Effect of Multi-Dose Dispensing on Medication Regimen Complexity: A Real-World Study.

(1) Background: Older patients frequently require dosing aids, such as multi-dose medication dispensing (MMD) when they experience medication regimen complexity (MRC) with increased drug use. However, the evaluations of the efficacy of MMD alterations remain limited. (2) Methods: A total of 1120 patients were included in the study who were discharged from hospital during the study period of January to March 2019. The Medication Regimen Complexity Index (MRCI) score, a validated 65-item tool in Korea (MRCI-K), was used to quantify MRC. The original MRCI-K scores, representing the typical administration based on prescription information, were compared to recalculated MRCI-K scores measured following MMD during the hospital dispensing period. Differences in MRCI-K across the top four wards based on the numbers of discharge prescription medications were assessed, and the overall scores were categorized into quartiles to identify MMD's impact within each group. We confirmed the effect of MMD based on the patient's admission diagnosis depending on MRCI. (3) Results: The mean (standard deviation) of original MRCI scores was 26.2 (13.4), which decreased to 18.9 (8.8) after applying MMD. The decrease in MRCI scores after MMD was statistically significant in all four wards, with the Orthopedic Surgery ward showing the biggest decrease. The patients with MRCI scores in the highest quartile group demonstrated the greatest improvement as a result of the implementation of MMD. Respiratory diseases exhibited the highest baseline MRCI scores due to formulation complexity, and ear, nose, and throat patients demonstrated the most significant reduction in MRC after MMD, depending on the diagnostic criteria at administration. (4) Conclusions: We confirmed the reduction in MRC after applying MMD, as a significant decrease in MRCI-K scores. This study highlights the need to deliver effective pharmacist-led services to identify patients who would benefit from MMD.

Population pharmacokinetics of everolimus in patients with seizures associated with focal cortical dysplasia.

Background: Everolimus is an inhibitor of mammalian target of rapamycin complex 1. As mutations in TSC1 and TSC2, which cause partial-onset seizures associated with TSC, were found in focal cortical dysplasia type Ⅱ (FCD Ⅱ) patients, a clinical trial has been performed to explore the efficacy and safety of everolimus in FCD patients. However, no dosage regimen was determined to treat FCD II. To recommend an optimal dose regimen for FCD patients, a population pharmacokinetic model of everolimus in FCD patients was developed. Methods: The data of everolimus were collected from September 2017 to May 2020 in a tertiary-level hospital in Korea. The model was developed using NONMEM® software version 7.4.1 (Icon Development Solutions, Ellicott City, MD, United States). Results: The population pharmacokinetics of everolimus was described as the one-compartment model with first-order absorption, with the effect of BSA on clearance. The final model was built as follows: TVCL = 12.5 + 9.71 × (BSA/1.5), TVV = 293, and TVKA = 0.585. As a result of simulation, a dose higher than 7 mg/m2 is needed in patients with BSA 0.5 m2, and a dose higher than 6 mg/m2 is needed in patients with BSA 0.7 m2. A dose of 4.5 mg/m2 is enough in the population with BSA higher than 1.5 m2 to meet the target trough range of 5-15 ng/mL. Conclusion: Based on the developed pharmacokinetics model, the optimal dose of everolimus in practice was recommended by considering the available strengths of Afinitor disperz®, 2 mg, 3 mg, and 5 mg.

An indirect comparison of efficacy including histologic assessment and safety in biologic therapy in ulcerative colitis: Systemic review and network meta-analysis.

