International Journal of Antimicrobial Agents最新文献_第8页

Pharmacodynamics of taniborbactam in combination with cefepime studied in an in vitro model of infection 在体外感染模型中研究了他尼巴坦与头孢吡肟联用的药效学。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-13 DOI: 10.1016/j.ijantimicag.2024.107304

Objectives

To define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 β-lactamases.

Methods

An in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1 h infusion 8 h. Taniborbactam was given in exposure ranging and fractionation simulations. Reduction in viable count at 24 h (Δ 24) was the primary end point and four strains were used: Escherichia coli expressing CTXM-15 or AmpC and Klebsiella pneumoniae expressing KPC or OXA-48 enzymes.

Results

Taniborbactam was administered as continuous infusions; ≥4 log kill was attained with taniborbactam concentrations of ≥0.01 mg/L against CTXM-15 E. coli, ≥0.5 mg/L against KPC- and OXA-48 K. pneumoniae, and ≥4 mg/L against AmpC E. coli. Analyses were conducted to determine the pharmacokinetic/dynamic driver for each strain. For E. coli (CTXM-15) and E. coli (AmpC), area under the concentration-time curve (AUC) was best related to change in viable count (R²0.74 and 0.72, respectively). For K. pneumoniae (KPC) AUC and T > 0.25 mg/L were equally related to bacterial clearance (R²0.72 for both), and for K. pneumoniae (OXA-48) T > 0.25 mg/L was the best predictor (R²0.94). The taniborbactam AUC range to produce a 1-log₁₀ reduction in viable count was 4.4–11.2 mg·h/L. Analysis of data from all strains indicated T > MIC divided by 4 was best related to change in viable count; however, curve fit was poor R² < 0.49.

Conclusions

Taniborbactam was effective in combination with cefepime in producing bacterial clearance for B lactam resistant Enterobacterales. The primary pharmacodynamic driver was AUC or time > threshold, both being closely related to antibacterial effect.

目的确定他尼巴坦对具有 CTXM-15、KPC、AmpC 和 OXA-48 β-内酰胺酶的肠杆菌的体外药效学：方法：使用体外药代动力学模型模拟头孢吡肟 2G 的血清浓度，每 8 小时输注 1 小时。在暴露范围和分馏模拟中给予他尼巴坦。24 小时存活计数减少（Δ 24）是主要终点，使用了四种菌株：使用了四种菌株：表达 CTXM-15 或 AmpC 的大肠杆菌和表达 KPC 或 OXA-48 酶的肺炎双球菌：连续输注他尼巴坦；对 CTXM-15 大肠杆菌的他尼巴坦浓度≥0.01mg/L，对 KPC- 和 OXA-48 肺炎双球菌的他尼巴坦浓度≥0.5mg/L，对 AmpC 大肠杆菌的他尼巴坦浓度≥4mg/L 时，杀灭率≥4 log。进行了分析以确定每种菌株的药代动力学/动态驱动力。对于大肠杆菌（CTXM-15）和大肠杆菌（AmpC），浓度-时间曲线下面积（AUC）与存活计数的变化关系最好（分别为 R20.74 和 0.72）。肺炎双球菌（KPC）的 AUC 和 T>0.25mg/L 与细菌清除率的关系相同（两者的 R20.72），而肺炎双球菌（OXA-48）的 T>0.25mg/L 是最佳预测指标（R20.94）。使存活菌数减少 1-log10 的他尼巴坦 AUC 范围为 4.4-11.2 mg∙h/L。对所有菌株数据的分析表明，T>MIC 除以 4 与存活计数的变化关系最佳；然而，曲线拟合较差：他尼巴坦与头孢吡肟联用可有效清除耐 B 内酰胺肠杆菌。主要的药效学驱动因素是 AUC 或时间>阈值，两者都与抗菌效果密切相关。

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引用次数: 0

Advancing research and development of anti-infectives for children: A clinical development perspective 推进儿童抗感染药物的研发：临床开发视角》。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-13 DOI: 10.1016/j.ijantimicag.2024.107306

