WO2012157751A1 - 尿検体を用いた呼吸器感染症の診断 - Google Patents
尿検体を用いた呼吸器感染症の診断 Download PDFInfo
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- WO2012157751A1 WO2012157751A1 PCT/JP2012/062797 JP2012062797W WO2012157751A1 WO 2012157751 A1 WO2012157751 A1 WO 2012157751A1 JP 2012062797 W JP2012062797 W JP 2012062797W WO 2012157751 A1 WO2012157751 A1 WO 2012157751A1
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Definitions
- the present invention relates to a method for detecting a respiratory tract infection accompanied by a bacterial infection, a method for selecting a respiratory tract infection patient to be administered an antibiotic, and the end of administration of the antibiotic in a respiratory tract infection patient to whom an antibiotic is administered.
- the present invention relates to a timing determination method. It also relates to a method for treating respiratory infections associated with bacterial infections.
- Respiratory infection is a disease frequently encountered in clinical settings, and there are mainly those caused by viral infections and those accompanied by bacterial infections.
- Antibiotics are ineffective against viral respiratory infections.
- antibiotics are administered by identifying the causative bacteria and selecting antibiotics based on their drug sensitivity.
- treatment with antibiotics is usually started before the pathogen is determined.
- detection sensitivity of bacteria in blood culture and sputum tests is not necessarily high, even if it is negative, bacterial infection cannot be denied. For this reason, antibiotics will be used for patients with respiratory infections suspected of bacterial infection, and the administration of antibiotics even to patients who are not needed originally contributes to the increase in resistant bacteria. (Non-Patent Document 1).
- Procalcitonin is also used as a diagnostic marker for sepsis, and is an index for determining sepsis when the blood concentration is 0.5 ng / mL or more and severe sepsis when the blood concentration is 2.0 ng / mL or more.
- the blood procalcitonin concentration in lower respiratory tract infections and pneumonia needs to detect changes in the range of 0.1 to 0.5 ng / mL, so that there is a restriction that it is necessary to use a highly sensitive assay. is there.
- Patent Document 1 there is a report that procalcitonin is stably present in the blood and thus decreases relatively slowly even when treatment is successful (Patent Document 1). If the blood half-life is long, it will be difficult to detect changes in concentration.
- sCD14-ST soluble CD14 antigen subtype; also known as preceptin
- SIRS systemic inflammatory response
- sCD14-ST is a diagnostic marker for sepsis It is considered useful (Non-patent Document 4, Patent Document 2).
- sCD14-ST is produced in the process of phagocytic cells phagocytosing and digesting foreign microorganisms and foreign substances, and in diseases such as arthritis where local autoimmune reactions and phagocytosis associated with infection occur. It has been reported that an increase in the concentration of sCD14-ST can be detected (Patent Document 3).
- An object of the present invention is to provide a method for appropriately selecting a respiratory infection patient to be administered with an antibiotic and optimizing the administration period of the antibiotic. That is, the object is to solve the problem of proper use of antibiotics in respiratory infections. Specifically, methods of detecting respiratory infections with bacterial infections, methods of selecting respiratory infection patients to receive antibiotics, administration of antibiotics to respiratory infection patients to whom antibiotics are administered A method for determining end timing is provided. For this reason, provision of a new marker for appropriately selecting a respiratory infection associated with a bacterial infection is required. In addition, there is a need for a sharp marker that rapidly decreases in concentration as the bacterial infection in the respiratory organ is reduced or eliminated. Further provided are methods for treating respiratory infections associated with bacterial infections.
- the present inventor appropriately selects a patient with respiratory infection to which an antibiotic should be administered by using the measurement value of sCD14-ST in urine as an index, and optimizes the administration period of the antibiotic.
- the present invention has been completed. The present invention will be described in detail as follows.
- the present invention provides methods for detecting respiratory infections with the following bacterial infections: (1-1) A method for detecting a respiratory infection associated with a bacterial infection, comprising measuring sCD14-ST in a urine sample derived from a subject. (1-2) A method for detecting a respiratory infection associated with a bacterial infection, comprising the following steps: 1) a step of measuring sCD14-ST in a subject-derived urine sample, and 2) using the measured value of sCD14-ST in the sample as an index to determine whether the subject has a respiratory infection associated with a bacterial infection Process.
- a method for detecting a respiratory infection associated with a bacterial infection comprising the following steps: 1) measuring sCD14-ST in a urine sample derived from a subject, 2) a step of comparing the measured value of sCD14-ST in the sample with a normal value, and 3) a step of determining whether the measured value of the sample is higher than the normal value.
- a method for detecting a respiratory infection associated with a bacterial infection comprising the following steps: 1) A step of measuring sCD14-ST in a urine sample derived from a subject.
- the method according to any one of (1-1) to (1-9) above, wherein at least one causative microorganism test is performed in addition to the measurement of sCD14-ST in a urine sample derived from a subject The method described.
- the causal microorganism test includes smear examination by staining, influenza virus, adenovirus, legionella, chlamydia, mycoplasma, aspergillus, candida, cryptococcus, cytomegalovirus or pneumococcal antigen, and blood, The method according to (1-10) above, which is at least one selected from the group consisting of culture tests of sputum or alveolar lavage fluid.
- a respiratory infection marker with bacterial infection characterized by comprising sCD14-ST.
- an inflammation marker consisting of TNF- ⁇ , lactate dehydrogenase, sialic acid, IL-1 ⁇ , IL-6 and IL-10, activated partial thromboplastin time, platelet count, fibrinogen, DIC diagnostic criteria, protein C , D-dimer, thrombin-antithrombin III complex and prothrombin fragment F1 + 2 thrombostasis-related marker, procalcitonin (PCT), C-reactive protein (CRP), blood urea nitrogen, leukocyte count, endotoxin, adrenomedullin, pro Adrenomedullin, MR-proADM, B-type natriuretic peptide, trigger receptor expressed on myeloid cell-1 and HMGB1 infection marker, cortisol and copeptin stress marker, and KL
- a method for detecting a respiratory infection associated with a bacterial infection comprising measuring sCD14-ST and at least one biomarker other than sCD14-ST in a urine sample derived from a subject.
- the biomarker other than sCD14-ST is at least one of the markers described in (1-13) above.
- the present invention provides a method for selecting a respiratory infection patient to be administered the following antibiotics.
- (2-1) A method for selecting a respiratory infection patient to be administered an antibiotic, which comprises measuring sCD14-ST in a urine sample derived from a patient.
- (2-2) A method for selecting a respiratory infection patient to be administered an antibiotic, comprising the following steps: 1) a step of measuring sCD14-ST in a patient-derived urine sample; and 2) using the measured value of sCD14-ST in the sample as an index to determine whether the patient has a respiratory infection with bacterial infection. Process.
- a method for selecting a respiratory infection patient to be administered an antibiotic comprising the following steps: 1) measuring sCD14-ST in a urine sample derived from a patient; 2) a step of comparing the measured value of sCD14-ST in the sample with a normal value, and 3) a step of determining whether the measured value of the sample is higher than the normal value.
- (2-5) The method according to any one of (2-1) to (2-4) above, wherein the respiratory infection is a lower respiratory tract infection or pneumonia.
- the present invention provides a method for determining the end timing of administration of antibiotics in patients with respiratory infections to which the following antibiotics are administered.
- (3-1) A method for determining the end of administration of an antibiotic in a respiratory infection patient to whom an antibiotic is administered, using the measured value of sCD14-ST in a patient-derived urine sample as an index.
- (3-2) A method for determining the end timing of administration of an antibiotic in a respiratory infection patient to whom an antibiotic is administered, comprising the following steps: 1) measuring sCD14-ST in a urine sample derived from a patient; 2) a step of comparing the measured value of sCD14-ST in the sample with a predetermined reference value, and 3) a step of determining the end of administration of the antibiotic when the measured value of the sample is lower than the predetermined reference value. (3-3) The method according to (3-2) above, wherein an average value + SD of measured values of sCD14-ST in a urine sample of a healthy person is used as the predetermined reference value.
- (3-4) A method of selecting a patient who terminates administration of an antibiotic from respiratory infection patients to whom an antibiotic is administered, using the measured value of sCD14-ST in a patient-derived urine sample as an index.
- (3-5) A method for selecting a patient who finishes administration of an antibiotic from respiratory infection patients who have been administered an antibiotic, comprising the following steps: 1) measuring sCD14-ST in a urine sample derived from a patient; 2) a step of comparing the measured value of sCD14-ST in the sample with a predetermined reference value, and 3) a step of determining the end of administration of the antibiotic when the measured value of the sample is lower than the predetermined reference value.
