Steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam administered by prolonged infusion in hospitalised patients

Shea, Katherine M.; Cheatham, S. Christian; Wack, Matthew F.; Smith, David W.; Sowinski, Kevin M.; Kays, Michael B.

doi:10.1016/j.ijantimicag.2009.07.004

Cited by 29 publications

(38 citation statements)

References 34 publications

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“…4). This target was also achieved in about 80% of simulated infants in the oldest PMA group (35 to 49 weeks) when the dosing interval was extended to 6 h. In addition, this dosing regimen achieved exposures comparable to those seen in adult patients receiving piperacillin-tazobactam for highly resistant infections (predicted drug concentration at the end of the dosing interval at steady state [C min ss ], 27.6 mg/liter following a dose of 4.5g q 8 h infused over 4 h) (22). The PMA-dosing regimen also compared favorably with dosing regimens recommended in Neofax and The Harriet Lane Handbook that use multiple PMA-PNA and GA-PNA categories, respectively (Table 6 and Fig.…”

Section: Resultsmentioning

confidence: 85%

“…Prolonging the duration of the piperacillin-tazobactam infusion does not improve target attainment rates in infants and therefore is not supported for this population. The proposed dosing regimen also provides drug exposures comparable with those seen for adult patients with highly resistant infections receiving piperacillin-tazobactam (22).…”

Section: Discussionmentioning

confidence: 92%

“…The proportion of simulated subject profiles that met the surrogate PD target was calculated for each dosing recommendation guideline and for various MICs. We also compared piperacillin exposures in the study population with exposures achieved in adults treated with piperacillin for highly resistant (MIC Ն 16 mg/liter) infections (22). DBS analysis.…”

Section: Methodsmentioning

confidence: 99%

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Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Cohen‐Wolkowiez

Watt

Zhou

et al. 2014

Antimicrob Agents Chemother

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f Piperacillin-tazobactam is often given to infants with severe infection in spite of limited pharmacokinetics (PK) data. We evaluated piperacillin-tazobactam PK in premature and term infants of ages <61 days with suspected systemic infection. Infants received intravenous piperacillin-tazobactam (80 to 100 mg/kg of body weight every 8 h [q 8 h]) based on gestational and postnatal age. Sparse plasma samples were obtained after first and multiple doses. Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effect modeling. Target attainment rates for the time unbound piperacillin concentrations remained above the MIC for 50% and 75% of the dosing interval at steady state were evaluated. Bias in population PK parameter estimates was assessed for dried blood spot (DBS) samples, and a comparability analysis was performed for DBS and plasma drug concentrations using linear regression. We obtained 128 plasma samples from 32 infants, median gestational age of 30 weeks (range, 23 to 40 weeks) and postnatal age of 8 days (range, 1 to 60). Piperacillin and tazobactam PK models included body weight (WT) and postmenstrual age (PMA) as covariates for clearance and WT for volume of distribution and were used to optimize dosing in infants. DBS drug concentrations were 50 to 60% lower than those in plasma, but when combined with plasma concentrations and a matrix effect, the data generated PK model parameters similar to those for plasma alone. With PMA-based dosing (100 mg/kg q 8 h, 80 mg/kg q 6 h, and 80 mg/kg q 4 h for PMA of <30, 30 to 35, and 35 to 49 weeks, respectively), 90% of simulated infants achieved the surrogate therapeutic target of time above the MIC (<32 mg/liter) for 75% of the dosing interval. P iperacillin-tazobactam is approved by the U.S. Food and Drug Administration for the treatment of adults and children of Ͼ2 months of age with infections due to susceptible bacteria; however, the drug is not approved for use in younger infants, including those born prematurely. In spite of this, piperacillin-tazobactam is extensively used "off-label" in young infants for treatment of systemic infections, including bacteremia and complicated intra-abdominal infections, such as necrotizing enterocolitis (1). Because these infections in premature infants are associated with devastating outcomes, such as death and neurodevelopmental impairment (2, 3), appropriate dosing recommendations for agents such as piperacillin-tazobactam are needed. Recommended piperacillin-tazobactam dosing for young infants in sources like Neofax (4) and The Harriet Lane Handbook (5) rely on combinations of birth weight, gestational age, postmenstrual age (PMA), and postnatal age (PNA), which are cumbersome to implement clinically and more importantly are supported by very small and limited clinical trials in this population.The pharmacokinetics (PK) of piperacillin-tazobactam has not been well characterized for premature infants. The drug is primarily renally eliminated by glomerular fi...

