Telavancin for the treatment of serious gram-positive infections,including hospital acquired pneumonia

Introduction: Hospital-acquired pneumonia is a common infection, associated with substantial mortality. Despite the increasing prevalence of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA), approved treatment options for this pathogen are limited.

Areas covered: This article reviews the pharmacokinetics, dosing, preclinical studies and clinical efficacy, and safety of telavancin, with a particular focus on results from trials in nosocomial pneumonia. PubMed and Congress websites were searched for relevant articles published between 2003 and 2010.

Expert opinion: Telavancin is a lipoglycopeptide antibiotic with rapid, bactericidal activity against MRSA, and may provide another option for the treatment of nosocomial pneumonia, owing to Gram-positive pathogens.     

The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid

Abstract

Background:

The rising prevalence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) and the recent emergence of community-associated MRSA are major clinical, public health, and economic challenges. MRSA is a leading cause of nosocomial pneumonia and complicated skin and soft-tissue infections (cSSTI). Vancomycin and linezolid are two commonly used antimicrobial agents with activity against Gram-positive pathogens, particularly MRSA, that are used to treat both nosocomial pneumonia and cSSTI. Recently, the therapeutic efficacy of vancomycin in the treatment of hospitalized patients with MRSA infections has been questioned due to the emergence of MRSA strains with reduced susceptibility to vancomycin together with concerns related to inadequate dosing and poor tissue penetration of the drug.     

Linezolid - the first oxazolidinone in the treatment of nosocomial MRSA pneumonia

The incidence of nosocomial pneumonia involving multi-drug resistant Staphylococcus aureus strains (MRSA) in particular is on the rise worldwide. For years, vancomycin has been used as the drug of choice in the treatment of MRSA infections and was recommended as such by clinical guidelines. Inadequate drug levels in pulmonary compartments due to large molecular size may be the cause of the comparatively low survival rates of patients with MRSA pneumonia treated with vancomycin, despite in vitro susceptibility of the bacterial isolates. Several trials demonstrated the clinical effectiveness of the novel oxazolidinone linezolid in nosocomial MRSA pneumonia. Linezolid achieves higher pulmonary concentrations than vancomycin which may be the cause of superior survival rates observed with linezolid in nosocomial MRSA pneumonia. Staphylococcus aureus strains with reduced susceptibility to vancomycin (VISA) are encountered with increasing frequency and may contribute to clinical failures of vancomycin. To date, linezolid-resistance appears to be rare and predominantly affects Enterococci, while very few linezolid-resistant S. aureus isolates were reported. Reduced susceptibility to linezolid is caused by point mutations in the 23S ribosomal RNA genes, which may be selected for by long-term therapy. The future development of linezolid resistance is hard to predict since the drug has been in use only for a limited period of time. This article describes the drug profile, patents and current data on the clinical efficacy of linezolid and reviews its role in treatment of MRSA pneumonia.     

医院内MRSA肺炎多重病原体感染及其药敏分析

探讨医院内 MRSA肺炎严重混合感染的病原体分布及其对常用抗生素药物敏感性。选择本实验室近 4年来确诊医院内 MRSA肺炎病人痰标本分离的致病菌 ,采用 K- B纸片及 E- test方法分别检测混合感染细菌和真菌对常用抗生素的体外敏感性。结果 6 4例次院内混合感染病原体中细菌 46例次占 71.88% ,真菌 18例占 2 8.13%。细菌对 13种常见抗生素呈现不同程度的严重耐药。其中除曲霉耐氟康唑外 ,部分白念珠菌也出现耐药 ,伊曲康唑和两性霉素 B效果较好。提示医院内 MRSA肺炎常合并多重高度耐药菌感染 ,治疗困难 ,必须进行严格的细菌学分析和耐药监测 ,及时选用有效抗生素。     

Emerging drugs for nosocomial pneumonia

Introduction: Hospital-acquired pneumonia (HAP) is one of the leading nosocomial infections worldwide and is associated with an elevated morbidity and mortality and increased hospital costs. Nevertheless, prompt and adequate antimicrobial treatment is mandatory following VAP development, especially in the face of multidrug resistant pathogens.

Areas covered: We searched Pubmed and ClinicalTrials.gov site reports in English language of phase III clinical trials, between 2000–2016 referring to the antibiotic treatment of nosocomial pneumonia. We provide a summary of latest approved drugs for HAP and emerging drugs with potential indication nosocomial pneumonia.