The HIV treatment landscape for adults has progressed dramatically in recent decades; however, paediatric populations continue to experience delayed and limited access to effective and safe antiretroviral therapy options. Despite current incentive programmes, formulation research and development and approved drug dosing for children have been limited, particularly for neonates (aged <4 wk). Regulatory approval of drug formulations and dosing in children may lag behind adult approvals by years. Formulation and trial design adjustments complicate paediatric drug development, all of which are vital to accommodate for physiological differences, organ maturation, and rapid weight gain, which are most significant in the youngest children. To facilitate more rapid anti-infective drug development for paediatric populations, regulatory agencies provide guidelines that include extrapolating efficacy and safety data from relevant populations; using pharmacokinetic (PK) bridging and modelling to reduce sample sizes and limit the number of PK studies needed before efficacy analyses; and enrolling age- or weight-based cohorts in parallel rather than sequentially for clinical trials. Ensuring access to approved drugs poses an additional challenge, as uncertainty in demand leads to manufacturing and supply complexity with potentially higher costs that can be a barrier to uptake. Here we summarise challenges in drug development for children living with HIV, which are not unique to antiretrovirals. We aim to propose strategies for how model-based approaches and global partnerships can overcome some of these barriers to accelerate paediatric drug development, with particular reference to HIV, and how lessons learnt from HIV could be extended to other anti-infectives.

近几十年来，成人艾滋病治疗领域取得了长足的进步；然而，儿科患者在获得有效、安全的抗逆转录病毒治疗方案方面仍然受到延误和限制。尽管有当前的激励计划，但针对儿童的制剂研发和获批药物剂量仍然有限，尤其是针对新生儿（年龄在 5 岁以下）的制剂研发和获批药物剂量。

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引用次数: 0

Increased risk of adverse drug reactions by higher linezolid dose per weight in multidrug-resistant tuberculosis 在耐多药结核病患者中增加利奈唑胺的单位重量剂量会增加药物不良反应的风险。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-13 DOI: 10.1016/j.ijantimicag.2024.107302

Objectives

Linezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB).

Methods

We conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992–2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0).

Results

Of all participants (n = 132), 43.2% were female and the median age 28 y. The median linezolid treatment was 6.5 months (IQR 3.0–12.7) with a median daily dose of 9.6 mg/kg/d. Any ADR was seen in 58.3% (n = 77) of participants, with 35.6% having peripheral neuropathy (n = 47), 27.3% anaemia (n = 36), 22.0% leukopenia (n = 36) while 6.1% (n = 8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1–5.9) and 8.3 months (6.2–10.7) for optic neuritis. A >2.0 mg/L trough concentration (n = 40) was associated with anaemia (P = 0.0038) and thrombocytopenia (P = 0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/d was associated with time to peripheral neuropathy (HR 2.89, 95% CI 1.08–7.74, P = 0.035), anaemia (HR 6.62, 95% CI 2.22–19.8, P = 0.001) and leukopenia (HR 5.23, 95% CI 1.48–18.5, P = 0.010).

Conclusions

Linezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.

利奈唑胺治疗的毒性风险很高，药物不良反应（ADR）也很常见。很少有研究对主要 ADR 的风险因素进行单独调查，因此，我们旨在评估主要 ADR（包括外周神经病变）与耐多药结核病（MDR-TB）高资源环境中利奈唑胺的风险因素和药物浓度水平的关系。我们开展了一项回顾性队列研究，研究对象包括 1992-2018 年期间在瑞典接受过含有利奈唑胺的 MDR-TB 治疗方案的患者。数据来自医疗记录。不良反应根据《不良事件通用术语标准》（5.0 版）进行分类。在所有参与者（n=132）中，43.2%为女性，中位年龄为28岁。利奈唑胺的中位治疗时间为6.5个月（IQR为3.0-12.7），中位日剂量为9.6毫克/千克/天。58.3%的参与者（样本数=77）出现了任何不良反应，其中35.6%出现周围神经病变（样本数=47），27.3%出现贫血（样本数=36），22.0%出现白细胞减少（样本数=36），6.1%（样本数=8）出现视神经炎。周围神经病变的中位时间为 3.6 个月（IQR 2.1-5.9），视神经炎的中位时间为 8.3 个月（6.2-10.7）。谷浓度大于 2.0 毫克/升（n=40）与贫血（p=0.0038）和血小板减少（p=0.009）有关，但与周围神经病变无关。在多变量分析中，剂量≥12 mg/kg/天与周围神经病变发生时间（HR 2.89，95%CI 1.08-7.74，p=0.035）、贫血（HR 6.62，95%CI 2.22-19.8，p=0.001）和白细胞减少症（HR 5.23，95%CI 1.48-18.5，p=0.010）相关。在高资源环境中，利奈唑胺ADR频发。对ADR进行有组织的定期随访，并根据体重调整剂量，同时尽早监测药物浓度，可降低毒性。

