New antimicrobial agents for the treatment of Gram-positive bacterial infections.

Since the 1970s, resistance to antimicrobial agents has become an escalating problem. In the last 25 years, treatment of infections caused by Gram-positive bacteria has been more problematical than ever, with infections being caused by multidrug-resistant organisms, particularly methicillin-resistant staphylococci, penicillin- and erythromycin-resistant pneumococci, and vancomycin-resistant enterococci. There is a continuing effort in the pharmaceutical industry to develop new antimicrobial agents for the treatment of resistant infections. Linezolid, quinupristin-dalfopristin, daptomycin, tigecyline, new glycopeptides and ceftobiprole are the main agents recently introduced or under clinical development. This review summarises their major properties, the results of recent studies with these agents, and future treatment possibilities.     

Re-establishing the utility of tetracycline-class antibiotics for current challenges with antibiotic resistance

The progressive increase in antibiotic resistance in recent decades calls for urgent development of new antibiotics and antibiotic stewardship programs to help select appropriate treatments with the goal of minimising further emergence of resistance and to optimise clinical outcomes. Three new tetracycline-class antibiotics, eravacycline, omadacycline, and tigecycline, have been approved within the past 15 years, and represent a new era in the use of tetracyclines. These drugs overcome the two main mechanisms of acquired tetracycline-class resistance and exhibit a broad spectrum of in vitro activity against gram-positive, gram-negative, anaerobic, and atypical pathogens, including many drug-resistant strains. We provide an overview of the three generations of tetracycline-class drugs, focussing on the efficacy, safety, and clinical utility of these three new third-generation tetracycline-class drugs. We also consider various scenarios of unmet clinical needs where patients might benefit from re-engagement with tetracycline-class antibiotics including outpatient treatment options, patients with known β-lactam antibiotic allergy, reducing the risk of Clostridioides difficile infection, and their potential as monotherapy in polymicrobial infections while minimising the risk of any potential drug-drug interaction.

KEY MESSAGES

• The long-standing safety profile and broad spectrum of activity of tetracycline-class antibiotics made them a popular choice for treatment of various bacterial infections; unfortunately, antimicrobial resistance has limited the utility of the early-generation tetracycline agents.
• The latest generation of tetracycline-class antibiotics, including eravacycline, tigecycline, and omadacycline, overcomes the most common acquired tetracycline resistance mechanisms.
• Based on in vitro characteristics and clinical data, these newer tetracycline agents provide an effective antibiotic option in the treatment of approved indications in patients with unmet clinical needs – including patients with severe penicillin allergy, with renal or hepatic insufficiency, recent Clostridioides difficile infection, or polymicrobial infections, and those at risk of drug–drug interactions.

     

肠杆菌科细菌SDD菌株特征及替加环素药敏结果分析

目的 分析医院肠杆菌科细菌剂量依赖性敏感(SDD)菌株的药物敏感性情况和检出分布特征,并检测产超广谱β内酰胺酶(ESBLs)大肠埃希菌和肺炎克雷伯菌对替加环素的敏感性,以指导临床对SDD菌株的抗菌药物及对ESBLs产酶株替加环素的选择.方法 采用VITEK 2 COMPACT全自动微生物分析仪进行细菌鉴定及仪器法抗菌药物敏感性试验.对50株ES-BLs阳性大肠埃希菌和50株肺炎克雷伯茼分别采用微量肉汤稀释法、MTS测试条法、Vitek2仪器检测法、纸片扩散法检测替加环素的敏感性.结果 采用M100-S24标准头孢吡肟判断为敏感的肠杆菌科细菌有3.58％～12.50％的菌株为SDD菌株;ESBLs阳性大肠埃希菌和肺炎克雷伯菌的SDD菌株检出率分别为13.31％和8.60％,显著高于ESBLs阴性菌株(P＜0.05);所有肠杆菌科细菌SDD菌株最低抑菌浓度(MIC)4 mg/L菌株检出率显著高于SDD菌株MIC 8 mg/L茼株检出率(P＜0.05);ESBLs阳性大肠埃希菌和肺炎克雷伯采用微量肉汤稀释法和MTS测试条法的敏感率均为100％.结论 当肠杆菌科细菌头孢吡肟MIC为4 mg/L或8 mg/L时,实验室应在检验报告提示SDD菌株的检出.替加环素对ESBLs阳性大肠埃希菌和肺炎克雷伯菌的敏感率为100％.     

