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1.
Alejandro Pérez-Pitarch Rafael Ferriols-Lisart Gerardo Aguilar Carlos Ezquer-Garín F. Javier Belda Beatriz Guglieri-López 《International journal of antimicrobial agents》2018,51(1):115-121
Introduction
The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration.Methods
Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively.Results
Concentration-time data were described by a two-compartment model. Body–weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L.Conclusion
The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection. 相似文献2.
Michael A. Pfaller Robert K. Flamm Mariana Castanheira Helio S. Sader Rodrigo E. Mendes 《International journal of antimicrobial agents》2018,51(4):608-611
Background
Osteomyelitis is a difficult-to-treat infection that regularly involves prolonged use of systemic antibiotics. Dalbavancin has demonstrated activity against Gram-positive isolates, and has been considered as a candidate for the treatment of osteomyelitis in adults and children. This study evaluated the activity of dalbavancin against pathogens isolated from bone and joint infections (BJI).Methods
Eight hundred and one Staphylococcus aureus, 160 coagulase-negative staphylococci (CoNS), 164 β-haemolytic streptococci (BHS), 82 Enterococcus faecalis and 45 viridans group streptococci (VGS) causing BJI were collected consecutively (2011–2016) and tested for susceptibility by broth microdilution methods.Results
S. aureus (64.0%) was the most common pathogen associated with BJI, followed by BHS (13.1%) and CoNS (12.8%). All S. aureus (33.3% meticillin-resistant) isolates were susceptible to dalbavancin, linezolid and vancomycin, while daptomycin and clindamycin showed susceptibility rates of 99.5% and 89.0%, respectively. The minimum inhibitory concentration (MIC) results for dalbavancin were at least eight-fold lower than these comparators against all S. aureus. Dalbavancin was the most potent agent against CoNS (63.1% meticillin-resistant), followed by daptomycin, linezolid and vancomycin. All E. faecalis isolates were inhibited by dalbavancin at ≤0.25?mg/L (US Food and Drug Administration susceptibility breakpoint), except for three vancomycin-resistant isolates. High susceptibility rates for ampicillin (98.8%), daptomycin (100.0%), linezolid (100.0%) and vancomycin (95.1%) were obtained against E. faecalis. Dalbavancin was very active against BHS (MIC90 ≤0.03?µg/mL), and was the most active agent against VGS (highest MIC ≤0.06?mg/L). Ceftriaxone, daptomycin and vancomycin were also active (93.3–100.0% susceptible) against VGS, whereas clindamycin (84.4% susceptible) had marginal activity.Conclusion
Dalbavancin appears to be a viable candidate for treating BJI/osteomyelitis caused by Gram-positive cocci. 相似文献3.
Konstantinos Z. Vardakas Georgios L. Voulgaris George Samonis Matthew E. Falagas 《International journal of antimicrobial agents》2018,51(1):1-9
Background
Inhaled colistin is becoming increasingly popular against respiratory tract infections caused by multidrug resistant (MDR) Gram-negative bacteria because it may overcome the problems associated with intravenous (IV) administration.Objective
To investigate the effectiveness and safety of inhaled colistin as monotherapy (without concomitant IV administration of colistin) in the treatment of respiratory tract infections caused by MDR or colistin–only susceptible Gram–negative bacteria.Methods
PubMed and Scopus databases were searched. A systematic review and meta-analysis were conducted.Results
Twelve studies (373 patients receiving inhaled colistin for respiratory tract infection) were included. Ten studies evaluated patients with pneumonia (including 8 studies with ventilator-associated pneumonia) and 2 studies evaluated patients with ventilator-associated tracheobronchitis. Patients with infections due to MDR Acinetobacter baumannii and Pseudomonas aeruginosa were mainly studied. Daily dose of inhaled colistin and treatment duration varied in the individual studies. The pooled all-cause mortality was 33.8% (95% CI 24.6% – 43.6%), clinical success was 70.4% (58.5% – 81.1%) and eradication of Gram-negative bacteria was shown in 71.3% (57.6% – 83.2%) of cases.Conclusions
Inhaled colistin monotherapy may deserve further consideration as a mode for colistin administration for the treatment of respiratory tract infections caused by MDR A. baumannii and P. aeruginosa. 相似文献4.
