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Kayo Ikeda - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment
    Antimicrobial agents and chemotherapy, 2011
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hiroki Ohge, Hartmut Derendorf, Akira Nakashima, Yoshiaki Murakami, Taijiro Sueda
    Abstract:

    The 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%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, 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.

  • Penetrability of Intravenous Biapenem Into the Peritoneal Fluid of Laparotomy Patients and the Peritoneal Pharmacodynamics Against Gram-negative Bacteria
    2009
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Mitsuru Sakashita, Hiroki Ohge, Taijiro Sueda
    Abstract:

    This study examined the penetrability of Biapenem into the peritoneal fluid (PF) of lapa rotomy patients and assessed the peritoneal pharmacodynamics against common gramnegative bacteria that cause intra-abdominal infections. Biapenem (300 mg) was administered by 0.5-h infusion to 10 patients before the laparotomy. The drug concentrations in both plasma and PF were determined, analyzed pharmacokinetically, and used for a stochastic simulation with the minimum inhibitory concentration (MIC) distribution data against clinical isolates. Intravenous Biapenem penetrated well into PF, with an area under the drug concentration–time

  • Pharmacodynamic evaluation of Biapenem in peritoneal fluid using population pharmacokinetic modelling and Monte Carlo simulation.
    International journal of antimicrobial agents, 2008
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hiroki Ohge, Taijiro Sueda
    Abstract:

    Abstract This study evaluated the pharmacodynamics of Biapenem in peritoneal fluid (PF). Biapenem (300 or 600 mg) was administered via a 0.5-h infusion to 19 patients before abdominal surgery. Venous blood and PF samples were obtained after 0.5, 1, 2, 3, 4, 5 and 6 h. Drug concentration data (108 plasma samples and 105 PF samples) were analysed using population pharmacokinetic modelling. A three-compartment model fits the data, with creatinine clearance (CL Cr ) as the most significant covariate: CL (L/h) = 0.036 × CL Cr  + 4.88, V1 (L) = 6.95, Q2 (L/h) = 2.05, V2 (L) = 3.47, Q3 (L/h) = 13.7 and V3 (L) = 5.91, where CL is the clearance, Q2 and Q3 are the intercompartmental clearances, and V1, V2 and V3 are the volumes of distribution of the central, peripheral and peritoneal compartments, respectively. A Monte Carlo simulation using the pharmacokinetic model showed the probabilities of attaining the bactericidal exposure target (30% of the time above the minimum inhibitory concentration ( T  > MIC)) in PF were greater than or equal to those in plasma. In the cases of CL Cr  = 90 and 60 mL/min, the site-specific pharmacodynamic-derived breakpoints (the highest MIC values at which the probabilities of target attainment in PF were ≥90%) were 2 μg/mL for 300 mg every 12 h, 4 μg/mL for Biapenem 300 mg every 8 h (q8h) and 8 μg/mL for 600 mg q8h. Thus, these results should support the clinical use of Biapenem as a treatment for intra-abdominal infections and facilitate the design of the dosing regimen.

  • Pharmacokinetic modeling and dosage adaptation of Biapenem in Japanese patients during continuous venovenous hemodiafiltration
    Journal of Infection and Chemotherapy, 2008
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hidemichi Suyama
    Abstract:

    The present study examined the pharmacokinetics of Biapenem during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamic exposure, based on a pharmacokinetic model, to consider Biapenem dosage adaptation in CVVHDF. Biapenem (300 mg) was administered by 2-h infusion to seven critically ill patients receiving CVVHDF. The flow rates were 60 ml/min for blood, 800 ml/h for filtrate, and 600 ml/h for dialysate. The drug concentrations in plasma and filtratedialysate were determined by high-performance liquid chromatography and analyzed pharmacokinetically. The sieving coefficient was 0.92 ± 0.06 (mean ± SD). The simulation curves, using a multicompartment model, were well fitted to the measurements in plasma and filtrate-dialysate. The clearance by CVVHDF and the clearance by non-CVVHDF routes were 1.29 ± 0.08 and 6.14 ± 1.89 l/h, respectively. The multicompartment model was used to assess the pharmacodynamic exposure (time above the minimum inhibitory concentration of 4 μg/ml) in plasma. When the total daily dose was 600 mg, the duration of time was greater at 300 mg every 12 h than at 600 mg every 24 h. The minimum dosages needed to achieve more than 30% of the dosing interval at filtrate-dialysate flow rates of 1.4, 2.8, and 5.6 l/h were 300 mg every 12 h, 600 mg every 12 h, and 600 mg every 12 h, respectively. These results suggested that low doses or increased dosing intervals should be avoided in patients receiving this renal replacement technique. Information on pharmacodynamic exposure obtained from this model may help us to determine the appropriate Biapenem dosage for CVVHDF. Moreover, our pharmacokinetic model may be useful for further pharmacokinetic studies of Biapenem.

