A multidisciplinary approach to antimicrobial stewardship: evolution into the 21st century

In the 21st century, we face the problems of escalating antibiotic resistance, difficult-to-treat infections and slowed new drug development. Healthcare practitioners are increasingly recognising the importance of good antimicrobial stewardship. Various strategies such as formulary management, prior approval, clinical pathways, post-prescribing evaluation and intravenous to oral conversion have been used singly or in combination to improve prescribing and reduce costs. Combining a multifaceted approach with a full-time dedicated multidisciplinary team appears to be capable of yielding satisfactory clinical and economic outcomes and most importantly, sustaining efforts of antimicrobial stewardship. The multidisciplinary approach to antibiotic management should be tailored to fit the individual needs of an institution. More data are needed to document effects on curbing resistance.     

Multidrug-resistant Gram-negative bacterial infections: the emerging threat and potential novel treatment options

Gram-negative bacterial infections constitute an emerging threat because of the development of multidrug-resistant organisms. There is a relative shortage of new drugs in the antimicrobial development pipeline that have been tested in vitro and evaluated in clinical studies. Antibiotics that are in the pipeline for the treatment of serious Gram-negative bacterial infections include the cephalosporins, ceftobiprole, ceftarolin and FR-264205. Tigecycline is the first drug approved from a new class of antibiotics called glycylcyclines, and there has been renewed interest in this drug for the treatment of some multidrug-resistant Gram-negative organisms. Carbapenems in the pipeline include tomopenem, with the approved drugs doripenem and faropenem, an oral agent, under evaluation for activity against multidrug-resistant Gram-negative bacterial infections. Polymyxins are old antibiotics traditionally considered to be toxic, but which are being used because of their activity against resistant Gram-negative organisms. New pharmacokinetic and pharmacodynamic data are available regarding the use of these agents. Finally, antimicrobial peptides and efflux pump inhibitors are two new classes of agents under development. This review of investigational antibiotics shows that several new agents will become available in the coming years, even though the pace of antimicrobial research is far from ideal.     

A new strategy for battling bacterial resistance: Turning potent,non-selective and potentially non-resistance-inducing biocides into selective ones

Antibiotic alternatives are in great need for combating antibiotic resistance. Selective delivery of a potent non-selective non-resistance-inducing biocide (C17) to MRSA was achieved by encapsulating it in solid lipid nanoparticles (SLNs) conjugated with a MRSA-specific antibody (termed as “Ab”). The C17-loaded Ab-conjugated SLNs (C17-SLN-Ab) demonstrated significantly better antimicrobial activity than its antibody free counterpart (C17-loaded SLN) and C17-loaded SLN with a non-specific IgG antibody. In a new MRSA/fibroblast co-culture assay, C17-SLN-Ab showed selective toxicity toward MRSA than fibroblast cells. C17-SLN-Ab possesses double selectivity, exhibiting higher toxicity to MRSA than to Pseudomonas aeruginosa. This same strategy was used to successfully increase C17’s selectivity against E. coli K12 by switching the conjugated anti-MRSA antibody to an anti-E. coli antibody, demonstrating versatility of this new strategy. This proof-of-concept research can be extended to other non-selective antimicrobials, against which bacterial resistance is unlikely to develop, to generate a new group of promising antibiotic alternatives.     

Antimicrobial peptides: Their physicochemical properties and therapeutic application

Antibiotic resistance has become a global public health problem, thus there is a need to develop a new class of antibiotics. Natural antimicrobial peptides have got an increasing attention as potential therapeutic agents. Antimicrobial peptides are small cationic peptides with broad antimicrobial activity. They can serve as critical defense molecules protecting the host from the invasion of bacteria. Even though they possess a different mode of action compared to traditional antibiotics, antimicrobial peptides couldn’t go into the drug markets because of problems in application such as toxicity, susceptibility to proteolysis, manufacturing cost, size, and molecular size. Nevertheless, antimicrobial peptides can be new hope in developing novel, effective and safe therapeutics without antibiotic resistance. Thus, it is necessary to discover new antimicrobial sources in nature and study their structures and physicochemical properties more in depth.     

