Acute Eosinophilic Pneumonia (AEP) Due to Daptomycin: Is Autoimmunity a Clinico-Pathophysiologic Bridge to AEP?

Daptomycin induced acute eosinophilic pneumonia is a rare and potentially life threatening condition characterized by rapid respiratory failure, pulmonary infiltrates and eosinophilia. Risk factors for acute eosinophilic pneumonia include smoking, environmental irritants or inhalants and certain medications such as Daptomycin [1]. In this review of literature, we aim to explore the potential triggers for developing acute eosinophilic pneumonia in patients exposed to Daptomycin. The exact immune mechanism for daptomycin induced AEP is unknown, however the current proposed mechanism describes a T helper 2 lymphocyte response to inactivated daptomycin in the pulmonary surfactant, which leads to eosinophilia. Disordered T regulatory cell function is seen in patients with certain cancers, allergies and autoimmune conditions. We propose that patients with these underlying risk factors may be at increased risk of developing AEP after becoming exposed to Daptomycin. Understanding potential risk factors is crucial for health care workers as it allows them to identify susceptible populations, explore preventative measures and treat accordingly.

脂肽类抗生素Daptomycin

daptomycin(LY146032)是 20世纪 80年代才发展起来的一种新的酸性脂肽类半合成抗生素,是A21978C的N-癸酰基衍生物,A21978C的产生菌是玫瑰抱链霉菌(S.rose-osporus NRRL 11379),该菌共产生5种结构类似物 A21978A、B、C、D、E.A21978C为主要组份,活性也最强.daptomycin具有脂肽类抗生素典型的化学结构:一个由13个氨基酸构成的环状肽和10碳的脂肪酸链,其结构式见图1.

Daptomycin and linezolid for severe methicillin-resistant Staphylococcus aureus psoas abscess and bacteremia:A case report and review of the literature

BACKGROUND Vancomycin remains a first-line treatment drug as per the treatment guidelines for methicillin-resistant Staphylococcus aureus(MRSA)bacteremia.However,a number of gram-positive cocci have developed resistance to several drugs,including glycopeptides.Therefore,there is an urgent need for effective and innovative antibacterial drugs to treat patients with infections caused by drugresistant bacteria.CASE SUMMARY A 24-year-old male was admitted to hospital owing to lumbago,fever,and hematuria.Computed tomography(CT)results showed an abscess in the psoas major muscle of the patient.Repeated abscess drainage and blood culture suggested MRSA,and vancomycin was initiated.However,after day 10,CT scans showed abscesses in the lungs and legs of the patient.Therefore,treatment was switched to daptomycin.Linezolid was also added considering inflammation in the lungs.After 10 d of the dual-drug anti-MRSA treatment,culture of the abscess drainage turned negative for MRSA.On day 28,the patient was discharged without any complications.CONCLUSION This case indicates that daptomycin combined with linezolid is an effective remedy for bacteremia caused by MRSA with pulmonary complications.

Modeling of Daptomycin Release from Medium-Dose Daptomycin-Xylitol-Loaded PMMA Bone Cements

Antibiotic-loaded poly (methyl methacrylate) bone cements (ALPBCs) are widely used as an agent to decrease the occurrence of periprosthetic joint infection (PJI). Most often, the antibiotic used in an ALPBC is gentamicin, tobramycin, or vancomycin. In many recent clinical studies, it has been reported that the pathogens that commonly present in PIJ are becoming resistant to these antibiotics. As such, a new generation of antibiotics is emerging, among which is daptomycin. Literature reports with a clinically relevant medium-dose daptomycin-loaded cement show that the daptomycin release rate from cylindrical specimens is low. Incorporation of a poragen, such as dextrose, glycine, or particulate xylitol, into the cement powder has been shown to be an effective way to increase daptomycin release rate. There are, however, no studies on modeling of daptomycin release from specimens of either a daptomycin-loaded cement or a daptomycin-poragen-loaded cement. In the present work, we determine the profiles of daptomycin release from cylindrical medium-dose daptomycin-xylitol-loaded cement specimens, as a function of the particulate xylitol loading. We used these results and relationships that have been shown to model antibiotic release from ALPBC specimens to obtain the best-fit relationship for the present cements. Through this approach, we demonstrated that, regardless of the xylitol loading, the daptomycin release profile is a mixture of initial burst followed by a slow Fickian diffusion.

