Clinical efficacy and safety of tigecycline based on therapeutic drug monitoring for carbapenem-resistant Gram-negative bacterium pneumonia in intensive care units.

BACKGROUND: We investigated the associations between the different doses of tigecycline, its efficacy and safety, and the role of tigecycline therapeutic drug monitoring for patients in the intensive care unit. METHODS: This study was a single-center cohort including patients infected with multidrug-resistant Acinetobacter baumannii (MDR-AB) and multidrug-resistant Klebsiella pneumoniae (MDR-KP) causing pulmonary infections. The steady-state plasma concentration after tigecycline administration was determined by High-Performance Liquid Chromatography (HPLC) in patients admitted to the ICU between October 2020 and December 2021. Multivariate analyses of tigecycline's clinical efficacy and safety were performed to control confounding factors. RESULTS: For this study, we included 45 patients and 45 blood samples to determine steady-state trough concentrations of tigecycline. All patients were divided into the High Dose (HD) and Standard Dose (SD) groups. The median trough concentration of tigecycline was 0.56 µg/mL in the HD group, which was higher than in the SD group (0,21 µg/mL), p = 0.000. There was no significant difference between the two groups of patients in terms of bacterial eradication rate, mortality rate, and clinical efficacy. Multiple regression analysis showed that the ICU days were correlated with mortality OR 1.030(1.005-1.056), p = 0.017. APACHE II was significantly associated with clinical efficacy OR 0.870(0.755-1.002), p = 0.045. The level of fibrinogen decline in the HD group was significantly higher than in the SD group (-3.05 ± 1.67 vs -1.75 ± 1.90), p = 0.038. We identified that age and tigecycline treatment duration influenced fibrinogen decline. CONCLUSIONS: Tigecycline plasma concentrations are significantly increased when using a high dose. However, the plasma concentration of tigecycline is not correlated with clinical efficacy and adverse reactions. Fibrinogen decline appears to be related to the patient's age and days of tigecycline. Large sample data are still needed to confirm the clinical guidance significance of tigecycline TDM.

Effect of Pharmacist-Led Interventions on Medication Adherence and Glycemic Control in Type 2 Diabetic Patients: A Study from the Chinese Population.

Purpose: Medication adherence plays an important role in glycemic control in type 2 diabetes mellitus (T2DM) self-management. To analyze the factors influencing medication adherence in T2DM patients and the effect of pharmacist-led interventions, we conducted a study in Beijing, China. Patients and Methods: T2DM patients with hypoglycemic drugs for at least 6 months were enrolled. A pharmacist-led survey was conducted followed by individualized interventions for those non-adherent patients monthly within 3 months. FPG, HbA1c, and 2hPG were measured as the comprehensive glycemic control. Medication adherence was determined according to the patient's self-reported compliance with prescribed medication during the last 3 months. Results: A total of 763 T2DM patients were included. The average age was 63.26±11.89 years, with 363 males. After pharmacist intervention, the patients with good adherence increased from 34.21% to 39.06%, while poor adherence decreased from 32.5% to 24.5% (p < 0.001). The average adherence score was a significant increase (p < 0.001) from 27.846±4.185 to 29.831±7.065. Furthermore, our study demonstrated that pharmacist-led interventions significantly increased glycemic control (FPG from 42.33% to 53.60%, p < 0.001; 2hPG from 41.68% to 48.75%, p = 0.005; HbA1c from 24.12% to 29.23%, p = 0.024). The results found that body mass index (OR 0.643, 95% CI 0.437-0.945), use of medications empirically (occasionally (OR=3.066, 95% CI 2.069-4.543); often (OR=2.984, 95% CI 1.107-8.044)), following the doctor's advice to visit (OR 2.129, 95% CI 1.079-4.202) and lifestyle compliance (OR 2.835, 95% CI 1.094-7.346) were the independent risk factors of non-adherence (p < 0.05), the area under the ROC curve was 0.716. Conclusion: Self-reported medication adherence and glycemic control in T2DM patients were poor which can be improved by pharmacist-led interventions. Interventions should focus on empirical medication behavior, non-adherence to lifestyle, and failure to follow the doctor's advice. The recall bias with self-reported results needs further objective data to verify.