Structural basis for TetM-mediated tetracycline resistance

Ribosome protection proteins (RPPs) confer tetracycline resistance by binding to the ribosome and chasing the drug from its binding site. The current model for the mechanism of action of RPPs proposes that drug release is indirect and achieved via conformational changes within the drug-binding site induced upon binding of the RPP to the ribosome. Here we report a cryo-EM structure of the RPP TetM in complex with the 70S ribosome at 7.2-Å resolution. The structure reveals the contacts of TetM with the ribosome, including interaction between the conserved and functionally critical C-terminal extension of TetM and the decoding center of the small subunit. Moreover, we observe direct interaction between domain IV of TetM and the tetracycline binding site and identify residues critical for conferring tetracycline resistance. A model is presented whereby TetM directly dislodges tetracycline to confer resistance.     

替加环素联合注射用头孢哌酮舒巴坦钠对ICU多重耐药菌感染患者症状改善及细菌清除率的影响

目的:探讨ICU多重耐药菌感染患者采用替加环素联合头孢哌酮舒巴坦钠(舒普深)治疗的临床疗效。方法:随机将2015年1月~2017年12月收治的88例ICU多重耐药菌感染患者分为两组。A组采用舒普深治疗,B组采用舒普深联合替加环素治疗,比较两组的治疗效果。结果:B组患者体温、肺部啰音、胸部X线平片和白细胞计数等症状体征恢复时间明显短于A组,且B组细菌清除率、治疗总有效率明显高于A组,差异有统计学意义(P<0.05)。结论:ICU多重耐药菌感染患者采用头孢哌酮舒巴坦钠联合替加环素治疗,能有效改善患者的症状体征,清除细菌,促进患者康复。     

Molecular epidemiology and mechanisms of tigecycline resistance in carbapenem-resistant Klebsiella pneumoniae isolates

BackgroundThe emergence and transmission of tigecycline‐ and carbapenem‐resistant Klebsiella pneumoniae (TCRKP) have become a major concern to public health globally. Here, we investigated the molecular epidemiology and mechanisms of tigecycline resistance in carbapenem‐resistant K pneumoniae (CRKP) isolates.MethodsForty‐five non‐duplicate CRKP isolates were collected from January 2017 to June 2019. We performed antimicrobial susceptibility tests, multilocus sequence typing (MLST), and pulsed‐field gel electrophoresis (PFGE). PCR and DNA sequencing were performed for the detection and mutation analysis of acrR, oqxR, ramR, rpsJ, tet(A), and tet(X) genes, which are related to tigecycline resistance. The expression levels of efflux pump genes acrB and oqxB and their regulator genes rarA, ramA, soxS, and marA were assessed by quantitative real‐time PCR.ResultsThe resistance rate to tigecycline in CRKP isolates was 37.8% (17/45). K pneumoniae ST307 was a predominant clone type (70.6%, 12/17) among the TCRKP isolates. The expression levels of acrB (P < .001) and marA (P = .009) were significantly higher in the tigecycline‐resistant group than in the tigecycline‐intermediate and tigecycline‐susceptible groups. Increased expression of acrB was associated with marA expression (r = 0.59, P = .013).ConclusionsWe found that the activated MarA‐induced overexpression of AcrAB efflux pump plays an important role in the emergence of tigecycline resistance in CRKP isolates.     

Combination therapy for carbapenem-resistant Gram-negative bacteria

The emergence of resistant to carbapenems Gram-negative bacteria (CR GNB) has severely challenged antimicrobial therapy. Many CR GNB isolates are only susceptible to polymyxins; however, therapy with polymyxins and other potentially active antibiotics presents some drawbacks, which have discouraged their use in monotherapy. In this context, along with strong pre-clinical evidence of benefit in combining antimicrobials against CR GNB, the clinical use of combination therapy has been raised as an interesting strategy to overcome these potential limitations of a single agent. Polymyxins, tigecycline and even carbapenems are usually the cornerstone agents in combination schemes. Optimization of the probability to attain the pharmacokinetic/pharmacodynamic targets by both cornerstone drug and adjuvant drug is of paramount importance to achieve better clinical and microbiological outcomes. Clinical evidence of the major drugs utilized in combination schemes and how they should be prescribed considering pharmacokinetic/pharmacodynamic characteristics against CR GNB will be reviewed in this article.     

