抗藥性結核菌的新藥 bedaquiline

FDA Approves Bedaquiline for Resistant TB Treatment

Miriam E. Tucker

Dec 31, 2012

The US Food and Drug Administration (FDA) approved bedaquiline today as part of the treatment regimen for multidrug-resistant tuberculosis (MDR-TB) when other agents are unavailable.

Bedaquiline, to be sold under the brand name Sirturo by Janssen Therapeutics, a division of Janssen Products LP, was approved under the FDA's accelerated approval program on the basis of phase 2 efficacy and safety data that used the surrogate study endpoint of sputum culture conversion rather than clinical cure. The FDA had allowed the company to move forward with the phase 2 data to support its new drug application for accelerated approval because of the unmet need. However, as a condition of submission under accelerated approval, the company is obligated to conduct a confirmatory phase 3 trial.

Bedaquiline is the first new TB drug since the introduction of rifampin in 1970.

"Multi-drug resistant tuberculosis poses a serious health threat throughout the world, and Sirturo provides much-needed treatment for patients who...don't have other therapeutic options available," Edward Cox, MD, MPH, director of the Office of Antimicrobial Products in the FDA's Center for Drug Evaluation and Research, said in an FDA news release. "However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don't have other treatment options."

Bedaquiline works via a novel mechanism of action — inhibition of a mycobacterial enzyme that is essential to the bacteria's action — and will be indicated as part of combination therapy for the treatment of pulmonary TB caused by MDR Mycobacterium tuberculosis in adults, to be administered under directly observed therapy.

The approval comes after an FDA advisory panel endorsed the efficacy of the drug at a hearing on November 28, 2012, although many panel members had expressed safety concerns. The vote was unanimous (18 to 0) in supporting bedaquiline's efficacy, but the panel had split 11 to 7 on safety in support of accelerated approval.

Janssen had presented data from 2 studies involving a total of 440 patients with MDR-TB, defined as TB that is resistant to at least rifampin and isoniazid. In a study that was placebo-controlled, bedaquiline resulted in a significant 33% faster culture conversion within 24 weeks, with approximately 79% of those taking bedaquiline converting at 24 weeks in both the placebo-controlled and an open-label trial.

Safety concerns reported by both Janssen and the FDA included signals for increased risks for QT interval prolongation, hepatotoxicity, and a greater number of deaths in the bedaquiline group compared with in the placebo group. The number of deaths was small, and at least half were deemed to be related to the TB itself, but the difference between bedaquiline and placebo (12.7% vs 2.5%) was statistically significant.

The drug will carry a boxed warning alerting patients and healthcare professionals that it can affect QT prolongation. The warning also notes deaths in patients treated with bedaquiline.

At the advisory committee hearing, Fred Gordin, MD, chief of infectious diseases at the Veterans Affairs Medical Center, Washington, DC, who voted yes on the efficacy but no on the safety of bedaquiline, had said he still supported the drug's approval "with the caveat that we need much more safety data.... There's clearly a role for this drug, but in many patients who have other options, I think it has to be very clear to providers that there are long-term safety issues."

Janssen's phase 3 trial is planned for 2013. It is designed as a double-blind study comparing 9 months of treatment with bedaquiline with treatment with placebo, both with a background regimen.

