Treatment Strategies for Carbapenem-resistant Enterobacteriaceae Infections
肖婷婷, 肖永红
浙江大学医学院附属第一医院传染病诊治国家重点实验室、感染性疾病诊治协同创新中心,杭州 310003
XIAO Tingting,, XIAO Yonghong,
State Key Laboratory for Diagnosis and Treatment of Infectious Disease,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,the First Affiliated Hospital,College of Medicine,Zhejiang University,Hangzhou 310003,China
Objective Carbapenem-resistant Enterobacteriaceae infections is becoming a major challenge to clinicians,which resulted in extremely high mortality owing to the limited antibiotics option.It is urgently to explore strategies to manage such bacterial infections.So far,the research is mainly focused on the research and development of new drugs,as well as the re-evaluation of classic antimicrobial drugs and the combined treatment regimens.Tigecycline is available in our country,but the clinical effect is still doubtful.Polymyxin has a good effect on drug sensitivity test in vitro,but the clinical dosing has not been established.Carbapenems combining with other drugs as optimizing treatment program is also being explored.Carbapenemase- inhibitor combination has not yet listed on Chinese market.In the mean time,it is urgent to prevent and to control carbapenem-resistant Enterobacteriaceae bacterial infection.
2.1.3 碳青霉烯酶抑制剂复方制剂 阿维巴坦(avibactam)和Relebactam属于二氮杂双环辛酮化合物(diazabicyclooctanes,DBOs),是一种新型非β-内酰胺类β-内酰胺酶抑制药,其抑酶谱广,与传统β-内酰胺酶抑制药不同,可与酶长效可逆性共价结合,可抑制 A 类、C 类和某些 D 类 β-内酰胺酶,但不能抑制B类金属β-内酰胺酶[22]。与DBOs不同的另一类抑制剂是硼基芳烃内酰胺酶抑制剂,已证明正在开发的RPX7009对A类碳青霉烯酶,包括ESBLs和KPC酶,有抑制作用,但不能抑制金属酶和D类酶[23]。头孢他啶/阿维巴坦复方已获批准在美国上市,联用可显著改善其对产 β-内酰胺酶的革兰阴性耐药菌的活性,主要用于成人复杂性腹腔感染及复杂性尿路感染,但目前用于CRE感染治疗的临床数据有限。氨曲南/阿维巴坦可能对产金属类β-内酰胺酶的菌株(如产NDM的CRE)感染有效,但仍需进一步研究。
TEMKINE,ADLERA,LERNERA,et al.Carbapenemres-istant Enterobacteriaceae:biology,epidemiology,and management[J].Ann New York Acad Sci ,2014,1323(1):22-42.
Introduced in the 1980s, carbapenem antibiotics have served as the last line of defense against multidrug-resistant Gram-negative organisms. Over the last decade, carbapenem-resistant Enterobacteriaceae (CRE) have emerged as a significant public health threat. This review summarizes the molecular genetics, natural history, and epidemiology of CRE and discusses approaches to prevention and treatment.
TEOJ,CAIY,TANGS,et al.Risk factors,molecular epi-demiology and outcomes of ertapenem-resistant,carbapenem-susceptible Enterobacteriaceae:a case-case-control study[J].PLoS One,2012,7(3):e34254.
Background Increasing prevalence of ertapenem-resistant, carbapenem-susceptible Enterobacteriaceae (ERE) in Singapore presents a major therapeutic problem. Our objective was to determine risk factors associated with the acquisition of ERE in hospitalized patients; to assess associated patient outcomes; and to describe the molecular characteristics of ERE. Methods A retrospective case-case-control study was conducted in 2009 at a tertiary care hospital. Hospitalized patients with ERE and those with ertapenem-sensitive Enterobacteriaceae (ESE) were compared with a common control group consisting of patients with no prior gram-negative infections. Risk factors analyzed included demographics; co-morbidities; instrumentation and antibiotic exposures. Two parallel multivariate logistic regression models were performed to identify independent variables associated with ERE and ESE acquisition respectively. Clinical outcomes were compared between ERE and ESE patients. Results Twenty-nine ERE cases, 29 ESE cases and 87 controls were analyzed. Multivariate logistic regression showed that previous hospitalization (Odds ratio [OR], 10.40; 95% confidence interval [CI], 2.19 49.20) and duration of fluoroquinolones exposure (OR, 1.18 per day increase; 95% CI, 1.05 1.34) were unique independent predictors for acquiring ERE. Duration of 4th-generation cephalosporin exposure was found to predict for ESE acquisition (OR, 1.63 per day increase; 95% CI, 1.05 2.54). In-hospital mortality rates and clinical response rates were significantly different between ERE and ESE groups, however ERE infection was not a predictor of mortality. ERE isolates were clonally distinct. Ertapenem resistance was likely to be mediated by the presence of extended-spectrum -lactamases or plasmid-borne AmpC in combination with impermeability due to porin loss and/or efflux pumps. Conclusion Prior hospitalization and duration of fluoroquinolone treatment were predictors of ERE acquisition. ERE infections were associated with higher mortality rates and poorer clinical response rates when compared to ESE infections.
