Pharmacokinetics and Pharmacodynamics of Cefepime in Adults with Hematological Malignancies and Febrile Neutropenia after Chemotherapy

Álvarez, José C; Cuervo, Sonia Isabel; Silva, Edelberto; Díaz, Jorge A. Soler; Jiménez, L.; Parra, Daniel S; Gómez, Juan Manuel; Pedraza, Ricardo Sánchez; Cortés, Jorge Alberto

doi:10.3390/antibiotics10050504

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…The purpose of this mini review was to briefly survey the techniques and decisions researchers made while performing cefepime PTA. Therefore, only the first 20 titles were reviewed, of which 14 met the inclusion criteria of a PTA study, with at least one evaluation of cefepime alone in adult patients ( Table 1 ) [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. A study by Das et al was excluded because cefepime was studied in combination with a novel beta-lactamase inhibitor, changing the risk benefit from cefepime alone [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

“…All authors reported a clear purpose for the PTA. Common purposes were to explore optimal doses in a special patient population, explore the success of achieving different PD targets, or exploring the success of one dosing regimen over another [ 14 , 15 , 17 , 18 , 25 ]. The number of virtual patients simulated varied from 1000 to 12,000.…”

Section: Resultsmentioning

confidence: 99%

“…Simulations were performed using Pumas v 1.1 [ 43 ]. A population PK model developed by Álvarez et al was used to simulate individual PK profiles [ 17 ]. This model was chosen because the PTA results were reproducible and parameter estimates were ideal for demonstrating how PTA results may change, with different assumptions in technique or clinical covariates.…”

Section: Methodsmentioning

confidence: 99%

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Beta-Lactam Probability of Target Attainment Success: Cefepime as a Case Study

et al. 2023

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Introduction: Probability of target attainment (PTA) analysis using Monte Carlo simulations has become a mainstay of dose optimization. We highlight the technical and clinical factors that may affect PTA for beta-lactams. Methods: We performed a mini review in adults to explore factors relating to cefepime PTA success and how researchers incorporate PTA into dosing decisions. In addition, we investigated, via simulations with a population pharmacokinetic (PK) model, factors that may affect cefepime PTA success. Results: The mini review included 14 articles. PTA results were generally consistent, given the differences in patient populations. However, dosing recommendations were more varied and appeared to depend on the definition of pharmacodynamic (PD) target, definition of PTA success and specific clinical considerations. Only 3 of 14 articles performed formal toxicological analysis. Simulations demonstrated that the largest determinants of cefepime PTA were the choice of PD target, continuous vs. intermittent infusion and creatinine clearance. Assumptions for protein binding, steady state vs. first dose, and simulating different sampling schemes may impact PTA success under certain conditions. The choice of one or two compartments had a minimal effect on PTA. Conclusions: PTA results may be similar with different assumptions and techniques. However, dose recommendation may differ significantly based on the selection of PD target, definition of PTA success and considerations specific to a patient population. Demographics and the PK parameters used to simulate time-concentration profiles should be derived from patient data applicable to the purpose of the PTA. There should be strong clinical rationale for dose selection. When possible, safety and toxicity should be considered in addition to PTA success.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Beta-Lactam Probability of Target Attainment Success: Cefepime as a Case Study

et al. 2023

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“…We found that FEP is often used to treat leukemia patients with combined infections. Compared with other cephalosporins, FEP not only has good stability against β-lactamase produced by bacteria and is less likely to induce resistance, 11 but also has good clinical application prospects in the treatment of ESBLs-positive E. coli infections. At the same time, giving a higher dose of FEP to Gram-negative rods can also achieve ideal therapeutic effects.…”

Section: Discussionmentioning

confidence: 99%

The Impact of ESBLs-Positive Escherichia coli’s Resistance to Cefepime and Its Guidance for Clinical Treatment

