[Implementation and Evaluation of Genetic Testing Seminars about Lifestyle-related Disease Prevention in Pharmacy Insurance-The Need for Cooperation between the Pharmacy and the University in Genetic Testing].

A seminar titled "Implementation and evaluation of genetic testing of lifestyle-related disease genes" was held for pharmacists, medical clerks, and clerks of pharmacy insurance, with the aim of holding seminars led by pharmacists for the general public (including patients) in the future. The subject of the seminar was single nucleotide polymorphisms in obesity-related genes and alcohol metabolism-related genes. The purpose of the seminar was to contribute to the prevention of lifestyle-related diseases of the general public. We evaluated it by administering a questionnaire to the participants before and after the seminar. After the seminar, 55% of pharmacists answered that they would like to or would strongly like to participate in genetic testing (for lifestyle-related diseases and drug metabolism-related genes) of the general public. However, some participants did not wish to do so. A customer satisfaction (CS) analysis found that this was mainly because they did not want to know the results of genetic testing of others, which they felt should be private. Most (82%) of the pharmacists answered that assistance and advice was "very necessary" or "necessary" in the participation of genetic testing. These findings show that collaboration between pharmacies and universities will be important for future seminars to the general public.

[Health assessment of local residents who made full use of symptomatology skills and test device].

A strategy named "Japan is back" adopted in June 2013 specifies that pharmacies shall be regarded as community-based places where health-related information is provided, and the public shall be encouraged to use the services of pharmacies and pharmacists who can advise on health and appropriate use of over-the-counter (OTC) drugs, and promote self medication. In Japan there are approximately 55000 pharmacies and 260000 pharmacists, and community residents are recommended to use these resources. As advisors on healthcare in the community, pharmacists are required to make judgments regarding drug use in individuals performing self medication and using OTC drugs in consideration of their symptoms and level of understanding of their health conditions, and recommend that they consult a medical center if necessary. To meet these requirements pharmacists need to have the skills to monitor each individual's lifestyle, behavior, and environment as well as trends in society, and assess their health status. However, education that allows pharmacists to practice such skills remains insufficiently developed. We consider that to be able to detect diseases early among community residents and appropriately support them using pharmacotherapy, it is very important to train pharmacists to do the following at pharmacies: 1) determine individuals who should be treated early using symptomatologic skills; 2) promote public awareness of disease; and 3) perform biochemical examination (blood is collected by fingerprick promptly to obtain biochemical data) in cooperation with the Department of Clinical Pharmacotherapy, Faculty of Pharmaceutical Sciences, Hiroshima University.

Determination of doripenem penetration into human prostate tissue and assessment of dosing regimens for prostatitis based on site-specific pharmacokinetic-pharmacodynamic evaluation.

Prostatic hypertrophy patients prophylactically received a 0.5-hour infusion of doripenem (250 or 500 mg) before transurethral resection of the prostate. Doripenem concentrations in plasma and prostate tissue were measured chromatographically, and analysed pharmacokinetically using a three-compartment model. The approved doripenem regimens were assessed based on the time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24 hours), an indicator for antibacterial effects, at the prostate. The prostate tissue/plasma ratios were 17.3% for the maximum drug concentration and 18.7% for the area under the drug concentration-time curve, and they were irrespective of the dose. Against Escherichia coli and Klebsiella species isolates, 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue.

Clinical pharmacokinetics of meropenem and biapenem in bile and dosing considerations for biliary tract infections based on site-specific pharmacodynamic target attainment.

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.

Pharmacokinetic­pharmacodynamic target attainment analysis of meropenem in Japanese adult patients.