Eyal Kleinhendler Matan J. Cohen Allon E. Moses Ora Paltiel Jacob Strahilevitz Amos Cahan 《International journal of antimicrobial agents》2018,51(1):71-76
Background
There are several empiric antibiotic treatment options for febrile neutropenia, yet there is no universally-accepted initial protocol. We aimed to assess the performance of a protocol (piperacillin, gentamicin and cefazolin) introduced over 40 years ago and compare its coverage against bacteria isolated from blood of neutropenic patients with that of various commonly used antibiotic treatment protocols.Methods
Adults with neutropenia admitted between 2003 and 2012 to the hemato-oncologic departments and in whom blood cultures were taken on admission were included. Appropriateness of several common antibiotic protocols was assessed based on the susceptibility of the blood isolates. Crude mortality rates were computed by the susceptibility of bacteria isolated from patients' blood to the actual treatment given.Results
In total, 180 admissions of neutropenic patients (95 in patients who had fever above 38?°C) with positive blood cultures were analyzed. The actual antibiotic regimen prescribed was deemed appropriate in 82% of bacteremia episodes. The recommended institutional protocol was used in 62% of bacteremia episodes in neutropenic patients. This protocol would have been appropriate in 85% of all neutropenic bacteremia episodes and 89% of episodes in febrile neutropenia patients compared with piperacillin/tazobactam (79%, P?=?0.13 and 76%, P?=?0.002, respectively) and imipenem (93%, P?=?0.004 and 92%, P?=?0.74, respectively). Isolation of bacteria resistant to the actual antibiotic treatment given was associated with higher mortality at one week and at 30 days.Conclusion
Common current antibiotic regimens provide similar coverage among febrile neutropenic patients, whereas broad spectrum antibiotic combinations maximize coverage among neutropenic patients. 相似文献5.
Michele Bartoletti Sara Tedeschi Renato Pascale Luigi Raumer Alberto Enrico Maraolo Giulia Palmiero Fabio Tumietto Francesco Cristini Simone Ambretti Maddalena Giannella Russell Edward Lewis Pierluigi Viale 《International journal of antimicrobial agents》2018,51(3):516-521
Objectives
We hypothesised that treatment with a tigecycline-based antimicrobial regimen for intra–abdominal infection (IAI) could be associated with lower rates of subsequent carbapenem-resistant Enterobacteriaceae (CRE) colonisation or Clostridium difficile infection (CDI) compared with a meropenem-based regimen.Methods
We performed a retrospective, single-centre, matched (1:1) cohort analysis of all patients who received at least 5 days of empirical or targeted tigecycline (TIG)- or meropenem (MER)-based treatment regimens for IAI over a 50-month period. Patients with previous CRE colonisation and CDI were excluded. Risk factors for CRE and CDI were assessed with a Cox regression model that included treatment duration as a time-dependent variable. Thirty-day mortality was assessed with Kaplan-Meier curves.Results
We identified 168 TIG-treated and 168 MER-treated patients. The cumulative incidence rate ratio of CDI was 10-fold lower in TIG-treated vs. MER-treated patients (incidence rate ratio [IRR] 0.10/1000 patient-days, 95%CI 0.002–0.72, P?=?0.007), but similar incidence rates were found for CRE colonisation (IRR 1.39/1000 patient-days, 95%CI 0.68–2.78, P?=?0.36). In a multivariate Cox regression model, the receipt of a TIG- vs. MER-based regimen was associated with significantly lower rates of CDI (HR 0.07, 95%CI 0.03–0.71, P?=?0.02), but not CRE (HR 1.12, 95% CI 0.45–2.83, P?=?0.80). All-cause 30-day mortality was similar in the two groups (P?=?0.46).Conclusion
TIG-based regimens for IAI were associated with a 10-fold lower incidence of CDI compared with MER-based regimens, but there was no difference in the incidence of CRE colonisation. 相似文献6.
