Drug monitoring and individual dose optimization of antimicrobial drugs: oxazolidinones

Introduction: Oxazolidinones are synthetic antibiotics with bacteriostatic activity against Gram-positive pathogens. Linezolid, the first marketed oxazolidinone, has shown also activity against Mycobaterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Recently, a second agent of this class (tedizolid) has been approved for the treatment of acute bacterial skin and skin structure infections, and other oxazolidinones are under active investigation in clinical trials.

Areas covered: In the present review, we consider factors that affect oxazolidinones pharmacokinetics and their role in reducing the effectiveness of these drugs and increasing the risk of drug-related adverse events. Furthermore, we review the potential role of strategies aimed at individualizing drug doses. A MEDLINE PubMed search for articles published from January 1990 to November 2015 was completed matching the terms oxazolidinones, linezolid, or tedizolid with pharmacokinetics, therapeutic drug monitoring, pharmacology or clinical trials. Moreover, additional studies were identified from the reference list of retrieved papers.

Expert opinion: Consistent evidence is now available showing that therapeutic drug monitoring and guided individual dose optimization of linezolid is justified and feasible in clinical practice to improve tolerability and possibly response to therapy. The role of individualized drug dosing regimens for other oxazolidinones remains to be proven.     

Recent developments in antibiotic agents for the treatment of complicated intra-abdominal infections

Introduction: Treatment of complicated intra-abdominal infections (cIAIs) is becoming increasingly difficult because of the widespread emergence of multidrug-resistant organisms.

Areas covered: In this review, we discuss the effectiveness of several new antibiotics for the treatment of cIAIs, including new β-lactamase inhibitor combinations (BLICs) and tetracycline-class drugs, recently developed aminoglycosides and quinolones, and novel lipoglycopeptides and oxazolidinones.

Expert opinion: Of the new BLICs, ceftolozane/tazobactam is associated with adequate clinical cure rates in patients with cIAIs. Currently, two new β-lactamase inhibitors, namely avibactam and MK-7655, are under development for clinical use in the treatment of cIAIs. Eravacycline, a novel, fully synthetic tetracycline-class drug, has been shown in Phase II and III clinical trials to be more potent than tigecycline against a significant number of multidrug-resistant organisms causing cIAIs. Plazomicin, a next-generation aminoglycoside, is a promising agent for treatment of cIAIs due to multidrug-resistant pathogens. Of the recently developed quinolones, delafloxacin and finafloxacin have been shown to be effective against pathogens that survive and multiply in mildly acidic environments, although further clinical studies examining their clinical utility in the treatment of cIAIs are warranted. Oritavancin, a new semisynthetic lipoglycopeptide agent, has been demonstrated to be a potent antibiotic in the treatment of cIAIs due to drug-resistant Gram-positive organisms. Several other new antibiotics in development also show promise and will hopefully broaden the possibilities for treatment of complicated intra-abdominal infections due to MDR pathogens.     

Discovery of novel antibacterials

Importance of the field: Antibiotics have existed in the environment for millennia, but it has only been in the past 80 years that humans have used them systematically to treat infections. This battle between humans and bacteria has led to an alarming increase in resistance to all clinically useful antibacterial agents. Thus, there is an imperative need for new agents to combat these resistant strains of bacteria.

Areas covered in this review: The topics covered include natural product screening, identification and validation of new antibacterial targets and approaches for the discovery and optimization of antibacterial compounds. Last, an assessment of the major challenges facing antibacterial discovery is presented.

What the reader will gain: The current strategies and methodologies for discovering and designing new antibacterial agents are evaluated as to their potential for generating the next round of therapeutics. Each topic is presented in a general, basic manner and will hopefully be a useful resource for students and newcomers to the field.

Take home message: New antibacterial agents are desperately needed to fight the increasing number of antibiotic resistant pathogenic bacteria. New methodologies as well as traditional approaches should both be used for discovering antibiotics to meet this serious medical need.     

Emerging drugs and alternative possibilities in the treatment of tuberculosis

Introduction: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB.

Areas covered: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB.

Expert opinion: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment.

The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation.

Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.     

In vitro evaluation of the antibacterial activity of extracts from 34 species of North American lichens

Context: The emergence of antibiotic resistant pathogens is a serious global health threat. Hence, the search for new antibiotic drugs from various natural sources should be given high priority. Lichens produce a variety of low molecular weight metabolic compounds and many cultures have utilized these compounds in traditional medicine for centuries.