- the present invention provides the following methods for treating respiratory infections associated with bacterial infections.
- (4-1) A method for treating a respiratory infection associated with a bacterial infection, which comprises the following steps: 1) measuring sCD14-ST in a urine sample derived from a patient; 2) a step of selecting a patient to be administered an antibiotic using the measured value of sCD14-ST in the sample as an index; and 3) a step of administering an antibiotic to the selected patient.
- the method according to (4-1) above, wherein the step of selecting a patient to be administered an antibiotic using the measured value of sCD14-ST in the sample as an index includes the following steps: : 1) a step of comparing a measured value of sCD14-ST in a sample with a normal value, and 2) a step of selecting a patient as an antibiotic administration target when the measured value of the sample is higher than the normal value.
- (4-3) The method according to (4-2) above, wherein the average value of measured values of sCD14-ST in normal human urine samples + 2SD is used as a normal value.
- (4-4) The method according to any one of (4-1) to (4-3) above, further comprising the following steps: 1) measuring sCD14-ST in a urine sample derived from a patient to whom an antibiotic is administered, over time; 2) a step of comparing the measured value of sCD14-ST in the sample with a predetermined reference value, and 3) a step of determining the end of administration of the antibiotic when the measured value of the sample is lower than the predetermined reference value.
- (4-5) The method according to (4-4) above, wherein an average value + SD of measured values of sCD14-ST in a urine sample of a healthy person is used as a predetermined reference value.
- (4-6) The method according to any one of (4-1) to (4-5) above, wherein the respiratory tract infection accompanying bacterial infection is lower respiratory tract infection or pneumonia.
- the present invention provides the following composition for treating respiratory infections accompanied by bacterial infection.
- sCD14-ST is measured in a urine sample derived from a patient suspected of respiratory infection accompanied by bacterial infection, the measured value is compared with a normal value, and the measured value of the sample is higher than the normal value
- (5-2) Respiratory tract infection with bacterial infection as described in (5-1) above, wherein the mean value of measured values of sCD14-ST in normal urine samples + 2SD is used as a normal value Therapeutic composition.
- sCD14-ST in a urine sample from a patient suspected of respiratory infection with bacterial infection is measured, and the measured value is compared with a normal value, and the measured value of the sample is higher than the normal value
- sCD14-ST in a urine sample is measured over time during the administration period, and when the measured value falls below a predetermined reference value, the administration is terminated.
- a composition for treating respiratory infection accompanying bacterial infection comprising an antibiotic as an active ingredient.
- the average value + 2SD of the measured values of sCD14-ST in the normal urine sample as a normal value, and the average value of the measured values of sCD14-ST in the normal urine sample + SD as a predetermined reference value The composition for treating respiratory tract infection accompanying bacterial infection as described in (5-3) above, wherein (5-5) Respiratory tract infection treatment with bacterial infection according to any of (5-1) to (5-4) above, wherein the respiratory tract infection with bacterial infection is lower respiratory tract infection or pneumonia Composition.
- a respiratory infection patient to whom an antibiotic is to be administered is appropriately selected, and the administration period of the antibiotic is optimized. It becomes possible.
- Antibiotics should be administered for diseases with bacterial infections.
- Urinary sCD14-ST measurement can detect respiratory infection patients with bacterial infection with excellent specificity and / or sensitivity.
- the antibiotic administration period can be shortened by determining the timing of antibiotic administration completion using the urinary sCD14-ST measurement as an index.
- FIG. 3 is a diagram showing a standard curve of the sCD14-ST measurement system created in Example 1.
- FIG. 4 is a graph showing the distribution of urinary sCD14-ST concentration in pneumonia patients measured in Example 2.
- the horizontal axis represents the number of days after the diagnosis of pneumonia to the day of sample collection, and the vertical axis represents the urinary sCD14-ST concentration.
- the solid line indicates the average value of healthy persons (3338 pg / mL), and the dotted line indicates the average value of healthy persons + 2SD (5758 pg / mL).
- FIG. 7 is a graph showing the distribution of urinary sCD14-ST concentration in pneumonia patients with bacterial infection and viral pneumonia patients measured in Example 5.
- FIG. 9 is a graph showing changes in blood sCD14-ST concentration and urine sCD14-ST amount when sCD14-ST was intravenously administered, measured in Example 6.
- the horizontal axis represents the time after administration
- the left vertical axis represents the amount of sCD14-ST in urine
- the right vertical axis represents the blood sCD14-ST concentration.
- sCD14-ST (also known as presepsin) is one of the molecular species of soluble CD14, and is characterized by migrating to a molecular weight of 13 ⁇ 2 kDa under SDS-PAGE under non-reducing conditions. It is what you hold.
- sCD14-ST has an amino acid sequence that is greatly deleted on the C-terminal side compared to full-length CD14, and both are different in three-dimensional structure, and thus show different immunogenicity.
- sCD14-ST has the property of specifically binding to an antibody prepared using a peptide consisting of 16 amino acid residues described in SEQ ID NO: 2 as an antigen. . Furthermore, sCD14-ST specifically binds to an antibody that binds to a peptide consisting of the 17th to 26th amino acids of SEQ ID NO: 3, does not bind to 3C10 antibody, and does not bind to MEM-18 antibody. In addition, any one or more of the characteristics that it has no LPS binding ability and can be obtained from human blood can be added.
- sCD14-ST is characterized in that the amino acid sequence has the amino acid sequence of SEQ ID NO: 1 at the N-terminal sequence, and more specifically, the N-terminus is at position 1 of the amino acid sequence described in SEQ ID NO: 3, It can be identified by the feature that the C-terminus is any one of positions 59 to 90 of the amino acid sequence shown in SEQ ID NO: 3.
- sCD14-ST is disclosed in detail in International Publication No. 2005/108429. In the present specification, sCD14-ST means human sCD14-ST unless otherwise specified.
- an immunoassay system that specifically detects sCD14-ST disclosed in International Publication No. 2004/044005 or International Publication No. 2005/108429 can be used.
- a sandwich immunoassay system using a combination with an antibody that competes with F1106-13-3 antibody or F1031-8-3 antibody can be used.
- the measured value of sCD14-ST in a urine sample can usually be expressed as the urine sCD14-ST concentration.
- the measured value of sCD14-ST may be corrected according to the urine concentration by creatinine correction or the like.
- the measured value of sCD14-ST may be a quantitative value, a semi-quantitative value, or a qualitative value.
- the sCD14-ST concentration can be displayed in stages such as 0, 1, 2, 3 or-, +, ++, +++.
- a value less than the reference value may be set to a level of 0 or ⁇ .
- a value less than the reference value may be set so that a value less than the reference value is negative and a value above the reference value is positive.
- Urinary sCD14-ST is blood sCD14-ST excreted in urine. Blood sCD14-ST is excreted in urine relatively quickly after production. Further, since sCD14-ST in circulating blood is concentrated and excreted in urine, urine sCD14-ST has a higher concentration than in blood. Therefore, by using the measured value of sCD14-ST in the urine sample as an index, the presence or absence of bacterial infection in the respiratory organ can be detected with high sensitivity.
- the present invention provides a method for detecting a respiratory infection associated with a bacterial infection, characterized by measuring sCD14-ST in a urine sample derived from a subject.
- Suitable examples of respiratory infections with bacterial infection are lower respiratory tract infections and pneumonia.
- Lower respiratory tract infections include acute lower respiratory tract infections and chronic lower respiratory tract infections.
- Acute lower respiratory tract infections include acute tracheitis, acute bronchitis, and acute bronchiolitis, mostly caused by viral infection of the upper respiratory tract that spreads to the lower respiratory tract, but in some cases secondary to bacteria Infection continues. Antibiotics are indicated for signs of secondary bacterial infection.
- Chronic lower respiratory tract infection is a pathological condition in which persistent infection of bacteria is established in the lower respiratory tract having an organic disorder such as bronchiectasis or chronic obstructive pulmonary disease, and persistent infection and acute ashamed exist.
- bronchiectasis chronic obstructive pulmonary disease
- chronic bronchitis diffuse panbronchiolitis
- old pulmonary tuberculosis pneumoconiosis
- nontuberculous mycobacterial disease allergy Bronchopulmonary aspergillosis, pulmonary fibrosis, chronic bronchial asthma and the like are included.
- Antibiotics are indicated for both persistent infection and acute exacerbation.
- Pneumonia includes community-acquired pneumonia and nosocomial pneumonia. Preferred is community-acquired pneumonia.
- Clinical findings include at least dyspnea or cough.
- those exhibiting at least one clinical finding selected from the group consisting of hemorrhoids, chest pain, wheezing, chest X-ray shadow, fever, and white blood cell count are preferred.
