New definitions of extended‐spectrum β‐lactamase conferring worldwide emerging antibiotic resistance

Although there is no consensus of the precise definition of ESBL, three kinds of ESBL definitions have been proposed. First, the classical definition includes variants derived from TEM‐1, TEM‐2, or SHV‐1; K1 (KOXY) of Klebsiella oxytoca. Second, the broadened definition has stretched the classical definition of ESBL to include: (1) β‐lactamases (CTX‐M‐ESBLs, GES‐ESBLs, and VEB‐ESBLs), with spectra similar to those of TEM and SHV variants (designated as TEM‐ and SHV‐ESBLs, respectively) but derived from other sources; (2) TEM and SHV variants with borderline ESBL activity; e.g., TEM‐12; and (3) various β‐lactamases conferring wider resistance than their parent types but not meeting the definition for group 2be; e.g., OXA‐types (OXA‐ESBLs) and mutant AmpC‐types (AmpC‐ESBLs), with increased activity against oxyimino‐cephalosporins and with resistance to clavulanic acid. Third, the all‐inclusive definition includes: (1) ESBL_A (named for class A ESBLs); (2) ESBL_M (miscellaneous ESBLs), which has been subdivided into ESBL_M‐C (class C; plasmid‐mediated AmpC) and ESBL_M‐D (class D); and (3) ESBL_CARBA (ESBLs with hydrolytic activity against carbapenems), which has been subdivided into ESBL_CARBA‐A (class A carbapenemases), ESBL_CARBA‐B (class B carbapenemases), and ESBL_CARBA‐D (class D carbapenemases). The consensus view about the ESBL definition is that the classical ESBL definition must be expanded to class A non‐TEM‐ and non‐SHV‐ESBLs (CTX‐M‐, GES‐, VEB‐ESBLs, etc.). However, these three definitions evoke rational debate on the question “Which would be included in the category of ESBLs among AmpC‐ESBLs, OXA‐ESBLs, and/or carbapenemases?” Therefore, there is a great need for consensus in the precise definition of ESBL. © 2010 Wiley Periodicals, Inc. Med Res Rev 32:216‐232, 2012     

Immunology of cardiovascular disease

Antimicrobial peptides (AMPs) are evolutionarily conserved molecules involved in the defense mechanisms of a wide range of organisms. Produced in bacteria, insects, plants and vertebrates, AMPs protect against a broad array of infectious agents. In mammals these peptides protect against bacteria, viruses, fungi, and certain parasites. Recently, novel biologic effects of AMPs have been documented such as endotoxin neutralization, chemotactic and immunomodulating activities, induction of angiogenesis and wound repair. Thus these ancestral molecules are crucial components of the innate immune system and attractive candidates for novel therapeutic approaches.     

Postoperative Chemotherapy with Cisplatin and 5-Fluorouracil in Cancer of the Oral Cavity and the Oropharynx - Long-Term Results

Abstract

Adjuvant chemotherapy has not yet been proven to have a survival benefit for patients with head and neck cancer. Studies dealing with this topic have had several faults like mingling tumor localizations and treatment modalities. To re-examine the role of postoperative chemotherapy in oral cavity cancer, a single-center study was conducted with the attempt to have higher homogeneity. 122 patients with primary squamous cell carcinoma of the lip, the oral cavity and the oropharynx have been treated with 100 mg/m² cisplatin bolus infusion and 120-h continuous infusion of 1000 mg/m² 5-fluorouracil following radical surgery; 99 patients completed all 3 cycles. The disease-free and overall survival are reported and compared to a control group of 161 patients with cancer of the lip, the oral cavity and oropharynx treated only with surgery, and a treatment-dependent prognostic index. After a median follow-up of 79 months (range 5-18 years), the current 5-year overall survival of the chemotherapy group was 67% and the 5-year disease-free survival was 57% while the respective data for the control group are 46% and 40%. This difference is statistically significant. The comparison with the prognostic index confirmed this result. The chemotherapy group suffered from fewer local and more neck relapses and had a much longer relapse latency (29 months versus 8 months). The toxicity of the chemotherapy regimen was tolerable. In a homogeneous population with resectable oral cavity and oropharyngeal cancer, postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil resulted in a high overall survival rate which was significantly better than in a comparable population treated only with surgery and better than the survival expectation calculated with the help of a prognostic index. A prospective randomized study of postoperative chemotherapy versus control, exclusively in patients with oral cancer, is warranted.     