中国制造到中国创造的远道重任

为加快国家制药行业创新体系的建设,国务院组织实施了“重大新药创制”科技重大专项,“十一五”期间专项建设取得了丰硕的成果：在平台建设方面,受到本次专项中平台建设资助的科研院所,其药物研发的硬件和软件都得到了能力上长足的提高,有些技术平台正在接近世界先进水平;在新药研发方面,国内新药的研发无论是数量还是速度都呈现了强劲的增长态势。但仔细分析专项建设期间研发的新药,可发现其中me-too的品种占据了绝大多数,不少只是“自主知识产权新药”,而非“自主创新新药”。中国制造到中国创造的突破,还需要全社会创新理念的培植,以及国家对“药物创新、技术进步”的持续支持,任重而道远。     

Regional efficacy assessment in multiregional clinical development

It is common in multiregional clinical development that data from a global trial and a local trial (in a target country) together will be used to support local filing in the target country. This approach is considered efficient drug development both globally and in the target country. However, it remains a challenge how to combine global trial data and local trial data toward local filing. To address this challenge, we propose an “interpretation-centric” evaluation criterion based on a weighted estimator that weights data from the target country and outside of the target country. This approach provides an unbiased estimate of a global treatment effect with appropriate representation of the target country patient population, where the “appropriate representation” is the desired proportion of the target country participants in a global trial and is measured by the weight parameter. This natural interpretation can facilitate drug development discussion with local regulatory agencies. Sample size of the local trial can be determined using the proposed weighted estimator. Approaches for weight determination are also discussed.     

Dual-acting hybrid antibiotics: a promising strategy to combat bacterial resistance

Importance of the field: The emerging and sustained resistance to currently available antibiotics and the poor pipeline of new antibacterials urgently call for the development of new strategies that can address the problem of growing antibacterial resistance. One such strategy is the development of dual-action hybrid antibiotics: two antibiotics that inhibit dissimilar targets in a bacterial cell covalently linked into one molecule. The possible benefits include: i) activity against drug-resistant bacteria, ii) expanded spectrum of activity and iii) reduced potential for generating bacterial resistance.

Areas covered in this review: In this article, we detail the recent activity in the design and development of dual-action hybrid drugs with a non-cleavable linker. We explore newly developed synergistic and antagonistic hybrid compounds with emphases on their potential to reduce resistance development.

What the reader will gain: Recently developed synergistic and antagonistic antibacterial drug–drug interactions and the impact of such interactions on the evolution of antibiotic drug resistance are described. Additionally, we discuss the implications of the latter observations on the development of hybrid antibiotics with the emphases on whether their synergistic or antagonistic effect will be more efficient at forestalling/reducing the development of new resistances.

Take home message: The approach of dual-acting hybrid antibiotics holds significant current promise in overcoming existing resistance mechanisms, as three of such compounds are entering clinical trials. However, the key challenge in this area should be a broader experimental demonstration of whether the “synergistic effect” or the “antagonistic effect” of the developed hybrid drug is better at preventing/reducing the evolution of resistance. This fundamental challenge must be overcome before yielding a successful drug.     

New anti-tuberculosis therapies

Tuberculosis (TB) is one of the most important global health problems in today's world. Poverty, inadequate health services, drug resistance and HIV/AIDS epidemic has hampered TB control, mostly in the developing nations, despite the worldwide availability of rifampicin-containing regimens with high antimycobacterial efficacy. Pharmaceutical companies have neglected the development of new anti-TB drugs in the last decades due to a lack of market incentives, while the public sector held only a meagre interest on TB control. However, novel initiatives, especially those merging in the Global Alliance for TB Drug Development, a public–private non-profit organisation backed by the World Health Organization, and a renewed interest in the research on Mycobacterium tuberculosis, have changed the TB pipeline in the last few years. At present, an unexpected number of new compounds are being developed in order to launch shorter and more efficient anti-TB therapies. This is the most active pipeline for TB drug development in known history.     

Increasing the success rate of lantibiotic drug discovery by Synthetic Biology

Introduction: Lantibiotics are post-translationally modified antimicrobial peptides produced by bacteria from diverse environments that exhibit an activity against pathogenic bacteria comparable to that of medically used antibiotics. The actual need for new antimicrobials in therapeutics has placed them in the pipeline of antibiotic research, due not only to their high antimicrobial activity but also to the fact that they are directed to novel targets.

Areas covered: This review covers the different approaches traditionally used in bacteriocin discovery, based on the isolation of bacteria from different habitats and determining their inhibitory spectrum against a set of relevant strains. It also elaborates on more recent approaches covering organic synthesis and semi-synthesis of lantibiotics, genomic and proteomic approaches and the application of Synthetic Biology to the field of antimicrobial drug discovery.