Wu,

Shi,

Huang

et al. 2023

IDR

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Background Escherichia coli ( E. coli ) is a common pathogen in bloodstream infections (BSI), and the production of extended-spectrum beta-lactamases (ESBLs) is its main mechanism of resistance. However, the impact of different ESBL genotypes of E. coli on the resistance to Cefepime (FEP) remains unclear. Methods A total of 2356 cases of BSI patients were collected. The experimental group included 188 ESBL-positive E. coli strains that were resistant to FEP but sensitive to ceftazidime (CAZ). Antibiotic usage and resistance rates were evaluated through antimicrobial susceptibility testing and antibiotic usage records. The ESBL genotypes were identified, and the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of FEP were determined. Results In ESBL-positive E. coli , three ESBL genotypes were identified: 188 strains of CTX-M, 130 strains of TEM-1, and 26 strains of OXA-10. Among them, 124 strains carried both CTX-M-9 and TEM-1 genotypes, 22 strains carried two CTX-M genotypes (CTX-M-1 and CTX-M-2), 20 strains carried both CTX-M-9 and OXA-10, and 6 strains carried three genotypes (CTX-M-9, CTX-TEM-1, and OXA-10). The MIC50, MIC90, MPC50, and MPC90 of the 188 ESBL-positive E. coli were 64, 256, 128, and 528, respectively. The MIC values ranged from 32 to 256, while the MPC values ranged from 64 to 528. The MIC50, MIC90, MPC50, and MPC90 of the 40 ESBL-negative E. coli were 0.5, 1, 64, and 128, respectively; the MIC values ranged from 0.25 to 4, while the MPC values ranged from 32 to 256, respectively. Conclusion ESBL-positive E. coli induces an increase in the MIC value of FEP, leading to an increase in FEP resistance. The inoculation effect also causes a significant increase in the MPC value of FEP, especially the increase in selection index value, indicating selective enrichment and amplification of drug-resistant mutants, resulting in clinical treatment failure.

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“…Compared with those in the nonfebrile neutropenia cohort, the vancomycin concentration/dose ratio was significantly lower, and vancomycin clearance was significantly higher in the febrile neutropenia cohort. Previous studies have indicated that febrile neutropenia alters the pharmacokinetics of several antibiotics, especially beta-lactams, such as cefepime, 24 doripenem, 25 ceftazidime, 26 and piperacillin. 27 In addition, the pharmacokinetics of drugs are dependent on elevated clearance and distribution volume.…”

Section: Discussionmentioning

confidence: 99%

Association of Vancomycin Trough Concentration and Clearance With Febrile Neutropenia in Pediatric Patients

Amano

Tanaka

Ono

et al. 2022

Therapeutic Drug Monitoring

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Background: Febrile neutropenia promotes renal drug excretion. Adult and pediatric patients with febrile neutropenia exhibit a lower vancomycin concentration/dose (relative to bodyweight) ratio than those with other infections. In pediatric patients, renal function relative to bodyweight varies depending on age, and vancomycin clearance is age dependent. This study aimed to analyze the effects of febrile neutropenia on the pharmacokinetics of vancomycin in age-stratified pediatric patients. Methods: This retrospective, single-center, observational cohort study analyzed 112 hospitalized pediatric patients who met the selection criteria and intravenously received vancomycin at the Department of Pediatrics of the Oita University Hospital between April 2011 and October 2019. Results: The febrile neutropenia (n = 46) cohort exhibited a significantly higher estimated glomerular filtration rate than the nonfebrile neutropenia (n = 66) cohort. Compared with those in the nonfebrile neutropenia cohort, the daily vancomycin dose relative to bodyweight and vancomycin clearance were significantly higher, and the vancomycin trough concentration and vancomycin concentration/dose ratio were significantly lower in the febrile neutropenia cohort. In the age groups of 1–6 and 7–12 years, compared with those in the nonfebrile neutropenia cohort, the vancomycin concentration/dose ratio was significantly lower, and vancomycin clearance was significantly higher in the febrile neutropenia cohort. Univariate and multivariate analyses identified febrile neutropenia as the independent factor influencing vancomycin concentration/dose ratio and clearance only in pediatric patients aged 1–6 years. Conclusions: Increased initial dosage and therapeutic drug monitoring-guided dose optimization are critical for the therapeutic efficacy of vancomycin in pediatric patients with febrile neutropenia, especially in those aged 1–6 years.

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Pharmacokinetics and Pharmacodynamics of Cefepime in Adults with Hematological Malignancies and Febrile Neutropenia after Chemotherapy

Cited by 9 publications

References 39 publications

Beta-Lactam Probability of Target Attainment Success: Cefepime as a Case Study

Beta-Lactam Probability of Target Attainment Success: Cefepime as a Case Study

The Impact of ESBLs-Positive Escherichia coli’s Resistance to Cefepime and Its Guidance for Clinical Treatment

Association of Vancomycin Trough Concentration and Clearance With Febrile Neutropenia in Pediatric Patients

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