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This study aimed to assess the dosing regimens of ampicillin/sulbactam for pneumonia based on pulmonary pharmacokinetic (PK)/pharmacodynamic (PD) target attainment. Using the literature data, we developed pulmonary PK models and estimated the probabilities of attaining PK/PD targets in lung tissue. Against bacteria other than A. baumannii (the general treatment), the PK/PD target was set as both 50% time above the minimum inhibitory concentration (T > MIC) for ampicillin and 50% T > 0.5 MIC for sulbactam. For the A. baumannii treatment, the PK/PD target was set as 60% T > MIC for sulbactam. The pulmonary PK/PD breakpoint was defined as the highest minimum inhibitory concentration (MIC) at which the target attainment probability in the lung tissue was ≥90%. The lung tissue/serum area under the drug concentration-time curve from 0 to 3 h (AUC0-3h) ratios for ampicillin and sulbactam were 0.881 and 0.368, respectively. The ampicillin/sulbactam AUC0-3h ratio in the lung tissue was 3.89. For the general treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 3 g four times daily in typical patients with creatinine clearance (CLcr) of 60 mL/min was 2 µg/mL, which covered the MIC90s (the MICs that inhibited the growth of 90% of the strains) of most gram-positive and gram-negative bacteria. For the A. baumannii treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 9 g 4-h infusion three times daily (27 g/day) in patients with a CLcr of 60 mL/min was 4 µg/mL, which covered the MIC90 of A. baumannii. A PK/PD evaluation for pneumonia should be performed in the lung tissue (the target site) rather than in the blood because sulbactam concentrations are lower in lung tissue. These findings should facilitate the selection of ampicillin/sulbactam regimens for pneumonia caused by various bacteria, including A. baumannii.
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INTRODUCTION: Cefmetazole (CMZ) has gained interest as a carbapenem-sparing alternative to the epidemic of extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales (ESBL-E). In this study, we investigated the pharmacokinetics (PK) of CMZ in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue to assess the dosing regimen needed to achieve pharmacodynamic (PD) goals at the target site. METHODS: Patients scheduled for elective lower gastrointestinal surgery were intravenously administered CMZ. Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected after CMZ infusion and during the surgery, and CMZ concentrations were measured. The non-compartmental and compartmental PK parameters were estimated and used to evaluate site-specific PD target attainment. RESULTS: A total of 38 plasma, 27 peritoneal fluid, 36 peritoneum, and 38 subcutaneous adipose tissue samples were collected from 10 patients. The non-compartmental PK analysis revealed the ratios of the mean area under the drug concentration-time curve (AUC0-3.5 h) of peritoneal fluid-to-plasma, peritoneum-to-plasma, and subcutaneous adipose tissue-to-plasma were 0.60, 0.36, and 0.11, respectively. The site-specific PD target attainment analyses based on the breakpoints for ESBL-E per the Japanese surgical site infection (SSI) surveillance (MIC90 = 8 mg/L) revealed that 2 g CMZ every 3.5 h achieved desired bactericidal effect at all sites and 2 g CMZ every 6 h achieved PD goals at peritoneum and peritoneal fluid. CONCLUSION: These findings clarify the PK of CMZ in abdominal tissues and could help decide optimal dosing regimens to treat intra-abdominal infection and prophylaxis of SSI.
