Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity.

Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.

Beta-lactam target attainment and associated outcomes in patients with bloodstream infections.

OBJECTIVES: To evaluate the association between early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters and therapy outcomes in bloodstream infection (BSI). METHODS: Adult patients who received cefepime, meropenem, or piperacillin/tazobactam for BSI and had concentrations measured were included. Beta-lactam exposure was generated and the time that free concentration remained above the minimum inhibitory concentration (fT>MIC) and four multiples of MIC (fT>4 × MIC) were calculated for times 0-24 h and 0-7 days of therapy. Multiple regression analysis was performed to evaluate the impact of PK/PD on microbiological and clinical outcomes. RESULTS: A total of 204 patients and 213 BSI episodes were included. The mean age was 58 years and weight 83 kg. Age, Sequential Organ Failure Assessment (SOFA) score, haemodialysis, Pitt bacteraemia score, and hours of empiric antibiotic therapy were significantly associated with certain outcomes and retained in the final model. In multiple regression analysis, fT>4 × MIC at 0-24 h and 0-7 days was a significant predictor of negative blood culture on day 7 (P=0.0161 and 0.0068, respectively). In the time-to-event analysis, patients who achieved 100% fT>4 × MIC at 0-24 h and 0-7 days had a shorter time to negative blood culture compared with those who did not (log-rank P=0.0004 and 0.0014, respectively). No significant associations were identified between PK/PD parameters and other outcomes, including improvement in symptoms at day 7 and 30-day mortality. CONCLUSION: Early and cumulative achievement of fT>4 × MIC was a significant predictor of microbiological outcome in patients with BSI.

Identification of DPYD variants and estimation of uracil and dihydrouracil in a healthy Indian population.

Aim: This study aimed to identify DPYD variants and the related but previously unexplored phenotype (plasma uracil, dihydrouracil [DHU], and the DHU-to-uracil ratio) in a healthy adult Indian population. Methods: Healthy adult volunteers (n = 100) had their uracil and DHU levels measured and were genotyped for selected variants. Results: Among the nine variants studied, c.1906-14763G>A and c.85T>C were the most prevalent. Participants with any of the variants except for c.85T>C and c.1627A>G had a significantly lower DHU-to-uracil ratio and those with c.1905+1G>A variant had significantly increased uracil concentration compared with wild-type. Conclusion: Participants with five variants were identified as having altered phenotypic measures, and 40% of the intermediate metabolizers had their phenotype in the terminal population percentiles.

Background: 5-fluorouracil (5-FU) is a medicine used in cancer treatment. It is eliminated from body by the enzyme DPD. Identifying deficiency in DPD before initiating 5-FU can save patients from oral, intestinal, and bone marrow toxic effects. Methods: The uracil and dihydrouracil (DHU, produced by DPD enzyme action) levels were measured and DPD gene (for identifying defects) was sequenced in 100 healthy adults. Results: Participants with DPD gene sequence that is known to be defective had higher plasma uracil levels and a low DHU-to-uracil ratio compared with those who did not have a defective gene. Conclusion: Measuring plasma uracil and DHU-to-uracil ratio can help identify people with defective DPD genes.

Model-Informed Rationale for Early Therapeutic Drug Monitoring of Colistin in Critically Ill Patients.

Adequate colistin exposure is important for microbiological clearance. This study was performed in critically ill patients >18 years old to develop a simplified nonparametric pharmacokinetic (PK) model of colistin for routine clinical use and to determine the role of dose optimization. The Non-Parametric Adaptive Grid algorithm within the Pmetrics software package for R was used to develop a PK model from 47 patients, and external validation of the final model was performed in 13 patients. A 1-compartment multiplicative gamma error model with 0-order input and first-order elimination of colistin was developed with creatinine clearance and serum albumin as covariates on elimination rate constant. An R2 for observed vs individual predicted colistin concentrations of 0.92 was obtained in the validation cohort. High interindividual variability in colistin steady-state area under the plasma concentration-time curve (AUC) from from 120 hours to 144 hours (coefficient of variation = 80.1%) and a high interoccasion variability (median coefficient of variation of AUC from time 0 to hours predicted every 8 hours for initial 96 hours after starting colistin = 23.8) was predicted in patients who received this antibiotic for a period of over 152 hours (n = 22). With the model-suggested dose regimen, only 20% of simulated profiles achieved AUC from time 0 to 24 hours in the range of 50 to 60 mg â€¢ h/L due to high variability in population PK. In this group of patients, steady-state colistin concentrations were predicted to be achieved >96 hours after initiation of colistimethate sodium. This study advocates the need for early and repeated therapeutic drug monitoring and dose optimization in critically ill patients to achieve adequate therapeutic concentration of colistin.

