Too much of a good thing: a retrospective study of β-lactam concentration–toxicity relationships

Imani, Sahand; Buscher, Hergen; Marriott, Debbie; Gentili, Sheridan; Sandaradura, Indy

doi:10.1093/jac/dkx209

Cited by 206 publications

(199 citation statements)

References 34 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…The risk of toxicity should be evaluated along with the benefit of attaining probability of target attainment ≥ 90%. Focus was placed on cefepime, ceftazidime, and piperacillin, drugs with a higher risk of toxicity in patients with kidney disease . Trough cefepime serum concentration >70 mg/L and ceftazidime serum concentration >100 mg/L have been associated with seizures .…”

Section: Methodsmentioning

confidence: 99%

“…Trough cefepime serum concentration >70 mg/L and ceftazidime serum concentration >100 mg/L have been associated with seizures . Neurotoxicity has been reported in 50% of critically ill patients who had piperacillin trough serum concentrations >361.4 mg/L . Keeping trough concentrations below these critical values was considered preferable to reduce the risk of drug‐induced neurotoxicity within this MCS .…”

Section: Methodsmentioning

confidence: 99%

“…Focus was placed on cefepime, ceftazidime, and piperacillin, drugs with a higher risk of toxicity in patients with kidney disease. 28,60,61 Trough cefepime serum concentration >70 mg/L and ceftazidime serum concentration >100 mg/L have been associated with seizures. 60,61 Neurotoxicity has been reported in 50% of critically ill patients who had piperacillin trough serum concentrations >361.4 mg/L.…”

Section: Optimal Dosing Regimenmentioning

confidence: 99%

“…Because of the rising incidence of cefepime‐induced toxicity, the US Food and Drug Administration released a safety announcement in 2012 to remind clinicians of the need to reduce cefepime doses in patients with renal impairment . Both ceftazidime and piperacillin are also associated with neurotoxicity . Currently, there is limited information on dosing cefepime, ceftazidime, and piperacillin/tazobactam in critically ill patients receiving prolonged intermittent renal replacement therapy.…”

mentioning

confidence: 99%

“…27 Both ceftazidime and piperacillin are also associated with neurotoxicity. 28 Currently, there is limited information on dosing cefepime, ceftazidime, and piperacillin/tazobactam in critically ill patients receiving prolonged intermittent renal replacement therapy.…”

mentioning

confidence: 99%

See 4 more Smart Citations

A Monte Carlo Simulation Approach for Beta‐Lactam Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

Jang

Gharibian

Lewis

et al. 2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Cefepime, ceftazidime, and piperacillin/tazobactam are commonly used beta-lactam antibiotics in the critical care setting. For critically ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic data are available to inform clinicians on the dosing of these agents. Monte Carlo simulations (MCS) can be used to guide drug dosing when pharmacokinetic trials are not feasible. For each antibiotic, MCS using previously published pharmacokinetic data derived from critically ill patients was used to evaluate multiple dosing regimens in 4 different prolonged intermittent renal replacement therapy effluent rates and prolonged intermittent renal replacement therapy duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis and hemofiltration modes). Antibiotic regimens were also modeled depending on whether drugs were administered during or well before prolonged intermittent renal replacement therapy therapy commenced. The probability of target attainment (PTA) was calculated using each antibiotic's pharmacodynamic target during the first 48 hours of therapy. Optimal doses were defined as the smallest daily dose achieving ≥90% probability of target attainment in all prolonged intermittent renal replacement therapy effluent and duration combinations. Cefepime 1 g every 6 hours following a 2 g loading dose, ceftazidime 2 g every 12 hours, and piperacillin/tazobactam 4.5 g every 6 hours attained the desired pharmacodynamic target in ≥90% of modeled prolonged intermittent renal replacement therapy patients. Alternatively, if an every 6-hours cefepime regimen is not desired, the cefepime 2 g pre-prolonged intermittent renal replacement therapy and 3 g post-prolonged intermittent renal replacement therapy regimen also met targets. For ceftazidime, 1 g every 6 hours or 3 g continuous infusion following a 2 g loading dose also met targets. These recommended doses provide simple regimens that are likely to achieve the pharmacodynamics target while yielding the least overall drug exposure, which should result in lower toxicity rates. These findings should be validated in the clinical setting.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Optimal Dosing Regimenmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

A Monte Carlo Simulation Approach for Beta‐Lactam Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

Jang

Gharibian

Lewis

et al. 2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

Two‐dimensional liquid chromatography measurement of meropenem concentration in synovial fluid of patients with periprosthetic joint infection

Jia‐Wei,

Jing,

et al. 2023

Biomedical Chromatography

View full text Add to dashboard Cite

Periprosthetic joint infection (PJI) is a catastrophic complication following joint replacement surgery. One potential treatment approach for PJI could be the combination of one‐stage revision and intra‐articular infusion of antibiotics. Meropenem is one of the commonly used intra‐articular antibiotics in our institution. Determining the concentration of meropenem in the joint cavity could be crucial for optimizing its local application, effectively eradicating biofilm infection, and improving PJI treatment outcomes. In this study, we developed a simple, precise, and accurate method of two‐dimensional liquid chromatography (2D‐LC) for determining the concentration of meropenem in human synovial fluid. The method was then validated based on the guidelines of the Food and Drug Administration and the Chinese Pharmacopoeia. Meropenem showed good linearity in the range of 0.31–25.01 μg/mL (r ≥ .999). Selectivity, intra‐day and inter‐day precision and accuracy, extraction recovery, and stability validation results were all within the acceptance range. This method has been successfully applied to the determination of synovial fluid samples from PJI patients, providing a useful detection method for meropenem therapeutic drug monitoring (TDM) in PJI patients.

show abstract

Variation in Target Attainment of Beta‐Lactam Antibiotic Dosing Between International Pediatric Formularies

Gastine

Hsia

Clements

et al. 2021

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. Beta‐lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta‐lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections—pneumonia, sepsis, and meningitis—pharmacokinetic models were identified for common for beta‐lactam antibiotics. Real‐world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future.

show abstract

Too much of a good thing: a retrospective study of β-lactam concentration–toxicity relationships

Cited by 206 publications

References 34 publications

A Monte Carlo Simulation Approach for Beta‐Lactam Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

A Monte Carlo Simulation Approach for Beta‐Lactam Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

Two‐dimensional liquid chromatography measurement of meropenem concentration in synovial fluid of patients with periprosthetic joint infection

Variation in Target Attainment of Beta‐Lactam Antibiotic Dosing Between International Pediatric Formularies

Contact Info

Product

Resources

About