This study was a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of meropenem in Japanese adult patients. Plasma drug concentration data (265 samples from 42 patients) were used for population PK modeling and Monte Carlo simulation to assess the probability of attaining the PK-PD target (40% of the time above the MIC for the bacterium). The final population PK model identified creatinine clearance (Cl(cr), ml/min) and body weight (BW, kg) as the most significant covariates: Cl (l/h) = 0.0905 × Cl(cr) + 2.03, V(c)(l) = 0.199 9 BW, Q (l/h) = 4.02, and V(p) (l) = 4.55, where Cl is the clearance, Vc and Vp are the volumes of distribution of the central and peripheral compartments, respectively, and Q is the intercompartmental clearance. The Monte Carlo simulation developed the PK-PD breakpoints (the highest MIC values at which the probabilities of target attainment in plasma are 80% or more) for meropenem regimens, the values of which varied with the Cl(cr) and BW of the patient. The simulation also demonstrated that 0.25 g every 12 h (0.5-h infusion) achieved a target attainment probability of 82.4-100% against Escherichia coli, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae isolates. However, against Pseudomonas aeruginosa isolates, 0.5 g every 8 h or 1 g every 8 h was required to achieve 80% or more probability in most typical patients. These results provide a PK-PD-based strategy for tailoring a meropenem regimen according to Clcr and BW of a Japanese adult patient and susceptibility of the causative bacteria.

Population pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients.

The aims of this study were to develop a population pharmacokinetic model for meropenem in Japanese pediatric patients, and to use this model to assess the pharmacodynamics of meropenem regimens against common bacterial populations. Pharmacokinetic data were pooled from nine separate studies (229 plasma samples and 61 urine samples from 40 infected children), modeled using the NONMEM program, and used for a pharmacodynamic simulation to estimate the probabilities of attaining the bactericidal target (40% of the time above the MIC for the bacterium). In the final population pharmacokinetic model, body weight (BW, kg) was the most significant covariate: Cl(r) (l/h) = 0.254 x BW, Cl(nr) (l/h) = 3.45, V (c) (l) = 0.272 x BW, Q (l/h) = 1.65, and V (p) (l) = 0.228 x BW, where Cl(r) and Cl(nr) are the renal and non-renal clearances, V (p) and V (c) are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central-peripheral) clearance. In most typical patients (BW = 10, 20, and 30 kg), the approved regimens of 10-40 mg/kg, three times a day (0.5-h infusions), achieved a target attainment probability of >80% against Escherichia coli, Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa isolates. The results of this study provide a better understanding of the pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients.

Assessment of micafungin regimens by pharmacokinetic-pharmacodynamic analysis: a dosing strategy for Aspergillus infections.

OBJECTIVES: A pharmacokinetic (PK)-pharmacodynamic (PD) analysis was conducted to assess various micafungin regimens for Candida and Aspergillus infections, as appropriate regimens have not been established, especially for Aspergillus infections. METHODS: Plasma drug concentrations (48 samples from 10 adult patients with haematological malignancies) were determined chromatographically, and used for population PK modelling and Monte Carlo simulation to evaluate the ability of regimens (1 h infusions) to attain genus-dependent PK-PD targets, namely fungistatic and fungicidal targets against Candida spp. [area under the plasma unbound (1%) drug concentration-time curve over 24 h/MIC (fAUC/MIC) = 10 and 20] and an effective concentration target against Aspergillus spp. (plasma unbound drug concentration = 0.05 mg/L). RESULTS: Mean (variance) values for two-compartment PK model parameters were: clearance, 0.762 L/h (15.4%); volume of central compartment, 9.25 L (24.6%); intercompartmental clearance, 7.02 L/h (fixed); and volume of peripheral compartment, 8.86 L (71.8%). The Monte Carlo simulation demonstrated that 50 mg once daily and 100 mg once daily for the fungistatic and fungicidal targets achieved a >95% probability of target attainment against Candida spp. To achieve such probability against Aspergillus spp., 250 mg once daily or 100 mg twice daily was required. CONCLUSIONS: These results rationalize the approved micafungin dosages for Candida infections (50 mg once daily for prophylaxis and 100-150 mg once daily for treatment), and on the basis of these results we propose a PK-PD-based dosing strategy for Aspergillus infections. A regimen of 200-250 mg/day should be initiated to ensure the likelihood of a favourable outcome. The regimen can be optimized by decreasing the dosing interval.

Population pharmacokinetic modeling and pharmacodynamic assessment of cefozopran in pediatric patients.

