International Journal of Antimicrobial Agents最新文献

Background: Extended spectrum β-lactamase-producing Escherichia coli remains a major cause of hospital-acquired bloodstream infections in countries with high antimicrobial stewardship compliance.

Methods: Isolates from bloodstream infections that occurred between 2010 and 2020 in a tertiary level hospital in North-East Scotland soon after introduction of the "4C" antimicrobial stewardship policy were analysed for phylogenetic structure, antimicrobial resistance, plasmid and virulence gene carriage. Growth fitness was measured in kinetic assays. Non-metric-multidimensional-scaling was used to evaluate clonal relationships, antimicrobial resistance, and virulence profiles in early and later years after the 4C policy introduction. Clonal and fitness trends over the study period were determined by generalized additive modelling. The relationship between clonal type, antimicrobial resistance, and fitness was evaluated by linear regression.

Results: Three hierarchical phylogenetic clusters were identified, with the most dominant cluster (O25:H4/fimH30) including all, and nearly exclusively, Clade C ST131 isolates as well as minor non-ST131 sequence types. The prevalence of ST131 was largely stable over the study period. Resistance to aminoglycosides and aztreonam in ST131 was lower (p=0.019 and p=0.004, respectively) during later years (2016-2020) by 28% on average compared to early years soon after 4C policy implementation (2010-2014). Carriage of virulence factors involved in bacterial adaptation was higher in ST131 compared to non-ST131 but mostly stable in early vs later years. Growth fitness of ST131 was lower than non-ST131 and declined steadily in later years (p<0.0001).

Conclusion: Despite stable virulence factor carriage, population structure and resistance to cephalosporins, we show increased susceptibility of ST131 to aminoglycosides and aztreonam and concurrent fitness decline years after the introduction of the 4C policy.

Background: Cefiderocol is a new catecholamine-containing siderophore cephalosporin. It, however, remains unclear how cefiderocol modulates the immune response of the host.

Objectives: This study elucidated whether cefiderocol exerts immunoprotective effects in an in vitro experimental model induced with lipopolysaccharide (LPS).

Methods: Mouse macrophage RAW 264.7 cells were exposed to LPS (100 ng/mL) or LPS + cefiderocol (40 mg/L) to assess the immunomodulatory effect of cefiderocol in vitro. ELISA was performed on cell culture supernatants to estimate cytokine levels. Ferroptosis level was also quantified by detecting intracellular reactive oxygen species (ROS) and iron levels through flow cytometry analysis. Malondialdehyde (MDA) and glutathione (GSH) levels were estimated by ELISA. We conducted western blotting assay for evaluating key ferroptosis pathway proteins.

Results: Cefiderocol alleviated LPS-induced inflammation by reducing IL-6, TNF-α, and IL-1β production levels and enhancing the IL-10 production level. Further analysis to determine the underlying mechanism revealed that cefiderocol inhibited ferroptosis; this was confirmed by reduced ROS, MDA, and Fe²⁺ ion levels; increased GSH levels; upregulated expression of solute carrier family 7 member 11, glutathione peroxidase 4, nuclear factor erythroid 2-related factor 2, and ferroptosis suppressor protein 1; and downregulated expression of acyl-CoA synthetase long-chain family member 4.

Conclusions: Cefiderocol may play a key role in reducing inflammation by decreasing inflammatory cytokine release and suppressing ferroptosis.

Objectives: Elizabethkingia spp. are resistant to multiple antibiotics. This study aimed to determine in vitro and in vivo activities of cefiderocol against Elizabethkingia spp. and to investigate resistance mechanisms.

Methods: Bloodstream isolates were collected from four hospitals. In vitro and in vivo activities were determined using broth microdilution and the wax moth model, respectively. Genome comparison and gene editing were used to confirm the contribution of target genes. Conjugation experiments and serial passage were used to determine transferability and stability, respectively. A MIC of ≤ 4 mg/L was designated as the susceptibility breakpoint.

