Macrocyclic Antibiotics Research Articles

Chiral selectors in CE: Recent developments and applications

This review article provides an overview of the recent advances in enantioanalysis by use of electrophoretic techniques. Due to the big number of publications in the subject mentioned above, this article is focused on chiral method developments and applications published from 2008 until 2011, and it demonstrates chiral selectors used in CE. Numerous chiral selectors have been used over the years, and these include the cyclic and the linear oligo- and polysaccharides, the branched polysaccharides, the polymeric and monomeric surfactants, the macrocyclic and other antibiotics, and the crown ethers. Different dual-selector systems are also presented in this article, and the results are compared with those obtained by use of a single chiral selector. Finally, several pharmaceutical and biomedical applications based on chiral recognition are summarized.

Separation performance of vancomycin-bonded stationary phase

Vancomycin is one of the macrocyclic antibiotics with complex molecular structure. Based on the various functional groups of vancomycin, a vancomycin-bonded stationary phase using glutaraldehyde as the spacer was prepared. Its chromatographic properties in reversed-phase, ion exchange and hydrophilic phase modes were investigated separately. The prepared stationary phase showed the typical characteristic of the reversed-phase stationary, when the organic solvent content was low in the mobile phase. On the contrary, its chromatographic characteristic transformed into hydrophilic phase mode with the organic solvent content increased in the mobile phase. Owing to the amino groups of vancomycin, ion exchange mode can also be applied to the separation method development. The vancomycin-bonded stationary phase was applied to the separation of eight achiral drugs and stevioside in reversed-phase, ion exchange and hydrophilic phase modes. The separations were achieved in three different kinds of separation modes by using appropriate chromatographic conditions. The results provide guidance for the design of new types of stationary phase, and method development of chromatographic stationary phases modified by special compounds with complex construction in corresponding separation modes.

Functional diversity and pharmacological profiles of the FKBPs and their complexes with small natural ligands.

From 5 to 12 FK506-binding proteins (FKBPs) are encoded in the genomes of disparate marine organisms, which appeared at the dawn of evolutionary events giving rise to primordial multicellular organisms with elaborated internal body plan. Fifteen FKBPs, several FKBP-like proteins and some splicing variants of them are expressed in humans. Human FKBP12 and some of its paralogues bind to different macrocyclic antibiotics such as FK506 or rapamycin and their derivatives. FKBP12/(macrocyclic antibiotic) complexes induce diverse pharmacological activities such as immunosuppression in humans, anticancerous actions and as sustainers of quiescence in certain organisms. Since the FKBPs bind to various assemblies of proteins and other intracellular components, their complexes with the immunosuppressive drugs may differentially perturb miscellaneous cellular functions. Sequence-structure relationships and pharmacological profiles of diverse FKBPs and their involvement in crucial intracellular signalization pathways and modulation of cryptic intercellular communication networks were discussed.

Synergistic Effect of Flt3L and Rapamycin On Immune Tolerance Induction Via Plasmacytoid Dendritic Cells and Treg.