Objective: Report the antibiotic properties of extracts from 34 North American lichens screened against four pathogenic bacteria.

Materials and methods: The micro-well dilution method was used to determine the minimum inhibitory concentration (MIC) of acetone and methanol extracts of 34 lichen species against four bacterial strains. Major chemical compounds in each species were identified using thin layer chromatography (TLC).

Results: Most of the lichen extracts demonstrated inhibitory effects against Staphylococcus aureus, Pseudomonas aeruginosa, and methicillin-resistant S. aureus (MRSA) with MIC values ranging from 3.9 to 500?µg/ml. In addition, extracts from three species, Letharia columbiana (Nutt.) J. W. Thomson (Parmeliaceae), Letharia vulpina (L.) Hue (Parmeliaceae), and Vulpicida canadensis (Räsänen) J.-E. Mattsson &; M. J. Lai (Parmeliaceae) (MIC?=?125–500?µg/ml) were also effective against Escherichia coli. Generally, acetone extractions were found to be more effective than methanol extractions.

Discussion and conclusion: Results of this study show that lichen extracts provide significant antimicrobial activity against both Gram-positive and Gram-negative bacteria. These results suggest that lichens may be an important potential source of antibacterial drugs.     

Discovery and characterization of ß-1,6-glucan inhibitors

Importance of the field: The increasing number of patient populations at high risk of opportunistic infections has highlighted the need for the improvement in antifungal treatments. Due to the limited number of currently available antifungal drugs and the concerns for possible prevalence of resistant strains, drugs with a new mechanism of action are most desirable.

Areas covered in this review: Although the cell wall is considered to be one of the ideal targets for antifungal drugs, insufficient information on the enzymes involved in its construction has restricted the discovery of new inhibitors. This review introduces the recent discovery of the inhibitors of β-1,6-glucan, one of the essential components of the yeast cell wall.

What the reader will gain: The readers will gain the strategy to obtain the β-1,6-glucan synthesis inhibitors, their mechanisms of actions, and antifungal activities in vitro as well as in vivo.

Take home message: The β-1,6-glucan inhibitors are considered to be promising candidates for new antifungal drugs which could give valuable options in a clinical setting, although their usage may be limited because of their fungistatic action and limited spectrum. Additionally, they can be useful tools in the study on β-1,6-glucan synthesis and the virulence of Candida species.     

Drug treatments for prosthetic joint infections in the era of multidrug resistance

Introduction: Despite many advances, the management of prosthetic joint infection is still a complex issue. Moreover, in recent years the problem of antimicrobial resistance has emerged as an important challenge.

Areas covered: We analysed recent advances in different aspects of prosthetic joint infections. The importance of biofilms needs to be considered for antibiotic selection because, when embedded in these structures, bacteria acquire resistant behaviour. Moreover, the presence of resistance mechanisms in some species of organisms increases the difficulty of management. In this sense, the growing importance of methicillin-resistant staphylococci, multidrug-resistant Enterobacteriaceae or Pseudomonas aeruginosa is of increasing concern. Together with these organisms, others with constitutive resistance against most antibiotics (like Enterococcus sp., mycobacteria or fungi) represent a similar problem for selection of therapy. Research into new materials that can be used as drug carriers opens a new field for management of these infections and will likely come to the front line in the coming years.

Expert opinion: Individualised therapies should carefully consider the aetiology, pathogenesis and antimicrobial susceptibility. Satisfactory clinical outcome could be further fostered by enhancing the multidisciplinary approach, with better collaboration in the antibiotic selection and the surgical management.     

Solution NMR studies on Helicobacter pylori proteins for antibiotic target discovery

ABSTRACT

Introduction: Helicobacter pylori (H. pylori) is a well-known widespread pathogenic bacterium that survives in the extremely acidic conditions of the human gastric mucosa. The global prevalence of H. pylori-resistant antibiotics has become an emerging issue in the 21st century and has necessitated the development of novel antibiotic drugs. Many efforts have aimed to discover antibiotic target proteins of H. pylori based on its genome of more than 1600 genes.

Areas covered: This article highlights NMR spectroscopy as a valuable tool for determining the structure and dynamics of potential antibiotic-targeted proteins of H. pylori and evaluating their modes of interaction with native or synthetic binding partners. The residue-specific information on binding in solution provides a structural basis to identify and optimize lead compounds.