NORDMANNP,NAAST,POIRELL.Global spread of car-bapenemase-producing Enterobacteriaceae[J].Emerg Infect Dis,2011,17(10):1791-1798.
Carbapenemases increasingly have been reported in Enterobacteriaceae in the past 10 years. Klebsiella pneumoniae carbapenemases have been reported in the United States and then worldwide, with a marked endemicity at least in the United States and Greece. Metallo-enzymes (Verona integron-encoded metallo--lactamase, IMP) also have been reported worldwide, with a higher prevalence in southern Europe and Asia. Carbapenemases of the oxacillinase-48 type have been identified mostly in Mediterranean and European countries and in India. Recent identification of New Delhi metallo--lactamase-1 producers, originally in the United Kingdom, India, and Pakistan and now worldwide, is worrisome. Detection of infected patients and carriers with carbapenemase producers is necessary for prevention of their spread. Identification of the carbapenemase genes relies mostly on molecular techniques, whereas detection of carriers is possible by using screening culture media. This strategy may help prevent development of nosocomial outbreaks caused by carbapenemase producers, particularly K. pneumoniae.
GUH AY,LIMBAGO BM,KALLEN AJ.Epidemiology and prevention of carbapenem-resistant Enterobacteriaceae in the United States[J].Expert Rev Anti Infect Ther, 2014,12(5):565-580.
Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug-resistant organisms with few treatment options that cause infections associated with substantial morbidity and mortality. CRE outbreaks have been increasingly reported worldwide and are mainly due to the emergence and spread of strains that produce carbapenemases. In the United States, transmission of CRE is primarily driven by the spread of organisms carrying the Klebsiella pneumoniae carbapenemase enzyme, but other carbapenemase enzymes, such as the New-Delhi metallo--lactamase, have also emerged. Currently recommended control strategies for healthcare facilities include the detection of patients infected or colonized with CRE and implementation of measures to prevent further spread. In addition to efforts in individual facilities, effective CRE control requires coordination across all healthcare facilities in a region. This review describes the current epidemiology and surveillance of CRE in the United States and the recommended approach to prevention.
HU FP,GUOY,ZHU DM,et al.Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance,2005-2014[J].Clin Microbiol Infect,2016,22(Suppl 1):9-14
With the aim of gathering temporal trends on bacterial epidemiology and resistance from multiple laboratories in China, the CHINET surveillance system was organized in 2005. Antimicrobial susceptibility testing was carried out according to a unified protocol using the Kirby-Bauer method or automated systems. Results were analyzed according to Clinical and Laboratory Standards Institute (CLSI) 2014 definitions. Between 2005 and 2014, the number of bacterial isolates ranged between 22774 and 84572 annually. Rates of extended-spectrum 尾-lactamase production among Escherichia coli isolates were stable, between 51.7 and 55.8%. Resistance of E.coli and Klebsiella pneumoniae to amikacin, ciprofloxacin, piperacillin/tazobactam and cefoperazone/sulbactam decreased with time. Carbapenem resistance among K.pneumoniae isolates increased from 2.4 to 13.4%. Resistance of Pseudomonas aeruginosa strains against all of antimicrobial agents tested including imipenem and meropenem decreased with time. On the contrary, resistance of Acinetobacter baumannii strains to carbapenems increased from 31 to 66.7%. A marked decrease of methicillin resistance from 69% in 2005 to 44.6% in 2014 was observed for Staphylococcus aureus. Carbapenem resistance rates in K.pneumoniae and A.baumannii in China are high. Our results indicate the importance of bacterial surveillance studies.
BAE IK,KANG HK,JANG IH,et al.Detection of carba-penemases in clinical enterobacteriaceae isolates using the VITEK AST-N202 card[J].Infect Chemother,2015,47(3):167-174.
