新型抗耐药革兰阳性菌药物研究进展

目的:综述各类新型抗耐药革兰阳性(G+)菌药物或候选物的研究进展。方法:以"新型抗菌药物""抗耐药G+菌""Novel antimicrobial agents""Multi-drug-resistant""Gram-positive"等为关键词,组合查询2005年1月至2014年2月维普中文检索数据库、Pub Med中有关新型抗耐药G+菌药物的研究文献,对各类新型抗耐药G+菌药物或候选物的研究资料进行汇总分析。结果:共查阅到90余条文献,得到有效文献47条。目前,各类新型抗耐药G+菌药物研发方向较多,主要包括新型糖肽类、新型头孢菌素类、新型碳青霉烯类、新型大环内酯类、四环素类、链阳霉素、新型唑烷酮类、脂肪酸合成酶抑制剂等。结论:目前出现了多种具有广阔临床应用前景的新型抗耐药G+菌药物或候选物,特别是特拉万星、达巴万星、奥利万星、头孢吡普、头孢洛林、喹红霉素、雷得唑来、泰地唑利、阿祖培南、托莫培南等,为耐甲氧西林金黄色葡萄球菌、耐万古霉素肠球菌等耐药G+菌株的治疗带来了新希望。     

新糖肽类抗菌药物奥利万星

摘 要 奥利万星(oritavancin, ORBACTIV^TM)是一种新型半合成糖肽类抗菌药物,FDA于2014年8月批准该药用于由敏感革兰阳性菌（包括MRSA）导致的急性细菌性皮肤和皮肤结构感染(ABSSSIs)成人患者的治疗。本文对奥利万星适应证、作用机制、药动学、抗菌活性、临床研究、药品不良反应等进行介绍,以期为临床应用提供参考。     

新型抗耐甲氧西林金葡菌抗生素研究进展

随着临床耐药病例日益增多,耐甲氧西林金葡菌(MRSA)己成为医院和社区获得性感染的主要元凶.MRSA蔓延趋势不断恶化,新型抗MRSA抗生素研究成为热点.本文综述新型抗MRSA抗生素特拉万星、头抱毗普与头抱洛林等新药的研究进展.     

奥利万星

<正>奥利万星(oritavancin)是Medicines公司开发的新型糖肽类抗菌药物,于2014年8月6日获美国食品药品监督管理局(FDA)批准上市,商品名为Orbactiv。该药用于治疗由敏感革兰阳性菌(包括耐甲氧西林金黄色葡萄球菌,MRSA)引起的急性细菌性皮肤和皮肤结构感染(acute bacterial skin and skin-structure infections,ABSSSIs)[1]。     

乙基西索米星和β-内酰胺类抗生素联合效果的探讨

抗生素的联用可以达到扩大抗菌谱、起增效作用、防止病原菌形成耐药和减轻药物的毒副作用等目的。作者以大肠杆菌、粘质沙雷氏菌、绿脓杆菌和摩根氏菌(M.catarr-halis)为试验病原菌株,探讨乙基西索米星(Netilmicia NTL)和第三代的头孢菌素 la-     

单核细胞增生李斯特菌血清型、耐药性研究

目的 了解河北省2005～2007年91株食源性致病菌单核细胞增生李斯特血清型、耐药性特点.方法 血清凝集试验确定实验菌株的血清型:微量肉汤稀释法检测实验菌株对β-内酰胺类、喹诺酮类、氨基糖苷类、四环素类、大环内酯类、糖肽类、磺胺类等抗生素的药物敏感性.结果 91株单核细胞增生李斯特菌分属5个血清型(1/2a,1/2b,1/2c,4b和3a),主要血清型为1/2a型,占49.5%,分离到8株致病力较强的4b血清型.耐药性分析表明单核细胞增生李斯特菌对四环素耐受最为严重,耐药率为15.4%(14/91),且4.4%(4,91)菌株对强力霉素交叉耐药;少量菌株对临床治疗李斯特菌病抗生素氨苄西林、庆大霉素、复方磺胺甲噁唑、万古霉素、红霉素出现耐药;有2株菌耐5种以上抗生素;所有菌株对氨苄西林/舒巴坦、亚胺培南、莫西沙星、左氧氟沙星敏感.结论 存在具有较强的致病性1/2a,1/2b和4b血清型菌株,及耐药株及多重耐药株出现,说明存在潜在的单核细胞增生李斯特菌引起食品安全问题.     