- the method for detecting a respiratory tract infection accompanying bacterial infection of the present invention includes 1) a step of measuring sCD14-ST in a urine sample derived from a subject, and 2) using the measured value of sCD14-ST in the sample as an index. It is characterized by including the process of determining whether it is a respiratory infection accompanying a bacterial infection. More specifically, the step 2) includes a step 3) a step of comparing the measured value of sCD14-ST in the sample with a normal value, and 4) a step of determining whether the measured value of the sample is higher than the normal value. It's okay.
- the subject By comparing the measured value of sCD14-ST in the sample with a predetermined reference value, it can be determined whether or not the subject has a respiratory infection associated with bacterial infection.
- a reference value used in the method for detecting a respiratory tract infection accompanying bacterial infection of the present invention it is preferable to use a normal value set based on the measured value of sCD14-ST in a urine sample of a healthy person.
- the normal value a value normalized by taking an average value or a range of the measurement results of sCD14-ST in a urine sample of a healthy person can be used.
- the background value in the measurement system is a measurement value when a buffer or an assay solution is added to the measurement system instead of a specimen.
- the values obtained by standardizing the measured values of the specimens derived from the subjects are the average value of healthy individuals +0.5 SD to +5 SD (SD is the standard deviation), and the measured values of healthy persons 5 to 95, 10 to 90, 15 to 85, or 25 to A 75th percentile value or the like can be used. Preferably, it is the average value of healthy individuals + SD, + 2SD or + 3SD.
- the sCD14-ST in a urine sample derived from a respiratory infection patient with bacterial infection measured in advance is set. You may consider a measured value. In this case, a cutoff value that optimizes the sensitivity and / or specificity of disease detection can be used as the normal value. For example, 5000 pg / mL.
- the subject Compare the measured value of the sample from the subject with the normal value, and if the measured value of the sample is higher than the normal value, the subject is likely to have respiratory infection with bacterial infection, that is, positive It can be judged. Further, it can be determined that the greater the measured value, the higher the degree of progression of the disease and / or the severity of the disease.
- SCD14-ST is hardly produced in blood in viral respiratory infections without bacterial infection, so the sCD14-ST concentration in urine does not increase. Therefore, by measuring sCD14-ST in a urine sample, it is possible to distinguish a respiratory infection associated with a bacterial infection from a viral respiratory infection.
- At least one causative microorganism test may be performed.
- the causative microorganism test it can be used by appropriately selecting from known techniques such as smear examination, antigen test, culture test and the like.
- Biomarkers other than sCD14-ST can be appropriately selected from inflammation markers, thrombostasis-related markers, infection markers, interstitial pneumonia markers, and the like. Suitable examples include, but are not limited to, procalcitonin, C-reactive protein (CRP), KL-6, and the like.
- the method for detecting a respiratory infection associated with a bacterial infection of the present invention can be paraphrased as a method for selecting a respiratory infection patient to be administered an antibiotic.
- a subject in whom a respiratory infection associated with a bacterial infection has been detected is a patient who is likely to have a respiratory infection associated with a bacterial infection and is a suitable subject for antibiotic administration.
- antibiotics should be administered when respiratory infections are associated with bacterial infections.
- the present invention provides a method for selecting a respiratory infection patient to be administered an antibiotic, characterized by measuring sCD14-ST in a patient-derived urine sample.
- the method for selecting a respiratory infection patient to which the antibiotic of the present invention is administered can be applied mutatis mutandis as it is in the method for detecting a respiratory infection associated with a bacterial infection.
- the present invention uses the measured value of sCD14-ST in a patient-derived urine sample as an index, and antibiotics are administered Provided is a method for determining the end timing of antibiotic administration in a patient with respiratory infection.
- the patient to be subjected to the method for determining the end timing of administration of the antibiotic of the present invention is not particularly limited as long as it is a respiratory infection patient to whom an antibiotic is administered. Suitable subjects are those who have been detected as respiratory infections with bacterial infections by the method described in 1), and are selected as patients with respiratory infections to which antibiotics are administered.
- the method for determining the timing of completion of administration of the antibiotic of the present invention includes 1) a step of measuring sCD14-ST in a patient-derived urine sample, and 2) using the measured value of sCD14-ST in the sample as an index.
- the method includes a step of determining an administration end timing. More specifically, the step 2) includes 3) a step of comparing the measured value of sCD14-ST in the sample with a predetermined reference value, and 4) when the measured value of the sample is lower than the predetermined reference value.
- the step of determining the end of administration of the antibiotic may be included.
- the method for determining the end timing of administration of the antibiotic of the present invention may be measured over time when measuring sCD14-ST in a patient-derived urine sample.
- antibiotics are usually administered over a period of about 5 to 14 days. To reduce the burden on patients and prevent the emergence of resistant bacteria, cure or improve the infection. It is desirable to end the administration as soon as it is confirmed.
- the urinary sCD14-ST concentration is useful as an index for determining the end of treatment because bacterial infection in the respiratory organs decreases and disappears rapidly as it decreases.
- the time of measurement may be appropriately set every 1 day or 2 days after the start of antibiotic administration, or on the 3rd, 5th, or 7th day.
- the measured value of sCD14-ST in the sample is an indicator of the presence or absence of bacterial infection in the patient, if the measured value of the sample falls below a predetermined reference value, it can be determined that the infection has been cured or improved, and an antibiotic agent
- the end of administration can be determined.
- the reference value used in the method for determining the end timing of administration of the antibiotic of the present invention may be any value that can confirm that the antibiotic has been successful. For example, a value such as 1/2, 1/5, or 1/10 of the measured value of sCD14-ST measured from before antibiotic administration to 24 hours after administration can be set as the reference value. In addition, 2.
- the normal value set based on the measured value of sCD14-ST in the urine sample of a healthy person described in the embodiment can be used as the reference value.
- the reference value For example, the average value of healthy individuals + SD, + 2SD, or + 3SD. If the measured value of sCD14-ST falls within the normal range, it can be considered that the infection has been cured or improved to a level equivalent to that of a healthy person.
- the sensitivity and / or specificity of disease detection is optimized.
- the method for determining the administration end timing of the antibiotic of the present invention can be paraphrased as a method for selecting a patient who finishes the administration of the antibiotic from the respiratory infection patients to whom the antibiotic is administered.
- the patient becomes the target of end of administration of the antibiotic, and the method of determining the timing of end of administration and the method of selecting the patient to end the administration are synonymous. That is, the present invention provides a method for selecting a patient who finishes administration of antibiotics from respiratory infection patients to whom antibiotics are administered, using the measured value of sCD14-ST in a patient-derived urine sample as an index. To do.
- the method for selecting a patient who finishes administration of the antibiotic of the present invention can be applied mutatis mutandis to the embodiment of the method for determining the timing of completion of administration of antibiotics.
- the present invention provides a method for treating a respiratory infection associated with a bacterial infection.
- the treatment method of the present invention is characterized in that a respiratory infection patient to be administered an antibiotic is selected using the measured value of sCD14-ST in a urine sample derived from a subject as an index, and an antibiotic is administered to the selected patient. It is a method of treating respiratory tract infection with bacterial infection by administering. Specifically, as described in 2. above. A patient having a respiratory infection to be administered with an antibiotic is selected by the method described in the embodiment, and the antibiotic is administered to the selected patient. In addition, the 3. More effective treatment can be performed by determining the administration end timing of the antibiotic by the method described in the embodiment.
- the present invention also provides a therapeutic agent (or a therapeutic pharmaceutical composition) for respiratory infections accompanied by bacterial infection, characterized in that an antibiotic is used in accordance with the above therapeutic method.
- the therapeutic composition contains an antibiotic as an active ingredient.
- any pharmaceutically acceptable additive / carrier may be included.
- the antibiotic used in the embodiment described in (1) is not particularly limited, but an antibiotic having at least an indication for lower respiratory tract infection and / or pneumonia is preferable.
- examples include penicillins, penems, carbapenems, cephems, monobactams, fosfomycins, glycopeptides, amino acid glycosides, macrolides, ketolides, lincomycins, tetracyclines, new quinolones, sulfonamides
- antibiotics such as oxazolidinone and streptogramin, and one or more antibiotics may be appropriately selected from these antibiotics.
- Example 1 Preparation of sCD14-ST measurement system (1-1) Preparation of peroxidase-labeled antibody
- F1106-13-3 antibody described in WO 2004/044005 is labeled with peroxidase. did.