Expert opinion: There are several promising compounds on their way, as tedizolid-a new oxazolidone, iclaprim-a novel drug, related to trimethoprim, plazomicin-a new aminoglycoside and two combinations of ceftazidime/avibactam and ceftolozane/tazobactam against MDR bacteria, especially against MRSA and Gram-negative ESBL bacteria.     

Current review of antimicrobial treatment of nosocomial pneumonia caused by multidrug-resistant pathogens

Nosocomial pneumonia (including ventilator-associated pneumonia; VAP), a consistently difficult-to-treat entity, is frequently caused by multidrug-resistant (MDR) or pandrug-resistant (PDR) bacteria. Given the high mortality rates caused by drug-resistant bacteria and the difficulty of developing new potent antibiotics to target the problematic pathogens, combination regimens are under ardent evaluation as new strategies to overcome increasing drug resistance. Adjustment of the administration method of certain β-lactams (meropenem, or imipenem/cilastatin), or combination of tigecycline with some agents, may show promise with regard to successful management of MDR or PDR Acinetobacter baumannii pneumonia. Additionally, vancomycin plus rifampicin is an effective regimen against nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) responding poorly to vancomycin monotherapy. The clinical appropriateness of parenteral colistin against pneumonia caused by MDR A. baumannii has been established in a clinical trial. Facing the decline of clinical vancomycin efficacy after initial use, linezolid might be the drug of choice with regard to the treatment of MRSA-VAP. The role of tigecycline monotherapy for the management of nosocomial pneumonia caused by MRSA and extended-spectrum β-lactamase-producing Enterobacteriaceae needs to be cautiously evaluated.     

利奈唑胺对比糖肽类抗菌药物治疗MRSA相关性院内获得性肺炎的疗效和安全性的Meta分析

目的:系统评价利奈唑胺对比糖肽类抗菌药物治疗耐甲氧西林金黄色葡萄球菌(MRSA)相关性院内获得性肺炎的疗效和安全性。方法:计算机检索Medline、EMBase、OVID、中国生物医学文献数据库、中国期刊全文数据库、维普及万方数据库,查找利奈唑胺对比糖肽类抗菌药物治疗MRSA相关性院内获得性肺炎的随机对照试验(RCT)。对符合条件的RCT进行资料提取和质量评价后,采用Rev Man 5.1统计软件进行Meta分析。结果:共纳入8项RCT,合计1 966例患者。Meta分析结果显示,利奈唑胺治疗MRSA相关性院内获得性肺炎的临床治愈率[RR=1.10,95%CI(1.01,1.20),P=0.03]、微生物清除率[RR=1.14,95%CI(1.03,1.27),P=0.01]均高于糖肽类抗菌药物;而两者的病死率[RR=0.86,95%CI(0.68,1.08),P=0.20]和不良反应发生率[RR=1.05,95%CI(0.94,1.16),P=0.41]比较差异无统计学意义。结论:利奈唑胺较糖肽类抗菌药物治疗MRSA相关性院内获得性肺炎可以提高患者的临床治愈率和微生物清除率,但是不能改善患者病死率及不良反应发生率。限于研究的设计及报告质量,该结论仍有进一步评价的必要。     

Staphylococcus aureus bacteraemia with known sources

Meticillin-resistant Staphylococcus aureus (MRSA), both hospital-acquired and community-acquired MRSA (CA-MRSA) strains, have increased in frequency in the last few years, reaching epidemic dimensions. This review discusses several clinical forms of staphylococcal infection leading to bacteraemia in a high proportion of cases. Staphylococcal (MRSA) bacteraemic pneumonia is predominantly seen in hospital-acquired pneumonia and ventilator-associated pneumonia, reaching a frequency of 8.4% of all bacteraemias, 30% of all nosocomial bacteraemias and 68% of all bacteraemias of patients hospitalised in Intensive Care Units. In patients with CA-MRSA pneumonia, the rate of bacteraemia is as high as 62%. Whereas in nosocomial bacteraemic pneumonia blood cultures become positive on the ninth day of pneumonia, in CA-MRSA bacteraemic pneumonia positive blood cultures appear early in the course of the infection. The pneumonia has a stormy course with the development of abscesses, empyema and extensive pulmonary damage. Vertebral osteomyelitis commonly occurs during intravenous catheter use, causing local thrombophlebitis that will seed to vertebral bodies and disks and may cause secondary sustained bacteraemia. Non-vertebral osteomyelitis is also on the increase, with a frequency that has doubled in recent years, mainly due to MRSA. Patients with haematological malignancies are particularly prone to this complication, usually following line infections. Epidural abscess is the most serious consequence of staphylococcal bacteraemia, leading to permanent neurological damage if not diagnosed early enough.     