基于突变选择窗理论的新型药代动力学/药效学模型的研究进展

目前,因为抗生素过度使用而导致的耐药菌株蔓延问题得到了广泛的关注。以防耐药突变浓度(MPC)和突变选择窗(MSW)理论为基础的新型药代动力学/药效学(PK/PD)模型,与旧的模型相比,可以通过关闭或缩小突变选择窗的方式有效地防止耐药突变菌株的产生。本文围绕突变选择窗、防耐药突变浓度的基本概念和原理及其在指导新型PK/PD模型建立方面的应用展开综述,为该模型在指导抗生素药物的合理应用及遏制耐药突变菌的出现提供一定的参考依据。     

莫西沙星与其他12种抗菌药物对呼吸道常见感染致病菌体外抗菌活性研究

目的比较研究莫西沙星与其他12种抗菌药物对临床常见致病菌的体外抗菌活性.方法采用琼脂平板二倍稀释法测定对411株临床分离菌株的最低抑菌浓度.结果金黄色葡萄球菌(包括MRSA)和肺炎链球菌(包括PISP和PRSP)对万古霉素的敏感性最高,敏感率为95.8%～100%,对莫西沙星、加替沙星的敏感性较高,对大环内酯类药物则比较耐药.流感嗜血杆菌、卡他莫拉菌对莫西沙星、加替沙星等4种氟喹诺酮类和5种头孢菌素类及阿齐霉素比较敏感.肺炎克雷伯菌(包括产ESBLs菌株)对莫西沙星等4种氟喹诺酮类和头孢美唑很敏感;非产ESBLs菌株对8种抗菌药物均敏感,但产ES-BLs菌株对第二、三代头孢菌素则显示了较高的耐药率.大肠埃希菌(包括产ESBLs菌株)对氟喹诺酮类敏感率在40%左右,非产ESBLs菌株对5种头孢菌素均较敏感,但产ESBLs菌株除对头孢美唑敏感外,对其他头孢菌素类耐药率较高;结论莫西沙星与其他12种抗菌药物比较,对革兰阳性菌(包括MRSA和PRSP)作用增强,对肺炎克雷伯菌(包括产ESBLs菌株)抗菌活性较强,大肠埃希菌对莫西沙星与其他氟喹诺酮类有一定的交叉耐药性.     

莫西沙星与其他12种抗菌药物对呼吸道常见感染致病菌体外抗菌活性研究

目的:比较研究莫西沙星与其他12种抗菌药物对临床常见致病菌的体外抗菌活性.方法:采用琼脂平板二倍稀释法测定对411株临床分离菌株的最低抑菌浓度.结果:金黄色葡萄球菌(包括MRSA)和肺炎链球菌(包括PISP和PRSP)对万古霉素的敏感性最高,敏感率为95.8%～100%,对莫西沙星、加替沙星的敏感性较高,对大环内酯类药物则比较耐药.流感嗜血杆菌、卡他莫拉菌对莫西沙星、加替沙星等4种氟喹诺酮类和5种头孢菌素类及阿齐霉素比较敏感.肺炎克雷伯菌(包括产ESBLs菌株)对莫西沙星等4种氟喹诺酮类和头孢美唑很敏感;非产ESBLs菌株对8种抗菌药物均敏感,但产ES-BLs菌株对第二、三代头孢菌素则显示了较高的耐药率.大肠埃希菌(包括产ESBLs菌株)对氟喹诺酮类敏感率在40%左右,非产ESBLs菌株对5种头孢菌素均较敏感,但产ESBLs菌株除对头孢美唑敏感外,对其他头孢菌素类耐药率较高;结论:莫西沙星与其他12种抗菌药物比较,对革兰阳性菌(包括MRSA和PRSP)作用增强,对肺炎克雷伯菌(包括产ESBLs菌株)抗菌活性较强,大肠埃希菌对莫西沙星与其他氟喹诺酮类有一定的交叉耐药性.     

