Impact of an integrated medication management model on the collaborative working relationship among healthcare professionals in a hospital: an explanatory mixed methods study.

An integrated medication management (IMM) model was implemented in a medical center ward to improve the delivery of clinical pharmaceutical services (CPSs). This model incorporated a ward-based clinical pharmacist who performed medication reconciliation and medication reviews. It was perceived to promote interprofessional collaboration between pharmacists and non-pharmacist healthcare professionals (NPHPs, including attending physicians, nurse practitioners, and registered nurses). This study aimed to evaluate the effects of the IMM on NPHPs' intentions to collaborate with pharmacists and understand the mechanism of the impact of the IMM on interprofessional collaboration. A sequential explanatory mixed methods design was employed in the study. Initially, a questionnaire was administered to assess the effects of the IMM on NPHPs' intentions to collaborate with pharmacists. The NPHPs' experiences with the IMM were then documented using semi-structured interviews with inductive thematic analysis. Fifty-eight NPHPs completed the questionnaire, and NPHPs from the intervention ward reported a higher intention to discuss patient-related medication issues with pharmacists, indicating collaboration. Eleven NPHPs were interviewed, and they stated having better working relationships with pharmacists, experiencing more effective CPSs, and noting improved communication with pharmacists. The integration of quantitative and qualitative findings demonstrates that the critical mechanism of the IMM in promoting collaborative relationships is to integrate pharmacists into medical practice, which familiarizes NPHPs with pharmacists' roles, improves communication, and enables pharmacists to identify NPHPs' needs. To summarize, allowing ward-based pharmacists to engage in medical teams on a regular basis appears vital for improving interprofessional teamwork. Furthermore, stakeholders aiming to promote CPS in their institutions should consider the needs and communication channels among NPHPs.

Impact of integrated medication management program on medication errors in a medical center: an interrupted time series study.

BACKGROUND: Medication errors (MEs) are harmful to patients during hospitalization, especially elderly patients. To reduce MEs, an integrated medication management (IMM) model was developed in a 2500-bed medical center, allowing a clinical pharmacist to participate in the daily ward round and perform medication reconciliation and medication reviews. This study aimed to evaluate the impact of the IMM model on MEs and medication utilization using a quasi-experimental design. METHODS: We conducted an interrupted time-series study using the aggregated data of monthly admissions from two wards of a medical center, where one ward served as the intervention and the other served as the external control. The pre- and post-intervention phases comprised of 40 and 12 monthly observational units, respectively. The primary outcome was the mean number of ME reports, which were further investigated for different ME types. The mean number of daily inpatient prescriptions, mean number of daily self-prepared medications, and median daily medication costs were measured. All outcomes were measured per admission episode. Segmented regression was used to evaluate the level and slope changes in the outcomes after IMM model implementation, and subgroup analyses were performed to examine the effects on different groups. RESULTS: After IMM model implementation, the mean number of ME reports increased (level change: 1.02, 95% confidence interval [CI]: 0.68 to 1.35, P < 0.001). The number of reports has shown a dramatic increase in omissions or medication discrepancies, inappropriate drug choices, and inappropriate routes or formulations. Furthermore, the mean number of daily inpatient prescriptions was reduced for patients aged ≥75 years (level change: -1.78, 95% CI: -3.06 to -0.50, P = 0.009). No significant level or slope change was observed in the control ward during the post-intervention phase. CONCLUSIONS: The IMM model improved patient safety and optimized medication utilization by increasing the reporting of MEs and decreasing the number of medications used.

Pharmacokinetics and dosing of vancomycin in patients undergoing sustained low efficiency daily diafiltration (SLEDD-f): A prospective study.

