International Journal of Antimicrobial Agents最新文献

Objectives

To investigate whether using the BioFire® FilmArray® Blood Culture Identification 2 panel (BCID2) leads to timely antimicrobial therapy and improves patient outcomes in critically ill patients with bloodstream infections (BSIs).

Methods

This retrospective observational study included patients with BSIs admitted to the intensive care unit from July 1, 2021, to August 31, 2023. Patients were divided into groups receiving appropriate or inappropriate antimicrobial therapy. Those receiving inappropriate therapy underwent adjustments using standard-of-care (SOC) testing or BCID2. Propensity score matching (PSM) was performed on the original cohort (Model 1) and a time-window bias-adjusted cohort (Model 2). Clinical impact of BCID2-guided antimicrobial adjustment was analysed in both models.

Results

A total of 181 patients received inappropriate antimicrobial therapy, with 33 undergoing BCID2 testing and 148 undergoing SOC testing. Following PSM and time-window bias adjustment, 66 patients were analysed in Model 1 and 46 patients in Model 2. BCID2 significantly reduced the median time to appropriate antimicrobial therapy (40.8 vs. 74.0 h in Model 1; 42.8 vs. 68.9 h in Model 2) and the day-28 mortality rate (27.8% vs. 77.1%, P < 0.001 in Model 1; 23.5% vs. 58.6%, P = 0.021 in Model 2). In multivariate regression analysis, BCID2-guided antimicrobial adjustment was an independent prognostic factor for day-28 mortality (adjusted odds ratio [aOR] 0.07 in Model 1 and aOR 0.12 in Model 2).

Conclusion

BCID2-guided antimicrobial stewardship was associated with a shorter time to appropriate antimicrobial therapy and reduced day-28 mortality in critically ill patients with BSIs receiving inappropriate antimicrobial therapy.

Objectives

Voriconazole is a classical antifungal drug that is often used to treat CNS fungal infections due to its permeability through the BBB. However, its clinical use remains challenging because of its narrow therapeutic window and wide inter-individual variability. In this study, we proposed an optimised and validated PBPK model by integrating in vitro, in vivo and clinical data to simulate the distribution and PK process of voriconazole in the CNS, providing guidance for clinical individualised treatment.

Methods

The model structure was optimised and tissue-to-plasma partition coefficients were obtained through animal experiments. Using the allometric relationships, the distribution of voriconazole in the human CNS was predicted. The model integrated factors affecting inter-individual variation and drug interactions of voriconazole—polymorphisms in the CYP2C19 gene and auto-inhibition and then was validated using real clinical data.

Results

The overall AFE value showing model predicted differences was 1.1420 in the healthy population; and in the first prediction of plasma and CSF in actual clinical patients, 89.5% of the values were within the 2-fold error interval, indicating good predictive performance of the model. The bioavailability of voriconazole varied at different doses (39%-86%), and the optimised model conformed to this pattern (46%–83%).

Conclusions

Combined with the relevant pharmacodynamic indexes, the PBPK model provides a feasible way for precise medication in patients with CNS infection and improve the treatment effect and prognosis.

Background

Efficacy for prolonged infusion beta-lactam dosing schemes has been previously described, but there has been less focus on the safety of standard vs. prolonged infusion protocols of beta-lactams. This study explored differences in adverse drug reactions (ADRs) reported for beta-lactams between each of these infusion protocols.

Methods

A systematic review of MEDLINE literature databases via PubMed was conducted and references were reviewed. Articles were compiled and assessed with specific inclusion/exclusion criteria. We included randomised and nonrandomised, prospective, and retrospective cohort studies that reported adverse drug reactions (ADRs) due to either standard (30–60 mins) or prolonged (≥3 h) infusions of beta-lactam infusions. Total ADRs between strategies were analysed by infusion methodology. The most consistently reported ADRs were subject to meta-analysis across studies.

Results

12 studies met inclusion/exclusion criteria with data for 4163 patients. There was insufficient data to systematically analyse neurotoxicity or cytopenias. Seven studies reported on nephrotoxicity outcomes with no significant difference in event rates between standard (n = 434/2258,19.2%) vs. prolonged infusion (n = 266/1271, 20.9%) of beta-lactams (OR = 1.08, 95% CI [0.91, 1.29]). Six studies observed diarrhoea in a total of 759 patients with no significant difference in patients of standard (n = 18/399, 4.5%) vs. prolonged (n = 19/360, 5.3%) infusion of beta-lactams (OR = 1.14, 95% CI [0.59,2.20]).