Origin of de novo daptomycin non susceptible enterococci

The emergence of daptomycin non-susceptible enterococci(DNSE) poses both treatment and infection control challenges.Clinicians should be vigilant that DNSE may be isolated from patients with or without(de novo DNSE) prior use of daptomycin.Recent epidemiological data suggest the presence of a community reservoir for DNSE which may be associated with environmental,foodborne and agricultural exposures.The mechanisms of nonsusceptibility to daptomycin have not been well characterized and may not parallel those for Staphylococcus aureus.The identification of daptomycin resistance genes in anaerobes,in farm animals and in an ecosystem that has been isolated for million years,suggest that the environmental reservoir for de novo DNSE may be larger than previously thought.Herein,the limited available scientific evidence regarding the possible origin of de novo DNSE is discussed.The current existing evidence is not sufficient to draw firm conclusions on the origin of DNSE.Further studies to determine the mechanisms of de novo daptomycin nonsusceptibility among enterococci are needed.

Daptomycin,Methicillin Resistant Staphylococcus hominis Catheter-Related Bacteraemia in a Hemodialysis Patient

We report a case of a haemodialysis patient that presented a catheter-related bacteraemia caused by a Coagulase negative Staphylococcus. With the utilization of molecular biology techniques the bacterial isolate recovered from catheter was surprisingly identified as S. hominis by sequencing of the 16S ribosomal gene. The S. hominis isolate, which is not often associated with infections in dialysis patients, was resistant to methicillin, being mecA positive, and to daptomycin. The patient was successfully treated with vancomycin together with the catheter retirement.

daptomycin标签出现嗜酸细胞性肺炎警告

美国FDA称，静脉给予Cubist公司的抗生素Cubicin（daptomycin，达托霉素）与嗜酸细胞性肺炎有短暂性联系。因而要求制造商在药品标签的“警告与注意事项”和“不良反应、售后经验”部分纳入上述这些信息。此产品于2003年获FDA批准用于严重皮肤感染，随后又用于血流感染。

顶空进样-气相色谱法检测达托霉素中残留溶剂

目的建立测定达托霉素中3种有机溶剂残留量的顶空进样-气相色谱法。方法色谱柱为Agilent DB-624毛细管柱(60 m×0.53 mm,3.0µm),载气为氮气(流速为5.0 mL/min),程序升温,氢火焰离子化检测器(FID)检测,进样口温度为200℃,检测器温度为230℃,分流比为5∶1(V/V),顶空瓶平衡温度为85℃,平衡时间为30 min,进样量为1µL。结果乙醇、异丙醇和正丁醇质量浓度均在10~200µg/mL范围内与峰面积线性关系良好(r=1.0000);检测限分别为0.75,0.30,0.75µg/mL,定量限分别为2.50,1.01,2.50µg/mL;精密度、稳定性、重复性试验结果的RSD均小于2.0%;平均回收率分别为101.85%,101.65%,102.33%,RSD分别为0.59%,0.77%,0.78%(n=9)。结论该方法专属性强,灵敏度高,精密度好,可用于达托霉素中前述3种有机溶剂残留量的测定。3批样品中检出的有机溶剂残留量远低于国家标准限度。

Self-enhanced targeted delivery of a cell wall– and membrane-active antibiotics,daptomycin, against staphylococcal pneumonia

Considering that some antibacterial agents can identify the outer structure of pathogens like cell wall and/or cell membrane, we explored a self-enhanced targeted delivery strategy by which a small amount of the antibiotic molecules were modified on the surface of carriers as targeting ligands of certain bacteria while more antibiotic molecules were loaded inside the carriers, and thus has the potential to improve the drug concentration at the infection site, enhance efficacy and reduce potential toxicity. In this study, a novel targeted delivery system against methicillin-resistant Staphylococcus aureus(MRSA)pneumonia was constructed with daptomycin, a lipopeptide antibiotic, which can bind to the cell wall of S.aureus via its hydrophobic tail. Daptomycin was conjugated with N-hydroxysuccinimidyl–polyethylene glycol–1,2-distearoyl-sn-glycero-3-phosphoethanolamine to synthesize a targeting compound(Dapt–PEG–DSPE) which could be anchored on the surface of liposomes, while additional daptomycin molecules were encapsulated inside the liposomes. These daptomycin-modified, daptomycin-loaded liposomes(DPD-L[D]) showed specific binding to MRSA as detected by flow cytometry and good targeting capabilities in vivo to MRSA-infected lungs in a pneumonia model. DPD-L[D] exhibited more favorable antibacterial efficacy against MRSA than conventional PEGylated liposomal daptomycin both in vitro and in vivo. Our study demonstrates that daptomycin-modified liposomes can enhance MRSAtargeted delivery of encapsulated antibiotic, suggesting a novel drug delivery approach for existing antimicrobial agents.

