Development and validation of a bleeding risk prediction score for patients with mitral valve stenosis and atrial fibrillation or mechanical heart valves receiving long-term warfarin therapy.

AIMS: This study aimed to develop and validate a new bleeding risk score to predict warfarin-associated major bleeding for patients with mitral valve stenosis with atrial fibrillation (MSAF) or mechanical heart valves (MHV). METHODS: A multicentre, retrospective cohort study was conducted at 3 hospitals in Thailand. Adult patients with MSAF or MHV receiving warfarin for ≥3 months during 2011-2015 were identified. Data collection and case validation were performed electronically and manually. Potential variables were screened using the least absolute shrinkage and selection operator. Multivariate logistic regression analysis using stepwise backward selection was used to construct a risk score. Predictive discrimination of the score was evaluated using the C-statistic. Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: There were 1287 patients (3903.41 patient-year of follow-up), with 192 experiencing bleeding (4.92 event/100 patient-year) in the derivation cohort. A new bleeding risk score termed, the HEARTS-60 + 3 score (hypertension/history of bleeding; external factors, e.g., alcohol/drugs [aspirin or nonsteroidal anti-inflammatory drugs]; anaemia/hypoalbuminaemia; renal/hepatic insufficiency; time in therapeutic range of <60%; stroke; age ≥60 y; target international normalized ratio of 3.0 [2.5-3.5]), was developed and showed good predictive performance (C-statistic [95% confidence interval] of 0.88 [0.85-0.91]). In the external validation cohort of 832 patients (2018.45 patient-year with a bleeding rate of 4.31 event/100 patient-year), the HEARTS-60 + 3 score showed a good predictive performance with a C-statistic (95% confidence interval) of 0.84 (0.81-0.89). CONCLUSION: The HEARTS-60 + 3 score shows a potential as a bleeding risk prediction score in MSAF or MHV patients.

Therapeutic drug monitoring of intravenous busulfan in Thai children undergoing hematopoietic stem cell transplantation: A pilot study.

Busulfan (Bu) is commonly used in myeloablative conditioning regimens for children undergoing hematopoietic stem cell transplantation. The standard target area under the concentration-time curve (AUC) of Bu is approximately 900-1500 µM min. In previous studies using five fixed doses (0.8-1.2 mg/kg) for Bu without dose adjustment, 75% patients achieved the target AUC. The aim of this pilot study was to determine the percentage of target AUC for intravenous (IV) Bu in Thai children. IV Bu was administered every 6 h over 16 doses. Blood samples were collected for pharmacokinetic (PK) analysis after the first, ninth, and thirteenth doses of Bu. Seven patients (2-14 years; median 6 years) were diagnosed with thalassemia (n = 4), acute myeloid leukemia (n = 2), and pure red cell aplasia. Three, two, and two patients received Bu at 1.1, 1.2, and 0.8 mg/kg, respectively. The AUC of Bu varied from 292-1714 µM min (median = 804). Nine (42.86%), eleven (52.38%), and one (4.76%) AUC values were within, below, and above the target, respectively. The median (range) Bu clearance was 5.93 (1.91-14.65) mL/min/kg. In this study, 42.86% AUC value achieved the target, which was lower than that in previous studies. Therapeutic drug monitoring (TDM) of Bu should be considered in Thai children receiving five fixed doses of IV Bu, and dose adjustment should be performed as necessary. Further PK studies for Bu with a larger sample size are warranted for confirming the necessity of TDM in every step dose of Bu.(Trial registration numbers; TCTR20190528003).

Microbial epidemiology and risk factors for relapse in gram-negative bacteria catheter-related bloodstream infection with a pilot prospective study in patients with catheter removal receiving short-duration of antibiotic therapy.