Results: Among 228 non-duplicated isolates, 226 exhibited a MIC of ≤ 4 mg/L with MIC_50/90 of 1/2 mg/L. Two isolates had a MIC of 128 mg/L; both source patients had multiple comorbidities, were ventilator-dependent, and had not received cefiderocol previously. Resistance was attributable to acquisition of bla_CfxA-3, carried by a conjugative transposon from Prevotella jejuni, and duplication of intrinsic bla_CME-3, which led to its overexpression. tetQ coexisted with bla_CfxA-3 in this conjugative transposon and minocycline facilitated its transfer among E. anophelis. Antibiotics prescribed for source patients did not induce bla_CME-3 duplication. The stabilities of bla_CfxA-3 and double bla_CME-3 were 100% and > 90%, respectively, after 10-day serial passage. Cefiderocol failed to rescue moth larvae infected with resistant strains, but removal of resistance mechanisms restored in vivo efficacy.

Conclusions: Cefiderocol was in vitro and in vivo active against Elizabethkingia spp. but resistance may emerge due to the availability, transferability, and/or stability of resistance mechanisms.

Objectives: To describe the set-up in 2022 of the PHAGEinLYON Clinic program dedicated to improve access to phage therapy in France using pharmaceutical-grade phages.

Methods: We described the process, prospectively collected all phage therapy requests received during 2022 and reviewed them retrospectively to analyze the decision and also the patient care pathway (NCT05883995).

Results: Among 143 phage therapy requests, the indication was confirmed by multidisciplinary team meetings for 57 (40%) of them, and 44 were infected with bacteria that could be easily targeted by phages in France. Finally, 33 patients were treated, including 26 at our institution as compassionate use or in a clinical trial. Main indications were complex bone and joint infections, endovascular infections and lung infections. To manage these patients, 172 pharmaceutic phage cocktails targeting S. aureus and/or P. aeruginosa were prepared; 57 were dedicated to local, and 99 to intravenous injections. During the follow-up, 18 (69%) patients had a favorable clinical evolution, 6 (23%) required subsequent phage therapy, with the same phages with a greater phage exposition, or with different phages from elsewhere.

Conclusions: The implementation of the PHAGEinLYON Clinic program in 2022 was associated with a groundbreaking access of phage therapy in France.

Hypervirulent Klebsiella pneumoniae (hvKp) poses a serious public health threat. Gas gangrene caused by hvKp was rarely reported, potentially resulting in a poor prognosis. In this study, we described the case of a hospitalized patient with gas gangrene and sepsis by hvKP. The carbapenem-susceptible hypervirulent Klebsiella pneumoniae (CS-hvKp) strains KPLSN and KPLSX were isolated from the knee joint pus and blood specimens of the patient for further investigations. Whole genome sequencing revealed that KPLSN and KPLSX were highly homologous (SNPs<10) and belonging to ST412/K57. The minimum inhibitory concentration and minimum bactericidal concentration under biofilm values of meropenem in KPLSN and KPLSX were significantly higher than planktonic state (>128 mg/L versus 0.25 mg/L, P<0.0001). These two strains had high biofilm formation ability, and fluorescence staining experiments results showed that they were not easily killed by meropenem in the biofilm state. KPLSN and KPLSX showed high capsular production and were confirmed with high virulence through experiments with the Galleria mellonella and BALB/c mice abdominal infection model. The persistent symptoms may be due to enhanced biofilm and capsule formation. Global ST412 strains phylogenetic analysis showed their evolution towards higher virulence and resistance. It emphasizes the critical need for judicious antibiotic use and novel therapeutic approaches to combat special infections caused by these pathogens.

Background: Tuberculosis (TB) is a major and severe opportunistic infection among solid organ transplant recipients. Chemoprophylaxis is advised for those with latent tuberculosis infection (LTBI). However, the effectiveness of an isoniazid (INH) prophylactic approach based on TB risk factors remains uncertain.