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引用次数: 0

Neisseria gonorrhoeae ST-1901 in Rio de Janeiro from 2006 to 2022: Phylogeny and antimicrobial resistance evolution of a well-succeeded pathogen 2006 年至 2022 年里约热内卢淋病奈瑟菌 ST-1901：一种成功病原体的系统发育和抗菌药耐药性演变。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-12 DOI: 10.1016/j.ijantimicag.2024.107299

Neisseria gonorrhoeae is a global threat to public health due to the accumulation of antimicrobial resistance mechanisms. ST-1901 is an internationally important sequence type (ST) because of its high incidence and the usual occurrence of chromosomally determined resistance. In this study, we describe the evolution of the ST-1901 and its single locus variants in Rio de Janeiro from 2006 to 2022. We analyzed 82 N. gonorrhoeae isolates according to antimicrobial susceptibility profile, resistance mechanisms, molecular typing, and phylogenetics. Six different single locus variants were detected. Phylogenetic analysis identified five clades, which share similar characteristics. Resistance rates for penicillin and tetracycline decreased due to the lower occurrence of resistance plasmids, but intermediary resistance to penicillin rose. Resistance to ciprofloxacin remained high throughout all clades and the years of the study. Regarding resistance to azithromycin, alterations in mtrR promoter and gene, and 23S rRNA encoding gene rrl were detected, with a notable rise in the incidence of C2611T mutations in more recent years occurring in four of five clades. In contrast, β-lactam resistance associated penA 34 mosaic was found only in one persisting clade (Clade D), and unique G45D and A39T mutations in mtrR gene and its promoter (Nm-Like) were found only in Clade B. Taken together, these data suggest that ST-1901, a persistently circulating lineage of N. gonorrhoeae in Rio de Janeiro, has undergone changes over the years and may evolve to develop resistance to the current recommended dual therapy adopted in Brazil, namely, ceftriaxone and azithromycin.

由于抗菌药耐药性机制的积累，淋病奈瑟菌对公共卫生构成了全球性威胁。ST-1901 是一种国际重要的序列类型（ST），因为它的发病率很高，而且通常会出现染色体决定的耐药性。在本研究中，我们描述了 2006 年至 2022 年期间里约热内卢的 ST-1901 及其单基因座变体的演变情况。我们根据抗菌药敏感性概况、耐药机制、分子分型和系统发育分析了 82 个淋球菌分离株。检测到了六个不同的单基因座变异。系统发育分析确定了五个支系，它们具有相似的特征。由于耐药质粒的出现率较低，对青霉素和四环素的耐药率下降，但对青霉素的中间耐药率上升。对环丙沙星的耐药性在所有支系和研究年份中都居高不下。关于对阿奇霉素的耐药性，检测到 mtrR 启动子和基因以及 23S rRNA 编码基因 rrl 发生了改变，近年来 C2611T 突变的发生率明显上升，5 个支系中有 4 个支系发生了这种情况。相比之下，仅在一个持续存在的支系（支系 D）中发现了与 penA 34 马赛克相关的β-内酰胺耐药性，仅在支系 B 中发现了 mtrR 基因及其启动子（Nm-Like）中独特的 G45D 和 A39T 突变。总之，这些数据表明，ST-1901 是里约热内卢淋球菌的一个持续循环系，多年来发生了变化，可能会对巴西目前推荐的头孢曲松和阿奇霉素双重疗法产生耐药性。

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引用次数: 0

Investigation of PhoP response regulator inhibition to overcome resistance in Gram-negative clinical bacteria 研究抑制 PhoP 反应调节器以克服革兰氏阴性临床细菌的抗药性。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-08 DOI: 10.1016/j.ijantimicag.2024.107298

引用次数: 0

Beware of resistance to 2nd-generation integrase inhibitors: A systematic meta-analysis of HIV-1 integrase inhibitors resistance and drug resistance mutations 警惕对第二代整合酶抑制剂的耐药性：HIV-1整合酶抑制剂耐药性和耐药突变的系统性元分析。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-07 DOI: 10.1016/j.ijantimicag.2024.107294

Objective

Assessing the prevalence of resistance and drug resistance mutations (DRMs) in HIV/AIDS patients towards integrase strand transfer inhibitors (INSTIs), particularly the 2nd-generation INSTIs, provides evidence for rational clinical drug use.