Burden of methicillin-resistant Staphylococcus aureus: focus on clinical and economic outcomes

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major public concern. Hospital-acquired MRSA rates have steadily increased over the past 25 years, and the bacterial strain is making inroads to the community. The morbidity and mortality burden of MRSA infection is compounded by delayed or inappropriate antibiotic treatment, taking a toll on health care resources that are already stretched thin. Vancomycin has historically been the drug of choice for this pathogen because its broad spectrum can address the multidrug resistance of most MRSA infections. Despite its sustained in vitro microbiologic inhibitory activity, researchers are beginning to question the continued utility of vancomycin for MRSA infections. Evidence against vancomycin is most notable with regard to nosocomial pneumonia and skin and soft tissue infections. In addition, because vancomycin must be administered intravenously, patients typically require prolonged hospitalization, which further increases the cost of MRSA treatment and exposes patients to additional nosocomial infections. Recent studies have shown that antibiotics with good bioavailability, such as linezolid, can be given orally to facilitate early hospital discharge, thus alleviating the economic burden of MRSA infections. Several agents have been developed over the past decade that have excellent in vitro activity against MRSA. Further studies are needed to determine if these drugs can better eradicate MRSA than vancomycin and remedy the adverse outcomes frequently observed with this organism.     

Current review of antimicrobial treatment of nosocomial pneumonia caused by multidrug-resistant pathogens

Nosocomial pneumonia (including ventilator-associated pneumonia; VAP), a consistently difficult-to-treat entity, is frequently caused by multidrug-resistant (MDR) or pandrug-resistant (PDR) bacteria. Given the high mortality rates caused by drug-resistant bacteria and the difficulty of developing new potent antibiotics to target the problematic pathogens, combination regimens are under ardent evaluation as new strategies to overcome increasing drug resistance. Adjustment of the administration method of certain β-lactams (meropenem, or imipenem/cilastatin), or combination of tigecycline with some agents, may show promise with regard to successful management of MDR or PDR Acinetobacter baumannii pneumonia. Additionally, vancomycin plus rifampicin is an effective regimen against nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) responding poorly to vancomycin monotherapy. The clinical appropriateness of parenteral colistin against pneumonia caused by MDR A. baumannii has been established in a clinical trial. Facing the decline of clinical vancomycin efficacy after initial use, linezolid might be the drug of choice with regard to the treatment of MRSA-VAP. The role of tigecycline monotherapy for the management of nosocomial pneumonia caused by MRSA and extended-spectrum β-lactamase-producing Enterobacteriaceae needs to be cautiously evaluated.     

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.     

Ceftobiprole: a new broad spectrum cephalosporin

Ceftobiprole, formerly designated BAL9141/Ro 63-9141, is a pyrrolidinone-3-ylidene-methyl cephalosporin with demonstrated in vitro activity against MRSA, Enterococcus faecalis, Enterobacteriaceae and Pseudomonas aeruginosa. Ceftobiprole has a low potential for inducing chromosomal AmpC β-lactamases but it is hydrolyzed by most extended spectrum β-lactamases and metallo-β-lactamases. Glomerular filtration is predominantly responsible for removal of the free drug from the systemic circulation. The efficacy of ceftobiprole in the treatment of complicated skin and ski-structure infections has been recently demonstrated in two Phase III randomized clinical trials involving 1600 patients. Two other Phase III clinical trials to assess ceftobiprole's efficacy in community-acquired pneumonia and nosocomial pneumonia have also concluded. While the drug met the noninferiority criteria for community-acquired pneumonia and nosocomial pneumonia involving non-ventilator associated pneumonia, ceftobiprole was less effective than the comparator in ventilator associated pneumonia subjects. Ceftobiprole was well tolerated with a safety profile consistent with the cephalosporin class of antibiotic. The most frequent drug-related adverse event was dysgeusia. Ceftobiprole is intended for use in the hospital for the treatment of infections that frequently involve β-lactam-resistant Gram-negative and Gram-positive organisms.     