BACKGROUND/PURPOSE: The pharmacokinetics of vancomycin in patients who undergo sustained low efficiency daily diafiltration (SLEDD-f) is not clear. This study aimed to determine the appropriate vancomycin dosage regimen for patients receiving SLEDD-f. METHODS: This prospectively observational study enrolled critically ill patients older than 18 years old that used SLEDD-f as renal replacement therapy and received vancomycin treatment. An 8-h SLEDD-f was performed with FX-60 (high-flux helixone membrane, 1.4 m2). Serial blood samples were collected before, during, and after SLEDD-f to analyse vancomycin serum concentrations. Effluent fluid samples (a mixture of dialysate and ultrafiltrate) were also collected to determine the amount of vancomycin removal. RESULTS: Seventeen patients were enrolled, and 10 completed the study. The amount of vancomycin removal was 447.4 ± 88.8 mg (about 78.4 ± 18.4% of the dose administered before SLEDD-f). The vancomycin concentration was reduced by 57.5 ± 14.9% during SLEDD-f, and this reduction was followed by a rebound with duration of one to three hours. The elimination half-life of vancomycin decreased from 64.1 ± 35.7 h before SLEDD-f to 7.0 ± 3.0 h during SLEDD-f. CONCLUSION: Significant amount of vancomycin removed during SLEDD-f. Despite the existence of post-dialysis rebound, a sufficient supplemental dose is necessary to maintain therapeutic range.

Factors affecting serum concentration of dabigatran in Asian patients with non-valvular atrial fibrillation.

BACKGROUND/PURPOSE: Dabigatran is effective in preventing ischemic stroke and systemic embolism in patients with atrial fibrillation. Although the therapeutic window for dabigatran is wide, its pharmacokinetic properties can differ between specific populations. This study aimed to establish a real-life plasma dabigatran concentration database and investigate potential factors affecting this concentration in Asians. METHODS: Patients under dabigatran therapy were recruited. Plasma dabigatran concentration was determined in trough and peak blood samples by using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Factors affecting the dabigatran concentration were investigated. RESULTS: A total of 46 patients (33 male, 71.7%) were prospectively enrolled. Most of them were receiving a low dose regimen (110 mg twice daily, n = 38, 82.6%). The trough and peak concentrations were significantly correlated (p < 0.001), and the trough concentration was higher in patients aged ≥75 years, body weight ≤60 kg, creatinine clearance (CrCl) ≤50 mL/min, CHA2DS2-VASc score >3 points, and HAS-BLED score ≥3 points. Multiple linear regression analysis identified body weight and serum creatinine as key factors predicting trough concentration (p = 0.003 and 0.005, respectively). Importantly, drug adherence was the only independent factor associated with low trough concentration, defined as the lowest 20th percentile in our study cohort (n = 10, hazard ratio = 9.07; 95% CI, 1.12 to 73.22; p = 0.004). CONCLUSION: Dabigatran monitoring may be considered for patients at risk of overexposure, especially those with low body weight and renal insufficiency, and also for detecting those with extremely low drug concentration.

Risk of stroke associated with use of nonsteroidal anti-inflammatory drugs during acute respiratory infection episode.

BACKGROUND: Previous studies suggested that acute respiratory infection (ARI) could trigger stroke and that use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with increased risk of stroke. In many countries, NSAIDs have been widely used among patients with ARI or common cold for pain and fever relief. However, studies evaluating whether NSAIDs use during ARI episodes may further increase the risk of stroke were very limited. METHODS AND RESULTS: During 2007 to 2011, 29 518 patients with an incident hospitalization of stroke were identified. The date of admission was defined as the index date. Using case-crossover design, we compared the following exposure status between the case period (1- to 7-d period before the index date) and matched control period (366- to 372-d period before the index date): NSAIDs use during ARI episodes, ARI episodes without NSAIDs use, NSAIDs use only, or no exposure. Multivariable conditional regression models were used to estimate odds ratios adjusting potential confounders. The results suggested that NSAIDs use during ARI episodes was associated with a 2.3-fold increased risk of stroke (ischemic: adjusted odds ratio, aOR 2.27, 95% confidence interval, 95% CI, 2.00-2.58; hemorrhagic: aOR 2.28, 95% CI, 1.71-3.02). We also determined that parenteral NSAIDs were associated with much higher risk of stroke in patients with ARI. CONCLUSIONS: Nonsteroidal anti-inflammatory drugs use during ARI episodes, especially parenteral NSAIDs use, was associated with a further increased risk of stroke.

Identifying Unmet Treatment Needs for Patients With Osteoporotic Fracture: Feasibility Study for an Electronic Clinical Surveillance System.