Quinoline based polymeric drug for biological applications: synthesis,characterization, antimicrobial,and drug releasing studies

Novel acrylate monomer of quinoline-based chalcone 1-(4-(7-chloroquinolin-4-ylamino)phenyl) acrylate (CPA) was synthesized using (4-(2-chloroquinolin-5-ylamino)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (CPE) and acryloyl chloride. CPA is characterized by different techniques like IR, ¹H NMR and UV–visible spectrometry techniques. Poly(CPA), poly(CPA-co-AA) and poly(CPA-co-HEA) are prepared by solution polymerization technique using CPA, acrylic acid (AA) and hydroxyethylacrylate (HEA), respectively. The antimicrobial activities of the compounds are tested using four different micro-organisms. In vitro cumulative drug release studies are done using UV visible spectroscopic technique. The molecular weights of these polymers are found to be around 5000 g/mol. The synthesized polymers showed two stages of thermal decomposition temperature centred around 220 and 350 °C, respectively. The antimicrobial activity of the polymer sample is found to be very high and especially for gram-negative bacteria with a minimum value of 3.91 μg/mL. The in vitro drug-releasing rate is dependent on the comonomer, pH and temperature of the medium.     

Current treatment of sepsis and endotoxaemia

This article reviews the new criteria for selecting the proper antimicrobial agent and dosage regimen for standard treatment of severe sepsis, with the intention of preventing septic shock. After introducing new concepts on the pathogenesis of sepsis and septic shock, the authors analyse the parameters of β-lactam antibacterial activity, the antibiotic-induced release of bacterial endotoxin and the interrelationships between pharmacokinetics and pharmacodynamics of antibiotics in the search for an optimum dosage regimen of antimicrobial mono- or polytherapy for severely ill septic patients admitted to the intensive care unit. The mortality rate resulting from severe bacterial sepsis, particularly that associated with shock, still approaches 50% in spite of appropriate antimicrobial therapy and optimum supportive care. Bacterial endotoxins that are part of the cell wall are one of the cofactors in the pathogenesis of sepsis and septic shock and are often induced by antimicrobial chemotherapy, even if administered rationally. Not all antimicrobial agents are equally capable of inducing septic shock; this is dependent on their mechanism of action rather than on the causative pathogen species. The quantity of endotoxin released depends on the drug dose and whether filaments or spheroplast formation predominate. Some antibiotics, such as carbapenems, ceftriaxone, cefepime, glycopeptides, aminoglycosides and quinolones, do not have the propensity to provoke septic shock because their rapid bactericidal activity induces mainly spheroplast or fragile spheroplast-like bacterial forms.     

Virulence as a target for antimicrobial chemotherapy

Bacterial resistance to present day antibiotics has become a dangerous threat to public health. Consequently, the pharmaceutical industry must provide new agents and novel classes to combat bacterial disease and to stay a step ahead of the rapid evolution of bacterial resistance mechanisms. The need for novel antibacterials has resulted in a search for previously unexplored targets for chemotherapy, utilising the new techniques of genomics to identify them. Several targets currently under investigation are involved in the process of bacterial virulence. These targets are unique in that their inhibition, by definition, should interfere with the process of infection rather than with bacterial viability. If successful, virulence inhibition may represent a ‘kinder, gentler’ approach to chemotherapy in which the pathogen is disarmed rather than killed outright.     

联合用药在治疗骨科术后耐甲氧西林金黄色葡萄球菌感染的临床分析

目的 探讨骨科植入物相关耐甲氧西林金黄色葡萄球菌（MRSA）感染患者临床合理应用抗菌药物的方法。方法 在2006～2010年对在宽城满族自治县医院治疗的骨科器械植入MRSA感染患者进行回顾性研究。结果 在中位随访时间391 d内有18例患者（35%）MRSA治疗失败。利用Cox比例危险率模型,发现手术保留人工植入物[风险比（HR）,4.9;95%CI,1.3～18.2;P=0.017]及单一药物抗菌治疗（HR,4.4;95%CI,1.2～16.3;P=0.025）为清创术后治疗失败的独立预测因素。结论 患有骨科器械植入MRSA的患者需要保留植入物时,应考虑联合使用抗菌药物。