- F1106-13-3 antibody was cleaved with lysyl endopeptidase (Wako Pure Chemical Industries, Ltd.) to prepare F (ab ′) 2. That is, F1106-13-3 antibody was dialyzed against 50 mM Tris-HCl (pH 8.5), mixed with antibody: lysyl endopeptidase (molar ratio 10: 1), and reacted at 37 ° C. for 1 hour.
- TLCK (Sigma) was added to a final concentration of 30 mM to stop the reaction.
- the reaction solution was added to a Protein A column (Prosep-A, Millipore) to recover unadsorbed.
- the collected non-adsorbed fraction was concentrated and purified by gel filtration (Superdex 75, GE Healthcare) to separate the contained F (ab ′) 2 and Fab.
- the obtained F (ab ′) 2 was concentrated and dialyzed against 10 mM carbonate buffer (pH 9.5). Next, according to the method of Nakane et al. (J. Histochem.
- Example 2 Measurement of urinary sCD14-ST Using the sandwich EIA system prepared in Example 1, 10 healthy subjects (purchased from Bioreclamation) and 6 pneumonia patients (community pneumonia) derived from bacterial infection ( A urine specimen (purchased from Bioreclamation) was diluted (200-fold dilution). As a result, as shown in Table 1, the urinary sCD14-ST concentration of healthy individuals was an average value of 3338 pg / mL and a standard deviation of 1210 pg / mL. It was 2591-7937 pg / mL in patients with pneumonia.
- urinary sCD14-ST concentration is high in patients with pneumonia with bacterial infection, and that improvement of symptoms by treatment is correlated with a decrease in urinary sCD14-ST concentration. That is, by using the urinary sCD14-ST concentration as an index (for example, the average value of healthy people + 2SD is used as a cut-off value), it is possible to detect a respiratory infection associated with a bacterial infection and select a patient to be administered an antibiotic. It has been shown.
- the urinary sCD14-ST concentration falls below a certain reference value (for example, the average value of healthy persons + 2SD, the average value of healthy persons + SD is set as a cutoff value when conditions are more severe), the end of antibiotic administration It was shown that it can be used as a judgment material.
- a certain reference value for example, the average value of healthy persons + 2SD, the average value of healthy persons + SD is set as a cutoff value when conditions are more severe
- Example 3 Selection of Respiratory Infectious Disease Patients Administering Antibiotics Using sCD14-ST as an Index Patients who present at least dyspnea or cough as clinical findings and suspected respiratory infectious diseases are treated with normal antibiotic treatment
- the control group is divided into the sCD14-ST group in which antibiotic treatment is performed using sCD14-ST as an index.
- the control group will be administered antibiotics at the discretion of the normal physician.
- the sCD14-ST group refers to the results of measuring sCD14-ST in the urine sample at the judgment of the doctor.
- Antibiotic administration is recommended if the sCD14-ST measurement is higher than normal. Antibiotic administration is not recommended if sCD14-ST measurements are within normal values.
- Both groups of patients will be evaluated for symptom improvement at 2, 4, 6 or 8 weeks after study entry. In addition, the presence or absence of antibiotics will be evaluated for 2 or 4 weeks after study participation.
- any of respiratory infections such as pneumonia, bronchitis, acute obstruction of chronic obstructive pulmonary disease, bronchial asthma, etc. Identify if it is a disease. Symptom improvement is assessed by improving clinical findings.
- self-evaluation of the patient's health condition (VAS, QOL questionnaire, etc.) and sCD14-ST measurement value may be added. As a result, there is no difference in symptom improvement between the two groups.
- antibiotic administration is significantly decreased in the sCD14-ST group.
- diseases that frequently involve bacterial infection eg, pneumonia
- diseases that rarely accompany bacterial infection eg, bronchial
- Asthma it can be confirmed that the proportion of antibiotic administration decreases.
- sCD14-ST as an index, patients with respiratory infections who should receive antibiotics are appropriately selected, and antibiotics are used (number of patients to be administered, without sacrificing safety and effectiveness of antibiotic treatment). Dose, duration of administration, or number of prescriptions).
- Example 4 Optimization of antibiotic administration period in pneumonia patients using sCD14-ST as an index
- a control group in which patients who have been diagnosed with pneumonia by clinical findings and who have received antibiotics are treated with normal antibiotics
- sCD14-ST as an index to sCD14-ST group to be treated with antibiotics.
- administration of antibiotics is terminated according to the judgment of a normal doctor.
- the sCD14-ST group refers to the results of measuring sCD14-ST in the urine sample at the judgment of the doctor. If the sCD14-ST measurement is within normal values, the end of antibiotic administration is recommended. It is desirable to measure sCD14-ST over time (eg, every day after the start of antibiotic administration).
- Patients in both groups will be evaluated for symptom improvement up to 2, 4, 6 or 8 weeks after the start of antibiotic administration. In addition, the period until the end of antibiotic administration is evaluated. As additional information, the severity of pneumonia is determined for both groups of patients. Symptom improvement is assessed by improving clinical findings. In particular, it is preferable to confirm the healing of pneumonia. As additional evaluation items, self-evaluation of the patient's health condition (VAS, QOL questionnaire, etc.) and sCD14-ST measurement value may be added. As a result, there is no difference in symptom improvement between the two groups. On the other hand, the antibiotic administration period is significantly decreased in the sCD14-ST group. By using sCD14-ST as an index, it is possible to appropriately determine the timing for terminating antibiotic administration, and to shorten the antibiotic administration period without impairing the safety and effectiveness of antibiotic treatment. Can do.
- Example 5 Measurement of urinary sCD14-ST
- the measurement conditions of the sandwich EIA system prepared in Example 1 were reviewed, and the reaction time described in Example 1 was set to the first reaction at 25 ° C for 1 hour and the second reaction 25. The temperature was changed to 2 hours.
- urine specimens (5-fold dilution) of 9 pneumonia patients with bacterial infection and 2 viral pneumonia patients purchasedd from Bioreclamation) were measured.
- the urinary sCD14-ST concentration was 419 to 3859 pg / mL (median 1885 pg / mL) in pneumonia patients with bacterial infection, and 115 to 517 pg / mL (median 316 pg / mL) in patients with viral pneumonia.
- the urinary sCD14-ST concentration in patients with viral pneumonia was below the average value for healthy subjects and was clearly lower than the urinary sCD14-ST concentration in pneumonia patients with bacterial infection that required antibiotic administration (FIG. 3). ).
- Example 6 Excretion of blood sCD14-ST into urine The rate of sCD14-ST excretion from blood into urine was confirmed.
- Recombinant sCD14-ST (rsCD14-ST described in WO 2005/108429) at a dose of 10 ⁇ g / kg was administered to a dog (male beagle dog, 7 or 8 months old, 3 animals, Kitayama Labes Co., Ltd.). It was administered intravenously, and blood and urine were collected over time up to 24 hours after administration.
- the sCD14-ST concentration in blood and the amount of sCD14-ST in urine were measured using the sandwich EIA system described in Example 1.
- the amount of sCD14-ST in urine was calculated as sCD14-ST concentration in urine (pg / mL) ⁇ urine volume (mL).
- Blood was collected before administration, 5 minutes, 10 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 4 hours, and 24 hours after administration, and centrifuged plasma was used as a measurement sample. .
- the urine was collected by catheter urination without anesthesia. Collect as much as possible of all urine collected in the bladder before administration, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 6 hours, and 24 hours after administration. did.
- 100 mL of physiological saline was loaded by oral administration after urine collection before administration.
- sCD14-ST The appearance and disappearance of sCD14-ST in the urine was very rapid, and it was considered to reflect the trend of sCD14-ST in the body produced by bacterial infection. That is, it was shown that when bacterial infection in the respiratory tract is reduced or eliminated, the urinary sCD14-ST concentration also decreases rapidly, and can be suitably used for determining the end of treatment with antibiotics.