Methods: This study included all living-donor kidney transplant recipients (KTRs) between January 2016 and December 2022. The recipients were categorized into three groups: the risk group with isoniazid (R-INH), the risk group without isoniazid (R-NINH), and the non-risk group (NR), based on the presence of TB risk factors and INH usage. The R-INH group received a 6-month INH prophylactic regimen to prevent post-transplant TB infection. The incidence of active TB among the groups was assessed.

Results: A total of 1348 patients were divided into R-INH (n=108), R-NINH (n=371), and NR (n=869). Forty-seven patients (3.49%) developed TB with an incidence rate of 16.0 per 1000 person-years. Compared to NR, the TB incidence in R-INH was not statistically different (HR, 0.55, 95% CI, 0.07-4.21, P = 0.564), whereas it was significantly higher in R-NINH (HR, 5.04, 95% CI, 2.64-9.62, P < 0.001). The median time from transplantation to TB was 19 months (IQR: 6-39), and 18 patients (38.3%) were diagnosed within one year of transplantation. Ninety-four patients (87.0%) completed INH prophylaxis, with adverse events including two cases of hepatotoxicity (1.85%) and one case of peripheral neuritis (0.93%).

Conclusions: A 6-month INH regimen based on TB risk factors is effective and well tolerated for preventing post-transplant TB in KTRs.

Skin injuries and infections are an inevitable part of daily human life, particularly with chronic wounds, becoming an increasing socioeconomic burden. In treating skin infections and promoting wound healing, bioactive peptides may hold significant potential, particularly those possessing antimicrobial and anti-inflammatory properties. However, obtaining these peptides solely through traditional wet laboratory experiments is costly and time-consuming, and peptides identified by current computer-assisted predictive models largely lack validation of their effects via wet laboratory experiments. Consequently, this study aimed to integrate computer-assisted methods and traditional wet laboratory experiments to identify anti-inflammatory and antimicrobial peptides. We developed a computer-assisted mining pipeline to screen potential peptides from the epitopes of the major histocompatibility complex class II (MHC-II). The peptide AIMP1 was identified, with the ability to physically damage Escherichia coli by increasing bacterial cell membrane permeability and with the ability to inhibit inflammation by binding to endotoxin-lipopolysaccharide. Additionally, in an LPS-induced inflammation animal model, AIMP1 slightly increased levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and in a skin wound infection animal model, AIMP1 effectively accelerated healing, reduced levels of these pro-inflammatory cytokines, and showed no acute hepatotoxicity or nephrotoxicity. In conclusion, this study not only developed a computer-assisted mining pipeline for identifying anti-inflammatory and antimicrobial peptides but also successfully pinpointed the peptide AIMP1, demonstrating its therapeutic potential for skin injury treatment.

The plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) stands out as the primary driver behind the dissemination of antimicrobial resistance (AMR). Developing effective inhibitors that target conjugative transfer represents an efficient strategy for addressing the issue of AMR. Here, we studied the effect of acetylshikonin (ASK), a botanical derivative, on plasmid conjugation. The conjugative transfer of RP4-7 plasmid inter and intra species was notably reduced by ASK. The conjugation process of IncI2 and IncX4 plasmids harboring the mobile colistin resistance gene (mcr-1), IncX4 and IncX3 plasmids containing the carbapenem resistance gene (bla_NDM-5), and IncFI and IncFII plasmids possessing the tetracycline resistance gene [tet(X4)] were also reduced by ASK. Importantly, the conjugative transfer frequency of mcr-1 positive IncI2 plasmid in mouse peritoneal conjugation model and gut conjugation model was reduced by ASK. The mechanism investigation showed that ASK disrupt the functionality of the bacterial cell membrane. Furthermore, the proton motive force (PMF) was dissipated. In addition, ASK blocked the electron transmission in bacteria's electron transport chain (ETC) through disturbing the quinone interaction, resulting in an insufficient energy supply for conjugation. Collectively, ASK is a potential conjugative transfer inhibitor, providing novel strategies to prevent the spread of AMR.