathological state, then CFB should predict Vd pip across subjects at each and every time point.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

Kaška¹,

Havel²,

Selke-Krulichova³

et al. 2018

BIOMED PAP

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“…In particular, simulation studies were used to explore the potential pharmacodynamic benefits of using an extended infusion, as suggested by Lodise et al (18), compared to the licensed schedule of administration for 30 min (14). Alternative TZP regimens were also explored in an effort to maximize the probability of target attainment (PTA) against a range of MICs at the higher end of the CLSI susceptibility range for nonfermentative Gram-negative pathogens.…”

mentioning

confidence: 99%

Population Pharmacokinetics of Extended-Infusion Piperacillin-Tazobactam in Hospitalized Patients with Nosocomial Infections

Felton

Hope

Lomaestro

et al. 2012

Antimicrob Agents Chemother

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e While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50% fT>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50% fT>MIC for MICs of >8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize fT>MIC in certain hospitalized populations. P iperacillin-tazobactam (TZP) is a combination of an extended-spectrum ␤-lactam antibiotic and a ␤-lactamase inhibitor and is frequently used for nosocomial infections (3, 21). For ␤-lactam antibiotics, the pharmacodynamic index that best links drug exposure with the observed antibacterial effect is the fraction of the dosing interval in which free drug concentrations are above the MIC (9). Near-maximal effect is generally observed when free concentrations exceed the MIC for at least 50% of the dosing interval (fTϾMIC 50%) (12). Although TZP is frequently administered as a rapid infusion, extended infusions of TZP are increasingly used in clinical practice because they facilitate the extension of the fTϾMIC.Although the method is more commonplace than rapid infusions, the impact of prolonging the infusion time of TZP on its pharmacokinetic (PK) profile has not been widely assessed. Here, we describe the population pharmacokinetics for both piperacillin and tazobactam among hospitalized patients receiving an extended infusion regimen. The goal was to identify the model that best explained the observed clearance of both piperacillin and tazobactam. When modeling piperacillin, it is important to consider linear, Michalis-Menten (MM), and parallel first-order/MM models. Piperacillin is cleared via a combination of renal tubular secretion and glomerular filtration (25). Whil...

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“…However, when ampicillin is administered as co-formulation for sulbactam, bacterial re-growth has been reported when sulbactam levels fall below "critical" concentrations [161]. Therefore, like other -lactamase inhibitors, sulbactam is probably best described as an AUC-dependent drug where bacterial killing is associated with the area under the concentration--time curve (AUC) [162]. To date, there are no studies measuring the importance of antibiotic exposure with development of resistance to ampicillin/sulbactam but, like other antibiotics, underdosing may lead to resistance [163].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Improving antimicrobial use in critically ill patients

Adnan¹

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Pharmacokinetic evaluation of piperacillin-tazobactam

Abstract: Where piperacillin-tazobactam is required for treatment, applying knowledge of PK and PD characteristics can facilitate optimal outcomes.

Cited by 74 publications

References 89 publications

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

Population Pharmacokinetics of Extended-Infusion Piperacillin-Tazobactam in Hospitalized Patients with Nosocomial Infections

Improving antimicrobial use in critically ill patients

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