m4C DNA methylation regulates biosynthesis of daptomycin in Streptomyces roseosporus L30

Despite numerous studies on transcriptional level regulation by single genes in drug producing Actinomyces,the global regulation based on epigenetic modification is not well explored.N4-methylcytosine(m4C),an abundant epigenetic marker in Actinomycetes’genome,but its regulatory mechanism remains unclear.In this study,we identify a m4C methyltransferase(SroLm3)in Streptomyces roseosporus L30 and multi-omics studies were performed and revealed SroLm3 as a global regulator of secondary metabolism.Notably,three BGCs inΔsroLm3 strain exhibited decreased expression compared to wild type.In-frame deletion of sroLm3 in S.roseosporus L30 further revealed its role in enhancing daptomycin production.In summary,we characterized a m4C methyltransferase,revealed the function of m4C in secondary metabolism regulation and biosynthesis of red pigment,and mapped a series of novel regulators for daptomycin biosynthesis dominated by m4C methylation.Our research further indicated that m4C DNA methylation may contribute to a metabolic switch from primary to secondary metabolism in Actinomyces.

达托霉素致横纹肌溶解1例

1例72岁男性患者,因“间断发热1周余”入院,既往长期口服瑞舒伐他汀片(5 mg,qd),入院诊断为“肺部感染”,予以抗感染治疗后好转。住院期间,患者再次发热,考虑导管相关性感染不除外,给予达托霉素(0.5 g,qd,ivgtt)治疗。用药第14 d,患者肌酸激酶(CK)588 IU·L^(−1)、肌酸激酶同工酶(CK-MB)35.40 ng·mL^(−1),血清肌红蛋白281.30 ng·mL^(−1),尿肌红蛋白2.30 ng·mL^(−1),临床诊断为横纹肌溶解,立即停用达托霉素和瑞舒伐他汀,并予以补液和碱化尿液对症治疗。3 d后复查,CK 87 IU·L^(−1),CK-MB 2.70 ng·mL^(−1),血清肌红蛋白87.30 ng·mL^(−1),尿中未再检测到肌红蛋白。1周后恢复瑞舒伐他汀使用,未再出现CK升高,患者病情稳定出院。

高效液相色谱法分离纯化达托霉素

采用高效液相色谱法对达托霉素粗品进行纯化,对反相硅胶种类、洗脱剂浓度、洗脱速度、上样量进行优选,并对关键杂质进行质量控制。结果表明,以反相硅胶UniSil C18 Ultra装柱、以10%乙醇为洗脱剂、洗脱速度为16~18 mL·min^(-1)、上样量为10~12 mg·mL^(-1),在此条件下,达托霉素精粉的HPLC含量超过99.0%,收率超过70.0%。该方法分离制备效率高,有机溶剂用量少,纯化精粉中的有关物质均满足质量要求,具有产业化应用前景。

ARTP-DES复合诱变结合前体耐受性选育达托霉素高产菌株

为提高玫瑰孢链霉菌AN-126的达托霉素产量,对菌株AN-126进行常压室温等离子体-硫酸二乙酯(ARTP-DES)复合诱变,并结合癸酸钠耐受性筛选,最终获得一株达托霉素高产菌株RR-447,摇瓶产量为(101.41±0.37)mg/L,是出发菌株的2.44倍。对高产菌株RR-447进行平板传代、菌落形态及BOX-PCR多态性分析。结果表明,高产菌株RR-447高产性能稳定遗传,与出发菌株的菌球形态有明显差异,且高产菌株RR-447基因组DNA在1.50~2.00 kb之间存在一条特异性条带。在5 L发酵罐中通过分阶段补加癸酸钠溶液评价了菌株RR-447的发酵性能,达托霉素产量达到512.64mg/L。ARTP-DES复合诱变结合癸酸钠耐受性是选育达托霉素高产菌株的一种有效育种手段,为达托霉素工业微生物育种以及其他菌株改良提供了技术参考。