Eman M. Alfadhli 《Saudi Pharmaceutical Journal》2018,26(7):965-969
Background
Patients with uncontrolled type 1 diabetes mellitus (T1DM) are at a high risk for Ramadan fasting and are exempt from fasting; however, most still insist on fasting. The aim of this study was to examine glucose level fluctuations in those patients during Ramadan fasting using a real-time continuous glucose monitoring system (RT-CGMS).Methods
This pilot study involved adult patients with uncontrolled T1DM (HbA1c?>?7%) who insisted on fasting during Ramadan in 2014 from Maternity and Children’s Hospital, Medina, Saudi Arabia. A Medtronic RT-CGMS was used to monitor the participants’ glucose levels for 3 consecutive days during fasting.Results
The study included 22 patients (mean age 22?±?6?years, duration of diabetes 10.9?±?7.2?years, HbA1c level 9.3?±?1.2). All participants were using the basal-bolus insulin regimen, except for one patient who was on an insulin pump. Sensor glucose (SG) profiles typically followed a pattern that was characterized by an exaggerated increase after iftar, which was sustained overnight, and a second rapid rise after suhoor, with a prolonged glucose decay over the daylight hours. The average SG was 199?±?104.1?mg/dl, which was lower during fasting 188.4?±?103.41?mg/dl than during the eating hours 212.5?±?103.51?mg/dl (P?=?0.00). There was a higher rate of hyperglycemia (48%) than hypoglycemia (10%).Conclusions
Patients with uncontrolled T1DM who fasted during Ramadan experienced a wide fluctuation of glucose levels between fasting and eating hours, exhibiting a greater tendency toward hyperglycemia. The long-term effects for this finding are not known and warrant further investigation. 相似文献7.
Maddalena Giannella Enrico Maria Trecarichi Daniele Roberto Giacobbe Francesco Giuseppe De Rosa Matteo Bassetti Alessandro Bartoloni Michele Bartoletti Angela Raffaella Losito Valerio del Bono Silvia Corcione Sara Tedeschi Francesca Raffaelli Carolina Saffioti Teresa Spanu Gian Maria Rossolini Anna Marchese Simone Ambretti Roberto Cauda Mario Tumbarello 《International journal of antimicrobial agents》2018,51(2):244-248
Objectives
To evaluate the impact of high-dose (HD) carbapenem-based combination therapy on clinical outcome in patients with monomicrobial carbapenem-resistant Klebsiella pneumoniae (CR-KP) bloodstream-infection (BSI).Methods
Post hoc analysis of all adult patients with CR-KP BSI who were treated with a combination antibiotic regimen, collected over a six-year period in six large Italian teaching hospitals. To control for confounding effects of HD carbapenem combination on 14-day mortality, a multivariate Cox regression analysis was performed. Due to imbalances between patients, a propensity score for receiving HD carbapenem was added to the model.Results
595 patients with CR-KP BSI were analysed, 77% of isolates showed a carbapenem MIC ≥16?mg/L, 428 (71.9%) received HD carbapenem-based combination therapy. Overall, 127 patients (21.3%) died within 14 days after BSI onset. Multivariate analysis showed the Charlson comorbidity index (HR 1.31, 95%CI 1.20–1.43, P?<0.001), septic shock at BSI onset (HR 3.14, 95%CI 2.19–4.50, P?<0.001), and colistin-resistant strain (HR 1.52, 95%CI 1.02–2.24, P?=?0.03) were independently associated with 14-day mortality, whereas admission to surgical ward (HR 0.44, 95%CI 0.25–0.78, P?=?0.005) and HD carbapenem use (HR 0.69, 95%CI 0.47–1.00, P?=?0.05) were protective factors. When adjusted for the propensity score, HD carbapenem use showed a greater protective effect (HR 0.64, 95%CI 0.43–0.95, P?=?0.03). Stratifying the model for carbapenem MIC, the benefit of HD carbapenem was also observed for strains with carbapenem MIC ≥16?mg/L.Conclusions
In patients receiving combination therapy for CR-KP BSI, the use of HD carbapenem seems to be associated with better outcome, even in the presence of high-level carbapenem resistance. 相似文献8.