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Cefmetazol , Procedimentos Cirúrgicos do Sistema Digestório , Humanos , Cefmetazol/uso terapêutico , Peritônio , Líquido Ascítico , Antibacterianos/farmacologia , Gordura Subcutânea , Testes de Sensibilidade MicrobianaRESUMO
INTRODUCTION: Recently, complicated intra-abdominal infections (cIAI) have been caused not only by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa, but also by extended-spectrum ß-lactamase-producing Enterobacterales members. Ceftolozane-tazobactam (CTLZ-TAZ) is considered to exhibit therapeutic effects against cIAI. Studies on the concentrations of antibiotics in abdominal tissues directly affected by cIAI are limited. Therefore, in this study, we investigated the pharmacokinetics of CTLZ-TAZ in abdominal tissue and simulated the administration regimen required to achieve the pharmacodynamic target for cIAI-causing bacteria. METHODS: Patients scheduled for elective lower gastrointestinal surgery were intravenously administered preoperative CTLZ-TAZ (1 g CTLZ and 0.5 g TAZ). Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected during the surgery, and CTLZ as well as TAZ concentrations were measured. The noncompartmental and compartmental pharmacokinetic parameters were then estimated. Site-specific pharmacodynamic target attainment analysis using 1.5 g of CTLZ-TAZ was performed. RESULTS: CTLZ-TAZ was administered to nine patients (once to five patients and twice to four patients). The mean peritoneal fluid-to-plasma ratio (one dose/two doses) for CTLZ was 0.74/1.15, which was slightly higher than the mean peritoneal fluid-to-plasma ratio for TAZ (0.95/1.13). The ratio for subcutaneous adipose was lower than those for peritoneal fluid and peritoneum tissues. We also discovered that the average ratio of CTLZ and TAZ concentrations in all tissues was maintained at or above 2:1. In our investigation of pharmacodynamic target attainment in each tissue, the desired bactericidal effect was attained with all CTLZ-TAZ (1.5 g) administration regimens [q12h (3 g/day), q8h (4.5 g/day), and q6h (6 g/day)]. CONCLUSION: To the best of our knowledge, this is the first study investigating the optimal pharmacodynamic level of CTLZ-TAZ in the abdominal tissue against cIAI-causing bacteria. This study also serves as a guideline for designing an optimal administration regimen based on pharmacodynamic target attainment for cIAI-causing bacteria. DETAILS OF THE TRIAL REGISTRATION: The institutional review board of Hiroshima University Hospital, CRB6180006. The Japan Registry of Clinical Trials, jRCTs061190025.
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INTRODUCTION: Flomoxef is generally used to treat abdominal infections and as antibiotic prophylaxis during lower gastrointestinal surgery. It is reportedly effective against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and an increasingly valuable alternative to carbapenems. However, its abdominal pharmacokinetics remain unclear. Herein, pharmacokinetic analysis of flomoxef in the abdominal tissue was conducted to simulate dosing regimens for pharmacodynamic target attainment in abdominal sites. METHODS: Flomoxef (1 g) was administered intravenously to a patient 30 min before commencing elective lower gastrointestinal surgery. Samples of plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue were collected during surgery. The flomoxef tissue concentrations were measured. Accordingly, non-compartmental and compartmental pharmacokinetic parameters were calculated, and simulations were conducted to evaluate site-specific pharmacodynamic target values. RESULTS: Overall, 41 plasma samples, 34 peritoneal fluid samples, 38 peritoneum samples, and 41 subcutaneous adipose samples from 10 patients were collected. The mean peritoneal fluid-to-plasma ratio in the areas under the drug concentration-time curve was 0.68, the mean peritoneum-to-plasma ratio was 0.40, and the mean subcutaneous adipose tissue-to-plasma was 0.16. The simulation based on these results showed the dosing regimens (q8h [3 g/day] and q6h [4 g/day]) achieved the bactericidal effect (% T > minimum inhibitory concentration [MIC] = 40%) in all tissues at an MIC of 1 mg/L. CONCLUSIONS: We elucidated the pharmacokinetics of flomoxef and simulated pharmacodynamics target attainment in the abdominal tissue. This study provides evidence concerning the use of optimal dosing regimens for treating abdominal infection caused by strains like ESBL-producing bacteria.
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Procedimentos Cirúrgicos do Sistema Digestório , Peritônio , Humanos , Peritônio/cirurgia , Líquido Ascítico , Antibacterianos/farmacologia , Enterobacteriaceae , Gordura Subcutânea , Testes de Sensibilidade Microbiana , Método de Monte CarloRESUMO
The bacterium Pseudomonas aeruginosa is known to be associated with nosocomial infections around the world. Pazufloxacin, a potent DNA gyrase inhibitor, is known to be an effective drug candidate. However, it has not been clarified whether the pharmacokinetic (PK)/pharmacodynamic (PD) of pazufloxacin was effective against P. aeruginosa. Herein, we demonstrated that the PK/PD index of pazufloxacin against P. aeruginosa infection is used to optimize the dosing regiments. We constructed an in vivo infection model by infecting P. aeruginosa into the thigh of a mouse to determine the PD, and we measured the serum concentration of pazufloxacin to construct the PK model using high-performance liquid chromatography. The therapeutic efficacy of pazufloxacin was correlated with the ratio of the area under the free concentration time curve at 24 h to the minimum inhibitory concentration (fAUC24/MIC), and the maximum free concentration to the MIC (fCmax/MIC). Each contribution rate (R2) was 0.72 and 0.65, respectively, whereas the time at which the free drug concentration remained above the MIC (R2 = 0.28). The target value of pazufloxacin fAUC24/MIC for stasis was 46.1, for 1 log10 it was 63.8, and for 2 log10 it was 100.8. Moreover, fCmax/MIC for stasis was 5.5, for 1 log10 it was 7.1, and for 2 log10 it was 10.8. We demonstrated that the in vivo concentration-dependent activity of pazufloxacin was effective against the P. aeruginosa infection, and successfully made the PK/PD model sufficiently bactericidal. The PK/PD model will be beneficial in preventing the spread of nosocomial infections.