BACKGROUND: Traditional clinical surveillance relied on the results from clinical trials and observational studies of administrative databases. However, these studies not only required many valuable resources but also faced a very long time lag. OBJECTIVE: This study aimed to illustrate a practical application of the National Taiwan University Hospital Clinical Surveillance System (NCSS) in the identification of patients with an osteoporotic fracture and to provide a high reusability infrastructure for longitudinal clinical data. METHODS: The NCSS integrates electronic medical records in the National Taiwan University Hospital (NTUH) with a data warehouse and is equipped with a user-friendly interface. The NCSS was developed using professional insight from multidisciplinary experts, including clinical practitioners, epidemiologists, and biomedical engineers. The practical example identifying the unmet treatment needs for patients encountering major osteoporotic fractures described herein was mainly achieved by adopting the computerized workflow in the NCSS. RESULTS: We developed the infrastructure of the NCSS, including an integrated data warehouse and an automatic surveillance workflow. By applying the NCSS, we efficiently identified 2193 patients who were newly diagnosed with a hip or vertebral fracture between 2010 and 2014 at NTUH. By adopting the filter function, we identified 1808 (1808/2193, 82.44%) patients who continued their follow-up at NTUH, and 464 (464/2193, 21.16%) patients who were prescribed anti-osteoporosis medications, within 3 and 12 months post the index date of their fracture, respectively. CONCLUSIONS: The NCSS systems can integrate the workflow of cohort identification to accelerate the survey process of clinically relevant problems and provide decision support in the daily practice of clinical physicians, thereby making the benefit of evidence-based medicine a reality.

Acute Respiratory Infection and Use of Nonsteroidal Anti-Inflammatory Drugs on Risk of Acute Myocardial Infarction: A Nationwide Case-Crossover Study.

Background: Previous studies have suggested that acute respiratory infection (ARI) and nonsteroidal anti-inflammatory drugs (NSAIDs) use could trigger acute myocardial infarction (AMI). In some countries, physicians prescribe NSAIDs for patients with ARI for symptom relief. However, there is no research evaluating whether NSAIDs use during ARI episodes may increase the risk of AMI. Methods: We identified 9793 patients with an incident hospitalization of AMI (index date) between 2007 and 2011. Using case-crossover design, we compared the following exposure status between the case (1-7-day before index date) and matched control period (366-372-day before index date): NSAIDs use during ARI episodes, ARI episodes without NSAIDs use, NSAIDs use only, or no exposure. Multivariable conditional logistic regression models were used to estimate odds ratios adjusted for potential confounders. Results: Nonsteroidal anti-inflammatory drugs use during ARI was associated with a 3.4-fold increased risk of AMI (adjusted odds ratio [aOR] = 3.41; 95% confidence interval [CI] = 2.80-4.16), ARI without NSAIDs use was associated with a 2.7-fold increased risk (aOR = 2.65; 95% CI = 2.29-3.06), and NSAIDs use only was associated with a 1.5-fold increased risk (aOR = 1.47; 95% CI = 1.33-1.62). Moreover, parenteral NSAIDs were associated with much higher risk in ARI patients (aOR = 7.22; 95% CI = 4.07-12.81). Conclusions: Nonsteroidal anti-inflammatory drugs use during ARI episodes, especially parenteral NSAIDs, was associated with a further increased risk of AMI.

Concomitant use of calcium channel blockers with dual antiplatelet therapy and re-hospitalization for acute coronary syndrome.