The rapid and accurate detection of carbapenemase-producing Enterobacteriaceae (CPE) in clinical microbiology laboratories is essential for the treatment and control of infections caused by these microorganisms. This study was performed to evaluate the ability of the VITEK AST-N202 card to detect CPE isolates.A total of 43 (Klebsiella pneumoniae, n = 37; Escherichia coli, n = 3; and Enterobacter cloacae, n = 3) CPE isolates and 79 carbapenemase-non-producing Enterobacteriaceae (CNE) isolates were included in this study. The CPE isolates harbored KPC-2 (n = 11), KPC-3 (n = 20), GES-5 (n = 5), VIM-2 (n = 2), IMP-1 (n = 1), NDM-1 (n = 2), or OXA-232 (n = 2). Of the 79 CNE isolates, eight K. pneumoniae isolates were resistant to ertapenem, imipenem, and meropenem, while the remaining 71 isolates were susceptible to the carbapenems. Antimicrobial susceptibilities were tested using the VITEK AST-N202 card, and the results were interpreted as positive when the isolates showed resistant or intermediate results. Modified-Hodge tests (MHTs) were performed using ertapenem or meropenem disks for the screening of carbapenemase production. Polymerase chain reaction (PCR) and direct sequencing were used to identify 尾-lactamase genes.Sensitivity of MHT with ertapenem and meropenem disks for the detection of carbapenemase was 81.4% (35/43) and 81.4% (35/43), respectively, and a combination with both antibiotic disks increased the sensitivity to 88.4% (38/43). Specificity of the MHT was 100% (79/79) for the CNE isolates. Sensitivity of ertapenem, imipenem, and meropenem as assessed by the VITEK AST-N202 card was 100% (43/43), 93% (40/43), and 95.3% (41/43), respectively. Specificity (89.8%, 71/79) of the test with each carbapenem was improved to 100% (71/71) when eight carbapenem-resistant CNE isolates were excluded from the testing.The VITEK AST-N202 card showed high sensitivity for the detection of carbapenemases in Enterobacteriaceae strains. PCR and sequencing experiments for the detection of carbapenemases are recommended when clinical Enterobacteriaceae isolates show non-susceptibility to carbapenems.
BANERJEEP,JAGGIT,HAIDERM,et al.Prevalence of carbapenemases and metallo-β-lactamases in clinical isolates of enterobacter cloacae[J].J Clin Diagn Res,2014,8(11):DM01-DM02.
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HUF,CHENS,XUX,et al.Emergence of carbapenem-resistant clinical Enterobacteriaceae isolates from a teaching hospital in Shanghai,China[J].J Med Microbiol,2012,61(Pt1):132-136.
Carbapenems such as imipenem and meropenem are first-line agents for the treatment of serious nosocomial infections caused by multidrug-resistant clinical isolates of bacteria belonging to the family Enterobacteriaceae. However, resistance to carbapenems has increased dramatically among members of the family Enterobacteriaceae isolated from a teaching hospital in Shanghai, China. In the present study, we investigated the prevalence and molecular characteristics of carbapenem-resistant clinical isolates of Enterobacteriaceae. None of the 77 clinical isolates collected from 2002 to 2009 were susceptible to ertapenem and only 6.5 % and 1.3 % of isolates were susceptible to imipenem and meropenem, respectively. Colistin and tigecycline were found to be the most active agents against carbapenem-resistant Enterobacteriaceae isolates, inhibiting 90 % of isolates at a concentration of 1 g ml(-1) and 4 g ml(-1), respectively. The results of PFGE analysis suggested that many of the KPC-2-producing isolates of Citrobacter freundii and Klebsiella pneumoniae were clonally related. Most of these isolates were isolated from the same ward, namely the neurosurgical ward, suggesting horizontal transfer of the KPC-2-encoding gene in these isolates. Of the 77 isolates, 84.4 % were found, by PCR, to be capable of carbapenemase production. SDS-PAGE analysis revealed that 75.3 % (58/77) of the isolates had lost at least one porin protein. Our results suggested that the prompt detection of carbapenemase-producing strains is critical for the containment of nosocomial transmission. As no novel antimicrobials have been identified for use in the treatment of these pan-drug-resistant isolates, further studies should focus on the rational use of available antibiotics, the implementation of active antibiotic resistance surveillance and the strict implementation of infection control measures to avoid the rapid spread or outbreak of carbapenemase-producing Enterobacteriaceae in health-care facilities.
LOGAN LK.Carbapenem-resistant Enterobacteriaceae:an emerging problem in children[J].Clin Infect Dis,2012,55(6):852-859.
Antibiotic resistance among gram-negative bacteria has reached critical levels. The rise of carbapenem resistance in Enterobacteriaceae carrying additional resistance genes to multiple antibiotic classes has created a generation of organisms nearly resistant to all available therapy. Carbapenem-resistant Enterobacteriaceae (CRE) infections are known to be associated with significant morbidity and mortality, and these pathogens have now made their way to the most vulnerable populations, including children. This review provides a brief overview of CRE, with a focus on CRE infections in children, and highlights available data on the epidemiology, clinical characteristics, carbapenemase types, risk factors, treatment, and outcomes of these multi-drug resistant infections in the pediatric population.