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WHAT IS KNOWN AND OBJECTIVE: Linezolid (LZD) may cause thrombocytopenia, which can result in discontinuation of treatment. In this study, the blood LZD trough concentration was estimated based on population pharmacokinetic (PK) parameters derived from two previously published models in the Japanese population to determine the rate of achieving the target trough value when the risk of thrombocytopenia is low and to clarify its relationship with the onset of thrombocytopenia. METHODS: This study included adult patients hospitalized at Shimane University Hospital, who received LZD treatment for at least 4 days from January 2010 to December 2017. Patients whose platelet count fell below 70% before LZD administration were categorized as the thrombocytopenic group. Patient PK parameters were calculated based on the population PK models described by Matsumoto et al. and Sasaki et al., and these parameters were designated A and B, respectively. Based on these parameters, the rate of achieving an LZD trough concentration of less than 8 µg/ml, which is the safety target achievement rate, was calculated using a random simulation for each patient. We further analysed the association between the incidence of thrombocytopenia and patient factors, including safety target achievement rate, through univariate, multivariate, and receiver operating characteristic (ROC) analyses. RESULTS AND DISCUSSION: Patients (n = 77) aged 72 ± 11 years and weighing 56.7 ± 10.9 kg, with a creatinine clearance (CLcr ) of 60.5 ± 47.2 ml/min and a cirrhosis prevalence of 9.1%, were analysed. All patients received LZD at a dose of 600 mg twice daily for a total of 10.9 ± 8.9 days. Univariate analyses revealed significant differences (p < 0.05) in the duration of LZD therapy, serum creatinine, creatinine clearance, LZD clearance, and the safety target achievement rate for parameters A and B between the thrombocytopenic and non-thrombocytopenic groups. A multivariate analysis of these factors stratified with the cutoff values obtained by ROC analysis revealed that the duration of LZD therapy and the safety target achievement rates for parameters A and B were significant factors (odds ratios for duration of LZD therapy: 7.436 [95% confidence interval (CI): 1.918-28.831] and 4.712 [95% CI: 1.567-14.163]; odds ratio for safety target achievement rate: 0.060 [95% CI: 0.016-0.232] and 0.167 [95% CI: 0.056-0.498] for parameters A and B, respectively). When the safety target achievement rates for patients treated with LZD were compared between the thrombocytopenic and non-thrombocytopenic groups, the safety target achievement rate was higher in the non-thrombocytopenic group in both the patients treated with LZD for less than 10 days and those for 10 days or more. Therefore, the safety target achievement rate estimated by the PK/PD simulation may represent to be an important index for risk assessment of LZD-induced thrombocytopenia. WHAT IS NEW AND CONCLUSION: The risk of LZD-induced thrombocytopenia, which increased with the duration of LZD therapy, may be predicted using the safety target achievement rate obtained by the blood concentration simulation.
