Background: Multidrug-resistant gram-negative (MDR GN) infections pose a significant threat to pediatric health. One of the treatment options in resource-limited settings is polymyxin-based combination therapy. However, evidence on the safety and clinical effectiveness of polymyxin B in children is scarce. Objectives: This study described the outcomes of mortality, bacteriologic cure and clinical response in pediatric patients with MDR GN infections treated with polymyxin-B-based combination therapy. Adverse drug events (ADE) are likewise described. Methodology: This is a retrospective descriptive study conducted at the Philippine General Hospital (PGH) among pediatric inpatients from December 2020 to June 2023 with MDR GN infections treated with polymyxin B (PmB), combined with at least one other antibiotic with gram-negative coverage for at least 48 hours. Frequency and rates of the outcomes were measured and analyzed, in relation to the bacterial groups (Enterobacterales, Acinetobacter spp., Pseudomonas aeruginosa) and combination antibiotic regimens used, i.e., meropenem- and fluoroquinolone-containing regimen (PmB+MEM vs PmB+FQ). Frequency of ADEs were measured. Results: A total of 172 cases in 136 patients were reviewed. The rates for 14-day mortality, failure in bacteriologic cure, and failure in clinical response were 26%, 15%, and 19%, respectively. In Enterobacterales infections, PmB+FQ demonstrated lower rates of mortality, failure in bacteriologic cure, and failure in clinical responses. On the other hand, in Acinetobacter infections, PmB+MEM numerically had lower rates for the same outcomes. The Pseudomonas group had conflicting data on which regimen is numerically more favorable overall. No statistically significant differences were found in the outcomes. ADEs noted were tubulopathy (5 cases), anaphylaxis (2 cases), and neurotoxicity (1 case). Conclusion Polymyxin-B-based combination therapy appears to be an acceptable treatment option for MDR GN infections in children, especially in settings where novel antibiotics are not accessible. Safety profiles indicate common but manageable adverse effects.
Polymyxin B ; Child

Humans ; Staphylococcus lugdunensis/genetics* ; Peptides, Cyclic ; Chromosomes ; Operon/genetics* ; Staphylococcal Infections/genetics* ; Bacterial Proteins/genetics* ; Anti-Bacterial Agents

This paper aimed to study the role of asparagine endopeptidase(AEP) gene in the biosynthesis mechanism of cyclic peptide compounds in Pseudostellaria heterophylla. The transcriptome database of P. heterophylla was systematically mined and screened, and an AEP gene, tentatively named PhAEP, was successfully cloned. The heterologous function verification by Nicotiana benthamiana showed that the expression of the gene played a role in the biosynthesis of heterophyllin A in P. heterophylla. Bioinformatics analysis showed that the cDNA of PhAEP was 1 488 bp in length, encoding 495 amino acids with a molecular weight of 54.72 kDa. The phylogenetic tree showed that the amino acid sequence encoded by PhAEP was highly similar to that of Butelase-1 in Clitoria ternatea, reaching 80%. The sequence homology and cyclase active site analysis revealed that the PhAEP enzyme may specifically hydrolyse the C-terminal Asn/Asp(Asx) site of the core peptide in the HA linear precursor peptide of P. heterophylla, thereby participating in the ring formation of the linear precursor peptide. The results of real-time quantitative polymerase chain reaction(RT-qPCR) showed that the expression level of PhAEP was the highest in fruits, followed by in roots, and the lowest in leaves. The heterophyllin A of P. heterophylla was detected in N. benthamiana that co-expressed PrePhHA and PhAEP genes instantaneously. In this study, the PhAEP gene, a key enzyme in the biosynthesis of heterophyllin A in P. heterophylla, has been successfully cloned, which lays a foundation for further analysis of the molecular mechanism of PhAEP enzyme in the biosynthesis of heterophyllin A in P. heterophylla and has important significance for the study of synthetic biology of cyclic peptide compounds in P. heterophylla.
Genes, vif ; Phylogeny ; Plant Leaves/genetics* ; Peptides, Cyclic ; Cloning, Molecular ; Caryophyllaceae/genetics*

OBJECTIVES: Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections. METHODS: In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed. RESULTS: Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection (P>0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 (P=0.005), intraoperative red blood cell infusion ≥12 U (P=0.013) and exposure to more than 2 intravenous antibiotics post-LT (P=0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 (OR=2.378, 95% CI 1.124 to 5.032, P=0.024) and intraoperative red blood cell transfusion ≥ 12 U (OR=2.757, 95% CI 1.227 to 6.195, P=0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT (OR=0.269, 95% CI 0.121 to 0.598, P=0.001). CONCLUSIONS Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.
Humans ; Daptomycin/therapeutic use* ; Linezolid/therapeutic use* ; Teicoplanin/therapeutic use* ; Gram-Positive Cocci ; Liver Transplantation/adverse effects* ; Tigecycline/therapeutic use* ; End Stage Liver Disease/drug therapy* ; Gram-Positive Bacterial Infections/microbiology* ; Severity of Illness Index ; Anti-Bacterial Agents/pharmacology* ; Vancomycin/therapeutic use* ; Microbial Sensitivity Tests