Benefit-risk assessment of linezolid for serious gram-positive bacterial infections

Linezolid is an oxazolidinone, a new class of antibacterial with a unique mechanism of action, namely inhibition of the formation of a functional 70S initiation complex in the 50S bacterial ribosomal subunit. Linezolid is highly active against multidrug-resistant Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate and vancomycin-resistant S. aureus, and vancomycin-resistant enterococci; its spectrum of activity also includes some anaerobic bacteria.Linezolid has been studied in several randomized controlled trials for the treatment of patients with community-acquired and nosocomial pneumonia, skin and soft tissue infections (SSTIs), urinary tract infections and bacteraemia. The available evidence suggests that linezolid is at least as effective as vancomycin for patients with nosocomial pneumonia, and there are some retrospective analyses supporting its superiority in comparison with vancomycin for MRSA nosocomial pneumonia, including ventilator-associated pneumonia. Linezolid is more effective than glycopeptides, macrolides and beta-lactams for SSTIs. The limited available data for the treatment of patients with bacteraemia suggest that it may be a better treatment option than vancomycin and beta-lactams for these patients, but questions have arisen regarding patients with catheter-related bacteraemias.Compared with other antibacterials, linezolid is associated with a greater frequency of adverse events, mainly nausea, vomiting, diarrhoea and headaches. Thrombocytopenia also occurs more frequently in patients taking linezolid but there is no increased frequency of anaemia. Other adverse events potentially related to linezolid therapy include fungal infections (moniliasis), hypertension and serotonin-like syndrome, tongue discolouration and taste alterations, dizziness, insomnia, rash and Clostridium difficile-related diarrhoea. The majority of adverse events develop after prolonged administration (i.e. >2 weeks) and subside shortly after discontinuation of linezolid. Peripheral or optic neuropathy, another possible adverse effect, is associated with an even longer duration of treatment (3-6 months).In conclusion, linezolid is an important treatment option for the treatment of patients with multidrug-resistant, Gram-positive bacterial infections. However, in order to reduce the possibility of development of resistance and preserve its activity, the use of linezolid should be restricted to treatment of patients with infections associated with high morbidity and mortality, particularly those caused by multidrug-resistant bacteria.     

利奈唑胺与万古霉素对耐甲氧西林金黄色葡萄球菌肺炎的有效性和安全性比较

目的:探讨利奈唑胺和万古霉素对治疗耐甲氧西林金黄色葡萄球菌(MRSA)引起肺炎的有效性和安全性。方法:本研究是前瞻是研究,研究对象为2012年5月-2015年1月在我院院内感染性肺炎成年患者。患者随机分为两组,分别接受利奈唑胺(每12 h 600 mg)和万古霉素(每12 h 15 mg·kg^-1)治疗,疗程7~14 d。治疗过程中根据药物浓度对万古霉素剂量进行调整。观察终点为试验结束(EOS)时患者的临床结果。其他指标还包括治疗结束(EOT)和试验结束(EOS)时意向性治疗(ITT)患者的临床疗效以及符合方案(PP)患者、ITT患者在EOT和EOS时的细菌学结果,评估患者存活率和药物安全性。结果:1184例院内感染性肺炎患者中,ITT患者448例(利奈唑胺组n=224,万古霉素组n=224),PP患者348例(利奈唑胺组n=172,万古霉素组n=176)。PP患者中,95/165例(57.6%)利奈唑胺治疗患者和81/174例(46.6%)万古霉素治疗患者在EOS时成功治愈(95% CI:0.5%~21.6%,P=0.042)。两组患者60 d死亡率(利奈唑胺组10.7%,万古霉素组17.0%)有明显差别,两组不良反应发病率相近,但万古霉素引发的肾脏毒性损伤更为常见(万古霉素组18.2%,利奈唑胺组8.4%)。结论:利奈唑胺治疗MRSA院内感染性肺炎临床预后要明显好于万古霉素,且肾毒性更小。     