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Anemia , Antibacterianos , Linezolida , Trombocitopenia , Adulto , Humanos , Anemia/induzido quimicamente , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Creatinina , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Contagem de Plaquetas , Medição de Risco , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologiaRESUMO
BACKGROUND: We aimed to develop population pharmacokinetic (PK) models of ampicillin and sulbactam using pooled data analysis and to optimize dosing regimens of ampicillin-sulbactam (combination ratio of 2:1) in pediatric patients. METHODS: Population PK models of ampicillin and sulbactam were separately developed by simultaneously fitting plasma and urine data from pediatric patients in 14 published studies. Based on these models, we estimated the probability of attaining a pharmacodynamic (PD) target [50% of time that free drug concentrations above the minimum inhibitory concentration, 50% fT > minimum inhibitory concentration (MIC)] against MIC90 [MIC that blocked the growth of 90% of the strains] of common bacteria in community-acquired pneumonia. RESULTS: The analysis included 54 pediatric patients (0.083-16.42 years of age, 4.0-77.0 kg of body weight). A total of 284 plasma concentrations and 90 urinary excretions from 0 to 6 hours after administration were used for population PK modeling. The data were adequately described by 2-compartment models for ampicillin and sulbactam. Age was not a statistically significant covariate in the PK of either drug. The PK/PD breakpoint MICs for 45 mg/kg 3 times daily and 75 mg/kg 4 times daily (q.i.d.) were 0.25 and 1 µg/mL, respectively. For empiric therapy of community-acquired pneumonia, because MIC90 values for the main target pathogens is high (MIC90 = 2 µg/mL for Streptococcus pneumoniae and MIC90 = 4 µg/mL for Haemophilus influenzae), 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage in United States) might be better than 45 mg/kg 3 times daily (within approved dosage in Japan) to cover many pathogens. CONCLUSIONS: From the results of this PK/PD approach, 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage) should be recommended in the empiric therapy of community-acquired pneumonia.
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Infecções Comunitárias Adquiridas , Sulbactam , Adolescente , Adulto , Idoso , Ampicilina/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Sulbactam/farmacocinética , Adulto JovemRESUMO
Ampicillin-sulbactam is a first-line therapy for pneumonia and is mainly excreted by the kidney. It is important to optimize the dose and dosing interval of ampicillin-sulbactam because in patients with decreased renal function and low skeletal muscle mass, such as the elderly, excess drug may burden renal function. In this study, we evaluated indices of renal function and optimized the dose and dosing interval of ampicillin-sulbactam based on pharmacokinetics (PK) and pharmacodynamics theory in elderly patients. The serum concentrations of ampicillin and sulbactam were measured by HPLC, and PK parameters were calculated. Correlations between the clearance of ampicillin or sulbactam and renal function were evaluated, and dosing optimization was calculated based on PK parameters. The PK parameters of ampicillin were CL = 6.5 ± 4.0 L/h, Vd = 19.3 ± 0.2 L, Ke = 0.4 ± 0.2, and t1/2 = 2.7 ± 1.6 h. The most correlated renal function index was estimated glomerular filtration rate (eGFRcys-c) calculated by serum cystatin-c (r = 0.7374, correlation formula; CL of ampicillin = 0.1937 × eGFRcys-c-0.6726). Based on this formula, we calculated the clearance of ampicillin and developed dosing regimens for the elderly. Serum cystatin-c concentration is an ideal index to optimize ampicillin-sulbactam antimicrobial therapy in elderly patients with pneumonia.
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Antibacterianos/administração & dosagem , Cistatina C/sangue , Pneumonia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Ampicilina/administração & dosagem , Ampicilina/farmacocinética , Antibacterianos/farmacocinética , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Rim/fisiologia , Masculino , Modelos Biológicos , Pneumonia/sangue , Eliminação Renal , Sulbactam/administração & dosagem , Sulbactam/farmacocinéticaRESUMO
Herein, we describe a case of an elderly patient with muscular dystrophy for whom control of the plasma vancomycin (VCM) concentration proved difficult when he developed a catheter-related bloodstream infection. The pharmacist initially carried out therapeutic drug monitoring using an estimate of the creatinine clearance (CLcr) level, which was based on the serum creatinine (SCr) and serum cystatin-C (CysC) levels, but was ultimately unable to control the plasma VCM concentration. Therefore, the plasma VCM concentration was predicted ex post facto using population pharmacokinetic parameters as a covariate; that is, directly including the glomerular filtration rate (GFRCysC) estimated from the CysC level, which is not affected by the muscle mass. As a result, the estimated VCM concentration was closer to the actual concentration than that predicted using CLcr. Furthermore, the results of examining the predictive accuracy according to the assessment of renal function at the time of initial VCM administration suggested that estimation of the trough concentration using GFRCysC might be useful in elderly patients with muscular dystrophy.
