JP2013543581A - 細菌性髄膜炎の治療方法 - Google Patents
細菌性髄膜炎の治療方法 Download PDFInfo
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Classifications
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56911—Bacteria
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56911—Bacteria
- G01N33/56944—Streptococcus
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- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4721—Cationic antimicrobial peptides, e.g. defensins
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Abstract
Description
− 個体が細菌性髄膜炎を有するか否かを決定することにおける使用のための、HBPの検出用の作用物質;
− 個体が細菌性髄膜炎を有するか否かを決定する方法における使用のための試験キットであって、個体におけるHBPの検出用の作用物質を含む上記試験キット;
− 個体の細菌性髄膜炎を治療する方法であって、
(i)本発明の方法を用いて、個体が細菌性髄膜炎を有するか否かを決定するステップと、
(ii)(i)においてリスクを有すると同定された個体に、細菌性髄膜炎の治療に好適な少なくとも一種の作用物質の治療的有効量を投与するステップと
を含む上記方法
を提供する。
診断
本発明は、対象が細菌性髄膜炎、特に、急性の細菌性髄膜炎を有するか否かを同定する方法に関する。したがって、本発明は、細菌性髄膜炎の診断に関する。本発明は、細菌性髄膜炎を類似の症状を引き起こす他の疾患、特に、ウイルス性髄膜炎又は脳炎(ウイルス性髄膜脳炎)及び神経ボレリア症から区別することに関する。
発熱/嘔吐;激しい頭痛;(幼児では一般的でない)項部硬直;羞明;音声恐怖;眠気(患者は典型的に非常に眠い/うつろである/覚醒が困難である);精神錯乱/狂乱状態;(すべてのケースで存在するわけではない)体の任意の場所における発疹;発作
のうちの1つ又は複数を呈するからである。
食べること/食べ物を与えられることに対する拒絶;(抱かれること/触られることを望まない)易刺激性;痙攣様の動きを伴う硬直した体、又はだらりとして立ち上がることができないこと;(生後6ヶ月までの対象における)泉門膨隆;甲高い鳴き声又はうめき声;脚の疼痛;手足の冷え;異常な皮膚の色
のうちの1つ又は複数を呈するからである。
− 地域社会環境、特に、多数の個体が初めて一緒に住んでいる環境に住んでいること。例えば、動員中の兵舎;大学キャンパス;
− 頭蓋骨への外傷;特に、脳基底部に影響を与えるか又は洞若しくは錯体突起まで広がる頭蓋骨骨折;
− 解剖学的異常、特に、外部環境と神経系の間の連続性を可能とする異常(典型例は、ヘテロトロピックな脳組織、髄膜腫、頭蓋底欠陥(例えば、篩骨、側頭骨錐体又は蝶形骨洞)、皮様嚢腫/類表皮嚢腫/皮膚洞管、頭蓋骨リンパ管腫状態、神経腸管嚢腫、内耳異常、又はモンディーニ奇形、又は髄膜瘤若しくは皮膚洞/皮様嚢胞などの腰仙部異常;などの頭蓋若しくは頸部の異常を含む);
− 蝸牛インプラント;又は脳のシャント若しくは関連装置(例えば、心室外ドレイン又はオマヤ槽)などの他の頭蓋又は脳神経外科インプラントの存在;
− 免疫系の障害/免疫不全、例えば、補体欠損症;
− HIV/AIDSの診断
− 最近の脳神経外科手術、例えば、脳室腹腔シャント若しくは脊髄手術、又はCSF漏出をもたらす他の形態の頭蓋若しくは顎顔面手術、又は最近の耳鼻咽喉科学的介入;
− 副鼻腔炎、中耳炎、乳様突起炎、骨髄炎、マフッチ症候群、神経線維腫症1型などの頭部及び/又は頸部における感染症の、最近の又は進行中の診断;
− エンテロウイルス、単純ヘルペスウイルス1型又は2型、バリセラ・ゾスターウイルス(水痘/帯状疱疹)、ムンプスウイルス、HIV、サイトメガロウイルス、又はLCMVなどの髄膜炎に関連するウイルスの、最近の又は進行中の診断
を含む。
本発明は、典型的に、個体から得られたサンプル中のHBPレベルをインビトロで測定することによって実施される。サンプルは、典型的に個体の体液を含む。体液サンプルは、血液、血漿、血清、尿、脳脊髄液又は関節滑液であってもよい。サンプルは好ましくは、脳脊髄液サンプルである。
