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　第四节第四节临床文献评价临床文献评价真实性真实性重要性重要性实用性实用性第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY临床科研设计书的主要内容临床科研设计书的主要内容1.研究题目：主要研究问题和次要研究问题，说明课题的科研究题目：主要研究问题和次要研究问题，说明课题的科学性与可行性学性与可行性2.样本含量估计：计算方法和本研究采用样本量的依据样本含量估计：计算方法和本研究采用样本量的依据3.研究对象的诊断、纳入、排除标准研究对象的诊断、纳入、排除标准4.设计方案、随机方法和研究地点设计方案、随机方法和研究地点5.效应指标和测量方法效应指标和测量方法6.控制偏倚的措施控制偏倚的措施7.统计分析统计分析8.医德问题医德问题第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY一、真实性评价一、真实性评价1.1.研究证据是否来源于真正的随机对照试验？研究证据是否来源于真正的随机对照试验？2.2.研究对象是否明确限定？研究对象是否明确限定？3.3.防治措施的具体内容是否明确？防治措施的具体内容是否明确？4.4.是否观察、报告了全部临床结果？是否观察、报告了全部临床结果？5.5.报道的结果是否包括了全部纳入的病例？报道的结果是否包括了全部纳入的病例？6.6.统计方法的使用是否合适？是否注意了统计统计方法的使用是否合适？是否注意了统计学意义与临床意义？学意义与临床意义？第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（一）研究证据是否来源于真正的随机对照试验？（一）研究证据是否来源于真正的随机对照试验？随机分组的方法是否交代、是否恰当、是否采用随机分组的方法是否交代、是否恰当、是否采用了隐匿？了隐匿？试验组和对照组例数是否相等或接近？试验组和对照组例数是否相等或接近？两组的基线资料和其它非试验因素是否可比？两组的基线资料和其它非试验因素是否可比？分层随机的分层因素是否合适？分层各组的样本分层随机的分层因素是否合适？分层各组的样本量要仔细计算。

量要仔细计算第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（二）研究对象是否明确限定？（二）研究对象是否明确限定？诊断标准诊断标准纳入标准纳入标准排除标准排除标准第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（三）防治措施的具体内容是否明确？（三）防治措施的具体内容是否明确？ 1.药物：剂量、剂型、给药方法与途径、疗程、药物：剂量、剂型、给药方法与途径、疗程、相应的配套治疗相应的配套治疗 2.保证防治措施的正确实施保证防治措施的正确实施 3.沾染和干扰的预防沾染和干扰的预防 4.依从性的检查依从性的检查第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（四）是否观察、报告了全部临床结果？（四）是否观察、报告了全部临床结果？效益和危害效益和危害---治疗作用与毒副反应治疗作用与毒副反应效应指标及其观察时间、空间和测量方式是否合适效应指标及其观察时间、空间和测量方式是否合适是否合适的采用盲法是否合适的采用盲法第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（五）报道的结果是否包括了全部纳入的病例？（五）报道的结果是否包括了全部纳入的病例？确保失访（确保失访（lost follow)lost follow)率率 10%10%。

如失访率如失访率  20%20%，没有多大的临床价值没有多大的临床价值失访率在失访率在10%--20%10%--20%之间：采用意愿治疗之间：采用意愿治疗分析分析( (intention-to-treat analysis)intention-to-treat analysis) 试验组失访人数按无效计算试验组失访人数按无效计算对照组失访人数按有效计算对照组失访人数按有效计算第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（六）统计方法的使用是否合适？是否注意了统（六）统计方法的使用是否合适？是否注意了统计学意义与临床意义？计学意义与临床意义？统计学意义只表明试验组与对照组之间的差统计学意义只表明试验组与对照组之间的差异来自防治措施的本身，只能评价这种差异的真异来自防治措施的本身，只能评价这种差异的真实程度，但并不表明疗效差异大小的临床意义实程度，但并不表明疗效差异大小的临床意义。

CER ARR NNT的应用第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY二、重要性评价二、重要性评价真正的阴性结果真正的阴性结果真正的尚有争议的结果真正的尚有争议的结果真实有效的结果真实有效的结果第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（一）效果究竟有多大？（一）效果究竟有多大？明确试验组与对照组事件发生率（如治愈率、死亡明确试验组与对照组事件发生率（如治愈率、死亡率、不良反应等）各有多大，以及组间的差值，对率、不良反应等）各有多大，以及组间的差值，对这些差值的临床意义做出评价这些差值的临床意义做出评价第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（二）试验效果的准确度如何？（二）试验效果的准确度如何？常用常用95%的可信区间表示（的可信区间表示（95%CI confidence interval)可信区间越小，可信度越可信区间越小，可信度越靠近真值，反之可信度就要差一些。

靠近真值，反之可信度就要差一些第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY三、实用性评价三、实用性评价患者的情况是否与我们的相一致？患者的情况是否与我们的相一致？可行性如何？可行性如何？干预措施的干预措施的“利利”与与“弊弊” 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（一）试验的证据是否与我们经治的患者情况一致（一）试验的证据是否与我们经治的患者情况一致？？根据患者的病情、病理损害程度、社会人口特点根据患者的病情、病理损害程度、社会人口特点（人种、性别、年龄等）、亚组的分析特点（人种、性别、年龄等）、亚组的分析特点“对号对号入座入座”（二）试验结果的可行性如何？（二）试验结果的可行性如何？技术的可行性技术的可行性病人接受的可行性病人接受的可行性经济的可行性经济的可行性第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY（三）试验结果的（三）试验结果的“利利”与与“弊弊”对试验结果施加给病人后可能获得多大程度对试验结果施加给病人后可能获得多大程度的效果和引起不良反应的风险度要权衡比较，的效果和引起不良反应的风险度要权衡比较，只有在确定只有在确定“利利”肯定大于肯定大于“弊弊”时才能接时才能接受、实践这种试验结果。

受、实践这种试验结果Likelihood of being helped versus harmed LHH第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY　 A Multicenter Study of Grepafloxacin (格雷沙格雷沙星）星）and Clarithromycin in the Treatment of Patients With Community-Acquired Pneumonia* S. Moola, MBChB; Lars Hagberg, MD, PhD; Gavin A. Churchyard, MBBCh; Joe S. Dylewski, MDCM; Sangeeta Sedani, BSc and Heather Staley, BSc Chest. 1999;116:974-983. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYStudy objectives: To compare the efficacies of 10-day regimens of grepafloxacin (GFX) (Raxar or Vaxar; Glaxo Wellcome; Greenford, UK), 600 qd, and clarithromycin (CLA) (Klacid, Biaxin, or Klaracid; Abbott Laboratories; Chicago, IL), 500 mg bid, in patients with community-acquired pneumonia (CAP), on the basis of clinical response, including radiographic evidence, and bacteriologic efficacy. Patient Population and Study DesignThis was a phase IIIb, double-blind, randomized, prospective, parallel-group, comparative study (protocol GFXB3003) conducted at 58 centers in 11 countries (Australia, Canada, Czech Republic, Germany, Italy, Israel, New Zealand, Poland, South Africa, Spain, and Sweden). Regulatory approval was obtained where appropriate, and the study was approved by local ethics committees. Written, informed consent was obtained for each participant in accordance with national guidelines and the Declaration of Helsinki (Hong Kong amendment, 1989). 