Drug-related problems in hospitalized patients with chronic kidney diseases and clinical pharmacist interventions.

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk of drug-related problems (DRPs) because of extensive comorbidities and pharmacokinetic changes. This study aimed to identify DRPs and possible contributing factors in hospitalized patients with CKD, and evaluate the efficacy of the clinical pharmacist services in detection and intervention of DRPs in a large general hospital in Zhejiang Province, eastern China. METHODS: With the approval of the Ethics Committee, patients with CKD admitted to the nephrology ward from January to December 2020 were enrolled in this prospective study. The clinical pharmacist identified and intervened the DRPs during hospitalization. The DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) DRP classification system, and all data were statistically analyzed using Statistical Package for Social Science (SPSS) version 26.0. RESULTS: A total of 914 patients with CKD were included, with 463 DRPs observed among 420 (45.95%) participants; the average DRP per patient was 0.51 (standard deviation [SD], 0.60) before pharmacist intervention. Treatment safety accounted for the highest proportion of problems (43.84%), followed by treatment efficacy, accounting for 43.20%. Drug selection was the most common cause of DRPs (60.26%), and antibiotics and cardiovascular agents were the most common drugs associated with DRPs (32.84% and 28.66%, respectively). A total of 85.53% of pharmaceutical intervention recommendations were followed, and 84.23% of DRPs were completely resolved after intervention by the clinical pharmacist. The proportion of patients who experienced DRPs decreased to 7.77%, with an average of 0.08 (SD 0.28) DRPs during hospitalization after pharmacist's intervention. Significant contributing factors for DRPs were CKD stage 4, number of comorbid diseases, number of prescribed medications, and hospitalization days in both the univariate and multivariate logistic regression models. CONCLUSION: DRPs are common among hospitalized patients with CKD in China. CKD stage 4, the number of comorbidities, use of multiple prescription drugs, and extended length of hospital stay are contributing factors for DRPs. Even only one clinical nephrology pharmacist in the nephrology ward, clinical pharmacist can play an important role in facilitating the identification of DRPs in patients with CKD and assisting physicians resolve DRPs in this single center study in China.

Cytokine Storm in Acute Viral Respiratory Injury: Role of Qing-Fei-Pai-Du Decoction in Inhibiting the Infiltration of Neutrophils and Macrophages through TAK1/IKK/NF-[Formula: see text]B Pathway.

COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF-[Formula: see text], IL-6, and IL-1[Formula: see text] in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF-[Formula: see text], MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK[Formula: see text]/[Formula: see text], and I[Formula: see text]B[Formula: see text] and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF-[Formula: see text]B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections.

Retrospective Analysis of Azithromycin-Resistant Ureaplasma urealyticum and Mycoplasma hominis Cervical Infection Among Pregnant Women.

Purpose: Ureaplasma urealyticum and Mycoplasma hominis began to show resistance to azithromycin, a macrolide antibiotic commonly used in pregnancy. Unfortunately, there are few effective and safe drugs in the clinic for genital mycoplasmas in pregnant women. In the present study, we investigated the prevalence of azithromycin-resistant U. urealyticum and M. hominis infections in pregnant women. The secondary research objects were possible influencing factors and consequences of insensitive Mycoplasma infection. Patients and methods: A retrospective analysis was carried out in pregnant women who underwent cervical Mycoplasma culture between October 2020 and October 2021 at a large general hospital in eastern China. The sociological characteristics and clinical information of these women were collected and analyzed. Results: A total of 375 pregnant women were enrolled, and 402 cultured mycoplasma specimens were collected. Overall, 186 (49.60%) patients tested positive cervical Mycoplasma infection, and 37 (9.87%) had infections caused by azithromycin-resistant Mycoplasma. In total, 39 mycoplasma samples were insensitive to azithromycin in vitro, also showing extremely high resistance to erythromycin, roxithromycin, and clarithromycin. Azithromycin was the only antibiotic used in women with Mycoplasma cervical infection, regardless of azithromycin resistance in vitro. Statistical results showed that azithromycin-resistant cervical Mycoplasma infection in pregnant women was unrelated to age, body mass index (BMI), gestational age, number of embryos, and assisted reproductive technology (ART) use, but led to a significantly increased incidence of adverse pregnancy outcomes (spontaneous abortion (SA), preterm birth (PTB), preterm prelabor rupture of membranes (PPROM), and stillbirth). Conclusion: Azithromycin-resistant U. urealyticum and M. hominis cervical infections are relatively common during pregnancy, and can increase the risk of adverse pregnancy outcomes; however, there is currently a lack of safe and effective drug treatments. Herein, we show that azithromycin-resistant mycoplasma infection requires timely intervention.