TSAI YK,FUNG CP,LIN JC,et al.Klebsiella pneumoniae outer membrane porins OmpK35 and OmpK36 play roles in both antimicrobial resistance and virulence[J].Antimicrob Agents Chemother,2011,55(4):1485-1493.
OmpK35 and OmpK36 are the major outer membrane porins of Klebsiella pneumoniae. In this study, a virulent clinical isolate was selected to study the role of these two porins in antimicrobial resistance and virulence. The single deletion of ompK36 (ΔompK36) resulted in MIC shifts of cefazolin, cephalothin, and cefoxitin from susceptible to resistant, while the single deletion of ompK35 (ΔompK35) had no significant effect. A double deletion of ompK35 and ompK36 (ΔompK35/36) further increased these MICs to high-level resistance and led to 8- and 16-fold increases in the MICs of meropenem and cefepime, respectively. In contrast to the routine testing medium, which is of high osmolarity, susceptibility tests using low-osmolarity medium showed that the ΔompK35 mutation resulted in a significant (≥ 4-fold) increase in the MICs of cefazolin and ceftazidime, whereas a ΔompK36 deletion conferred a significantly (4-fold) lower increase in the MIC of cefazolin. In the virulence assays, a significant (P < 0.05) defect in the growth rate was found only in the ΔompK35/36 mutant, indicating the effect on metabolic fitness. A significant (P < 0.05) increase in susceptibility to neutrophil phagocytosis was observed in both ΔompK36 and ΔompK35/36 mutants. In a mouse peritonitis model, the ΔompK35 mutant showed no change in virulence, and the ΔompK36 mutant exhibited significantly (P < 0.01) lower virulence, whereas the ΔompK35/36 mutant presented the highest 50% lethal dose of these strains. In conclusion, porin deficiency in K. pneumoniae could increase antimicrobial resistance but decrease virulence at the same time.
FRANK MK,FADIA DH,WENCHIS,et al.High-level carbapenem resistance in a Klebsiella pneumoniae clinical isolate is due to the combiniation of b/aACT-1 β-lactamase production,porin OmpK35/36 insertional inactiviation,and down-regulation of the phosphate transport porin phoE[J].Antimicrob Agents Chemother,2006,50(10):3396-3406.
HOBBS EC,YINX,PAULA BJ,et al.Conserved small protein associates with the multidrug efflux pump AcrB and differentially affects antibiotic resistance[J].Proc Natl Acad Sci U S A,2012,109(41):16696-16701.
ZHANGR,CAI JC,ZHOU HW,et al.Genotypic charac-terization and in vitro activities of tigecycline and polymyxin B for members of the Enterobacteriaceae with decreased susceptibility to carbapenems[J].J Med Microbiol,2011,60(Pt 12):1813-1819.
Carbapenem resistance in members of the Enterobacteriaceae is increasing. To evaluate the effects of tigecycline and polymyxin B against carbapenem-non-susceptible pathogens, 89 representative clinical carbapenem-non-susceptible Enterobacteriaceae isolates were recovered from seven hospitals from four cities in China during 2006-2009: 30 Serratia marcescens, 35 Klebsiella pneumoniae, seven Enterobacter cloacae, six Enterobacter aerogenes, five Escherichia coli, four Citrobacter freundii and two Klebsiella oxytoca isolates. Twenty-eight S. marcescens isolates were indistinguishable. The 35 K. pneumoniae isolates belonged to 12 clonal strains. Among the 89 Enterobacteriaceae isolates, 82 produced KPC-2, seven produced IMP (three produced KPC-2 simultaneously), three did not produce any carbapenemases and nine were deficient in porins. Polymyxin B was much more active than tigecycline against carbapenem-non-susceptible Enterobacteriaceae. The MIC(50) and MIC(90) of imipenem, meropenem, ertapenem, polymyxin B and tigecycline were 8 and 32 08g ml(-1), 8 and 32 08g ml(-1), 16 and 128 08g ml(-1), 0.5 and 16 08g ml(-1), and 4 and 16 08g ml(-1), respectively. Rates of susceptibility to imipenem, meropenem, ertapenem and polymyxin B were 30.0%, 27.5%, 2.5% and 89.2% by CLSI criteria. The rate of susceptibility to tigecycline was 40% and 17.5% by Food and Drug Administration (MIC ≤2 08g ml(-1)) and European Committee on Antimicrobial Susceptibility Testing (MIC ≤1 08g ml(-1)) criteria, respectively. KPC-2- or IMP-producing E. coli transconjugants exhibited reduced susceptibility to carbapenems but were susceptible to polymyxin B and tigecycline with an MIC range of 0.5-2 08g ml(-1), 0.25-2 08g ml(-1), 0.5-4 08g ml(-1), 0.5 08g ml(-1) and 0.5-1 08g ml(-1). In conclusion, carbapenem resistance in Enterobacteriaceae is mainly due to production of KPC-2, and polymyxin B is active for the carbapenem-resistant Enterobacteriaceae.
