Considerations for Higher Doses of Daptomycin in Critically Ill Patients With Methicillin-Resistant Staphylococcus aureus Bacteremia

Falcone, Marco; Russo, Alessandro; Venditti, Mario; Novelli, Andréa; Pai, Manjunath P.

doi:10.1093/cid/cit582

Cited by 123 publications

(102 citation statements)

References 18 publications

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“…Our group has demonstrated through the use of TDM that the current daptomycin dosing recommendations on body weight and kidney function are no better than fixed dosing at achieving the AUC target for effect in critically ill patients (8). Specifically, use of 750 mg/day in patients with sepsis and 500 mg/day in patients not in sepsis is expected to achieve PTA comparable to those …”

Section: Discussionmentioning

confidence: 99%

“…The raw concentration-time data from a previous study evaluating the multiple-dose plasma PK of daptomycin at 6 to 8 mg/kg in 50 patients were used (8). The AUC 24 (reference standard) was calculated using the aforementioned maximum a priori Bayesian probability procedure in ADAPT 5 by integration (14).…”

Section: Methodsmentioning

confidence: 99%

“…More recently, experts have suggested that higher daptomycin dosages, 8 to 10 mg/kg/day, should be considered to treat MRSA BSI (7). Our group has shown that the use of daptomycin at 6 to 8 mg/kg does not reliably optimize the pharmacokinetic-pharmacodynamic (PK-PD) profile of this agent in critically ill patients (8). Use of an empirical average fixed dose of 750 mg is forecast to achieve comparable probability of target attainment (PTA) as 10 mg/kg for effect but with a lower probability for trough concentrations associated with toxicity (8).…”

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confidence: 99%

“…Our group has shown that the use of daptomycin at 6 to 8 mg/kg does not reliably optimize the pharmacokinetic-pharmacodynamic (PK-PD) profile of this agent in critically ill patients (8). Use of an empirical average fixed dose of 750 mg is forecast to achieve comparable probability of target attainment (PTA) as 10 mg/kg for effect but with a lower probability for trough concentrations associated with toxicity (8). However, a fundamental limitation of any population-predicted average dose is that it cannot guarantee with absolute certainty that optimal PK-PD target attainment is achieved on an individual level.…”

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Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example

Pai

Russo

Novelli

et al. 2014

Antimicrob Agents Chemother

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The effects of several antimicrobial agents are predicted by the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). Peak (C p ) and trough (C t ) concentrations are often measured clinically as surrogates of AUC because actual computation of AUC from 1 or 2 samples requires sophisticated mathematical methods. Given that the effects of daptomycin are predicted by AUC/MIC, our objective was to compare simple equation calculated AUC based on C p and C t to model integrated AUC. A standard population pharmacokinetic model was used to simulate 5,000 daptomycin concentration-time profiles after 5 doses of 6 mg/kg of body weight/day (0.5-h infusions). The AUC for the 24-h period was computed by integration and by equations with 110 C p -C t combination pairs. The C p time points were in 15-min increments between 0.5 h and 3 h and C t in 15-min increments within an hour of the end of the dosing interval for each dose. The precision and bias of the calculated AUC relative to the integrated AUC were determined to identify C p -C t pairs associated with the lowest bias and highest precision. The equations were further validated using two daptomycin concentration-time data sets from healthy volunteers and critically ill patients. The precision and bias of calculated AUC were based primarily on C p , and use of a daptomycin C p 1.5 h to 3 h from the start of infusion was associated with a bias of <10% and an R 2 of >0.95. Data from the healthy volunteers and critically ill patients also demonstrated declining bias with use of C p >1.5 h from the start of infusion with relatively good precision. Simplified equations using a daptomycin C p approximately 2 h from the start of infusion and a C t within an hour of the end of the dosing interval should yield precise and unbiased estimates of daptomycin AUC.

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confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example

Pai

Russo

Novelli

et al. 2014

Antimicrob Agents Chemother

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“…In MRSA with vancomycin MIC >1 mg/l, the vancomycin dose which is needed to achieve an AUC/MIC >400, a ratio associated with a favorable outcome, is in the range associated with nephrotoxicity. Daptomycin, proposed as an alternative, shows marked PK variability due to high clearance; in critically ill patients, doses of 8-10 mg/kg/day are necessary at therapy onset [14].…”

Section: A Plea For Pk-oriented De-escalation Through Antimicrobial Smentioning

confidence: 99%

Focus on optimization of early antimicrobial therapy in ICU-acquired infections

Timsit

Paiva²,

Bassetti

2016

Intensive Care Med

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Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation

Olney,

Howard,

Burgess

2024

The Journal of Clinical Pharma

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Daptomycin is an antibiotic with Gram‐positive activity, including methicillin‐resistant Staphylococcus aureus, for which optimal pediatric dosing is unknown. This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0‐24:MIC) ≥666 was used to determine the PTA for efficacy (PTAE). Minimum concentration (Cmin) ≥24.3 mg/L determined the PTA for toxicity (PTAT). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTAE and ≤5% PTAT. Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTAE in children 13‐24 months, 39.5% PTAE in children 2‐6 years, 30.1% PTAE in children 7‐11 years, and 50.1% PTAE in adolescents ≥12 years. To achieve the combined efficacy and safety target, doses of 18‐24 mg/kg in children 3‐12 months, 20‐24 mg/kg in children 13‐24 months, 19‐24 mg/kg in children 2‐6 years, 17‐19 mg/kg in children 7‐11 years, and 10‐14 mg/kg in adolescents ≥12 years are necessary. Package label dosing resulted in suboptimal exposure for the majority of pediatric patients in all age groups evaluated. If targeting validated efficacy and safety endpoints, daily daptomycin doses of at least 20 mg/kg in children ≤6 years, 17 mg/kg in children 7‐11 years, and 10 mg/kg in adolescents ≥12 years are necessary. Clinical studies evaluating these higher doses are needed.

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Considerations for Higher Doses of Daptomycin in Critically Ill Patients With Methicillin-Resistant Staphylococcus aureus Bacteremia

Abstract: A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients.

Cited by 123 publications

References 18 publications

Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example

Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example

Focus on optimization of early antimicrobial therapy in ICU-acquired infections

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation

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