BACKGROUND: Infectious Diseases Society of America (IDSA) guidelines suggest 7-14 days' duration of antibiotic treatment for uncomplicated Gram-negative bacteria (GNB) catheter-related bloodstream infection (CRBSI). The objectives of this study were to review microbial epidemiology, to determine rate and risk factors for relapse, and to compare clinical outcomes in patients receiving long- versus short-duration antibiotic therapy. METHODS: A retrospective phase 1 study was conducted between January 2010 and October 2016 to review microbial epidemiology and to determine the incidence of and risk factors for relapse in patients with GNB CRBSI, according to the IDSA guidelines diagnostic criteria. In phase 2 of the study, patients without risk factors for relapse between November 2016 and October 2017 were prospectively recruited to receive antibiotic therapy for 7 days after catheter removal. Matched patients from the retrospective phase 1 study who had received antibiotic therapy for ≥14 days were selected as a phase 2 control group to compare outcomes. RESULTS: In phase 1, three most common pathogens identified among 174 cases were Pseudomonas aeruginosa (22.0%), Klebsiella pneumoniae (16.7%), and Stenotrophomonas maltophilia (13.4%). Eighty-nine episodes of infection occurred while patients were receiving antibiotic therapy. Of 140 cases, the relapse rate was 6.4%. Catheter retention was the only risk factor strongly associated with relapse (odds ratio = 145.32; 95% confidence interval 12.66-1667.37, P < 0.001). In phase 2, 11 patients with catheter removal were prospectively recruited to receive short-duration therapy. The number of patients with relapse receiving long- or short-duration therapy was 1 (3%) and 0 (0%), respectively (P = 1.000). CONCLUSIONS: For the management of patients with uncomplicated GNB CRBSI, empiric broad-spectrum antibiotic therapy with adequate coverage of P. aeruginosa should be chosen. Catheter removal should be performed to prevent relapse and shortening the duration of treatment could be considered. TRIAL REGISTRATION: Thai Clinical Trial Registry: TCTR20190914001 . Retrospectively registered on 13 September 2019.

Relationship of anemia and clinical outcome in heart failure patients with preserved versus reduced ejection fraction in a rural area of Thailand.

BACKGROUND: Heart failure (HF) has become a significant health burden in developing countries where anemia is highly prevalent. Limited data exists on the effects of anemia on HF in these population. METHODS: A retrospective observational study was conducted in all adult patients hospitalized due to HF at Buriram Hospital in Thailand, during July 2010 to June 2015. Survival analysis was performed to evaluate the impact of anemia on 1- year all-cause mortality for the overall cohort, patients with HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). RESULTS: A total of 414 HF patients including 287 HFpEF patients (69.3%) and 127 HFrEF patients (30.7%) were included in our analysis. Mean age was 62.51 ±â€¯14.89 years, with 55% female. Overall prevalence of anemia in HF was 62.6% (259 patients). One-year all-cause mortality was significantly higher in patients with anemia than in non-anemia groups (20.08% vs 12.26%, p = 0.041). When analyzed based on types of HF, anemia significantly increased mortality risk in HFpEF group [adjusted hazard ratio (HR) 2.667, 95%CI, 1.216-5.853, p = 0.014] but not with HFrEF group (adjusted HR 0.901, 95%CI, 0.376-2.155, p = 0.804). The mortality of anemic patients who were left untreated was significantly higher than those who were treated (adjusted HR 2.13, 95%CI, 1.13-3.99, p = 0.027). CONCLUSION: Anemia significantly increased mortality in HF patients, especially among HFpEF. Attempts to identify, diagnose and manage anemia should be integrated in HF care plan in developing countries with high prevalence of anemia.

The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients.

Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT recipients. Eligible patients were enrolled to receive TAC-BID (Prograf®) and then converted to TAC-OD (Advagraf®) by 1:1 ratio, approximately 14 days after KT (range 9-22). Blood samples were investigated for pharmacokinetic parameters before and 7-14 days after the conversion. Fifteen patients were included and provided AUC0-24 of 202.9 ± 44.4 ng h/mL for TAC-BID (pre-conversion) and 193.0 ± 63.4 ng h/mL for TAC-OD (post-conversion) (p = 0.41). Mean trough blood concentration (Cmin) of TAC-BID and TAC-OD was 6.4 ± 1.4 ng/mL and 4.9 ± 1.6 ng/mL (p = 0.01). Correlation coefficient (r) between Cmin and AUC0-24 of TAC-BID and TAC-OD were 0.620 and 0.875. Additional analysis found that patients with a drop of Cmin > 30% had a significant lower AUC0-24 after conversion. Renal function remains stable. We conclude that early conversion to TAC-OD is safe and well tolerated with an indifferent systemic exposure. However, patients with a drop of Cmin > 30% after conversion to TAC-OD will require additional dose adjustment.