BACKGROUNDS AND AIMS: There are currently no studies comparing histologic remission of FDA-approved biologics for moderate to severe ulcerative colitis (UC), except for one head-to-head VARSITY trial. The current study employs a network meta-analysis to compare the efficacy, including histologic remission and safety of biologic agents for UC. METHODS: Using four electronic databases, including Pubmed, EMBASE, The Cochrane Library, and ClinicalTrials.gov, a search was conducted of all literature published until September 2022. Included were studies of randomized controlled trials with adult patients with moderate to severe UC using biologics approved by the FDA. An odd ratio with a 95 percent credible interval and ranking information was calculated for each endpoint. RESULTS: The results of the network meta-analysis did not reveal statistically significant differences among biological agents. However, the ranking information for each biological agent exhibited the following patterns. Vedolizumab was ranked first for overall efficacy endpoints in the maintenance phase, including histologic remission. Except for histologic remission, Ustekinumab was identified as the top-ranked drug for induction phase efficacy endpoints other than histologic remission. Adalimumab was identified as the top-ranked drug for maintenance phase corticosteroid-free remission. Vedolizumab was identified as the top-ranked drug in the induction phase for Treatment Emergent Adverse Events (TEAE). Adalimumab was identified as the top-ranked drug in the induction phase for infection. For TEAE and infection in the maintenance phase and Treatment Emergent Severe Adverse Events (TESAE) in both the induction and maintenance phases, Ustekinumab was determined to be the top-ranked medication. CONCLUSIONS: Including histologic remission, for the overall efficacy endpoints in the maintenance phase, VDZ was identified as the first rank drug, but there was no statistically significant difference between biologics. Therefore, the generalization of the results of this study is bounded due to the intrinsic limitations of the study provided.

Effect of Pharmacist-Led Intervention in Elderly Patients through a Comprehensive Medication Reconciliation: A Randomized Clinical Trial.

PURPOSE: Polypharmacy can cause drug-related problems, such as potentially inappropriate medication (PIM) use and medication regimen complexity in the elderly. This study aimed to investigate the feasibility and effectiveness of a collaborative medication review and comprehensive medication reconciliation intervention by a pharmacist and hospitalist for older patients. MATERIALS AND METHODS: This comprehensive medication reconciliation study was designed as a prospective, open-label, randomized clinical trial with patients aged 65 years or older from July to December 2020. Comprehensive medication reconciliation comprised medication reviews based on the PIM criteria. The discharge of medication was simplified to reduce regimen complexity. The primary outcome was the difference in adverse drug events (ADEs) throughout hospitalization and 30 days after discharge. Changes in regimen complexity were evaluated using the Korean version of the medication regimen complexity index (MRCI-K). RESULTS: Of the 32 patients, 34.4% (n=11/32) reported ADEs before discharge, and 19.2% (n=5/26) ADEs were reported at the 30-day phone call. No ADEs were reported in the intervention group, whereas five events were reported in the control group (p=0.039) on the 30-day phone call. The mean acceptance rate of medication reconciliation was 83%. The mean decreases of MRCI-K between at the admission and the discharge were 6.2 vs. 2.4, although it was not significant (p=0.159). CONCLUSION: As a result, we identified the effect of pharmacist-led interventions using comprehensive medication reconciliation, including the criteria of the PIMs and the MRCI-K, and the differences in ADEs between the intervention and control groups at the 30-day follow-up after discharge in elderly patients. TRIAL REGISTRATION: (Clinical trial number: KCT0005994).

Dose Optimization of Meropenem in Patients on Veno-Arterial Extracorporeal Membrane Oxygenation in Critically Ill Cardiac Patients: Pharmacokinetic/Pharmacodynamic Modeling.

Background: Our objective was to determine an optimal dosage regimen of meropenem in patients receiving veno-arterial extracorporeal membrane oxygenation (V-A ECMO) by developing a pharmacokinetic/pharmacodynamic (PK/PD) model. Methods: This was a prospective cohort study. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF). The population pharmacokinetic model was developed using nonlinear mixed-effects modeling. A Monte Carlo simulation was used (n = 10,000) to assess the probability of target attainment. Results: Thirteen adult patients on ECMO receiving meropenem were included. Meropenem pharmacokinetics was best fitted by a two-compartment model. The final pharmacokinetic model was: CL (L/h) = 3.79 × 0.44CRRT, central volume of distribution (L) = 2.4, peripheral volume of distribution (L) = 8.56, and intercompartmental clearance (L/h) = 21.3. According to the simulation results, if more aggressive treatment is needed (100% fT > MIC target), dose increment or extended infusion is recommended. Conclusions: We established a population pharmacokinetic model for meropenem in patients receiving V-A ECMO and revealed that it is not necessary to adjust the dosage depending on V-A ECMO. Instead, more aggressive treatment is needed than that of standard treatment, and higher dosage is required without continuous renal replacement therapy (CRRT). Also, extended infusion could lead to better target attainment, and we could provide updated nomograms of the meropenem dosage regimen.

