Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial

Sime, Fekade Bruck; Roberts, Michael S.; Tiong, Ing Soo; Gardner, Julia H.; Lehman, Sheila; Peake, Sandra; Hahn, Uwe; Warner, Morgyn S.; Roberts, Jason A.

doi:10.1093/jac/dkv123

Cited by 72 publications

(72 citation statements)

References 24 publications

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“…In such patients, extended infusion over half of the dosing interval may significantly improve the probability of target attainment without increasing the total dose administered, thus minimizing the apparent toxicity concerns (15,39). Clinical studies have reported increased percentage of fT ϾMIC with prolonged infusion for cefepime (39,40) and other ␤-lactam antibiotics (15,41). Current PK/PD understanding is that improved exposure can potentially translate into improved clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Adequacy of High-Dose Cefepime Regimen in Febrile Neutropenic Patients with Hematological Malignancies

Sime

Roberts

Tiong

et al. 2015

Antimicrob Agents Chemother

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i While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic/pharmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic/pharmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic/pharmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC (fT >MIC ). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of fT >MIC was also estimated by log-linear regression analysis. All patients achieved >60% fT >MIC in the 3rd and 6th dosing intervals. A 100% fT >MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is <4 mg/liter but may fail to cover less susceptible organisms.T he introduction of cefepime into clinical practice was widely accepted due to its broad-spectrum activity. Cefepime is active against such organisms as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae with relatively low MICs compared to those of other broad-spectrum ␤-lactam antibiotics (1, 2). Therefore, it is considered a good choice for the empirical management of febrile neutropenia, either as a monotherapy agent or as part of combination regimens (3, 4).While several comparative outcome trials suggest cefepime is clinically as effective as other ␤-lactam antibiotics, meta-analyses (5, 6) of data from these trials report an increased risk of mortality associated with cefepime therapy, which was particularly high in febrile neutropenic patients (7). Conversely, a later meta-analysis by the U.S. Food and Drug Administration (FDA), which included several additional unpublished trials, concluded that there is no such association (8, 9). In addition, specific analysis of trials of febrile neutropenic patients did not show any statistically significant increase in mortality (9). The controversy continues as the methodological issues of the FDA's and previous meta-analyses are challenged and debated (7,(10)(11)(12). However, there is little biological plausibility for the claimed risk of mortality, which was originally suggested to be related to unrecognized toxicity or poor in viv...

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Section: Discussionmentioning

confidence: 99%

Adequacy of High-Dose Cefepime Regimen in Febrile Neutropenic Patients with Hematological Malignancies

Sime

Roberts

Tiong

et al. 2015

Antimicrob Agents Chemother

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“…Accordingly, we conducted a randomized controlled study to test the utility of piperacillin TDM in febrile neutropenic patients (6). We found that TDM was able to increase the success rate of target attainment from a baseline of 19% to 73%, in contrast to a decrease from 25% to 7% in the control group.…”

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confidence: 98%

Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia

Sime

Hahn

Warner

et al. 2017

Antimicrob Agents Chemother

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Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A twocompartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 Ϯ 12 years [means Ϯ standard deviations] and weight of 77 Ϯ 16 kg). Parameter estimates were CL of 18.0 Ϯ 4.8 liters/h, volume of distribution of the central compartment of 14.3 Ϯ 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 Ϯ 1.35 h Ϫ1 , and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 Ϯ 7.81 h Ϫ1 . High creatinine clearance (CL CR ) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of Ͼ90% for an unbound concentration of piperacillin remaining above the MIC (fT ϾMIC ) of 50%. Only continuous regimens achieved Ͼ90% PTA for 100% fT ϾMIC when CL CR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (Ͻ85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT ϾMIC . FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL CR or with known/presumed infections from high-MIC bacteria.KEYWORDS febrile neutropenia, piperacillin, population pharmacokinetics

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“…Immuno assays are usually an attractive choice as they do not require special expertise, equipment or significant resources. Yet, immunoassays which have provided such advantages for antibiotics as aminoglycosides, do not exist for β-lactams and attempts for the establishment of such techniques have been difficult [6,55]. Therefore, with the current limitations the use of immunoassays for antibiotics' TDM is not considered as a priority for further development and efforts have been directed to explore other alternatives such as the use of chromatographic techniques.…”

Section: Overview Of Published Analytical Methods Optimized For Theramentioning

confidence: 99%

“…Even after treatment with oseltamivir, all patients died from respiratory tract infection and multiple organs failure [5]. Recent studies show that the dosing regimen of two β-lactam antibiotics (cefepime and piperacillin), prescribed for febrile neutropenic patients with hematological malignancies, requires adjustment [6,7] especially in the presence of organ dysfunction [8]. The need for dose adjustment is mainly due to the fact that the pathophysiological changes encountered in ICU patients substantially affect the pharmacokinetic profile of a drug predisposing the patients to toxic or sub-therapeutic concentrations, when standard doses are applied.…”

Section: Introductionmentioning

confidence: 99%

The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients

El‐Najjar

Gessner

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Cancer remains a leading cause of mortality and morbidity worldwide. In addition to organ failure, the most frequent reasons for admission of cancer patients to intensive care units (ICU) are: infections and sepsis. As critically ill, the complexity of the health situation of cancer patients renders the standard antimicrobial regimen more complex and even inadequate which results in increased mortality rates. This is due to pathophysiological changes in the volume of distribution, increased clearance, as well as to organ dysfunction. While in the former cases a decrease in drug efficacy is observed, the hallmark of the latter one is overdosing leading to increased toxicity at the expense of efficacy. Furthermore, an additional risk factor is the potential drug-drug interaction between antibiotics and antineoplastic agents. Therefore, therapeutic drug monitoring (TDM) is a necessity to improve the clinical outcome of antimicrobial therapy in cancer patients. To be applied in routine analysis the method used for TDM should be cheap, fast and highly accurate/sensitive. Furthermore, as ICU patients are treated with a cocktail of antibiotics the method has to cover the simultaneous analysis of antibiotics used as a first/second line of treatment. The aim of the current review is to briefly survey the pitfalls in the current antimicrobial therapy and the central role of TDM in dose adjustment and drug-drug interaction's evaluation. A major section is dedicated to summarize the currently published analytical methods and to shed light on the difficulties and potential problems that can be encountered during method development.

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Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial

Abstract: Conventional doses of piperacillin/tazobactam may not offer adequate piperacillin exposure in febrile neutropenic patients. TDM provides useful feedback of dosing adequacy to guide dose optimization.

Cited by 72 publications

References 24 publications

Adequacy of High-Dose Cefepime Regimen in Febrile Neutropenic Patients with Hematological Malignancies

Adequacy of High-Dose Cefepime Regimen in Febrile Neutropenic Patients with Hematological Malignancies

Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia

The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients

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