Optimization of Intermittent Vancomycin Dosage Regimens for Thai Critically Ill Population Infected by MRSA in the Era of the "MIC Creep" Phenomenon.

BACKGROUND: the shifting of minimum inhibitory concentration (MIC) of methicillin-resistant Staphylocuccus aureus (MRSA) strains to the higher value has emerged to worsen clinical outcome to the patients particularly critically ill population.  The aim of this study was to identify the most appropriate dosage regimen of vancomycin to treat infection caused by MRSA with higher MIC in critically ill Thai population. METHODS: 10,000 replications of intermittent vancomycin dosage regimens were performed using Monte Carlo simulation. Pharmacokinetic parameters were derived from a population pharmacokinetic study conducted specifically in Thai population. The probability of target attainment (PTA) and cumulative fraction of response (CFR) of each dosage regimen were calculated. Risk of nephrotoxicity was also calculated and used as a consideration in determining the most appropriate dosage regimen of vancomycin. RESULTS: in order to achieve desired PTA > 80% vancomycin at higher dosing regimens were needed including 3g/day and 4 g/day for MIC 1.5mg/L and 2.0 mg/L, respectively. Highest CFR of 94.40% and 93.57% were from vancomycin 1 g every 6 h and 2 g every 12h. Standard dose of vancomycin and total dose of vancomycin 3 g/day provided approximately 51% and 73% CFR. Risk of nephrotoxicity afforded by giving 1.5g every 12h and 2g every 12h of vancomycin were 26.59% and 31.20%, respectively. CONCLUSION: the result from this study recommended intermittent dosage regimen 1.5g every 12h and 2g every 12h should be implemented as definite antibiotic treatment when considered infection caused by MRSA with MIC 1.5 and 2.0 mg/L, respectively.

Comparative performance of pharmacogenetics-based warfarin dosing algorithms derived from Caucasian, Asian, and mixed races in Thai population.

AIM: This study was conducted to compare predictive accuracy of the available pharmacogenetics (PGx)-guided warfarin dosing algorithms derived from Caucasian, Asian, and mixed population to identify a suitable algorithm for Thai population. METHODS: Ten warfarin dosing algorithms derived from different population including Caucasian, East Asian, South-East Asian, and mixed races were selected and tested with clinical and genetic data of Thai patients. Comparative performances of these algorithms were tested using mean dose error (MDE) between actual warfarin maintenance dose (AWMD) and predicted dose generated by each dosing algorithm, and percentage of ideal dose prediction (IDP). Sensitivity analysis for predictive accuracy was also conducted by stratifying patients into low (AWMD ≤21 mg/wk), intermediate (AWMD >21 to <49 mg/wk), and high maintenance dose (AWMD ≥49 mg/wk) groups. RESULTS: Data of 165 patients were included for the analyses. Mean actual warfarin dose of the study population was 25.03 ± 10.53 mg/wk. Large variability of MDE, ranging from -12.11 to 11.24 mg/wk, among algorithms was observed. International Warfarin Pharmacogenetics Consortium, Gage et al, and Ohno et al algorithms had comparable performances to Sangviroon et al algorithm, as observed by MDE of <1 mg/wk with percentage of IDP ≥40%. Further sensitivity analyses among patients requiring low and intermediate maintenance doses confirmed such findings with IDP percentage ranging from 37.8% to 59.2%. Among high-dose group, only Ohno et al and Sarapakdi et al algorithms had acceptable performance. CONCLUSIONS: Warfarin PGx-guided dosing algorithms derived from large, mixed population performed comparably to Sangviroon et al algorithm. Certain algorithms should be avoided due to significant dose prediction error.

Trough level from twice daily to once daily tacrolimus in early conversion kidney transplant recipients: a prospective study.

