OBJECTIVE: To explore the mechanism of antibiotic delivery system targeting bacterial biofilm with linezolid (LZD) based on ε-poly- L-lysine (ε-PLL) and cyclodextrin (CD) (ε-PLL-CD-LZD), aiming to enhance antibiotic bioavailability, effectively penetrate and disrupt biofilm structures, and thereby improve the treatment of bone and joint infections. METHODS: ε-PLL-CD-LZD was synthesized via chemical methods. The grafting rate of CD was characterized using nuclear magnetic resonance. In vitro biocompatibility was evaluated through live/dead cell staining after co-culturing with mouse embryonic osteoblast precursor cells (MC3T3-E1), human umbilical vein endothelial cells, and mouse embryonic fibroblast cells (3T3-L1). The biofilm-enrichment capacity of ε-PLL-CD-LZD was assessed using Staphylococcus aureus biofilms through enrichment studies. Its biofilm eradication efficacy was investigated via minimum inhibitory concentration (MIC) determination, scanning electron microscopy, and live/dead bacterial staining. A bone and joint infection model in male Sprague-Dawley rats was established to validate the antibacterial effects of ε-PLL-CD-LZD. RESULTS: In ε-PLL-CD-LZD, the average grafting rate of CD reached 9.88%. The cell viability exceeded 90% after co-culturing with three types cells. The strong biofilm enrichment capability was observed with a MIC of 2 mg/L. Scanning electron microscopy observations revealed the effective disruption of biofilm structure, indicating potent biofilm eradication capacity. In vivo rat experiments demonstrated that ε-PLL-CD-LZD significantly reduced bacterial load and infection positivity rate at the lesion site ( P<0.05). CONCLUSION The ε-PLL-CD antibiotic delivery system provides a treatment strategy for bone and joint infections with high clinical translational significance. By effectively enhancing antibiotic bioavailability, penetrating, and disrupting biofilms, it demonstrated significant anti-infection effects in animal models.
Biofilms/drug effects* ; Animals ; Anti-Bacterial Agents/pharmacology* ; Polylysine/chemistry* ; Cyclodextrins/administration & dosage* ; Humans ; Linezolid/pharmacology* ; Staphylococcus aureus/physiology* ; Rats, Sprague-Dawley ; Mice ; Rats ; Male ; Drug Delivery Systems ; Staphylococcal Infections/drug therapy* ; Microbial Sensitivity Tests ; Human Umbilical Vein Endothelial Cells ; Osteoblasts/cytology*

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

BACKGROUNDStaphylococcus aureus is one of the predominant causes of skin and soft tissue infections (SSTIs), but limited data were available regarding the characterization of S. aureus from SSTIs patients in Jiangsu Province in China. We aimed to investigate the molecular epidemiology of S. aureus among SSTIs patients in two hospitals of Jiangsu Province.

METHODSSixty-two patients with SSTIs from two Chinese hospitals in Jiangsu Province were enrolled in this study, and 62 S. aureus isolates were collected from February 2014 to January 2015. S. aureus isolates were characterized by antimicrobial susceptibility testing, toxin gene detection, and molecular typing with sequence type, Staphylococcus protein A gene type, accessory gene regulator (agr) group, and Staphylococcal cassette chromosome mec t ype.

RESULTSSixteen (25.8%) methicillin-resistant S. aureus (MRSA) isolates were detected, and there was no isolate found resistant to vancomycin, teicoplanin, sulfamethoxazole-trimethoprim, and linezolid. The sei was the toxin gene most frequently found, and no lukS/F-PV-positive isolates were detected among the SSTIs' patients. Molecular analysis revealed that ST398 (10/62, 16.1%; 2 MRSA and 8 methicillin-susceptible S. aureus) to be the dominant clone, followed by ST5 (8/62, 12.9%) and ST7 (8/62, 12.9%).

CONCLUSIONSThe livestock ST398 was the most common clone among patients with S. aureus SSTIs in Jiangsu Province, China. Surveillance and further studies on the important livestock ST398 clone in human infections are necessarily requested.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anti-Bacterial Agents ; pharmacology ; Child ; Child, Preschool ; China ; Female ; Hospitals ; Humans ; Infant ; Linezolid ; pharmacology ; Male ; Methicillin-Resistant Staphylococcus aureus ; drug effects ; isolation & purification ; Microbial Sensitivity Tests ; Middle Aged ; Molecular Epidemiology ; Soft Tissue Infections ; microbiology ; Staphylococcal Infections ; microbiology ; Staphylococcal Skin Infections ; microbiology ; Staphylococcus aureus ; drug effects ; isolation & purification ; Teicoplanin ; pharmacology ; Trimethoprim, Sulfamethoxazole Drug Combination ; pharmacology ; Vancomycin ; pharmacology ; Young Adult

