贵州小吃
管理员怎么禁言Efficacy and safety of tigecycline monotherapy vs.imipenem/cilastatin in Chine patients with complic
ated intra-abdominal infections:a randomized controlled trial
Zhangjing Chen 1,Jufang Wu 1,Yingyuan Zhang 1*,Junming Wei 2,Xisheng Leng 3,Jianwei Bi 4,Rong Li 5,Lunan Yan 6,Zhiwei Quan 7,Xiaoping Chen 8,Yunsong Yu 9,Zhiyong Wu 10,Dawei Liu 11,Xiaochun Ma 12,Robert Maroko 13,Angel Cooper 13
*Correspondence: 1
Huashan Hospital,Fudan University,Shanghai,China
Chen et al .BMC Infectious Dias 2010,10:217
/1471-2334/10/217
©2010Chen et al;licene BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution Licen (creativecommons/licens/by/2.0),which permits unrestricted u,distribution,and reproduction in any medium,provided the original work is properly cited.
Background
The management of complicated intra-abdominal infec-tions(cIAIs)remains a challenge to physicians becau of their polymicrobial nature coupled with the high risk of quelae and mortality in verely ill patients with the infections[1-3].While most infections contain a mixture of aerobic and anaerobic bacteria with a pre-ponderance of ,Escherichia coli) [1,2],resistant and uncommon ,Entero-coccus,Staphylococcus,Enterobacter,Pudomonas and Candida spp.)are often isolated in patients with noso-comial infection or tertiary peritonitis[4].
Selection of empiric antimicrobial therapy must con-sider the likelihood of encountering isolates that posss multiple resistance ,extended-spectrum beta-lactamas[ESBLs],vancomycin-resistant enterococci [VRE])[1,2].Recently published treatment guidelines recommend broad-spectrum monotherapy or combina-tion ,carbapenem monotherapy,third-or fourth-generation cephalosporins or fluoroquinolones plus metronidazole)for high-risk patients with vere or postoperative nosocomial intra-abdominal infections wherein polymicrobial infections and/or resistant flora are more prevalent[1,2].Notably,inappropriate antibio-tic choices have been linked to delayed clinical resolu-tion,longer hospital stay,and an incread risk of mortality[5,6].While adjunctive antimicrobial therapy is vital to achieving desired outcomes,surgical intervention is esnti
al in the management of patients with cIAIs. Tigecycline,a first-in-class expanded broad-spectrum glycylcycline antibiotic approved for u in patients with cIAIs,overcomes the2major mechanisms of resistance to ,drug-specific efflux pump acquisition and ribosomal protection)[7,8].Tigecycline has broad-spectrum in vitro activity against bacteria commonly encountered in cIAIs,including aerobic and facultative Gram-positive and Gram-negative bacteria and anaero-bic bacteria[9-11].Furthermore,tigecycline has in vitro activity against multidrug-resistant bacteria such as VRE,ESBL-and carbapenema-producing enteric Gram-negative bacteria,and methicillin-resistant S.aur-eus(MRSA)[12-14].Tigecycline also exhibits linear pharmacokinetics and has a large volume of distribution, suggesting extensive tissue penetration[15].
Two global pha3double-blind trials,which com-pared the efficacy of tigecycline and imipenem/cilastatin in hospitalized patients with cIAIs,have demonstrated that tigecycline is efficacious for this condition[16].Imi-penem/cilastatin was chon as the comparative agent becau it has a wide spectrum of activity,it is effective in the treatment of hospitalized patients with intra-abdominal infections,and is widely available and ud in the treatment of cIAI.In the current trial,tigecycline monotherapy was evaluated for safety and efficacy vs.imipenem/cilastatin in hospitalized Chine patients with cIAI as a supplement to the2double-blinded pivo-tal global studies in cIAI[16].