Objective:b> To assess the efficacy and safety of polymyxin B in neutropenic patients with hematologic disorders who had refractory gram-negative bacterial bloodstream infection. Methods:b> From August 2021 to July 2022, we retrospectively analyzed neutropenic patients with refractory gram-negative bacterial bloodstream infection who were treated with polymyxin B in the Department of Hematology of the First Affiliated Hospital of the Soochow University between August 2021 to July 2022. The cumulative response rate was then computed. Results:b> The study included 27 neutropenic patients with refractory gram-negative bacterial bloodstream infections. Polymyxin B therapy was effective in 22 of 27 patients. The median time between the onset of fever and the delivery of polymyxin B was 3 days [interquartile range (IQR) : 2-5]. The median duration of polymyxin B treatment was 7 days (IQR: 5-11). Polymyxin B therapy had a median antipyretic time of 37 h (IQR: 32-70). The incidence of acute renal dysfunction was 14.8% (four out of 27 cases), all classified as "injury" according to RIFLE criteria. The incidence of hyperpigmentation was 59.3%. Conclusion:b> Polymyxin B is a viable treatment option for granulocytopenia patients with refractory gram-negative bacterial bloodstream infections.
Humans ; Polymyxin B/adverse effects* ; Retrospective Studies ; Gram-Negative Bacterial Infections/complications* ; Fever/drug therapy* ; Sepsis/drug therapy* ; Anti-Bacterial Agents/therapeutic use* ; Bacteremia/complications*

Objective:b> Analysis and investigation of pathogenic characteristics of polymyxin-and carbapenem-resistant Klebsiella pneumoniae (PR-CRKP). Methods:b> A total of 23 PR-CRKP strains isolated from clinical specimens from the General Hospital of Southern Theater Command from March 2019 to July 2021 were retrospectively collected, Whole-genome sequencing was performed on 23 PR-CRKP strains, resistance genes were identified by comparison of the CARD and the ResFinder database, high-resolution typing of PR-CRKP strains was analyzed by core genomic multilocus sequencing (cgMLST) and single nucleotide polymorphism (SNP); polymyxin resistance genes were determined by PCR and sequencing. Results:b> All PR-CRKP strains were KPC-2 producing ST11 types. cgMLST results showed that the evolutionary distance between the PR-CRKP strains and Klebsiella pneumoniae in mainland China was 66.44 on average, which is more closely related than foreign strains; the 23 PR-CRKP strains were divided into 3 main subclusters based on SNP phylogenetic trees, with some aggregation among Clade 2-1 in the isolation department and date. The two-component negative regulatory gene mgrB has seven mutation types including point mutations, different insertion fragments and different insertion positions. Conclusion:b> The close affinity of PR-CRKP strains indicate the possibility of nosocomial clonal transmission and the need to strengthen surveillance of PR-CRKP strains to prevent epidemic transmission of PR-CRKP.
Humans ; Carbapenems/pharmacology* ; Anti-Bacterial Agents/therapeutic use* ; Klebsiella pneumoniae/genetics* ; Polymyxins/pharmacology* ; beta-Lactamases ; Phylogeny ; Retrospective Studies ; Multilocus Sequence Typing ; Microbial Sensitivity Tests

Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.
Humans ; Anti-Bacterial Agents/therapeutic use* ; China ; Drug Monitoring/methods* ; Polymyxin B ; Practice Guidelines as Topic

Biological Products ; Peptides, Cyclic ; Antiviral Agents

Circular RNA (circRNA) is a single-stranded circular closed RNA molecule formed from linear RNA through reverse splicing. circRNAs are stable, highly conserved, and tissue-specific. circRNAs can regulate physiological and pathological processes through various mechanisms such as formation of competing endogenous RNA and interaction with binding proteins. It has been recently revealed that circRNAs can be translated into peptides and proteins to participate in the initiation and development of cancer. circRNAs are promising diagnostic and prognostic markers for human cancers as well as potential drug targets for cancer therapy. This review summarized the research progresses related to circRNA-encoded peptides and proteins in a variety of cancers. These peptides and proteins are translated through two different mechanisms that depend on internal ribosome entry site and m6A, respectively. We also summarized the potential use of circRNA-encoded peptides and proteins in the diagnosis, treatment, prognosis and mechanistic studies of various cancers.
Humans ; Internal Ribosome Entry Sites ; Neoplasms/genetics* ; Peptides, Cyclic ; RNA/genetics* ; RNA, Circular/genetics*

One new cyclopeptide was isolated from the ethyl acetate fraction of the 75% EtOH extract of Selaginella tamariscina by various column chromatography methods(HP-20, polyamide and semi-preparative HPLC). Its structure was identified as selapeptin A(1) by extensive spectroscopic analysis(HR-ESI-MS, 1 D and 2 D NMR). Compound 1 was evaluated for cytotoxic activities by MTT assay. It showed potent cytotoxic activity against B16 F10 with the inhibition rate of 51.57%±4.34% at 40 μmol·L~(-1) while had no impacts on MDA-MB-231 and MDA-MB-468 at 100 μmol·L~(-1).
Chromatography, High Pressure Liquid ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Peptides, Cyclic/pharmacology* ; Selaginellaceae/chemistry*