Trough serum concentrations of β-lactam antibiotics in cancer patients: inappropriateness of conventional schedules to pharmacokinetic/pharmacodynamic properties of β-lactams

Navas, Dominique; Caillon, Jocelyne; Batard, Éric; Conte, Philippe Le; Kergueris, Marie‐France; Moreau, Philippe; Potel, G.

doi:10.1016/j.ijantimicag.2005.09.016

Cited by 23 publications

(11 citation statements)

References 34 publications

(42 reference statements)

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“…The FDA‐approved dosage for treatment of febrile neutropenia is 2 g every 8 hours administered intravenously over 30 minutes . However, evaluation of cefepime trough plasma levels in 38 patients with cancer demonstrated that only 24% of cefepime plasma trough concentrations exceeded the MIC for most organisms . Thus current FDA‐approved dosing strategies for cefepime may lead to underdosing among patients with febrile neutropenia.…”

Section: Discussionmentioning

confidence: 99%

“…13 However, evaluation of cefepime trough plasma levels in 38 patients with cancer demonstrated that only 24% of cefepime plasma trough concentrations exceeded the MIC for most organisms. 19 Thus current FDA-approved dosing strategies for cefepime may lead to underdosing among patients with febrile neutropenia. Likewise, additional insights into cefepime PK/PD have recently been garnered.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation

et al. 2016

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“…The high-dose regimen is also supported by previous studies with less frequent dosing schedules (2 g i.v. every 12 h [q12h]) that have shown that trough concentrations can be low for the majority of febrile neutropenic patients (17). Similar findings in critically ill patients suggest that such low dosing regimens are inadequate when considering empirical therapy against less susceptible Gram-negative organisms (27,34).…”

Section: Discussionmentioning

confidence: 99%

“…q8h) was used in most of the published comparative clinical trials with adult febrile neutropenic patients (about 60%) included in the meta-analyses that initially suggested increased mortality with cefepime therapy; while low-dose regimens (1 to 2 g twice daily) were used in the rest (5,6). Whereas studies that monitored cefepime concentrations from the low-dose regimens (17,27,34) suggest that underexposure is likely, measured concentrations from this and other studies (27) of the high-dose therapy indicate that this may occur only if high-MIC organisms are involved. Given the sample size limitation of this study, more data from large trials may be necessary to exclusively rule out underexposure against usually susceptible organisms in the presence of variable and continually changing susceptibility to current antibiotics.…”

Section: Discussionmentioning

confidence: 99%

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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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Population pharmacokinetics of the piperacillin component of piperacillin/tazobactam in pediatric oncology patients with fever and neutropenia

Cies

Jain

Kuti

2014

Pediatric Blood & Cancer

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Trough serum concentrations of β-lactam antibiotics in cancer patients: inappropriateness of conventional schedules to pharmacokinetic/pharmacodynamic properties of β-lactams

Cited by 23 publications

References 34 publications

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation

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

Population pharmacokinetics of the piperacillin component of piperacillin/tazobactam in pediatric oncology patients with fever and neutropenia

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