MEAGHER AK,AMBROSE PG,GRASELA TH,et al.The pharmacokinetic and pharmacodynamic profile of tigecycline[J].Clin Infect Dis,2005,41(Suppl 5):333-340.
Tigecycline, a first-in-class expanded-spectrum , has demonstrated efficacy in the treatment of complicated intra-abdominal and skin and skin-structure . This new antibiotic is available as an intravenous formulation and exhibits linear pharmacokinetics. It is rapidly distributed and has a large volume of distribution, indicating extensive tissue penetration. After a 100-milligram loading dose, followed by 50 milligrams every 12 h, the steady-state maximum concentration in serum after a 1-h infusion is approximately 0.6 microg/mL, the 24-h steady-state area under the concentration-time curve is approximately 5-6 microg.h/mL, and the terminal elimination half-life is approximately 40 h. The major route of elimination of tigecycline is through the feces, primarily as unchanged drug. The pharmacokinetic profile is not affected by severe or , nor is it significantly altered by hemodialysis. The pharmacokinetics of tigecycline are also not affected by food, although tolerability is increased if the drug is administered following a meal.
NOSKIN GA.Tigecycline:a new glycylcycline for treat-ment of serious infections[J].Clin Infect Dis,2005,41(Suppl 5):S303-314.
Tigecycline is a new semisynthetic glycylcycline for the treatment of serious . Of the glycylcyclines, tigecycline is the most studied and appears to hold promise as a new that can be administered as monotherapy to patients with many types of serious . For patients with serious , the initial choice for empirical therapy with broad-spectrum antibiotics is crucial, and, if the choice is inappropriate, it may have adverse consequences for the patient. Tigecycline has been designed to overcome many existing mechanisms of resistance among and confers broad antibiotic coverage against -resistant enterococci, -resistant , and many species of multidrug-resistant gram-negative . Tigecycline has been efficacious and well tolerated in clinical phase 2 studies, which warranted further evaluation of tigecycline in larger studies for treatment of many indications, including complicated skin and skin-structure , complicated , and of the lower respiratory tract.
FALAGAS ME,VARDAKAS KZ,TSIVERIOTIS KP,et al.Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections[J].Int J Antimicrob Agents,2014,44(1):1-7.
Here we review the effectiveness and safety of high-dose tigecycline (200mg daily). A systematic search was performed in PubMed and Scopus databases as well as of abstracts presented at scientific conferences. Eight studies (263 patients; 58% critically ill) were included, comprising one randomised controlled trial (RCT), four non-randomised cohorts and three case reports. Klebsiella pneumoniae was the most commonly isolated pathogen (reported in seven studies). In the RCT, response in the clinically evaluable patients was 85.0% (17/20) in the 100mg every 12h (q12h) group and 69.6% (16/23) in the 75mg q12h group (P=0.4). More episodes of diarrhoea, treatment-related nausea and vomiting developed in the high-dose group (14.3% vs. 2.8%, 8.6% vs. 2.8% and 5.7% vs. 2.8%, respectively; P>0.05 for all comparisons). Three (8.6%) and 7 (19.6%) patients died in the 200mg and 150mg daily dose groups, respectively. The cohort studies enrolled patients with severe infections, including ventilator-associated pneumonia and complicated intra-abdominal infections. Mortality with high-dose tigecycline (100mg q12h) in the cohort studies ranged from 8.3% to 26%; mortality in the low-dose groups (50mg q12h) ranged from 8% to 61% and depended on the severity of the underlying infection. There are limited available data regarding the effectiveness and safety of high-dose tigecycline. Most of the data come from critically ill patients with difficult-to-treat infections. Pharmacokinetic/pharmacodynamic properties of tigecycline suggest that high-dose regimens may be more effective than low-dose regimens. Candidates for administration of high-dose tigecycline should be also defined.
YAHAVD,LADORA,PAULM,et al.Efficacy and safety of tigecycline:a systematic review and meta-analysis[J].J Antimicrob Chemother,2011,66(9):1963-1971.