The aims of this study were to develop a population pharmacokinetic model for cefozopran in pediatric patients, and to use this model to evaluate the pharmacodynamics of cefozopran regimens against common bacterial populations. Plasma drug concentration data (110 samples from 31 pediatric patients) were modeled using the NONMEM program. The mean estimate and interindividual variance of the model were used in a Monte Carlo simulation to estimate the probabilities of attaining the bactericidal target for cefozopran (the time which the drug concentration remains above the minimum inhibitory concentration for the bacterium is 70% of the dosing interval). A two-compartment model fitted the data and body weight (BW, kg) was the most significant covariate. The final model was: Cl (l/h) = 0.674 x BW0.538, Vc (l) = 0.00233 x BW2.25 + 1.85, Q (l/h) = 1.46, and Vp (l) = 0.0964 x BW, where Cl is the clearance, Vc, and Vp are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental clearance. The approved regimens of 20- or 40-mg/kg four times a day (0.5-h infusions), which were more effective than the corresponding three times a day-regimens, provided sufficient bactericidal effects on common bacterial populations (Escherichia coli, Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa) in most typical patients. These results better define the pharmacokinetics of cefozopran and help in the choice of appropriate regimens for pediatric patients.

Pharmacokinetic-pharmacodynamic target attainment analysis of biapenem in adult patients: a dosing strategy.

BACKGROUND: A pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis to build a dosing strategy for biapenem in adult patients has not been conducted. METHODS: A total of 321 plasma concentration samples from 68 adult patients (1-6 samples per patient) were assayed biologically and chromatographically, and used for a population PK modeling and Monte Carlo simulation to assess the probability of attaining the PK-PD target (40% of the time above the minimum inhibitory concentration). RESULTS: The population PK model was based on the standard two-compartment model, and creatinine clearance (Cl(cr)) was the most significant covariate that affected the drug clearance. The Monte Carlo simulation demonstrated that the dosages up to 600 mg Q12H (0.5-h infusions) achieved a PK-PD target attainment probability of > or =90%, which varied with Cl(cr) of the patient and susceptibility of the tested bacterium; however, higher dosage with prolonged infusion time (600 mg Q8H, 3 h infusion) was required for a high probability against Pseudomonas aeruginosa and Haemophilus influenzae isolates in the case of Cl(cr) = 90 ml/min. CONCLUSION: These results provide guidance for constructing a PK-PD-based strategy for tailoring biapenem regimens in adult patients.

Pharmacodynamic assessment of doripenem in peritoneal fluid against Gram-negative organisms: use of population pharmacokinetic modeling and Monte Carlo simulation.

This study aimed to assess the peritoneal pharmacodynamics of intravenous doripenem using population pharmacokinetic modeling and Monte Carlo simulation. Drug concentrations in peritoneal fluid (PF) and serum from 11 laparotomy patients and MIC distributions against clinical isolates in Japan for 4 Gram-negative organisms were used. The probabilities of attaining the pharmacodynamic target (40% T > MIC) were greater in PF than in serum. To achieve a > or =90% probability of target attainment in PF, 0.25 g tid and 0.5 g tid (0.5-h infusions) had to be sufficient against Escherichia coli, Klebsiella spp., and Enterobacter cloacae; however, 1 g tid (0.5-h infusion) was required against Pseudomonas aeruginosa. Prolonged (4-h) infusion regimens resulted in increase of the target attainment probabilities in PF for P. aeruginosa. These results should help to achieve a better understanding of the peritoneal pharmacodynamics of doripenem while also helping to rationalize and optimize the dosing regimen for intra-abdominal infections.

Development of breakpoints of carbapenems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in peritoneal fluid.