BACKGROUND: Existing studies suggested that concomitant use of calcium channel blockers (CCBs) may interfere with the antiplatelet effect of clopidogrel. The objective of this study was to examine the effect of concomitant use of CCBs and clopidogrel on risks of acute coronary syndrome (ACS) re-hospitalization in patients receiving percutaneous coronary intervention. METHODS: Using the Taiwan National Health Insurance Research Database, we identified 51 925 patients who were admitted for newly diagnosed ACS, received percutaneous coronary intervention, and used clopidogrel within 1 year after discharge. We further stratified them into three groups based on their uses of guideline-recommended secondary prevention medications for ACS (fully, partially, and non-compliant groups) to assess the potential modification effect of guideline compliance. For each group, we conducted a 1:1 propensity score matching to minimize selection bias. Cox proportional hazard models were used to investigate the effect of concomitant use of CCBs (overall, subclasses, and individual CCBs) and clopidogrel on risks of ACS re-hospitalization. RESULTS: Concomitant use of CCBs in patients discharged with clopidogrel was significantly associated with a lower risk of ACS re-hospitalization in the fully compliant group (HRfully compliant = 0.82 [95% confidence interval 0.75-0.89], p < 0.001) but was associated with increased risk of ACS re-hospitalization in the non-compliant group (HRnon-compliant = 1.22 [1.03-1.45], p = 0.0252). CONCLUSIONS: Different guideline compliance of secondary prevention medications could modify the potential drug-drug interaction between clopidogrel and CCBs. Concomitant use of CCBs and clopidogrel was significantly associated with increased risk of ACS re-hospitalization in ACS patients not compliant to guideline-recommended secondary prevention drugs. Copyright © 2017 John Wiley & Sons, Ltd.

Cost-effectiveness of the pharmacist-assisted warfarin monitoring program at a Medical Center in Taiwan.

OBJECTIVE: To investigate the cost-effectiveness of the first patient self-paying pharmacist-assisted warfarin monitoring (PAWM) program in Taiwan. DESIGN: A Markov model with a 1-month cycle length and a 20-year time horizon was employed in this study. The model is composed of the following eight states: three no-event states (i.e. 'subtherapeutic,' 'within therapeutic' and 'supratherapeutic' states), two serious adverse events (AEs) (i.e. bleeding and thromboembolism), two sequelae states and death. The likelihood of events, costs and utilities were derived from local databases and literature, if applicable. This study was conducted with a payer's perspective and all costs were discounted with a rate of 3%. SETTING: A pharmacist-led clinic. PARTICIPANTS: A hypothetical cohort of 10 000 participants. INTERVENTION(S): PAWM versus usual care. MAIN OUTCOME MEASURE(S): Average quality-adjusted life-years (QALYs) gained and cost increments per patient, and incremental cost-effectiveness ratios (ICERs). RESULTS: The PAWM program resulted in an average of 0.13 QALYs gained and a cost increment of NT$53 850 (US$1683) per patient. As the ICER (NT$410 749 [US$12 836]) was less than the gross domestic product per capita (NT$631 142 [US$19 723]), the PAWM was considered to be very cost-effective. The sensitivity analyses suggested that our result was robust and that the PAWM program had an 86% probability of being very cost-effective. CONCLUSIONS: Even if the costs saved from avoiding AEs were thought to be minimal due to the low-medical expenditures in Taiwan, the PAWM program was demonstrated to be economical. According to our findings, the policymakers should consider reimbursing such a service.

Selective Intracellular Delivery of Recombinant Arginine Deiminase (ADI) Using pH-Sensitive Cell Penetrating Peptides To Overcome ADI Resistance in Hypoxic Breast Cancer Cells.

Arginine depletion strategies, such as pegylated recombinant arginine deiminase (ADI-PEG20), offer a promising anticancer treatment. Many tumor cells have suppressed expression of a key enzyme, argininosuccinate synthetase 1 (ASS1), which converts citrulline to arginine. These tumor cells become arginine auxotrophic, as they can no longer synthesize endogenous arginine intracellularly from citrulline, and are therefore sensitive to arginine depletion therapy. However, since ADI-PEG20 only depletes extracellular arginine due to low internalization, ASS1-expressing cells are not susceptible to treatment since they can synthesize arginine intracellularly. Recent studies have found that several factors influence ASS1 expression. In this study, we evaluated the effect of hypoxia, frequently encountered in many solid tumors, on ASS1 expression and its relationship to ADI-resistance in human MDA-MB-231 breast cancer cells. It was found that MDA-MB-231 cells developed ADI resistance in hypoxic conditions with increased ASS1 expression. To restore ADI sensitivity as well as achieve tumor-selective delivery under hypoxia, we constructed a pH-sensitive cell penetrating peptide (CPP)-based delivery system to carry ADI inside cells to deplete both intra- and extracellular arginine. The delivery system was designed to activate the CPP-mediated internalization only at the mildly acidic pH (6.5-7) associated with the microenvironment of hypoxic tumors, thus achieving better selectivity toward tumor cells. The pH sensitivity of the CPP HBHAc was controlled by recombinant fusion to a histidine-glutamine (HE) oligopeptide, generating HBHAc-HE-ADI. The tumor distribution of HBHAc-HE-ADI was comparable to ADI-PEG20 in a mouse xenograft model of human breast cancer cells in vivo. In addition, HBHAc-HE-ADI showed increased in vitro cellular uptake in cells incubated in a mildly acidic pH (hypoxic conditions) compared to normal pH (normoxic conditions), which correlated with pH-sensitive in vitro cytotoxicity in hypoxic MDA-MB-231 and human prostate cancer PC3 cells. Together, we conclude that the HBHAc-HE-based peptide delivery offers a useful means to overcome hypoxia-induced resistance to ADI in breast cancer cells, and to target the mildly acidic tumor microenvironment.