Abstract 2209In vivo induction and expansion of Treg is a powerful tool to limit unwanted immune responses and promote tolerance. For example, we have been successful inducing tolerance to factors VIII and FIX in hemophilic mice when the coagulation factor antigen was administered with the mTOR inhibitor rapamycin (J Thromb Haemost 7:1523 and 9:1524, Front Microbiol 2:244). Rapamycin, a macrocyclic triene antibiotic, is an immunosuppressant used to avoid transplant rejection. It suppresses the mTOR1 (and upon prolonged exposure also mTOR2) signaling pathway. Importantly, while mTOR blockage results in deletion of Teff, Treg can be induced and expanded because they are able to utilize alternative (STAT) signaling pathways. Others have shown that existing Treg can be expanded in vivo upon administration of Fms-like tyrosine kinase ligand-3 (Flt3L), a cytokine that drives generation of dendritic cells (DC) from hematopoietic progenitor cells and DC proliferation. This link between DC homeostasis and Treg is evident from the low Treg numbers found in Flt3L-deficient mice and from prevention of graft vs host disease upon treatment with Flt3L. This raises the question of whether a combined approach of rapamycin administration and Flt3L-induced DC generation would result in an optimal immune tolerance protocol. Interestingly, it has been reported that rapamycin blocks Flt3L-induced differentiation of progenitor cells into DC, indicating that Flt3L signaling in DC occurs through the mTOR pathway. However, we find in mice transgenic for an ovalbumin-specific CD4+ T cell receptor (but deficient in recombinase activating gene, rag-2) that ova peptide antigen administration results in substantially enhanced deletion of Teff and in induction of CD4+CD25+FoxP3+CD62L+GITR+ Treg when combined with these two drugs. This was accomplished by repeated administration (twice per week) of a cocktail of the 3 components. Antigen plus either drug causes Teff deletion, while rapamycin is required for Treg induction (which is further enhanced by Flt3L). Antigen, rapamycin, and Flt3L all impact changes in the numbers and frequencies of DC subsets in the spleen during the regimen. The combination all 3 components most potently directs a substantial (3–5 fold, P<0.001) increase in CD11cloPDCA+ plasmacytoid DC numbers (but not of conventional CD11chiPDCA− DCs). While pDCs are known to provide innate anti-viral responses, they also play an important role in immune tolerance. Consequently, when pDC were partially depleted with anti-PDCA, Treg induction was significantly impaired. Furthermore, the protocol caused an increase in the frequency of Indoleamine-pyrrole 2,3-dioxygenase (IDO)-expressing pDCs (which is known to activate resting Treg for suppressor activity). Finally, FLt3L-induced expansion of Treg (but not of DCs) is less effective in GITR-L −/− mice. Combined, these data demonstrate that i) Flt3L and rapamycin can be used synergistically for induction of T cell tolerance, ii) pDCs can be expanded within a rapamycin regimen, iii) and Fl3tL-induced pDC expansion facilitates Treg induction, which is partially dependent on GITR-L (a co-stimulatory molecule primarily expressed by pDCs that promotes cross talk to Treg by engagement of the GITR receptor). In order to establish relevance of this protocol for treatment of disease, we intravenously injected a F.VIII protein/rapamycin/Flt3L cocktail into hemophilia A mice (C57BL6/129 F8e16 −/−) twice per week for 1 month. Subsequently, mice received 1 month of factor replacement therapy (1 IU human FVIII, IV, once per week). Control mice without prior immune modulatory regiment or that received non-specific immune suppression (rapamycin and Flt3L only) formed high-titer inhibitors against FVIII (70–80 BU), which was significantly suppressed to ∼10 BU (P<0.001, n=5 per group). Importantly, inhibitor titers were only mildly reduced (to ∼40 BU) when Flt3L was omitted from the tolerogenic cocktail, thereby confirming the synergistic effect of flt3L and rapamycin in tolerance induction. This approach combines expansion of regulatory antigen presenting and T cells and should be of broad relevance for cell and organ transplantation as well as for treatment of inherited protein deficiencies and of autoimmune diseases. Disclosures:No relevant conflicts of interest to declare.

Sirolimus Monotherapy in Liver Transplant Recipients with De Novo Tumors

Background: Sirolimus is a macrocyclic antibiotic with antifungal, antifibrotic and immunosuppressive properties that can inhibit metastatic tumor growth and angiogenesis in vivo mouse models. It can be used as a substitute for calcineurin inhibitors (CNI) because it may reduces the likelihood of recurrent hepatocellular carcinoma (HCC) or the rate of de novo tumors in high risk transplant patients. Sirolimus protects allografts from rejection while simultaneously inhibits tumor growth. Patients and methods: Between April 1986 and December 2010 we performed 1500 orthotopic liver transplants (OLT). Fifty-seven patients received immunosuppressive treatment with sirolimus, and 26 patients of them due to de novo tumors. Currently, 20 of these patients are with sirolimus monotherapy. We analyze the outcome of liver transplant recipients who developed de novo tumors and were treated with sirolimus monotherapy. Results: There were 20 patients (18 males and 2 females), with a mean age at OLT of 50.3±12.1 years, and mean follow-up of 111.5 months. The main indications for OLT were alcoholic cirrhosis (40%), and HCV cirrhosis (15%). The most frequently immunosuppressive therapy used at discharge was tacrolimus+prednisone (55%). Premonoterapy immunosuppression most frequently used was tacrolimus+sirolimus (50%), and mycophenolate+sirolimus (40%). The mean time from OLT to sirolimus treatment was 74.6 months, and from then until the beginning of monotherapy was 9.5 months with a mean time of 24.7 months in monotherapy. The location of de novo tumors was: aerodigestive tract (45%), skin (20%), lymphoproliferative disorders (15%), urologic tract (10%), gynecological (5%), and central nervous system (5%). There was only one case of rejection (5%) in the presence of adequate drug levels, successfully treated with reintroduction of tacrolimus. Adverse effects were seen in 80% of patients, and the most frequent were: dyslipidemia (11 patients), edema (5 patients), and oral thrush (4 patients). Regarding lipid profile, mean cholesterol value before sirolimus was 168 mg/dl, and postmonotherapy was 211 mg/dl (p =0.0001). Seven patients are treated with hypolipemiant. Mean value of pre-sirolimus triglycerides was 104 mg/dl and post-monotherapy was 130 mg/dl (p=0.071). Regarding renal function, mean creatinine clearance pre-sirolimus was 70.6 ml/min and post-monotherapy was 75.6 ml/min (p>0.05). Conclusions: Sirolimus is a potent immunosuppressant with antitumoral properties, with low rate of rejection, which represents a good option OLT with de novo malignancies. More than half of the patients presented side effects, but they were well tolerated or controlled with medical treatment (dyslipidemia as the most frequent). There was an improvement of renal function showing an increase in creatinine clearance.