Expert opinion: Lantibiotics show a great potential in fulfilling the requirements for new antimicrobials. Culture-dependent techniques are still applied to lantibiotic discovery producing successful results that can be furthered by employing high-throughput screening techniques and peptidogenomics. The necessity of culturing bacteria and growing them in specific conditions for lantibiotic expression, can hamper the discovery rate, especially in exotic or unculturable bacteria. Thus, a combination of genome mining procedures, to detect novel lantibiotic-related sequences, with heterologous production systems and high-throughput screening, offers a promising strategy. Furthermore, the characterization of the mechanism of action of many lantibiotics, and the development of “plug and play” peptide biosynthesis systems, offers the possibility of initiating the rational design of non-natural lantibiotics based on structure–activity relationships.     

Synthetic cathinones: an evolving class of new psychoactive substances

Abstract

Synthetic cathinones (SCat) are amphetamine-like psychostimulants that emerged onto drug markets as “legal” alternatives to illicit drugs such as ecstasy, cocaine, and amphetamines. Usually they are sold as “bath salts,” “plant food,” or “research chemicals,” and rapidly gained popularity amongst drugs users due to their potency, low cost, and availability. In addition, internet drug sales have been replacing the old way of supplying drugs of abuse, contributing to their rapid spread. Despite the legislative efforts to control SCat, new derivatives continue to emerge on the recreational drugs market and their abuse still represents a serious public health issue. To date, about 150 SCat have been identified on the clandestine drugs market, which are one of the largest groups of new psychoactive substances (NPS) monitored by the United Nations Office on Drugs and Crime and the European Monitoring Center for Drugs and Drug Addiction. Similar to the classical stimulants, SCat affect the levels of catecholamines in the central nervous system, which results in their psychological, behavioral and toxic effects. Generally, the effects of SCat greatly differ from drug to drug and relatively little information is available about their pharmacology. The present work provides a review on the development of SCat as substances of abuse, current patterns of abuse and their legal status, chemical classification, known mechanisms of action, and their toxicological effects.     

Antimicrobial resistance,respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients

Lung infection is the main cause of morbidity and mortality in patients with cystic fibrosis and is mainly dominated by Pseudomonas aeruginosa. The biofilm mode of growth makes eradication of the infection impossible, and it causes a chronic inflammation in the airways. The general mechanisms of biofilm formation and antimicrobial tolerance and resistance are reviewed. Potential anti-biofilm therapeutic targets such as weakening of biofilms by quorum-sensing inhibitors or antibiotic killing guided by pharmacokinetics and pharmacodynamics of antibiotics are presented. The vicious circle of adaptive evolution of the persisting bacteria imposes important therapeutic challenges and requires development of new drug delivery systems able to reach the different niches occupied by the bacteria in the lung of cystic fibrosis patients.     

Antibiotics in the clinical pipeline in 2011

The emergence of multi-drug-resistant bacteria and the lack of new antibiotics in the antibiotic drug development pipeline, especially those with new modes of action, is a major health concern. This review lists the 20 new antibiotics launched since 2000 and records the 40 compounds currently in active clinical development. Compounds in the pipeline from new antibiotic classes are reviewed in detail with reference to their development status, mode of action, spectrum of activity and lead discovery. In addition, the NP or synthetic derivation is discussed, with activity against Gram-negative bacteria highlighted.     

Investigational antimicrobial drugs for bloodstream infections

Bloodstream infections, especially those arising from multidrug-resistant strains, are an alarming public health threat requiring continuous efforts for new drug development. In this review, antibiotics at an advanced development stage for the treatment of patients with bloodstream infections are identified through a search of the available literature sources. Eight compounds currently undergoing phase II and/or phase III trials were identified. Isavuconazole, a triazole, is undergoing a phase III trial for the potential treatment of candidemia. Ceftobiprol medocaril, which belongs to the cephalosporin class, is undergoing regulatory review for the treatment of skin infections. Three lipoglycopeptides, oritavancin, dalbavancin and telavancin, are being tested against Gram-positive cocci in clinical trials. Also, human lactoferrin peptide 1-11, which appears to be a promising agent, is being tested in patients with Staphylococcus epidermidis bacteremia and in patients with candidemia. Iclaprim, a novel dihydrofolate reductase inhibitor, has completed two phase III trials for complicated skin and skin structure infections. The revival of an old class of antibiotics, polymyxins, in an effort to combat resistance, has also necessitated further investigation of these agents; colistin (polymyxin E) is at the forefront of this class of compounds, and is being assessed in a phase III efficacy trial. This overview of investigational antibiotics for bloodstream infections highlights that the pace of antimicrobial drug research and development is slower than the evolution of resistance. Only eight relevant compounds were identified in the pipeline of antibiotic research, none of which demonstrate a novel mechanism of action.     