Telavancin: TD 6424, TD-6424

Telavancin [TD-6424, ARBELIC] is an injectable, bactericidal lipoglycopeptide antibacterial that is in clinical development with Theravance (formerly Advanced Medicine) in the US. Telavancin, which was discovered by Theravance through the application of multivalent drug design, has a broad spectrum of activity against Gram-positive pathogens. Telavancin is currently in phase III development for complicated skin and soft tissue infections (including those caused by methicilin-resistant Staphylococcus aureus [MRSA]), nosocomial pneumonia, as well as other Gram-positive pathogens. The antibacterial effects of telavancin are mediated through multiple mechanisms, including inhibition of cell wall (peptidoglycan) synthesis. The drug also produces changes in bacterial cell membrane permeability. The multiple mechanisms of action may be responsible for the low frequency of spontaneous resistance to telavancin. Theravance and Astellas Pharma entered into a licensing agreement for telavancin in November 2005. The two companies will collaborate for the development and commercialisation of the antibacterial agent worldwide, except Japan. Under the terms of the agreement, Astellas will make a 65 million US dollars up-front payment and royalties on global sales to Theravance; in addition, Theravance is eligible to receive 156 million US dollars in clinical and regulatory milestones payments, including 136 million US dollars for completing enrollment, filling and approval of ongoing phase III programmes, and 20 million US dollars if phase III data indicate telavancin's superiority over vancomycin for the treatment of MRSA. Theravance will continue to explore partnering opportunities in the Japanese market. Telavancin was granted fast-track status by the US FDA in March 2005 for the treatment of complicated skin and skin structure infections (cSSSIs), as well as hospital-acquired pneumonia (nosocomial pneumonia). The compound is currently in phase III trials for these indications in the US. Theravance has also conducted two randomised, double-blind phase II trials (FAST and FAST 2) of telavancin in patients with cSSSIs caused by Gram-positive bacteria, in which telavancin (7 or 10 mg/kg) was compared with standard vancomycin therapy. Results showed that while telavancin was comparable to standard therapy overall, telavancin was associated with superior MRSA eradication rates.     

An evaluation of tedizolid for the treatment of MRSA infections

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA)is a common pathogen in acute bacterial skin and soft tissue infections (ABSSSIs), nosocomial pneumonia, bacteremia, endocarditis, as well as diabetic foot, bone, and joint infections.

Areas covered: This review summarizes the randomized controlled trials that evaluated the clinical efficacy of tedizolid in ABSSSIs, which is currently the only United States Food and Drug Administration-labeled indication for tedizolid.

Expert opinion: Tedizolid has several potential advantages over linezolid including once-daily dosing, shorter duration of therapy, and increased tolerability. However, its cost will likely limit its adoption for ABSSSIs with MRSA because other oxazolidinone antibiotics are available in less costly generic versions. Tedizolid is also currently being investigated for its use in other MRSA infections including nosocomial pneumonia as well as diabetic foot, bone, and joint infections and tedizolid’s use in these disease states appears more promising. Potential indications for future clinical investigation of tedizolid’s efficacy and safety include bacteremia and meningitis.     

Unmet medical needs in antibacterial therapy

The innate and evolutionary resourcefulness of bacterial pathogens virtually guarantees that there will always be important areas in which antimicrobial therapy can be improved. Current areas of need, or ones that are anticipated to be problematic in the near future include nosocomial infections caused by multi-resistant Gram-negative bacteria, where the variety and prevalence of multidrug efflux pumps provides a particular challenge to the designers of new drugs. In the community setting, the current prevalence of ampicillin and trimethoprim-sulfamethoxazole resistance, and the growing prevalence of fluoroquinolone resistance in Escherichia coli portend a need for new classes of oral agents to address this important need. On the Gram-positive side, the rapid increase in virulent community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections as a cause of pneumonia emphasizes the importance of developing more agents that are active against MRSA and that are effective for treating pneumonia. Finally, the importance of indwelling devices as a nidus for nosocomial infections emphasizes the need for effective agents for treating biofilm-associated device infection both inside and outside of the hospital.     

Perspectives on synthetic pharmacotherapy for the treatment of nosocomial pneumonia

ABSTRACT

Introduction: Nosocomial pneumonia is the second most common infection in hospital settings, resulting in substantial increases in morbidity, mortality, and length of hospital stay. The rapid increase in resistance of nosocomial pathogens to many antibiotics and the high dissemination of resistance genes highlight the need for innovative approaches to combat difficult-to-treat nosocomial respiratory infections.

Areas covered: This review summarizes the synthetic antimicrobials that are currently in development for the treatment of nosocomial pneumonia, focusing on antibiotics in the final phases of clinical development and on the strategies employed by novel synthetic antimicrobial peptides.

Expert opinion: Several novel synthetic antimicrobials are currently in the pipeline, and it appears that new antimicrobial peptides or mimetics will soon be made available, expanding the opportunities to treat nosocomial pneumonia. However, the approval process for use in the treatment of nosocomial pneumonia is arduous. Given that significant investments by pharmaceutical companies have ended in failure to obtain the approval of regulatory agencies, novel platforms for antimicrobial discovery are needed. The identification of new and fully synthetic chemical structures with activity against nosocomial pathogens needs to be followed by preclinical studies in large animals and by pharmacokinetic and pharmacodynamic studies in specific critically ill populations to assess lung penetration.     