In Vitro Activity of Tigecycline Against Orientia tsutsugamushi

Scrub typhus is a zoonosis caused by Orientia tsutsugamushi (O. tsutsugamushi) occurring mainly in autumn in Korea. The need of new antibiotics has arisen with a report on strains resistant to antibiotics and chronic infection. This study aims to identify susceptibility of tigecycline in-vitro as a new therapeutic option for O. tsutsugamushi. Antibacterial activity of tigecycline against the O. tsutsugamushi was compared with doxycycline using flow cytometry assay. The inhibitory concentration 50 (IC₅₀) was 3.59×10^-3 µg/mL in doxycycline-treated group. Whereas in 0.71×10^-3 µg/mL tigecycline-treated group. These findings indicate that tigecycline may be a therapeutic option for the treatment of scrub typhus.     

高剂量替加环素在感染性休克患者体内的药物监测及药代动力学

建立感染性休克患者替加环素检测方法,采用Ultimate AQ-C₁₈色谱柱(3.0 mm×100 mm,3 μm),流动相为含0.2%甲酸,5 mmol/L醋酸铵水溶液-乙腈,梯度洗脱方式,电喷雾离子化正离子扫描模式下,用于定量分析的离子对分别为m/z 586.4→513.3(替加环素)、m/z 338.2→296.0(利奈唑胺)。替加环素血药浓度在50.15~2 006 ng/mL范围内线性关系良好,批内、批间RSD均小于15%,稳定性良好。11名感染性休克患者高剂量给药替加环素后,药物在体内药峰浓度(c_max)和药时曲线下面积(AUC_{0-12 h})分别为(1.97±0.87)μg/mL和(9.10±3.58)mg·h/L。研究结果表明,多重耐药菌所致感染性休克患者给予高剂量替加环素后,虽给药剂量翻倍,较之于常规剂量给药的院内获得性肺炎重症患者其AUC数值并未明显增加,且略低于同等高剂量给药脓毒血症患者,未达到预期杀菌效果,这可能由于感染性休克患者高血流动力学加快药物清除速率,以及感染综合症导致毛细血管通透性增加联合间隙水肿,药物的分布容积增加有关。综上所述,推荐在多药耐药所致感染性休克患者中使用替加环素的推荐剂量区间应为150~200 mg,须对重症患者进行替加环素治疗药物浓度监测,并根据患者病程的不同阶段及时调整给药剂量。     

MTS法与仪器MIC法检测耐碳青霉烯类肺炎克雷伯菌对替加环素敏感性的差异

目的了解耐碳青霉烯类肺炎克雷伯菌(CRKP)临床分布特点,分析菌株产酶情况及验证替加环素的体外抗菌活性。方法分析某院2015年1—12月临床患者送检标本中分离的53株CRKP的药敏结果,对目标菌株进行改良Hodge试验检测碳青霉烯酶,同时采用EDTA协同试验检测金属β-内酰胺酶,使用MIC测试条(MTS)确认仪器MIC法中替加环素药敏结果。结果 53株CRKP科室分布主要为重症监护病房(ICU)14株,占26.42%,烧伤科13株(24.53%);标本来源主要为痰23株(43.40%),创面分泌物15株(28.30%);年龄分布主要为≥60岁患者,检出35株(66.04%)。CRKP对替加环素的敏感率最高(96.2%)。经改良Hodge试验确认有48株产碳青霉烯酶,阳性率90.6%,同时15株产金属β-内酰胺酶。仪器MIC法判读为替加环素耐药的菌株经MTS法验证后均应判读为敏感。结论该院CRKP主要产碳青霉烯酶,其中部分菌株可产2类不同的β-内酰胺酶;替加环素在药敏试验中对CRKP具有良好的抗菌活性,经仪器MIC法检测为替加环素耐药的菌株须进行MTS法确认。