Clinical Efficacy, Antibiotic Resistance Genes, Virulence Factors and Outcome of Hospital-Acquired Pneumonia Induced by Klebsiella pneumoniae Carbapenemase 2-Producing with Tigecycline Treatment in the ICU.

Purpose: Tigecycline is an agent for carbapenemase-producing Klebsiella pneumonia (KPC-KP), given its penetration into lung tissues. Our study focused on the molecular and clinical efficacy of tigecycline for hospital-acquired pneumonia (HAP) in the ICU. Patients and Methods: A retrospective cohort study of 52 adult KPC-KP HAP patients by searching hospital medical records from January 2018 to December 2020 was established to investigate the epidemiology of KPC-KP infections for tigecycline treatment and the associated clinical efficacy of tigecycline. The KPC-KP isolates underwent multilocus sequence typing. Molecular typing, antimicrobial resistance, and virulence profiling were also analyzed by whole-genome sequencing of KPC-KP. Results: Among 52 patients with KPC-KP, the ICU mortality rate was 14/52 (27%), and there was no significant statistical difference in mortality between the effective group and failure group (p = 0.754). However, the duration of tigecycline was statistically different between the two groups of patients (14.4 vs 10 days, p=0.046). The total bacterial clearance rate was 6/52 (11.5%). There was no significant statistical difference in both groups (p=0.416). Antibiotic resistance genes (aac3iia) and virulence gene (AREO-iutA, Capsule-wzc) were negatively correlated with clinical efficacy (p = 0.011, OR = 1.237). Conclusions: Blakpc was the main carbapenemase in all K. pneumoniae strains. ST11-KL64 KPC-KP was the most common virulence factors in KPC-KP isolates. This study suggested that antibiotic resistance genes (aac3iia) and virulence gene (AREO-iutA, Capsule-wzc) were independent mortality risk factors for patients with Klebsiella pneumoniae carbapenemase-2 producing K. pneumoniae infections, when during the tigecycline treatment. Molecular analysis of K. pneumoniae may provide an option when choosing the antimicrobial treatment.

Physician-pharmacist collaborative management in patients after percutaneous coronary intervention: a retrospective propensity score matching cohort study.

AIM: Evaluate the effect of the Physician-Pharmacist Collaborative Management (PPCM) practice model in patients after percutaneous coronary intervention (PCI). METHOD: A retrospective cohort study was conducted in post-PCI patients. The study enrolled patients who underwent PCI at our hospital from May 1, 2018, to January 31, 2020. Patients were divided into two groups: the PPCM group if they utilized the Complex Coronary Interventions Medication Therapy Management (CCI-MTM) clinic and the usual care (UC) group if they used the physician-only cardiology clinic. Patients had clinic visits monthly, and data were analyzed after 6-months of follow-up. A propensity score matching (PSM) method was used to control confounding bias between groups. RESULTS: A total of 727 patients met the inclusion criteria, including 67 patients in the PPCM group and 660 patients in the UC group. Using the 1:2 nearest neighbor matching method, 61 pairs were successfully matched; this included 61 patients in the PPCM group and 122 patients in the UC group. The proportion of patients reaching both LDL-C (73.8% versus 41.0%, P < 0.001) and heart rate (14.8% versus 4.1%, P = 0.007) goals in the PPCM was higher compared to the UC group. The median time to achieving the goal LDL-C was shorter in the PPCM group (31 days versus 126 days, P = 0.001). The utilization rates of [Formula: see text]-receptor blockers (73.8% versus 56.6%, P = 0.005) and ACEIs or ARBs (72.1% versus 56.6%, P = 0.018) were higher in the PPCM group compared to the UC group. There was no significant difference in adverse drug events between the two groups (P > 0.05). All recommendations to resolve drug-related problems were accepted by the physicians and patients. CONCLUSION: The pharmaceutical care provided by the pharmacist in the PPCM clinic improved risk factor control and increased the utilization of preventive drugs in post-PCI patients.

Efficacy of ACEIs/ARBs vs CCBs on the progression of COVID-19 patients with hypertension in Wuhan: A hospital-based retrospective cohort study.