Methods

A systematic search was conducted on five databases to identify relevant literature reporting original data on INSTIs resistance. Meta-analyses, cumulative meta-analyses, subgroup analyses and meta-regression analyses were performed using selected models based on the results of heterogeneity tests.

Results

A total of 81 studies were included in this analysis. The prevalence of pre-treatment drug resistance (PDR) to 1st-generation INSTIs and 2nd-generation INSTIs were 0.41% (95% CI: 0.19%–0.70%) and 0.04% (95% CI: 0.00%–0.13%), respectively; and the prevalence of acquired drug resistance (ADR) were 7.60% (95% CI: 3.54%–12.92%) and 4.93% (95% CI: 1.78%–9.36%), respectively, and ADR showed an increasing and then decreasing time trend. The results of subgroup analyses showed differences in ADR to 2nd-generation INSTIs between regions and economic levels, with the highest ADR of 12.83% (95% CI: 3.24%–27.17%) in the European region. DRMs varied among HIV patients and reduced drug sensitivity to varying degrees.

Conclusion

The prevalence of PDR and DRMs in 2nd-generation INSTIs is currently low, but as the use of DTG-based ART expands, population-level drug resistance monitoring and individual-level genetic testing should be strengthened in order to maximise treatment efficacy. Additionally, attention should be paid to ADR to INSTIs to provide personalised treatments for HIV-infected patients.

目的：评估艾滋病毒/艾滋病患者对整合酶链转移抑制剂（INSTIs），尤其是第二代 INSTIs 的耐药性和耐药突变（DRMs）的发生率，为临床合理用药提供证据：在五个数据库中进行了系统检索，以确定报告 INSTIs 耐药性原始数据的相关文献。根据异质性检验结果，采用选定的模型进行元分析、累积元分析、亚组分析和元回归分析：本次分析共纳入了 81 项研究。第一代INSTIs和第二代INSTIs治疗前耐药（PDR）的发生率分别为0.41%（95% CI：0.19%-0.70%）和0.04%（95% CI：0.00%-0.13%）；获得性耐药（ADR）的发生率分别为7.60%（95% CI：3.54%-12.92%）和4.93%（95% CI：1.78%-9.36%），且ADR呈先增后减的时间趋势。亚组分析结果显示，第二代 INSTIs 的 ADR 在不同地区和经济水平之间存在差异，欧洲地区的 ADR 最高，为 12.83%（95% CI：3.24%-27.17%）。HIV患者的DRM各不相同，药物敏感性也有不同程度的降低：目前，第二代 INSTIs 的 PDR 和 DRM 发生率较低，但随着基于 DTG 的抗逆转录病毒疗法使用范围的扩大，应加强人群耐药性监测和个体基因检测，以最大限度地提高治疗效果。此外，还应关注 INSTIs 的 ADR，以便为艾滋病毒感染者提供个性化治疗。

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引用次数: 0

Immunomodulator AS101 restores colistin susceptibility of clinical colistin-resistant Escherichia coli and Klebsiella pneumoniae in vitro and in vivo 免疫调节剂 AS101 可在体外和体内恢复临床耐大肠杆菌和肺炎克雷伯菌对大肠菌素的敏感性。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-06 DOI: 10.1016/j.ijantimicag.2024.107285

Objectives

Colistin (COL) was once considered to be the last line of defence against multidrug-resistant bacteria belonging to the family Enterobacteriaceae. Due to the misuse of COL, COL-resistant (COL-R) Enterobacteriaceae have emerged. To address this clinical issue and combat COL resistance, novel approaches are urgently needed.

Methods

In this study, the in vitro and in vivo antimicrobial and antibiofilm effects of the immunomodulator AS101 were investigated in combination with COL against COL-R Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae).