The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations.

BACKGROUND: Carbapenem antibiotics (CBPMs) may significantly reduce the serum concentration of valproic acid (VPA), but the extent of this effect among various CBPMs is unknown. This study compared the extent and onset of the interactions among ertapenem, imipenem/cilastatin, and meropenem. METHODS: A 5-year retrospective study was performed. Hospitalized patients over 18 years old who received VPA and a CBPM concurrently were enrolled via the pharmacy computer system. Patients who lacked VPA serum concentration measurements before or during CBPMs' use, had concurrent medication(s) that might interfere with VPA metabolism, or had a history of liver cirrhosis were excluded. Total VPA serum concentrations before and during CBPMs' use and after its discontinuation were recorded, and differences among various CBPMs were analyzed. RESULTS: Fifty-two patients were included in this analysis. Irrespective of the route of administration, VPA serum concentrations were subtherapeutic in 90% of the subjects during CBPMs' use. There was a significant decrease (P < 0.001) in VPA serum concentrations during the use of CBPMs: 72% ± 17%, 42% ± 22%, and 67% ± 19% in the ertapenem (N = 9), imipenem/cilastatin (N = 17), and meropenem (N = 26) groups, respectively. The effect of ertapenem and meropenem on VPA was significantly more expressed than that of imipenem/cilastatin (P < 0.005). The onset of this drug interaction occurred within 24 hours of CBPMs' administration, and VPA serum concentrations returned to 90% of baseline within 7 days of CBPMs' discontinuation along with a 20% increase in VPA dose. Increasing VPA dose during the use of ertapenem or meropenem did not result in elevating VPA serum concentrations to therapeutic levels during the combined therapy period. CONCLUSIONS: CBPMs reduced VPA serum concentration within 24 hours of administration by approximately 60%. Ertapenem and meropenem had a greater effect on VPA serum concentration than imipenem/cilastatin. Because of the dramatic reduction of VPA serum concentration during CBPMs' use, concomitant use of VPA and CBPMs should be avoided.

Drug-related problems vary with medication category and treatment duration in Taiwanese heart failure outpatients receiving case management.

BACKGROUND/PURPOSE: Heart failure (HF) patients are at high risk of having drug-related problems (DRPs). We aim to describe the frequency, types, and temporal occurrence of DRPs in Taiwanese HF outpatients receiving case management. METHODS: In this study, we included 141 patients from HF clinics in three hospitals in Taiwan from October 2008 to December 2010. Nurse case managers at each of the participating sites registered case report forms (CRFs) for patients during clinic visits. DRPs were classified using the Pharmaceutical Care Network Europe Foundation (PCNE) classification system and documented by pharmacists after reviewing CRFs and participating in multidisciplinary team discussions. RESULTS: For 141 clinic participants, the average duration of medication use was 17 months, and 796 DRPs were reported. The DRPs most frequently recorded were the need for laboratory tests (32.7% of total DRPs), followed by potential interaction (29.6%), nonallergic side effects (13.3%), and insufficient awareness of health and disease (9.5%). The drugs most frequently causing a DRP were angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, diuretics, warfarin, spironolactone, and ß-blockers. The incidence rates of total DRPs was maximal during the initial 3 months of medication treatment, whereas the incidence rates of each category of DRPs showed multiform changes over time among various drug classes. CONCLUSION: In Taiwan where the clinical pharmacist system is not well organized, HF outpatients still had a high prevalence of DRPs despite intensive monitoring by nurse case managers. Clinical pharmacists play critical roles in detecting potential DRPs during long-term medication treatment for this population.