Methods
Study design and treatment regimens
This study was a pha3,multicenter,open-label trial of hospitalized Chine patients at least18years of age who were candidates for or had undergone a laparot-omy,laparoscopy,or percutaneous drainage of an intra-abdominal abscess and had a known or suspected diag-nosis of cIAI.Specific enrollment criteria are outlined in Table1.Following approval of the study protocol by the institutional review board or ethical review committee at each participating center,each patient or his or her legal reprentative provided written informed connt prior to undergoing any study procedures.
Patients were randomly assigned using a computerized enrollment system in a1:1ratio to receive tigecycline (initial100-mg do given by intravenous[IV]infusion over a30-minute period,followed by50mg IV every12 hours)or IV imipenem/cilastatin(500mg/500mg every 6hours or do-adjusted bad on weight and creatinine clearance).Patients were to receive study drug for up to 2weeks,unless deemed a treatment failure after at least 4dos of tigecycline or8dos of imipenem/cilastatin. Baline aerobic and anaerobic cultures from the pri-mary intra-abdominal site of infection and two ts of blood cultures were obtained within24hours of the first do of study drug.
Clinical and microbiologic evaluations
At rial visits throughout the study,the clinical status of the patient’s intra-abdominal infection was assd bad upon the prence or abnce of the following signs and symptoms:fever;localized or diffu abdom-inal wall rigidity or involuntary guarding;abdominal tenderness or pain;ileus or hypoactive bowel sounds; naua or vomiting.The clinical respon to study drug was determined by the investigator at the test-of-cure (TOC)visit(12-37days after therapy)and categorized as cure,failure,or indeterminate.
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Microbiologic respon by patient was categorized at the TOC visit as eradication,persistence,superinfection (i.e.,the emergence of a new isolate was documented at the site of infection with worning signs and symptoms of infection),or indeterminate.The microbiologic respon for each baline isolate at the TOC visit was categorized as eradication,persistence,or indeterminate. Safety and tolerability asssments
All patients who received at least one do of study drug were evaluated for safety.Safety was assd from clinical obrvations and findings from rial electrocardiograms
(ECGs),rum chemistry,hematology,coagulation,and urinalysis tests.Adver events(AEs)were reco
rded throughout the study period,up to and including the TOC visit or14days after last do of study medication (whichever was longer),and were subjectively rated by the investigator as to their verity and relationship to the study drug.Investigators also recorded whether the AE resulted in temporary or permanent discontinuation and whether any remedial action was taken.Serious AEs (,tho that were life-threatening,led to prolon-gation of the existing hospitalization,caud persistent or significant disability or incapacity,led to cancer,or death) were also recorded.
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Statistical analysis
Three primary populations of patients were assd for safety,clinical,and bacteriologic outcomes;the modified intent-to-treat(mITT),microbiologic modified ITT(m-mITT),and the microbiologically evaluable(ME)popu-lations.ITT patients who received at least one do of study drug were included in the mITT population. Patients in the mITT population who had clinical evidence of complicated intra-abdominal infection com-prid the clinical-mITT(c-mITT)population.The m-mITT population consisted of patients in the c-mITT population who had≥1isolate identified at the baline asssment.Clinically evaluable(CE)patients were c-mITT patients who met all inclusion/exclusion criteria; did not receive concomitant antibiotics after the baline intra-abdominal culture was obtained through the test-of-cure visit;received no more than1d
o of a prohib-ited antibacterial treatment after the baline intra-abdominal culture was obtained but before the first do of study drug;received at least5days of study drug and between80%and120%of planned dos;had a test-of-cure visit12to37days after the last do of study drug. Tho patients included in the microbiologically evalu-able(ME)population were CE patients who had at least one identifiable baline bacterial isolate(s)taken from the primary site of infection that was susceptible to both study drugs and who had a microbiologic respon ,eradication,persistence,or superinfection, at the TOC visit.