立克菌星在烧伤感染中的应用

立克菌星系半合成的氨基糖甙类抗生素，通过对烧伤创面多元耐药菌株的抗菌活性及对败血症患者的治疗，证实立克菌星对耐庆大霉素菌株及耐β－内酰胺类的耐药金黄色葡萄球菌均有强大的抗菌活性，且无明显的耳、肾毒性、很有临床使用价值。     

新型糖肽类抗生素奥利万星

奥利万星(oritavancin,LY333328)是一种半合成的新型的糖肽类抗生素,作用机制与万古霉素和替考拉宁相同,即抑制G 菌细胞壁的生物合成。具有独特的药动学性质。其抗菌谱包括金葡球菌、耐甲氧西林金葡球菌(MRSA);表皮葡萄球菌及凝固酶阴性葡萄球菌(CoNS),包括耐甲氧西林及一些耐替考拉宁菌;肠球菌,包括耐万古霉素替考拉宁(vanA)屎肠球菌和粪肠球菌;链球菌,包括化脓性链球菌和肺炎链球菌,包括耐青霉素肺炎链球菌;G 厌氧菌,包括消化链球菌属、短小棒状杆菌和艰难梭状芽胞杆菌。在治疗皮肤和软组织感染上已取得了良好的效果。现对其作用机制、抗菌活性、药动学及临床研究做一综述。     

Oritavancin--an investigational glycopeptide antibiotic

Antibiotics save countless lives each year; however, increasing rates of drug-resistant bacteria have limited antibiotic selection. Currently, there are few available options for treating resistant Gram-positive organisms. Oritavancin, a novel glycopeptide antibiotic with bactericidal activity, has been developed and recently completed the first round of Phase III clinical trials for the treatment of complicated skin and skin structure infections. Investigations into oritavancin's efficacy will be explored in catheter-related bacteraemia and nosocomial pneumonia. Oritavancin demonstrates similar activity to vancomycin but possesses extended activity against vancomycin-resistant Staphylococcus and Enterococcus. The pharmacokinetics and pharmacodynamics of oritavancin appear to be favourable and once-daily dosing is likely. The incidence of multi-drug resistant bacteria is increasing and explorations into additional treatment options are essential. Further development of oritavancin is necessary to determine clinical efficacy.     

Multiple‐Dose Oritavancin Evaluation in a Retrospective Cohort of Patients with Complicated Infections

Objective

Oritavancin is a lipoglycopeptide antibiotic approved for use in acute bacterial skin and skin structure infections as a single 1200‐mg parenteral dose. Because of oritavancin's long half‐life and broad gram‐positive activity, interest in its use for other infections is high.

Methods

This study is a retrospective cohort evaluation of patients receiving oritavancin at a single academic medical center. All patients receiving more than one dose of oritavancin were included. Patients were excluded if therapy was interrupted by more than 14 days. Efficacy, defined a priori as clinical success, improvement, or failure, and adverse drug effect outcomes were collected.

Results

Seventeen patients received multiple oritavancin doses (range 2–18 doses) for the treatment of complicated infections including osteomyelitis, surgical site infection, intravascular infections, and pneumonia. All patients achieved clinical success or improvement with oritavancin. Four patients (24%) had an adverse event requiring oritavancin discontinuation that reversed rapidly.

Conclusions

Off‐label oritavancin use may be a safe and effective alternative to daily antibiotic infusions to treat complicated infectious disease processes. This study is limited by small sample size and retrospective design, but it provides information on using oritavancin in these complex gram‐positive infections.     