Marjan Wouthuyzen-Bakker Eduard Tornero Laura Morata Prashant V. Nannan Panday Paul C. Jutte Guillem Bori Greetje A. Kampinga Alex Soriano 《International journal of antimicrobial agents》2018,51(1):38-42
Objectives
The combination of a fluoroquinolone with rifampin is one of the cornerstones in the treatment of prosthetic joint infections (PJI) caused by staphylococci. Moxifloxacin is highly active against methicillin–susceptible Staphylococcus aureus (MSSA) and, therefore, is an attractive agent to use. However, several studies reported a lowering in serum moxifloxacin levels when combined with rifampin. The clinical relevance remains unclear. We determined the outcome of patients with early acute PJI caused by MSSA treated with either moxifloxacin/rifampin or levofloxacin/rifampin.Methods
Medical files of patients treated with moxifloxacin/rifampin (University Medical Centre Groningen) or levofloxacin/rifampin (Hospital Clinic Barcelona) were retrospectively reviewed (2005–2015). Treatment failure was defined as the need for revision surgery and/or suppressive therapy, death by infection or a relapse of infection during follow-up.Results
Differences in baseline characteristics between the two cohorts were observed, but prognostic parameters for failure, as defined by the KLIC-score (Kidney failure, Liver cirrhosis, Index surgery, C–reactive protein and Cemented prosthesis), were similar in the two groups (2.9 [1.5 SD] for the moxifloxacin group vs. 2.2 [1.2 SD] for the levofloxacin group [P?=?0.16]). With a mean follow-up of 50 months (36 SD) in the moxifloxacin group, and 67 months (50 SD) in the levofloxacin group (P?=?0.36), treatment was successful in 89% vs. 87.5%, respectively (P?=?0.89). None of the failures in the moxifloxacin group were due to rifampin– or moxifloxacin–resistant S. aureus strains.Conclusion
Our data indicate that moxifloxacin combined with rifampin is as clinically effective as levofloxacin/rifampin for early acute PJI caused by MSSA. 相似文献9.
Mansour Alsharidah Metab. Algeffari Abdel-Moneim Hafez Abdel-Moneim Mohamed Faisal Lutfi Haila Alshelowi 《Saudi Pharmaceutical Journal》2018,26(1):1-6
Background
Type 2 diabetes is a chronic condition that requires pharmacotherapy interventions. Metformin and gliclazide are widely used drugs in monotherapy. However, their complementary action made utilization of the combination of these drugs an appealing approach.Aims
The study compared major therapeutic potentials of combined metformin/gliclazide treatment over metformin monotherapy based on the following parameters: oxidative stress, lipid profile, and hepatorenal functions.Subjects and methods
This is a comparative study was conducted from March 2015 to March 2016. The study screened 80 type 2 diabetic patients, of which 40 patients underwent combined metformin?+?gliclazide therapy (500?mg BD?+?80?mg OD, respectively). The other 40 were matched for age and duration of diabetes mellitus with the previous group and received metformin monotherapy (500?mg BD). The levels of fasting blood glucose (FBG), total glycated hemoglobin (HbA1c), lipid peroxidation, total antioxidant capacity, serum creatinine, aspartate and alanine transaminases, total cholesterol, triglycerides, high-density lipoproteins, and low-density lipoproteins were measured according to the standard methods.Results
Oxidative stress, lipid profile, and hepatorenal functions were comparable in patients of both groups. However, patients on metformin treatment showed significantly lower levels of FBG [7.61 (6.70–8.89) mmol/L vs. 9.00 (7.30–10.68) mmol/L; P?=?.022] and HBA1c [7.00 (6.40–7.65)% vs. 8.20 (7.20–9.75)%; P?<?.001] compared to those on combined therapy.Conclusion
Oxidative stress, lipids profile, and hepatorenal functions were not different in patients who were on combined metformin/gliclazide therapy and compared to those metformin alone. In contrast, glycemic control was poor in the diabetic patients undergoing combined therapy. 相似文献10.