Sodium-Glucose Cotransporter-2 Inhibitors Could Help Delay Renal Impairment in Patients with Type 2 Diabetes: A Real-World Clinical Setting.

This study compared the renoprotective effects of sodium−glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM). We performed a retrospective cohort study using electronic medical records of patients with T2DM. The primary outcome was the first occurrence of an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 after the index date. We analyzed changes in repeatedly measured laboratory data, such as eGFR and serum uric acid (SUA). We included 2396 patients (1198 patients in each group) in the present study. The rate of renal events was significantly lower in the SGLT2 inhibitors group than that in the DPP-4 inhibitors group (hazard ratio, 0.46; 95% CI, 0.29 to 0.72; p = 0.0007). The annual mean change in the eGFR was significantly smaller in the SGLT2 inhibitors group than that in the DPP-4 inhibitors group, with a between-group difference of 0.86 ± 0.18 mL/min/1.73 m2 per year (95% CI, 0.49 to 1.23; p < 0.0001). Moreover, the mean change in SUA was lower in the SGLT2 inhibitors group. Considering the lower incidence of renal impairment, the slower decline in eGFR, and reduced SUA, SGLT2 inhibitors could help delay renal impairment in patients with T2DM.

Prothionamide Dose Optimization Using Population Pharmacokinetics for Multidrug-Resistant Tuberculosis Patients.

Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop a population PK model for prothionamide and then apply the model to determine the optimal dosing regimen for MDR-TB patients. Multiple plasma samples were collected from 27 MDR-TB patients who had been treated with prothionamide at 2 different study hospitals. Prothionamide was administered according to the weight-band dose regimen (500 mg/day for weight <50 kg and 750 mg/day for weight >50 kg) recommended by the World Health Organization. The population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment, based on systemic exposure and MIC, was used as a response target. Fixed-dose regimens (500 or 750 mg/day) were simulated to compare the efficacies of various dosing regimens. PK profiles adequately described the two-compartment model with first-order elimination and the transit absorption compartment model with allometric scaling on clearance. All dosing regimens had effectiveness >90% for MIC values <0.4 µg/mL in 1.0-log kill target. However, a fixed dose of 750 mg/day was the only regimen that achieved the target resistance suppression of ≥90% for MIC values of <0.2 µg/mL. In conclusion, fixed-dose prothionamide (750 mg/day), regardless of weight-band, was appropriate for adult MDR-TB patients with weights of 40 to 67 kg.

Real-world experience of angiotensin receptor neprilysin inhibitor on the glucose-lowering effect.

We investigated the effect of angiotensin receptor neprilysin inhibitor (ARNI) on glycemic control in Korean patients. This retrospective cohort study was conducted at a single tertiary hospital. We compared the HbA1c level reduction between the ARNI and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in chronic heart failure patients with diabetes. We also examined whether the target HbA1c level was reached and the time to start insulin between the two groups. Over the study period, ARNI did not significantly lower the HbA1c level after adjusting confounding factors compared to ACEIs or ARBs. However, as a result of a simple comparison using Mann-Whitney U test, ARNI group showed significant decrease in HbA1c at 6, 12, and 24 months compared to ACEIs or ARBs group (p = 0.003, 0.009, and 0.026, respectively). The initiation of insulin was delayed in the ARNI group, but this difference was not significant based on the result of hazard ratio, but cumulative incidence was significantly lower in the ARNI group. In the real world, the blood glucose-control effects of ARNI were not superior to those of ACEIs or ARBs. However, long-term studies are needed as ARNI use increases to obtain more statistically significant results.

Model-Based Efficacy and Toxicity Comparisons of Moxifloxacin for Multidrug-Resistant Tuberculosis.