本発明は、本発明の方法によって細菌性髄膜炎を有することが同定された個体の治療にも関する。したがって、細菌性髄膜炎の治療における使用のための物質は、本発明の方法によって細菌性髄膜炎を有することが同定された個体の治療における使用のための医薬品の製造において使用されてよい。したがって、本発明の方法によって細菌性髄膜炎を有することが同定された個体の状態は、かかる物質の投与によって改善されることができる。細菌性髄膜炎の治療のために有用な物質の治療的有効量が、本発明の方法によってそれを必要とすることが同定された個体に与えられてよい。細菌性髄膜炎の治療に好適な物質は、典型的に、一種又は複数種の抗生物質及び/又は一種又は複数種の静脈内輸液及び/又は一種の抗炎症剤を含む。一種又は複数種の抗生物質は、典型的に広域抗生物質である。該広域抗生物質は、典型的に、一種又は複数種のアミノグリコシド、グリコペプチド、セファロスポリン、フルオロキノロン、リンコサミド、マクロライド、ペニシリン、カルバペネム、スルホンアミド又はテトラサイクリンから選ばれる。例えば、好適な抗生物質は、ゲンタマイシン、カナマイシン、ネオマイシン、ストレプトマイシン、トブラマイシン、バンコマイシン、セファゾリン、セファレキシン、セファピリン、セフラジン、セフロキシム、セフィキシム、セフォタキシム、セフタジジム、セフチゾキシム、セフトリアキソン、シプロフロキサシン、レボフロキサシン、オフロキサシン、クリンダマイシン、アジスロマイシン、クラリスロマイシン、エリスロマイシン、アモキシシリン、アンピシリン、アンピシリン−スルバクタム、クロキサシリン、ジクロキサシリン、メズロシリン、ナフシリン、オキサシリン、ペニシリンGベンザチン、ペニシリンGカリウム、ペニシリンGプロカイン、ペニシリンVカリウム、ピペラシリン、チカルシリン、チカルシリン−クラブラン酸カリウム、イミペネム、メロペネム、ピリメタミン−スルファドキシン、スルファジジン、スルフィソキサゾール、スルフメトキサゾール、トリメトプリム−スルファメトキサゾール、クロルテトラサイクリン、ドキシサイクリン、及びテトラサイクリンを含むが、これらに限定されない。
試験対象母集団
二つの異なるコホートからの計174人の患者由来のCSFサンプルを分析した。腰椎穿刺を受けた臨床的に髄膜炎が疑われる159人の成人患者を、2006年3月及び2009年11月にClinic for Infectious Diseases,Lund University Hospital,Swedenにおける前向き研究に登録した。疑われるウイルス性CNS感染症又は神経ボレリア症によるCSF髄液細胞増加を有するが、微生物学的診断が証明されていない14人の患者は除外したため、計145人の患者を含めた。さらに、Clinic for Infectious Diseases,Sahlgrenska University Hospital,Gothenburg,Swedenにおいて1995年2004年のから間に集めた、細菌性髄膜炎を有する16人の患者及びHSV−1脳炎を有する13人の患者の別の既往コホートを含めた。これは、試験材料、特に前向きに集めた患者材料において不足したHSV−1脳炎患者の数を拡張させるため、及びより珍しい細菌性髄膜炎病原体の数を増加させるためにも行った。HBPの結果を知らない担当医師が、標準的な試験室試験及び微生物学的試験を用いて患者の精密検査及び最終診断を行った。患者を5つの群:1.急性細菌性髄膜炎、2.ウイルス性脳炎、3.ウイルス性髄膜炎、4.神経ボレリア症、5.正常なCSF WBC数を有する対照患者に分類した。
日常の患者管理の一部として、担当医師がCSFサンプルを集めた。HBP濃度は、常法を用いてELISAにより決定した。すなわち、コーティング緩衝液(0.05M NaHCO3、pH9.6)中1.1μg/mLのヒトHBPに対するマウスモノクローナル抗体(2F23A)でマイクロタイタープレート(NUNC)をコーティングした。プレートをPBST(0.05%Tweenを含むリン酸緩衝食塩水)で洗浄し、PBST中2%のウシ血清アルブミン(Sigma)でブロッキングした。次いで、サンプル緩衝液(1M NaCl)で1/40に希釈した患者のCSFサンプルを二連でウエルに添加し、37℃で60分間インキュベートした。各プレートは、既知濃度の組換えヒトHBP(0〜600ng/mL)の較正サンプルも含んだ。洗浄後、プレートを、1/7000に希釈したヒトHBPに対するポリクローナルウサギ抗血清とともにインキュベートした。結合した抗体を、ペルオキシダーゼと結合した抗ウサギIgG抗体(Bio−Rad)(1/3000)とともにインキュベートすることによって検出した。プレートを発色させ、常法を用いて405nmにおける光学密度を決定した。各患者サンプル中のHBPのレベルを、二つ組の平均光学密度を計算し、これを標準曲線からの結果に相関させることによって決定した。アッセイの日日変動は、10%未満の変動係数を有した。CSF中のWBC、グルコース、及びタンパク質の分析は、標準的手順であり、Lund及びSahlgrenska University Hopitalにおける臨床化学試験室での日常的試験として実施した。CSFサンプル中の乳酸濃度は、Cobas c501(Amazonas)において製造者の指示に従う試薬で分析した。