  • Population pharmacokinetics and pharmacodynamics of Biapenem in paediatric patients
    Journal of clinical pharmacy and therapeutics, 2008
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Mizuka Miki, Shin-ichiro Nishimura, Masao Kobayashi
    Abstract:

    Summary Objective:  To develop a population pharmacokinetic model for Biapenem in paediatric patients and to use the parameter estimates to assess pharmacodynamic exposure of common bacterial populations. Methods:  Biapenem plasma concentrations (n = 125) from 25 paediatric patients were analysed using nonmem. The parameter estimates were used in a Monte Carlo simulation to predict the exposure time during which the drug concentration remains above the minimum inhibitory concentration. Results:  A two-compartment model fitted the data, and creatinine clearance (CLcr) and total body weight (TBW) were the most significant covariates. The final model was CL (L/h) = 0·0458 × CLcr, Vc (L) = 0·162 × TBW, Q (L/h) = 2·05, Vp (L) = 1·73, where CL is the clearance, Vc is the volume of distribution of the central compartment, Q is the intercompartmental clearance and Vp is the volume of distribution of the peripheral compartment. Biapenem regimens of 5 mg/kg q8h and 10 mg/kg q8h provided sufficient pharmacodynamic exposures to Pseudomonas aeruginosa and Streptococcus pneumoniae in most typical patient populations. Conclusion:  These results better define the pharmacokinetics of Biapenem and help in the choice of the appropriate dosage regimens for paediatric.

Kazuro Ikawa - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of the efficacy and safety of Biapenem against pneumonia in the elderly and a study on its pharmacokinetics
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 2012
    Co-Authors: Fumi Karino, Naoko Deguchi, Hibiki Kanda, Miki Ohe, Keiichi Kondo, Mitsuhiro Tada, Takashige Kuraki, Nobuhiro Nishimura, Hidehiko Moriyama, Kazuro Ikawa
    Abstract:

    Although Biapenem is used in the treatment of pneumonia, the clinical data on elderly patients are yet insufficient. Therefore, the purpose of this study was evaluating the efficacy and safety of Biapenem against pneumonia in the elderly and its pharmacokinetics. The subjects were patients 65 years of age or older with pneumonia. Biapenem (300 mg) was administered once to three times per day. For some cases, the drug concentrations in plasma were measured chronologically. The clinical efficacy was evaluated in reference to the improvement in subjective symptoms and objective opinion. The primary outcome was efficacy rate at the end of treatment. Biapenem was effective in 17 of 20 subject cases (85.0 %). Regarding safety, although 4 cases experienced hepatic dysfunction and 1 case had nausea, these effects were not severe in all cases and administration was continued. There was no deterioration of renal function associated with Biapenem. In 13 cases in which the trough value of Biapenem was measured, there were no unacceptable side effects and the trough values were generally low. It is believed that Biapenem (300 mg once to three times a day), even when taken by elderly people, does not accumulate and that the dosage is safe and appropriate. The changes in the predicted concentrations calculated with the pharmacokinetic–pharmacodynamic (PK–PD) software, which is based on previously reported population pharmacokinetic parameters, and those in the measured concentrations approximately matched. It is useful to plan Biapenem administration using the PK–PD software when performing antibiotic chemical treatment.

  • Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment
    Antimicrobial agents and chemotherapy, 2011
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hiroki Ohge, Hartmut Derendorf, Akira Nakashima, Yoshiaki Murakami, Taijiro Sueda
    Abstract:

    The 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%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, 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.