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Abstract
Description
本発明をより詳細に説明すれば、次のとおりとなる。
(1-1)被験者由来の尿検体中のsCD14-STを測定することを特徴とする、細菌感染を伴う呼吸器感染症の検出方法。
(1-2)下記の工程を含むことを特徴とする、細菌感染を伴う呼吸器感染症の検出方法:
1)被験者由来の尿検体中のsCD14-STを測定する工程、および
2)検体中のsCD14-STの測定値を指標とし、被験者が細菌感染を伴う呼吸器感染症であるか否かを判定する工程。
(1-3)下記の工程を含むことを特徴とする、細菌感染を伴う呼吸器感染症の検出方法:
1)被験者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-ST測定値を正常値と比較する工程、および
3)検体の測定値が正常値より高値であるかを判定する工程。
(1-4)前記正常値として健常人の尿検体中のsCD14-STの測定値の平均値+2SDを用いることを特徴とする、上記(1-3)に記載の方法。
(1-5)以下の工程を含むことを特徴とする、細菌感染を伴う呼吸器感染症の検出方法:
1)被験者由来の尿検体中のsCD14-STを測定する工程。
(1-6)以下の工程をさらに含むことを特徴とする、上記(1-5)に記載の検出方法:
2)前記尿検体中のsCD14-STの測定値を正常値と比較する工程。
(1-7)以下の工程をさらに含むことを特徴とする、上記(1-6)に記載の検出方法:
3)前記測定値が正常値より高値であるか否かを判定する工程。
(1-8)前記細菌感染を伴う呼吸器感染症が、下気道感染症または肺炎である上記(1-1)~(1-7)のいずれかに記載の方法。
(1-9)ウイルス感染による呼吸器感染症との鑑別診断が可能である、上記(1-1)~(1-8)のいずれかに記載の方法。
(1-10)被験者由来の尿検体中のsCD14-STの測定に加え、少なくとも1つの原因微生物検査を行うことを特徴とする、上記(1-1)~(1-9)のいずれかに記載の方法。
(1-11)前記原因微生物検査が、染色による塗抹鏡検検査、インフルエンザウイルス、アデノウイルス、レジオネラ、クラミジア、マイコプラズマ、アスペルギルス、カンジダ、クリプトコッカス、サイトメガロウイルスまたは肺炎球菌の抗原検査、ならびに、血液、喀痰または肺胞洗浄液の培養検査からなる群から選択される少なくとも1つである、上記(1-10)に記載の方法。
(1-12)sCD14-STを含むことを特徴とする、細菌感染を伴う呼吸器感染症マーカー。
(1-13)さらに、TNF-α、乳酸デヒドロゲナーゼ、シアル酸、IL-1β、IL-6およびIL-10からなる炎症マーカー、活性化部分トロンボプラスチン時間、血小板数、フィブリノゲン、DIC診断基準、プロテインC、D-ダイマー、トロンビン・アンチトロンビンIII複合体およびプロトロンビンフラグメントF1+2からなる血栓止血関連マーカー、プロカルシトニン(PCT)、C反応性蛋白質(CRP)、血中尿素窒素、白血球数、エンドトキシン、アドレノメデュリン、プロアドレノメデュリン、MR-proADM、B型ナトリウム利尿ペプチド、ミエロイド細胞-1上に発現したトリガー受容体およびHMGB1からなる感染症マーカー、コルチゾルおよびコペプチンからなるストレスマーカーならびにKL-6、SP-A、SP-DおよびMCP-1からなる間質肺炎マーカーからなる群から選択される少なくとも1つを含む、上記(1-12)に記載のマーカー。
(1-14)被験者由来の尿検体中のsCD14-STおよび少なくとも1つのsCD14-ST以外のバイオマーカーを測定することを特徴とする、細菌感染を伴う呼吸器感染症の検出方法。
(1-15)sCD14-ST以外のバイオマーカーが上記(1-13)に記載のマーカーの少なくとも1つである、上記(1-14)に記載の方法。
(2-1)患者由来の尿検体中のsCD14-STを測定することを特徴とする、抗生剤を投与する呼吸器感染症患者を選択する方法。
(2-2)下記の工程を含むことを特徴とする、抗生剤を投与する呼吸器感染症患者を選択する方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、および
2)検体中のsCD14-STの測定値を指標とし、患者が細菌感染を伴う呼吸器感染症であるか否かを判定する工程。
(2-3)下記の工程を含むことを特徴とする、抗生剤を投与する呼吸器感染症患者を選択する方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-ST測定値を正常値と比較する工程、および
3)検体の測定値が正常値より高値であるかを判定する工程。
(2-4)前記正常値として健常人の尿検体中のsCD14-STの測定値の平均値+2SDを用いることを特徴とする、上記(2-3)に記載の方法、
(2-5)前記呼吸器感染症が、下気道感染症または肺炎である上記(2-1)~(2-4)のいずれかに記載の方法。
(3-1)患者由来の尿検体中のsCD14-STの測定値を指標とし、抗生剤が投与されている呼吸器感染症患者における抗生剤の投与終了タイミングを決定する方法。
(3-2)下記の工程を含むことを特徴とする、抗生剤が投与されている呼吸器感染症患者における抗生剤の投与終了タイミングの決定方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-ST測定値を予め定めた基準値と比較する工程、および
3)検体の測定値が予め定めた基準値を下回った場合、抗生剤の投与終了を決定する工程。
(3-3)前記予め定めた基準値として健常人の尿検体中のsCD14-STの測定値の平均値+SDを用いることを特徴とする、上記(3-2)に記載の方法。
(3-4)患者由来の尿検体中のsCD14-STの測定値を指標とし、抗生剤が投与されている呼吸器感染症患者から、抗生剤の投与を終了する患者を選択する方法。
(3-5)下記の工程を含むことを特徴とする、抗生剤が投与されている呼吸器感染症患者から、抗生剤の投与を終了する患者を選択する方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-ST測定値を予め定めた基準値と比較する工程、および
3)検体の測定値が予め定めた基準値を下回った場合、抗生剤の投与終了を決定する工程。
(3-6)前記予め定めた基準値として健常人の尿検体中のsCD14-STの測定値の平均値+SDを用いることを特徴とする、上記(3-5)に記載の方法。
(3-7)前記呼吸器感染症が、下気道感染症または肺炎である上記(3-1)~(3-6)のいずれかに記載の方法。
(4-1)下記の工程を含むことを特徴とする、細菌感染を伴う呼吸器感染症を治療する方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-STの測定値を指標とし、抗生剤を投与する患者を選択する工程、および
3)選択された患者に対し抗生剤を投与する工程。
(4-2)検体中のsCD14-STの測定値を指標とし、抗生剤を投与する患者を選択する工程が下記の工程を含むことを特徴とする、上記(4-1)に記載の方法:
1)検体中のsCD14-ST測定値を正常値と比較する工程、および
2)検体の測定値が正常値より高値である場合、抗生剤の投与対象として患者を選択する工程。
(4-3)正常値として健常人の尿検体中のsCD14-STの測定値の平均値+2SDを用いることを特徴とする、上記(4-2)に記載の方法。
(4-4)さらに下記の工程を含むことを特徴とする、上記(4-1)~(4-3)のいずれかに記載の方法:
1)抗生剤が投与されている患者由来の尿検体中のsCD14-STを経時的に測定する工程、
2)検体中のsCD14-ST測定値を予め定めた基準値と比較する工程、および
3)検体の測定値が予め定めた基準値を下回った場合、抗生剤の投与終了を決定する工程。
(4-5)予め定めた基準値として健常人の尿検体中のsCD14-STの測定値の平均値+SDを用いることを特徴とする、上記(4-4)に記載の方法。
(4-6)前記細菌感染を伴う呼吸器感染症が、下気道感染症または肺炎である上記(4-1)~(4-5)のいずれかに記載の方法。
(5-1)細菌感染を伴う呼吸器感染症が疑われる患者由来の尿検体中のsCD14-STを測定し、測定した値を正常値と比較し、かつ検体の測定値が正常値より高値である場合に前記患者に投与されるように用いられることを特徴とする、抗生剤を有効成分として含有する細菌感染を伴う呼吸器感染症治療用組成物。
(5-2)正常値として健常人の尿検体中のsCD14-STの測定値の平均値+2SDを用いることを特徴とする、上記(5-1)に記載の細菌感染を伴う呼吸器感染症治療用組成物。
(5-3)細菌感染を伴う呼吸器感染症が疑われる患者由来の尿検体中のsCD14-STを測定し、測定した値を正常値と比較し、かつ検体の測定値が正常値より高値である場合に前記患者に投与され、かつ投与期間中に尿検体中のsCD14-STを経時的に測定し、測定値が予め定めた基準値を下回った場合、投与を終了するように用いられることを特徴とする、抗生剤を有効成分として含有する細菌感染を伴う呼吸器感染症治療用組成物。
(5-4)正常値として健常人の尿検体中のsCD14-STの測定値の平均値+2SDを、予め定めた基準値として健常人の尿検体中のsCD14-STの測定値の平均値+SDを用いることを特徴とする、上記(5-3)に記載の細菌感染を伴う呼吸器感染症治療用組成物。
(5-5)細菌感染を伴う呼吸器感染症が、下気道感染症または肺炎である上記(5-1)~(5-4)のいずれかに記載の細菌感染を伴う呼吸器感染症治療用組成物。