二つの異なる群の間の比較をノンパラメトリックなマン−ホイットニー(Mann−Whitney)U検定によって行い、二つ超の群の間の比較においては、ノンパラメトリックなクラスカル−ウォリス(Kruskal−Wallis)一元配置ANOVA分析を使用した。0.05未満の両側P値を統計学的に有意であるとみなした。患者群間の相関関係を計算するために、スピアマンのノンパラメトリックな相関係数を使用した。HBPに関する様々なカットオフレベルを図解するために、受信者操作特性(ROC)曲線及び曲線下面積(AUC)を作図した。AUC値は、95%信頼区間(95%CI)とともに報告する。計算のために、SPSS 14.0ソフトウエアシステム(SPSS)及びGraph−Pad Prism 5.0(Graph−Pad software、La Jolla、CA)を使用した。
患者特性
41人の患者が細菌性髄膜炎を有すると分類され、19人はウイルス性脳炎、10人はウイルス性髄膜炎、7人は神経ボレリア症、及び97人は正常なCSF WBC数(5×106/L未満)を有し、CNS感染症を有さない対照群とみなされた。人口学的特性(年齢及び性別)は、感染症を有する上記4つの患者群間で類似した(表1)。対照群においては、平均年齢42才(範囲18〜85才)で、男性/女性比は41/56であった。対照群における97人の患者のうち39人は、CNS感染症を伴わない発熱と頭痛を有し、後に様々な細菌性及びウイルス性感染症と診断された。細菌性髄膜炎群(n=41)においては、急性の地域感染型細菌性髄膜炎を有する37人の患者及び脳神経外科手術後の術後細菌性髄膜炎を有する4人の患者がいた。23人の患者(56%)はCSF培養で陽性、13人は16SrDNAで陽性、1人はCSF抗原試験で陽性、及び4人の患者は血液培養で陽性であった。細菌性の病因は、肺炎連鎖球菌(n=16)、髄膜炎菌(n=5)、リステリア・モノシトゲネス(Listeria monocytogenes)(n=5)、インフルエンザ菌(Haemophilus Influenzae)(n=2)、大腸菌(Esherichia coli)(n=2)、A群連鎖球菌(group A streptococci)(n=2)、G群連鎖球菌(group G streptococci)(n=2)及びそれぞれ1人の黄色ブドウ球菌(Staphylococcus aureus)、皮膚常在菌(Staphylococcus epidermis)、α連鎖球菌(α−streptococci)、大便連鎖球菌(Enterococcus faecalis)、ゲメラ属(Gemella)種、肺炎桿菌(Klebsiella pneumoniae)、及び緑膿菌(Pseudomonas aeruginosa)であった。細菌性髄膜炎群の前向き部分では、28日間死亡率は16%であった。ウイルス性CNS感染症の群においては、脳炎を有する19人の患者(HSV−1 n=15、TBE n=4)、及び髄膜炎を有する10人の患者(エンテロウイルス n=4、バリセラ−ゾスターウイルス(VZV) n=3、単純ヘルペスウイルス2型(HSV−2) n=2、及びサイトメガロウイルス(Cytomegalovirus)(CMV) n=1)がいた。HSV−1脳炎患者の中では、5人の患者が腰椎穿刺時にアシクロビルによる治療を受けず、腰椎穿刺前のアシクロビル治療の時間の中央値は、48時間(範囲0〜8日)であった。
CSF中の総WBC、ポリ及びモノ数は、両群の間でかなりの重複があったにもかかわらず、ウイルス性CNS感染症及び神経ボレリア症群に比べて細菌性髄膜炎群において有意に高かった(p<0.01)(図1B〜D)。また、ウイルス性CNS感染症群中の2人の患者が好中球優位を有した一方、細菌感染症を有する11人の患者(27%)は単核球優位であり、17人の患者(41%)は1000細胞未満の総CSF WBC数を有した(図1B)。CSFタンパク質及び乳酸レベルが、3つの他の群に比べて細菌性髄膜炎群において有意に高かったにもかかわらず(p<0.01)、CSFグルコースレベルは有意に低かった(p=0.01)(図1E〜G)。CSF特性を比較した場合、ウイルス性髄膜炎又は脳炎と神経ボレリア症の群の間には有意差はなかった(p>0.05)(図1B〜F)。