Rifampicin and Parkinson’s disease

Rifampicin is a macrocyclic antibiotic used extensively for the treatment of Mycobacterium tuberculosis and other mycobacterial infections. Recently, it was discovered that rifampicin exhibits neuroprotective effects. It has been shown to protect PC12 cells against MPP(+)-induced apoptosis and inhibit the expression of α-synuclein multimers. In in vitro studies, rifampicin pretreatment protects PC12 cells against rotenone-induced cell death. Qualitative and quantitative analyses uncover that rifampicin significantly suppresses rotenone-induced apoptosis by ameliorating mitochondrial oxidative stress. It reduces microglial inflammation and improves neuron survival. Our results indicate that rifampicin is cytoprotective under a variety of experimental conditions, and suggest that it may be useful in PD therapeutics. It is the aim of this paper to review the experimental neuroprotection data reported using rifampicin with a focus on the molecular and cellular mechanisms of cytoprotective effect in in vitro models of PD.

Inhibition of Lipopolysaccharide Transport to the Outer Membrane in Pseudomonas aeruginosa by Peptidomimetic Antibiotics

The asymmetric outer membrane (OM) of Gram-negative bacteria contains lipopolysaccharide (LPS) in the outer leaflet and phospholipid in the inner leaflet. During OM biogenesis, LPS is transported from the periplasm into the outer leaflet by a complex comprising the OM proteins LptD and LptE. Recently, a new family of macrocyclic peptidomimetic antibiotics that interact with LptD of the opportunistic human pathogen Pseudomonas aeruginosa was discovered. Here we provide evidence that the peptidomimetics inhibit the LPS transport function of LptD. One approach to monitor LPS transport involved studies of lipid A modifications. Some modifications occur only in the inner membrane while others occur only in the OM, and thus provide markers for LPS transport within the bacterial envelope. We prepared a conditional lptD mutant of P. aeruginosa PAO1 that allowed control of lptD expression from the rhamnose promoter. With this mutant, the effects caused by the antibiotic on the wild-type strain were compared with those caused by depleting LptD in the mutant strain. When LptD was depleted in the mutant, electron microscopy revealed accumulation of membrane-like material within cells and OM blebbing; this mirrored similar effects in the wild-type strain caused by the antibiotic. Moreover, the bacterium responded to the antibiotic, and to depletion of LptD, by introducing the same lipid A modifications, consistent with inhibition by the antibiotic of LptD-mediated LPS transport. This conclusion was further supported by monitoring the radiolabelling of LPS from [¹⁴C]acetate, and by fractionation of IM and OM components. Overall, the results provide support for a mechanism of action for the peptidomimetic antibiotics that involves inhibition of LPS transport to the cell surface.

Safety Analysis of Fidaxomicin in Comparison With Oral Vancomycin for Clostridium difficile Infections

Fidaxomicin is a novel macrocyclic antibiotic recently approved by the US Food and Drug Administration for the treatment of Clostridium difficile–associated diarrhea in adults. We reviewed safety data from nonclinical studies and clinical trials (phases 1, 2A, and 3) with fidaxomicin. In nonclinical studies, fidaxomicin was administered orally at approximately 1 g/kg/d to dogs for up to 3 months with no significant target-organ toxicities observed. A total of 728 adults have received oral fidaxomicin in clinical trials to date: 116 healthy volunteers and 612 patients with C. difficile infection. In phase 3 clinical trials, fidaxomicin was well tolerated, with a safety profile comparable with oral vancomycin. There were no differences in the incidence of death or serious adverse events between the 2 drugs. Fidaxomicin appears to be well tolerated. Continued monitoring of adverse events in the postmarketing setting will provide additional information about the full safety profile of fidaxomicin.