(6)尿検体中のsCD-14濃度の測定において、細菌感染を伴う肺炎患者の平均値は、健常人の平均値を超え、ウイルス性の肺炎患者の平均値は、健常人の平均値未満である、上記(1-1)~(5-5)のいずれかに記載の方法、マーカーまたは組成物。
(7)尿検体中のsCD-14濃度の測定において、同一被検者の血液検体中のsCD-14濃度の測定および測定値との比較を行う、上記(1-1)~(6)のいずれかに記載の方法、マーカーまたは組成物。
1.sCD14-ST
sCD14-ST(別名:プレセプシン(presepsin))は可溶性CD14の分子種の一つであり、非還元条件下 SDS-PAGEにおいて分子量13±2kDaに泳動されることを特徴とし、CD14のN端部を保持しているものである。また、sCD14-STは全長CD14と比べると、C端側が大きく欠失したアミノ酸配列を有しており、両者は立体構造の点で異なるため、異なる免疫原性を示す。そのため、結合する抗体により両者を区別することが可能であり、sCD14-STは配列番号2に記載の16アミノ酸残基からなるペプチドを抗原として作製した抗体に特異的に結合する、という性質を有する。さらに、sCD14-STは、配列番号3に記載のアミノ酸配列の17番目~26番目からなるペプチドに結合する抗体に特異的に結合すること、3C10抗体に結合しないこと、MEM-18抗体に結合しないこと、LPS結合能を有さないこと、ヒト血液から得られうること、という特徴のうち任意の一つ以上を付け加えることができる。sCD14-STはアミノ酸配列としては、N末端配列に配列番号1のアミノ酸配列を有する、という特徴を有し、より詳細には、N末端が配列番号3に記載のアミノ酸配列の1位であり、C末端が配配列番号3に記載のアミノ酸配列の59~90位のいずれかである、という特徴により特定することができる。sCD14-STは詳細には国際公開第2005/108429号に開示されている。本明細書中においてsCD14-STは、特に断りのない限りヒトsCD14-STを意味する。
本発明は、被験者由来の尿検体中のsCD14-STを測定することを特徴とする、細菌感染を伴う呼吸器感染症の検出方法を提供する。
下気道感染症には急性下気道感染症と慢性下気道感染症が含まれる。急性下気道感染症には急性気管炎、急性気管支炎、急性細気管支炎が含まれ、多くは上気道へのウイルス感染が下気道に波及することにより発症するが、一部で細菌による二次感染が続発する。細菌二次感染の兆候が見られた場合は抗生剤投与の適応となる。慢性下気道感染症は、気管支拡張症や慢性閉塞性肺疾患などで器質的障害を有する下気道に細菌の持続的な感染が成立した病態であり、持続感染と急性憎悪が存在する。下気道の器質的障害を発生させる疾患には、気管支拡張症、慢性閉塞性肺疾患、慢性気管支炎、びまん性汎細気管支炎、陳旧性肺結核、じん肺、非結核性抗酸菌症、アレルギー性気管支肺アスペルギルス症、肺線維症、慢性気管支喘息などが含まれる。持続感染、急性憎悪ともに抗生剤投与の適応となる。
肺炎には市中肺炎、院内肺炎が含まれる。好ましくは市中肺炎である。
本発明は、患者由来の尿検体中のsCD14-STの測定値を指標とし、抗生剤が投与されている呼吸器感染症患者における抗生剤の投与終了タイミングを決定する方法を提供する。
本発明は、細菌感染を伴う呼吸器感染症の治療方法を提供する。本発明の治療方法は、被験者由来の尿検体中のsCD14-STの測定値を指標として、抗生剤を投与する呼吸器感染症患者を選択することを特徴とし、選択された患者に抗生剤を投与することにより細菌感染を伴う呼吸器感染症を治療する方法である。具体的には、前記2.の態様に説明されている方法により抗生剤を投与する呼吸器感染症患者を選択し、選択された患者に抗生剤を投与する。また、前記3.の態様に説明されている方法により抗生剤の投与終了タイミングを決定することで、より効率のよい治療を行うことができる。
(1-1)ペルオキシダーゼ標識抗体の調製
サンドイッチELISA系を作製するため、国際公開第2004/044005号に記載のF1106-13-3抗体をペルオキシダーゼで標識した。まずF1106-13-3抗体をリシルエンドペプチダーゼ(和光純薬)で切断し、F(ab’)2を調製した。すなわち、F1106-13-3抗体を50mM Tris-HCl(pH8.5)で透析し、抗体:リシルエンドペプチダーゼ(モル比10:1)で混合し、37℃で1時間反応した。TLCK(シグマ)が最終濃度30mMとなるように添加し、反応を停止した。次にFcを除去する為、反応液をProteinAカラム(Prosep-A、ミリポア)に添加し、未吸着を回収した。回収した未吸着画分を濃縮し、含まれているF(ab’)2とFabを分離する為、ゲル濾過(Superdex75、GEヘルスケア)により精製した。得られたF(ab’)2を濃縮後、10mM炭酸緩衝液(pH9.5)で透析した。
次に、中根らの方法(J.Histochem.Cytochem.,22,1084,1974)に従い、1mgのペルオキシダーゼ(東洋紡)を蒸留水に溶解し、蒸留水で溶解した100mMの過ヨウ素酸を添加し25℃で15分間反応した。反応終了後1.5%エチレングリコールを添加し25℃で20分間反応後1mM酢酸緩衝液(pH4.4)に対して透析した。翌日、F1106-13-3F(ab’)2抗体1mgに対して0.2M炭酸緩衝液(pH9.5)を添加して活性化した0.8mgのペルオキシダーゼを混合し25℃で2時間反応した。4mg/mLの水素化ホウ素ナトリウムを添加しさらに2時間4℃で反応した。反応液をPBS(pH7.4)に透析しペルオキシダーゼ標識抗体を得た。液量を測定し使用した抗体量より抗体濃度を算出した。
国際公開第2004/044005号に記載のS68-ペプチド ポリクローナル抗体をD-PBS(pH7.4)で5μg/mLに希釈し、イムノプレート(Maxisorp、NUNC)の各ウエルに50μL添加した。4℃で一晩反応後、イオン交換水で5回洗浄し、0.1%StabilGuard(SurModics,Inc)と0.1%Tween20を含むD-PBSを各ウエルに200μL添加しブロッキングした。次に1%CD14吸収血清、0.1%BSAを含むD-PBS(pH7.4)を希釈液として0、0.015、0.031、0.063、0.125、0.25、0.5ng/mLのsCD14―ST蛋白質標準品希釈系列を調製した。sCD14―ST蛋白質標準品は、国際公開第2005/108429号に記載のrsCD14―STを用いた。標準品希釈系列をウエル当たり50μL添加し、25℃で1時間反応(第一反応)させた。反応終了後、0.05%Tween20を含む生理食塩水で5回洗浄し、2%ラット血清、1%マウス血清、0.1%Tween20を含むPBS(pH7.4)で0.25μg/mLに希釈したペルオキシダーゼで標識したF1106-13-3F(ab’)2抗体を各ウエルに50μL添加した。25℃で1時間反応(第二反応)後、同様に5回洗浄し、テトラメチルベンジジン溶液(TMB、BioFix)50μLを各ウエルに添加し、室温で20分間反応後、0.5M硫酸溶液50μLで反応を停止した。プレート分光光度計(マルチスキャンJX、サーモエレクトロン社)で450/630nmの吸光度を測定した。図1に作成した標準曲線を示した。
実施例1で作製したサンドイッチEIA系を用いて健常人10例(Bioreclamation社より購入)及び細菌感染に由来する肺炎患者(市中肺炎)6例(Bioreclamation社より購入)の尿検体(200倍希釈)を測定した。その結果、表1に示すように健常人の尿中sCD14-ST濃度は平均値3338pg/mL、標準偏差1210pg/mLであった。肺炎患者では2591~7937pg/mLであった。参考として、肺炎患者について、尿検体と同日に採取した血液検体中のsCD14-ST濃度を測定したところ、尿中sCD14-ST濃度の高低は血中sCD14-ST濃度の高低と相関しており、また尿中濃度のほうが血中濃度に比べ約5倍の高濃度を示した。このことより、循環血中sCD14-STが比較的速やかに、濃縮されて尿中に排泄されていることが推察された。図2に示すように、肺炎患者の診断日から検体採取日までの日数を横軸にとり、縦軸にsCD14-ST濃度をプロットした場合、診断日に近い患者では高値を示し、後になるほど低値となった。なお、肺炎患者は診断後4時間以内に抗生剤投与を開始することが推奨されている。以上のことから細菌感染が存在する肺炎患者では尿中sCD14-ST濃度が高値を示すこと、治療による症状の改善と尿中sCD14-ST濃度の低下が相関することが明らかになった。すなわち、尿中sCD14-ST濃度を指標とする(例えば健常人平均値+2SDをカットオフ値とする)ことで、細菌感染を伴う呼吸器感染症を検出し、抗生剤を投与する患者を選択できることが示された。また、尿中sCD14-ST濃度がある基準値(例えば健常人平均値+2SD、より条件を厳しくする場合は健常人平均値+SDをカットオフ値とする)を下回った場合に、抗生剤投与終了の判断材料とできることが示された。
臨床所見として少なくとも呼吸困難または咳を呈し、呼吸器感染症が疑われる患者を、通常の抗生剤治療を行うコントロール群と、sCD14-STを指標として抗生剤治療を行うsCD14-ST群に振り分ける。コントロール群は通常の医師の判断により抗生剤投与を行う。sCD14-ST群は医師の判断にあたり尿検体中のsCD14-STを測定した結果を参考とする。sCD14-ST測定値が正常値より高値の場合、抗生剤投与が推奨される。sCD14-ST測定値が正常値以内である場合、抗生剤投与は推奨されない。
両群の患者について、試験参加の2、4、6または8週間後の症状改善状況を評価する。また、試験参加後2または4週間までの抗生剤の投与の有無を評価する。付加情報として、両群の患者について、X線陰影、血液検査、呼吸機能検査等から、呼吸器感染症のうち、肺炎、気管支炎、慢性閉塞性肺疾患の急性憎悪、気管支喘息等のいずれの疾患に該当するかを同定する。
