Clinical characteristics of bacteraemia caused by extended-spectrum β-lactamase-producing Enterobacteriaceae in the era of CTX-M-type and KPC-type β-lactamases

Clin Microbiol Infect 2012; 18: 887-893 ABSTRACT: A multicentre, case-control study was conducted to assess risk factors and patient outcomes of bacteraemia caused by Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs). One hundred and five and 20 patients with bacteraemia caused by ESBL-producing and KPC-producing organisms were matched to controls who had bacteraemia caused by non-ESBL/KPC-producing organisms, respectively. Independent risk factors for ESBL production included admission from a nursing home (OR 4.64; 95% CI 2.64-8.16), chronic renal failure (OR 2.09; 95% CI 1.11-3.92), the presence of a gastrostomy tube (OR 3.36; 95% CI 1.38-8.18), length of hospital stay before infection (OR 1.02; 95% CI 1.01-1.03), transplant receipt (OR 2.48; 95% CI 1.24-4.95), and receipt of antibiotics with Gram-negative activity in the preceding 30 days (OR 1.76; 95% CI 1.00-3.08). Twenty-eight-day crude mortality rates for patients infected with ESBL-producing or KPC-producing organisms and controls were 29.1% (34/117) and 19.5% (53/272), respectively (OR 1.70; 95% CI 1.04-2.80). On multivariate analysis, inadequate empirical therapy (OR 2.26; 95% CI 1.18-4.34), onset of bacteraemia while in the intensive-care unit (OR 2.74; 95% CI 1.47-5.11), Apache II score (OR 1.17; 95% CI 1.12-1.23) and malignancy (OR 2.66; 95% CI 1.31-5.41) were independent risk factors for mortality. CTX-M was the most common ESBL type in Escherichia coli, whereas SHV predominated in Klebsiella spp. and Enterobacter spp.     

Ertapenem: a new carbapenem

Ertapenem is a new 1-β-methyl carbapenem, stable to dehydropeptidase, which binds preferable to penicillin-binding proteins (PBP) 2 and 3. Ertapenem has a broad antibacterial spectrum with MIC₉₀ values < 0.5 mg/l for penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, methicillin-sensitive Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Citrobacter spp., Klebsiella spp., Serratia spp., Proteus spp., Clostridium perfringens, Fusobacterium spp. Peptostreptococcus spp. and anaerobic Streptococcus spp. Ertapenem exhibits a bactericidal mode of action as shown by time-killing curves and exhibits a short PAE of 1.4 - 2.6 h against the Gram-positive strains but no PAE against Gram-negative strains. In an infection model in mice, it has been shown that ertapenem and imipenem were highly efficacious at a level of 2 mg/kg in bacterial clearance in comparison to ceftriaxone, cefepime, ceftazidime, cefazolin, cefonicid, cefotaxime and meropenem. In comparison to other available carbapenems, ertapenem has a long half-life of 4.5 h and is developed as a single daily dose carbapenem. The protein binding is dose-dependent and is estimated to 94% at concentrations under 100 mg/l and approximately 85% at 300 mg/l. C_max after a dose of 1 g in healthy volunteers has been estimated to 190 mg/l. Given the pharmacokinetic/pharmacodynamic data, it may be predicted that ertapenem will have an effect on most Gram-positive and Gram-negative bacteria with the exception of Pseudomonas aeruginosa, Enterococcus spp. and Acinetobacter spp. For pathogens with a MIC of 0.5 mg/l, the estimated T > MIC will be 50% (of 24 h) and for pathogens with a MIC of 1 mg/l 31%. For anaerobic bacteria with MIC values between 1 -2 mg/l, the T > MIC may not be sufficient for bacterial eradication. However, clinical trials have to confirm this hypothesis.     

Prediction of pharmacokinetics of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic,in humans using animal data

The pharmacokinetics of CS-023 (RO4908463, formerly R-115685), a novel parenteral carbapenem antibiotic, in humans was successfully predicted using the data collected from mice, rats, rabbits, and dogs; while inclusion of the monkey data led to a significant underestimation of the total plasma clearance (CL). Double logarithmic plots of CL and distribution volume at the steady-state (V_ss) vs. body weight in four animal species were linear with high correlation coefficients; and the predicted CL and V_ss values in humans agreed well with the observed values after administration of CS-023 by an intravenous drip infusion for 30?min. The plasma concentration–time profile in humans, which was predicted using a bi-exponential equation fitted to a complex Dedrick plot of the animal data, approximated the observed profile. An underestimation of CL caused by including the monkey data in a prediction is quite likely due to the net tubular reabsorption in monkeys, but not at least in rabbits, dogs, and humans.     