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPatients with chest radiographs taken within 2 days of the start of study medication confirming pulmonary infiltration or consolidation （实变）（实变）likely to be caused by pneumonia, and patients presenting with one or more of the clinical signs and symptoms consistent with CAP—pleuritic chest pain, cough, fever ( 38°C), and auscultatory findings such as rales and/or evidence of consolidation—were included in the study. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYSputum production was not a requirement for study entry; however, when patients were producing sputum, a sample was collected for culture. Patients could be treated in the community or could be admitted to the hospital, depending on the standard medical practice in different countries. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPatients were excluded if they had nosocomial （院内）（院内）pneumonia; required immediate IV antibiotic therapy; had received antibiotic therapy within 3 days before study entry; or had bronchial carcinoma, empyema（脓胸）（脓胸）, lung abscess, uncontrolled asthma, pulmonary tuberculosis, or cystic fibrosis.第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYAs well as other standard exclusion criteria for clinical trials, patients with an immunocompromised status, malabsorption （吸收障碍）（吸收障碍）syndromes, hepatic or renal impairment, and history of seizure（癫痫）（癫痫） disorders were excluded, as were those with known sensitivity to any quinolone or macrolide antibiotic. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPatients were randomized to receive either oral GFX, 600 mg qd for 10 days (251 patients) or oral CLA, 500 mg bid for 10 days (253 patients). In addition to the active medication, patients received concurrent placebo for study-blinding purposes. Administration of additional antimicrobials was not permitted for the duration of the study, and a record was kept of any medication taken concomitantly. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYAssessmentsAfter entry into the study and pretreatment assessment, patients were reassessed during treatment (4 to 6 days after treatment initiation), after treatment (1 to 3 days after completion), and at follow-up (28 to 35 days after treatment completion). At each assessment, patients were evaluated for resolution of signs and symptoms of pneumonia. Before treatment and at follow-up (or withdrawal), chest radiography and physical examinations were performed. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYAt each assessment, sputum samples were collected (if available) for Gram's stain, culture, and susceptibility testing (only samples meeting the recognized criteria of 25 neutrophils and 10 epithelial cells per low-power field were cultured). Blood was collected for culture at the pretreatment assessment, and if the results were positive or if the subject remained febrile, blood was collected for culture at the posttreatment and follow-up assessments. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPrimary identification of isolated pathogens was performed using routine laboratory culture methods. Bacterial isolates were tested by disk diffusion for susceptibility to GFX and CLA; in addition, the minimal inhibitory concentration was determined. Production of ß-lactamase was determined by the nitrocefin method where appropriate. For S pneumoniae isolates, susceptibility testing to penicillin was performed. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYIn addition, serology was performed by a central laboratory on pretreatment and follow-up blood or urine samples for detection of the atypical respiratory pathogens Mycoplasma pneumoniae, Chlamydia pneumoniae（衣原体）（衣原体）, and L pneumophila. The presence of Chlamydia and Mycoplasma spp was established using indirect fluorescent antibody assay kits for both IgG and IgM (MRL Diagnostics; Cypress, CA and Zeus Scientific; Raritan, NJ). Tests were interpreted from comparisons of pretreatment and follow-up samples according to the instructions of the manufacturer.第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYAt least a fourfold rise in reciprocal (互补）互补）value titer for IgG or IgM from pretreatment to follow-up was required to indicate a positive test result. For M pneumoniae, an IgG titer of 1:128 was required unless a fourfold increase in IgM was also present, when a titer of 1:64 was acceptable. Legionella spp were detected using radioimmune assays (Bimax; Portland, ME) of urine samples. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYC-reactive protein (CRP) determinations were made on blood samples taken before and after treatment to evaluate this test as an additional surrogate（替代）（替代） marker to indicate the presence of bacterial infection. The number of patients with a CRP value > 50 mg/L at the pretreatment and posttreatment assessments was determined and was also analyzed in conjunction with clinical outcome. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYDetails of adverse events and any other problems elicited by nonspecific questioning were recorded at each visit. Efficacy MeasuresThe primary measure of efficacy was the clinical and radiographic response at follow-up; this was assessed for all patients and for patients with documented infection with either typical or atypical pathogens. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYTable 1. Definitions of Clinical Responses Clinical ResponsesDefinitionsCure Improvement or resolution of clinical signs and symptoms after treatment and absence, including radiographic evidence, at follow-upImprovement Improvement but incomplete resolution of clinical signs and symptoms, including radiographic evidence, at followFailure No improvement during or after treatment or discontinuation of therapy because of a drug-related adverse eventRecurrence Resolution or improvement after treatment with recurrence of clinical symptoms, including radiographic evidence, at follow-upUnable to be Significant deviations from protocol evaluatedTo grade the clinical outcome, the radiographic response was classified at follow-up as resolved (areas of infiltration or consolidation completely clear), improved (areas of infiltration or consolidation still exist but show evidence of clearing), or unchanged or worse (areas of infiltration or consolidation unchanged or show evidence of spread or increased density). 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYTable 2. Definitions of Bacteriologic Responses Bacteriologic Responses DefinitionsCure Initial pathogen eradicatedPresumed cure Clinical cure or improvement in the absence of sputum or blood cultureCure with superinfection Eradication of initial pathogen with isolation of new organism(s) associated with clinical symptoms of infectionCure with colonization Eradication of initial pathogen with isolation of new nonpathogenic organism(s) not associated with clinical symptoms of infectionRecurrence Initial bacteriologic cure with reisolation of original pathogen at follow-upFailure Initial pathogen not eradicated during treatmentPresumed failure Clinical failure in the absence of sputum or blood cultureFailure with superinfection Initial pathogen not eradicated plus isolation of new pathogen(s)Failure with resistance Initial pathogen(s) developing resistance during therapyUnable to be evaluated Inability to identify or culture pretreatment pathogens, and any other deviation from protocolStatistical AnalysisA satisfactory response rate (clinical cure or improvement) of 80 to 89% at follow-up with a broad-spectrum antibiotic was assumed. Assuming an inability to evaluate rate of 25%, at least 450 patients were required to establish equivalence in both the intent-to-treat (ITT, patients who were randomly assigned and received at least one dose of the study medication) and clinically evaluated populations (eg, patients who were able to be clinically evaluated (CE) in accordance with the study protocol criteria), 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYusing a 95% confidence interval (CI) calculated for a two-tailed test of significance at the 15% level with 90% power.9 Equivalence was demonstrated if the lower limit of the 95% CI of the difference in response rate among patients receiving GFX minus the response rate to CLA was > -15%. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPrimary efficacy data were analyzed for the ITT and CE populations. Analyses were also performed on the microbiologic intent-to-treat (MITT; patients in the ITT population who had a pathogen isolated on study entry) and the microbiologically and clinically evaluated (MCE; patients in the MITT population who were able to be clinically evaluated) study populations. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYResults:1. Patient Demographics and Disposition2. Primary Assessment of Clinical Response at the Follow-Up Visit3. Posttreatment Assessment of Clinical Response4. Assessment of Clinical Response in Patients With Confirmed Infection5. Bacteriologic Response6. Pathogens Isolated and Antibiotic Susceptibility7. Safety第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYResults Patient Demographics and DispositionPatients were recruited at 58 centers in 11 countries; 43% of the patients were treated in the community setting (general practice or outpatient clinic), and 57% of patients were hospitalized in accordance with the standard medical management of such patients in different countries. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPatient demographics were similar with respect to age, sex, and ethnic origin between the two study groups (Table 3 ). The majority of patients, 73%, were > 35 years old, with 23% being > 65 years old. Sixty-two percent of patients had a preexisting medical condition on entry into the study, with cardiovascular (23%) and respiratory (17%) conditions being the most common. The most commonly reported pretreatment symptoms were cough and adventitial sounds, recorded for 95% and 85% of the patients, respectively. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYTable 3. Summary of Demographic and Baseline Characteristics*Patient Characteristics GFX, n = 251 CLA, n = 253 Total, n = 504SexFemale 106 (42.2) 98 (38.7) 204 (40.5)Male 145 (57.8) 155 (61.3) 300 (59.5)Ethnic origin Asian 4 (1.6) 7 (2.8) 11 (2.2)Black 40 (15.9) 41 (16.2) 81 (16.1)White 198 (78.9) 202 (79.8) 400 (79.4)Other 9 (3.6) 2 (1.2) 12 (2.4)Height, cm 169.8 ± 9.4 170.3 ± 9.6 170.1 ± 9.5 A total of 504 patients were recruited to the study (ITT population), of whom 251 patients were randomized to receive GFX and 253 to receive CLA. There were 106 withdrawals (21%) from the study (51 GFX, 55 CLA; p = 0.78) because of lack of efficacy (4%), adverse events (7%), failure to return for assessment (4%), or other reasons (6%; Fig 1 ). Compliance was good, with > 99% of urine test results being positive for the presence of antibiotic and 84% of patients taking their medication in accordance with the protocol. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY HOMEInstitutInstitution: ion: Beijing Beijing Book Book CompanyCompany || Sign In as Member/Non-Member(Individual) HELPFEEDBACKSUBSCRIPTIONSARCHIVESEARCHTABLE OF CONTENTS[HELP with high resolution image viewing][HELP with high resolution image viewing] [Return to Article] Figure 1. Patient flow through trial. *Two patients in the GFX group and four in the CLA group had both typical and atypical pathogens present before treatment. [Return to Article] HOMEHELPFEEDBACKSUBSCRIPTIONSARCHIVESEARCHTABLE OF CONTENTS Radiographic findings and the nature and severity of signs and symptoms were comparable in the two treatment groups. At the pretreatment assessment, 78%, 43%, 48%, and 48% of patients reported moderate or severe cough, dyspnea, pleuritic chest pain, and chills, respectively, compared with 3%, 3%, 1%, and 1% of patients at follow-up. No differences were demonstrated between the two treatment groups. Likewise, adventitial sounds, dullness to percussion, friction rub, arthralgia, and myalgia were markedly reduced at follow-up. Sputum was purulent or mucopurulent in 43% of patients at pretreatment and in only 3% of patients at follow-up第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPretreatment CRP measurements were obtained for 462 patients. A wide range of values was obtained, from 1 to 577 mg/L, with a median of 109 mg/L and SD of 141 mg/L. However, of the 462 patients, 68% had a value > 50 mg/L, suggesting the presence of active infection; values were comparable for the two treatment groups. For the 126 patients in whom a pretreatment pathogen was confirmed and CRP measured, 76% of patients had a value > 50 mg/L. The proportion of patients with a pretreatment value > 50 mg/L was similar for patients with typical and atypical pathogens, although the median value was higher for the former, 171 mg/L compared with 97 mg/L. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPrimary Assessment of Clinical Response at the Follow-Up VisitAssessment of the primary efficacy end point of the study was made using the CE population at follow-up. Clinical signs and symptoms and radiographic evidence were used to assess outcome. Of the 504 patients in the ITT population, 174 (35%) were unable to be clinically evaluated because of a lack of planned posttreatment or follow-up assessments, consumption of prohibited medication, adverse effects unrelated to the study drug, or other significant protocol violations (Fig 1) . Thus, 330 patients composed the CE population (163 GFX, 167 CLA). 