达托霉素致药品不良反应文献分析

目的分析与探讨达托霉素所致药品不良反应的发生特点及规律,为临床合理用药提供参考。方法检索万方、知网、维普、Web of Science、PubMed等数据库,收集达托霉素所致药品不良反应的相关文献,并进行统计与分析。结果共检索到59篇达托霉素所致的药品不良反应案例报道,以男性患者为主(70.83%),平均年龄为(61.5±14.3)岁,中位年龄(四分位数范围)为61(53.0~70.2)岁,多数为中老年患者;达托霉素多用于治疗骨、关节感染(61.11%);用药后药品不良反应发生的时间跨度较大,累及呼吸系统的不良反应最为常见(46.11%),其中以嗜酸性粒细胞肺炎为主。结论临床应用达托霉素时,医护人员应警惕相关药品不良反应的发生,药师应针对性地加强用药监护及药品不良反应干预,确保患者用药安全。

癸酸抗性突变株流加发酵法生产达托霉素

采用He-Ne激光对达托霉素产生菌玫瑰孢链霉菌LC-54进行诱变,筛选前体癸酸抗性突变株,在此基础上进一步考察了一次补料、间歇补料和恒速流加补料等不同补料策略对达托霉素发酵生产的影响．结果表明,选育前体癸酸抗性突变株可以提高达托霉素的生产能力,并最终获得了达托霉素发酵效价较出发菌株提高了37．2%的高产突变株LC-KS-54．采用恒速流加策略,能够有效地提高达托霉素产量,经过130 h的恒速流加培养,细胞干重达到15．4g/L,达托霉素产量达到258 mg/L,明显优于其他前体补料策略．

达托霉素发酵液大孔树脂吸附分离的研究

目的研究大孔吸附树脂从发酵液中提取达托霉素的工艺条件。方法采用树脂动态吸附-解吸方法,建立HPLC检测方法测定达托霉素的含量,并对该工艺进行评价。结果大孔吸附树脂HZ818对达托霉素的动态饱和吸附量为3550μg/ml,采用75%乙醇即可将吸附在树脂柱上的达托霉素有效解吸,解吸率可达90%。结论大孔吸附树脂HZ818是从发酵液中分离和提纯达托霉素的一种适宜吸附剂。该工艺简捷,分离效果好,可满足工业化要求。

利奈唑胺、替加环素、达托霉素、头孢吡普等抗菌药物对MRSA的抗菌活性

目的多中心研究我国2005年MRSA的耐药现状，评价利奈唑胺、替加环素、达托霉素和头孢吡普等药物的抗菌活性。方法收集2005年1月至2005年12月14个地区连续分离的非重复金葡菌809株，采用琼脂稀释法测定抗菌药物的MIC。结果MRSA发生率为50．3％，其中MRSA发生率最高的为大连（93．3％）、上海（80．3％），其次为南宁（63．6％）、北京（55．5％）、青岛（53．8％）。MRSA对红霉素的敏感性为4．2％，喹诺酮类药物为4．4％～12．6％，庆大霉素为9．6％，四环素为11．1％，对MRSA活性较高的有氯霉素（82．3％）和复方磺胺甲嗯唑（78．6％）；MRSA对替考拉宁、万古霉素、利奈唑胺、替加环素、达托霉素和头孢吡普均全部敏感。头孢吡普、达托霉素、替加环素、利奈唑胺的MIC50和MIC90分别为2，2mg／L；0．5，0．5mg／L；0．125，0．25mg／L；1，2mg／L。MIC范围分别为0．125～2mg／L，0．125～1mg／L,0.064～0．5mg／L，0．25～2mg／L。结论我国MRSA发生率高，多重耐药严重，不同地区MRSA发生率有所差异，头孢吡普、达托霉素、替加环素和利奈唑胺对于MRSA具有很高的抗菌活性。

达托霉素发酵培养基的响应面法优化

采用Plackett-Burman设计、最陡爬坡试验与响应面设计相结合的方法优化达托霉素发酵培养基组成,利用Design Expert7.0软件设计试验并分析数据。结果表明,培养基中的糊精、酵母粉、酪蛋白水解物是影响达托霉素产量的主要因素。优化后的培养基组成/g·L-1为:糊精10.6,酵母粉1.6,酪蛋白水解物1.3,硫酸钾8,L-门冬氨酸1.5;pH6.5。在此条件下,达托霉素产量为37.16mg/L。进一步优化前体癸酸的添加量,最终达托霉素产量达46.54mg/L。