  • Penetrability of Intravenous Biapenem Into the Peritoneal Fluid of Laparotomy Patients and the Peritoneal Pharmacodynamics Against Gram-negative Bacteria
    2009
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Mitsuru Sakashita, Hiroki Ohge, Taijiro Sueda
    Abstract:

    This study examined the penetrability of Biapenem into the peritoneal fluid (PF) of lapa rotomy patients and assessed the peritoneal pharmacodynamics against common gramnegative bacteria that cause intra-abdominal infections. Biapenem (300 mg) was administered by 0.5-h infusion to 10 patients before the laparotomy. The drug concentrations in both plasma and PF were determined, analyzed pharmacokinetically, and used for a stochastic simulation with the minimum inhibitory concentration (MIC) distribution data against clinical isolates. Intravenous Biapenem penetrated well into PF, with an area under the drug concentration–time

  • Pharmacodynamic evaluation of Biapenem in peritoneal fluid using population pharmacokinetic modelling and Monte Carlo simulation.
    International journal of antimicrobial agents, 2008
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hiroki Ohge, Taijiro Sueda
    Abstract:

    Abstract This study evaluated the pharmacodynamics of Biapenem in peritoneal fluid (PF). Biapenem (300 or 600 mg) was administered via a 0.5-h infusion to 19 patients before abdominal surgery. Venous blood and PF samples were obtained after 0.5, 1, 2, 3, 4, 5 and 6 h. Drug concentration data (108 plasma samples and 105 PF samples) were analysed using population pharmacokinetic modelling. A three-compartment model fits the data, with creatinine clearance (CL Cr ) as the most significant covariate: CL (L/h) = 0.036 × CL Cr  + 4.88, V1 (L) = 6.95, Q2 (L/h) = 2.05, V2 (L) = 3.47, Q3 (L/h) = 13.7 and V3 (L) = 5.91, where CL is the clearance, Q2 and Q3 are the intercompartmental clearances, and V1, V2 and V3 are the volumes of distribution of the central, peripheral and peritoneal compartments, respectively. A Monte Carlo simulation using the pharmacokinetic model showed the probabilities of attaining the bactericidal exposure target (30% of the time above the minimum inhibitory concentration ( T  > MIC)) in PF were greater than or equal to those in plasma. In the cases of CL Cr  = 90 and 60 mL/min, the site-specific pharmacodynamic-derived breakpoints (the highest MIC values at which the probabilities of target attainment in PF were ≥90%) were 2 μg/mL for 300 mg every 12 h, 4 μg/mL for Biapenem 300 mg every 8 h (q8h) and 8 μg/mL for 600 mg q8h. Thus, these results should support the clinical use of Biapenem as a treatment for intra-abdominal infections and facilitate the design of the dosing regimen.

  • Pharmacokinetic modeling and dosage adaptation of Biapenem in Japanese patients during continuous venovenous hemodiafiltration
    Journal of Infection and Chemotherapy, 2008
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hidemichi Suyama
    Abstract:

    The present study examined the pharmacokinetics of Biapenem during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamic exposure, based on a pharmacokinetic model, to consider Biapenem dosage adaptation in CVVHDF. Biapenem (300 mg) was administered by 2-h infusion to seven critically ill patients receiving CVVHDF. The flow rates were 60 ml/min for blood, 800 ml/h for filtrate, and 600 ml/h for dialysate. The drug concentrations in plasma and filtratedialysate were determined by high-performance liquid chromatography and analyzed pharmacokinetically. The sieving coefficient was 0.92 ± 0.06 (mean ± SD). The simulation curves, using a multicompartment model, were well fitted to the measurements in plasma and filtrate-dialysate. The clearance by CVVHDF and the clearance by non-CVVHDF routes were 1.29 ± 0.08 and 6.14 ± 1.89 l/h, respectively. The multicompartment model was used to assess the pharmacodynamic exposure (time above the minimum inhibitory concentration of 4 μg/ml) in plasma. When the total daily dose was 600 mg, the duration of time was greater at 300 mg every 12 h than at 600 mg every 24 h. The minimum dosages needed to achieve more than 30% of the dosing interval at filtrate-dialysate flow rates of 1.4, 2.8, and 5.6 l/h were 300 mg every 12 h, 600 mg every 12 h, and 600 mg every 12 h, respectively. These results suggested that low doses or increased dosing intervals should be avoided in patients receiving this renal replacement technique. Information on pharmacodynamic exposure obtained from this model may help us to determine the appropriate Biapenem dosage for CVVHDF. Moreover, our pharmacokinetic model may be useful for further pharmacokinetic studies of Biapenem.

Norifumi Morikawa - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment
    Antimicrobial agents and chemotherapy, 2011
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hiroki Ohge, Hartmut Derendorf, Akira Nakashima, Yoshiaki Murakami, Taijiro Sueda
    Abstract:

    The 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%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, 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.