BACKGROUND: Moxifloxacin (MOX) is used as a first-choice drug to treat multidrug-resistant tuberculosis (MDR-TB); however, evidence-based dosing optimization should be strengthened by integrative analysis. The primary goal of this study was to evaluate MOX efficacy and toxicity using integrative model-based approaches in MDR-TB patients. METHODS: In total, 113 MDR-TB patients from 5 different clinical trials were analyzed for the development of a population pharmacokinetics (PK) model. A final population PK model was merged with a previously developed lung-lesion distribution and QT prolongation model. Monte Carlo simulation was used to calculate the probability target attainment value based on concentration. An area under the concentration-time curve (AUC)-based target was identified as the minimum inhibitory concentration (MIC) of MOX isolated from MDR-TB patients. RESULTS: The presence of human immunodeficiency virus (HIV) increased clearance by 32.7% and decreased the AUC by 27.4%, compared with HIV-negative MDR-TB patients. A daily dose of 800 mg or a 400-mg, twice-daily dose of MOX is expected to be effective in MDR-TB patients with an MIC of ≤0.25 µg/mL, regardless of PK differences resulting from the presence of HIV. The effect of MOX in HIV-positive MDR-TB patients tended to be decreased dramatically from 0.5 µg/mL, in contrast to the findings in HIV-negative patients. A regimen of twice-daily doses of 400 mg should be considered safer than an 800-mg once-daily dosing regimen, because of the narrow fluctuation of concentrations. CONCLUSIONS: Our results suggest that a 400-mg, twice-daily dose of MOX is an optimal dosing regimen for MDR-TB patients because it provides superior efficacy and safety.

Population Pharmacokinetics and Dosing Optimization of Piperacillin-Tazobactam in Critically Ill Patients on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy.

Critical illness and extracorporeal circulation, such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), may alter the pharmacokinetics of piperacillin-tazobactam. We aimed to develop a population pharmacokinetic model of piperacillin-tazobactam in critically ill patients during ECMO or CRRT and investigate the optimal dosage regimen needed to achieve ≥90% of patients attaining the piperacillin pharmacodynamic target of 100% of dosage time above MIC of 16 mg/L. This prospective observational study included 26 ECMO patients, of which 13 patients received continuous venovenous hemodiafiltration (CVVHDF). A population pharmacokinetic model was developed using nonlinear mixed-effects models, and Monte Carlo simulations were performed to evaluate creatinine clearance (CrCL) and infusion method in relation to the probability of target attainment (PTA) in four patient groups according to combination of ECMO and CVVHDF. A total of 244 plasma samples were collected. In a two-compartment model, clearance decreased during ECMO and CVVHDF contributed to an increase in the volume of distribution. The range of PTA reduction as CrCL increased was greater in the order of intermittent bolus, extended infusion, and continuous infusion method. Continuous infusion should be considered in critically ill patients with CrCL of ≥60 mL/min, and at least 12, 16, and 20 g/day was required for CrCL of <40, 40 to 60, and 60 to 90 mL/min, respectively, regardless of ECMO or CVVHDF. In patients with CrCL of ≥90 mL/min, even a continuous infusion of 24 g/day was insufficient to achieve adequate PTA. Therefore, further research on permissible high continuous infusion dose focused on the risk of toxicity is required. (This trial has been registered at ClinicalTrials.gov under registration no. NCT02581280, December 1, 2014.) IMPORTANCE To the best of our knowledge, this is the first large prospective pharmacokinetic/pharmacodynamic (PK/PD) study of piperacillin-tazobactam in ECMO patients. We used piperacillin-tazobactam plasma concentration data from four different cases (concomitant use of ECMO and CVVHDF, receiving ECMO only, weaned from ECMO and receiving CVVHDF, and weaned from ECMO and not receiving CVVHDF) to provide preliminary insights into the incremental effects of critical illness, ECMO, and CVVHDF on PK. Our analysis revealed that volume of distribution increased in patients on CVVHDF and clearance decreased during ECMO and as creatinine clearance was reduced. When targeting 100% fT>MIC (16 mg/L, clinical breakpoint for Pseudomonas aeruginosa), continuous infusions would have achieved the highest percentage of target attainment compared to intermittent bolus or extended infusion if the total daily dose was the same. Continuous infusion should be considered in critically ill patients with creatinine clearance of ≥60 mL/min, regardless of ECMO or CVVHDF.

Antihypertensive effects of rosuvastatin in patients with hypertension and dyslipidemia: A systemic review and meta-analysis of randomized studies.