Results

Checkerboard assay, time-kill assay, and scanning electron microscopy confirmed the in vitro antimicrobial phenotype, whereas, crystal violet staining and multidimensional confocal laser scanning microscopy with live/dead staining confirmed the antibiofilm capability of the combination therapy. Moreover, the Galleria mellonella infection model and the mouse infection model indicated the high in vivo efficacy of the combination therapy. Additionally, cytotoxicity experiments performed using human kidney-derived HK-2 cells and haemolysis assays performed using human erythrocytes collectively demonstrated safety at effective combination concentrations. Furthermore, quantification of the expression of inflammatory cytokines via enzyme-linked immunosorbent assay confirmed the anti-inflammatory advantage of combination therapy. At the mechanistic level, changes in outer and inner membrane permeability and accumulation of ROS levels, which might be potential mechanisms for synergistic antimicrobial effects.

Conclusions

This study found that AS101 can restore COL susceptibility in clinical COL-R E. coli and K. pneumoniae and also has synergistic antibiofilm and anti-inflammatory capabilities. This study provided a novel strategy to combat clinical infections caused by COL-R E. coli and K. pneumoniae.

可乐定（COL）曾一度被认为是抵抗肠杆菌科多重耐药细菌的最后一道防线。由于滥用 COL，出现了对 COL 耐药（COL-R）的肠杆菌科细菌。为解决这一临床问题并对抗 COL 耐药性，迫切需要新的方法。本研究研究了免疫调节剂 AS101 与 COL 联用对 COL-R 大肠埃希菌（大肠杆菌）和肺炎克雷伯菌（肺炎克雷伯菌）的体外和体内抗菌和抗生物膜作用。棋盘试验、时间杀伤试验和扫描电子显微镜证实了体外抗菌表型，而水晶紫染色和多维共焦激光扫描显微镜活/死染色证实了联合疗法的抗生物膜能力。此外，黑线梭菌感染模型和小鼠感染模型也表明，该组合疗法在体内具有很高的疗效。此外，利用人体肾脏衍生的 HK-2 细胞进行的细胞毒性实验和利用人体红细胞进行的溶血实验共同证明了有效组合浓度下的安全性。此外，通过酶联免疫吸附试验（ELISA）对炎症细胞因子的表达进行量化，证实了联合疗法的抗炎优势。在机理层面，外膜和内膜通透性的变化以及 ROS 水平的积累，可能是协同抗菌作用的潜在机制。总之，本研究发现 AS101 可恢复临床 COL-R 大肠杆菌和肺炎双球菌对 COL 的敏感性，同时还具有协同抗生物膜和抗炎能力。这项研究为抗击由 COL-R 大肠杆菌和肺炎双球菌引起的临床感染提供了一种新策略。

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引用次数: 0

Is There Evidence on the Optimal Duration of Aminoglycoside Therapy in β-Lactam/Aminoglycoside Combination Regimens Used for the Treatment of Gram-Negative Bacterial Infections? A Systematic Review 是否有证据表明治疗革兰氏阴性菌感染的β-内酰胺/氨基糖苷类复方疗法中氨基糖苷类药物治疗的最佳持续时间？-系统综述。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-05 DOI: 10.1016/j.ijantimicag.2024.107297

Background

The optimal duration of therapy of aminoglycosides in combination regimens is expected to be different from that of monotherapy regimens, and shorter durations could help minimize toxicity without compromising efficacy. The aim of this review was to assess the evidence for the optimal duration of aminoglycosides in β-lactam/aminoglycoside combinations used for the treatment of Gram-negative bacterial infections.

Materials and Methods

PubMed, Cochrane, Embase, Scopus, Web of Science, and CINHAL databases were searched. Covidence software was used for article screening and management. Studies were included if they clearly reported the duration of therapy of aminoglycosides in β-lactam/aminoglycoside combinations used against Gram-negative bacteria. The protocol is registered with PROSPERO (CRD42023392709).

Results

A total of 45 β-lactam/aminoglycoside combination courses from 32 articles were evaluated. The duration of therapy of aminoglycosides in combinations regimens ranged from 1 to 14 days, varying with the type of infection treated. In half (51.1%; (23/45) of the combinations, aminoglycosides were administered for a duration ranging from 6 to 9 days. In 26.7% (12/45) of the combinations, the duration of aminoglycoside therapy was ≤ 5 days. In the remaining 22.2% (10/45) of these combinations, the aminoglycosides were administered for a duration of ≥ 10 days. Aminoglycosides were administered for a longer duration of 7-14 days in 12 (75%) of the 16 combination courses that induced toxicity.

Conclusions

Long duration of aminoglycoside use is associated with increased risk of toxicity. However, there is a lack of evidence on defining an optimal duration of aminoglycoside therapy in β-lactam/aminoglycoside combination regimens that ensures clinical efficacy outcomes whilst minimizing toxicity outcomes.