 Medscape Medical News © WebMD, LLC

2012年十大科學進展

2012年十大科學進展 上帝粒子居首 〔編譯張沛元／綜合二十日外電報導〕美國「科學」期刊二十日公佈二○一二年十大科學進展，排名第一的重大科學進展，是歐洲核子研究組織今年七月發現了有「上帝粒子」之稱的希格斯玻色子（Higgs Boson）。 科學家深信，倘若沒有希格斯玻色子，地球與宇宙中其他組合原子都不會存在。能解釋物質奧秘的次原子粒子希格斯玻色子，是分別以現年八十三歲、一九六四年就提出希格斯理論的英國科學家彼得．希格斯，以及已辭世多年的印度物理學家薩特延德拉．納特．玻色命名，比利時物理學家恩格勒特，對上帝粒子理論也有所貢獻。科學期刊說，該項發現是人類智慧的勝利。 其他獲選的二○一二年十大科學成就還包括： ◎丹尼索瓦人的ＤＮＡ 透過在西伯利亞一處洞穴發現、有八萬年歷史的一小片手指骨所取得的樣本，德國科學家利用新技術，竟然能排列出丹尼索瓦人（Denisovan）的完整基因組，象徵ＤＮＡ定序領域的重大進步。目前只知道丹尼索瓦人與現代人表親尼安德塔人屬於同一時期。 ◎幹細胞造卵 日本科學家以取自成年雌鼠皮膚的iPS細胞（誘導性多功能幹細胞）成功造卵，並利用體外受精讓實驗鼠生出仔鼠，為全球成功實驗首例，或許有助於治療不孕症。 ◎好奇號降落火星 透過創新的懸吊降落系統，美國航太總署（ＮＡＳＡ）的工程師成功讓三．三噸重、暱稱「好奇號」（Curiosity）的「火星科學實驗室」探測車降落火星。科學期刊指出，此一毫無瑕疵的降落令太空擘畫者深信，ＮＡＳＡ終有一日能在好奇號附近進行第二次的火星降落任務，取得好奇號蒐集到的火星樣本並帶回地球。 ◎Ｘ光雷射 科學家利用一種亮度是傳統同步加速器光源十億倍的Ｘ光雷射，確認一種跟非洲嗜睡症傳染有關的蛋白質結構，此一進展顯示Ｘ光雷射在破解蛋白質結構上的潛力。 ◎基因組工程 一種讓研究人員能修改實驗動物的基因或使之失去活性的新工具。此一科技比現行鎖定基因的技術來得有效率與廉價，也能讓研究人員找出在健康者與病患身上，特定基因與突變所扮演的角色。 ◎馬約拉納費米子 科學家證實新微型粒子「馬約拉納費米子」（Majorana fermion）存在，此粒子能做為本身的反物質與自我毀滅。科學家深信，組成馬約拉納費米子的量子位元（qubit）在儲存與處理資料上，會比現行電腦使用的位元更有效率。 ◎ENCODE計畫 找出人類基因組內所有功能要素的「基因解碼後續計畫」（Encyclopedia of DNA Elements, ENCODE）顯示，基因組內高達八十％的ＤＮＡ活躍運作，且靠著數百萬個扮演開關角色的基因調控蛋白質環環相扣，影響罹病機率，大大顛覆了過去認為基因組內大部分是不活躍的「垃圾ＤＮＡ」觀念。 ◎腦機介面 美國研究人員研發出透過意志控制的新型機器手，讓癱瘓者能靠意志移動手臂與進行三度空間移動。此一實驗性科技未來或許有助於因中風與脊髓受傷而癱瘓的病患。 ◎微中子振盪 台大與全球卅七所大學共同在中國參與的「大亞灣實驗」，發現到第三種新的「微中子振盪模式」。微中子是不帶電的粒子，目前已知有三種類型，微中子在傳播過程中可不斷地由一類轉化成另外兩類，稱為微中子振盪現象。該發現暗示微中子物理或許有朝一日能協助研究人員解釋宇宙為何有這麼多物質與這麼少的反物質。

人工關節感染時的處理指引 (IDSA發佈的首次對這問題的指引)

First Guidelines for Managing Prosthetic Joint Infections

Norra MacReady

Dec 10, 2012

The Infectious Diseases Society of America has published a set of clinical practice guidelines for the evaluation and management of prosthetic joint infections (PJIs).

The guidelines, the first on the subject issued by the society, call for close collaboration among all clinicians involved in a patient's care.

"It is anticipated that consideration of these guidelines may help reduce morbidity, mortality, and the costs associated with PJI," lead author Douglas R. Osmon, MD, and colleagues write in the guidelines, published online December 6 in Clinical Infectious Diseases. Dr. Osmon is an infectious diseases expert at the Mayo Clinic Medical School in Rochester, Minnesota.

Although total hip arthroplasty (THA) and total knee arthroplasty (TKA) can significantly improve quality of life, PJI is "one of the most serious complications of prosthetic joint implantation," the authors explain. Patients may require repeat surgery, prolonged courses of antibiotics, and in the most serious cases, amputation.