症状改善は、臨床所見の改善をもって評価する。付加的な評価項目として、患者の健康状態の自己評価(VAS、QOL質問票等)、sCD14-ST測定値を加えてもよい。
結果として、両群間において症状改善状況には差を認めない。一方、抗生剤の投与はsCD14-ST群において有意に減少する。また、sCD14-ST群においては、呼吸器感染症のうち、細菌感染を伴うことが多い疾患(例:肺炎)では抗生剤投与の割合が高く、細菌感染を伴うことが少ない疾患(例:気管支喘息)では抗生剤投与の割合が少なくなることが確認できる。
sCD14-STを指標とすることで、抗生剤を投与すべき呼吸器感染症患者を適切に選択し、抗生剤治療の安全性・有効性を損なうことなく、抗生剤使用(投与対象患者数、投与量、投与期間、または処方数)を減らすことができる。
臨床所見により肺炎と診断され、抗生剤投与の対象となった患者を、通常の抗生剤治療を行うコントロール群と、sCD14-STを指標として抗生剤治療を行うsCD14-ST群に振り分ける。コントロール群は通常の医師の判断により抗生剤の投与を終了する。sCD14-ST群は医師の判断にあたり尿検体中のsCD14-STを測定した結果を参考とする。sCD14-ST測定値が正常値以内となった場合、抗生剤投与の終了が推奨される。sCD14-STは経時的(例:抗生剤の投与開始後1日毎)に測定することが望ましい。
両群の患者について、抗生剤投与開始後2、4、6または8週間目までの症状改善状況を評価する。また、抗生剤投与終了までの期間を評価する。付加情報として、両群の患者について、肺炎の重症度を判定する。
症状改善は、臨床所見の改善をもって評価する。特に、肺炎の治癒を確認することが好ましい。付加的な評価項目として、患者の健康状態の自己評価(VAS、QOL質問票等)、sCD14-ST測定値を加えてもよい。
結果として、両群間において症状改善状況には差を認めない。一方、抗生剤の投与期間はsCD14-ST群において有意に減少する。
sCD14-STを指標とすることで、抗生剤の投与を終了するタイミングを適切に決定することができ、抗生剤治療の安全性・有効性を損なうことなく、抗生剤の投与期間を短縮することができる。
実施例1で作製したサンドイッチEIA系の測定条件を再検討し、実施例1に記載の反応時間を第一反応25℃1時間、第2反応25℃2時間に変更した。本系を用いて、細菌感染を伴う肺炎患者9例およびウイルス性の肺炎患者2例(Bioreclamation社より購入)の尿検体(5倍希釈)を測定した。その結果、尿中sCD14-ST濃度は、細菌感染を伴う肺炎患者では419~3859pg/mL(中央値1885pg/mL)、ウイルス性の肺炎患者では115~517pg/mL(中央値316pg/mL)であった。ウイルス性の肺炎患者の尿中sCD14-ST濃度は、健常人平均値以下であり、抗生剤投与が必要な、細菌感染を伴う肺炎患者の尿中sCD14-ST濃度より明らかに低かった(図3)。尿検体中のsCD14-STを測定することにより、細菌感染を伴う呼吸器感染症をウイルス性の呼吸器感染症と鑑別することが可能であることが示された。
sCD14-STの血中から尿中への排泄速度を確認した。イヌ(雄性ビーグル犬、7または8カ月齢、3頭、北山ラベス株式会社)に、組換え体sCD14-ST(国際公開第2005/108429号に記載のrsCD14-ST)を10μg/kgの用量で静脈内投与し、投与後24時間までの血液および尿を経時的に採取した。血中のsCD14-ST濃度および尿中のsCD14-ST量を実施例1に記載のサンドイッチEIA系を用いて測定した。尿中のsCD14-ST量は、尿中のsCD14-ST濃度(pg/mL)×尿量(mL)として算出した。
血液は投与前、投与5分後、10分後、30分後、60分後、90分後、120分後、4時間後、および24時間後に採取し、遠心分離した血漿を測定サンプルとした。尿は、無麻酔下においてカテーテル導尿により採取した。投与前、投与15分後、30分後、60分後、90分後、120分後、150分後、6時間後、および24時間後に、膀胱内に貯留するすべての尿を可能な限り採取した。また、投与前の採尿後、経口投与にて生理食塩液100mLを負荷した。
血中sCD14-ST濃度および尿中sCD14-ST量の推移を図4に示す。sCD14-STの血中半減期は投与1時間以内では25分であり、それ以後では58分であり、2相性を示した。また、血中sCD14-ST濃度は投与120分後には投与5分後の血中濃度の約6%にまで濃度が低下し、24時間後には完全に血中から消失していた。尿中sCD14-ST量は投与30分後にピークに達し、投与150分後にはピーク時の約4%にまで低下し、24時間後には完全に尿中からも消失していた。
この結果より、血中のsCD14-STは1時間以内に尿中に排泄され始めること、尿中からも3時間以内にはほとんどが消失することが明らかとなった。尿中へのsCD14-STの出現と消失は非常に速やかであり、細菌感染により産生された体内のsCD14-STの動向を鋭敏に反映していると考えられた。すなわち、呼吸器における細菌感染が縮小・消失した場合には尿中sCD14-ST濃度も速やかに低下し、抗生剤による治療終了の判断等に好適に用い得ることが示された。
Claims (20)
- 被験者由来の尿検体中のsCD14-STを測定することを特徴とする、細菌感染を伴う呼吸器感染症の検出方法。
- 下記の工程を含むことを特徴とする、細菌感染を伴う呼吸器感染症の検出方法:
1)被験者由来の尿検体中のsCD14-STを測定する工程、および
2)検体中のsCD14-STの測定値を指標とし、被験者が細菌感染を伴う呼吸器感染症であるか否かを判定する工程。 - 下記の工程を含むことを特徴とする、細菌感染を伴う呼吸器感染症の検出方法:
1)被験者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-ST測定値を正常値と比較する工程、および
3)検体の測定値が正常値より高値であるかを判定する工程。 - 前記細菌感染を伴う呼吸器感染症が、下気道感染症または肺炎である請求項1乃至3のいずれかに記載の方法。
- 患者由来の尿検体中のsCD14-STを測定することを特徴とする、抗生剤を投与する呼吸器感染症患者を選択する方法。
- 下記の工程を含むことを特徴とする、抗生剤を投与する呼吸器感染症患者を選択する方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、および
2)検体中のsCD14-STの測定値を指標とし、患者が細菌感染を伴う呼吸器感染症であるか否かを判定する工程。 - 下記の工程を含むことを特徴とする、抗生剤を投与する呼吸器感染症患者を選択する方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-ST測定値を正常値と比較する工程、および
3)検体の測定値が正常値より高値であるかを判定する工程。 - 前記呼吸器感染症が、下気道感染症または肺炎である請求項5乃至7のいずれかに記載の方法。
- 患者由来の尿検体中のsCD14-STの測定値を指標とし、抗生剤が投与されている呼吸器感染症患者における抗生剤の投与終了タイミングを決定する方法。
- 下記の工程を含むことを特徴とする、抗生剤が投与されている呼吸器感染症患者における抗生剤の投与終了タイミングの決定方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-ST測定値を予め定めた基準値と比較する工程、および
3)検体の測定値が予め定めた基準値を下回った場合、抗生剤の投与終了を決定する工程。 - 患者由来の尿検体中のsCD14-STの測定値を指標とし、抗生剤が投与されている呼吸器感染症患者から、抗生剤の投与を終了する患者を選択する方法。
- 下記の工程を含むことを特徴とする、抗生剤が投与されている呼吸器感染症患者から、抗生剤の投与を終了する患者を選択する方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-ST測定値を予め定めた基準値と比較する工程、および
3)検体の測定値が予め定めた基準値を下回った場合、抗生剤の投与終了を決定する工程。 - 前記呼吸器感染症が、下気道感染症または肺炎である請求項9乃至12のいずれかに記載の方法。
- 下記の工程を含むことを特徴とする、細菌感染を伴う呼吸器感染症を治療する方法:
1)患者由来の尿検体中のsCD14-STを測定する工程、
2)検体中のsCD14-STの測定値を指標とし、抗生剤を投与する患者を選択する工程、および
3)選択された患者に対し抗生剤を投与する工程。 - 前記検体中のsCD14-STの測定値を指標とし、抗生剤を投与する患者を選択する工程が下記の工程を含むことを特徴とする、請求項14に記載の方法:
1)検体中のsCD14-ST測定値を正常値と比較する工程、および
2)検体の測定値が正常値より高値である場合、抗生剤の投与対象として患者を選択する工程。 - さらに下記の工程を含むことを特徴とする、請求項14または15に記載の方法:
1)抗生剤が投与されている患者由来の尿検体中のsCD14-STを経時的に測定する工程、
2)検体中のsCD14-ST測定値を予め定めた基準値と比較する工程、および
3)検体の測定値が予め定めた基準値を下回った場合、抗生剤の投与終了を決定する工程。 - 前記細菌感染を伴う呼吸器感染症が、下気道感染症または肺炎である請求項14乃至16のいずれかに記載の方法。
- 細菌感染を伴う呼吸器感染症が疑われる患者由来の尿検体中のsCD14-STを測定し、測定した値を正常値と比較し、かつ検体の測定値が正常値より高値である場合に前記患者に投与されるように用いられることを特徴とする、抗生剤を有効成分として含有する細菌感染を伴う呼吸器感染症治療用組成物。
