Looking for the new preparations for antibacterial therapy. V. New antimicrobial agents from the oxazolidinones groups in clinical trials

This paper is the fifth part of the series concerning the search for new preparations for antibacterial therapy and discussing new compounds belonging to the oxazolidinone class of antibacterial chemotherapeutics. This article presents five new substances that are currently at the stage of clinical trials (radezolid, sutezolid, posizolid, LCB01-0371 and MRX-I). The intensive search for new antibiotics and antibacterial chemotherapeutics with effective antibacterial activity is aimed at overcoming the existing resistance mechanisms in order to effectively fight against multidrug-resistant bacteria, which pose a real threat to public health. The crisis of antibiotic resistance can be overcome by the proper use of these drugs, based on bacteriological and pharmacological knowledge. Oxazolidinones, with their unique mechanism of action and favorable pharmacokinetic and pharmacodynamic parameters, represent an alternative way to effectively treat serious infections caused by Gram-positive microorganisms.

Looking for new preparations for antibacterial therapy. IV. New antimicrobial agents from the aminoglycoside, macrolide and tetracycline groups in clinical trials.

This paper is the fourth in a series on the search for new antibacterial therapies, and covers new compounds belonging to the aminoglycoside, macrolide and tetracycline groups of antibiotics. The article describes eight new substances at the clinical trial stage of development. One of them is an aminoglycoside (plazomicin), four are macrolides, collectively known as ketolides (cethromycin, solithromycin, EDP-420 and EDP-788), and the remaining three are members of the tetracycline group (omadacycline, eravacycline, sarecycline). Despite the long-term and very expensive process of collecting documentation proving the efficacy of antimicrobial drugs, there is a possibility, that particular compounds find use as active ingredients of medicinal products allowing for the triumph over the clinically relevant, dangerous bacteria.

Recent development of potent analogues of oxazolidinone antibacterial agents.

The oxazolidinones are a new and potent class of antimicrobial agents with activity mainly against Gram-positive strains. The commercial success of linezolid, the only FDA-approved oxazolidinone, has prompted many pharmaceutical companies to devote resources to this area of investigation. Until now, four types of chemical modifications of linezolid and oxazolidinone-type antibacterial agents, including modification on each of the A-(oxazolidinone), B-(phenyl), and C-(morpholine) rings as well as the C-5 side chain of the A-ring substructure, have been described. Division into sections according to side chain modification or the type of ring will be used throughout this review, although the process of synthesis usually involves the simultaneous modification of several elements of the linezolid substructure; therefore, assignment into the appropriate section depends on the structure-activity relationships (SAR) studies. This review makes an attempt to summarise the work carried out in the period from 2006 until mid-2012.

Looking for the new preparations for antibacterial therapy III. New antimicrobial agents from the quinolones group in clinical trials.

There is an essential need for searching for the new compounds effective in the treatment of infections caused by multidrug-resistant bacteria. This paper is the third part of a series associated with the exploration of new antibacterial agents and it discusses the compounds belonging to the group of quinolones and substances possessing a hybrid structure composed of the quinolone molecule and other compounds. Eleven new substances at the stage of clinical trials are presented. Three of them belong to the group of non-fluorinated quinolone (nemonoxacin, ozenoxacin and KRP-AM 1977X), while six are the quinolones containing fluorine atom at 6 position of the carbon atom in the quinoline ring (zabofloxacin, finafloxacin, delafloxacin, JNJ-Q2, WCK771 and KPI-10). The remaining two compounds possess a hybrid construction composed of the quinolone structure and other molecules (cadazolid and CBR-2092). There is a chance in the near future, that the presented compounds can extend the range of existing antibacterial drugs and provide an alternative to currently available medicinal products.

Looking for the new preparations for antibacterial therapy. II. Clinical trials; new beta-lactam antibiotics and beta-lactamase inhibitors.