The cumulative incidence of PJIs is 1% to 2% during the life of the joint. In other words, of the 1 million THAs and TKAs performed each year, about 20,000 patients will develop PJIs. By 2030, it is projected that 4 million THAs and TKAs will be performed annually in the United States, with the incidence of PJIs rising accordingly.

Despite the growing popularity of these procedures, many unanswered questions persist regarding the diagnosis and optimal management of PJIs, the authors state.

Where enough evidence was available, the new guidelines are offered in the form of consensus statements. Where the evidence was thinner, the panel provides expert opinions, "realizing that the amount of data to support a specific recommendation is limited, and that there are diverse practice patterns which seem to be equally effective for a given clinical problem."

The panel emphasizes that effective intervention requires a strong collaborative approach among the various clinicians involved in a patient's care, including plastic and orthopaedic surgeons, infectious disease specialists, and internists.

The panel developed the guidelines by conducting an extensive review and analysis of literature in the field published between 1966 and 2011. The strength of the recommendations and the quality of the evidence were assigned letter and numeric grades, respectively, according to the volume and quality of the studies and reviews available. The major issues the panel considered were preoperative evaluation and diagnosis; surgical strategies; medical treatment after debridement, resection arthroplasty, and reimplantation; and medical treatment after amputation.

For each question, the panel provides its recommendations followed by a summary of the evidence used to develop those recommendations.

These guidelines are a good complement to the ones released by the American Academy of Orthopaedic Surgeons in 2010-2011, according to Andrew Urquhart, MD, associate professor of orthopaedic surgery at the University of Michigan Medical School in Ann Arbor. "They are designed for a wider audience that includes primary care and infectious disease physicians and address the issue of when the clinician should consider the possibility of a prosthetic joint infection in a patient."

PJIs are "a huge problem and a huge cost to society," Dr. Urquhart told Medscape Medical News. "As we are seeing more and more hip and knee replacements performed, and the association of prosthetic joint infections with obesity and tobacco use, I think everybody, whether they are a primary care physician or an infectious disease specialist or a community or academic orthopaedic physician, should have a high index of suspicion for these infections, and as long as everyone is on the same page, patients will get the highest level of care."

Guidelines are important because they "minimize the variability in practice that in the past confounded accurate comparison and interpretation of clinical research outcomes on the subject. They basically allow all interested parties to speak the same language," Erik N. Hansen, MD, assistant professor of orthopaedic surgery in the Division of Adult Reconstructive Surgery, University of California, San Francisco, School of Medicine, told Medscape Medical News via email. "Standardizing management practices provides clinicians with an accurate baseline by which we can judge and measure our treatment effects and make informed decisions when and how to alter our practices. Without standardization, it is very difficult to determine what factors contributed to the success or failure of a given patient's course, and therefore it is hard to move the field forward."

Unanswered questions include risk factors for developing PJIs, epidemiologic information best suited for improving the diagnosis and management of PJIs even further, the best laboratory tests and biomarkers for diagnosing the infections, medical and surgical algorithms for optimal management, and preventive methods such as the use of prophylactic antibiotics in dental procedures and higher oxygen therapy administered during surgery, the authors write. The authors plan to review the guidelines annually, with revisions recommended when deemed appropriate.

Dr. Osmon has received research grants from Cubist Pharmaceuticals and Ortho-McNeil. Other authors of the guidelines also report receiving funding from Cubist Pharmaceuticals and Ortho-McNeil, as well as Orthopedic Research. One author receives royalties from the Stryker Corporation and has been a board member of Pfizer as well as served on the speakers' bureaus of Pfizer and Synthes. One author is a member of the board of Basilea. One author was awarded a Pfizer Visiting Professorship to the Division of Allergy and Infectious Diseases at the University of Washington, Seattle. Dr. Urquhart and Dr. Hansen have disclosed no relevant financial relationships.

Clin Infect Dis. Published online December 6, 2012. Full text

Medscape Medical News © 2012 WebMD, LLC

 

2012 Ben et al in Plano