Some studies have suggested the antihypertensive effects of statins, a class of lipid-lowering agents, particularly in patients with hypertension. However, the evidence for the role of statins in blood pressure (BP) lowering is controversial, and no meta-analysis of rosuvastatin therapy has been conducted to assess its BP-lowering effects. Therefore, the aim of this meta-analysis of randomized controlled trials (RCTs) was to investigate the effects of rosuvastatin on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with hypertension. We systematically searched the electronic databases MEDLINE, EMBASE, and Cochrane Library to identify RCTs in which patients were assigned to groups of rosuvastatin plus antihypertensive agents vs. antihypertensive agents. The three authors independently selected the studies, extracted data, and assessed methodological quality. We included five RCTs in this meta-analysis with 288 patients treated with rosuvastatin and 219 patients without rosuvastatin. The mean DBP in the rosuvastatin group was significantly lower than that in the non-rosuvastatin group by -2.12 mmHg (95% confidence interval (CI) -3.72 to -0.52; Pfixed-effects model = 0.009; I2 = 0%, Pheterogeneity = 0.97). Rosuvastatin treatment also lowered the mean SBP compared with the non-rosuvastatin treatment by -2.27 mmHg, but not significantly (95% CI - 4.75 to 0.25; Pfixed-effects model = 0.08; I2 = 0%, Pheterogeneity = 0.82). In this study, we reviewed the antihypertensive effects of rosuvastatin in patients with hypertension and dyslipidemia. We demonstrated a modest significant reduction of DBP and a trend toward a lowered SBP in patients with hypertension with rosuvastatin therapy. Rosuvastatin could be beneficial to control hypertension and, consequently, contribute toward reducing the risk of cardiovascular events in patients with hypertension and dyslipidemia.

Effect of Low FODMAPs Diet on Irritable Bowel Syndromes: A Systematic Review and Meta-Analysis of Clinical Trials.

We conducted a meta-analysis exploring the effect of a low fermentable oligo-, di-, monosaccharides, and polyols diet (LFD) on the overall symptoms, quality of life, and stool habits of irritable bowel syndrome (IBS) patients. The meta-analysis was performed using a random-effects method. The effect size was presented as weighted standardized mean difference (SMD) and 95% confidence interval (CI). Subgroup analyses were conducted to determine the potential effects of covariates on the outcome. Twenty-two papers were included. The LFD group showed a moderate reduction in symptom severity and a slight improvement in quality of life compared to the control group (SMD, -0.53 and 0.24; 95% CI, -0.68, -0.38 and 0.02, 0.47, respectively). IBS symptom improvement was consistent between subgroups stratified according to proportions of female patients, study durations, IBS subtypes, assessment methods, and control interventions. Three studies regarding stool habits change in IBS-D patients showed a significant decrease in stool frequency (mean differences [MD], -5.56/week; 95% CI, -7.40, -3.72) and a significant improvement in stool consistency (MD, -0.86; 95% CI, -1.52, -0.19) in the LFD group compared to the control group. This is the most updated meta-analysis including studies that adopted diverse control interventions such as dietary interventions, supplementation, habitual diets, and lifestyle changes.

Population pharmacokinetics and dose optimization of vancomycin in neonates.

The pharmacokinetics of vancomycin vary among neonates, and we aimed to conduct population pharmacokinetic analysis to determine the optimal dosage of vancomycin in Korean neonates. From a retrospective chart review, neonates treated with vancomycin from 2008 to 2017 in a neonatal intensive care unit (NICU) were included. Vancomycin concentrations were collected based on therapeutic drug monitoring, and other patient characteristics were gathered through electronic medical records. We applied nonlinear mixed-effect modeling to build the population pharmacokinetic model. One- and two-compartment models with first-order elimination were evaluated as potential structural pharmacokinetic models. Allometric and isometric scaling was applied to standardize pharmacokinetic parameters for clearance and volume of distribution, respectively, using fixed powers (0.75 and 1, respectively, for clearance and volume). The predictive performance of the final model was developed, and dosing strategies were explored using Monte Carlo simulations with AUC0-24 targets 400-600. The patient cohort included 207 neonates, and 900 vancomycin concentrations were analyzed. Only 37.4% of the analyzed concentrations were within trough concentrations 5-15 µg/mL. A one-compartment model with first-order elimination best described the vancomycin pharmacokinetics in neonates. Postmenstrual age (PMA) and creatinine clearance (CLcr) affected the clearance of vancomycin, and model evaluation confirmed the robustness of the final model. Population pharmacokinetic modeling and dose optimization of vancomycin in Korean neonates showed that vancomycin clearance was related to PMA and CLcr, as well as body weight. A higher dosage regimen than the typical recommendation is suggested.