Conclusion

Prolonged and standard infusion schemes for beta-lactams demonstrated similar adverse event rates. Future research should focus on improved standardisation of adverse effect definitions and a priori aim to study neurotoxicity and cytopenias. Consistent recording of ADRs and standardised definitions of these reactions will be paramount to further study of this subject.

The incidence of secondary bacterial infections has increased in recent decades owing to various viral pandemics. These infections further increase the morbidity and mortality rates associated with viral infections and remain a significant challenge in clinical practice. Intensive antibiotic therapy has mitigated the threat of such infections; however, overuse and misuse of antibiotics have resulted in poor outcomes, such as inducing the emergence of bacterial populations with antimicrobial resistance (AMR) and reducing the therapeutic options for this crisis. Several antibiotic substitutes have been suggested and employed; however, they have certain limitations and novel alternatives are urgently required. This review highlights host immunomodulation as a promising strategy against secondary bacterial infections to overcome AMR. The definition and risk factors of secondary bacterial infections, features and limitations of currently available therapeutic strategies, host immune responses, and future perspectives for treating such infections are discussed.

Objectives

Given the challenges posed by toxicity and drug resistance in the treatment of cryptococcal infections, we sought to explore the antifungal potential of verapamil (VER), a calcium channel blocker, against Cryptococcus neoformans (C. neoformans), and its potential synergy with antifungals, specifically caspofungin (CAS).

Materials and Methods

In vitro and in vivo (Galleria mellonella) models were employed to assess VER's antifungal activity and its interaction with CAS. Mechanisms underlying the synergism were explored through analysis of cell wall integrity, membrane permeability, and gene expression related to the calcineurin pathway. Additionally, the influence of Ca²⁺ on chitin deacetylase activity was investigated.

Results

VER exhibited a pronounced antifungal effect on C. neoformans and synergized with CAS, enhancing antifungal efficacy in Galleria mellonella. VER reduced chitosan content and disrupted cell wall integrity, evidenced by melanin leakage and fluorescence staining. VER+CAS modified membrane permeability, triggering intracellular ROS accumulation and mitochondrial membrane potential alterations. VER mitigated CAS-induced calcium fluctuations and downregulated calcineurin pathway genes. Furthermore, it was found that the enzyme activity of chitin deacetylase of C. neoformans is significantly influenced by the presence of Ca²⁺, suggesting that the use of VER may affect this activity.

Conclusions

The synergistic antifungal effect of VER and CAS represents a promising therapeutic strategy for cryptococcal infections. The multifaceted mechanisms, including disruption of cell wall integrity and modulation of membrane permeability, and regulation of intracellular calcium signaling pathways, offer new insights into antifungal drug development.

Objectives

Piperacillin (PIP)/tazobactam is a frequently prescribed antibiotic; however, over- or underdosing may contribute to toxicity, therapeutic failure, and development of antimicrobial resistance. An external evaluation of 24 published PIP-models demonstrated that model-informed precision dosing (MIPD) can enhance target attainment. Employing various candidate models, this study aimed to assess the predictive performance of different MIPD-approaches comparing (i) a single-model approach, (ii) a model selection algorithm (MSA) and (iii) a model averaging algorithm (MAA).

Methods

Precision, accuracy and expected target attainment, considering either initial (B1) or initial and secondary (B2) therapeutic drug monitoring (TDM)-samples per patient, were assessed in a multicentre dataset (561 patients, 11 German centres, 3654 TDM-samples).

Results

The results demonstrated a slight superiority in predictive performance using MAA in B1, regardless of the candidate models, compared to MSA and the best single models (MAA, MSA, best single models: inaccuracy ±3%, ±10%, ±8%; imprecision: <25%, <31%, <28%; expected target attainment >77%, >71%, >73%). The inclusion of a second TDM-sample notably improved precision and target attainment for all MIPD-approaches, particularly within the context of MSA and most of the single models. The expected target attainment is maximized (up to >90%) when the TDM-sample is integrated within 24 h.

Conclusions

In conclusion, MAA streamlines MIPD by reducing the risk of selecting an inappropriate model for specific patients. Therefore, MIPD of PIP using MAA implicates further optimisation of antibiotic exposure in critically ill patients, by improving predictive performance with only one sample available for Bayesian forecasting, safety, and usability in clinical practice.