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYAt the follow-up visit, 147 of 163 CE patients (90%) receiving GFX and 148 of 167 CE patients (89%) receiving CLA had a satisfactory clinical response (p = 0.78; 95% CI, -6 to 9%; Fig 2 ). Hence, formal equivalence was demonstrated between 10-day treatment regimens of GFX, 600 mg qd, and CLA, 500 mg bid, in the treatment of patients with radiographically confirmed CAP. Similarly, equivalence between the two treatment groups was demonstrated in the ITT population, in which 75% and 76% showed a satisfactory response rate for GFX and CLA, respectively (p = 0.88; 95% CI, -9 to 7%; Fig 2 )第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY HOMEInstitutInstitution: ion: Beijing Beijing Book Book CompanyCompany || Sign In as Member/Non-Member(Individual) HELPFEEDBACKSUBSCRIPTIONSARCHIVESEARCHTABLE OF CONTENTS[HELP with high resolution image viewing][HELP with high resolution image viewing] [Return to Article] Figure 2. Response by pathogen type after treatment and at follow-up (MCE population). Responses (bacteriologic) for typical pathogens are based on an assessment of presumed cure or failure, taking into account clinical signs and symptoms because of very few valid posttreatment samples suitable for bacteriology. Responses (clinical) for atypical pathogens detected by serologic methods are from clinical and radiographic data. [Return to Article] HOMEHELPFEEDBACKSUBSCRIPTIONSARCHIVESEARCHTABLE OF CONTENTS Clinical equivalence between the GFX and CLA treatment groups was demonstrated in all four study populations. However, some differences in the rates of satisfactory clinical and radiographic response were observed in certain subpopulations of patients able to be evaluated, although these were not statistically significant第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYRates of satisfactory clinical response were slightly better for both GFX and CLA in younger patients, with this age-related difference more apparent in the CLA treatment group. Response rates for patients < 65 years were 93% and 92% for GFX and CLA, respectively; corresponding response rates for patients 65 years were 81% and 74%. In addition, women treated with GFX had a higher rate of satisfactory clinical response than those treated with CLA (91% vs 85%). No difference was observed in men, with 90% response for each treatment group. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPosttreatment Assessment of Clinical ResponseThe clinical response among the ITT population after treatment was also assessed and was similar in each group, with the proportion of patients assessed as having a satisfactory response (clinical cure or improvement) being 88% and 85% in the GFX and CLA treatment groups, respectively (Table 4 ). Analysis of the differences between the satisfactory clinical response rates demonstrated equivalence between groups (p = 0.31; 95% CI, -3 to 10%). 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYAnalysis of the CE population after treatment showed clinical response rates of 95% and 92% in the GFX and CLA treatment groups, respectively, a distribution comparable with that observed with the ITT population and also demonstrating equivalence between the two treatment groups (p = 0.40; 95% CI, -3 to 9%; Fig 2 ). Formal statistical equivalence was also established in the MITT and MCE populations. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYTable 4. Clinical Assessment of Response After Treatment and Follow-Up* ITT CE GFX, CLA, p (95% CI) GFX, CLA, p (95% CI) n = 251 n = 253 n = 163 n = 167 Time Responses of AssessmentAfter treatment Satisfactory 222 (88) 215 (85) 0.31 (-3 to 10) 155 (95) 154 (92) 0.40 (-3 to 9) (cure or improvement) Unsatisfactory 29 (12) 38 (15) 8 (5) 13 (8) (failure or unevaluable)Follow-up Satisfactory 188 (75) 192 (76) 0.88 (-9 to 7) 147 (90) 148 (89) 0.78 (-6 to 9) (cure or improvement) Unsatisfactory 63 (25) 61 (24) 16 (10) 19 (11) (failure or unevaluable) Posttreatment CRP values were obtained for 444 patients; 413 of these had a satisfactory clinical outcome. For these patients values ranged from 1 to 201 mg/L, with a median of 4 mg/L and SD of 23 mg/L, with only 4% having a CRP value > 50 mg/L. In contrast, for patients who did not have a satisfactory clinical outcome, CRP values ranged from 4 to 377 mg/L, with a median of 74 mg/L and SD of 105 mg/L, with 58% having a CRP value > 50 mg/L. Results were similar for the two treatment groups. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYAssessment of Clinical Response in Patients With Confirmed InfectionPatients from whom a pathogen was cultured or who had positive serologic evidence of Legionella, Chlamydia, or Mycoplasma infection responded satisfactorily (MITT population n = 131). Statistical equivalence of satisfactory clinical response incorporating radiographic evidence was demonstrated in this population (p = 0.67; 95% CI, -11 to 20%), with 80% and 76% of patients in the GFX and CLA treatment groups, respectively, classified as cured or improved at follow-up. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYThere was no evidence to suggest that patients with confirmed pathogens on entry into the study had a poorer outcome at follow-up compared with patients for whom no pathogen was detected. Of the 80 patients confirmed as having a typical pathogen before treatment, 30 (75%) in the GFX group and 29 (73%) in the CLA group showed a satisfactory clinical and radiographic response at follow-up. In the CE subpopulation, 23 of 26 patients (88%) responded satisfactorily to GFX compared with 24 of 26 patients (92%) in the CLA group. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYIn comparison, in the subgroup of patients with atypical pathogens on entry (MITT atypical group n = 57), those treated with GFX showed a higher clinical response rate, 91%, compared with a response rate of 82% (p = 0.58) for those receiving CLA. However, the relatively small sample size means that this difference was not statistically significant. In the CE subpopulation, the trend was similar, with 18 of 18 patients (100%) responding satisfactorily to GFX compared with 23 of 26 patients (88%) responding to CLA (p = 0.39; Fig 2 ). 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYFor the 126 of 131 patients in whom a pretreatment pathogen was confirmed and CRP measured, 76% of patients had a CRP value > 50 mg/L. Most values were very high (median, 145.5 mg/L). After treatment, in patients with a satisfactory response, the median value fell to 4 mg/L. Patients with an unsatisfactory response maintained a high CRP value with a median of 146 mg/L. Posttreatment results were similar for the two treatment groups and for patients with typical or atypical pretreatment pathogens. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYBacteriologic ResponseMost of the assessments of bacteriologic response for patients with typical pathogens were based on either presumed cure or presumed failure, taking into account clinical signs and symptoms. Despite the relatively small numbers of patients, equivalence between the GFX and CLA groups was demonstrated within the MITT population after treatment but with higher response rates obtained for GFX. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYOf the 40 patients in the typical MITT population receiving GFX, 80% showed a satisfactory response (cure, presumed cure, or cure with colonization) compared with 73% of the 40 patients receiving CLA (p = 0.60; 95% CI, -14 to 29%). In the MCE population, 24 of 26 patients (92%) responded satisfactorily to GFX and 22 of 24 patients (92%) responded to CLA (Fig 2) . 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYPathogens Isolated and Antibiotic SusceptibilityPretreatment pathogens were confirmed in 131 patients (MITT population), with typical pathogens isolated in 80 patients (40 GFX, 40 CLA) and atypical pathogens in 57 patients (23 GFX, 34 CLA). Six patients had both an atypical and a typical pathogen present. Twenty-five bacterial pathogens were isolated from pretreatment blood cultures (11 in the GFX group and 14 in the CLA group) and 67 from sputum (33 in the GFX group and 34 in the CLA group). 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYS pneumoniae was the most prevalent organism and was recovered from 15 of 25 blood samples and 18 of 67 sputum samples. The other blood culture isolates were coagulase-negative Staphylococcus spp (five isolates), Streptococcus spp (three isolates), Proteus mirabilis(one isolate), and Escherichia coli (one isolate). 