Glycopeptides and glycodepsipeptides in clinical development: a comparative review of their antibacterial spectrum, pharmacokinetics and clinical efficacy

Hemi-synthetic derivatives of glycopeptides have demonstrated bactericidal activity towards Gram-positive bacteria, including vancomycin-resistant strains (oritavancin and telavancin), and a prolonged half-life, allowing for once-daily (oritavancin and telavancin) or once-weekly (dalbavancin) administration. These compounds have proved effective for the treatment of infections caused by multidrug-resistant Gram-positive bacteria, including complicated skin and skin structure infections (oritavancin, telavancin and dalbavancin), bacteremia (oritavancin and dalbavancin) and nosocomial pneumonia. This review compares the antibacterial activity and clinical activity of three glycopeptides, oritavancin, telavancin and dalbavancin, and the natural lipoglycopeptide, ramoplanin, which, being unstable in the bloodstream, is administered orally to treat Clostridium difficile colitis and for digestive tract decontamination. All of these compounds, with the exception of oritavancin, have received Fast Track designation from the FDA because of their clinical efficacy.     

Oritavancin for skin infections

Oritavancin (LY-333328) is a semisynthetic lipoglycopeptide for the treatment of serious infections with Gram-positive pathogens, especially methicillin-resistant Staphylococcus aureus and complicated skin and soft tissue infections. A New Drug Application for oritavancin administered intravenously once daily for 3 to 7 days for complicated skin and soft tissue infections was filed with the U.S. Food and Drug Administration in April 2008. This article provides an overview of the publicly available data and includes data presented at the European Congress of Clinical Microbiology and Infectious Disease in April 2008. Although several agents are currently or soon to be available for resistant Gram-positive infections, oritavancin has several key features: (i) multiple mechanisms of antibacterial action; (ii) broad spectrum and high potency against Gram-positive pathogens; (iii) bactericidal activity and long duration of the postantibiotic effect with excellent activity against stationary-phase bacteria and biofilms; (iv) long half-life, allowing infrequent dosing and potentially allowing the entire course of therapy to be a single dose; and (v) documented clinical efficacy and safety.     

Successful Treatment of Methicillin Susceptible Staphylococcus aureus Osteomyelitis with Oritavancin

Staphylococcus aureus remains the most common causative pathogen in osteomyelitis. New or alternative therapies are often needed to treat S. aureus infections adequately in patients with drug allergies, treatment failures, or drug interactions. Oritavancin is a novel long‐acting lipoglycopeptide approved by the U.S. Food and Drug Administration in 2014 for the treatment of acute bacterial skin and skin structure infections. With a terminal half‐life of 8–10 days, oritavancin dosing regimens with infrequent parenteral administration now exist to treat infectious diseases such as osteomyelitis that would otherwise require daily dosing of intravenous antimicrobials for weeks; however, clinical experience is lacking. In this article, the first case of S. aureus osteomyelitis resulting from traumatic injury, successfully treated with oritavancin, is presented. Removal of the nail used for a comminuted tibial shaft fracture repair followed by a 6‐week treatment course with oritavancin resulted in clinical response.     

Oritavancin. Eli Lilly & Co

Oritavancin (LY-333328), a lead glycopeptide from a series targeted at vancomycin-resistant bacteria, especially enterococci, is under development by Eli Lilly for the potential treatment of bacterial infections. It entered phase III trials in the US in January 2001 [396223] and the company expects to submit an NDA by 2003 [396478]. Oritavancin has been reported to have activity comparable to that of vancomycin and teicoplanin (Aventis Pharma AG), but retains activity against glycopeptide-resistant bacterial strains [407519]. The bactericidal activity of oritavancin suggests that it may prove useful as a single agent therapy in the treatment of antibiotic-resistant enterococci. Although its mechanism of action is unclear, dimerization of the glycosyl portion stabilizing D-Ala-D-Ala binding has been suggested [337644].     