Macrocyclic Antibiotic Selectors in Direct HPLC Enantioseparations

In the past few decades, macrocyclic antibiotic molecules have become among the most useful chiral selectors in analytical HPLC, thin-layer chromatography and capillary electrophoresis and also in preparative methods. The macrocyclic glycopeptides, such as teicoplanin, vancomycin and ristocetin A and its analogs, are perhaps the most useful selectors for the enantioseparation of nonprotected and N-protected peptides and amino acids, β-blockers, β-agonists, nonsteroidal anti-inflammatory drugs, antineoplastics and various other biologically important compounds. This article discusses the physicochemical properties, method developments, mechanisms and applications for separations on macrocyclic antibiotics. Since comprehensive reviews on the HPLC separation of biologically important analytes on macrocyclic antibiotic chiral stationary phases have been published up to the middle of the 2000s, the recent progress covers the period 2006–2010, focussing on the HPLC applications of antibiotic phases.

Fidaxomicin: A novel macrocyclic antibiotic for the treatment of Clostridium difficile infection

The pharmacology, clinical efficacy, safety, dosage and administration, and place in therapy of fidaxomicin for the treatment of Clostridium difficile infection (CDI) are reviewed. Fidaxomicin, a macrocyclic antibiotic, has a narrow spectrum of activity against gram-positive anaerobes and is bactericidal against C. difficile. It has no activity against gram-negative bacteria. Fidaxomicin has minimal activity against Bacteroides species, which may be advantageous in maintaining colonization resistance and protecting the gastrointestinal tract from colonization by C. difficile. The minimum inhibitory concentration for 90% of organisms for fidaxomicin against C. difficile ranged from 0.0078 to 2 μg/mL in in vitro studies. After oral administration, fecal concentrations are detected and are directly proportional to the dose administered. Fidaxomicin resistance in vivo has not been reported. In clinical trials, fidaxomicin has been shown to be noninferior to vancomycin in the management of mild-to-moderately severe CDI. The adverse-effect profile of fidaxomicin is comparable to that of vancomycin. The recommended dosage for treatment of CDI is fidaxomicin 200 mg orally twice daily for 10 days. Fidaxomicin should be considered for patients who previously received treatment with metronidazole or vancomycin for CDI and who are diagnosed with recurrent CDI in which a non-NAP1/BI/027 strain is isolated. At institutions where strain typing is not available, fidaxomicin may be considered in patients with recurrent CDI who have not responded to treatment with the regimen used for the first episode of CDI. Fidaxomicin is a well-tolerated agent for the treatment of CDI and has been shown to be noninferior to vancomycin in the management of mild-to-moderately severe CDI.

Validated Densitometric TLC-Method for the Simultaneous Analysis of (R)- and (S)-Citalopram and its Related Substances using Macrocyclic Antibiotic as a Chiral Selector: Application to the Determination of Enantiomeric Purity of Escitalopram

A novel economic procedure for the simultaneous stereospecific separation and analysis of (R)- and (S)-citalopram and its related substances or impurities has been developed and validated. Chromatography was performed on silica gel 60 F254 plates with acetonitrile: methanol: water (15:2.5:2.5: v/v/v) as a mobile phase containing 1.5 mM norvancomycin or 2.5 mM vancomycin as a selector at ambient temperature. (R)- and (S)-citalopram enantiomers in presence of its related substances; citalopram citadiol and citalopram N-oxide were well separated with significant Rf values of 0.33 ± 0.02, 0.85 ± 0.02, 0.45 ± 0.02 and 0.22 ± 0.02, respectively. The spots were detected with either iodine vapor, or by use of a UV lamp followed by densitometric measurement at 239 nm. All variables affecting the resolution, such as concentration of chiral selectors, mobile phase system at different temperatures and pH-values were investigated and the conditions were optimized. Calibration plots for analysis of (R)- and (S)-enantiomers were linear in the range of 0.2-16.8 µg/10 µl (R≥0.9994, n-6) with acceptable precision (%RSD&lt;2.0) and accuracy (99.70 ± 0.85% and 99.51 ± 0.61% for (S)-citalopram and escitalopram, respectively). The limit of detection and quantification were 0.08 µg/10 µl and 0.25 µg/10 µl, respectively, for (R)- and (S)-citalopram. The proposed method is simple, selective, and robust and can be applied for quantitative determination of enantiomeric purity of (R)- and (S)-citalopram (escitalopram) as well as the related impurities in drug substances and pharmaceutical preparations. The method can be useful to investigate adulteration of pure isomer with the cheep racemic form.

