International Journal of Antimicrobial Agents最新文献

Objective: Antibiotic resistance is a growing global healthcare challenge, treatment of bacterial infections with fluoroquinolones being no exception. These antibiotics can induce genetic instability through several mechanisms, one of the most significant being the activation of the SOS response. During exposure to sublethal concentration, this stress response increases mutation rates, accelerating resistance evolution.

Methods: To explore the role of the SOS response in fluoroquinolone adaptation, we induced de novo resistance by exposure to step-wise increasing concentrations Escherichia coli wild-type (MG1655) and a ΔrecA mutant strain, which is deficient in SOS activation. Both strains were exposed to stepwise increasing concentrations of ciprofloxacin and enrofloxacin - two fluoroquinolones that differ only by a single methyl group.

Results: Development of resistance against both fluoroquinolones was severely hampered in the ΔrecA mutant. While these antibiotics are often assumed to elicit similar cellular responses, our data revealed distinct genomic and adaptive differences. Building on these findings, we performed a comparative proteomics analysis to investigate how E. coli adapts to ciprofloxacin and enrofloxacin at the protein level.

Conclusions: The results demonstrate that the slight structural variation between ciprofloxacin and enrofloxacin leads to unique proteomic adaptations. These findings suggest that even subtle chemical differences can lead to distinct adaptive trajectories and illustrate the flexibility of cellular stress responses.

Mycobacterium abscessus (Mab) poses serious therapeutic challenges, largely due to its intrinsic resistance to many antibiotics. The development of targeted therapeutic strategies necessitates the identification of bacterial factors that contribute to its reduced susceptibility to antibiotics and/or to the killing by its host cells. In this study, we discovered that Mab strains with disrupted mtrA, mtrB or both, or a gene-edited mtrA encoding MtrA with Tyr102Cys mutation, exhibited highly increased sensitivity to various drugs compared to the wild-type Mab. In a murine model, three antibiotics inactive against the wild-type Mab demonstrated efficacy against the mtrA and mtrB knockout strains, significantly reducing pulmonary bacterial burdens compared to untreated controls. Notably, the virulence of all the mtrA, mtrB and mtrAB knockout mutants was highly diminished, evidenced by a reduced bacterial load in mouse lungs, undetectable level in spleens, and defective growth in macrophage RAW264.7. Morphological analysis revealed elongated cell length and multiple septa in knockout strains, suggesting both MtrA and MtrB regulate cell division of Mab. Furthermore, the absence of mtrA, mtrB or both significantly increased cell envelope permeability and reduced biofilm formation. Transcriptome sequencing showed altered expression levels of multiple genes related to plasma membrane, fatty acid metabolism and biosynthesis pathways in wild-type Mab and mtrA knockout strain. In summary, this study suggests that MtrA and MtrB play a crucial role in the intrinsic resistance and virulence of Mab by affecting cell division and altering cell permeability. Consequently, MtrA and MtrB represent promising targets for the discovery of anti-Mab drugs.

Objectives: The research aimed to provide a worldwide evaluation of antimicrobial resistance (AMR), focusing specifically on AMR related to lower respiratory infections (LRI).

Methods: The data were derived from the Global Antimicrobial Resistance Burden 2021 (GARB 2021). Two counterfactuals were utilized to estimate the deaths attributable to AMR and the deaths associated with AMR. The primary estimation process involved various statistical methodologies, including polynomial estimation and ensemble spatiotemporal Gaussian regression models. Using the DisMod-MR 2.1 modeling framework, the incidence and prevalence of LRI were estimated, the mortality rates were subsequently calculated, and stratified by pathogens, regions, and age groups. In addition, these indexes were identified and visualized to present global burden of AMR.

Results: In 2021, there were 20.89 (95% uncertain interval: 18.27-23.50) deaths per 100 000 individuals associated with AMR in LRI, and 5.05 (95% UI: 4.29-5.51) deaths per 100 000 individuals attributable to AMR in LRI. Trimethoprim-sulfamethoxazole-resistant S. pneumoniae exhibited the highest mortality rate of 5.15 (95% UI: 3.96- 6.34) deaths per 100 000 individuals associated with AMR, while Carbapenem -resistant S. pneumoniae exhibited the highest mortality rate of 0.66 (95% UI: 0.45-0.86) deaths per 100 000 individuals attributable to AMR. S. pneumoniae exhibited the greatest burden of AMR, followed by S. aureus. Central Sub-Saharan Africa had the highest AMR burden, with mortality rates of 73.75 (95% UI: 56.61-90.89) deaths per 100 000 individuals associated with AMR and 17.73 (95% UI: 12.71-2.74) deaths per 100 000 individuals attributable to AMR, followed by Eastern Sub-Saharan Africa and Western Sub-Saharan Africa. The individuals aged under 5 and over 65 years exhibited high prevalence of antibiotic resistance especially to Carbapenems, Methicillin, and Fluoroquinolones.