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Infecções Relacionadas a Cateter/tratamento farmacológico , Infecções Relacionadas a Cateter/etiologia , Cistatina C/sangue , Monitoramento de Medicamentos/métodos , Rim/fisiopatologia , Distrofias Musculares/complicações , Vancomicina/administração & dosagem , Vancomicina/sangue , Idoso , Infecções Relacionadas a Cateter/sangue , Taxa de Filtração Glomerular , Humanos , Distrofias Musculares/sangue , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Vancomicina/farmacocinéticaRESUMO
OBJECTIVES: Pharmacokinetic/pharmacodynamic (PK/PD) analysis using murine infection models is a well-established methodology for optimising antimicrobial therapy. Therefore, we investigated the PK/PD indices of teicoplanin againstStaphylococcus aureus using a murine thigh infection model. METHODS: Mice were rendered neutropenic by administration of a two-step dosing of cyclophosphamide. Then, isolates of methicillin-susceptibleS. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) were inoculated into the thighs of neutropenic mice. PK/PD analyses were performed by non-linear least-squared regression using the MULTI program. RESULTS: Target values offCmax/MIC (r2 = 0.94) of teicoplanin for static effect and 1 log10 kill against MSSA were 4.44 and 15.44, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MSSA were 30.4 and 70.56, respectively. Target values of fCmax/MIC (r2 = 0.91) of teicoplanin for static effect and 1 log10 kill against MRSA were 8.92 and 14.16, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MRSA were 54.8 and 76.4, respectively. CONCLUSION: These results suggest thatfCmax/MIC and fAUC24/MIC are useful PK/PD indices of teicoplanin against MSSA and MRSA.
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Staphylococcus aureus Resistente à Meticilina , Staphylococcus aureus , Animais , Camundongos , Testes de Sensibilidade Microbiana , Teicoplanina/farmacologia , Coxa da PernaRESUMO
This study aims to define the penetration of ampicillin and sulbactam into prostate tissue, develop a prostatic pharmacokinetic model of each drug, and assess the appropriateness of ampicillin-sulbactam regimens for the treatment of prostatitis and the prophylaxis of postoperative infection, based on a pharmacokinetic and pharmacodynamic simulation. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-hour infusion of 1.5 g (1:0.5 g) or 3 g (2:1 g) ampicillin-sulbactam before transurethral resection of the prostate. Ampicillin and sulbactam concentrations in plasma and prostate tissue were measured. The prostate tissue/plasma ratios of both ampicillin and sulbactam were approximately 0.37 (area under the drug concentration-time curve), and penetration was similar. The prostatic population pharmacokinetic model, which included a covariate analysis, adequately predicted prostate tissue concentrations in our patient population. For therapeutic use, aiming for a bactericidal target of 50% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability against only Enterococcus faecalis in typical patients with a creatinine clearance (CLcr ) of 30 mL/min. For prophylactic use, aiming for a bacteriostatic target of 30% T > MIC, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability of attaining the bacteriostatic target against E. faecalis and Proteus species when CLcr was 30 mL/min. Based on prostatic simulations, the present study provides helpful recommendations for the treatment of bacterial prostatitis and preoperative prophylaxis in prostatectomy.
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Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antibioticoprofilaxia/métodos , Prostatite/tratamento farmacológico , Idoso , Ampicilina/farmacocinética , Ampicilina/farmacologia , Ampicilina/uso terapêutico , Antibacterianos/farmacologia , Creatinina/sangue , Relação Dose-Resposta a Droga , Humanos , Masculino , Testes de Sensibilidade Microbiana , Modelos Biológicos , Estudos Prospectivos , Próstata/efeitos dos fármacos , Sulbactam/farmacocinética , Sulbactam/farmacologia , Sulbactam/uso terapêutico , Ressecção Transuretral da Próstata/métodosRESUMO
The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen-minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration-time curve over 24 h ≥ 96 µg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75-101) years, were investigated. The plasma-concentration-time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr - 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr - 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 µg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50-60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.