Eric Wenzler Kristen L. Bunnell Larry H. Danziger 《International journal of antimicrobial agents》2018,51(5):700-706
Background
There is a need to identify practice patterns of polymyxin use, quantify gaps in knowledge, and recognize areas of persistent confusion.Methods
A structured electronic survey was distributed to physicians, pharmacists and microbiologists. Demographic information was obtained, along with data regarding availability, stewardship principles, therapeutic usage, dosing, microbiological testing, and knowledge, attitudes and beliefs regarding the polymyxins.Results
In total, there were 420 respondents with a median of 8 (interquartile range 4–15) years of experience in infectious diseases (52.5%) and critical care (35%). Of the respondents who reported that only one polymyxin was available for use, 17.1% used polymyxin B. Over half (52.5%) of the respondents utilized a loading dose very often/always, and 66.8% dosed both polymyxins in milligrams, with the most common doses of colistin and polymyxin B being 2.5?mg/kg twice daily (60.3%) and 1.5?mg/kg twice daily (65%), respectively, for patients with normal renal function. Polymyxins were most often used for respiratory infections (63%) in combination with a carbapenem (63.6%). Approximately 85% of respondents reported their knowledge level to be fair, good or very good, although 34.9% answered two of the three knowledge questions incorrectly. More than 70% of respondents agreed that confusion exists in all surveyed areas of polymyxin use. Almost all respondents (91.2%) agreed that a polymyxin guideline would be a helpful resource.Conclusions
This survey revealed objective and subjective variability in the use and perception of the polymyxins, and identified several areas in which they were being used contrary to the available evidence. The information provided herein lays the framework to harmonize clinical practice, guide future research and shape consensus guidelines. 相似文献11.
Zahra Khalil Alsairafi Felicity J. Smith Kevin Michael Geoffrey Taylor Fatemah Alsaleh Abdulnabi T. Alattar 《Saudi Pharmaceutical Journal》2018,26(4):487-495
Background
Diabetes is a threat to peoples’ lives around the world, particularly in the Middle East. Medicine misuse and poor glycaemic control are prevalent among patients with type 2 diabetes, especially insulin-dependent patients (Alsairafi et al., 2016). With advances in medical technology, insulin pumps became a treatment option for patients with type 1 diabetes and those with insulin-dependent type 2 diabetes. However, use of these devices is still lacking in Kuwait, particularly in patients with type 2 diabetes. Information on how patients manage these devices and their efficacy and safety from the perspectives of patients is also lacking (Alsaleh et al., 2016).Objective
To examine the views and experiences of adults with type 2 diabetes regarding the use of insulin pumps compared to their previous insulin delivery methods, in terms of glycaemic control, quality of life, preference, convenience and adherence to doses.Setting
The main five secondary-care hospitals in Kuwait: Mobarak Al-Kabeer, Al Amiri, Al Adan, Al Farwaniya and Al Jahra.Method
All adults with type 2 diabetes who used an insulin pump were invited to participate. Data were collected through semi-structured interviews. Data analysis was performed using MAXQDA-11.Results
A total of eight patients were interviewed. Interviews with patients revealed that using an insulin pump improved patients’ glycaemic control and quality of life as a consequence of improved satisfaction and adherence to doses.Conclusion
From the perspective of adults with type 2 diabetes, there are lots of benefits of using insulin pumps over other insulin delivery methods, mainly seen by the improvement of quality of life and patients’ adherence to doses. Policy-makers and healthcare professionals (HCPs) must be aware of such benefits and should support the wider implementation of this technology in the country by including patients with type 2 diabetes. Results of this study will help to inform healthcare provision and guideline modifications and to provide guidance for new patients using this therapy. 相似文献12.
Paul Rolan Jacqueline A Gibbons Lin He Eppie Chang Drew Jones Matthew I Gross Jennifer Bahr Davidson Laura M Sanftner Kirk W Johnson 《British journal of clinical pharmacology》2008,66(6):792-801
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
- Ibudilast is an oral drug approved in Asia for asthma.
- Tolerability of 10-mg regimens has been described previously.
- Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers.
WHAT THIS STUDY ADDS
- Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers.
