Clinical pharmacokinetics of meropenem in pancreatic juice and site-specific pharmacodynamic target attainment against Gram-negative bacteria: Dosing considerations

Pancreatology ◽  
2014 ◽  
Vol 14 (2) ◽  
pp. 95-99 ◽  
Author(s):  
Naru Kondo ◽  
Kazuro Ikawa ◽  
Yoshiaki Murakami ◽  
Kenichiro Uemura ◽  
Takeshi Sudo ◽  
...  
Keyword(s):  
Pancreatic Juice ◽  
Gram Negative Bacteria ◽  
Target Attainment ◽  
Clinical Pharmacokinetics ◽  
Site Specific ◽  
Gram Negative

scholarly journals Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Amol T. Kothekar ◽  
Jigeeshu Vasishtha Divatia ◽  
Sheila Nainan Myatra ◽  
Anand Patil ◽  
Manjunath Nookala Krishnamurthy ◽  
...  
Keyword(s):  
Septic Shock ◽  
Severe Sepsis ◽  
Modeling And Simulation ◽  
Empirical Therapy ◽  
Gram Negative Bacteria ◽  
Clinical Pharmacokinetics ◽  
Gram Negative ◽  
Arterial Blood ◽  
Days Of Therapy ◽  
Extended Infusion

Abstract Background Optimal anti-bacterial activity of meropenem requires maintenance of its plasma concentration (Cp) above the minimum inhibitory concentration (MIC) of the pathogen for at least 40% of the dosing interval (fT > MIC > 40). We aimed to determine whether a 3-h extended infusion (EI) of meropenem achieves fT > MIC > 40 on the first and third days of therapy in patients with severe sepsis or septic shock. We also simulated the performance of the EI with respect to other pharmacokinetic (PK) targets such as fT > 4 × MIC > 40, fT > MIC = 100, and fT > 4 × MIC = 100. Methods Arterial blood samples of 25 adults with severe sepsis or septic shock receiving meropenem 1000 mg as a 3-h EI eight hourly (Q8H) were obtained at various intervals during and after the first and seventh doses. Plasma meropenem concentrations were determined using a reverse-phase high-performance liquid chromatography assay, followed by modeling and simulation of PK data. European Committee on Antimicrobial Susceptibility Testing (EUCAST) definitions of MIC breakpoints for sensitive and resistant Gram-negative bacteria were used. Results A 3-h EI of meropenem 1000 mg Q8H achieved fT > 2 µg/mL > 40 on the first and third days, providing activity against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. However, it failed to achieve fT > 4 µg/mL > 40 to provide activity against strains susceptible to increased exposure in 33.3 and 39.1% patients on the first and the third days, respectively. Modeling and simulation showed that a bolus dose of 500 mg followed by 3-h EI of meropenem 1500 mg Q8H will achieve this target. A bolus of 500 mg followed by an infusion of 2000 mg would be required to achieve fT > 8 µg > 40. Targets of fT > 4 µg/mL = 100 and fT > 8 µg/mL = 100 may be achievable in two-thirds of patients by increasing the frequency of dosing to six hourly (Q6H). Conclusions In patients with severe sepsis or septic shock, EI of 1000 mg of meropenem over 3 h administered Q8H is inadequate to provide activity (fT > 4 µg/mL > 40) against strains susceptible to increased exposure, which requires a bolus of 500 mg followed by EI of 1500 mg Q8H. While fT > 8 µg/mL > 40 require escalation of EI dose, fT > 4 µg/mL = 100 and fT > 8 µg/mL = 100 require escalation of both EI dose and frequency.

scholarly journals Construction of p16Slux, a Novel Vector for Improved Bioluminescent Labeling of Gram-Negative Bacteria

2007 ◽  
Vol 73 (21) ◽  
pp. 7092-7095 ◽  
Author(s):  
Christian U. Riedel ◽  
Pat G. Casey ◽  
Heidi Mulcahy ◽  
Fergal O'Gara ◽  
Cormac G. M. Gahan ◽  
...  
Keyword(s):  
Bacterial Chromosome ◽  
Gram Negative Bacteria ◽  
Site Specific ◽  
Gram Negative ◽  
Site Specific Integration ◽  
Murine Infections

ABSTRACT A novel vector has been constructed for the constitutive luminescent tagging of gram-negative bacteria by site-specific integration into the 16S locus of the bacterial chromosome. A number of gram-negative pathogens were successfully tagged using this vector, and the system was validated during murine infections of living animals.

scholarly journals Formation of a β-barrel membrane protein is catalyzed by the interior surface of the assembly machine protein BamA

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
James Lee ◽  
David Tomasek ◽  
Thiago MA Santos ◽  
Mary D May ◽  
Ina Meuskens ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Molecular Mechanisms ◽  
Gram Negative Bacteria ◽  
Site Specific ◽  
Gram Negative ◽  
Interior Surface ◽  
Essential Component ◽  
Bam Complex ◽  
Β Sheet

The β-barrel assembly machine (Bam) complex in Gram-negative bacteria and its counterparts in mitochondria and chloroplasts fold and insert outer membrane β-barrel proteins. BamA, an essential component of the complex, is itself a β-barrel and is proposed to play a central role in assembling other barrel substrates. Here, we map the path of substrate insertion by the Bam complex using site-specific crosslinking to understand the molecular mechanisms that control β-barrel folding and release. We find that the C-terminal strand of the substrate is stably held by BamA and that the N-terminal strands of the substrate are assembled inside the BamA β-barrel. Importantly, we identify contacts between the assembling β-sheet and the BamA interior surface that determine the rate of substrate folding. Our results support a model in which the interior wall of BamA acts as a chaperone to catalyze β-barrel assembly.