ウイルス性脳炎(中央値5.0ng/mL、範囲3.0〜41ng/mL)、ウイルス性髄膜炎(中央値4.2ng/mL、範囲3.1〜40ng/mL)、神経ボレリア症(中央値3.6ng/mL、範囲3.2〜10ng/mL)を有する患者及びCSF中の髄液細胞増加を有さない対照群の患者(中央値3.5ng/mL、範囲2.4〜8.7ng/mL)に比べて、細菌性髄膜炎患者(中央値376ng/mL、範囲12〜858ng/mL)では、HBPレベルが有意に高かった(p<0.01)(図1A)。
CNSの細菌性及びウイルス性感染症を有する患者の臨床的特徴には非常に類似しており、CSFにおける結果は決定的なものではないかも知れない。これは、CSF中の好中球由来HBPの存在を調査した最初の研究であり、私たちの知見は、HBPが細菌性及びウイルス性CNS感染症を有する患者の間の差別化における有用な診断マーカーであることを示す。伝統的に、CSF中の髄液細胞増殖は、細菌性及びウイルス性病因の鑑別における有用なツールと考えられており、低度の髄液細胞増殖又は相対的リンパ球増加は非細菌性の起源を示す。しかしながら、明白なCSF髄液細胞増殖のない細菌性髄膜炎の確認された症例が数報あったことを認識するのは重要である。Rossら(J Neurosurg 1988 Nov;69(5):669〜74ページ)は、1000×106細胞/L超のCSF髄液細胞増殖は、術後の脳神経外科手術患者におけるCSF感染症の診断マーカーとしてわずかに61%の感度と68%の特異度しか有さなかったことを報告した。さらに、細菌性髄膜炎患者の94%が好中球優位であったにもかかわらず、この基準は、わずかに28%の特異度しか有さなかった。私たちの試験においては、細菌性髄膜炎患者の61%とウイルス性CNS感染症を有するものの3%が、1000×106細胞/L超のCSF髄液細胞増殖を有した。好中球優位は、細菌性髄膜炎患者とウイルス性CNS感染症患者のそれぞれ、73%と7%で見出された。
Claims (17)
- 個体が細菌性髄膜炎を有するか否かを同定する方法であって、前記個体においてHBPを測定し、それによって前記個体が細菌性髄膜炎を有するか否かを決定することを含む上記方法。
- 前記HBPが前記個体から採取されたサンプルにおいて測定される、請求項1に記載の方法。
- 前記サンプルが体液サンプル、好ましくは脳脊髄液(CSF)サンプルである、請求項2に記載の方法。
- 前記個体が細菌性髄膜炎を有するか否かを決定することが、前記サンプル中のHBPの濃度が15ng/ml超、好ましくは25ng/ml超、より好ましくは35ng/ml超、最も好ましくは50ng/ml超であるか否かを決定することを含む、請求項2又は3に記載の方法。
- 前記サンプル中のHBPのレベル又は濃度が、HBPのベースラインレベル又は濃度を基準として、少なくとも3倍又は4倍増加している、請求項2又は3に記載の方法。
- 前記個体が髄膜炎を有することが疑われる、請求項1から5までのいずれか1項に記載の方法。
- 前記個体が、最近、脳神経外科手術を受けた、請求項6に記載の方法。
- 前記個体が、頭蓋骨外傷及び/又は頭蓋骨、頸部若しくは腰仙部領域に影響を与える解剖学的異常の病歴を有する、請求項6に記載の方法。
- 前記個体が、免疫力が低下している;蝸牛インプラントを有する患者;頭蓋若しくは脳神経外科インプラントを有する患者、又はその任意の組み合わせである、請求項6から8までのいずれか1項に記載の方法。
- 前記個体が、細菌性髄膜炎の治療をすでに受けている、請求項6から9までのいずれか1項に記載の方法。
- 前記個体が哺乳類である、請求項1から10までのいずれか1項に記載の方法。
- 前記哺乳類がヒトである、請求項11に記載の方法。
- 個体が細菌性髄膜炎を有するか否かを決定することにおける使用のための、HBPの検出用の作用物質。
- HBP特異的抗体又はそのHBP結合断片を含む、請求項13に記載の作用物質。
- 個体の細菌性髄膜炎を治療する方法であって、
(i)請求項1から14までのいずれか1項に記載の方法を用いて、個体が細菌性髄膜炎を有するか否かを決定するステップと、
(ii)(i)においてリスクを有すると同定された個体に、細菌性髄膜炎の治療に好適な作用物質の治療的有効量を投与するステップと
を含む上記方法。 - 前記細菌性髄膜炎の治療に好適な作用物質が抗生物質である、請求項15に記載の方法。
- 個体が細菌性髄膜炎を有するか否かを決定する方法における使用のための試験キットであって、個体におけるHBPの検出用の作用物質を含む上記試験キット。
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