- 細菌感染を伴う呼吸器感染症が疑われる患者由来の尿検体中のsCD14-STを測定し、測定した値を正常値と比較し、かつ検体の測定値が正常値より高値である場合に前記患者に投与され、かつ投与期間中に尿検体中のsCD14-STを経時的に測定し、測定値が予め定めた基準値を下回った場合、投与を終了するように用いられることを特徴とする、抗生剤を有効成分として含有する細菌感染を伴う呼吸器感染症治療用組成物。
- 前記細菌感染を伴う呼吸器感染症が、下気道感染症または肺炎である請求項18または19に記載の細菌感染を伴う呼吸器感染症治療用組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014102333A1 (en) * | 2012-12-28 | 2014-07-03 | Mitsubishi Chemical Medience Corporation | Use of scd14 or its fragments or derivatives for risk stratisfaction, diagnosis and prognosis |
WO2023277130A1 (ja) | 2021-06-30 | 2023-01-05 | 株式会社Lsiメディエンス | 尿細管間質障害の検出用バイオマーカー並びにその用途 |
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CN113092756A (zh) * | 2019-12-23 | 2021-07-09 | 首都医科大学附属北京世纪坛医院 | 尿液凝血酶原及其多肽片段在过敏性疾病中的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004044005A1 (ja) | 2002-11-12 | 2004-05-27 | Mochida Pharmaceutical Co., Ltd. | ヒト低分子量cd14測定キットおよび抗体 |
WO2005108429A1 (ja) | 2004-05-11 | 2005-11-17 | Mochida Pharmaceutical Co., Ltd. | 新規可溶性cd14抗原 |
WO2008104321A1 (en) | 2007-02-28 | 2008-09-04 | B.R.A.H.M.S. Aktiengesellschaft | Method for the selective determination of procalcitonin 1-116 for diagnostic purposes and antibodies and kits for carrying out such a method |
WO2009142303A1 (ja) | 2008-05-23 | 2009-11-26 | 持田製薬株式会社 | 食細胞の機能評価方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002095411A1 (en) | 2001-05-18 | 2002-11-28 | Virogates Aps | A method of diagnosing or prognosticating major respiratory bacterial pathogens in a subject |
US7608684B2 (en) * | 2002-11-12 | 2009-10-27 | Mochida Pharmaceuticals Co., Ltd. | Soluble CD14 antigen |
US7892563B2 (en) * | 2003-05-20 | 2011-02-22 | Wyeth Holdings Corporation | Methods for treatment of severe acute respiratory syndrome (SARS) |
WO2012096245A1 (ja) * | 2011-01-11 | 2012-07-19 | 三菱化学メディエンス株式会社 | 敗血症の予後の予測方法 |
RU2723554C2 (ru) | 2011-05-19 | 2020-06-16 | Мотида Фармасьютикал Ко., Лтд. | Диагностика инфекционного заболевания дыхательных путей с использованием образцов крови |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004044005A1 (ja) | 2002-11-12 | 2004-05-27 | Mochida Pharmaceutical Co., Ltd. | ヒト低分子量cd14測定キットおよび抗体 |
WO2005108429A1 (ja) | 2004-05-11 | 2005-11-17 | Mochida Pharmaceutical Co., Ltd. | 新規可溶性cd14抗原 |
WO2008104321A1 (en) | 2007-02-28 | 2008-09-04 | B.R.A.H.M.S. Aktiengesellschaft | Method for the selective determination of procalcitonin 1-116 for diagnostic purposes and antibodies and kits for carrying out such a method |
WO2009142303A1 (ja) | 2008-05-23 | 2009-11-26 | 持田製薬株式会社 | 食細胞の機能評価方法 |
Non-Patent Citations (9)
Title |
---|
"The Japanese Respiratory Society Guidelines for Management of Adult Community-Acquired Pneumonia", ASU NO RINSHO, vol. 19, no. 1, 2007, pages 41 - 61 |
"The Japanese Respiratory Society Kokyuki Kansensho ni Kansuru Guideline Sakusei Iinkai", THE JRS GUIDELINES FOR THE MANAGEMENT OF COMMUNITY-ACQUIRED PNEUMONIA IN ADULTS, vol. 19, no. 1, 25 June 2007 (2007-06-25), pages 41 - 61, XP008171390 * |
BALL ET AL., JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 49, pages 31 - 40 |
CHRIST-CRAIN ET AL., AM J RESPIRE CRITCARE MED, vol. 174, 2006, pages 84 - 93 |
CHRIST-CRAIN ET AL., THE LANCET, vol. 363, 2004, pages 600 - 607 |
NAKANE ET AL., J. HISTOCHEM. CYTOCHEM., vol. 22, 1974, pages 1084 |
See also references of EP2711710A4 |
YAEGASHI ET AL., JOURNAL OF INFECTION AND CHEMOTHERAPY, vol. 11, 2005, pages 234 - 238 |
YASUNORI YAEGASHI: "Evaluation of a newly identified soluble CD14 subtype as a marker for sepsis", JOURNAL OF INFECTION AND CHEMOTHERAPY, vol. 11, no. 5, October 2005 (2005-10-01), pages 234 - 238, XP019374906 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014102333A1 (en) * | 2012-12-28 | 2014-07-03 | Mitsubishi Chemical Medience Corporation | Use of scd14 or its fragments or derivatives for risk stratisfaction, diagnosis and prognosis |
KR20150105366A (ko) * | 2012-12-28 | 2015-09-16 | 가부시키가이샤 엘에스아이 메디엔스 | 위험의 계층화, 진단 및 예후를 위한 sCD14 또는 그의 단편 또는 유도체의 사용 |
KR102182938B1 (ko) * | 2012-12-28 | 2020-11-25 | 가부시키가이샤 엘에스아이 메디엔스 | 위험의 계층화, 진단 및 예후를 위한 sCD14 또는 그의 단편 또는 유도체의 사용 |
WO2023277130A1 (ja) | 2021-06-30 | 2023-01-05 | 株式会社Lsiメディエンス | 尿細管間質障害の検出用バイオマーカー並びにその用途 |
KR20240027717A (ko) | 2021-06-30 | 2024-03-04 | 피에이치씨 주식회사 | 요세관간질 장애의 검출용 생체표지자 및 그 용도 |
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