A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus

This article compares vancomycin, teicoplanin, quinupristin-dalfopristin, linezolid, daptomycin, tigecyline, dalbavancin, telavancin, ceftobiprole, oritavancin, and ramoplanin for the treatment of complicated skin and skin structure infections (cSSSI), methicillin-resistant Staphylococcus aureus (MRSA), enterococcus, and vancomycin-resistant enterococcus. Vancomycin, a glycopeptide antibiotic, is administered intravenously, and is the mainstay of treatment for MRSA and cSSSI. While not available in the U.S., teicoplanin, another glycopeptide antibiotic, can be administered intramuscularly and has simpler dosing and monitoring requirements than vancomycin. Quinupristin/dalfopristin treats vancomycin-resistant Enterococcus faecium (VREF) infections but inhibits cytochrome P450 A3P4, and has only modest activity against MRSA pneumonia. Daptomycin effectively treats cSSSI but not pneumonia caused by MRSA, and is effective against all strains of Staphylococcus. Linezolid, available orally and intravenously, is approved to treat community-acquired and nosocomial pneumonia, cSSSI, and infections caused by MRSA and vancomycin-resistant enterococci including infections with concurrent bacteraemia and VREE Tigecycline, a glycylcycline derived from minocycline, has been approved by the FDA to treat cSSSI and complicated intraabdominal infections, and might be effective against Acinetobacter baumannii; its primary side effect is digestive upset. Dalbavancin, effective against MRSA and administered intravenously once weekly, possesses coverage similar to vancomycin. Telavancin deploys multiple mechanisms of action and is effective against MRSA and Gram-positive bacteria resistant to vancomycin. Ceftobiprole, a cephalosporin effective against MRSA, has few side effects. Oritavancin demonstrates similar activity to vancomycin but possesses extended activity against vancomycin-resistant Staphylococcus and enterococci. Ramoplanin, a macrocyclic depsipeptide, is unstable in the bloodstream but can be taken orally to treat Clostridium difficile colitis.     

Treatment of chronic osteomyelitis with multidose oritavancin: A case series and literature review

Osteomyelitis remains difficult to treat, typically requiring a prolonged course of intravenous (i.v.) antibiotics. The optimal route and duration of antibiotics remains ill-defined due to limited prospective clinical trials. Oritavancin is a long-acting, semisynthetic lipoglycopeptide antibiotic with rapid concentration-dependent bactericidal activity against many Gram-positive organisms. Favourable pharmacokinetics makes oritavancin an appealing alternative to currently available antibiotics requiring daily infusion to decrease the risk of vascular access complications associated with outpatient antimicrobial therapy. The purpose of this study was to report the outcomes of nine patients with chronic osteomyelitis receiving multidose oritavancin. Using electronic medical records, patients aged ≥18 years treated with i.v. oritavancin between September 2015 and April 2018 at Downtown Dublin Wound Center, a hospital-owned outpatient wound care clinic and infusion centre affiliated with Meadows Regional Health System in Dublin, GA, were identified. Of 12 cases reviewed, 9 patients received at least two doses of i.v. oritavancin for the treatment of chronic osteomyelitis. All nine patients experienced clinical cure at 6-month follow-up after the last dose of oritavancin. Multidose oritavancin was found to be a safe and efficacious option for chronic osteomyelitis when treatment options are limited by patient complexities or barriers in their ability to access healthcare services.     

Oritavancin for acute bacterial skin and skin structure infections

Introduction: Inpatient treatment of acute bacterial skin and skin structure infections (ABSSSIs) exerts a significant economic burden on the healthcare system. Oritavancin is a concentration-dependent, rapid bactericidal agent approved for the treatment of ABSSSIs. Its prolonged half-life with one-time intravenous (i.v.) dosing offers a potential solution to this burden. In addition, oritavancin represents an alternative therapy for Streptococci and multidrug-resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Animal models have also shown promising results with oritavancin for other disease states including those that require long courses of i.v. therapy.

Areas covered: This review covers oritavancin’s basic chemistry, spectrum of activity, pharmacodynamics/pharmacokinetics and efficacy in clinical trials, and provides expert opinion on future directions. To compose this review, a search of PubMed was performed, and articles written in the English language were selected based on full text availability.

Expert opinion: If oritavancin is proven to be a cost-effective strategy for outpatient treatment and prevents complications of prolonged i.v. therapy, it will be sought as an alternative antibiotic therapy for ABSSSIs. In addition, further clinical data demonstrating efficacy in Gram-positive infections requiring prolonged therapy such as endocarditis and osteomyelitis could support oritavancin’s success in the current market.