Ceftobiprole Medocaril: BAL5788, JNJ 30982081, JNJ30982081, RO 65-5788, RO 655788

Ceftobiprole medocaril [BAL 5788, RO 65-5788, JNJ 30982081] is a prodrug in phase III clinical development with Basilea Pharmaceutica and Cilag AG (Johnson & Johnson) for the potential treatment of serious bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA). Ceftobiprole medocaril is the water-soluble prodrug of the pyrrolidinone cephalosporin, ceftobiprole [BAL 9141, RO 63-9141]. Because of the low water solubility of ceftobiprole, its clinical application was limited and Basilea began its investigations into ceftobiprole medocaril for further development. Ceftobiprole medocaril is being developed for IV administration and is currently undergoing phase III trials for complicated skin and skin structure infections (including MRSA) and hospital-acquired (nosocomial) pneumonia. Ceftobiprole medocaril has a broad spectrum of activity against Gram-positive bacteria (including methicillin-resistant staphylococci, penicillin-resistant pneumococci and Enterococcus faecalis) and Gram-negative bacteria. Ceftobiprole medocaril inhibits all transpeptidases, including the penicillin-binding protein (PBP) 2a, by a unique combination of features. PBP 2a is the primary enzyme responsible for beta-lactam drug resistance in MRSA; PBP 2a also acts as a key defense mechanism by interacting with the bacterial cell wall to form a chemical barricade that is impervious to antibiotics. Ceftobiprole medocaril has been designed specifically to bind to this penicillin-resistant target. Ceftobiprole medocaril is bactericidal and has not shown resistance development in vitro or in stringent animal models. Studies conducted by Basilea have demonstrated that ceftobiprole medocaril is readily converted to ceftobiprole, and shows markedly improved water solubility. In February 2005, Basilea Pharmaceutica AG entered into an exclusive worldwide agreement with Cilag AG International (Johnson & Johnson) to develop, manufacture and market ceftobiprole medocaril. Ortho-McNeil Pharmaceutical (Johnson & Johnson) will market ceftobiprole medocaril in the US, and its affiliate companies, known as Janssen-Cilag, will market the product outside the US (entered as World in the Licensee table). Basilea has retained an option to co-promote ceftobiprole medocaril in the US, major European countries, Japan and China. Johnson & Johnson Pharmaceutical Research and Development LLC will develop ceftobiprole medocaril in collaboration with Basilea. Roche previously retained an opt-in right on ceftobiprole medocaril. However, following Roche's decision not to exercise this right in May 2004, Basilea gained full global commercialisation rights for ceftobiprole medocaril. Roche retains its major shareholding in Basilea. Ceftobiprole medocaril is currently in phase III trials for complicated skin and skin structure infections due to MRSA, and nosocomial pneumonia (including ventilator-associated pneumonia) due to suspected or proven MRSA, and community-acquired pneumonia. The US FDA has granted fast-track status to the compound for these two indications. Phase III results are expected in 2006 and an NDA is expected to be submitted to the FDA in 2007. An additional pivotal phase III trial (STRAUSS 2, STudy of Resistant Staphyloccocus aureus in Skin and Skin structure infections) of ceftobiprole medocaril was initiated in October 2005 for complicated skin infections, including diabetic foot infections. This trial will be conducted in conjunction with Johnson & Johnson Pharmaceutical Research and Development.     

万古霉素与利奈唑胺在中国治疗耐甲氧西林金黄色葡萄球菌感染的医院获得性肺炎的成本-效果分析

目的：评估万古霉素与利奈唑胺在确诊为耐甲氧西林金黄色葡萄球菌（MRSA）引起的医院获得性肺炎（HAP）中的成本效果。方法：建立决策树模型,其中包含来源于既往研究和专家意见的有关临床参数如疗效、死亡率、严重不良事件发生率、治疗持续时间和住院时间。以成本效果比（CER）对两种治疗方案进行评估,并对结果进行单变量和概率灵敏度分析。结果：该模型得出万古霉素的成本为12 447.90元,利奈唑胺的成本为14 162.09元。万古霉素相对于利奈唑胺的增量成本为-1 714.19元,增量疗效为-2.69%。利奈唑胺相对于万古霉素的增量成本效果比（ICER）为63 488.51元。结论：首选万古霉素治疗MRSA引起的HAP成本效果优于首选利奈唑胺,但ICER在人均GDP的1~3倍之间,增加成本可以接受,首选利奈唑胺作为备选方案。