Cefepime Daily Exposure and the Associated Impact on the Change in Sequential Organ Failure Assessment Scores and Vasopressors Requirement in Critically Ill Patients Using Repeated-Measures Mixed-Effect Modeling.

IMPORTANCE: Sepsis and septic shock are major healthcare problems that need early and appropriate management. OBJECTIVES: To evaluate the association of daily cefepime pharmacokinetic/pharmacodynamic (PK/PD) parameters with change in Sequential Organ Failure Assessment (SOFA) score and vasopressors requirement. DESIGN SETTING AND PARTICIPANTS: This is a retrospective study. Adult ICU patients who received cefepime for Gram-negative pneumonia or bloodstream infection (BSI) and had cefepime concentrations measured were included. Daily cefepime exposure was generated and PK/PD parameters calculated for patients. Repeated-measures mixed-effect modeling was used to evaluate the impact of PK/PD on the outcomes. MAIN OUTCOMES AND MEASURES: Change in daily SOFA score and vasopressors requirement. RESULTS: A total of 394 and 207 patients were included in the SOFA and vasopressors analyses, respectively. The mean (±sd) age was 55 years (19) and weight 81 kg (29). For the change in SOFA score, daily SOFA score, mechanical ventilation, renal replacement therapy, and number of vasopressors were included. In the vasopressors analysis, daily SOFA score, day of therapy, and hydrocortisone dose were significant covariates in the final model. Achieving cefepime concentrations above the minimum inhibitory concentration (MIC) (T>MIC) for 100% of the dosing interval was associated with 0.006 µg/kg/min decrease in norepinephrine-equivalent dose. Cefepime PK/PD did not have an impact on the daily change in SOFA score. CONCLUSIONS AND RELEVANCE: Achieving 100% T>MIC was associated with negligible decrease in vasopressors requirement in ICU patients with Gram-negative pneumonia and BSI. There was no impact on the change in SOFA score.

Efficacy of Crushed Delayed-Release Posaconazole Tablets in Rhino-Orbito-Cerebral Mucormycosis.

A significant proportion of patients with Rhino-orbito-cerebral mucormycosis (ROCM) develop oroantral fistulas. Due to the unclear efficacy of crushed delayed-release posaconazole tablets (DRPT) via nasogastric tube in this group of patients, clinicians often use inferior alternatives like posaconazole suspension. In this prospective study, we report good plasma concentrations (median, 2,639 ng/mL; interquartile range [IQR], 1,690 to 3,575 ng/mL; and range, 1,004 to 4,835ng/mL) and complete cure and survival at 3 and 6 months in 19 such patients.

Using Machine Learning To Define the Impact of Beta-Lactam Early and Cumulative Target Attainment on Outcomes in Intensive Care Unit Patients with Hospital-Acquired and Ventilator-Associated Pneumonia.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC (fT>MIC) and the time free concentration remained above four multiples of the MIC (fT>4×MIC) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Analytical and clinical validation of dried blood spot and volumetric absorptive microsampling for measurement of tacrolimus and creatinine after renal transplantation.

BACKGROUND: Serial monitoring of tacrolimus and serum creatinine after renal transplantation is of vital importance. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the estimation of tacrolimus and creatinine, obtained from dried blood spots (DBS) or by volumetric absorptive microsampling (VAMS) was validated and the two sampling strategies were compared with traditional venous sampling. METHODS: The LC-MS/MS assay was validated using a shared extract for the estimation of tacrolimus and creatinine from DBS and VAMS independently. The relationship between the concentrations in DBS/VAMS specimens and in venous samples was assessed using Passing-Bablok (PB) analysis and the bias between the two methods was determined by the Bland Altman (BA) analysis. RESULTS: The imprecision and bias of tacrolimus and creatinine estimated from DBS and VAMS samples was <12% and was independent of the hematocrit (Hct). Samples were stable for five days at ambient temperature. From the PB regression analysis, correction equations were generated for the prediction of tacrolimus and creatinine values from DBS and VAMS samples. In a separate cohort of patients for validation, the corrected DBS and VAMS concentrations had a mean (95% CI) bias for tacrolimus of -0.64 (-2.98 to 1.70)% and -0.92 (-3.69 to 1.85)% respectively and for creatinine of 1.00 (-2.73 to 4.72)% and -0.71 (-3.74 to 2.32)% respectively. Using DBS and VAMS respectively, for tacrolimus, 91.8 and 89.8% of patient values and for creatinine, 69.4 and 81.6% of patient values were within the limits of clinical acceptance (within 15% agreement against the venous samples). CONCLUSION: We conclude that VAMS is the preferred single sampling option for estimating tacrolimus and creatinine in renal transplant patients.

