Prospective Determination of Plasma Imipenem Concentrations in Critically Ill Children

Giannoni, Éric; Moreillon, Philippe; Cotting, Jacques; Moessinger, Adrien C.; Billé, Jacques; Décosterd, L.A.; Zanetti, Giorgio; Majcherczyk, Paul; Bugnon, Denis

doi:10.1128/aac.01149-05

Cited by 28 publications

(34 citation statements)

References 22 publications

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“…Similar observations were also made with imipenem in adult patients [2,3], suggesting that drug adjustment algorithms used at the bedside might not be always accurate in unstable ICU patients, and that drug monitoring should be used more often [1]. …”

Section: Introductionmentioning

confidence: 61%

Prospective monitoring of cefepime in intensive care unit adult patients

et al. 2010

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IntroductionCefepime has been associated with a greater risk of mortality than other beta-lactams in patients treated for severe sepsis. Hypotheses for this failure include possible hidden side-effects (for example, neurological) or inappropriate pharmacokinetic/pharmacodynamic (PK/PD) parameters for bacteria with cefepime minimal inhibitory concentrations (MIC) at the highest limits of susceptibility (8 mg/l) or intermediate-resistance (16 mg/l) for pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. We examined these issues in a prospective non-interventional study of 21 consecutive intensive care unit (ICU) adult patients treated with cefepime for nosocomial pneumonia.MethodsPatients (median age 55.1 years, range 21.8 to 81.2) received intravenous cefepime at 2 g every 12 hours for creatinine clearance (CLCr) ≥ 50 ml/min, and 2 g every 24 hours or 36 hours for CLCr < 50 ml/minute. Cefepime plasma concentrations were determined at several time-points before and after drug administration by high-pressure liquid chromatography. PK/PD parameters were computed by standard non-compartmental analysis.ResultsSeventeen first-doses and 11 steady states (that is, four to six days after the first dose) were measured. Plasma levels varied greatly between individuals, from two- to three-fold at peak-concentrations to up to 40-fold at trough-concentrations. Nineteen out of 21 (90%) patients had PK/PD parameters comparable to literature values. Twenty-one of 21 (100%) patients had appropriate duration of cefepime concentrations above the MIC (T>MIC ≥ 50%) for the pathogens recovered in this study (MIC ≤ 4 mg/l), but only 45 to 65% of them had appropriate coverage for potential pathogens with cefepime MIC ≥ 8 mg/l. Moreover, 2/21 (10%) patients with renal impairment (CLCr < 30 ml/minute) demonstrated accumulation of cefepime in the plasma (trough concentrations of 20 to 30 mg/l) in spite of dosage adjustment. Both had symptoms compatible with non-convulsive epilepsy (confusion and muscle jerks) that were not attributed to cefepime-toxicity until plasma levels were disclosed to the caretakers and symptoms resolved promptly after drug arrest.ConclusionsThese empirical results confirm the suspected risks of hidden side-effects and inappropriate PK/PD parameters (for pathogens with upper-limit MICs) in a population of ICU adult patients. Moreover, it identifies a safety and efficacy window for cefepime doses of 2 g every 12 hours in patients with a CLCr ≥ 50 ml/minute infected by pathogens with cefepime MICs ≤ 4 mg/l. On the other hand, prompt monitoring of cefepime plasma levels should be considered in case of lower CLCr or greater MICs.

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Section: Introductionmentioning

confidence: 61%

Prospective monitoring of cefepime in intensive care unit adult patients

et al. 2010

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“…Since January 2010, TDM has been available 4 days per week. TDM measurement: Prior to 2010, plasma concentrations of imipenem/cilastatin and meropenem were measured separately by high-performance liquid chromatography coupled with ultraviolet detection, using adaptations of previously published methods [31,32]. Since 2010, imipenem/cilastatin and meropenem have been analyzed simultaneously using a multiplex assay by ultra-performance liquid chromatography coupled with tandem mass spectrometry [24,25].…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Impact of the introduction of real-time therapeutic drug monitoring on empirical doses of carbapenems in critically ill burn patients

Fournier

Eggimann

Pagani

et al. 2015

Burns

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“…One study reported that the PK of imipenem in critically ill children (median [range] age of 0.8 years [0.02 to 12.9]) was highly variable with unpredictable plasma concentrations observed in several children [127]. The mean (± SD) steady-state half-life, CL and V D were 1.35 hours (± 0.38), 0.34 L/h/kg (± 0.14), and 0.46 L/kg (± 0.25), respectively [127]. These values were similar to the values reported in other non-critically ill children and healthy adults [125,126].…”

Section: Pharmacokinetic Studies In Critically Ill Childrenmentioning

confidence: 99%

“…Nonetheless, some physiological parameters during critical illness altered imipenem PK, including blood pressure, creatinine clearance, and bicarbonate and lactate levels. For instance, elimination rates were reduced in patients with high lactate and low bicarbonate levels, possibly due to poor perfusion to the kidneys, and elimination rates correlated with creatinine clearance [127]. …”

Section: Pharmacokinetic Studies In Critically Ill Childrenmentioning

confidence: 99%

Clinical Pharmacology Studies in Critically Ill Children

et al. 2016

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Developmental and physiological changes in children contribute to variation in drug disposition with age. Additionally, critically ill children suffer from various life-threatening conditions that can lead to pathophysiological alterations that further affect pharmacokinetics (PK). Some factors that can alter PK in this patient population include variability in tissue distribution caused by protein binding changes and fluid shifts, altered drug elimination due to organ dysfunction, and use of medical interventions that can affect drug disposition (e.g., extracorporeal membrane oxygenation and continuous renal replacement therapy). Performing clinical studies in critically ill children is challenging because there is large inter-subject variability in the severity and time course of organ dysfunction; some critical illnesses are rare, which can affect subject enrollment; and critically ill children usually have multiple organ failure, necessitating careful selection of a study design. As a result, drug dosing in critically ill children is often based on extrapolations from adults or non-critically ill children. Dedicated clinical studies in critically ill children are urgently needed to identify optimal dosing of drugs in this population. This review will summarize the effect of critical illness on pediatric PK, the challenges associated with performing studies in this vulnerable subpopulation, and the clinical PK studies performed to date for commonly used drugs.

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Prospective Determination of Plasma Imipenem Concentrations in Critically Ill Children

Cited by 28 publications

References 22 publications

Prospective monitoring of cefepime in intensive care unit adult patients

Prospective monitoring of cefepime in intensive care unit adult patients

Impact of the introduction of real-time therapeutic drug monitoring on empirical doses of carbapenems in critically ill burn patients

Clinical Pharmacology Studies in Critically Ill Children

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