  • Penetrability of Intravenous Biapenem Into the Peritoneal Fluid of Laparotomy Patients and the Peritoneal Pharmacodynamics Against Gram-negative Bacteria
    2009
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Mitsuru Sakashita, Hiroki Ohge, Taijiro Sueda
    Abstract:

    This study examined the penetrability of Biapenem into the peritoneal fluid (PF) of lapa rotomy patients and assessed the peritoneal pharmacodynamics against common gramnegative bacteria that cause intra-abdominal infections. Biapenem (300 mg) was administered by 0.5-h infusion to 10 patients before the laparotomy. The drug concentrations in both plasma and PF were determined, analyzed pharmacokinetically, and used for a stochastic simulation with the minimum inhibitory concentration (MIC) distribution data against clinical isolates. Intravenous Biapenem penetrated well into PF, with an area under the drug concentration–time

  • Pharmacodynamic evaluation of Biapenem in peritoneal fluid using population pharmacokinetic modelling and Monte Carlo simulation.
    International journal of antimicrobial agents, 2008
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hiroki Ohge, Taijiro Sueda
    Abstract:

    Abstract This study evaluated the pharmacodynamics of Biapenem in peritoneal fluid (PF). Biapenem (300 or 600 mg) was administered via a 0.5-h infusion to 19 patients before abdominal surgery. Venous blood and PF samples were obtained after 0.5, 1, 2, 3, 4, 5 and 6 h. Drug concentration data (108 plasma samples and 105 PF samples) were analysed using population pharmacokinetic modelling. A three-compartment model fits the data, with creatinine clearance (CL Cr ) as the most significant covariate: CL (L/h) = 0.036 × CL Cr  + 4.88, V1 (L) = 6.95, Q2 (L/h) = 2.05, V2 (L) = 3.47, Q3 (L/h) = 13.7 and V3 (L) = 5.91, where CL is the clearance, Q2 and Q3 are the intercompartmental clearances, and V1, V2 and V3 are the volumes of distribution of the central, peripheral and peritoneal compartments, respectively. A Monte Carlo simulation using the pharmacokinetic model showed the probabilities of attaining the bactericidal exposure target (30% of the time above the minimum inhibitory concentration ( T  > MIC)) in PF were greater than or equal to those in plasma. In the cases of CL Cr  = 90 and 60 mL/min, the site-specific pharmacodynamic-derived breakpoints (the highest MIC values at which the probabilities of target attainment in PF were ≥90%) were 2 μg/mL for 300 mg every 12 h, 4 μg/mL for Biapenem 300 mg every 8 h (q8h) and 8 μg/mL for 600 mg q8h. Thus, these results should support the clinical use of Biapenem as a treatment for intra-abdominal infections and facilitate the design of the dosing regimen.

  • Pharmacokinetic modeling and dosage adaptation of Biapenem in Japanese patients during continuous venovenous hemodiafiltration
    Journal of Infection and Chemotherapy, 2008
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Hidemichi Suyama
    Abstract:

    The present study examined the pharmacokinetics of Biapenem during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamic exposure, based on a pharmacokinetic model, to consider Biapenem dosage adaptation in CVVHDF. Biapenem (300 mg) was administered by 2-h infusion to seven critically ill patients receiving CVVHDF. The flow rates were 60 ml/min for blood, 800 ml/h for filtrate, and 600 ml/h for dialysate. The drug concentrations in plasma and filtratedialysate were determined by high-performance liquid chromatography and analyzed pharmacokinetically. The sieving coefficient was 0.92 ± 0.06 (mean ± SD). The simulation curves, using a multicompartment model, were well fitted to the measurements in plasma and filtrate-dialysate. The clearance by CVVHDF and the clearance by non-CVVHDF routes were 1.29 ± 0.08 and 6.14 ± 1.89 l/h, respectively. The multicompartment model was used to assess the pharmacodynamic exposure (time above the minimum inhibitory concentration of 4 μg/ml) in plasma. When the total daily dose was 600 mg, the duration of time was greater at 300 mg every 12 h than at 600 mg every 24 h. The minimum dosages needed to achieve more than 30% of the dosing interval at filtrate-dialysate flow rates of 1.4, 2.8, and 5.6 l/h were 300 mg every 12 h, 600 mg every 12 h, and 600 mg every 12 h, respectively. These results suggested that low doses or increased dosing intervals should be avoided in patients receiving this renal replacement technique. Information on pharmacodynamic exposure obtained from this model may help us to determine the appropriate Biapenem dosage for CVVHDF. Moreover, our pharmacokinetic model may be useful for further pharmacokinetic studies of Biapenem.