Tigecycline is a novel glycylcycline that exhibits broad-spectrum antibacterial activity. Recently, the US FDA issued a warning concerning increased mortality with tigecycline in randomized controlled trials (RCTs).We conducted a systematic review and meta-analysis of RCTs that compared tigecycline with any other antibiotic regimen for the treatment of any infection. A comprehensive search, without publication status or other restrictions, was conducted. The primary outcome was overall 30 day mortality. The secondary outcome included clinical and microbiological failure, superinfections and adverse events (AEs). The trials' risks of bias and their effects on results were assessed. Two reviewers independently extracted the data. Individual trials' relative risks (RRs) were pooled using a fixed effect meta-analysis.Fifteen trials (7654 patients) were included. Overall mortality was higher with tigecycline compared with other regimens [RR 1.29, 95% confidence interval (CI) 1.02-1.64, without heterogeneity]. The type of infection assessed and the trials' reported risks of bias did not affect this result. Clinical failure was significantly higher with tigecycline (RR 1.16, 95% CI 1.06-1.27) and non-statistically significant higher rates of microbiological failure were demonstrated (RR 1.13, 95% CI 0.99-1.30). Development of septic shock was significantly more frequent with tigecycline (RR 7.01, 95% CI 1.27-38.66). Superinfections were significantly more common with tigecycline and so were AEs, including all AEs and AEs requiring discontinuation.In the light of the increased mortality, probably explained by decreased clinical and microbiological efficacy, clinicians should avoid tigecycline monotherapy in the treatment of severe infections and reserve it as a last-resort drug.
PRASADP,SUNJ,DANNER RL,et al.Excess deaths associated with tigecycline after approval based on noninferiority trials[J].Clin Infect Dis,2012,54(12):1699-1709.
Background. On the basis of noninferiority trials, tigecycline received Food and Drug Administration (FDA) approval in 2005. In 2010, the FDA warned in a safety communication that tigecycline was associated with an increased risk of death.
SOLOMKIN JS,RAMESH MK,CESNAUSKASG,et al.Phase 2,randomized,double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community acquired complicated intra-abdominal infections[J].Antimicrob Agents Chemother,2014,58(4):1847-1854.
Eravacycline is a novel fluorocycline, highly active against Gram-positive and Gram-negative pathogens in vitro, including those with tetracycline and multidrug resistance. This phase 2, randomized, double-blind study was conducted to evaluate the efficacy and safety of two dose regimens of eravacycline compared with ertapenem in adult hospitalized patients with complicated intra-abdominal infections (cIAIs). Patients with confirmed cIAI requiring surgical or percutaneous intervention and antibacterial therapy were randomized (2:2:1) to receive eravacycline at 1.5 mg/kg of body weight every 24 h (q24h), eravacycline at 1.0 mg/kg every 12 h (q12h), or ertapenem at 1 g (q24h) for a minimum of 4 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 10 to 14 days after the last dose of study drug therapy. Overall, 53 patients received eravacycline at 1.5 mg/kg q24h, 56 received eravacycline at 1.0 mg/kg q12h, and 30 received ertapenem. For the ME population, the clinical success rate at the TOC visit was 92.9% (39/42) in the group receiving eravacycline at 1.5 mg/kg q24h, 100% (41/41) in the group receiving eravacycline at 1.0 mg/kg q12h, and 92.3% (24/26) in the ertapenem group. The incidences of treatment-emergent adverse events were 35.8%, 28.6%, and 26.7%, respectively. Incidence rates of nausea and vomiting were low in both eravacycline groups. Both dose regimens of eravacycline were as efficacious as the comparator, ertapenem, in patients with cIAI and were well tolerated. These results support the continued development of eravacycline for the treatment of serious infections, including those caused by drug-resistant Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01265784.).
NAKAMURAR,TOBAS,TSUJIM,et al.A novel sidero-phore cephalosporin:IV.In vivo ef cacy in various murine infection models[C].Presented at 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014),Washington,DC:Poster ,2014:5-9.
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MACVANE SH,CRANDON JL,NICHOLS WW,et al.In vivo efficacy of humanized exposures of ceftazidime- avibactam in comparison with ceftazidime against contemporary enterobacteriaceae isolates[J].Antimicrob Agents Chemother,2014,58(11):6913-6919.
Ceftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of the in vivo efficacy of the combination against these targeted ceftazidime- and carbapenem-resistant Enterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam against Enterobacteriaceae exhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinical Enterobacteriaceae isolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10 CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against the Enterobacteriaceae isolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (fT>MIC of 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistant Enterobacteriaceae.
DRAWZ SM,PAPP-WALLACE K M,BONOMO R A.New beta-lactamase inhibitors:a therapeutic renaissance in an MDR world[J].Antimicrob Agents Chemother,2014,58(4):1835-1846.