To obtain a status of a medicinal product, a compound possessing potential antimicrobial activity and displaying no cytotoxicity, must undergo three phases of clinical trials to prove its therapeutic efficacy, safety and quality. Properties of the compound should be based on the results of studies meeting specific criteria. Studies should be: randomized, double-blind, involving sufficient number of volunteers, concerning the infections localized in strictly defined area and caused by identified microorganisms. After the medicinal product is authorized to be on the market, clinical trials of the fourth phase are carried out to detect adverse effects, overdose symptoms, interactions of the new drug with other medicinal products and to establish characteristic of activity among groups such as children, elderly, women in pregnancy and patients suffering from other diseases, but only if the benefits of receiving treatment outweigh the risks. This article is a second part of the series associated with searching for new antibacterial agents and it relates to performance of clinical trials and the new compounds belonging to the class of beta-lactams. Among the 9 presented compounds, candidates to become medicinal products, two belong to the cephalosporins (CXA-101, S-649266), one to carbapenems (razupenem), three to monobactams (BAL30072, BAL30376, MC-1) and three to beta-lactamase inhibitors (NXL-104, MK-7655, ME1071).

[Looking for the new preparations for antibacterial therapy. I. New antibiotics and chemotherapeutics on the market]. / Poszukiwanie nowych preparatów do terapii Przeciwbakteryjnej. I. Nowe antybiotyki i chemioterapeutyki dopuszczone do obrotu.

Development of new mechanisms of resistance and relatively easy and fast transferring of resistance genes between cells have resulted in emergence of large number of multi-drug resistant bacteria in recent years. Therefore, it is important to intensively search for new, effective compounds possessing antibacterial potential and apply them as active ingredients of medicinal products. This procedure may lead to eradication of clinically relevant, dangerous bacteria. In the twentyfirst century, three new classes of antibacterial agents: oxazolidinones, lipopeptides and pleuromutilins were introduced into the therapy. Compounds from the last group, such as tiamulin, were used previously, but only in veterinary. New 18 antimicrobial compounds, belonging to known therapeutic groups, have been registered since 2000. The largest group among antibacterial chemotherapeutics is quinolones. Group of natural compounds includes: new carbapenems, cephalosporins of V generation and other agents, like telithromycin, tigecycline, telavancin and fidaxomicin. This article is a part of the series associated with searching for new antibacterial agents and it relates to new antibiotics and antibacterial chemotherapeutics approved for the world-wide market since 2000. The next parts of this cycle will be devoted to compounds ongoing the clinical trials.

Identification and determination of related substances of ceftaroline fosamil in medicinal product by high performance liquid chromatography with diode array detection and tandem mass spectrometry.

Ceftaroline fosamil, the prodrug of ceftaroline, is an advanced-generation cephalosporin antibacterial agent approved for treatment in the European Union in 2012. The drug is dedicated to curing complicated skin and soft tissue infections and community-acquired pneumonia. The developed analytical method of high performance liquid chromatography (HPLC) followed by diode array detector (DAD) set at 243nm was used to identify and determine degradation products of ceftaroline fosamil. The elaborated method demonstrated good selectivity and linearity [r>0.998 for the range 0.8-1.2mg/mL (80-120%) and r>0.997 for the range 0.005-0.015mg/mL (0.5-1.5%)]. Limit of detection (LOD) and limit of quantification (LOQ) values were equal to 0.15µg/mL and 0.5µg/mL, respectively. The forced decomposition of ceftaroline fosamil carried out under acidic, basic, oxidative, photolytic and thermal conditions revealed the high sensitivity of ceftaroline on photodegradation and thermolysis processes. Representative ceftaroline samples were selected and analysed by LC coupled with electrospray ionisation time-of-flight mass spectrometry (LC-ESI-Q-TOF-MS) to identify the related substances that appeared under stress conditions. The LC-DAD method was transferred without any modification to LC-MS/MS system, allowing it to correlate results back to the LC-DAD method. Eight unknown signals were detected in the photolytic and thermal stress solutions for ceftaroline fosamil. The evaluated method was applied to the analysis of a medicinal product containing ceftaroline fosamil - Zinforo™, 600mg, powder for concentrate for solution for infusion. Moreover, the optimised conditions allowed for the successful separation of eight cephalosporin antibiotics possessing a molecular structure similar to ceftaroline (cefepime, cefapirin, ceftazidime, cefpirome, cefalonium, cefotaxime, cefquinome, cefalotin).