To evaluate the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) vs calcium channel blockers (CCBs) on the progression of Corona Virus Disease 2019 (COVID-19) patients with hypertension in Wuhan. This retrospective single-center case series analyzed COVID-19 patients with hypertension, treated with ACEIs/ARBs or CCBs at the Tongji Hospital of Wuhan City, China from 25th January to 15th March 2020. After propensity score matching analysis, 76 patients were selected into two groups. Univariate and multivariable analyses were conducted to determine factors related to improvement measures and outcome measures by Cox proportional hazard regression models. Among 157 patients with confirmed COVID-19 combined hypertension, including 73 males and 84 females, a median age of 67.28 ± 9.11 vs 65.39 ± 10.85 years. A univariable analysis indicated that clinical classification, lymphocyte count, and interleukin-2 receptor were associated with a lengthened negative time of nucleic acid, with a significant difference between two groups (P = .036). Furthermore, we found no obvious difference in nucleic acid conversion time between ACEIs/ARBs and CCBs groups (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: [0.97, 3.38]; P = .18) in the multivariable analysis as well as chest computed tomography improved time (HR: 0.73; 95% CI [0.45, 1.2]; P = .87), and hospitalization time between ACEIs/ARBs and CCBs groups (HR: 1.06; 95% CI [0.44, 1.1]; P = .83). Our study provided additional evidence of no obvious difference in progress and prognosis between ACEIs/ACEIs and CCBs group, which may suggest ACEIs/ARBs may have scarcely influence on increasing the clinical severe situations of COVID-19 patients with hypertension.

Remission of hepatotoxicity in chronic pulmonary aspergillosis patients after lowering trough concentration of voriconazole.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) is a rare syndrome that is often accompanied by gradual lung tissue destruction. Voriconazole is usually employed as the first-line agent for CPA treatment. However, some patients can develop hepatotoxicity and often were forced to stop voriconazole treatment. AIM: To record the improving trend of liver function and the therapeutic effects in patients after lowering the trough concentration of voriconazole. METHODS: This study retrospectively analyzed 12 adult CPA patients who developed hepatotoxicity during the voriconazole treatment. In these patients, the oral dose was reduced to 3/4 or 1/2 of the standard dose (4 mg/kg, twice daily), and the lower limit of voriconazole trough concentration was maintained more than 0.5 µg/mL. The trend of remission of liver toxicity after drug reduction in 12 patients was recorded. During the same period, 25 patients who received standard doses served as the control group. Data from the two groups were collected and analyzed for different parameters such as demographic characteristics, underlying pulmonary disorders, laboratory tests, and therapeutic effect. The differences between the two groups were statistically compared. RESULTS: Hepatotoxicity occurred in 12 patients within 28-65 d after oral voriconazole treatment. Hepatotoxicity was mainly manifested by the significantly increased level of gamma-glutamyltransferase and a slight increase of alanine aminotransferase and aspartate aminotransferase. The oral dose of voriconazole was reduced to approximately 3 mg/kg in seven patients and approximately 2 mg/kg in five patients. The average trough concentrations for the 12 patients before and after voriconazole oral dose reduction were 3.17 ± 1.47 µg/mL (1.5-6.0 µg/mL) and 1.70 ± 0.78 µg/mL (0.6-3.3 µg/mL), respectively (P = 0.02). After lowering the trough concentrations, the hepatotoxicity was alleviated in all the patients. However, gamma-glutamyltransferase levels declined slowly. After 4 mo of treatment, 7 of the 12 patients were successfully treated in the low trough concentrations group (41.7%). Similarly, 8 of the 25 patients in the standard treatment dose group (32.0%) were effectively treated. There was no statistical difference between the groups (P = 0.72). CONCLUSION: Reducing the lower limit of the voriconazole trough concentration to 0.5 µg/mL can alleviate the hepatotoxicity and maintained certain clinical efficacy in CPA patients; however, patients should be closely monitored.

High-Dose Tigecycline in Elderly Patients with Pneumonia Due to Multidrug-Resistant Acinetobacter baumannii in Intensive Care Unit.