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BACKGROUND: Metronidazole-induced encephalopathy (MIE) is a rare disease caused by an adverse reaction to metronidazole (MNZ). Furthermore, the pharmacokinetics of MNZ during hemodialysis (HD) treatment have not been revealed. CASE PRESENTATION: In a 70-year-old woman undergoing maintenance HD, MNZ was administered intermittently for the treatment of recurrent hepatic cyst infections. She complained of vomiting, dizziness, and dysarthria after 65 consecutive days of MNZ administration. In brain fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), we found a high signal intensity in the cerebellar dentate nuclei and splenium of the corpus callosum. We diagnosed the patient with MIE. MNZ administration was withdrawn immediately, and HD treatment was performed for 3 consecutive days. Accompanying the remarkable decrease in serum MNZ levels, MIE symptoms were attenuated after three consecutive days of HD. In a brain MRI at 9 days, the high-intensity areas in the cerebellar dentate nuclei and splenium of the corpus callosum had disappeared. CONCLUSION: In this patient, we diagnosed MIE in the early stage using MRI, and 3 consecutive days of HD rapidly attenuated the symptoms associated with MIE, accompanied by a significant decrease in serum MNZ levels.
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Encefalopatias/induzido quimicamente , Metronidazol/efeitos adversos , Metronidazol/farmacocinética , Diálise Renal/métodos , Administração Oral , Idoso , Feminino , HumanosRESUMO
Flomoxef is used to treat bacterial prostatitis; however, its prostatic pharmacokinetics have not been fully clarified. Flomoxef (500 or 1000 mg) was administered to patients with benign prostatic hypertrophy (n = 54). After a 0.5-h infusion, venous blood samples were drawn at time points of 0.5-5 h, and prostate tissue samples were collected at time points of 0.5-1.5 h during transurethral resection of the prostate. The drug concentrations in plasma and prostate tissue were analyzed pharmacokinetically and used for a stochastic simulation to predict the probability of attaining pharmacodynamic target in prostate tissue. Showing dose linearity in the prostatic pharmacokinetics, flomoxef rapidly penetrated into prostate tissue, with a prostate/plasma ratio of 0.48-0.50 (maximum drug concentration) and 0.42-0.55 (area under the drug concentration-time curve). Against the tested populations of Escherichia coli, Klebsiella and Proteus species isolates, 0.5-h infusion of 1000 mg three times daily achieved a ≥90% expected probability of attaining the bactericidal target (70% of the time above the minimum inhibitory concentration [MIC]) in prostate tissue. The site-specific pharmacodynamic-based breakpoint (the highest MIC at which the target-attainment probability in prostate tissue was >90%) values were 0.25 mg/L (MIC for 90th percentile of E. coli and Klebsiella species) for 500 mg four times daily and 0.5 mg/L (MIC90 of Proteus species) for 1000 mg four times daily. These results help to fully characterize the prostatic pharmacokinetics of flomoxef, while also helping to rationalize and optimize the dosing regimens for prostatitis based on site-specific pharmacodynamic target attainment.
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Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Hiperplasia Prostática/tratamento farmacológico , Prostatite/tratamento farmacológico , Idoso , Antibacterianos/administração & dosagem , Cefalosporinas/administração & dosagem , Escherichia coli/efeitos dos fármacos , Humanos , Klebsiella/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , Próstata/microbiologia , Próstata/cirurgia , Hiperplasia Prostática/sangue , Hiperplasia Prostática/cirurgia , Prostatite/sangue , Prostatite/microbiologia , Prostatite/cirurgia , Proteus/efeitos dos fármacos , Ressecção Transuretral da PróstataRESUMO
OBJECTIVES: Chlamydia trachomatis is one of the major pathogens causing acute epididymitis. Azithromycin (AZM) has a good efficacy against C. trachomatis; however, the ability of AZM to penetrate into human epididymal tissue has not yet been fully elucidated. Here, we examined the appropriate dosage of oral AZM for human epididymal tissue by site-specific pharmacokinetic/pharmacodynamic (PK/PD) analysis. METHODS: Patients with prostate cancer who underwent orchiectomy were included in this study. All patients received a 1-g dose of AZM before orchiectomy. Both epididymal tissue and blood samples were collected during surgery, and the drug concentrations were measured by high-performance liquid chromatography. All concentration-time data were analyzed with a three-compartment model with first-order absorption and elimination processes to simulate AZM concentrations in serum and epididymal tissue. RESULTS: A total of 10 patients were enrolled in the current study. For the observed values, the ratio of the epididymal concentration to the serum concentration was 5.13 ± 3.71 (mean ± standard deviation). For the simulated values, the maximum concentrations were 0.64 µg/mL at 2.42 h in serum and 1.96 µg/g at 4.10 h in epididymal tissue. The 24-h concentrations were 0.239 µg/mL in serum and 0.795 µg/g in epididymal tissue. CONCLUSIONS: The penetration of oral AZM into human epididymal tissue was examined to assess the potential application of AZM for the treatment of acute epididymitis. Based on the previous reports mentioning drug-susceptibility of C. trachomatis, multiple doses of oral AZM 1 g would be recommended for epididymitis based on the site-specific PK/PD.