Optimal Practice for Vancomycin Therapeutic Drug Monitoring: Position Statement From the Anti-infectives Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

ABSTRACT: Individualization of vancomycin dosing based on therapeutic drug monitoring (TDM) data is known to improve patient outcomes compared with fixed or empirical dosing strategies. There is increasing evidence to support area-under-the-curve (AUC24)-guided TDM to inform vancomycin dosing decisions for patients receiving therapy for more than 48 hours. It is acknowledged that there may be institutional barriers to the implementation of AUC24-guided dosing, and additional effort is required to enable the transition from trough-based to AUC24-based strategies. Adequate documentation of sampling, correct storage and transport, accurate laboratory analysis, and pertinent data reporting are required to ensure appropriate interpretation of TDM data to guide vancomycin dosing recommendations. Ultimately, TDM data in the clinical context of the patient and their response to treatment should guide vancomycin therapy. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology, the IATDMCT Anti-Infectives Committee, provides recommendations with respect to best clinical practice for vancomycin TDM.

Systemic exposure to 5-fluorouracil and its metabolite, 5,6-dihydrofluorouracil, and development of a limited sampling strategy for therapeutic drug management of 5-fluorouracil in patients with gastrointestinal malignancy.

AIMS: 5-Fluorouracil (5-FU) is widely used in combination chemotherapy, and literature suggests pharmacokinetic-guided dosing to improve clinical efficacy and reduce toxicity. This study aimed to determine the pharmacokinetic exposure of both 5-FU and its metabolite, 5,6-dihydrofluorouracil (DHFU), in patients with gastrointestinal malignancy and to establish a simplified strategy to assist in therapeutic drug management for dose optimization. METHODS: This was a prospective, observational study, performed in 27 patients diagnosed with gastrointestinal malignancy who were prescribed 5-FU. Multiple samples were collected per patient over the slow bolus (15-20 min) and continuous infusion period (over 44 h) in doses 1 and 3, and the concentrations of 5-FU and DHFU were measured. RESULTS: A higher proportion of patients had exposures within the therapeutic range in dose 3 (50%) as compared to dose 1 (37.5%) with 5-FU. There was an association between delayed time to maximum concentration of DHFU and a high maximum concentration of 5-FU. A limited sampling strategy was developed with 4 samples, 2 during the bolus period and 2 during the continuous period (at 18 h and the end of infusion), which accurately predicted the total area under the curve of 5-FU. CONCLUSION: Using body surface area-based dosing with 5-FU, 50-60% of patients were outside of the therapeutic range. In the absence of genotype testing, measurement of the metabolite DHFU could be a phenotypical measure of dihydropyrimidine dehydrogenase enzyme activity. A limited sampling strategy was developed in patients who were prescribed a combination regimen of slow bolus, followed by a 44-hour continuous infusion of 5-FU to assist in the therapeutic drug management of patients.

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India.

AIMS: Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens. METHODS: Data were collected from 41 children, aged 2-16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed-effects model. RESULTS: Isoniazid pharmacokinetics were described by a one-compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one-compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed-dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed-dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg-1 , was found to provide adequate drug exposure in most children. CONCLUSIONS: The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose-effect relationship of higher doses of rifampicin.

Inhibition of Spontaneous Contractility of Isolated Caprine Ureter by Flupirtine.

CONTEXT: Kv7 potassium channels are expressed in several types of smooth muscles and could mediate physiological responses in the tissues expressed. Flupirtine is an analgesic that acts by opening Kv7 potassium channels. It has been shown to inhibit the contractility of several types of isolated smooth muscle. AIMS: This study investigated the ability of flupirtine to inhibit the spontaneous contractility of isolated distal caprine (goat) ureter. SETTINGS AND DESIGN: Spontaneous contractility of the isolated goat ureter was recorded using a physiograph. MATERIALS AND METHODS: The ability of 1, 3, 10, 30, and 90 µM concentrations of flupirtine maleate to inhibit the spontaneous contractility of isolated distal goat ureter was investigated. The ability of the nonspecific potassium channel blocker 4-aminopyridine (4-AP; 1 mM) and the specific Kv7 channel blocker XE-991 (100 µM) to reverse the inhibitory effect of flupirtine on ureteric contractility was also investigated. STATISTICAL ANALYSIS USED: Both parametric and nonparametric statistical tests were used. RESULTS: At 10, 30, and 90 µM concentrations, flupirtine significantly inhibited the spontaneous contractility of the isolated goat ureter. The EC50 of flupirtine for a contact period of 10 min was 17.7 µM. The inhibitory effect of flupirtine on ureteric contractility was significantly reversed by 4-AP and XE-991. CONCLUSIONS: Flupirtine inhibits the spontaneous contractility of the isolated goat ureter by opening Kv7 channels.