This study aimed to develop breakpoints of carbapenems for intraabdominal infections, based on pharmacokinetics (PK) and pharmacodynamics (PD) at the target site. Imipenem, meropenem, and doripenem were each administered to 8-11 patients before abdominal surgery, and venous blood and peritoneal fluid samples were obtained. The drug concentrations in plasma and peritoneal fluid were determined and analyzed using population pharmacokinetic modeling. Using the pharmacokinetic model parameters, a Monte Carlo simulation was performed to estimate the probabilities of attaining the bacteriostatic and bactericidal targets (20% and 40% of the time above the minimum inhibitory concentration [MIC], respectively) in peritoneal fluid. The bacteriostatic and bactericidal breakpoints were defined as the highest MIC values at which the bacteriostatic and bactericidal probabilities in peritoneal fluid were 80% or more. The breakpoints for the minimum and maximum approved dosages of each drug were identical for imipenem, meropenem, and doripenem, and some of these values varied with dosing interval and infusion time. Site-specific PK-PD-based breakpoints are proposed here for the first time, and should help us to select appropriate carbapenem regimens for intraabdominal infections.

Peritoneal pharmacokinetics of cefepime in laparotomy patients with inflammatory bowel disease, and dosage considerations for surgical intra-abdominal infections based on pharmacodynamic assessment.

This study aimed to examine the peritoneal pharmacokinetics of cefepime and to assess its pharmacodynamic exposure in peritoneal fluid (PF). Cefepime (1 g) was administered to eight patients with inflammatory bowel disease before abdominal surgery. Venous blood and PF samples were obtained at the end of the 0.5-h infusion and at 1, 2, 3, 4, 5, and 6 h thereafter. Drug concentrations in plasma and PF were determined, analyzed pharmacokinetically, and used for a Monte Carlo simulation with minimum inhibitory concentration (MIC) data. Cefepime penetrated well into PF, with a maximum drug concentration in a PF/plasma ratio of 0.59 +/- 0.15 (mean +/- SD, n = 8), and an area under the concentration-time curve ratio of 0.90 +/- 0.10. The probabilities of attaining the bacteriostatic and bactericidal targets (40% and 70% of the time above the MIC, respectively) in PF were > or =85% against Escherichia coli, Klebsiella species, and Enterobacter cloacae with 0.5 g every 12 h, 1 g every 12 h, 1 g every 8 h, and 2 g every 12 h. However, 1 g every 8 h or 2 g every 12 h was required for bacteriostatic and bactericidal probabilities > or =85% against Pseudomonas aeruginosa. These conventional regimens did not achieve a high probability against Bacteroides species. These results should help to give us a better understanding of the peritoneal pharmacokinetics of cefepime while also helping to choose the appropriate dosage to prevent surgical intra-abdominal infections on the basis of the pharmacodynamic assessment.

Pharmacokinetic-pharmacodynamic target attainment analysis of cefozopran in Japanese adult patients.

This study aimed to perform a pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis to create a dosing strategy for cefozopran in Japanese adult patients. A total of 145 plasma concentration samples from 32 adult patients were used for a population pharmacokinetic modeling and Monte Carlo simulation to assess the probability of attaining the PK-PD target (70% of the time above the minimum inhibitory concentration for the bacterium). The final population pharmacokinetic model was based on a two-compartment model, and creatinine clearance (Cl(cr)) and body weight (BW) were the most significant covariates: Cl(l/h) = 0.0263 x Cl(cr) + 1.49, V (c)(l) = 0.185 x BW(0.931), Q(l/h) = 4.55, V (p)(l) = 5.86, where Cl is the clearance, V (c) is the volume of distribution of the central compartment, Q is the intercompartmental clearance, and V (p) is the volume of distribution of the peripheral compartment. The Monte Carlo simulation demonstrated that 1 g q 12 h achieved a PK-PD target attainment probability of > or =85% against Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae isolates. However, against Haemophilus influenzae and Pseudomonas aeruginosa isolates, 1 g q 8 h and (2 g, 1 g, 1 g) q 8 h were required to achieve a high probability, which value varied with the Cl(cr) and BW of the patient. These results provide a PK-PD-based strategy for tailoring cefozopran regimens in Japanese adult patients.

Development of breakpoints of cephems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in the peritoneal fluid of patients.