[Reduning Injection protects flu-infected mice by inhibiting infiltration of inflammatory cells in lung and down-regulating cytokine storm].

This study aimed to explore the protective effect of Reduning Injection(RDN) on mice infected by influenza virus A/PR/8(PR8) and its immune regulatory roles during viral infection. In in vivo experiments, female C57 BL/6 mice were randomly divided into phosphate buffered saline(PBS) group, PR8-infected group, oseltamivir treatment group(OSV) and RDN treatment group. After 2 h of PR8 infection, mice in the oseltamivir group were gavaged with oseltamivir 30 mg·kg~(-1), and those in the RDN treatment group were injected intraperitoneally with RDN 1.5 mL·kg~(-1)once per day for seven consecutive days. The body weight of mice in each group was recorded at the same time every morning for 16 consecutive days. The line chart of body weight change was created to analyze the protective effect of RDN on flu-infected mice. The relative mRNA expression of different cytokines(IL-6, TNF-α, MCP-1, IL-1ß, MIP-2, IP-10 and IL-10) in lung samples of flu-infected mice was detected by PCR. Flow cytometry was utilized to analyze the composition of immune cells of mouse BALF samples on day 5 after infection. Mouse macrophage cell line RAW264.7 was planted and treated by different concentrations of RDN(150, 300, 600 µg·mL~(-1)) for 24 h or 48 h, and cell proliferation was detected by CCK-8 assay. RAW264.7 cells and mouse primary peritoneal macrophages were stimulated with synthetic single stranded RNA(R837), which elicited the inflammatory response by mimicking the infection of single-stranded RNA viruses. The expression of cytokines and chemokines in the supernatants of above culture system was detected by ELISA and qPCR. On days 4, 5, 6, 7 and 15 after infection, the body weight loss of mice in the RDN treatment group was alleviated compared with that of PR8-infected mice(P<0.05). RDN treatment obviously reduced lung index and the production of IL-6, TNF-α, MCP-1 and MIP-2 in lung tissues of flu-infected mice(P<0.05). The proportions of macrophages, neutrophils and T cells in mouse BALF samples were analyzed by flow cytometry, and compared with PR8-infected mice, RDN decreased the proportion of macrophages in BALF of flu-infected mice(P<0.05), and the proportion of T cells was recovered dramatically(P<0.001). In CCK-8 assay, the concentrations of RDN(150, 300, 600 µg·mL~(-1)) failed to cause cytotoxicity to RAW264.7 cells. In addition, RDN lowered the expression of inflammatory cytokines such as IL-6, TNF-α,MCP-1, IL-1ß, RANTES, and IP-10 and even anti-inflammatory cytokine IL-10 in R837-induced macrophages. RDN reduced the infiltration of inflammatory macrophages and the production of excessive inflammatory cytokines, alleviated the body weight loss of flu-infected mice. What's more, RDN restored the depletion of T cells, which might prevent secondary infection and deteriorative progression of the disease. Taken together, RDN may inhibit cytokine production and therefore down-regulate cytokine storm during the infection of influenza virus.

Cost-effectiveness analysis of 4 GLP-1RAs in the treatment of obesity in a US setting.

Background: The number of obese people continues to increase worldwide, and obesity-related complications add to every country's health burden. Consequently, new weight-loss medications, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), are attracting increasing attention. This study sought to assess the cost effectiveness for weight loss of 4 GLP-1RAs in adult patients with obesity in the United States. Methods: Four GLP-1RA groups that received Liraglutide (1.8 mg QD), Semaglutide (1.0 mg QW), Dulaglutide (1.5 mg QW), or Exenatide (10 µg BID), and one no-treatment group were compared using a decision-tree model. All the estimated parameters were derived from published articles. Quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) were adopted as the study endpoints. We analyzed the results with the willingness-to-pay (WTP) threshold, and conducted deterministic and probabilistic sensitivity analyses. Results: The GLP-1RAs produced effective weight-loss results; however, not all the GLP-1RAs were cost effective compared to no treatment based on a WTP threshold of $195000/QALY. Among the 4 GLP-1RAs, Semaglutide provided a cost-effective strategy with an ICER of $135467/QALY. The sensitivity analyses showed that these results are reliable. Conclusions: Among the 4 GLP-1RAs, Semaglutide was the most cost-effective obesity medication.

Integration of the blaNDM-1 carbapenemase gene into a novel SXT/R391 integrative and conjugative element in Proteus vulgaris.