Risk factors of ifosfamide-related encephalopathy in adult patients with cancer: A retrospective analysis.

BACKGROUND/PURPOSE: Ifosfamide, a widely used chemotherapeutic agent, has been frequently associated with encephalopathy. A larger-scale study was conducted to identify risk factors of ifosfamide-related encephalopathy, including hepatic function. METHODS: Adult patients who had completed at least one cycle of ifosfamide between January 2008 and December 2010 were included. Those with renal failure or liver failure were excluded. Data were collected through chart review. Patients with encephalopathy and patients without encephalopathy were compared on age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), baseline serum creatinine (SCr) level, albumin level, white blood cell count, liver function, brain metastasis, and dosage of ifosfamide. Chi-square test or Fisher's exact test, Student t test, and univariate and multivariate logistic regressions were used for analysis. RESULTS: This study enrolled 337 patients. Thirty-eight patients (11%) had ifosfamide-related encephalopathy. They had poorer ECOG PS; higher SCr level, white blood cell count, and aspartate aminotransferase level; and lower serum albumin level compared with patients without encephalopathy. Ifosfamide dosage, brain metastasis, and age were not significant risk factors. Multivariate analysis indicated that only ECOG PS, SCr level, and albumin level contributed significantly to the risk. CONCLUSION: To date, this is the largest-scale study to have analyzed the risk factors of ifosfamide-related encephalopathy. This study confirms that an ECOG PS of 2-4 and increased SCr level are significant risk factors of ifosfamide-related encephalopathy, whereas increased albumin level decreases the risk, consistent with previous reports. Higher aspartate aminotransferase levels have no significant impact. In contrast to previous studies, ifosfamide dosage and brain metastasis are not significant contributing factors.

Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Extracorporeal membrane oxygenation (ECMO) alters the pharmacokinetics (PK) of vancomycin in neonates; but data on adults is limited. METHODS: This is a prospective, matched cohort, single center, pharmacokinetic study. For each adult patient who received vancomycin therapy in the ECMO group (with either centrifugal pump or roller pump), a control patient was matched by age (≥ 60 years or < 60 years), gender, and creatinine clearance (CLCr) in intensive care units. After vancomycin was administered for at least four doses, serial blood samples were drawn at 0.5 hours, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 11 hours, 23 hours, 35 hours, and 47 hours post vancomycin infusion according to the dosing intervals. The serum concentration-time profile was fitted to a noncompartment model and a nonlinear mixed effect model to determine the PK parameters. RESULTS: Twenty-two critically ill adults without renal replacement therapy were enrolled. There were no significant differences between the ECMO group and the matched group in demographics, renal function, and PK parameters. However, vancomycin clearance in the roller pump group was significantly lower than that in the matched control (0.83 ± 0.43 mL/min/kg vs. 0.97 ± 0.43 mL/min/kg, p = 0.002). CONCLUSION: Vancomycin clearance in patients receiving ECMO with a roller pump was significantly lower than that in the matched cohort. Vancomycin PK parameters in patients on ECMO with a centrifugal pump were comparable to those in the matched control group.

Epidemiology, clinical profile and treatment patterns of venous thromboembolism in cancer patients in Taiwan: a population-based study.

BACKGROUND: Venous thromboembolism (VTE) is a clinically significant complication that is well documented among Caucasian cancer patients. However, evidence regarding VTE incidence and treatment among Asian cancer patients is very limited. The objective of this study is to investigate the incidence, risk factors and management of VTE among Taiwanese cancer patients. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 43,855 newly diagnosed cancer patients between 2001 and 2008. Two alternative algorithms for identifying VTE event were explored to better quantify a range of incidence rates of VTE in our cancer patients. Multivariable logistic regression models were used to explore VTE risk factors. RESULTS: The incidence rates of VTE were 9.9 (algorithm 1) and 3.4 (algorithm 2) per 1,000 person-years, respectively. The incidence rates were higher in certain cancers, particularly liver, pancreas, and lung. Significant risk factors for VTE were site of cancer, prior history of VTE, chemotherapy and major surgeries. Long-term anticoagulant therapy was initiated in 64.1% patients with VTE and 72.2% of them received warfarin alone. Approximately two-thirds of patients with VTE received ≤ 3 months of anticoagulant therapy. CONCLUSION: Incidence of cancer-related VTE is lower among Taiwanese compared to Caucasian populations. Nevertheless, risk factors for cancer-related VTE found in our study were consistent with current literature.