PANKUCH GA,LING,KUBOA,et al.Activity of ACHN-490 tested alone and in combination with other agents against Pseudomonas aeruginosa[J].Antimicrob Agents Chemother,2011,55(5):2463-2465.
Abstract ACHN-490 was tested alone and in combination with cefepime, doripenem, imipenem, or piperacillin-tazobactam in a synergy time-kill analysis against 25 Pseudomonas aeruginosa strains with different resistance phenotypes. Each combination was synergistic against most isolates at 24 h, and antagonism was not observed. Combinations of ACHN-490 with cefepime, doripenem, imipenem, or piperacillin-tazobactam yielded synergies in 09090670% and 09090680% of strains at 6 and 12 h, respectively, and in 09090668% at 24 h.
LANDERSDORFER CB,NATION RL.Colistin:how shou-ld it be dosed for the critically ill?[J].Semin Respir Crit Care Med,2015,36(1):126-135.
ABSTRACT Colistin, an "old" polymyxin antibiotic, is increasingly being used as last-line treatment against infections caused by multidrug-resistant gram-negative bacteria. It is administered in patients, parenterally or by inhalation, as its inactive prodrug colistin methanesulfonate (CMS). Scientifically based recommendations on how to optimally dose colistin in critically ill patients have become available over the last decade and are extremely important as colistin has a narrow therapeutic window. A dosing algorithm has been developed to achieve desired plasma colistin concentrations in critically ill patients. This includes the necessary dose adjustments for patients with impaired kidney function and those on renal replacement therapy. Due to the slow conversion of CMS to colistin, a loading dose is needed to generate effective concentrations within a reasonable time period. Therapeutic drug monitoring is warranted, where available; because of the observed high interpatient variability in plasma colistin concentrations. Combination therapy should be considered when the infecting pathogen has a colistin minimum inhibitory concentration above 1 mg/L, as increasing the dose may not be feasible due to the risk for nephrotoxicity. Inhalation of CMS achieves considerably higher colistin concentrations in lung fluids than is possible with intravenous administration, with negligible plasma exposure. Similarly, for central nervous system infections, dosing CMS directly into the cerebrospinal fluid generates significantly higher colistin concentrations at the infection site compared with what can be achieved with systemic administration. While questions remain to be addressed via ongoing research, this article reviews the significant advances that have been made toward optimizing the clinical use of colistin. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
SATLIN MJ,KUBIN CJ,BLUMENTHAL JS,et al.Com-parative effectiveness of aminoglycosides,polymyxin B,and tigecycline for clearance of carbapenem-resistant Klebsiella pneumoniae from urine[J].Antimicrob Agents Chemother,2011,55(12):5893-5899.
Abstract Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an increasingly common cause of health care-associated urinary tract infections. Antimicrobials with in vitro activity against CRKP are typically limited to polymyxins, tigecycline, and often, aminoglycosides. We conducted a retrospective cohort study of cases of CRKP bacteriuria at New York-Presbyterian Hospital from January 2005 through June 2010 to compare microbiologic clearance rates based on the use of polymyxin B, tigecycline, or an aminoglycoside. We constructed three active antimicrobial cohorts based on the active agent used and an untreated cohort of cases that did not receive antimicrobial therapy with Gram-negative activity. Microbiologic clearance was defined as having a follow-up urine culture that did not yield CRKP. Cases without an appropriate follow-up culture or that received multiple active agents or less than 3 days of the active agent were excluded. Eighty-seven cases were included in the active antimicrobial cohorts, and 69 were included in the untreated cohort. The microbiologic clearance rate was 88% in the aminoglycoside cohort (n = 41), compared to 64% in the polymyxin B (P = 0.02; n = 25), 43% in the tigecycline (P < 0.001; n = 21), and 36% in the untreated (P < 0.001; n = 69) cohorts. Using multivariate analysis, the odds of clearance were lower for the polymyxin B (odds ratio [OR], 0.10; P = 0.003), tigecycline (OR, 0.08; P = 0.001), and untreated (OR, 0.14; P = 0.003) cohorts than for the aminoglycoside cohort. Treatment with an aminoglycoside, when active in vitro, was associated with a significantly higher rate of microbiologic clearance of CRKP bacteriuria than treatment with either polymyxin B or tigecycline.
BULIK CC,TESSIER PR,KEEL RA,et al.In vivo com-parison of CXA-101 (FR264205) with and without tazobactam versus piperacillin-tazobactam using human simulated exposures against phenotypically diverse gram-negative organisms[J].Antimicrob Agents Chemother,2012,56(1):544-549.