背景：氨基糖苷类药物在联合治疗方案中的最佳疗程预计与单药治疗方案不同；较短的疗程有助于在不影响疗效的前提下最大限度地减少毒性。本综述旨在评估用于治疗革兰氏阴性菌感染的β-内酰胺/氨基糖苷类药物联合疗法中氨基糖苷类药物最佳用药时间的证据：方法：检索了 PubMed、Cochrane、Embase、Scopus、Web of Science 和 CINHAL 数据库。文章筛选和管理采用 Covidence 软件。如果研究明确报告了针对革兰氏阴性菌的β-内酰胺类/氨基糖苷类复方制剂中氨基糖苷类药物的治疗持续时间，则将其纳入研究。该方案已在 PROSPERO 注册（CRD42023392709）：结果：共评估了 32 篇文章中的 45 个β-内酰胺/氨基糖苷类复方疗程。复合疗法中氨基糖苷类药物的疗程从 1 天到 14 天不等，因治疗的感染类型而异。在半数（51.1%；23/45）的联合用药中，氨基糖苷类药物的疗程为 6 至 9 天。在 26.7%（12/45）的组合中，氨基糖苷类药物的治疗时间不超过 5 天。其余22.2%（10/45）的组合中，氨基糖苷类药物的治疗时间≥10天。在16个引起毒性的联合用药疗程中，有12个（75%）的氨基糖苷类药物用药时间较长，为7-14天：结论：氨基糖苷类药物的长期使用与毒性风险增加有关。结论：氨基糖苷类药物用药时间过长与毒性风险增加有关。然而，目前还缺乏证据来确定β-内酰胺类/氨基糖苷类药物联合疗法中氨基糖苷类药物的最佳用药时间，以确保临床疗效，同时最大限度地减少毒性结果。

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引用次数: 0

A metagenomics-based approach to decipher the resistome and mobilome of two seahorse species, Hippocampus barbouri and Hippocampus comes 基于元基因组学的方法解密两种海马--Hippocampus barbouri 和 Hippocampus comes 的抗性基因组和动员基因组。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-03 DOI: 10.1016/j.ijantimicag.2024.107296

Objective

This study aimed to explore the abundance and diversity of antibiotic resistance genes (ARGs) in seahorses (Hippocampus barbouri and Hippocampus comes) and their surrounding environment.

Methods

A combination of shotgun metagenomics and bioinformatics was used to investigate the resistome of both seahorse species.

Results

The analyses demonstrated a higher abundance of ARGs in seahorse-associated microbiomes, particularly in skin and gut samples, compared to those from water and sediment. Interestingly, genes conferring multidrug resistance (e.g., acrB, acrF, cpxA, msbA, and oqxB) were highly prevalent in all samples, especially in skin and gut samples. High levels of genes conferring resistance to fluoroquinolones (e.g., mfd and emrB), β-lactam (e.g., bla_CMY-71, bla_OXA-55, and penA), aminocoumarin (e.g., mdtB and mdtC), and peptide antibiotics (arnA, pmrE, and rosA) were also observed in skin and gut samples. An enrichment of mobile genetic elements (MGEs) was also observed in the analysed samples, highlighting their potential role in facilitating the acquisition and spread of ARGs. In fact, the abundance of mobilisation (MOB) relaxases (e.g., MOBF, MOBP, MOBT, and MOBV) in gut and skin samples suggests a high potential for conjugation events.

Conclusions

The occurrence of ARGs and MGEs in seahorses and the surrounding environment raises concerns about their transmission to humans, either through direct contact or the consumption of contaminated seafood. To the best of our knowledge, this study represents the first comprehensive analysis of ARGs in seahorse-associated microbiomes, and its results emphasise the need for monitoring and controlling the spread of ARGs in environmental settings.

