Randomized, Open-Label, Comparative Study of Piperacillin-Tazobactam Administered by Continuous Infusion versus Intermittent Infusion for Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection

Lau, William K.; Mercer, David F.; Itani, Kamal M.F.; Nicolau, David P.; Kuti, Joseph L.; Mansfield, Debra; Dana, Adrian

doi:10.1128/aac.00329-06

Cited by 122 publications

(143 citation statements)

References 28 publications

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“…Furthermore, as expected, we found that more frequent intermittent piperacillin doses produced a higher PTA across all BMI categories. We also found that piperacillin extended and continuous infusions greatly improved the PTA (an MIC up to at least 8 mg/liter) in the presence of different BMIs and measured CL CR s. These data support those of other investigators (19)(20)(21), which suggest that extended and continuous infusions can normalize any effects of altered weight and renal function on achievement of therapeutic concentrations.…”

Section: Resultssupporting

confidence: 89%

Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

Alobaid

Wallis

Jarrett

et al. 2017

Antimicrob Agents Chemother

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The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean Ϯ standard deviation age, weight, and BMI were 50 Ϯ 15 years, 104 Ϯ 35 kg, and 38.0 Ϯ 15.0 kg/m 2 , respectively. The concentration-time data were best described by a two-compartment linear model. The mean Ϯ SD parameter estimates for the final covariate model were a clearance of 14.0 Ϯ 7.1 liters/h, a volume of distribution of the central compartment of 49.0 Ϯ 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 Ϯ 0.6 liters · h Ϫ1 , and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 Ϯ 2.8 liters · h Ϫ1 . A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.

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Section: Resultssupporting

confidence: 89%

Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

Alobaid

Wallis

Jarrett

et al. 2017

Antimicrob Agents Chemother

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“…Currently, we do not know whether different PIP-TZ administration modalities (13,14,16) or higher PIP-TZ doses can improve the PIP-TZ penetration into PJ. Knowledge of the elimination of antibiotics with the PJ is important for the efficacy of therapy, since the amount of drug secreted into the PJ is an indicator of greater concentrations in the pancreatic tissue.…”

mentioning

confidence: 99%

Piperacillin-Tazobactam Penetration into Human Pancreatic Juice

Minelli

Benini

Franco

et al. 2008

Antimicrob Agents Chemother

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Piperacillin-tazobactam was administered as a single dose (4.5 g intravenous) to five patients with stabilized external pancreatic fistula. The penetration into pancreatic juice was prompt, and inhibitory concentrations were achieved and maintained for different periods (0.5 to 6 h) according to bacterial susceptibility and patients' characteristics. Piperacillin and tazobactam showed superimposable pharmacokinetics in both serum and pancreatic juice.Piperacillin-tazobactam (PIP-TZ), a ␤-lactam/␤-lactamase inhibitor combination, appears to have a useful role in the treatment of patients with complicated intra-abdominal infections (5, 12, 15); however, PIP-TZ's use has not been established for pancreatic infections, and it is unknown whether the degree of PIP and TZ penetration into human pancreatic juice (PJ) is high enough to eradicate relevant pathogens.For that reason, we evaluated the elimination of PIP-TZ in PJ and the pharmacodynamic properties of the combination against clinical isolates.This was a single-dose, open-label, noncomparative study. The protocol was approved by the local hospital ethics committee, and informed consent was obtained from all patients.Five patients, operated on by duodenopancreatectomy for periampullary tumors, and their Wirsung-cutaneous stabilized, high-output pancreatic fistulas managed with external surgical drains were given 4 g PIP and 0.5 g TZ (8:1 ratio) (Tazocin; Wyeth Lederle, Aprilia, Italy) as a single dose by 30 min of intravenous (i.v.) infusion. Treatment started after complete surgical recovery with normalization of pancreatic exocrine function, when PJ may be considered similar to that produced by the normal pancreas.Venous blood samples were obtained from an indwelling contralateral catheter immediately before (time zero) and 5, 60, 90, 120, 360, and 480 min after PIP-TZ administration. Simultaneously, PJ samples were obtained from stabilized external pancreatic fistula. Serum and PJ samples were frozen at Ϫ80°C until analysis.Antibiotic concentrations in serum, PJ, and standards were processed in parallel by high-performance liquid chromatography (HPLC) and bioassay (antimicrobial activity in the presence of PJ).The concentrations of PIP and TZ were determined using a gradient elution, reverse-phase HPLC method with UV detection (214 nm) according to Westphal et al. (26) with lower limits of sensitivity of 0.1 mg/liter for PIP and 0.05 mg/liter for TZ both in serum and in PJ.Pharmacokinetic parameters were determined by the model-independent approach (noncompartmental analysis)