Conclusion: AMR in the LRI is still a pressing global health issue, particularly in developing countries and neonatal age groups. Global interventions need to be taken to reduce the prevalence of AMR.

Introduction: To date, the global prevalence of New Delhi metallo-β-lactamase (NDM) in carbapenem-resistant Enterobacterales (CRE) has been of concern, which is not inhibited by classical β-lactamase inhibitors (BLIs). In this study, we investigated the newly developed antimicrobial agents or inhibitors against NDM-producing Enterobacterales (NPEs).

Methods: The in vitro activities of cefiderocol, cefepime/taniborbactam, meropenem/taniborbactam, cefepime/zidebactam, meropenem/nacubactam, aztreonam/nacubactam and aztreonam/avibactam were analyzed in 204 NPE strains collected in China. The potential resistance mechanisms were identified by whole genome sequencing.

Results: Of 204 NPE strains, 18.1% (37/204) were resistant to cefiderocol, in which cirA deleterious alteration, PBP3 insertion and NDM production were taken as potential resistance mechanisms; 28.9% (59/204) were resistant to cefepime/zidebactam, involving K. pneumoniae with ompK35 deleterious alteration; 22.5% (46/204) were resistant to cefepime/taniborbactam, in which YRIN or YRIK inserted in PBP3 and altered ompC are more frequently detected in the resistant E. coli isolates; 27.9% (57/204) were resistant to meropenem/taniborbactam. Aztreonam/avibactam and aztreonam/nacubactam exhibited excellent activity against NPE. However, meropenem/nacubactam had the lowest activity, with only 49.0% (100/204) of all isolates having MICs of <4/4 mg/L.

Conclusions: Aztreonam/avibactam and aztreonam/nacubactam showed the highest activity against NPE. The potential resistance mechanisms of novel antimicrobial agents against NPE should be under active surveillance.

Treatment of multidrug resistant infections is challenging due to limited therapeutic options. To maximise treatment success of such infections, our infectious disease-trained pharmacists employ a two-pronged approach, using both in vitro antibiotic combination testing and therapeutic drug monitoring, to individualise antibiotic combination regimens for our patients, akin to precision medicine. This approach ensures that the most optimal antibiotic combination and dosing regimens are prescribed for our patients with multidrug resistant infection, to ensure adequate antibiotic exposure and maximal clinical efficacy. We describe the implementation of such 2-pronged approach in two of our patients infected with extensively drug-resistant Acinetobacter baumannii infections. Doses higher than manufacturer-approved regimens were administered. Both cases achieved treatment success with no adverse effects.

Objectives: This study aimed to evaluate the clinical effectiveness of combined aerosolized (AER) and intravenous (IV) polymyxin B in managing patients with hospital-acquired pneumonia (HAP) caused by carbapenem-resistant gram-negative organism (CRO).

Methods: This multicenter prospective cohort study was conducted across six intensive care units in municipal and above-municipal hospitals in Shaanxi, China, from January 1, 2021 to December 31, 2022. Patients with CRO pneumonia were categorized into the intravenous group (IV polymyxin B alone) and the combination group (AER plus IV polymyxin B). Primary outcomes included ICU mortality, 28-day mortality and bacterial clearance, while secondary outcomes included the duration of mechanical ventilation and length of ICU stay.

Results: A total of 64 patients were included in the study, with 29 receiving AER plus IV polymyxin B and 35 receiving IV polymyxin B alone. On the seventh day of treatment, the combination group showed a significant reduction in the APACHE II score (17.86 ± 5.03 vs. 19.17 ± 11.02, P = 0.041) and procalcitonin levels (1.27 ± 0.20 vs. 3.18 ± 0.69, P < 0.001) compared to the intravenous group. Additionally, the combination group exhibited a higher bacterial eradication rate (62.1% vs. 42.9%), lower ICU mortality (27.6% vs. 37.1%), shorter duration of mechanical ventilation (371.39 ± 68.97 h vs. 563.94 ± 100.25 h), and reduced ICU stay (34.41 ± 17.87 d vs. 35.03 ± 21.66 d), although the differences were not statistically significant.

Conclusions: In patients with CRO pneumonia, combination therapy resulted in significant reductions in APACHE II scores and procalcitonin, but did not lead to statistically significant improvements in clinical outcomes, compared to IV polymyxin B alone.