OBJECTIVES: To characterize the genetic environment of the carbapenem resistance determinant in Proteus vulgaris of swine origin. METHODS: The carbapenem-resistant P. vulgaris strain BC22 was isolated from a faecal swab from a diseased pig with diarrhoea in Sichuan Province of China in 2018. The presence of carbapenemase genes was screened by PCR. WGS and bioinformatics analysis were performed to analyse the genetic environment of the carbapenem resistance determinant. RESULTS: P. vulgaris strain BC22 was found to harbour the carbapenemase gene blaNDM-1. WGS data revealed that blaNDM-1 was located in a truncated ISAba125 composite transposon. The carbapenem resistance gene blaNDM-1 and 20 other resistance genes, including the multiresistance gene cfr and the bifunctional aminoglycoside/quinolone resistance gene aac(6')-lb-cr, were located in a novel SXT/R391 integrative and conjugative element (ICE). This new SXT/R391 ICE of 148.7 kb was chromosomally located, and could be transferred to Escherichia coli. CONCLUSIONS: Here, we report a carbapenemase gene, blaNDM-1, integrated into an SXT/R391 ICE. Our study highlights that this SXT/R391 ICE may facilitate the dissemination of clinically important resistance genes such as blaNDM-1, cfr and aac(6')-lb-cr.

Whole-genome sequencing of Enterococcus hirae CQP3-9, a strain carrying the phenicol-oxazolidinone-tetracycline resistance gene poxtA of swine origin in China.

OBJECTIVES: The aim of this study was to characterise the whole genome sequence of linezolid-intermediate Enterococcus hirae strain CQP3-9 isolated from a large-scale swine farm in Sichuan Province, China, in August 2018. METHODS: An Illumina MiSeq platform (400-bp paired-end reads with 230-fold average coverage) and PacBio RS II sequencing instrument (100-fold average read depth) were used for genome sequencing. The chromosome and two plasmids were assembled using the software SMRT portal v.3.2.0. Acquired antimicrobial resistance genes were identified using ResFinder 3.1. RESULTS: The genome of E. hirae strain CQP3-9 consists of one 2 695 881-bp chromosome, one 125 915-bp plasmid (pCQP3-9_1) and one 33 132-bp plasmid (pCQP3-9_2). The genome of CQP3-9 contains 2458 coding sequences and 89 RNA genes. The poxtA gene is the only linezolid resistance gene in CQP3-9, located on plasmid pCQP3-9_2 that co-harbours erm(B) (macrolide resistance), fexB (chloramphenicol and florfenicol resistance), and tet(M) and tet(L) (tetracycline resistance). CONCLUSION: Here we report for the first time the phenicol-oxazolidinone-tetracycline resistance gene poxtA in E. hirae, located on a plasmid that co-harbours erm(B), fexB, tet(L) and tet(M). The genome sequence of E. hirae CQP3-9 provides valuable information for the dissemination of poxtA among enterococci.

Detection of transferable oxazolidinone resistance determinants in Enterococcus faecalis and Enterococcus faecium of swine origin in Sichuan Province, China.

OBJECTIVES: The aim of this study was to detect transferable oxazolidinone resistance determinants (cfr, optrA and poxtA) in Enterococcus faecalis and Enterococcus faecium isolates of swine origin in Sichuan Province, China. METHODS: A total of 158 enterococcal isolates (93 E. faecalis and 65 E. faecium) isolated from 25 large-scale swine farms (2016-2017) were screened for the presence of cfr, optrA and poxtA by PCR. The genetic environments of cfr, optrA and poxtA were characterised by whole-genome sequencing. Transfer of oxazolidinone resistance determinants was determined by conjugation or electrotransformation experiments. RESULTS: The transferable oxazolidinone resistance determinants cfr, optrA and poxtA were detected in zero, six and one enterococcal isolates, respectively. The poxtA gene in one E. faecalis isolate was located on a 37 990-bp plasmid that co-harboured fexB, cat, tet(L) and tet(M) and could be conjugated to E. faecalis JH2-2. One E. faecalis isolate harboured two different OptrA variants, including one variant with a single substitution (Q219H) that has not been reported previously. Two optrA-carrying plasmids, pC25-1 (45 581bp) and pC54 (64 500bp), shared a 40 494-bp identical region containing the genetic context IS1216E-fexA-optrA-erm(A)-IS1216E that could be electrotransformed into Staphylococcus aureus. Four different chromosomal optrA gene clusters were found in five strains, in which optrA was associated with Tn554 or Tn558 inserted into the radC gene. CONCLUSION: This study highlights the fact that mobile genetic elements, such as plasmids, IS1216E, Tn554 and Tn558, may facilitate the horizontal transmission of optrA and poxtA genes.

An IncX1 plasmid isolated from Salmonella enterica subsp. enterica serovar Pullorum carrying blaTEM-1B, sul2, arsenic resistant operons.