Coagulase-negative staphylococci (CoNS) are reported to be the leading cause of nosocomial bloodstream infections. Staphylococcus pettenkoferi is a novel member of CoNS that was first isolated from the human blood and bursitis wound in 2002. We have reported cases of 6 S. pettenkoferi strains isolated from blood specimens, including one pathogen and 5 contaminants and catheter colonizers. Brucker Biotyper (Brucker Daltonics, Bremen, Germany) and molecular typing with 16S rRNA gene sequencing confirmed the 6 isolates as S. pettenkoferi. The conventional phenotypic identification of these isolates is not reliable owing to their inconsistent biochemical characteristics. Five of the 6 isolates were found to be resistant to oxacillin, and all isolates showed susceptibility to vancomycin and linezolid. For accurate identification of this novel species, advanced methods by using Brucker Biotyper or molecular methods such as 16S rRNA gene sequencing are required.
Aged ; Aged, 80 and over ; Anti-Bacterial Agents/pharmacology/therapeutic use ; DNA, Bacterial/chemistry/metabolism ; Drug Resistance, Bacterial/drug effects ; Female ; Humans ; Linezolid/pharmacology ; Male ; Microbial Sensitivity Tests ; Middle Aged ; Oxacillin/pharmacology ; Phenotype ; RNA, Ribosomal, 16S/chemistry/genetics/metabolism ; Sequence Analysis, DNA ; Staphylococcal Infections/drug therapy/*microbiology/pathology ; Staphylococcus/drug effects/*genetics/isolation & purification ; Vancomycin/pharmacology

BACKGROUNDVancomycin-resistant Enterococci (VRE) cause serious infections that are difficult to treat. We carried out this study to determine the mutant prevention concentration (MPC) of linezolid when combined with minocycline against VRE strains, to determine the mechanism of drug resistance in vitro, and to provide a theoretical basis for the rational use of drugs against VRE.

METHODSThe minimum inhibitory concentrations (MICs) of linezolid and minocycline against 30 Enterococci (E.) isolates (including 20 VRE strains) were determined by the broth microdilution method. Drug interactions were assessed by the checkerboard microdilution tests and confirmed by time-kill studies. Two vancomycin-susceptible strains N27 and N40 (linezolid MIC, 2 g/ml; minocycline MIC, 4 µg/ml) and control strains E. faecalis ATCC 29212 and ATCC 51299 were also tested. The MPCs of linezolid and minocycline (alone and combined) were determined using the agar dilution method. Strains showing stable resistance were analyzed by polymerase chain reaction (PCR) amplification of domain V of the 23S rRNA gene.

RESULTSCheckerboard titration studies revealed synergistic effects of combination therapy in 26.7% of 30 E. isolates. Antagonism was not observed. The G2576U mutation was detected in stable linezolid-resistant strains of ATCC 29212, N40, and N27 before and after resistance screening, and MIC values increased with the number of G2576U mutations. The MPC of linezolid against E. decreased dramatically when combined with minocycline, and vice versa.

CONCLUSIONLinezolid or minocycline alone produce resistant strains; however, their joint use may reduce the MPC of each agent against VRE, thereby decreasing resistant mutants and bacterial infections.

Acetamides ; pharmacology ; Anti-Bacterial Agents ; pharmacology ; Anti-Infective Agents ; pharmacology ; Drug Therapy, Combination ; Enterococcus ; drug effects ; genetics ; Linezolid ; Microbial Sensitivity Tests ; Minocycline ; pharmacology ; Mutation ; Oxazolidinones ; pharmacology ; Vancomycin Resistance

AIMTo synthesize oxazolindinone derivatives and test their antibacterial activities.

METHODS3-Halo-4-methylaniline was acylated with benzyl chloroformate, followed by cyclization with (R)-glycidyl butyrate, acylation with methanesulfonyl chloride, substitution with NaN3, reduction with H2 + Pd/C or P(OMe)3 + HCl, acylation with Ac2O, and bromination with NBS to form bromides VIIIa and VIIIb, Substitution of the bromides with various amines including aliphatic amine and aromatic amine provided the target compounds IXa and IXb. The in vitro antibacterial activity of the target compounds was tested.

RESULTSFifty one new compounds were designed and synthesized. And their structures were confirmed by 1H NMR and elemental analyses or MS. Some physical constants such as [alpha]D25 were reported also. Compounds VIIb, IXa1, IXa2, IXa7, IXb1, IXb3, IXb10, IXb16 and IXb23 had moderate in vitro antibacterial activity against G+ bacteria but they were less active than linezolid or norfloxacin.

CONCLUSIONInsertion of methylene group between 4-position of phenyl and morpholinyl group in linezolid derivatives can not increase the antibacterial activity.

Acetamides ; pharmacology ; Anti-Bacterial Agents ; chemical synthesis ; chemistry ; pharmacology ; Linezolid ; Microbial Sensitivity Tests ; Molecular Structure ; Oxazolidinones ; chemical synthesis ; chemistry ; pharmacology ; Staphylococcus ; drug effects ; Streptococcus ; drug effects