PURPOSE: The association between clinical and microbiological outcomes and high-dose tigecycline (TGC) was assessed in elderly (≥60 years old) patients with hospital-acquired and ventilator-associated pneumonia due to multidrug-resistant Acinetobacter baumannii(A. baumannii). This study also assessed tigecycline combination with different antibiotics and its influence on the outcome. PATIENTS AND METHODS: An observational retrospective cohort study was conducted. Patients over 60 years old were treated with standard-dose (SD) TGC (100-mg intravenous TGC initially, followed by 50-mg doses administered intravenously twice daily) and high-dose (HD) TGC (200-mg intravenous TGC initially, followed by 100-mg doses administered intravenously twice daily) for a microbially confirmed infection. The outcome was 30-day crude mortality, co-administered antimicrobial agent and the microbial eradication percentage in both groups. RESULTS: A total of 48 multidrug-resistant A. baumannii respiratory patients were identified. Tigecycline was administered to 85% of ventilation-associated pneumonia (VAP) patients (28/33) in the SD group and 80% of VAP patients (12/15) in the HD group. Combined therapy was the major treatment option in both groups, accounting for 85% and 87%, respectively. Median treatment duration in both groups was 7.36 vs 8.6 days, respectively. Survival days were 13.61 vs 12.4 days (P=0.357), respectively. The 30-day crude mortality was 39.4% (13/33) for the SD group and 14% (2/15) for the HD group (P=0.098). The microbial eradication rate of respiratory specimens in the SD group was higher than that in the HD group (P=0.02). The variables associated with 30-day crude mortality were chronic obstructive pulmonary disease (hazard ratio [HR] 11.63, 95% CI 1.094-123.058; P=0.042), tigecycline treatment duration (HR 0.690, 95% CI 0.515-0.926; P=0.013), and surgery before infection (HR 79.276, 95% CI 6.983-899.979; P=0.000). High-dose tigecycline was not associated with 30-day crude mortality (adjusted HR 0.329, 95% CI 0.074-1.460; P=0.145). Combined antibiotics was also not different between the two groups. CONCLUSIONS: High-dose tigecycline was not associated with 30-day crude mortality in elderly patients with pneumonia due to multidrug-resistant A. baumannii, although the microbial eradication rate was high.

Efficacy and safety of tigecycline monotherapy versus combination therapy for the treatment of hospital-acquired pneumonia (HAP): a meta-analysis of cohort studies.

The broad spectrum antibiotic tigecycline shows promising efficacy against many multiple drug resistant (MDR) pathogens. However, its clinical efficacy in the treatment of hospital-acquired pneumonia (HAP) is unclear. Several studies have reported on the treatment failures of tigecycline monotherapy, suggesting that it may not be sufficient to control severe infections. Combination therapy has become an option to treat MDR bacterial infections. We conducted a literature search using PubMed, Cochrane Library, Embase, Elsevier and the Web of Knowledge databases up to 29 February 2017 to identify relevant published studies. Studies were considered eligible if they were a cohort study that assessed mortality and the safety of tigecycline monotherapy versus combination therapy with other antimicrobial agents for HAP. The primary outcome was treatment mortality rate, while the secondary outcomes were adverse events. Meta-analysis was done using fixed-effects models. Five trials were included. The monotherapy tigecycline had a higher mortality compared to the combination therapy group. There was a significant difference for the treatment of HAP. However, two prospective cohort studies showed that there was no significant difference in mortality rate between the tigecycline monotherapy and the tigecycline combination therapy. Three retrospective cohort studies showed that tigecycline monotherapy had a high mortality rate. Tigecycline combination therapy efficiently treats HAP. There is a great need for well-designed studies to evaluate the effectiveness and safety of combination therapies as they compare to tigecycline monotherapy.

[The coagulation factor VII gene polymorphisms in patients with myocardial infarction in Ningxia Hui and Han populations].