Expert opinion: NMR spectroscopy is a powerful method for obtaining details of biomolecular interactions with a broad range of binding affinities. This strength facilitates the identification of the binding interface of the encounter complex that plays an integral role in a variety of biological functions. This low-affinity complex is difficult to crystallize, which impedes structure determination using X-ray crystallography. Additionally, the relative binding affinities can be predicted from the type of spectral change upon binding. High-resolution NMR spectroscopy in combination with advanced computer simulation would provide more confidence in complex structures. The application of NMR to studies of the H. pylori protein could contribute to the development of these targeted novel antibiotics.     

New molecular targets beyond KIT and PDGFRA in gastrointestinal stromal tumors: present and future

Introduction: The biological complexity of gastrointestinal stromal tumors (GISTs) and the concomitant increase in patients' life expectancy have enhanced the need for new therapeutic options to overcome the development of primary and secondary resistance to tyrosine kinase inhibitors. Aided by more sophisticated molecular biology techniques, researchers have recently sought to identify new therapeutic targets with a defined role in GISTs pathogenesis and a potential application in clinical practice.

Areas covered: The first aim of this review is to describe new targets and drugs in GISTs, alone or in combination, both in pre-clinical and clinical settings. The second aim is to discuss the criticism in this field, the role of molecular biology, and future perspectives in light of the recent development of more sophisticated whole-genomic technologies.

Expert opinion: Several targets involved in GIST pathogenesis have been identified and novel biological drugs have recently been developed, offering new treatment options in the scenario of GIST therapy. However, the identification of new therapeutic targets represents a long process and requires a global overview of the problem and a multi-step approach to convert an initial intuition or casual finding into a systematic analytical process.     

Targeting integrins in hepatocellular carcinoma

Introduction: Integrins, which are heterodimeric membrane glycoproteins, consist of a family of cell-surface receptors mediating cell–matrix and cell–cell adhesion. Analysis of tumor-associated integrins has revealed an important relationship between integrins and tumor development, bringing new insights into integrin-based cancer therapies. Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide and integrins appeal to be a novel group of potential therapeutic targets for HCC.

Areas covered: This review summarizes the current knowledge of integrins involved in HCC and the potential of integrin-targeted drugs in HCC therapy. A brief introduction on the structure, biological function and regulatory mechanism of integrins is given. The distinct expression patterns and biological functions of HCC-associated integrins are described. Finally, the current situation of integrin-based therapies in HCC and other tumor types are extensively discussed in the light of their implications in preclinical and clinical trials.

Expert opinion: To date, increasing numbers of integrin-targeted drugs are undergoing development and they exhibit diverse effects in cancer clinical trials. Tumor heterogeneity should be emphasized in developing effective integrin-targeted drugs specific for HCC. A better understanding of how integrins cooperatively function in HCC will assist in designing more successful integrin-targeted therapeutic drugs and corresponding approaches.     

Emerging therapies in metastatic bone pain

Introduction: Current treatment for metastatic bone pain is mainly palliative. Recent insights into the molecular mechanisms involved in bone metastases have led to the identification of promising therapeutic targets. This review offers an update of preclinical and clinical data on new drugs for metastatic bone pain.

Areas covered: Biphosphonates are the gold standard of bone-targeted therapy in bone metastases, for their anti-resorptive and analgesic effects. New drugs aim at breaking the ‘vicious cycle’ of bone metastatic disease, due to the bidirectional interaction between cancer cells and bone microenvironment. Osteoprotegerin, RANK/RANKL interaction, cathepsin K, the Wnt/beta-catenin pathway and sclerostin are emerging targets for modulation of cancer-induced bone desorption. Other promising targets are those expressed in cancer cells that metastasize to bone, including Src, nerve growth factor, endothelin A, TGF-beta and CXCR4. Interesting therapeutic options include targets on nociceptors that innervate the bone, such as TPRV1, Trk and cannabinoid receptors.

Expert opinion: Emerging therapies promise, in the next 10 years, a significant expansion in the array of therapeutic options for bone metastases. Most of these drugs are still in an early phase of development. Further clinical trials are needed to support the evidence of their efficacy and tolerability profile.     