  • Population pharmacokinetics and pharmacodynamics of Biapenem in paediatric patients
    Journal of clinical pharmacy and therapeutics, 2008
    Co-Authors: Kazuro Ikawa, Kayo Ikeda, Norifumi Morikawa, Mizuka Miki, Shin-ichiro Nishimura, Masao Kobayashi
    Abstract:

    Summary Objective:  To develop a population pharmacokinetic model for Biapenem in paediatric patients and to use the parameter estimates to assess pharmacodynamic exposure of common bacterial populations. Methods:  Biapenem plasma concentrations (n = 125) from 25 paediatric patients were analysed using nonmem. The parameter estimates were used in a Monte Carlo simulation to predict the exposure time during which the drug concentration remains above the minimum inhibitory concentration. Results:  A two-compartment model fitted the data, and creatinine clearance (CLcr) and total body weight (TBW) were the most significant covariates. The final model was CL (L/h) = 0·0458 × CLcr, Vc (L) = 0·162 × TBW, Q (L/h) = 2·05, Vp (L) = 1·73, where CL is the clearance, Vc is the volume of distribution of the central compartment, Q is the intercompartmental clearance and Vp is the volume of distribution of the peripheral compartment. Biapenem regimens of 5 mg/kg q8h and 10 mg/kg q8h provided sufficient pharmacodynamic exposures to Pseudomonas aeruginosa and Streptococcus pneumoniae in most typical patient populations. Conclusion:  These results better define the pharmacokinetics of Biapenem and help in the choice of the appropriate dosage regimens for paediatric.

Gyanu Lamichhane - One of the best experts on this subject based on the ideXlab platform.

  • In vitro and in vivo activity of Biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis.
    The Journal of antimicrobial chemotherapy, 2017
    Co-Authors: Amit Kaushik, Nicole C. Ammerman, Rokeya Tasneen, Elizabeth Story-roller, Kelly E. Dooley, Susan E. Dorman, Eric Nuermberger, Gyanu Lamichhane
    Abstract:

    Background Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in Biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis . Objectives Our objective was to evaluate the synergy of Biapenem/rifampicin against both low- and high-level rifampicin-resistant strains of M. tuberculosis , in vitro and in the mouse model. Methods Biapenem/rifampicin activity was evaluated using three strains of M. tuberculosis : strain 115R (low-level rifampicin resistance); strain 124R (high-level rifampicin resistance); and the drug-susceptible H37Rv parent strain. Biapenem/rifampicin synergy was evaluated in vitro by chequerboard titration. In vivo , we first conducted a dose-ranging experiment with Biapenem against H37Rv in the mouse model. We then evaluated Biapenem/rifampicin activity in mice infected with each M. tuberculosis strain. Results In vitro , synergy was observed between Biapenem and rifampicin against H37Rv and strain 115R. In vivo , Biapenem exhibited clear dose-dependent activity against H37Rv, with all Biapenem doses as active or more active than rifampicin alone. Biapenem and rifampicin had synergistic bactericidal activity against H37Rv in the mouse model; no synergy was observed in mice infected with either of the rifampicin-resistant strains. Biapenem alone was active against all three strains. Conclusions Our preclinical experiments indicate that Biapenem has potential for use as an anti-TB drug, including for use against rifampicin-resistant TB. Thus, Biapenem has promise for repurposing as a 'new' - and desperately needed - drug for the treatment of drug-resistant TB.

  • Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase Ldt_Mt2 by Biapenem and tebipenem
    BMC Biochemistry, 2017
    Co-Authors: Mario A. Bianchet, Ying H. Pan, Leighanne A. Brammer Basta, Harry Saavedra, Evan P. Lloyd, Pankaj Kumar, Rohini Mattoo, Craig A. Townsend, Gyanu Lamichhane
    Abstract:

    Background The carbapenem subclass of β-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of β-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 → 3 linkages in bacterial peptidoglycan. The carbapenems Biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis ( Mtb ). Results Here, we report the X-ray crystal structures of Mtb L,D -transpeptidase-2 (Ldt_Mt2) complexed with Biapenem or tebipenem. Despite significant variations in carbapenem sulfur side chains, Biapenem and tebipenem ultimately form an identical adduct that docks to the outer cavity of Ldt_Mt2. We propose that this common adduct is an enzyme catalyzed decomposition of the carbapenem adduct by a mechanism similar to S-conjugate elimination by β-lyases. Conclusion The results presented here demonstrate Biapenem and tebipenem bind to the outer cavity of Ldt_Mt2, covalently inactivate the enzyme, and subsequently degrade via an S-conjugate elimination mechanism. We discuss structure based drug design based on the findings and propose that the S-conjugate elimination can be leveraged to design novel agents to deliver and locally release antimicrobial factors to act synergistically with the carbapenem carrier.

  • Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase LdtMt2 by Biapenem and tebipenem.
    BMC biochemistry, 2017
    Co-Authors: Mario A. Bianchet, Ying H. Pan, Leighanne A. Brammer Basta, Harry Saavedra, Evan P. Lloyd, Pankaj Kumar, Rohini Mattoo, Craig A. Townsend, Gyanu Lamichhane
    Abstract:

    The carbapenem subclass of β-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of β-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 → 3 linkages in bacterial peptidoglycan. The carbapenems Biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis (Mtb). Here, we report the X-ray crystal structures of Mtb L,D-transpeptidase-2 (LdtMt2) complexed with Biapenem or tebipenem. Despite significant variations in carbapenem sulfur side chains, Biapenem and tebipenem ultimately form an identical adduct that docks to the outer cavity of LdtMt2. We propose that this common adduct is an enzyme catalyzed decomposition of the carbapenem adduct by a mechanism similar to S-conjugate elimination by β-lyases. The results presented here demonstrate Biapenem and tebipenem bind to the outer cavity of LdtMt2, covalently inactivate the enzyme, and subsequently degrade via an S-conjugate elimination mechanism. We discuss structure based drug design based on the findings and propose that the S-conjugate elimination can be leveraged to design novel agents to deliver and locally release antimicrobial factors to act synergistically with the carbapenem carrier.

  • Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase LdtMt2 by Biapenem and tebipenem
    BMC, 2017
    Co-Authors: Mario A. Bianchet, Ying H. Pan, Harry Saavedra, Evan P. Lloyd, Pankaj Kumar, Rohini Mattoo, Craig A. Townsend, Leighanne Brammer A. Basta, Gyanu Lamichhane
    Abstract:

    Abstract Background The carbapenem subclass of β-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of β-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 → 3 linkages in bacterial peptidoglycan. The carbapenems Biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis (Mtb). Results Here, we report the X-ray crystal structures of Mtb L,D-transpeptidase-2 (LdtMt2) complexed with Biapenem or tebipenem. Despite significant variations in carbapenem sulfur side chains, Biapenem and tebipenem ultimately form an identical adduct that docks to the outer cavity of LdtMt2. We propose that this common adduct is an enzyme catalyzed decomposition of the carbapenem adduct by a mechanism similar to S-conjugate elimination by β-lyases. Conclusion The results presented here demonstrate Biapenem and tebipenem bind to the outer cavity of LdtMt2, covalently inactivate the enzyme, and subsequently degrade via an S-conjugate elimination mechanism. We discuss structure based drug design based on the findings and propose that the S-conjugate elimination can be leveraged to design novel agents to deliver and locally release antimicrobial factors to act synergistically with the carbapenem carrier

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  • correlation between in vitro and in vivo models of proconvulsive activity with the carbapenem antibiotics Biapenem imipenem cilastatin and meropenem
    Toxicology Letters, 1995
    Co-Authors: Ivana P. Day, Joy Goudie, Katsutuki Nishiki, Patricia D. Williams
    Abstract:

    The present study evaluated the proconvulsant liability of Biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of Biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the carbapenems were tested for their ability to inhibit [3H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1-10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, Biapenem and meropenem did not inhibit [3H]muscimol binding to the GABAA receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABAA binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that Biapenem possesses a low proconvulsive liability.

  • Correlation between in vitro and in vivo models of proconvulsive activity with the carbapenem antibiotics, Biapenem, imipenem/cilastatin and meropenem.
    Toxicology letters, 1995
    Co-Authors: Ivana P. Day, Joy Goudie, Katsutuki Nishiki, Patricia D. Williams
    Abstract:

    The present study evaluated the proconvulsant liability of Biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of Biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the carbapenems were tested for their ability to inhibit [3H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1-10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, Biapenem and meropenem did not inhibit [3H]muscimol binding to the GABAA receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABAA binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that Biapenem possesses a low proconvulsive liability.