OBJECTIVE: To investigate the characteristics for activated coagulation factor VII(F VIIa) and the R353Q, -323 0/10 bp, HVR4 polymorphisms in the gene in patients with coronary heart disease (CHD) and myocardial infarction from Ningxia Hui and Han populations. METHODS: Four hundred and twenty angiographically proven CHD patients in the Hui population, and 508 healthy blood donors were tested for their plasma levels of coagulation factor VII using recombinant tissue factor method. The coagulation factor VII gene R353Q, -323 0/10 bp and HVR4 genotypes were identified by polymerase chain reaction. In addition, 600 Han patients with CHD and 604 healthy Han control subjects were also investigated. RESULTS: (1) The plasma F VIIa levels was significantly higher in patients with CHD and myocardial infarction than that in healthy control subjects and angor pectoris (P<0.01) in both Hui and Han populations. (2) There were significant differences in the distribution of genotypes and allelic frequencies of the R353Q between myocardial infarction and angor pectoris disease in the Hui population (P<0.05). So was the -323 0/10 bp locus in both the Hui and Han population. (3) The F VIIa level was significantly higher in individuals with RR genotype than those of Q allele carriers in the Hui population. CONCLUSION: There are polymorphisms of the F VII gene R353Q, -323 0/10 bp and HVR4 in the Hui and Han populations. The Q allele might be a protective factor against myocardial infarction in the Hui, and the plasma F VIIa level may be influenced by the R353Q polymorphism of the F VII gene. The 10 allele may be a protective factor against myocardial infarction in both the Hui and Han populations.

Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling.

PURPOSE: To evaluate the effects of CYP2C19 and CYP2C9 genotypes on the pharmacokinetic variability of valproic acid (VPA) in epileptic patients using a population pharmacokinetic (PPK) approach. METHODS: VPA concentrations were measured in 287 epileptic patients, who were genotyped for CYP2C19*2/*3 and CYP2C9*3. Patients who were on monotherapy with VPA were divided into two groups, a PPK-model group (n = 177) and a PPK-valid group (n = 110). The PPK parameter values for VPA were calculated in the PPK-model group by using the NONMEM software. Ultimately, a biological model and a final model were established. Each model was then used to independently predict the concentrations of the PPK-valid group to validate the two models. RESULTS: There was a significant effect of the CYP2C19 and CYP2C9 genotypes on the pharmacokinetic (PK) variability (P < 0.01) in the final PPK model of CL/F. The interindividual CL was calculated according to the final model: CL/F = 0.0951 x (1 + e(0.0267 x (3 - genotype))) + 0.0071 x age (L/h). The coefficient of variation (CV) (omega CL/F) of the final model was 29.3%, while that of the biological model was 31.7%. Based on the genotype, the individual PK parameters can be calculated more accurately than before. CONCLUSION: The CYP2C19 and CYP2C9 genotypes significantly influenced the PK variability of VPA, as quantified by NONMEM software.

Population pharmacokinetics of valproate in Chinese children with epilepsy.

AIM: The aim of the present study is to establish a population pharmacokinetic (PPK) model of valproate (VPA) in Chinese epileptic children to promote the reasonable use of anti-epileptic drugs. METHODS: Sparse data of VPA serum concentrations from 417 epileptic children were collected. These patients were divided into 2 groups: the PPK model group (n=317) and the PPK valid group (n=100). The PPK parameter values of VPA were calculated by NONMEM software using the data of the PPK model group. A basic model and a final model were set up. To validate the 2 models, the concentrations of PPK valid group were predicted by each model, respectively. The mean prediction error (MPE), mean squared prediction error (MSPE), root mean squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were also calculated. Then, the values between the 2 models were compared. RESULTS: The PPK of VPA was determined by a 1-compartment model with a first-order absorption process. The basic model was: Ka=3.09 (h(-1)), V/F=20.4 (L), CL/F=0.296 (L/h). The final model was: Ka=0.251+2.24 x (1-HS) (h(-1)), V/F=2.88+0.157 x WT (L), CL/F=0.106(0.98 x CO)+ 0.0157 x AGE (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -23.53 (-30.36, -16.70), 3728.96 (2872.72, 4585.20), 39.62 (34.34, 44.90), and -0.06 (-0.14, 0.02), respectively. For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -1.16 (-4.85, 2.53), 1002.83 (1050.64, 1143.61), 23.04 (21.12, 24.96), and 0.08 (-0.04, 0.20), respectively. The final model was more optimal than the basic model. CONCLUSION: The PPK model of VPA in Chinese epileptic children was successfully established. It will be valuable to facilitate individualized dosage regimens.