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.

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.

Physicians' knowledge, attitude, and prescribing behavior regarding stress ulcer prophylaxis in China: a multi-center study.

BACKGROUND: Perioperative patients are at risk of developing stress ulcers (SU), which can cause clinically important bleeding. Stress ulcer prophylaxis (SUP) is widely applied to the patients in Intensive care unit (ICU) as well as the general ward, so it may lead to overmedication. However, there have been no surveys regarding SUP knowledge or prescribing habits. OBJECTIVE: Our study assessed the knowledge, attitudes, and prescribing behavior of the surgeons toward perioperative patients regarding SUP and determined factors associated with low knowledge and high level of prescribing behaviors. METHODS: We performed a cross-sectional survey using questionnaires, randomly sampling 1266 surgeons on their current SUP practices. RESULTS: Proton pump inhibitors for SUP were used the most (94%); 43% used lansoprazole. Guideline awareness was inconsistent; the most familiar guideline was the National Medical Journal of China, and 46% were unaware of any guidelines. The predictors of low knowledge score regarding SUP in multivariable analysis were the hospital grade (p = 0.000), the type of hospital (p = 0.044), attendance at continuing education programs (p = 0.037), the awareness of clinical practice guidelines (CPGs) for SUP (p = 0.000). Twenty-one percent of physicians were high prescribers. High prescribing behavior was associated with hospital grade(p = 0.000), education level(p = 0.010) and attendance at continuing education programs (p = 0.000). CONCLUSION: We found that most surgeons used SUP, primarily proton pump inhibitors. However, surgeons knew little about the SUP guidelines, which may lead to insufficient SUP knowledge and overmedication. In addition, hospital grade, the type of hospital and attendance at continuing education programs may also affect the low knowledge of SUP. Hospital grade, education level and attendance at continuing education programs may affect high prescribing behavior.

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.

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.