This trial was designed to enroll200patients.By assuming an evaluability rate of50%,this would allow for the evaluation of100ME patients.The expected percentage of patients with a favorable clinical respon (cure)was70%at the TOC asssment.With a sample
Table1Enrollment criteria
Inclusion*Exclusion†
君子之交淡如水的意思Men and non-pregnant,non-lactating women≥18years of age who required a surgical procedure for a complicated intra-abdominal infection (cIAI)
打印的英文
cIAI defined as the following:
An intra-abdominal abscess(including liver and spleen)that developed in a postsurgical patient after receiving standard antibacterial ,at least48hours,but not more than5days of antibiotics);
Appendicitis complicated by perforation and/or a periappendiceal abscess;
Perforated diverticulitis complicated by abscess formation or fecal contamination;
粉葛搭配什么食材煲汤Complicated cholecystitis with evidence of perforation or empyema; perforation of a gastric or duodenal ulcer with symptoms exceeding24 hours;
Purulent peritonitis or peritonitis associated with fecal contamination; Perforation of the large or small intestine with abscess or fecal contamination,or traumatic bowel perforation with symptoms lasting at least12hours before an operation Preoperative suspicion of a diagnosis of spontaneous bacterial peritonitis, simple cholecystitis,gangrenous cholecystitis without rupture,simple appendicitis,acute suppurative cholangitis,pancreatic abscess,or infected necrotizing pancreatitis;
Acute Physiologic and Chronic Health Evaluation(APACHE)II score greater than30;
Surgical procedure requiring that fascia or deep muscular layers be left open or expectation of planned abdominal re-exploration either in or out of the operating room;
U of immunosuppressive therapy that would decrea the patient’s ability to eradicate the infection,including u of high-do ,40mg or more of prednisone or an equivalent per day for more than3weeks before randomization)or known diagnosis of acquired immunodeficiency syndrome;
Current intra-abdominal infection known to be caud by one or more bacterial isolates not susceptible to either of the study ,P. aeruginosa,Proteus mirabilis);
Active or treated leukemia or systemic malignancy that requires chemotherapy,immunotherapy,radiation therapy,or antineoplastic therapy within the3months before enrollment,or any metastatic malignancy to the abdomen with life expectancy<6months; Prence of any uncontrolled central nervous system dia; Significant hepatic ,aspartate aminotransfera[AST]or alanine aminotransfera[ALT]level>10times the upper limit of normal [ULN]or total bilirubin value>3times the ULN)or acute hepatic failure or acute decompensation of chronic hepatic failure;
Significant renal ,calculated creatinine clearance<41mL/ min/1.73m2after adequate hydration);
Neutropenia with absolute neutrophil count<1000mm3(however, neutrophil counts as low as500cells/mm3permitted if condary to the acute infectious process);
Concomitant treatment with ganciclovir
*Patients had to satisfy the inclusion criteria to be considered eligible for study participation
†Patients were ineligible for study participation if they had one or more of the listed exclusions
size of50evaluable patients in a treatment group,if 35patients showed a favorable clinical respon,then the2-sided exact95%CI would equal55.4,82.1.
The primary efficacy endpoints were clinical respon at the TOC visit for the m-mITT and ME populations.Microbiological respon at the TOC visit by patient and isolate was performed as a condary analysis.Becau the study was not powered to demonstrate non-inferiority between tigecycline and imipenem/cilastatin,no formal statistical analysis was performed for the primary and condary efficacy end-points of this study.Two-sided95%confidence inter-vals(CIs)were calculated for the respon rates in each treatment group for descriptive purpos using the“exact”method of Clopper and Pearson.Two-sided 95%CIs for differences between groups were calcu-lated bad on
the asymptotic method corrected for continuity,except for differences in subgroup analys where the Wilson score method corrected for continu-ity was ud.Secondary efficacy analys included the determination of susceptibility to tigecycline(MIC50, MIC90)and the development of decread susceptibil-ity(at least a4-fold increa in MIC from baline). Susceptibility was analyzed by using the Fisher exact test.
A post-hoc Cochran-Mantel-Haenszel analysis(strati-fied by protocol)was performed on the2co-primary efficacy endpoints to evaluate equality across the current trial and the2global cIAI studies[16].The Breslow-Day test was ud to evaluate equality across the strata with a P value of<0.05indicating statistical significance from study to study with respect to clinical respon. The Global Biostatistics and Programming Depart-ment of Wyeth Rearch performed all statistical analys.