A Larger Dose of Vancomycin Is Required in Adult Neurosurgical Intensive Care Unit Patients Due to Augmented Clearance.

BACKGROUND: The objective of this study was to explore the pharmacokinetics of vancomycin and determine an appropriate dosage regimen for vancomycin in adult neurosurgical intensive care unit (ICU) patients. METHODS: First, a 20-month therapeutic drug monitoring database at a medical center was used to retrospectively analyze the pharmacokinetic parameters of vancomycin in adult neurosurgical patients. Significant covariates were selected through Pearson or Spearman correlation tests and multiple linear regressions. Pharmacokinetic models were built using significant covariates to predict vancomycin clearance. Second, a 12-month prospective cohort of neurosurgical ICU patients was recruited to validate the models. Urine and cerebrospinal fluid samples were collected, and vancomycin concentrations were determined using a high-performance liquid chromatography assay. The relation between the model-predicted and observed pharmacokinetic parameters was assessed by Pearson correlation. RESULTS: In the retrospective cohort, 98 sets of peak/trough serum concentrations obtained from 73 patients were analyzed. These patients had a mean age of 54 ± 16 years, an estimated creatinine clearance (eClCr) of 83 ± 29 mL/min, a total vancomycin clearance (ClVan) of 101 ± 41 mL/min, and a volume of distribution (Vd) of 0.93 ± 0.27 L/kg. In a subgroup analysis, the ClVan of ICU patients was higher than the ClVan of non-ICU patients (1.57 ± 0.34-fold versus 1.16 ± 0.32-fold of eClCr, P < 0.05). Fifteen patients enrolled in the prospective cohort had an average age of 67 ± 12 years, an eClCr of 108 ± 44 mL/min, a ClVan of 112 ± 29 mL/min, and a Vd of 1.03 ± 0.55 L/kg. CONCLUSIONS: Adult neurosurgical ICU patients have a significantly elevated ClVan. In this study, 2 dosing equations were derived to achieve optimal serum vancomycin concentrations for this special population.

Formulation and stability of an extemporaneous 0.02% chlorhexidine digluconate ophthalmic solution.

BACKGROUND/PURPOSE: Acanthamoeba keratitis is difficult to treat because Acanthamoeba cysts are resistant to the majority of antimicrobial agents. Despite the efficacy of 0.02% chlorhexidine in treating Acanthamoeba keratitis, a lack of data in the literature regarding the formulation's stability limits its clinical use. The objective of this study was to develop an optimal extemporaneous 0.02% chlorhexidine digluconate ophthalmic formulation for patients in need. METHODS: With available active pharmaceutical ingredients, 0.02% chlorhexidine digluconate sample solutions were prepared by diluting with BSS Plus Solution or acetate buffer. Influences of the buffer, type of container, and temperature under daily-open condition were assessed based on the changes of pH values and chlorhexidine concentrations of the test samples weekly. To determine the beyond-use date, the optimal samples were stored at 2-8°C or room temperature, and analyzed at time 0 and at Week 1, Week 2, Week 3, Week 4, Week 5, Week 8, Week 12, and Week 24. RESULTS: Despite chlorhexidine exhibiting better stability in acetate buffer than in BSS solution, its shelf-life was < 14 days when stored in a light-resistant low-density polyethylene container. The acetate-buffered 0.02% chlorhexidine digluconate solution stored in light-resistant high-density polyethylene eyedroppers did not exhibit significant changes in pH or strength at any time interval. CONCLUSION: The acetate-buffered 0.02% chlorhexidine digluconate ophthalmic solution stored in light-resistant high-density polyethylene eyedroppers demonstrated excellent stability at 2-25°C for 6 months after being sealed and for 1 month after opening. This finding will enable us to prepare 0.02% chlorhexidine digluconate ophthalmic solutions based on a doctor's prescription.