Clinical pharmacokinetics of flomoxef in prostate tissue and dosing considerations for prostatitis based on site-specific pharmacodynamic target attainment

2020 ◽  
Vol 26 (2) ◽  
pp. 236-241
Author(s):  
Kogenta Nakamura ◽  
Kazuro Ikawa ◽  
Genya Nishikawa ◽  
Ikuo Kobayashi ◽  
Motoi Tobiume ◽  
...  
Keyword(s):  
Prostate Tissue ◽  
Target Attainment ◽  
Clinical Pharmacokinetics ◽  
Site Specific

scholarly journals Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment

2011 ◽  
Vol 55 (12) ◽  
pp. 5609-5615 ◽  
Author(s):  
Kazuro Ikawa ◽  
Akira Nakashima ◽  
Norifumi Morikawa ◽  
Kayo Ikeda ◽  
Yoshiaki Murakami ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Drug Concentration ◽  
Venous Blood ◽  
Target Attainment ◽  
Time Curve ◽  
Clinical Pharmacokinetics ◽  
Site Specific ◽  
Content Type ◽  
Drug Concentrations ◽  
Tract Infections

ABSTRACTThe present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (n= 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (≥90%) againstEscherichia coli,Klebsiella pneumoniae, andEnterobacter cloacaeisolates. However, againstPseudomonas aeruginosaisolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was ≥90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.

scholarly journals Pharmacokinetic/pharmacodynamic target attainment of intravenous β-lactam regimens against Gram-negative bacteria isolated in a Brazilian teaching hospital

2015 ◽  
Vol 48 (5) ◽  
pp. 539-545 ◽  
Author(s):  
Guilherme Henrique Furtado ◽  
Leandro Cardinal ◽  
Rodrigo Spineli Macedo ◽  
Juliana Oliveira Silva ◽  
Eduardo Alexandrino Medeiros ◽  
...  
Keyword(s):  
Teaching Hospital ◽  
Gram Negative Bacteria ◽  
Target Attainment ◽  
Gram Negative

scholarly journals Population Pharmacokinetics and Pharmacodynamic Target Attainment of Meropenem in Critically Ill Young Children

2017 ◽  
Vol 22 (4) ◽  
pp. 276-285 ◽  
Author(s):  
Jeffrey J. Cies ◽  
Wayne S. Moore ◽  
Adela Enache ◽  
Arun Chopra
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Children ◽  
Gram Negative Bacteria ◽  
Target Attainment ◽  
Gram Negative ◽  
Patients Âgés ◽  
Dosage Regimens ◽  
Optimal Probability ◽  
Gram Negative Organisms

OBJECTIVE This study aims to describe the population pharmacokinetics and pharmacodynamic target attainment of meropenem in critically ill children. METHODS The study involved a retrospective medical record review from a 189-bed, freestanding children's tertiary care teaching hospital of patients ages 1 to 9 years who received meropenem with concurrent therapeutic drug monitoring. RESULTS There were 9 patients ages 1 to 9 years (mean age, 3.1 ± 2.9 years) with a mean weight of 17.1 ± 11.9 kg who met the inclusion/exclusion criteria and were included in the pharmacokinetic analysis. Meropenem concentrations were best described by a 2-compartment model with first-order elimination, with an R2 and bias of 0.91 and 13.2 mg/L, respectively, for the observed versus population predicted concentrations, and an R2, bias, and imprecision of 1, 0.0675, and 1 mg/L, respectively, for the observed versus individual predicted concentrations. The mean total body drug clearance for the population was 6.99 ± 2.5 mL/min/kg, and Vc was 0.57 ± 0.47 L/kg. The calculated population estimate for the total volume of distribution was 0.78 ± 0.73 L/kg. Standard 0.5-hour meropenem infusions did not provide for appropriate pharmacodynamic exposures of 40% free time > minimum inhibitory concentration (40% fT > MIC) for Gram-negative organisms with susceptible MICs. Dosage regimens employing prolonged and continuous infusion regimens did provide appropriate pharmacodynamic exposures of 40% fT > MIC for Gram-negative organisms up to the break point for Pseudomonas aeruginosa of 4 mg/L. CONCLUSION These data suggest the reference dosage regimens for meropenem (20–40 mg/kg per dose every 8 hours) do not meet an appropriate pharmacodynamic target attainment in critically ill children ages 1 to 9 years. Based on these data, only the 3- to 4-hour prolonged infusion and 24-hour continuous infusion regimens were able to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 40% fT > MIC. Dosage regimens of 120 and 160 mg/kg/day as continuous infusion regimens may be necessary to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 80% fT > MIC. Based on these findings, confirmation with a larger, prospective investigation in critically ill children is warranted.

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