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYS pneumoniae was the most frequently isolated typical pathogen, followed by H influenzae (26 isolates; Fig 3 ). All isolates were susceptible to the study drugs, correlating with a high number of patients experiencing a satisfactory bacteriologic response rate (cure, presumed cure, and cure with colonization). For patients with S pneumoniae isolated from pretreatment blood cultures, seven of eight in the GFX group and six of seven in the CLA group had a successful clinical and radiologic outcome. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY HOMEInstitutInstitution: ion: Beijing Beijing Book Book CompanyCompany || Sign In as Member/Non-Member(Individual) HELPFEEDBACKSUBSCRIPTIONSARCHIVESEARCHTABLE OF CONTENTS[HELP with high resolution image viewing][HELP with high resolution image viewing] [Return to Article] Figure 3. Pathogens detected before treatment: 153 pathogens from 131 patients. [Return to Article] HOMEHELPFEEDBACKSUBSCRIPTIONSARCHIVESEARCHTABLE OF CONTENTSOf the patients identified with pathogens on entry into the study, 57 of 131 patients (43%) had an atypical pneumonia attributed to M pneumoniae (38 patients), C pneumoniae (16 patients), or L pneumophila (5 patients). No significant differences were observed in the overall clinical response at follow-up; 18 of 18 CE patients (100%) receiving GFX showed a satisfactory clinical response compared with 23 of 26 CE patients (88%) receiving CLA. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYSafetyDetails of any adverse events were recorded at each assessment (Table 5 ); the most frequently reported events were GI in nature. The most common events were an abnormal or unusual taste, nausea (which was considered to be a CNS symptom in some patients), diarrhea, dizziness, and vomiting. With the exception of dizziness, which was higher in the GFX group (4% compared with < 1% for CLA), the frequency of these events was similar in the two treatment groups. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYThirty-three patients experienced serious adverse events, although these events were generally not associated with the study medication (two in the GFX group and five in the CLA group were classified by the investigator as treatment related). Two patients in the GFX treatment group died during the study (one of cor pulmonale, the second of circulatory collapse); both deaths were considered unrelated to treatment by the investigator. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYThe number of subjects who withdrew from the study (at any time) because of adverse events was 6% for GFX and 9% for CLA (Table 5) . The incidence of patients discontinuing treatment because of adverse events was comparable in both treatment groups ( 7%). Six patients (2%) in the GFX group and eight (3%) in the CLA group withdrew because of treatment-related adverse events; of these, none in the GFX group and two in the CLA group were considered serious in nature. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYTable 5. Frequency of Most Common Drug-Related Adverse Effects and Withdrawals in Each Treatment Group* Adverse Events GFX, n = 251 CLA, n = 253Most common drug-related adverse events ( 3% occurrence)Abnormal/unusual taste 29 (12) 24 (9)Nausea 24 (10) 17 (7)Diarrhea 9 (4) 12 (5)Dizziness 9 (4) 2 (< 1) Vomiting 4 (2) 8 (3)Patients withdrawn from entire study 16 (6) 22 (9) because of any adverse eventPatients withdrawn from treatment 16 (6) 18 (7) because of any adverse eventPatients withdrawn from treatment 6 (2) 8 (3because of drug-related adverse eventsPatients with serious treatment-related 2 (1) 5 (2)adverse events Conclusion Grepafloxacin, 600 mg once daily, was clinically equivalent to clarithromycin, 500 mg twice daily, in the treatment of CAP. Both agents were given for 10 days. Both agents were well tolerated, with mild GI effects as the most frequently reported adverse events; the frequency of dizziness was slightly higher with GFX. Six percent of patients receiving GFX and 9% given CLA withdrew from the study because of adverse events, with 3% of patients in each treatment group discontinuing treatment because of drug-related adverse events. CRP was measured during the study and correlated well with the presence of bacterial infection; this may also be of potential use as a surrogate marker in assessing clinical outcome. 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITYThis article has been cited by other articles: BTS Guidelines for the Management of Community Acquired Pneumonia in AdultsThorax, December 1, 2001; 56(90004): iv1 - 64. [Full Text] [PDF] 第四军医大学训练部第四军医大学训练部TRAINING DEP. OF FOURTH MILITARY MEDICAL UNIVERSITY。

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