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Antibacterianos/farmacocinética , Azitromicina/farmacocinética , Epididimo/metabolismo , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Infecções por Chlamydia/tratamento farmacológico , Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/efeitos dos fármacos , Chlamydia trachomatis/patogenicidade , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana , Epididimo/microbiologia , Epididimite/tratamento farmacológico , Epididimite/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Orquiectomia , Neoplasias da Próstata/cirurgia , Distribuição TecidualRESUMO
PURPOSE: The purpose of this study was to identify the optimum dosing regimen of linezolid in sepsis patients with and without renal dysfunction and sepsis patients on low-dose continuous renal replacement therapy (CRRT) using a pharmacokinetics/pharmacokinetics (PK/PD) approach. METHODS: Sepsis patients with and without renal dysfunction (creatinine clearance < 50 mL/min), and sepsis patients on low-dose CRRT (dose: 800 mL/h) were studied. The PK data were modeled using a two-compartment model, and then used for simulation. The target PK/PD was the 24-h area under the concentration-time curve to minimum inhibitory concentration ratio of ≥ 80. Dosing regimens were evaluated using cumulative fraction of response (CFR) and safety probability (trough level < 7 µg/mL) by Monte Carlo simulation. RESULTS: Twenty-seven patients, including 8 patients with preserved renal function, 9 patients with renal dysfunction, and 10 patients on CRRT, were studied. The proposed regimen to attain CFR ≥ 90% was 800 mg every 12 h (safety probability 82.4%) for patients with preserved renal function. By contrast, the target CFR was attained with a decreased regimen in patients with renal dysfunction and those on CRRT [600 mg every 24h (safety probability 68.6%) and 800 mg every 24h (42.1%)]. CONCLUSIONS: We identified different dosage strategies to achieve target linezolid concentrations according to renal function and use of CRRT in sepsis patients. Because of unassured safety probability in patients without preserved renal function, dosing regimens should be adjusted based on the therapeutic drug monitoring.
Assuntos
Antibacterianos/farmacocinética , Linezolida/farmacocinética , Terapia de Substituição Renal/métodos , Sepse/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Humanos , Rim/fisiopatologia , Linezolida/administração & dosagem , Linezolida/sangue , Pessoa de Meia-Idade , Método de Monte Carlo , Estudos Prospectivos , Infecções Estafilocócicas/tratamento farmacológicoRESUMO
The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500 mg, n = 23; 1000 mg, n = 25) for 0.5 h prior to transurethral prostate resection. Drug concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC = 100 and maximum concentration (Cmax)/MIC = 8. Prostatic penetration of pazufloxacin was good with mean Cmax ratios (prostate tissue/plasma) of 0.82-0.99 and for AUC, 0.80-0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25 mg/L for 500 mg every 24 h (500 mg daily), 0.5 mg/L for 500 mg every 12 h (1000 mg daily), 1 mg/L for 1000 mg every 24 h (1000 mg daily), and 2 mg/L for 1000 mg every 12 h (2000 mg daily). Importantly, the 2000 mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2 mg/L.
Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Fluoroquinolonas/farmacologia , Fluoroquinolonas/farmacocinética , Oxazinas/farmacologia , Oxazinas/farmacocinética , Próstata/metabolismo , Prostatite/tratamento farmacológico , Infecção da Ferida Cirúrgica/prevenção & controle , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Escherichia coli/efeitos dos fármacos , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/sangue , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Oxazinas/administração & dosagem , Oxazinas/sangue , Próstata/microbiologia , Hiperplasia Prostática/cirurgia , Prostatite/microbiologia , Ressecção Transuretral da PróstataRESUMO
Piperacillin-tazobactam (PIP-TAZ) is commonly used to treat intraabdominal infections; however, its penetration into abdominal sites is unclear. A pharmacokinetic analysis of plasma, peritoneal fluid, and peritoneum drug concentrations was conducted to simulate dosing regimens needed to attain the pharmacodynamic target in abdominal sites. PIP-TAZ (4 g-0.5 g) was intravenously administered to 10 patients before abdominal surgery for inflammatory bowel disease. Blood, peritoneal fluid, and peritoneum samples were obtained at the end of infusion (0.5 h) and up to 4 h thereafter. PIP and TAZ concentrations were measured, both noncompartmental and compartmental pharmacokinetic parameters were estimated, and a simulation was conducted to evaluate site-specific pharmacodynamic target attainment. The mean peritoneal fluid:plasma ratios in the area under the drug concentration-time curve (AUC) were 0.75 for PIP and 0.79 for TAZ, and the mean peritoneal fluid:plasma ratios in the AUC were 0.49 for PIP and 0.53 for TAZ. The mean PIP:TAZ ratio was 8.1 at both peritoneal sites. The regimens that achieved a bactericidal effect with PIP (time above minimum inhibitory concentration [MIC] >50%) at both peritoneal sites were PIP-TAZ 4.5 g twice daily for an MIC of 8 mg/L, as well as 4.5 g three times daily, and 3.375 g four times daily for an MIC of 16 mg/L. These findings clarify the peritoneal pharmacokinetics of PIP-TAZ, and help consider the dosing regimens for intraabdominal infections based on site-specific pharmacodynamic target attainment.
Assuntos
Antibacterianos/farmacocinética , Líquido Ascítico/química , Ácido Penicilânico/análogos & derivados , Peritônio/química , Plasma/química , Inibidores de beta-Lactamases/farmacocinética , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Doenças Inflamatórias Intestinais/cirurgia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Ácido Penicilânico/farmacocinética , Piperacilina/farmacocinética , Combinação Piperacilina e Tazobactam , Cuidados Pré-Operatórios , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Tazobactam/piperacillin (TAZ/PIPC), which is often combined with continuous renal replacement therapy (CRRT), induces renal excretion and is thought to have a high component removal rate for blood purification. CRRT procedures vary depending on the country, region, and institution. It is not clear whether the dose of TAZ/PIPC for use in Japan can be determined based on studies conducted in other countries. Therefore, in this study, we examined the suitability of recommended dose in Japan. METHODS: The study subjects consisted of 10 patients who received TAZ/PIPC during CRRT in the intensive care unit of Hyogo College of Medicine, Nishinomiya, Japan. We used a one-compartment model to characterize and parameterize the pharmacokinetics of TAZ/PIPC because their blood levels were eliminated monoexponentially. RESULTS: Compared with the data of healthy adults, the half-lives (t1/2) of both PIPC and TAZ were prolonged while their clearance rates decreased. CONCLUSION: For the continuous hemodiafiltration procedure adopted in Japan, we concluded that the dose and frequency were appropriate because the patients who received PIPC/TAZ 2.25 g twice a day during continuous hemodiafiltration maintained appropriate blood levels of both PIPC and TAZ.
RESUMO
OBJECTIVES: This study aimed to investigate the penetration of fluoroquinolones into human epididymal tissue. METHODS: The penetration of levofloxacin (LVFX) 500 mg or sitafloxacin (STFX) 100 mg into epididymal tissue was examined. Patients with prostate cancer who were referred for orchiectomy were included. LVFX 500 mg (n = 9) or STFX 100 mg (n = 9) was administered orally 1 h before orchiectomy, and 0.5 g of epididymal tissue and blood samples were collected simultaneously during surgery. Drug concentrations were measured by high-performance liquid chromatography, and patient characteristics and adverse events were analyzed. RESULTS: The mean ratio of the epididymal concentration to the serum concentration was 1.48 ± 0.45 for LVFX and 1.54 ± 0.81 for STFX. For LVFX, the simulated curves estimated the following: maximum concentrations (Cmax) of 8.84 µg/ml in serum and 14.1 µg/g in epididymal tissue and area under the concentration-time curve for 24 h (AUC24) of 68.5 µg h/ml in serum and 108.9 µg h/g in epididymal tissue. For STFX, the Cmax was 1.22 µg/ml in serum and 1.66 µg/g in epididymal tissue, and the AUC24 was 9.58 µg h/ml in serum and 13.1 µg h/g in epididymal tissue. Neither treatment-related adverse events nor postoperative urogenital infections were observed. CONCLUSIONS: The results of this study suggest that oral administration of LVFX 500 mg or STFX 100 mg achieves effective epididymal concentrations for treatment of epididymitis.