Results
The disposition of Chine patients participating in this trial and the analysis populations are summarized in Figure1.Overall,199patients received at least1do of a study drug and comprid the mITT(safety) population.
The demographic and baline medical characteristics for the mITT patients were comparable between the2 treatment groups(Table2)with the exception that tige-cycline-treated patients were statistically significantly older(P=0.021)and the verity of intra-abdominal ill-ness was statistically significantly greater in the tigecy-cline cohort(mean APACHE II score was 5.1for tigecycline vs.4.1for imipenem/cilastatin;P=0.038). Complicated appendicitis was the most common intra-abdominal infection diagnosis in both groups(76.3% vs.76.5%for tigecycline and imipenem/cilastatin, respectively).Clinical efficacy
For the ME population,clinical cure rates were86.5% for tigecycline and97.9%for imipenem/cilastatin(95% CI for the difference,-23.5,0.7)(Table3).All patients had APACHE II scores≤15.Corresponding clinical cure rates for the m-mITT population were81.7%and90.9%, respectively(95%CI for the difference,-23.4,4.9).Clini-cal cure rates stratified by monomicrobial and polymi-crobial infections are found in Table3.For complicated appendicitis,by far the most frequent diagnosis in this study,clinical cure rates at the TOC visit for the ME population were87.0%for tigecycline and100.0%for imipenem/cilastatin(95%CI for the difference,-27.0, -0.6)(Table4).
The findings in Chine patients were similar to results in2global double-blind clinical trials[16], wherein the clinical respon of tigecycline was found to be non-inferior to imipenem/cilastatin(Figur
e2).The results of the Breslow-Day test indicate that there was no significant difference in clinical respon across the3 studies in the ME(P=0.0979)or the m-mITT popula-tion(P=0.1655)for the current study in Chine patients(Study316)and the2pivotal global studies (Study301and Study306).
仓鼠吃什么水果A total of6tigecycline-and3imipenem/cilastatin-treated patients in the ME population had positive pre-therapy blood culture results,including7isolates in tigecycline patients and4in imipenem/cilastatin patients.All blood culture isolates were Gram-negative rods.All9patients with bacteremia were reported as having a clinical cure/bacteriologic eradication at the TOC visit.
Microbiologic efficacy
For the ME population,presumed eradication of intra-abdominal isolates at the patient level bad upon clini-cal respon mirrored the clinical cure rates:86.5%for tigecycline-and97.9%for imipenem/cilastatin-treated patients(Table5).Eradication rates stratified by mono-microbial and polymicrobial infection are also summar-ized in Table5.
Eradication rates at the TOC visit for the most com-mon types of isolated intra-abdominal pathogens are outlined in Table6for the two treatment groups.For E. coli,the most commonly isolated bacteria,eradication rates were88.1%for tigecycline vs.97.7%for imipenem/ cilastatin.There were no
obvious differences in eradica-tion rates of other aerobic and anaerobic bacteria, although the number of isolates per species was small, making comparisons difficult.
Overall,MIC values for tigecycline against the most commonly isolated aerobes and anaerobes was≤2.0μg/ mL.li(n=86),MIC50and MIC90values were 0.125μg/mL and0.5μg/mL for tigecycline,respectively,
and0.25μg/mL and0.5μg/mL for imipenem/cilastatin, respectively.For patients in the tigecycline group who had li infections(5isolates;11.9%),MIC values ranged from0.125to0.5μg/mL.Bacterial sus-ceptibilities to tigecycline were consistent with clinical respons,and no isolates from later cultures with a decread susceptibility(≥4-fold increa in MIC from baline)to tigecycline were identified.
Safety and tolerability
The mITT population received a median of5and6 days of tigecycline or imipenem/cilastatin treatment,
populations and patient disposition:Tigecycline(TGC)vs.imipenem-cilastatin(I/C)in complicated