Eye, hepatobiliary, and renal disorders of erlotinib in patients with non-small-cell lung cancer: A meta-analysis.

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used to treat EGFR mutation positive non-small-cell lung cancer (NSCLC). Skin rash and diarrhea are well-known and common adverse events in patients receiving erlotinib, whereas other adverse events, including eye, liver, or renal disorders have not been evaluated adequately. This meta-analysis aimed to evaluate the ocular, hepatobiliary, and renal toxicities of erlotinib in patients with NSCLC cancers. METHODS: In total, sixty studies were assessed, and the results of the included studies were quantitatively integrated using meta-analysis. The incidence of ocular, hepatobiliary (alanine aminotransferase [ALT] and bilirubin elevations; other hepatic adverse events), and renal adverse events were estimated. Additionally, the erlotinib-treated groups and the control groups (placebo or other treatment) were compared with respect to ocular disorders and ALT elevation. The study protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758. RESULTS: The overall incidence of ocular disorders was 3.30% (95% confidence interval [CI] 2.20%-5.00%). The incidence of ALT elevation, bilirubin elevation, and other hepatobiliary disorders was 6.40% (95% CI 3.90%-10.4%), 3.80% (95% CI 2.30%-6.10%), and 1.00% (95% 0.60%-1.80%), respectively. The incidence of renal disorder was 3.10% (95% CI 1.90%-5.00%). The risk of ocular toxicity in the erlotinib treatment group was significantly increased (risk ratio = 2.91; 95% CI 1.70-4.98) compared to that in the control group. ALT elevation was not significantly different between the two groups. CONCLUSION: Based on the results, careful monitoring of ocular toxicity in patients receiving erlotinib should be recommended and closer monitoring of hepatic toxicity should be also recommended in patients with liver-related risk factors.

Dose Optimization of Cefpirome Based on Population Pharmacokinetics and Target Attainment during Extracorporeal Membrane Oxygenation.

To obtain the optimal dosage regimen in patients receiving extracorporeal membrane oxygenation (ECMO), we developed a population pharmacokinetics model for cefpirome and performed pharmacodynamic analyses. This prospective study included 15 patients treated with cefpirome during ECMO. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF) at predose and 0.5 to 1, 2 to 3, 4 to 6, 8 to 10, and 12 h after cefpirome administration. The population pharmacokinetic model was developed using nonlinear mixed effects modeling and stepwise covariate modeling. Monte Carlo simulation was used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) according to the MIC distribution. Cefpirome pharmacokinetics were best described by a two-compartment model. Covariate analysis indicated that serum creatinine concentration (SCr) was negatively correlated with clearance, and the presence of ECMO increased clearance and the central volume of distribution. The simulations showed that patients with low SCr during ECMO-ON had lower PTA than patients with high SCr during ECMO-OFF; so, a higher dosage of cefpirome was required. Cefpirome of 2 g every 8 h for intravenous bolus injection or 2 g every 12 h for extended infusion over 4 h was recommended with normal kidney function receiving ECMO. We established a population pharmacokinetic model for cefpirome in patients with ECMO, and appropriate cefpirome dosage regimens were recommended. The impact of ECMO could be due to the change in patient status on consideration of the small population and uncertainty in covariate relationships. Dose optimization of cefpirome may improve treatment success and survival in patients receiving ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.).

Correction: Effect of anti-epileptic drugs on the survival of patients with glioblastoma multiforme: A retrospective, single-center study.

[This corrects the article DOI: 10.1371/journal.pone.0225599.].

Effect of anti-epileptic drugs on the survival of patients with glioblastoma multiforme: A retrospective, single-center study.