Colistin monotherapy vs. combination therapy: evidence from microbiological, animal and clinical studies

Colistin is commonly the last resort for treatment of infections caused by multidrug-resistant Gram-negative bacteria. In clinical practice, it is frequently used as combination therapy in order to improve its antibacterial activity, despite the consequent increase in toxicity. The available evidence from various studies (microbiological, animal and clinical studies, retrieved from the PubMed and Scopus databases) regarding the comparative effectiveness of colistin monotherapy and colistin combination therapy was evaluated. Most of the microbiological studies examined colistin monotherapy vs. combinations with rifampicin (nine studies) or carbapenems (three studies) for Pseudomonas aeruginosa or Acinetobacter baumannii infections. A synergistic effect was detected in all the studies examining the combination of colistin and rifampicin, whereas carbapenems exhibited a synergistic effect in two of three studies. Most of the animal studies examined colistin monotherapy vs. combinations with rifampicin, carbenicillin, piperacillin and imipenem for treatment of P. aeruginosa , A. baumannii or Escherichia coli infections. Mortality rates were significantly lower in the combination treatment arm in three of six relevant studies. However, data from the small number (four) of relevant human studies suggest non-inferiority of colistin monotherapy as compared with combination therapy. In conclusion, microbiological studies suggest superiority of colistin combination treatment, which is in contrast to preliminary data from studies in humans. Results from animal study data are equivocal. There is an urgent need for appropriately designed and powered clinical trials addressing this apparently controversial situation.     

Tebipenem pivoxil hydrobromide—No PICC,no problem!

Tebipenem pivoxil hydrobromide is a novel orally bioavailable prodrug of tebipenem, a carbapenem antimicrobial, that binds to penicillin-binding proteins, inhibiting the synthesis of the bacterial cell wall. This results in weakening of peptidoglycan, leading to lysis of bacterial cells. Tebipenem displays a broad spectrum of activity against anaerobic, gram-positive, and gram-negative pathogens, including extended-spectrum β-lactamase producing Enterobacterales. In a large phase 3 clinical trial (ADAPT-PO), oral tebipenem pivoxil hydrobromide 600 mg every 8 h was shown to be non-inferior to intravenous ertapenem 1 g every 24 h. Overall response at test of cure was 58.8% [264/449] in the tebipenem pivoxil hydrobromide group compared to 61.6% [258/419] in the ertapenem group for the treatment of complicated urinary tract infections, including acute pyelonephritis. At the test of cure, clinical cure rates were 93.1% and 93.6% and microbiological eradication was 59.5% and 63.5% with tebipenem pivoxil hydrobromide and ertapenem, respectively. The most common adverse reactions associated with tebipenem pivoxil hydrobromide are diarrhea, headache, and nausea. As with other carbapenems, tebipenem pivoxil hydrobromide is expected to have the potential to decrease the seizure threshold and will likely require renal dosage adjustment for patients with altered renal function due to high renal clearance. If approved in the United States, tebipenem pivoxil hydrobromide can serve as a potential oral antimicrobial option to decrease hospital length of stay and prevent hospital admissions due to resistant pathogens.     

仪征地区鲍曼不动杆菌碳青霉烯类抗菌药耐药相关酶表型和基因型分析

摘要： 目的 研究仪征地区 鲍曼不动杆菌对碳青霉烯类药物耐药相关酶表型和基因型的分布情况,探讨该 地区广泛耐药鲍曼不动杆菌对碳青霉烯类耐药的主要机制。方法 根据常规药敏试验结果将鲍曼不动杆菌临床分离株分为广泛耐药组和普通组,分别选取25株和23株用改良EDTA纸片增效法检测金属β-内酰胺酶;用碳青霉烯失活法检测碳青霉烯酶;用双纸片协同试验法和三维试验法分别检测染色体和质粒介导的AmpC酶;用PCR方法检测耐药基因blaOXA-23、blaOXA-24、blaTEM 、blaAmpC、blaVIM、blaNDM-1,对部分阳性产物进行测序比对。结果 鲍曼不动杆菌广泛耐药组和普通组分别占62.5%和37.5%。广泛耐药组中金属β-内酰胺酶阳性1株、碳青霉烯酶阳性4株、染色体和质粒介导的AmpC酶阳性分别为1株和23株;普通组中均未检出上述酶表型。广泛耐药组全部检出耐药基因blaOXA-23、blaTEM 、blaAmpC,均未检出blaOXA-24、blaVIM、blaNDM-1;普通组中blaOXA-23、blaOXA-24、blaTEM 、blaAmpC分别检出4株、5株、22株、12株,未检出blaVIM、blaNDM-1。两组比较,质粒介导的AmpC酶和blaOXA-23、blaAmpC基因携带率的差别具有统计学意义（χ2分别为40.627、34.183、15.511;P=0.000）。基因测序结果发现部分菌株的序列存在碱基插入或置换的改变。结论 鲍曼不动杆菌耐药性严重,产质粒介导的AmpC酶和blaOXA-23、blaAmpC基因介导的耐药机制是仪征地区 鲍曼不动杆菌广泛耐药的主要机制 。     