CYCLODEXTRINS AND THEIR DERIVATIVES IN THE RESOLUTION OF CHIRAL NATURAL PRODUCTS: A REVIEW

Many natural compounds of biological and pharmacological interest are asymmetric and show optical activities; for example, optical isomers of ephedrine produce different amphetamine-like stimulus effects, and (S)-(-)-α-ionone (woody-like taste) and (R)-(-)-α-ionone (violet taste) possess different olfactory properties, etc. Consequently, the need for enantiomerically pure natural compounds is a growing concern for active research in pharmacology, biochemistry, and the quality control of chiral natural compounds. Different kinds of chiral selectors including crown ether, macrocyclic antibiotics, cellulose, and cyclodextrins (CDs) have been investigated to resolve optical natural products. Among them, cyclodextrins and their derivatives are the most frequently employed chiral selectors and are used as stationary phase or additives in the separation of natural products for their powerful ability in chiral resolution and the various available products in the market. This review first summarizes the utility of CDs and their derivatives as stationary or additives in the chiral resolution of natural products, typically flavanones, alkaloids, lignans, coumarins, terpenoids, amino acids, peptides, etc. In addition, analytical techniques of gas chromatography (GC), high-performance liquid chromatography (HPLC), capillary electrophoresis (CE), and capillary zone electrophoresis (CZE) applied in separation of optical natural products using CDs or their derivatives as chiral selectors are also summarized.

MTOR as a Target of Everolimus in Refractory/Relapsed Hodgkin Lymphoma

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.

Macrocyclic antibiotics: a novel class of drug for the treatment of Clostridium difficile infection

At the 2011 Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Professor David Livermore commented in his keynote address that “the good are denied as p...

Fidaxomicin: A Milestone in the Treatment ofClostridium difficileInfections New Perspectives

Clostridium difficile (C.difficile) is the major cause of antibiotic associated pseudomembranous colitis (PMC) and has surpassed Methicillin resistant Staphylococcus aureus to become the leading cause of nosocomial infections. The management of PMC involves stopping the causative agent but recurrence is a major problem. Currently, vancomycin and metronidazole are the mainstay of treatment but a recurrence rate of 25–30% after their use has been reported. Moreover, hypervirulent strains, reduced susceptibility and resistance to metronidazole further complicate the treatment. Fidaxomicin is a narrow spectrum macrocyclic antibiotic recently approved by FDA for treatment of Clostridium difficile infections. Comparative Phase 3 trials with vancomycin showed fidaxomicin to be equal to vancomycin in terms of achieving clinical cure rates but superior in terms of having lower recurrence rates and global cure rates. Lower recurrence is attributed to preservation of normal microflora by fidaxomicin. Most common side effects are gastrointestinal (GI) disorders and general disorders. Safety and efficacy of fidaxomicin prove it to be a welcome addition to existing armamentarium to combat Clostridium difficile.

High-performance liquid chromatographic enantioseparation of unusual isoxazoline-fused 2-aminocyclopentanecarboxylic acids on macrocyclic glycopeptide-based chiral stationary phases

The enantiomers of four unusual isoxazoline-fused 2-aminocyclopentanecarboxylic acids were directly separated on chiral stationary phases containing macrocyclic glycopeptide antibiotics teicoplanin (Astec Chirobiotic T and T2), teicoplanin aglycone (Chirobiotic TAG), vancomycin (Chirobiotic V) and vancomycin aglycone (Chirobiotic VAG) as chiral selectors. The effects of the mobile phase composition, the structure of the analytes and temperature on the separations were investigated. Experiments were performed at constant mobile phase compositions in the temperature range 5–45°C to study the effects of temperature, and thermodynamic parameters were calculated from plots of lnk or lnα versus 1/T. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes. It was found that the enantiomeric separations were in most cases enthalpy-driven. The sequence of elution of the enantiomers was determined in all cases.