本研究旨在探索海马（Hippocampus barbouri和Hippocampus comes）及其周围环境中抗生素耐药基因（ARGs）的丰度和多样性。霰弹枪元基因组学和生物信息学相结合的研究表明，与水和沉积物相比，海马相关微生物组（尤其是皮肤和肠道样本）中的 ARGs 丰度更高。有趣的是，赋予多重耐药性的基因（如acrB、acrF、cpxA、msbA 和 oqxB）在所有样本中都非常普遍，尤其是在皮肤和肠道样本中。在皮肤和肠道样本中还观察到对氟喹诺酮类（如 mfd 和 emrB）、β-内酰胺类（如 blaCMY-71、blaOXA-55 和 penA）、氨基香豆素类（如 mdtB 和 mdtC）和肽类抗生素（arnA、pmrE 和 rosA）具有高水平抗性的基因。在分析的样本中还观察到富集的移动遗传因子（MGEs），这突显了它们在促进 ARGs 获取和传播方面的潜在作用。事实上，肠道和皮肤样本中存在大量的动员（MOB）弛豫酶（如 MOBF、MOBP、MOBT 和 MOBV），这表明发生共轭事件的可能性很大。海马和周围环境中出现的 ARGs 和 MGEs 引起了人们对其通过直接接触或食用受污染海产品传播给人类的担忧。据我们所知，本研究是首次对海马相关微生物组中的 ARGs 进行全面分析，其结果强调了监测和控制 ARGs 在环境中传播的必要性。

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引用次数: 0

Outcome of intravenous and inhaled polymyxin B treatment in patients with multidrug-resistant gram-negative bacterial pneumonia 耐多药革兰氏阴性菌肺炎患者静脉注射和吸入多粘菌素 B 的治疗效果。

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2024-08-02 DOI: 10.1016/j.ijantimicag.2024.107293

Purpose

The incidence of pneumonia caused by multidrug-resistant gram-negative bacteria (MDR GNB) is increasing, which imposes significant burden on public health. Inhalation combined with intravenous polymyxins has emerged as a viable treatment option. However, pharmacokinetic studies focusing on intravenous and inhaled polymyxin B (PMB) are limited.

Methods

This study included seven patients with MDR GNB-induced pneumonia who were treated with intravenous plus inhaled PMB from March 1 to November 30, 2022, in the intensive care unit of the First Affiliated Hospital of Zhejiang University School of Medicine. Clinical outcomes and therapeutic drug monitoring data of PMB in both plasma and epithelial lining fluid (ELF) were retrospectively reviewed.

Results

Median PMB concentrations in the ELF were 7.83 (0.72–66.5), 116.72 (17.37–571.26), 41.1 (3.69–133.78) and 33.82 (0.83–126.68) mg/L at 0, 2, 6 and 12 h, respectively, and were much higher than those detected in the serum. ELF concentrations of PMB at 0, 2, 6 and 12 h were higher than the minimum inhibitory concentrations of pathogens isolated from the patients. Steady-state concentrations of PMB in the plasma were >2 mg/L in most patients. Of the patients, 57.14% were cured and 71.43% showed a favourable microbiological response. The incidence of side effects with PMB was low.

Conclusions

Inhaled plus intravenous PMB can achieve high ELF concentrations and favourable clinical outcomes without an increased adverse effect profile. This treatment approach appears promising for the treatment of patients with pneumonia caused by MDR-GNB.

目的：耐多药革兰氏阴性菌（MDR GNB）引起的肺炎发病率不断上升，给公共卫生造成了巨大负担。吸入联合静脉注射多粘菌素已成为一种可行的治疗方案。然而，以静脉注射和吸入多粘菌素 B（PMB）为重点的药代动力学研究十分有限：本研究纳入了浙江大学医学院附属第一医院重症监护室于2022年3月1日至11月30日期间接受静脉和吸入多粘菌素B治疗的7例MDR GNB诱发肺炎患者。回顾性分析了血浆和上皮内衬液（ELF）中PMB的临床结果和治疗药物监测数据：结果：上皮内衬液中 PMB 的中位浓度在 0、2、6 和 12 h 分别为 7.83 (0.72-66.5)、116.72 (17.37-571.26)、41.1 (3.69-133.78) 和 33.82 (0.83-126.68) mg/L，远高于血清中的浓度。PMB在0、2、6和12小时的ELF浓度均高于从患者体内分离出的病原体的最低抑制浓度。大多数患者血浆中 PMB 的稳态浓度大于 2 毫克/升。57.14%的患者痊愈，71.43%的患者对微生物反应良好。PMB的副作用发生率很低：结论：吸入加静脉注射 PMB 可达到较高的 ELF 浓度和良好的临床效果，同时不会增加不良反应。这种治疗方法似乎有望用于治疗由 MDR-GNB 引起的肺炎患者。

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