Prothrombin complex concentrate (Beriplex P/N)-related renal and cerebral infarctions in a patient with warfarin-associated intracerebral hemorrhage.

A 45-year-old man receiving warfarin treatment suffered from an intracerebral hemorrhage. Four-factor prothrombin complex concentrate (PCC) was administered to correct coagulopathy. However, bilateral renal infarcts and a cerebral infarct developed on day 5 and 7, respectively after PCC administration. Although the occurrence of PCC-related thromboembolism is low, health care practitioners should closely follow-up the symptoms and signs of thrombosis after PCC administration.

Sheltering effect and indirect pathogenesis of carbapenem-resistant Acinetobacter baumannii in polymicrobial infection.

The role of carbapenem-resistant Acinetobacter baumannii (CRAb) in polymicrobial infection remains elusive. Having observed the ability of CRAb to shelter other susceptible bacteria from carbapenem killing, we sought to determine the factors contributing to this sheltering effect by transforming different recombinant plasmids into recipient A. baumannii cells. The sheltering effects of CRAb were reproduced in recipient A. baumannii cells that highly expressed carbapenem-hydrolyzing class D ß-lactamases (CHDLs) through their associated strong promoter. With the use of Western blot analysis and a bioassay, the highly expressed CHDLs were found to be extracellularly released and led to hydrolysis of carbapenem. The level of extracellular CHDLs increased after challenge with a higher concentration of CHDL substrates, such as carbapenem and ticarcillin. This increased CHDL may, in part, be attributed to cell lysis, as indicated by the presence of extracellular gyrase. In the planktonic condition, the sheltering effect for the cocultured susceptible bacteria might represent an indirect and passive effect of the CRAb self-defense mechanism, because coculture with the susceptible pathogen did not augment the amount of the extracellular CHDLs. Polymicrobial infection caused by CRAb and a susceptible counterpart exerted higher pathogenicity than monomicrobial infection caused by either pathogen alone in mice receiving carbapenem therapy. This study demonstrated that CHDL-producing CRAb appears to provide a sheltering effect for carbapenem-susceptible pathogens via the extracellular release of CHDLs and, by this mechanism, can enhance the pathogenesis of polymicrobial infection in the presence of carbapenem therapy.

Intracellular delivery of recombinant arginine deiminase (rADI) by heparin-binding hemagglutinin adhesion peptide restores sensitivity in rADI-resistant cancer cells.

Recombinant arginine deiminase (rADI) has been used in clinical trials for arginine-auxotrophic cancers. However, the emergence of rADI resistance, due to the overexpression of argininosuccinate synthetase (AS), has introduced an obstacle in its clinical application. Here, we have proposed a strategy for the intracellular delivery of rADI, which depletes both extracellular and intracellular arginine, to restore the sensitivity of rADI-resistant cancer cells. In this study, the C terminus of heparin-binding hemagglutinin adhesion protein from Mycobacterium tuberculosis (HBHAc), which contains 23 amino acids, was used to deliver rADI into rADI-resistant human breast adenocarcinoma cells (MCF-7). Chemical conjugates (l- and d-HBHAc-SPDP-rADI) and a recombinant fusion protein (rHBHAc-ADI) were produced. l- and d-HBHAc-SPDP-rADI showed a significantly higher cellular uptake of rADI by MCF-7 cells compared to that of rADI alone. Cell viability was significantly decreased in a dose-dependent manner in response to l- and d-HBHAc-SPDP-rADI treatments. In addition, the ratio of intracellular concentration of citrulline to arginine in cells treated with l- and d-HBHAc-SPDP-rADI was significantly increased by 1.4- and 1.7-fold, respectively, compared with that obtained in cells treated with rADI alone (p < 0.001). Similar results were obtained with the recombinant fusion protein rHBHAc-ADI. Our study demonstrates that the increased cellular uptake of rADI by HBHAc modification can restore the sensitivity of rADI treatment in MCF-7 cells. rHBHAc-ADI may represent a novel class of antitumor enzyme with an intracellular mechanism that is independent of AS expression.