Background Early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) provides a greater benefit of reducing under-exposure of TAC-OD during the first period after transplantation. Information regarding the conversion dose among Asian kidney transplant recipients is still limited. Objective This study aimed to compare the trough levels (Cmin) of TAC-BID (Prograf®) and TAC-OD (Advagraf®). The values were obtained from early conversion intervention by 1:1 milligram per-milligram. Setting A university-based hospital. Method This study employed a single-center, open-label, prospective and single-armed design. Fifteen de novo standard risk kidney transplant recipients were enrolled. Fourteen days after transplantation, the Cmin of TAC-BID (pre-conversion Cmin) was determined. Subsequently, TAC-BID was converted to TAC-OD with a similar dose. The Cmin of TAC-OD was first measured at a steady state (immediate post-conversion Cmin) and compared. All enrolled patients received therapeutic monitoring at the first and second months. Main outcome measure Pre-conversion Cmin of TAC-BID and immediate post-conversion Cmin of TAC-OD. Results The immediate post-conversion Cmin was found to be 23% lowered than the pre-conversion Cmin. However, the Cmin of TAC-OD was found to be similar to the pre-conversion Cmin compared during the follow-up period. Renal function was found to be stable in all patients over 2 months. Conclusion Early conversion therapy was associated with a significantly lower immediate post-conversion Cmin but comparable Cmin throughout the follow-up period. The "one to one conversion ratio" from TAC-BID to TAC-OD could be performed among Asian de novo kidney transplant recipients at an early period after transplantation.

Implementation of a Nutrition Program Reduced Post-Discharge Growth Restriction in Thai Very Low Birth Weight Preterm Infants.

Very low birth weight (VLBW) preterm infants are vulnerable to growth restriction after discharge due to cumulative protein and energy deficits during their hospital stay and early post-discharge period. The current study evaluated the effectiveness of the preterm infant, post-discharge nutrition (PIN) program to reduce post-discharge growth restriction in Thai VLBW preterm infants. A prospective, non-randomized interventional cohort study was undertaken to assess the growth of 22 VLBW preterm infants who received the PIN program and compared them with 22 VLBW preterm infants who received conventional nutrition services. Infant's growth was recorded monthly until the infants reached six months' corrected age (6-moCA). Intervention infants had significantly greater body weights (p = 0.013) and head circumferences (p = 0.009). Also, a greater proportion of the intervention group recovered their weight to the standard weight at 4-moCA (p = 0.027) and at 6-moCA (p = 0.007) and their head circumference to the standard head circumference at 6-moCA (p = 0.004) compared to their historical comparison counterparts. Enlistment in the PIN program thus resulted in significantly reduced post-discharge growth restriction in VLBW preterm infants. Further research on longer term effects of the program on infant's growth and development is warranted.

Population pharmacokinetics of vancomycin in Thai patients.

Population pharmacokinetics of vancomycin in Thai adult patients was determined by non-linear mixed-effects approach using 319 vancomycin serum concentrations from 212 patients. The data were best fitted by a two-compartment model and it was used to examine the effect of patient characteristics on the vancomycin pharmacokinetics. In the final model, there was a linear relationship between vancomycin clearance, CL (L/h), and creatinine clearance calculated by Cockcroft-Gault equation, CL(Cr) (mL/min): CL = 0.044 × L(Cr). Meanwhile, volume of central compartment, V(1) (L), was linearly related with the age (years old): V(1) = 0.542 × Age. Intercompartment clearance (Q) and volume of peripheral compartment (V(2)) was 6.95 L/h and 44.2 L, respectively. The interindividual variability for CL, V(1), Q, and V(2) was 35.78, 20.93, 39.50, and 57.27%, respectively. Whereas, the intraindividual variability was 4.51 mg/L. Final model then was applied to predict serum vancomycin concentrations on validation group. Predictive performance revealed a bias of -1.43 mg/L (95% CI: -5.82-2.99) and a precision of 12.2 mg/L (95% CI: -1.60-26.16). In conclusion, population pharmacokinetic of vancomycin in Thai adult patients was developed. The model could be used to create vancomycin dosage regimen in the type of patient similar with the present study.