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Section: Resultsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Cohen‐Wolkowiez

Watt

Zhou

et al. 2014

Antimicrob Agents Chemother

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“…22 Extending infusion times of antipseudomonal beta-lactams has been shown to improve pharmacodynamic target attainment in both adults and children and has been associated with reduced mortality in critically ill adults with serious gram-negative bacterial infections. 21,[23][24][25][26] This is especially important when treating infections where the site of infection may be difficult to penetrate with antibiotics or infections caused by organisms with higher MICs, such as Pseudomonas aeruginosa. Failed initial treatment with a 30-minute interval could have been related to lack of achievement of 40% T>MIC which could lead to suboptimal or incomplete killing and potential organism regrowth.…”

Section: Discussionmentioning

confidence: 99%

Success With Extended-Infusion Meropenem After Recurrence of Baclofen Pump-Related Achromobacter Xylosoxidans Meningitis in an Adolescent

Nichols

Knoderer

Jackson

et al. 2015

Journal of Pharmacy Practice

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Abstract:A 13-year-old female experienced a recurrence of baclofen pump-related central nervous system (CNS) infection caused by Achromobacter, despite absence of retained foreign material. Due to the failure of meropenem (120 mg/kg/d in divided doses every 8 hours and infused over 30 minutes) in the initial infection, the dose was infused over 4 hours during the recurrence. Meropenem is an antibiotic for which efficacy is time dependent, and 4-hour versus 30-minute infusions have been shown to prolong the time the concentration of the antibiotic exceeds the minimum inhibitory concentration (MIC) of the organism at the site of infection (T>MIC). Meropenem serum concentrations were obtained and indicated that T>MIC was at least 75% of the dosing interval. Our patient improved with no noted recurrences or adverse effects on the extended-infusion meropenem regimen. Utilization of extended-infusion betalactam dosing whenever possible in the treatment of serious infections caused by gram-negative organisms should be considered, as this dosing appears to be safe and improves the probability of achieving pharmacokinetic/pharmacodynamic goals.2

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“…Using the Sawchuk-Zaske method, the pharmacokinetic parameters were determined using systemic clearance (CL) in mL・ min -1 , volume of distribution (Vd) in L, and elimination half-life (t 1/2 ) in h. Descriptive statistics (mean ± SD) were used to summarize the pharmacokinetic parameters of CAZ and PIPC. In each patient, the profile of the concentration-time curve was simulated using patient-specific pharmacokinetic values, and the %T > MIC from 0 h (time of administration) to 24 h was calculated by using a single-dose infusion model with the following equation [12]:…”

Section: Pharmacokinetic-pharmacodynamic Analysesmentioning

confidence: 99%

Application of Beta-lactam Therapeutic Drug Monitoring in Clinical Practice Using HPLC

Aoki¹

2013

JBABM

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In beta-lactam therapy, investigation of the pharmacokinetic-pharmacodynamic (PK-PD) relationship has provided surrogate makers to predict clinical outcome. This study was designed to verify the therapeutic efficacy and clinical utility of beta-lactam therapeutic drug monitoring (TDM) in critically ill patients using high-performance liquid chromatography (HPLC). This cohort study included 13 patients who were intravenously administered ceftazidime (n = 6), cefepime (n = 1), imipenem (n = 1), meropenem (n = 1), or piperacillin (n = 4). Blood samples were collected at 3 time points fitted to a 1-compartment model, and concentrations were determined using HPLC. The PK-PD target was the percentage of the dosing interval during which the antibiotic concentration exceeded the minimum inhibitory concentration for the pathogens (%T > MIC), which is 50% for penicillins (piperacillin), 60% for cephalosporins (ceftazidime and cefepime), and 40% for carbapenems (imipenem and meropenem). Our process using HPLC enables the analytical results of TDM to be available within half a day. The results revealed significant inter-patient pharmacokinetic variability. During the initial regimen, beta-lactam concentrations reached the target %T > MIC in all patients, and dosage reduction was required for 5 patients (38%). Of the 13 evaluable patients, clinical improvement was observed in 11 (85%), and microbiological success was observed in 10 (77%). In summary, beta-lactam TDM achieved the treatment goals and might also allow for the personalization to prevent overdosing for variable pharmacokinetic changes in critically ill patients. These findings indicate that beta-lactam TDM using HPLC can be used in the standard pharmacy clinical practice for critically ill patients.

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Steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam administered by prolonged infusion in hospitalised patients

Cited by 29 publications

References 34 publications

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Success With Extended-Infusion Meropenem After Recurrence of Baclofen Pump-Related Achromobacter Xylosoxidans Meningitis in an Adolescent

Application of Beta-lactam Therapeutic Drug Monitoring in Clinical Practice Using HPLC

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