Background: Despite the widespread use of voriconazole in antifungal treatment, its high pharmacokinetic and pharmacodynamic variability may lead to suboptimal efficacy, especially in intensive care unit (ICU) patients. Machine learning (ML), an artificial intelligence modeling approach, is increasingly being applied to personalized medicine. The effectiveness of ML models for predicting voriconazole blood concentrations in ICU patients, compared to traditional population pharmacokinetics (popPK) models, has been uncertain until now. This study aims to identify the most effective modeling strategy for voriconazole.

Methods: We developed six ML models using 244 concentrations from 62 patients in our previous popPK dataset. Another additional dataset, consisting of 282 trough concentrations from 177 patients, was used to externally evaluate both ML models and five other published popPK models, utilizing prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting.

Results: The XGBoost model exhibited superior predictive performance among the six ML models, achieving an R² of 0.73. Its performance metrics (RMSE%: 127.21 %, median absolute prediction error: 29.65 %, median prediction error: 9.82 %, F20: 34.04 %, F30: 50.71 %) outperformed those of the best popPK model (RMSE%: 152.41 %, median absolute prediction error: 44.75 %, median prediction error: -0.99 %, F20: 23.40 %, F30: 36.88 %), suggesting greater accuracy and precision in predicting pharmacokinetics.

Conclusions: Both ML and popPK models can be utilized for individualized voriconazole therapy. Our comparative study provides insights into the most effective methods for modeling and predicting voriconazole concentrations.

Aztreonam-avibactam (ATM-AVI) is a promising β-lactam/β-lactamase inhibitor combination with an antimicrobial spectrum covering serine carbapenemase- or metallo-β-lactamase-producing Enterobacterales. Although ATM-AVI has not been widely used in clinical practice, resistance to it in Escherichia coli has been widely reported. In this study, we investigated an ATM-AVI-resistant Klebsiella pneumoniae strain, designated as 1705R, derived from K. pneumoniae ATCC BAA-1705 by induction, with a minimal inhibitory concentration of 128 µg/mL. The 1705R strain contained two copies of the bla_KPC-2 variant, which encodes for a K. pneumoniae carbapenemase (KPC) variant with a Ser109Pro substitution, as well as a premature termination in OmpK36 and OmpK35 porins. This KPC variant decreased susceptibility to ATM-AVI by four-fold and demonstrated a reduced affinity for ATM and AVI in molecular docking analysis. In porin-deficient strains harbouring this KPC variant, ATM-AVI susceptibility was further diminished, exhibiting a 32-fold reduction. Whole-genome sequencing revealed that the transposition of Tn4401 carrying bla_KPC from the IncFIB/FIIK plasmid into the ColRNAI plasmid produced a second copy of bla_KPC. Quantitative polymerase chain reaction revealed that the copy number of bla_KPC and its carrier plasmid increased, which significantly up-regulated their mRNA expression. Overexpression of the AcrAB-TolC efflux pump may also be associated with high levels of ATM-AVI resistance. Furthermore, collateral susceptibility and costs of growth and biofilm formation developed after the acquisition of ATM-AVI resistance. This study demonstrates that multiple molecular mechanisms collectively contribute to ATM-AVI resistance in K. pneumoniae 1705R strain, which may represent a mode of resistance to ATM-AVI.

Objective: Mycobacterium avium complex bacteria cause chronic pulmonary disease (MAC-PD) in susceptible patients. The recommended treatment regimen (rifampicin, ethambutol and azithromycin) achieves 65% cure rates but with considerable toxicity and drug-drug interactions [2,3]. Minocycline proved active in monotherapy experiments using the hollow-fibre model [4]. We compared the efficacy of the recommended regimen with a minocycline, ethambutol and azithromycin regimen using this model.

Methods: Epithelial lining fluid pharmacokinetic (PK) profiles of the recommended regimen and minocycline, ethambutol, azithromycin regimen were simulated. THP-1 cells infected with M. avium ATCC 700898 were exposed to these regimens for 21 d. PK profiles were determined at d 0 and d 21. The pharmacodynamic effect was measured by determining bacterial densities at d 0, 3, 7, 14 and 21 for intra- and extracellular fractions. Emergence of macrolide-resistance was monitored by inoculating azithromycin-containing agar, MIC measurements and resistance mutation analysis.

Results: The minocycline-containing regimen exhibited a 1.5 log10 CFU/mL lower bacterial burden than the recommended regimen at d 7, though both regimens lost effectiveness over time. Treatment failure in both arms was not linked to the emergence macrolide-resistance. PK profiles simulated in the model matched those in MAC-PD patients.

Conclusions: Replacing rifampicin with minocycline increased the antimycobacterial activity of the MAC-PD treatment regimen in the hollow-fibre model, without jeopardizing the prevention of macrolide-resistance. This promising minocycline-containing regimen is a candidate for inclusion in clinical trials.