东莞地区耐碳青霉烯类肠杆菌科细菌的临床分布及耐药性

目的了解东莞地区耐碳青霉烯类肠杆菌科细菌(CRE)的临床分布及其耐药性。方法回顾性分析2015年1月—2016年6月东莞市22所二级甲等及以上参加细菌耐药监测的医疗机构的住院患者分离的CRE菌株,应用WHONET5.6软件进行耐药性分析。结果共检出CRE71株,检出率0.34%(71/20 713)。CRE来源患者主要为15~60岁(53株,74.65%);男性(46株,64.79%);来源科室主要为重症监护病房(36株,50.70%);来源标本主要为痰(34株,47.89%),其次为尿(11株,15.49%)、伤口分泌物(6株,8.45%);感染类型主要为医院感染(64株,90.14%);主要来源于三级医院(56株,78.87%)。三级医院CRE检出率为0.41%(56/13 677),二级医院为0.21%(15/7 036)。71株CRE对亚胺培南均耐药,对美罗培南耐药率81.12%,耐药率40%的药物仅有阿米卡星(21.38%)和妥布霉素(38.79%),对复方磺胺甲口恶唑的耐药率为48.23%,而对氟喹诺酮类、第三代头孢菌素及其含酶抑制剂等药物的耐药率均超过60%。结论东莞地区医疗机构CRE检出率低于全国及其他省份,应针对CRE检出的重点人群、科室采取有效预防控制措施,合理使用抗菌药物。     

MTS法与仪器MIC法检测耐碳青霉烯类肺炎克雷伯菌对替加环素敏感性的差异

目的了解耐碳青霉烯类肺炎克雷伯菌(CRKP)临床分布特点,分析菌株产酶情况及验证替加环素的体外抗菌活性。方法分析某院2015年1—12月临床患者送检标本中分离的53株CRKP的药敏结果,对目标菌株进行改良Hodge试验检测碳青霉烯酶,同时采用EDTA协同试验检测金属β-内酰胺酶,使用MIC测试条(MTS)确认仪器MIC法中替加环素药敏结果。结果 53株CRKP科室分布主要为重症监护病房(ICU)14株,占26.42%,烧伤科13株(24.53%);标本来源主要为痰23株(43.40%),创面分泌物15株(28.30%);年龄分布主要为≥60岁患者,检出35株(66.04%)。CRKP对替加环素的敏感率最高(96.2%)。经改良Hodge试验确认有48株产碳青霉烯酶,阳性率90.6%,同时15株产金属β-内酰胺酶。仪器MIC法判读为替加环素耐药的菌株经MTS法验证后均应判读为敏感。结论该院CRKP主要产碳青霉烯酶,其中部分菌株可产2类不同的β-内酰胺酶;替加环素在药敏试验中对CRKP具有良好的抗菌活性,经仪器MIC法检测为替加环素耐药的菌株须进行MTS法确认。     

Antibiotic susceptibility patterns of Pseudomonas aeruginosa at a tertiary care hospital in Gujarat, India

Objectives:

The present study was undertaken to assess the antibiotic susceptibility patterns of Pseudomonas aeruginosa at a tertiary care hospital in Gujarat, India. Due to significant changes in microbial genetic ecology, as a result of indiscriminate use of anti-microbials, the spread of anti-microbial resistance is now a global problem.

Materials and Methods:

Out of 276 culture positive samples, 56 samples of Pseudomonas aeruginosa were examined and 10 different types of specimen were collected. Microbial sensitivity testing was done using disk diffusion test with Pseudomonas species NCTC 10662, as per CLSI guidelines.

Results:

The highest number of Pseudomonas infections was found in urine, followed by pus and sputum. Pseudomonas species demonstrated marked resistance against monotherapy of penicillins, cephalosporins, fluoroquinolones, tetracyclines and macrolides. Only combination drugs like Ticarcillin + Clavulanic acid, Piperacillin + Tazobactum, Cefoperazone + Sulbactum, Cefotaxime + Sulbactum, Ceftriaxome + Sulbactum and monotherapy of amikacin showed higher sensitivity to Pseudomonas infections; however, the maximum sensitivity was shown by the Carbapenems.

Conclusion:

From the present study, we conclude that urinary tract infection was the most common hospital acquired infection. Also, co-administration of β -lactamase inhibitors markedly expanded the anti-microbial sensitivity of semi-synthetic penicillins and cephalosporins. The aminoglycoside group of antibiotics - amikacin - demonstrated maximum sensitivity against pseudomonas species. Therefore, use of amikacin should be restricted to severe nosocomial infections, in order to avoid rapid emergence of resistant strains. Periodic susceptibility testing should be carried out over a period of two to three years, to detect the resistance trends. Also, a rational strategy on the limited and prudent use of anti-Pseudomonal agents is urgently required.