Glioblastoma multiforme (GBM) is a lethal and aggressive malignant tumor of the central nervous system. The World Health Organization classifies it as a grade IV astrocytoma. Controlling seizures is essential during GBM treatment because they are often present and closely associated with the quality of life of GBM patients. Some antiepileptic drugs (AEDs) exhibit antitumor effects and could decrease the mortality of patients with GBM. In this retrospective cohort study, we examined 418 patients treated with surgery, radiotherapy, and chemotherapy with temozolomide (TMZ) at Severance Hospital in South Korea, per the current protocol. Median overall survival (OS) was 21 months [95% confidence interval (CI): 18.1-23.9] in the levetiracetam (LEV) treatment group, whereas it was 16 months [95% CI: 14.1-17.9] in the group without LEV, exhibiting a statistically significant difference between the two groups (P < 0.001). Of nine AED groups, only LEV treatment [P = 0.001; hazard ratio (HR), 0.65; 95% CI: 0.51-0.83] exhibited a statistically significant difference in the OS, in the univariate analysis. In the risk analysis of the baseline characteristics, age, administration of LEV, and O6-methylguanine-DNA methyltransferase (MGMT) promoter status correlated with OS. The use of LEV in the group with a methylated MGMT promoter resulted in a positive impact on the OS [P = 0.006; HR, 0.174; 95% CI: 0.050-0.608], but the effect of LEV on the OS was not statistically significant in the unmethylated MGMT promoter group (P = 0.623). This study suggests that, compared with other AEDs, the administration of LEV may prolong the survival period in GBM patients with methylated MGMT promoters, who are undergoing chemotherapy with TMZ.

Optimized Treatment for Infantile Spasms: Vigabatrin versus Prednisolone versus Combination Therapy.

Hormone therapies and vigabatrin are first-line agents in infantile spasms, but more than one-third of patients fail to respond to these treatments. This was a retrospective study of patients with infantile spasms who were treated between January 2005 and December 2017. We analyzed the response rates of initial treatment and second-line treatment. Responders were defined as those in whom cessation of spasms was observed for a period of at least one month, within 2 weeks of treatment initiation. Regarding the response rate to initial treatment, combination therapy of vigabatrin with prednisolone showed a significantly better response than that of vigabatrin monotherapy (55.3% vs. 39.1%, p = 0.037). Many drugs, such as clobazam, topiramate, and levetiracetam, were used as second-line agents after the failure of vigabatrin. Among these, no antiepileptic drug showed as good a response as prednisolone. For patients who used prednisolone, the proportion of responders was significantly higher in the higher-dose group (≥40 mg/day) than in the lower-dose group (66.7% vs. 12.5%, p = 0.028). Further studies of combination therapy to assess dosage protocols and long-term outcomes are needed.

Population pharmacokinetics of intravenous sufentanil in critically ill patients supported with extracorporeal membrane oxygenation therapy.

BACKGROUND: Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations. METHODS: This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96 h during infusion and 72 h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses. RESULTS: A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL = 37.8 × EXP (0.207 × (temperature - 36.9)) L h-1, central volume of distribution (V1) = 229 L, V2 = 1640 × (total plasma protein/4.5)2.46 L, and intercompartmental clearance (Q) = 41 L h-1. Based on Monte Carlo simulation results, an infusion of 17.5 µg h-1 seems to reach target sufentanil concentration (0.3-0.6 µg L-1) in most ECMO patients except hypothermic patients (33 °C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low. CONCLUSIONS: This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery. TRIAL REGISTRATION: Clinicaltrials.gov NCT02581280 , December 1st, 2014.

Comparison of acute kidney injury and clinical prognosis of vancomycin monotherapy and combination therapy with beta-lactams in the intensive care unit.

Antibiotics induced acute kidney injury (AKI) risk in critically ill patients is not well known. This study aimed to evaluate the AKI development and clinical outcomes in critically ill adult patients treated with vancomycin (VAN) or combined with piperacillin-tazobactam (TZP) or meropenem (MEM). This was a retrospective study on critically ill adult patients who were given VAN, TZP or MEM and maintained for at least 48 h. The risk of AKI development and clinical outcomes were compared using the simple analysis and multivariate logistic regression. Three hundred forty patients were eligible. The incidence of any AKI was significantly higher in patients treated with VAN + TZP than those with VAN + MEM or VAN alone (52.7% vs. 27.7% vs. 25.7%; p < .0001). The adjusted odds of AKI increased 2.43-fold in VAN + TZP versus VAN, but not different in VAN + MEM versus VAN. However, AKI duration and recovery rate were not statistically different. In addition, all-cause death within 30 days after AKI onset was not significantly associated with antibiotic regimens. AKI incidence is higher in critically ill patients administered with VAN + TZP than those with VAN + MEM or VAN. However, no obvious evidence was found to prove that antibiotic-induced AKI leads to poor clinical outcomes.