We developed breakpoints for cephem antibacterial agents for intraabdominal infections based on pharmacokinetics (PK) and pharmacodynamics (PD) at the target site. Cefepime (CFPM), cefotiam (CTM), cefozopran (CZOP), and flomoxef (FMOX) were each administered to 8-10 patients before abdominal surgery, and venous blood and peritoneal fluid (PF) samples were obtained. The drug concentrations in plasma and PF were determined and analyzed using population pharmacokinetic modeling. Using the pharmacokinetic model parameters, a Monte Carlo simulation was conducted to estimate the probabilities of attaining the bacteriostatic and bactericidal targets (40% and 70% of the time above the minimum inhibitory concentration (T > MIC), respectively) in PF. The bacteriostatic and bactericidal breakpoints were determined as the highest MIC values at which the bacteriostatic and bactericidal probabilities in PF were > or =80%, which values varied with drug and dosing regimen. Site-specific PK-PD-based breakpoints for CFPM, CTM, CZOP, and FMOX are proposed, and should help us to select appropriate cephems and design their dosing regimens for intraabdominal infections.

Penetration into and exposure of cefozopran in pelvic retroperitoneal space exudate.

This study aimed to examine the penetration into and exposure of cefozopran in the pelvic retroperitoneal space exudate of patients undergoing radical hysterectomy and pelvic lymphadenectomy. Cefozopran (1 g) was administered by 1-h infusion after the end of surgery, and venous blood and exudate samples were obtained 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 8 h thereafter. Drug concentrations in serum and the exudate were determined by a bioassay, analyzed pharmacokinetically, and used for a Monte Carlo simulation with minimum inhibitory concentration (MIC) data. The exudate/serum ratio of the area under the drug concentration-time curve was 0.76 +/- 0.19 (mean +/- SD), and the simulated concentrations were higher in the exudate than in serum after 2.4 h post-dose. The probability of attaining the pharmacodynamic exposure target (70% of the time above the MIC; i.e., probability of target attainment; PTA) was 94.9% and 100%, respectively, against Escherichia coli and Klebsiella species with 1 g every 12 h; however, 1 g every 8 h was required for a PTA value of 90% or more at an MIC of 8 microg/ml. We consider that these results will help clinicians to better understand the penetration into and exposure of cefozopran in the female genital cavity, while also helping to rationalize the dosage of this agent for gynecological-surgery infections.

Pharmacodynamic evaluation of biapenem in peritoneal fluid using population pharmacokinetic modelling and Monte Carlo simulation.

This study evaluated the pharmacodynamics of biapenem in peritoneal fluid (PF). Biapenem (300 or 600mg) 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 6h. 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 x 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 60mL/min, the site-specific pharmacodynamic-derived breakpoints (the highest MIC values at which the probabilities of target attainment in PF were >or=90%) were 2microg/mL for 300mg every 12h, 4microg/mL for biapenem 300mg every 8h (q8h) and 8microg/mL for 600mg 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.

Pharmacokinetics and pharmacodynamic assessment of imipenem in the intraperitoneal fluid of abdominal surgery patients.

BACKGROUND: Imipenem is used to treat intra-abdominal infections, however, this treatment would benefit from a better understanding of imipenem penetration into the abdominal cavity. METHODS: Imipenem 500 mg was infused to 10 laparotomy patients. The total drug concentrations in plasma and intraperitoneal fluid were analyzed noncompartmentally and 3-compartmentally (population pharmacokinetic analysis), and used for a Monte Carlo simulation with minimum inhibitory concentration data. RESULTS: The AUC(0-infinity) ratio of the intraperitoneal fluid to the plasma was 0.82 +/- 0.06 (mean +/- SD, n = 6). The pharmacodynamic exposures in the intraperitoneal fluid were higher than in the plasma. The probabilities of achieving a bacteriostatic/bactericidal target (20/40% of the time above minimum inhibitory concentration for 24 h) in the intraperitoneal fluid using a regimen of 500 mg every 8 h against the Bacteroides fragilis group, Escherichia coli and Klebsiella species were 97.3/89.1, 98.8/97.2 and 100/98.2%, respectively. However, a regimen of 1,000 mg every 8 h was needed to achieve 96.7/89.3% against Pseudomonas aeruginosa. CONCLUSION: These results may help us to understand the intraperitoneal penetration of imipenem and to determine the dosing regimen for intra-abdominal infections.

