Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia

Aitken, Samuel L; Altshuler, Jerry; Guervil, David J.; Hirsch, Elizabeth B.; Ostrosky-Zeichner, Luis; Ericsson, Charles D.; Tam, Vincent H.

doi:10.1016/j.ijantimicag.2014.12.018

Cited by 56 publications

(34 citation statements)

References 15 publications

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“…The pharmacodynamic target fC min /MIC ratio of 2.1 or greater has also been shown to correlate with clinical success in the treatment of gram‐negative pneumonia . The current study found a mean ± SD first dose fC min /MIC 8 of 2.92 ± 1.26 and steady‐state dose fC min /MIC 8 of 5.65 ± 1.83, showing successful attainment of the pharmacodynamic target in a study population in which EI cefepime was prescribed for treatment of pneumonia in all but one patient.…”

Section: Discussionsupporting

confidence: 62%

Pharmacokinetics and Pharmacodynamics of Extended‐Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open‐Label Study

et al. 2019

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Study Objective To evaluate extended‐infusion (EI) cefepime pharmacokinetics (PK) and pharmacodynamic target attainment in critically ill patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD). Design Prospective, open‐label, PK study. Setting Intensive care units at a large, academic, tertiary‐care medical center. Patients Ten critically ill adults who were receiving cefepime 2 g intravenously every 8 hours as a 4‐hour infusion while receiving CVVH (eight patients) or CVVHD (two patients). Intervention Two sets of five serum cefepime concentrations were collected for each patient to assess pharmacokinetics before and during presumed steady state. Concurrent serum and CRRT effluent samples were collected at hours 1, 2, 3, 4, and 8 after the first cefepime dose and after either the fourth, fifth, or sixth (steady‐state) cefepime doses. Measurements and Main Results Reversed‐phase high‐performance liquid chromatography was used to determine free cefepime concentrations. PK analyses included CRRT clearance, half‐life, and sieving coefficient or saturation coefficient. Cefepime peak (4 hrs) concentrations, trough (8 hrs) concentrations (Cmin), and minimum inhibitory concentration breakpoint of 8 µg/ml for the pathogen (MIC8) were used to evaluate attainment of pharmacodynamic targets: 100% of the dosing interval that free drug remains above MIC8 (100% fT > MIC8), 100% fT > 4 × MIC8 (optimal), percentage of time fT > 4 × MIC8 (%fT > 4 × MIC8) at steady state, and ratio of Cmin to MIC8 (fCmin/MIC8). Total CRRT effluent flow rate was a mean ± SD of 30.1 ± 5.4 ml/kg/hr, CRRT clearance was 39.6 ± 9.9 ml/min, and half‐life was 5.3 ± 1.7 hours. Sieving coefficient or saturation coefficient were 0.83 ± 0.13 and 0.69 ± 0.22, respectively. First and steady‐state dose Cmin were 23.4 ± 10.1 µg/ml and 45.2 ± 14.6 µg/ml, respectively. All patients achieved 100% fT > MIC8 on first and steady‐state doses. First and steady‐state dose 100% fT > 4 × MIC8 were achieved in 22% (2/9 patients) and 87.5% (7/8 patients) of patients, respectively. The mean %fT > 4 × MIC8 at steady state was 97.5%. The fCmin/MIC8 was 2.92 ± 1.26 for the first dose and 5.65 ± 1.83 at steady state. Conclusion Extended‐infusion cefepime dosing in critically ill patients receiving CRRT successfully attained 100% fT > MIC8 in all patients and an appropriate fCmin/MIC8 for both first and steady‐state doses. All but one patient achieved 100% fT > 4 × MIC8 at steady state. No significant differences were observed in PK properties between first and steady‐state doses among or between patients. It may be reasonable to initiate an empiric or definitive regimen of EI cefepime in critically ill patients receiving concurrent CRRT who are at risk for resistant organisms. Further research is needed to identify the optimal dosing regimen of EI cefepime in this patient population.

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Section: Discussionsupporting

confidence: 62%

Pharmacokinetics and Pharmacodynamics of Extended‐Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open‐Label Study

et al. 2019

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“…In addition, 4 out of 12 patients did not complete cefepime therapy due to persisting fever. Even though this observation does not allow any conclusion (small sample size), a recent study also reported clinical failure with cefepime therapy despite achievement of 100% fT ϾMIC (44). In addition to this, a previous study has challenged the ability of existing cefepime breakpoints to predict clinical outcomes (45).…”

Section: Discussionmentioning

confidence: 96%

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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“…These antibiotics are considered to be time-dependent, which means that the duration of the dosing interval for which the concentration exceeds the minimum inhibitory concentration (MIC) of the pathogen is the best descriptor of bacterial killing. In vitro and animal pharmacodynamic (PD) models have shown that for cephalosporins, a time that the drug concentration exceeds the MIC (%T >MIC ) between two administrations of 60-70% was associated with maximal killing [5], whilst retrospective studies in critically ill patients suggest that higher targets such as 100% T >MIC might be needed to treat life-threatening infections [6][7][8]. However, several studies have shown that the pharmacokinetic (PK) behaviour of these hydrophilic antibiotics is profoundly disturbed in critically patients owing to different pathophysiological changes [9].…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics and dosing simulations of cefepime in septic shock patients receiving continuous renal replacement therapy

Carlier¹,

Taccone²,

Beumier³

et al. 2015

International Journal of Antimicrobial Agents

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Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia

Cited by 56 publications

References 15 publications

Pharmacokinetics and Pharmacodynamics of Extended‐Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open‐Label Study

Pharmacokinetics and Pharmacodynamics of Extended‐Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open‐Label Study

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

Population pharmacokinetics and dosing simulations of cefepime in septic shock patients receiving continuous renal replacement therapy

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