A case of septicaemic melioidosis: Utility of therapeutic drug monitoring and high-dose meropenem in successful management.

Melioidosis is an emerging infectious disease of major public health importance. We describe a patient who presented with septicaemic melioidosis with multi-organ dysfunction. He had only marginal response on standard doses of meropenem. Therapeutic drug monitoring (TDM) revealed suboptimal concentration of meropenem following which drug dose was increased, with which he showed rapid clinical improvement and microbiological clearance. Melioidosis presents with multisystem involvement with disseminated abscess, standard dosing of meropenem may not be sufficient in achieving therapeutic levels and TDM with increased dosing in these critically ill patients will improve outcome.

Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India.

Suboptimal plasma drug concentrations in antitubercular therapy (ATT) may lead to delayed treatment response and the emergence of acquired drug resistance. This study aimed (i) to determine and compare plasma concentrations of isoniazid (INH) and rifampicin (RIF) in children treated for tuberculosis receiving a daily or intermittent ATT regimen and (ii) to study the effect of INH and RIF exposure on clinical outcome at the end of therapy (EOT). A total of 41 children aged 2-16 years initiated on either a daily or three-times weekly (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 4 and 6 h post-dose. Concentrations of INH and RIF were analysed using validated liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography assays, respectively. The maximum plasma concentration (Cmax), the area under the concentration-time curve from 0-6 h (AUC0-6h) and treatment outcome were determined. Ninety-two percent of patients had an INH Cmax > 3 µg/mL. Seventy-seven percent of patients had a RIF Cmax < 8 µg/mL and 28% of patients had a RIF AUC0-24h < 13 mg ⋅ h/L. INH and RIF exposure did not differ between daily and intermittent ATT regimens on the day of administration. All children had a favourable outcome at EOT. Since 77% of children had low RIF exposure, we recommend routine use of therapeutic drug monitoring to prevent relapse and to support implementation of the revised RNTCP 2012 doses.

Inhibition by Benidipine of Contractility of Isolated Proximal and Distal Caprine Ureter.

CONTEXT: Benidipine is a calcium channel blocker that blocks all the major types (L, N, and T) of calcium channels. It has been shown to inhibit the contractility of many isolated smooth muscles but not isolated ureter. AIMS: This study evaluated the ability of benidipine to inhibit the spontaneous contractility of isolated proximal and distal caprine (goat) ureter. SETTINGS AND DESIGN: Spontaneous contractility of isolated goat ureter was recorded using a physiograph. MATERIALS AND METHODS: Benidipine at concentrations in the range of 1 nM to 10 µM was analyzed for its inhibitory effects on the spontaneous contractility of the isolated proximal and distal caprine ureter. STATISTICAL ANALYSIS USED: Both parametric and nonparametric statistical tests were used. RESULTS: The EC50 of benidipine for inhibiting contractility in the distal ureter was found to be 54.68 nM. Benidipine was found to have a greater inhibitory effect on the distal ureter than on the proximal ureter. It was also found to inhibit amplitude of spontaneous ureteric contractility more readily than the frequency of spontaneous ureteric contractility. CONCLUSIONS: These results suggest that benidipine has differential inhibitory effects on the spontaneous contractility of the isolated ureter. Benidipine could be useful in the management of clinical conditions like ureteric colic due to its inhibitory effects on the contractility of the ureter.

A Nonparametric Pharmacokinetic Approach to Determine the Optimal Dosing Regimen for 30-Minute and 3-Hour Meropenem Infusions in Critically Ill Patients.

BACKGROUND: Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population. METHODS: This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% T > minimum inhibitory concentration (MIC), with a probability >0.9) for doubling MICs was determined for different regimens of meropenem. RESULTS: A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 × (Equation is included in full-text article.), Vc = Vc0 × Weight). The Ke and Vc [geometric mean (range)] of the individuals were 0.54 (0.01-2.61)/h and 9.36 (4.35-21.62) L, respectively. The probability of attaining the target, T > MIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat. CONCLUSIONS: This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function.