From bench to FDA to bedside: US regulatory trends for new stem cell therapies

The phrase “bench-to-bedside” is commonly used to describe the translation of basic discoveries such as those on stem cells to the clinic for therapeutic use in human patients. However, there is a key intermediate step in between the bench and the bedside involving governmental regulatory oversight such as by the Food and Drug Administration (FDA) in the United States (US). Thus, it might be more accurate in most cases to describe the stem cell biological drug development process in this way: from bench to FDA to bedside. The intermediate development and regulatory stage for stem cell-based biological drugs is a multifactorial, continually evolving part of the process of developing a biological drug such as a stem cell-based regenerative medicine product. In some situations, stem cell-related products may not be classified as biological drugs in which case the FDA plays a relatively minor role. However, this middle stage is generally a major element of the process and is often colloquially referred to in an ominous way as “The Valley of Death”. This moniker seems appropriate because it is at this point, and in particular in the work that ensues after Phase 1, clinical trials that most drug product development is terminated, often due to lack of funding, diseases being refractory to treatment, or regulatory issues. Not surprisingly, workarounds to deal with or entirely avoid this difficult stage of the process are evolving both inside and outside the domains of official regulatory authorities. In some cases these efforts involve the FDA invoking new mechanisms of accelerating the bench to beside process, but in other cases these new pathways bypass the FDA in part or entirely. Together these rapidly changing stem cell product development and regulatory pathways raise many scientific, ethical, and medical questions. These emerging trends and their potential consequences are reviewed here.     

Antibiotic discovery: history,methods and perspectives

Antimicrobial resistance is considered a major public-health issue. Policies recommended by the World Health Organization (WHO) include research on new antibiotics. No new class has been discovered since daptomycin and linezolid in the 1980s, and only optimisation or combination of already known compounds has been recently commercialised. Antibiotics are natural products of soil-living organisms. Actinobacteria and fungi are the source of approximately two-thirds of the antimicrobial agents currently used in human medicine; they were mainly discovered during the golden age of antibiotic discovery. This era declined after the 1970s owing to the difficulty of cultivating fastidious bacterial species under laboratory conditions. Various strategies, such as rational drug design, to date have not led to the discovery of new antimicrobial agents. However, new promising approaches, e.g. genome mining or CRISPR-Cas9, are now being developed. The recent rebirth of culture methods from complex samples has, as a matter of fact, permitted the discovery of teixobactin from a new species isolated from soil. Recently, many biosynthetic gene clusters were identified from human-associated microbiota, especially from the gut and oral cavity. For example, the antimicrobial lugdunin was recently discovered in the oral cavity. The repertoire of human gut microbiota has recently substantially increased, with the discovery of hundreds of new species. Exploration of the repertoire of prokaryotes associated with humans using genome mining or newer culture approaches could be promising strategies for discovering new classes of antibiotics.     

Rare diseases, orphan drugs and their regulation: questions and misconceptions

Sustained advocacy efforts driven by patients' organizations to make rare diseases a health priority have led to regulatory and economic incentives for industry to develop drugs for these diseases, known as orphan drugs. These incentives, enacted in regulations first introduced in the United States in 1983 and later in Japan, Europe and elsewhere, have resulted in substantial improvements in the treatment for patients with a range of rare diseases. However, the advent of orphan drug development has also triggered several questions, from the definition of rarity to the pricing of orphan drugs and their impact on health-care systems. This article provides an industry perspective on some of the common questions and misconceptions related to orphan drug development and its regulation, with the aim of facilitating future progress in the field.     

Discovering new antimicrobial agents

Although there has been a relentless increase in resistance to antimicrobial agents amongst important bacterial pathogens throughout the world, it is well known that the number of new antimicrobial agents being brought to the market has undergone a steady decline in the past several decades. There are a number of reasons for this, which are detailed in this article, but there is also a great deal of continuing research to find new effective antimicrobials, much of it now being carried out in academic centres and especially in small biotechnology companies, rather than by large pharma. Whilst classic screening methods and chemical modification of known antimicrobial agents continue to produce potential leads for new antimicrobial agents, a number of other approaches are being investigated. These include the search for potentiators of the activity of known antimicrobial agents and the development of hybrid agents, novel membrane-active drugs, and inhibitors of bacterial virulence and pathogenesis. A number of new bacterial targets are also being exploited, as are bacteriophages and their lytic enzymes. Given the amount of investigation presently underway, it is clear that although the antibiotic pipeline is not as promising as it was half a century ago, it is far from dry.