- Higher-dose regimens are relevant for testing in new neurological indications.
- LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast).
AIMS
To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen.METHODS
Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite.RESULTS
Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median Tmax was 4–6 h. Mean (SD) steady-state plasma Cmax and AUC0–24 were 60 (25) ng ml−1 and 1004 (303) ng h ml−1, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent.CONCLUSIONS
Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day−1) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models. 相似文献13.
Objective:
The present study was designed to investigate the ameliorative potential and possible mechanism of hydroalcoholic extract of flowers of P. granatum in glycerol-induced acute renal failure (ARF) in rats.Materials and Methods:
The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 ml/kg) and the animals were sacrificed after 24 hours of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury.Results:
Pretreatment with hydroalcoholic extract of flowers of P. granatum (125 and 250 mg/kg p.o. twice daily for 3 days) significantly attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner. BADGE (Bisphenol-A-diglycidyl ether) (30 mg/kg), a peroxisome proliferator-activated receptor (PPAR)-γ antagonist, and N(omega)-nitro-l-arginine-methyl ester (L-NAME) (10, 20, and 40 mg/kg), nitric oxide synthase inhibitor, were employed to explore the mechanism of renoprotective effects of Punica granatum. Administration of BADGE (30 mg/kg) and L-NAME (40 mg/kg) abolished the beneficial effects of P. granatum in glycerol-induced renal dysfunction.Conclusion:
Hydroalcoholic extract of flowers of P. granatum has ameliorative potential in attenuating myoglobinuric renal failure and its renoprotective effects involve activation of PPAR-γ and nitric oxide-dependent signaling pathway. 相似文献14.
Meta-analysis: the adjuvant role of thymopentin on immunological response to hepatitis B virus vaccine in end-stage renal disease 总被引：2，自引：0，他引：2
Summary
Background
It has been calculated that 30–40% of dialysis patients fail to produce antibodies to HBsAg antigen after vaccination towards hepatitis B virus. Several authors have reported on the benefit of thymopentin (TP5) as adjuvant to vaccine against hepatitis B virus in patients receiving regular dialysis. However, consistent information on this issue is still lacking.Aims
To evaluate efficacy and safety of thymopentin as adjuvant to hepatitis B vaccine in dialysis patients by performing a systematic review with a meta‐analysis of clinical trials.Methods
We used the random effects model of DerSimonian and Laird, with heterogeneity and sensitivity analyses.Results
We identified 11 studies involving 272 unique patients with end‐stage renal disease. Only prospective, controlled trials were included. Pooling of study results did not show a significant increase in seroresponse rate among study (thymopentin plus hepatitis B virus vaccine) vs. control (hepatitis B virus vaccine alone) patients; the pooled odds ratio of failure to respond to hepatitis B virus vaccine was 0.677 (95% confidence intervals: 0.285–1.605); no heterogeneity was found (P = 0.0001). Thymopentin significantly improved the seroresponse rate in the subgroup of trials based on greater thymopentin doses (OR: 0.184; 95% CI: 0.085–0.398).Conclusions
Our meta‐analysis showed that thymopentin significantly improved the seroresponse rate towards hepatitis B vaccine only in dialysis patients treated with higher thymopentin doses. The limited number of patients precluded definitive conclusions.15.
Purpose
To characterize population pharmacokinetic (PK) of naldemedine, to identify factors which influence naldemedine PK, and to evaluate their clinical relevancy based on exposure-response relationships.Methods
A population PK model was developed with pooled naldemedine concentrations from healthy subjects, patients with chronic non-cancer pain and opioid-induced constipation (OIC), and cancer patients with OIC. Exposure-response analyses were performed with efficacy (responder or non-responder) and safety (occurrence of gastrointestinal disorders or not) data in phase 2b and phase 3 studies.Results
Naldemedine plasma concentrations were adequately described by a 2-compartment model with first-order absorption and absorption lag time. The final model included the effects of age, creatinine clearance, race, and gender on apparent total clearance; the effects of body weight, health status, and food condition on apparent volume of central compartment; and the effect of age on first-order rate of absorption. When subjects took 0.2 mg of naldemedine once daily, the probability of spontaneous bowel movement (SBM) responders was predicted to be approximately 50%, while that of severe gastrointestinal disorders was predicted to be less than 3%. The influence of the covariates on PK was not considered clinically significant because similar efficacy and safety were expected based on the exposure-response analysis.Conclusions
The covariates are identified in the population PK analysis; however, no dose-adjustment is required for them based on the exposure-response analysis.16.
