Pharmacokinetics of High-Dose Meropenem in Adult Cystic Fibrosis Patients

Bui, Khanh Q.; Ambrose, Paul G.; Nicolau, David P.; Lapin, Craig; Nightingale, Charles H.; Quintiliani, Richard

doi:10.1159/000063216

Cited by 28 publications

(24 citation statements)

References 13 publications

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“…Thus, our conclusions are not specific to any one particular CVVH methodology; instead, the results are generalizable to CVVH apparatuses utilizing high-flux membranes at rates consistent with the studies we based our pharmacokinetics on. However, consistent with acute renal failure, the mean total body clearance of meropenem in these CVVH patients (6.24 l/h) was lower than that reported in studies with healthy volunteers (10.5–17.5 l/h) and other patients not receiving CVVH (9.3 l/h) [19, 20, 21, 22]. The total body clearance was greater than the ultrafiltration rates in any of the studies we utilized, suggesting that many of these patients additionally had some minimal contributory urine output.…”

Section: Discussionsupporting

confidence: 67%

“…Nevertheless, the reduced clearance simulated would result in accumulation of the drug and would therefore require reduced dosages or extended dosing intervals. However, the mean volume of distribution in these patients was 29.05 liters and higher than that reported in healthy volunteers and many other patient populations [19, 20, 21, 22]. Increases in volume of distribution require larger doses or shorter dosing intervals to keep drug concentrations above the MIC of the pathogen.…”

Section: Discussionmentioning

confidence: 54%

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Derivation of Meropenem Dosage in Patients Receiving Continuous Veno-Venous Hemofiltration Based on Pharmacodynamic Target Attainment

Kuti

Nicolau

2005

Chemotherapy

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Background: Dosage recommendations for antibiotics in patients receiving continuous veno-venous hemofiltration (CVVH) should be based on pharmacodynamic requirements. For meropenem, this would be achieving appropriate time above the minimum inhibitory concentration (T > MIC). We employed Monte Carlo simulation to calculate the bactericidal target attainment for various dosing regimens of meropenem against Pseudomonas aeruginosa and Acinetobacter species. Methods: Target attainment at 40% T > MIC was calculated for 5,000 simulated subjects receiving meropenem 1,000 mg every 12 and 8 h, and 500 mg every 12, 8 and 6 h. Pharmacokinetics were extrapolated from primary literature sources utilizing similar methods of CVVH. MIC data for P. aeruginosa and Acinetobacter species were derived from the US 2003 MYSTIC study. Target attainment at the breakpoint of 4 µg/ml was also calculated. Results: Only regimens of 1,000 mg every 8 h and 500 mg every 6 h essentially achieve 100% target attainment at the breakpoint. However, due to higher peak concentrations, 1,000 mg every 8 h is able to attain improved target attainment against more resistant populations of P. aeruginosa and Acinetobacter species, thus providing the greatest probability of bactericidal exposure. Conclusion: Meropenem 1,000 mg every 8 h optimizes the pharmacodynamic profile in patients undergoing CVVH. Lower doses or increased dosing intervals should not be advocated for inpatients receiving this renal replacement technique.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 54%

Derivation of Meropenem Dosage in Patients Receiving Continuous Veno-Venous Hemofiltration Based on Pharmacodynamic Target Attainment

Kuti

Nicolau

2005

Chemotherapy

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“…Half of these patients are admitted more than once per year, and a quarter are admitted three or more times each year (24). It is instructive to estimate the respective total amounts (quantities) of CAZ and P to which patients could be exposed annually on the basis of three courses of 15 days of treatment per year.…”

Section: Discussionmentioning

confidence: 99%

How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

Bourget¹,

Amin

Dupont³

et al. 2014

Antimicrob Agents Chemother

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Ceftazidime is particularly efficient against Pseudomonas aeruginosa in cystic fibrosis patients. Thus, the spontaneous production of pyridine, which is a toxic product, raises some concern. Our aim was to examine the kinetics of degradation of ceftazidime in portable infusion pumps either at 4°C, 22°C, or 33°C and to propose some recommendations in order to reduce the pyridine exposure. Two administration models were studied in vitro. In model 1, we administered 12 g of ceftazidime infused over 23 h (once-daily infusion) compared to 6 g infused over 11.5 h in model 2 (twice-daily regimen). Samples were collected at 0 h and then every 4 and 2 h after the shaping of portable infusion pumps in models 1 and 2, respectively. Both ceftazidime and pyridine were analyzed using an ultraviolet high-performance liquid chromatograph. Production of pyridine is highly depending on the temperature. The in situ production of pyridine per day of treatment decreases at a ratio close to 1/6 and 1/3 between 33°C and 4°C in models 1 and 2, respectively. Regardless of the conditions, the production of pyridine is significantly lower in model 2, whereas the total delivery amount of ceftazidime is significantly higher at 4°C and 33°C compared to that in model 1. According to a the precautionary principle, these findings lead to three major recommendations: (i) exposing a solution of ceftazidime to over 22°C should be strictly avoided, (ii) a divided dose of 6 g over 11.5 h instead of a once-daily administration is preferred, and (iii) infusion should be administered immediately after reconstitution.

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“…[1][2][3][4][5][6][7] As demonstrated, meropenem observes linear pharmacokinetics in the dose range from 0.25 to 2 g over a 0.5-hour infusion. Because of its broad-spectrum activity against both Gram-positive bacteria and Gramnegative bacteria, including Pseudomonas aeruginosa and Acinetobacter species, it is also used for the treatment of other serious nosocomial infections, such as pneumonia and bacteremia, that are often caused by these multidrug-resistant pathogens.…”

mentioning

confidence: 82%

Population Pharmacokinetic Analysis and Dosing Regimen Optimization of Meropenem in Adult Patients

Kuti

Nightingale

et al. 2006

The Journal of Clinical Pharma

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151

133

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The objectives of this study were to develop a meropenem population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria. We gathered concentration data from 79 patients (ages 18-93 years) who received meropenem 0.5, 1, or 2 g over 0.5- or 3-hour infusion every 8 hours. Meropenem population pharmacokinetic analysis was performed using the NONMEM program. A 2-compartment model fit the data best. Creatinine clearance, age, and body weight were the most significant covariates to affect meropenem pharmacokinetics. Monte Carlo simulation was applied to mimic the concentration-time profiles while 1 g meropenem was administrated via infusion over 0.5, 1, 2, and 3 hours. The 3-hour prolonged infusion improved the likelihood of obtaining both bacteriostatic and bactericidal exposures most notably at the current susceptibility breakpoints.

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Pharmacokinetics of High-Dose Meropenem in Adult Cystic Fibrosis Patients

Cited by 28 publications

References 13 publications

Derivation of Meropenem Dosage in Patients Receiving Continuous Veno-Venous Hemofiltration Based on Pharmacodynamic Target Attainment

Derivation of Meropenem Dosage in Patients Receiving Continuous Veno-Venous Hemofiltration Based on Pharmacodynamic Target Attainment

How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

Population Pharmacokinetic Analysis and Dosing Regimen Optimization of Meropenem in Adult Patients

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