Impact of a new guideline for central venous catheter care on sepsis in total parenteral nutrition: experience in Ramathibodi Hospital.

BACKGROUND: Total parenteral nutrition (TPN) is the essential treatment for hospitalized patients in whom normal enteral nutrition is inadequate or not feasible. However, TPN-related sepsis is the most serious and fatal complication of the treatment and the catheter is the most common cause of infection. Therefore, the Nutrition Support team in Ramathibodi Hospital has developed a new guideline for central venous catheter care for TPN patients and has used it for at least a year. OBJECTIVE: Survey the current incidence of TPN-related sepsis in the hospital, the predisposing factors of the TPN-related sepsis, and the pathogenic organisms of the sepsis. MATERIAL AND METHOD: Between July 1999 and February 2000, 52 TPN treatments (catheter count) in 40 surgical and medical patients were prospectively recruited. Microbiological studies were done in all cases of TPN-related sepsis. RESULTS: The incidence of TPN-related sepsis was 15% per catheter or 12.64/1000 catheter-days. Although no statistically significant predisposing factors were found for the sepsis, some factors such as postoperative TPN and short interval (< or = 2 days) for TPN line change (OR = 3.33, 95% CI = 0.33-30.34) showed a higher risk for TPN-related sepsis. The most common pathogenic organisms were Coagulase-negative staphylococci, Candida albicans, and gram-negative bacteria. The organisms were found from hemoculture in septic patients and were well correlated with those found in the catheter line. Thus, the significant pathogenic role of Coagulase-negative staphylococci emphasizes the importance of aseptic technique during catheterization. CONCLUSION: The Ramathibodi guideline rendered support for a good policy to improve and standardize the TPN treatment. Along with a practical guideline, the well-trained and highly responsible personnel would also be crucial to avoid the infectious complications.

Comparison of essential trace elements in blood of patients receiving Ramathibodi Standard Parenteral Nutrition with Ramatrace or a commercial formular.

OBJECTIVE: Commercially intravenous trace element product is very expensive compared to Ramatrace. Therefore, the present research was designed to compare the levels of zinc, copper chromium and manganese in the blood of patients receiving Ramathibodi Standard Parenteral Nutrition (STD) containing the Ramatrace or the commercial product. MATERIAL AND METHOD: Two groups of patients receiving STD were recruited. Group 1 (19 males and 11 females) received Ramatrace and Group 2 (19 males and 11 females) received a commercial product. Blood samples on day 0, day 3 and day 10 were measured for zinc, copper chromium and manganese levels by atomic absorption spectrophotometer (model 3100, Perkin Elmer). RESULTS: The present results showed that levels of zinc, copper, chromium and manganese were not significantly different between the two groups. On day 0, day 3 and day 10, the levels of zinc, copper and manganese in the blood of both groups were significantly increased (p < 0.05). Blood chromium levels of Group 1 were significantly increased from day 0 (0.14 +/- 0.02 microg/dL) to day 3 (0.23 +/- 0.02 microg/dL) but there was no significant difference between day 3 and day 10. In Group 2, the blood levels of chromium from day 0 to day 10 were significantly increased. CONCLUSION: In patients receiving STD, Ramatrace could improve the levels of zinc, copper, chromium and manganese as well as the commercial product. This may be one way to reduce the cost of treatment.

Time-kill curves as a tool for targeting ceftazidime serum concentration during continuous infusion for treatment of septicaemic melioidosis.

Melioidosis is a fatal community-acquired infection endemic in tropical areas. Ten isolates of the causative microorganism were subjected to time-kill study using a range of ceftazidime concentrations. This study demonstrated that a ceftazidime concentration of eight times the minimum inhibitory concentration yielded an optimal bactericidal effect and should be the target concentration administered by continuous infusion.

Effect of diabetes drug counseling by pharmacist, diabetic disease booklet and special medication containers on glycemic control of type 2 diabetes mellitus: a randomized controlled trial.