Elena Soto Satoshi Shoji Chieko Muto Yoshiro Tomono Scott Marshall 《British journal of clinical pharmacology》2014,77(3):509-521
Aims
The aims of this study were to develop a population pharmacokinetic (PK) model of ampicillin and sulbactam, to identify patient characteristics influencing the PK, and to explore the relationship between dose regimen and degree of renal impairment with exposure and time above minimum inhibitory concentration (MIC).Methods
This analysis was performed on PK data for ampicillin and sulbactam and MIC data from a clinical trial in Japanese patients with community acquired pneumonia. Simulations were performed to investigate the effects of different dosing intervals on exposure and time above MIC in various degrees of renal impairment.Results
The plasma concentrations from 47 patients were adequately described by a two compartment model with simultaneous fit of ampicillin and sulbactam PK data, where creatinine clearance on clearance and body weight on volume in the peripheral compartment were identified as covariates for both drugs. Creatinine clearance contributed to reducing inter-individual variability of clearance by 16%. Mean clearance (inter-individual variability) for ampicillin and sulbactam was estimated to be 10.7 l h−1 (14.8%) and 10.4 l h−1 (15.2%), respectively. The time above MIC for each pathogen was generally > 50% of the treatment period. Simulations for exposure and time above MIC supported currently recommended dose adjustments.Conclusions
This study provided a PK model for ampicillin and sulbactam, the time above MICs for identified pathogens and associated simulation results. These findings provide useful information and augment evidence for the established dosage regimens in patients with various degrees of renal impairment. 相似文献17.
Purpose
LY3015014 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to the catalytic domain of PCSK9 and reduce low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia that is poorly controlled by maximally tolerated statin therapy. The objective of this pharmacokinetic/pharmacodynamics (PK/PD) analysis was to characterize the PK and PD properties of LY3015014 and assess the effect of covariates on the LY3015014 PK-PD profiles.Methods
Single and multiple dose data from three phase1 studies in healthy subjects (n?=?133), as well as a phase 2 study in hypercholesterolemia patients (n?=?527) were combined into a single dataset for analysis. In this dataset, healthy subjects received single intravenous (IV) doses of 0.03 to 10 mg/kg, or multiple subcutaneous (SC) doses of 1.0 to 3.0 mg/kg, administered every 2 to 4 weeks, while patients received 20 to 300 mg every 4 weeks or 100 to 300 every 8 weeks. PK/PD analysis was performed using NONMEM (ICON, software version 7.0 level 3). PK and PD modeling were conducted sequentially, with PK parameters fixed during the development of the PK/PD model. PD parameters and estimated intersubject and intrasubject variability were obtained based on pharmacological drug exposure-response relationships. Age, baseline total PCSK9, body weight, diabetes diagnosis, hypercholesterolemia disease status, dose, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and satin administration were evaluated as potential covariates in the PK model. Baseline total PCSK9, baseline LDL-C, diabetes diagnosis, disease status, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and Statin administration were evaluated as potential covariates in the PD model.Results
LY3015014 PK profile was consistent across all the studies and between healthy subjects and hypercholesterolemia patients. The PK time course data were well described by a two compartment PK model with first order absorption, and covariates identified for PK parameters included weight on both clearance (CL) and central volume (V2), dose on CL, race on bioavailability (F), and age on V2. The PD (LDL-C) was described using an indirect response model with LY3015014 acting to stimulate the elimination of LDL-C. Covariates identified to have a statistically significant impact on PD were coadministration of statins, baseline LDL-C, metabolic syndrome status and gender.Conclusions
The population PK/PD model adequately describes the PK and PD profiles of LY3015014. Identification of clinically significant covariates will support the design and dose selection for the pivotal registration studies, ensuring that patients are dosed appropriately.18.