The anti-mitochondrial antifungal assay for the discovery and development of new drugs

Introduction: New targets and drugs are constantly searched for to effectively combat fungal infections and diseases such as cancer. Mitochondria, as the main powerhouses of eukaryotic cells, must be regarded as important targets for the development of new therapies. This has lead to the development of a fungal assay that shows potential in the selection of new antifungal and anticancer drugs as well as the identification of compounds that are toxic to human mitochondria.

Areas covered: In this review the authors discuss the development of a potential method of drug discovery that targets mitochondrial function. The authors cover the application of new nanotechnology as well as fungal systematic research where the link between fungal fruiting structures, cell growth, increased mitochondrial activity and susceptibility to a variety of anti-mitochondrial drugs is assessed.

Expert opinion: This assay shows potential to select anti-mitochondrial drugs as a first screen. This should be followed up by more specific in vitro and in vivo tests to pinpoint the type of anti-mitochondrial activity exerted by these drugs, if any. This is because the possibility exists that compounds regarded as anti-mitochondrial may not inhibit mitochondrial function but other fruiting structure developmental stages and therefore yield false positives. To enhance our knowledge on how these drugs act at the structural level, the authors recommend Nano Scanning Auger Microscopy as the tool of choice.     

The preclinical discovery of amyotrophic lateral sclerosis drugs

Introduction: Amyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig's disease, is characterized by the progressive loss of cells in the brain and spinal cord that leads to debilitation and death in 3 – 5 years. Only one therapeutic drug, riluzole, has been approved for ALS and this drug improves survival by 2 – 3 months. The need for new therapeutics that can postpone or slow the progression of the motor deficits and prolong survival is still a strong unmet medical need.

Areas covered: Although there are a number of drugs currently in clinical trials for ALS, this review provides an overview of the most promising biological targets and preclinical strategies that are currently being developed and deployed. The list of targets for ALS was compiled from a variety of websites including individual companies that have ALS programs and include those from the author's experience.

Expert opinion: Progress is being made in the identification of possible new therapeutics for ALS with recent efforts in understanding the genetic causes of the disease, susceptibility factors and the development of additional preclinical animal models. However, many challenges remain in the identification of new ALS therapeutics including: the use of relevant biomarkers, the need for an earlier diagnosis of the disease and additional animal models. Multiple strategies need to be tested in the clinic in order to determine what will be effective in patients.     

Drug-induced parkinsonism

Introduction: Drug-induced parkinsonism (DIP) is the second most common cause of parkinsonism after idiopathic Parkinson's disease (iPD). Initially reported as a complication of antipsychotics, it was later recognized as a common complication of antidepressants, calcium channel antagonists, gastrointestinal prokinetics, antiepileptic drugs and many other compounds. Despite being a major health problem in certain populations, it seems to be frequently overlooked by the medical community.

Areas covered: This paper approaches the concept of DIP, reviews its epidemiology, clinical features and ancillary tests recommended for a correct diagnosis. The authors discuss the different drugs and its pathogenic mechanisms. The relevance of an early recognition and recommendations for a correct management are commented.

Expert opinion: Prescribers need to remain vigilant for DIP, particularly in the elderly, patients taking multiple drugs and those with genetic risk factors involved in iPD. Cessation of the causing agent is the main treatment and there is no evidence of benefit for the use of anticholinergics or levodopa. If the medication cannot be withdrawn, it should be switched to agents with a lower risk of DIP.     

Comparison of in vitro activity of ertapenem with other carbapenems against extended-spectrum beta-lactamase-producing Escherichia coli and Kleibsella species isolated in a tertiary children's hospital

Objective: The purpose of this study was to evaluate the susceptibility of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae clinical isolates to ertapenem in a tertiary pediatric care center in Turkey.

Design/methods: All isolates of ESBL-producing Enterobacteriaceae were collected from clinical specimens from children, and susceptibility tests were done using the Vitek 2 compact system.

Results: Ninety-nine per cent of the ESBL-producing Escherichia coli isolates were found to be susceptible to ertapenem, 99.5% to imipenem and 100% to meropenem. In the Klebsiella species, 91.5% of the isolates were susceptible to ertapenem, 99.3% to imipenem and 100% to meropenem.

Conclusion: The results of our data, including isolates from children, showed that ertapenem had high in vitro activity against the majority of the ESBL-producing E. coli and Klebsiella species, as reported in previously published studies. However, additional clinical studies are required to assess the clinical activity of ertapenem and the clinical importance of the resistant isolates.