BACKGROUND: type 2 diabetes mellitus continues to increase in prevalence worldwide. Many factors have been cited as contributing to compliance, such as family and social support, education, number of tablets per dose, frequency of administration and health care provider communication. Toward these goals, the present study was developed to measure the effect offactors on glycemic control such as diabetes education by pharmacists, a diabetes disease booklet and special medication containers. MATERIAL AND METHOD: A total of 360 volunteers with type 2 DM patients were recruited, participants were simple randomized to control 180 and intervention 180 patients. Which intervention categorized to 4 groups; all intervention groups received diabetes drug counseling by a pharmacist, one group received plus a diabetes booklet, one received plus special medical containers and the last group received all of them. The interventions were done at the 1st time of visit. Both the control and intervention groups were monitored for fasting plasma glucose and HbA1c at 0, 3, 6 months and glycemic level in both groups was compared. RESULTS: After 3 months, mean fasting plasma glucose and HbA1c decreased wiih the intervention group vs. control group (152.36 +/- 39.73 to 131.52 +/- 35.22 mg%) and (150.16 +/- 41.78 to 153.98 +/- 47.95 mg%) respectively; (p < 0.001). HbA1c level 8.16 +/- 1.44 to 7.72 +/- 1.26 vs 8.01 +/- 1.51 to 8.38 +/- 1.46 respectively; (p < 0.001). After 6 months, mean fasting plasma glucose and HbA1c decreased with the intervention group vs. control group (152.36 +/- 39.73 to 145.20 +/- 46.07 mg%) and (150.16 +/- 41.78 to 159.16 +/- 54.90 mg%) respectively; (p < 0.013). HbA1c level 8.16 +/- 1.44 to 7.91 +/- 1.27 vs. 8.01 +/- 1.51 to 8.80 +/- 1.36 respectively; (p < 0.001). The most favorable glycemic outcome was the group that received all of the interventions; mean FPG was reduced from 147.46 +/- 36.07 to 125.38 +/- 31.12 mg% (p < 0.000) in 1nd visit (3 months later) and still reducing effect on the 2nd visit (6 month later) mean FPG from 147.46 +/- 36.07 to 130.21 +/- 33.96 mg% (p < 0.016) also the same way in HbA 1c level. The group that received only drug counseling by pharmacist had no significant reduction in FPG and HbA1c. (p > 0.05). CONCLUSION: Drug counseling by a pharmacist has little beneficial effect on diabetes management outcome compared to the diabetes booklet and special drug container. To improve glycemic control of type 2 DM is to integrate self-management in daily life, wide a variety of education, drug taken behavior and health care provider available communication produce improvement in patient management and is somewhat better when used in combination.

Pharmacokinetics of ofloxacin in drug-resistant tuberculosis.

The pharmacokinetics of ofloxacin were investigated in 11 drug-resistant pulmonary tuberculosis (TB) patients with a mean age (SD) of 38.09 (11.97) years. All patients received ofloxacin 10 mg/kg once daily combined with other active anti-TB drugs. Following an 8-h overnight fast, serum samples were drawn prior to and from 0.25 up to 24 hours after dosing. Serum ofloxacin concentrations were determined by high performance liquid chromatography (HPLC) assay. Pharmacokinetics of ofloxacin were well described by a linear, 2-compartment open model with first-order absorption and first-order elimination. Mean +/- SD of Cmax was 9.61 +/- 2.17 microg/ml occurred at 1.68 +/- 1.21 hours. Means +/- SD of AUC(0-24) and AUC(0-infinity) were 70.57 +/- 26.40 and 82.45 +/- 43.64 microg x h/ml, respectively. Ofloxacin distributed widely with a mean +/- SD of Vss/F of 1.37 +/- 0.24 L/kg. Mean +/- SD of CL/F was 8.19 +/- 2.53 L/h, whereas mean +/- SD of T(1/2beta) and mean residence time were 8.03 +/- 3.37 and 10.77 +/- 4.55 hours, respectively. The free Cmax/MIC of Mycobacterium tuberculosis of 7.7-15.4:1 was estimated. These suggested that ofloxacin 10 mg/kg once daily combined with other active anti-TB drugs provides sufficient Cmax/MIC ratio and long T(1/2beta) which supported its use in drug-resistant TB.