Background:
Clinicians commonly rely on tertiary drug information references to guide drug dosages for patients who are receiving continuous renal replacement therapy (CRRT). It is unknown whether the dosage recommendations in these frequently used references reflect the most current evidence.Objective:
To determine the presence and accuracy of drug dosage recommendations for patients undergoing CRRT in 4 drug information references.Methods:
Medications commonly prescribed during CRRT were identified from an institutional medication inventory database, and evidence-based dosage recommendations for this setting were developed from the primary and secondary literature. The American Hospital Formulary System—Drug Information (AHFS–DI), Micromedex 2.0 (specifically the DRUGDEX and Martindale databases), and the 5th edition of Drug Prescribing in Renal Failure (DPRF5) were assessed for the presence of drug dosage recommendations in the CRRT setting. The dosage recommendations in these tertiary references were compared with the recommendations derived from the primary and secondary literature to determine concordance.Results:
Evidence-based drug dosage recommendations were developed for 33 medications administered in patients undergoing CRRT. The AHFS–DI provided no dosage recommendations specific to CRRT, whereas the DPRF5 provided recommendations for 27 (82%) of the medications and the Micromedex 2.0 application for 20 (61%) (13 [39%] in the DRUGDEX database and 16 [48%] in the Martindale database, with 9 medications covered by both). The dosage recommendations were in concordance with evidence-based recommendations for 12 (92%) of the 13 medications in the DRUGDEX database, 26 (96%) of the 27 in the DPRF5, and all 16 (100%) of those in the Martindale database.Conclusions:
One prominent tertiary drug information resource provided no drug dosage recommendations for patients undergoing CRRT. However, 2 of the databases in an Internet-based medical information application and the latest edition of a renal specialty drug information resource provided recommendations for a majority of the medications investigated. Most dosage recommendations were similar to those derived from the primary and secondary literature. The most recent edition of the DPRF is the preferred source of information when prescribing dosage regimens for patients receiving CRRT. 相似文献19.
Kavita Sekhri Ruchika Nandha Amit Mandal Deepak Bhasin Harpal Singh 《Indian journal of pharmacology》2013,45(6):608-611
Objectives:
Studies have established the effectiveness and safety of polymyxins in treating multidrug resistant (MDR) pathogens. However, the challenge is whether these nephrotoxic drugs can be administered in compromised renal states. The present study was undertaken to establish their role in such patients. The effectiveness and nephrotoxicity of polymyxins in critically ill-patients harboring MDR Gram-negative bacteria with already compromised renal functions was compared with those with normal renal functions.Materials and Methods:
This retrospective cohort study (March 2008-March 2010) was conducted in the intensive care unit of a tertiary care hospital. A total of 48 eligible critically ill-patients receiving polymyxins were enrolled. A comparison was carried out (length of stay in hospital, mortality, renal function) between patients with acute kidney injury (AKI, n = 18; defined by the RIFLE classification) and patients with normal renal function (non-AKI, n = 30).Results:
Patients with baseline AKI had a significantly higher adjusted mortality rate at admission when compared with the non-AKI group. At the end of therapy with polymyxins, 26.66% non-AKI patients developed renal dysfunction while 38.88% of patients in the AKI group had worsening of renal function (P = 0.006). However, there was no significant difference in the length of hospital stay (23.9 ± 13.24 vs. 30.5 ± 22.50; P = 0.406) and overall mortality (44.4% vs. 36.7%; P = 0.76) between two groups.Conclusion:
Polymyxins can be administered in AKI patients with favorable results provided used judiciously with strict monitoring of renal functions, dose modification according to creatinine clearance and aggressive fluid management.KEY WORDS: Multidrug resistant Gram-negative septicemia, nephrotoxicity, polymyxin B, polymyxin E, renal dysfunction 相似文献20.
Yan Feng Eric Masson David Dai Susan M Parker David Berman Amit Roy 《British journal of clinical pharmacology》2014,78(1):106-117