Abstract CXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum β-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6 Pseudomonas aeruginosa isolates [piperacillin-tazobactam MIC range, 8 to 64 μg/ml], 4 Escherichia coli isolates (2 ESBL and 2 non-ESBL expressing), and 4 Klebsiella pneumoniae isolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 μg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 μg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhanced in vitro potency and resultant increased in vivo exposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam.
GROUP C X C W,GUANX,HEL,et al.Laboratory diag-nosis,clinical management and infection control of the infections caused by extensively drug-resistant Gram-negative bacilli:a Chinese consensus statement[J].Clin Microbiol Infect,2016,22( Suppl 1):S15-S25.
Extensively drug-resistant (XDR) Gram-negative bacilli (GNB) are defined as bacterial isolates susceptible to two or fewer antimicrobial categories. XDR-GNB mainly occur inEnterobacteriaceae,Acinetobacter baumannii,Pseudomonas aeruginosa, andStenotrophomonas maltophilia. The prevalence of XDR-GNB is on the rise in China and in other countries, and it poses a major public health threat as a result of the lack of adequate therapeutic options. A group of Chinese clinical experts, microbiologists and pharmacologists came together to discuss and draft a consensus on the laboratory diagnosis, clinical management and infection control of XDR-GNB infections. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created according to documents from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). Multiple risk factors of XDR-GNB infections are analyzed, with long-term exposure to extended-spectrum antimicrobials being the most important one. Combination therapeutic regimens are summarized for treatment of XDR-GNB infections caused by different bacteria based on limited clinical studies and/or laboratory data. Most frequently used antimicrobials used for the combination therapies include aminoglycosides, carbapenems, colistin, fosfomycin and tigecycline. Strict infection control measures including hand hygiene, contact isolation, active screening, environmental surface disinfections, decolonization and restrictive antibiotic stewardship are recommended to curb the XDR-GNB spread.
DAVID VAD,KEITH SK,ELIZABETHA,et al.Carba-penem-resistant enterobacteriaceae:a review of treatment and outcomes[J].Diagn Microbiol Infect Dis,2013,75(2):115-120.
The emergence of carbapenem resistance in Enterobacteriaceae is an important threat to global health. Reported outcomes of infections with carbapenem-resistant Enterobacteriaceae (CRE) are poor. Very few options remain for the treatment of these virulent organisms. Antibiotics which are currently in use to treat CRE infections include aminoglycosides, polymyxins, tigecycline, fosfomycin, and temocillin. In addition, the role of combination therapy, including carbapenem containing regimens, remains to be defined. There are several important concerns regarding all of these treatment options such as limited efficacy, increasing reports of resistance, and specific toxicities. Data from retrospective studies favor combination therapy over single-agent therapy for the treatment of CRE bloodstream infections. In summary, new antibiotics are greatly needed, as is additional prospective research.
TUMBARELLOM,VIALEP,VISCOLIC,et al.Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K.pneumoniae:importance of combination therapy[J].Clin Infect Dis,2012,55(6):943-950.
F1000Prime Recommended Article: Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy.
FRIEDMAN ND,CARMELIY,WALTON AL,et al.Car-bapenem-resistant enterobacteriaceae:a strategic roadmap for infection control[J].Infect Control Hosp Epidem,2017,38(5):580-594.
Abstract The incidence of carbapenem-resistant Enterobacteriaceae (CRE) has increased worldwide with great regional variability. Infections caused by these organisms are associated with crude mortality rates of up to 70%. The spread of CRE in healthcare settings is both an important medical problem and a major global public health threat. All countries are at risk of falling victim to the emergence of CRE; therefore, a preparedness plan is required to avoid the catastrophic natural course of this epidemic. Proactive and adequate preventive measures locally, regionally, and nationally are required to contain the spread of these bacteria. The keys to success in preventing the establishment of CRE endemicity in a region are early detection through targeted laboratory protocols and containment of spread through comprehensive infection control measures. This guideline provides a strategic roadmap for infection control measures based on the best available evidence and expert opinion, to enable preparation of a multifaceted preparedness plan to abort epidemics of CRE. Infect Control Hosp Epidemiol 2017;1-15.
High-level carbapenem resistance in a clinical isolate is due to the combiniation of b/a β-lactamase production,porin OmpK35/36 insertional inactiviation,and down-regulation of the phosphate transport porin phoE
Phase 2,randomized,double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community acquired complicated intra-abdominal infections
com-parison of CXA-101 (FR264205) with and without tazobactam versus piperacillin-tazobactam using human simulated exposures against phenotypically diverse gram-negative organisms
Laboratory diag-nosis,clinical management and infection control of the infections caused by extensively drug-resistant Gram-negative bacilli:a Chinese consensus statement
, 肖永红