We have identified an IncX1 plasmid named pQJDSal1 from Salmonella enterica subsp. enterica serovar Pullorum (S. Pullorum). The plasmid is 67,685 bp in size and has 72 putative genes. pQJDSal1 harbors a conserved IncX1-type backbone with predicted regions for conjugation, replication and partitioning, as well as a toxin/antitoxin plasmid addiction system. Two regions (A and B) that have not been previously reported in IncX1 plasmids are inserted into the backbone. Region A (10.7 kb), inserted between parA and taxD, consists of a new Tn6168-like transposon containing an arsenic resistant operon arsB2CHR and sulfonamide resistance gene sul2. Region B contains another arsenic resistant operon arsADHR, resistance gene blaTEM-1B and three transposable elements. Conjugation experiments showed that pQJDSal1 could transfer from S. Pullorum to Escherichia coli (E. coli) J53. Statistical analysis of 70 sequenced IncX1 plasmids revealed that IncX1 plasmids harbored various antibiotic resistance genes. The results highlight the importance of IncX1 plasmids in disseminating antibiotic resistance genes.

Various Sequence Types of Enterobacteriaceae Isolated from Commercial Chicken Farms in China and Carrying the blaNDM-5 Gene.

A total of 108 meropenem-resistant Enterobacteriaceae isolates were obtained from 1,658 rectal swabs collected from 15 unrelated commercial chicken farms in China between 2014 and 2016. These samples yielded 16 Escherichia coli and 2 Klebsiella pneumoniae isolates of diverse sequence types carrying a blaNDM-5-bearing IncX3 plasmid. K. pneumoniae strain sequence type 709 (ST709) has two blaNDM-5-carrying plasmids that were transferred together to E.coli.

Colocation of the Polymyxin Resistance Gene mcr-1 and a Variant of mcr-3 on a Plasmid in an Escherichia coli Isolate from a Chicken Farm.

A colistin-resistant Escherichia coli isolate from a commercial poultry farm in China carried two colistin resistance genes, mcr-1 and variant of mcr-3, in an IncP plasmid. The variant of the mcr-3 gene, named mcr-3.11, encoded two amino acid substitutions compared with the mcr-3 gene. A novel genetic structure, ISKpn40-mcr-3-dgkA-ISKpn40, might be the key element mediating the translocation of mcr-3 through the formation of a circular form. The mcr-1 and mcr-3 genes, which are colocated on a plasmid, might pose a huge threat to public health.

Effects of repeated allopurinol administration on rat cytochrome P450 activity.

Allopurinol is a popular and widely-prescribed anti-hyperuricemic agent that has been implicated in drug interactions with substrates of several cytochrome P450 (CYP) enzymes. The effect of repeated allopurinol administration (20 mg/kg, once daily for 14 days) on metabolic activity of CYP was assessed in rats. This was a randomized, double-blind, two-way crossover study with a 4-week washout period between phases. The substrates used in this study were phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19) and dextromethorphan (CYP2D6). Validated HPLC-MS/MS was used to quantify all compounds. Our study showed that allopurinol administration inhibited CYP1A2 activity, causing a significant increase in AUC (0-infinity) (P < 0.01) and t1/2 (P < 0.05) of phenacetin, and a distinct decline in CL (P < 0.01). However, there were no significant differences of another three probe drugs in plasma concentrations and the corresponding pharmacokinetic parameters between the allopurinol-treated and normal saline-treated rats. The findings in this study suggested that allopurinol could inhibit CYP1A2 but did not influence CYP2C9, CYP2C19 and CYP2D6 enzymes.

[Near-infrared spectroscopy technology for online monitoring of the column separation and purification process of active components of Centella asiatica L. Urban].

The present paper is to study and develop a method for online monitoring of the column separation and purification process of active components that are madecassoside and asiaticoside of Centella asiatica L. Urban using near-infrared (NIR) spectroscopy technology. After collecting 50%-ethanol eluant, we detected their NIR spectra and developed the high performance liquid chromatography (HPLC) assay method of active components. Then, partial least square (PLS) was used to develop linear correlation between their NIR spectra and contents. During modeling, correlation coefficient (R2) and root mean square errors of cross-validation (RMSECV) were regarded as the indexes to select optimal wavenumbers and preprocessing methods. The optimal wavenumbers of madecassoside and asiaticoside were in the range of 12 000.8-7 499.8 cm(-1) and 12 000.8-9 750.3 cm(-1), respectively; R2 were 96.44 and 96.07, respectively, and RMSECV were 0.084 80 and 0.000 99, respectively. The above developed model was used for online monitoring of the contents of madecassoside and asiaticoside during the column separation and purification process of Centella asiatica L. Urban. The predicted results were satisfactory. This method was proved to be fast, convenient and precise. It can be used in online monitoring and quality control of the manufacturing of madecassoside and asiaticoside.