Optimized dosage and frequency of cefozopran for patients with febrile neutropenia based on population pharmacokinetic and pharmacodynamic analysis.

OBJECTIVES: To establish a cefozopran (a fourth-generation cephem) 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. METHODS: We conducted a prospective clinical trial of cefozopran for haematological patients with febrile neutropenia (FN). Twenty-two patients (30 episodes) were selected to receive intravenous cefozopran every 8 h on a daily basis. We gathered concentration data and performed the NONMEM program. The Monte Carlo simulation was performed to assess the pharmacodynamic exposure based on the population pharmacokinetics and MIC. RESULTS: The NONMEM program demonstrated that a two-compartment model provided a best fit for the data, that is, CL of 4.62 (L/h), V1 of 10.3 (L), Q of 4.47 (L/h), and V2 of 4.48 (L). On the basis of the Japanese national surveillance findings for Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus, coagulase-negative Staphylococcus, viridans group streptococci, Escherichia coli and Klebsiella pneumoniae, Monte Carlo simulation data showed that probability of target attainment(T>MIC = 70%) is 67% to 97% for dosing every 8 h, and 48% to 88% for dosing every 12 h. For the patients in whom the efficacy of cefozopran could be evaluated, 17 of 22 patients (77.2%) survived the episode of FN without requiring further antibacterial treatment. CONCLUSIONS: Our study proved that Monte Carlo simulation based on population pharmacokinetics can determine optimized dosage and method. The optimal regimen for this cephem was found to be three times daily.

Pharmacokinetics and pharmacodynamics of biapenem in critically ill patients under continuous venovenous hemodiafiltration.

To characterize the PK/PD of biapenem (BIPM) in critically ill patients under continuous venovenous hemodiafiltration (CVVHDF), we conducted a prospective, open-label study in nine adult CVVHDF patients with acute renal failure at the Critical Care Medical Center, Hiroshima Prefectural Hospital. Plasma and filtrate samples were obtained at six time points. The concentrations of BIPM in plasma and filtrate were determined by HPLC. PK parameters were analyzed using Monte Carlo simulation with MIC data. BIPM concentrations in the plasma and CVVHDF filtrate peaked at the end of infusion, and the values were similar. The drug clearance by CVVHDF and non-CVVHDF was 1.28 +/- 0.14 and 9.05 +/- 4.05 L/h, respectively. Monte Carlo simulation showed that the more administration times, there were the higher the probability. In conclusion, a dosing regimen of 300 mg BIPM q8h had a higher probability of therapeutic efficacy than q12h in patients with severe sepsis under CVVHDF.

Peritoneal penetration and pharmacodynamic exposure of intravenous cefozopran in abdominal surgery patients.

This study aimed to examine the peritoneal penetration and pharmacodynamic exposure of intravenous cefozopran. Cefozopran 1 g was administered to 10 patients before abdominal surgery. Venous blood and peritoneal fluid (PF) samples were obtained at the end of the 0.5-h infusion and at 1, 2, 3, 4, 5 and 6 h thereafter. Drug concentrations in plasma and PF were determined, analysed pharmacokinetically and used for a Monte Carlo simulation with minimum inhibitory concentration (MIC) data. Cefozopran penetrated well into PF, with a mean (+/-standard deviation) maximum drug concentration in PF/plasma ratio of 0.65+/-0.17 (n=10) and area under the concentration-time curve ratio of 0.92+/-0.13. The probabilities of attaining the pharmacodynamic exposure target (PTA), defined as 70% of the time above the MIC, in PF were almost identical to those in plasma. The PTAs were 95-100% against Escherichia coli, Enterobacter spp. and Staphylococcus aureus with 0.5 g every 12 h; however, 1 g every 8 h or 1 g every 6 h was required for 93-98% PTA against Pseudomonas aeruginosa. These results should help us to understand the peritoneal pharmacokinetics of cefozopran whilst also helping to choose the appropriate dosage for surgical intra-abdominal infections.