Thiostrepton inhibits stable 70S ribosome binding and ribosome-dependent GTPase activation of elongation factor G and elongation factor 4

Thiostrepton, a macrocyclic thiopeptide antibiotic, inhibits prokaryotic translation by interfering with the function of elongation factor G (EF-G). Here, we have used 70S ribosome binding and GTP hydrolysis assays to study the effects of thiostrepton on EF-G and a newly described translation factor, elongation factor 4 (EF4). In the presence of thiostrepton, ribosome-dependent GTP hydrolysis is inhibited for both EF-G and EF4, with IC(50) values equivalent to the 70S ribosome concentration (0.15 µM). Further studies indicate the mode of thiostrepton inhibition is to abrogate the stable binding of EF-G and EF4 to the 70S ribosome. In support of this model, an EF-G truncation variant that does not possess domains IV and V was shown to possess ribosome-dependent GTP hydrolysis activity that was not affected by the presence of thiostrepton (>100 µM). Lastly, chemical footprinting was employed to examine the nature of ribosome interaction and tRNA movements associated with EF4. In the presence of non-hydrolyzable GTP, EF4 showed chemical protections similar to EF-G and stabilized a ratcheted state of the 70S ribosome. These data support the model that thiostrepton inhibits stable GTPase binding to 70S ribosomal complexes, and a model for the first step of EF4-catalyzed reverse-translocation is presented.

Advances in the enantioseparation of β‐blocker drugs by capillary electromigration techniques

β-Blocker drugs or β-adrenergic blocking agents are an important class of drugs, prescribed with great frequency. They are used for various diseases, particularly for the treatment of cardiac arrhythmias, cardioprotection after myocardial infarction (heart attack), and hypertension. Almost all β-blocker drugs possess one or more stereogenic centers; however; only some of them are administered as single enantiomers. Since both enantiomers can differ in their pharmacological and toxicological properties, enantioselective analytical methods are required not only for pharmacodynamic and pharmacokinetic studies but also for quality control of pharmaceutical preparations with the determination of enantiomeric purity. In addition to the chromatographic tools, in recent years, capillary electromigration techniques (CE, CEC, and MEKC) have been widely used for enantioselective purposes employing a variety of chiral selectors, e.g. CDs, polysaccharides, macrocyclic antibiotics, proteins, chiral ion-paring agents, etc. The high separation efficiency, rapid analysi,s and low consumption of reagents of electromigration methods make them a very attractive alternative to the conventional chromatographic methods. In this review, the development and applications of electrodriven methods for the enantioseparation of β-blocker drugs are reported. The papers concerning this topic, published from January 2000 until December 2010, are summarised here. Particular attention is given to the coupling of chiral CE and CEC methods to MS, as this detector provides high sensitivity and selectivity.

Fidaxomicin: A Macrocyclic Antibiotic for the Treatment of Clostridium difficile Infection

Clostridium difficile is an emerging pathogen in certain health care systems and community-based populations that is associated with high rates of morbidity and mortality, as well as increased costs for the health care system. As recurrence rates increase, new pharmacologic agents to treat C. difficile infection are needed. Fidaxomicin, a novel macrocyclic antibiotic, was recently approved by the United States Food and Drug Administration for the treatment of C. difficile-associated diarrhea. Originally isolated from fermentation broth of Dactylosporangium aurantiacum subspecies hamdenensis, the drug has a selective spectrum, distinctive pharmacokinetic and pharmaco-dynamic properties, and a favorable adverse-effect profile. Fidaxomicin has demonstrated similar clinical cure rates (i.e., resolution of diarrhea) compared with vancomycin, with lower recurrence rates and higher global cure rates (i.e., resolution of diarrhea without recurrence) in non-restriction endonuclease analysis type BI, North American Pulsed Field type 1 (NAP1), polymerase chain reaction ribotype 027 (or non-BI/NAP1/027) strains. Overall, fidaxomicin has been generally well tolerated, with the most common adverse effects reported as mild gastrointestinal complaints. Fidaxomicin appears to be a useful agent in the treatment of severe C. difficile infection, demonstrating decreased rates of recurrence.

Fidaxomicin—The Next Step? A New Narrow-Spectrum Macrocyclic Antibiotic for the Management of Clostridium Difficile Infection

Fidaxomicin—The Next Step? A New Narrow-Spectrum Macrocyclic Antibiotic for the Management of Clostridium Difficile Infection