Assessment of cefepime toxicodynamics: comprehensive examination of pharmacokinetic/pharmacodynamic targets for cefepime-induced neurotoxicity and evaluation of current dosing guidelines

Lau, Cindy; Marriott, Deborah; Schultz, Hayley B.; Gould, Michael K.; Andresen, David; Wicha, Sebastian G.; Alffenaar, Jan-Willem; Penm, Jonathan; Reuter, Stephanie E

doi:10.1016/j.ijantimicag.2021.106443

Cited by 14 publications

(7 citation statements)

References 18 publications

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“…Hence, using a PK/PD target (for example C ss 10 times the MIC) to avoid toxicity is not relevant. As Lau et al [46] and others [47][48][49][50][51] observed, beta-lactam drug toxicity is most likely linked to the through concentrations. This finding is especially worrisome, as prolonged infusions of beta-lactam antibiotics will, by definition, lead to higher through (or, in the case of continuous infusion, steady state) concentrations.…”

Section: Bacterial Cell Kill Is Not the Only Goalmentioning

confidence: 99%

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

2022

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The surge in antimicrobial resistance and the limited availability of new antimicrobial drugs has fueled the interest in optimizing antibiotic dosing. An ideal dosing regimen leads to maximal bacterial cell kill, whilst minimizing the risk of toxicity or antimicrobial resistance. For beta-lactam antibiotics specifically, PK/PD-based considerations have led to the widespread adoption of prolonged infusion. The rationale behind prolonged infusion is increasing the percentage of time the beta-lactam antibiotic concentration remains above the minimal inhibitory concentration (%fT>MIC). The ultimate goal of prolonged infusion of beta-lactam antibiotics is to improve the outcome of infectious diseases. However, merely increasing target attainment (or the %fT>MIC) is unlikely to lead to improved clinical outcome for several reasons. First, the PK/PD index and target are dynamic entities. Changing the PK (as is the case if prolonged instead of intermittent infusion is used) will result in different PK/PD targets and even PK/PD indices necessary to obtain the same level of bacterial cell kill. Second, the minimal inhibitory concentration is not a good denominator to describe either the emergence of resistance or toxicity. Therefore, we believe a different approach to antibiotic dosing is necessary. In this perspective, we introduce the concept of the maximum tolerable dose (MTD). This MTD is the highest dose of an antimicrobial drug deemed safe for the patient. The goal of the MTD is to maximize bacterial cell kill and minimize the risk of antimicrobial resistance and toxicity. Unfortunately, data about what beta-lactam antibiotic levels are associated with toxicity and how beta-lactam antibiotic toxicity should be measured are limited. This perspective is, therefore, a plea to invest in research aimed at deciphering the dose–response relationship between beta-lactam antibiotic drug concentrations and toxicity. In this regard, we provide a theoretical approach of how increasing uremic toxin concentrations could be used as a quantifiable marker of beta-lactam antibiotic toxicity.

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Section: Bacterial Cell Kill Is Not the Only Goalmentioning

confidence: 99%

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

2022

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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%

“…Delattre et al recommended 4 G loading dose followed by 4 G q 6 h, which is markedly higher than the highest FDA labeled dose of 2 G q 8 h [ 36 ]. Several authors made no strong recommendation and took the approach of reporting PTA at accepted clinical doses [ 15 , 16 , 23 ].…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, cefepime is associated with possible neurotoxicity at exposure levels of 60 mg/L [ 41 ]. Although it was likely considered by all studies, only 3 of the 14 studies in the mini review performed a formal toxicodynamic analysis for cefepime [ 14 , 16 , 22 ]. Given the ongoing research and literature discussions about optimal beta-lactam PD targets and the risk for neurotoxicity, the final cefepime dosing recommendations should be based on a multi-disciplinary approach, considering the PTA, toxicity and the specific clinical and resource setting.…”

Section: Discussionmentioning

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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“…Cefepime-associated neurotoxicity has been abundantly reported in adults with studies demonstrating increased risk of neurotoxicity in patients with underlying neurologic abnormalities and renal dysfunction, often when trough concentrations are above 20–30 mg/L ( Lamoth et al, 2010 ; Huwyler et al, 2017 ; Payne et al, 2017 ; Boschung-Pasquier et al, 2020 ; Lau et al, 2020 ) A toxicodynamic study recommends using a highest trough threshold of 50 mg/L for precision dosing ( Lau et al, 2021 ). Suspected cefepime-associated neurotoxicity in children is limited to case reports, ( Alpay et al, 2004 ; Landgrave et al, 2012 ; Guzman-Limon et al, 2017 ; Shah and Bland, 2021 ; Hambrick et al, 2022 ), all in children with renal dysfunction; one case reported a cefepime concentration of >60 mg/L days after cefepime discontinuation and another reported a trough concentration of 80 mg/L when the patient was experiencing neurotoxic symptoms.…”

Section: Who Might Benefit From β-Lactam Precision Dosing?mentioning

confidence: 99%

β-lactam precision dosing in critically ill children: Current state and knowledge gaps

et al. 2022

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There has been emerging interest in implementing therapeutic drug monitoring and model-informed precision dosing of β-lactam antibiotics in critically ill patients, including children. Despite a position paper endorsed by multiple international societies that support these efforts in critically ill adults, implementation of β-lactam precision dosing has not been widely adopted. In this review, we highlight what is known about β-lactam antibiotic pharmacokinetics and pharmacodynamics in critically ill children. We also define the knowledge gaps that present barriers to acceptance and implementation of precision dosing of β-lactam antibiotics in critically ill children: a lack of consensus on which subpopulations would benefit most from precision dosing and the uncertainty of how precision dosing changes outcomes. We conclude with opportunities for further research to close these knowledge gaps.

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Assessment of cefepime toxicodynamics: comprehensive examination of pharmacokinetic/pharmacodynamic targets for cefepime-induced neurotoxicity and evaluation of current dosing guidelines

Cited by 14 publications

References 18 publications

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

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

β-lactam precision dosing in critically ill children: Current state and knowledge gaps

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