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“…We also found that piperacillin extended and continuous infusion greatly improved PTA (MIC up to at least 8 mg/L) in the presence of different BMIs and measured CLCR. These data support others 60,144,145 , which suggest that extended and continuous infusions can normalise any effects of altered weight and renal function on achievement of therapeutic concentrations.…”

Section: Key Findingssupporting

confidence: 87%

An investigation of the pharmacokinetics of piperacillin, meropenem and fluconazole in critically ill obese patients

Alobaid¹

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The increasing numbers of critically ill obese patients in the intensive care unit (ICU) and the high frequency of antimicrobial prescription in these patients present a challenge for prescribing effective antimicrobial doses. Critically ill obese patients have greater infectionrelated morbidity and mortality than their non-obese counterparts. The underlying explanation for these inferior outcomes remains unclear, although sub-optimal antimicrobial dosing may be a contributing factor. Unfortunately there is a paucity of research and no recognised guidelines to assist clinicians with dosing antimicrobials in these patients who commonly develop dramatic physiological changes that can lead to significantly altered drug concentrations, and therefore, sub-optimal treatment.Critical illness pathologies, such as sepsis and septic shock are reported to alter the pharmacokinetics of many antimicrobials, including piperacillin, meropenem and fluconazole. Along with the alterations in the pharmacokinetics of these agents caused by obesity, sub-therapeutic concentrations of these drugs are likely in critically ill obese patients.This Thesis addresses the limitations of current knowledge by describing the plasma pharmacokinetics of piperacillin, meropenem and fluconazole in critically ill non-obese, obese and morbidly obese patients. The Thesis then provides dosing recommendations which can be used for more effective antibiotic dosing.Firstly a structured review of the effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients was performed. The review concluded that the presence of obesity augments the pharmacokinetic changes of antimicrobials in critical illness. Furthermore, this chapter also provides suggested dosing regimens for use in critically ill obese patients based on the published literature.To investigate the effect of obesity on antimicrobial trough concentrations and achievement of target exposures in obese and non-obese critically ill patients, a large retrospective study (n = 1400) of therapeutic drug monitoring data of piperacillin and meropenem was performed. This study found that piperacillin concentrations were significantly affected by the presence of obesity, with no significant differences evident for meropenem. IIITo further explore the effect of obesity using a more descriptive approach, prospective pharmacokinetic studies were conducted with piperacillin/ tazobactam (n=37), meropenem (n=19) and fluconazole (n=21) in critically ill patients across different body mass index (BMI) classifications including non-obese (BMI 18.5 -29.9 kg/m 2 ), obese kg/m 2 ), and morbidly-obese (BMI ≥ 40 kg/m 2 ). The included patients had widely varying BMIs, but typical age and sex distributions as encountered in ICUs. Using a population pharmacokinetic modelling approach, it was concluded that BMI only had a small effect on antimicrobial volume of distribution, whilst measured creatinine clearance had a significant effect on drug clearance. Using Monte Carlo dosing simulations, it...

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Randomized, Open-Label, Comparative Study of Piperacillin-Tazobactam Administered by Continuous Infusion versus Intermittent Infusion for Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection

Cited by 122 publications

References 28 publications

Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

Piperacillin-Tazobactam Penetration into Human Pancreatic Juice

An investigation of the pharmacokinetics of piperacillin, meropenem and fluconazole in critically ill obese patients

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