Antifungal activity of immunosuppressants used alone or in combination with fluconazole

Fungal infections remain a challenge to clinicians due to the limited available antifungals. With the increasing use of antifungals in clinical practice, drug resistance has been emerging continuously, especially to fluconazole (FLC). Thus, a search for new antifungals and approaches to overcome antifungal resistance is needed. However, the development of new antifungals is usually costly and time consuming; discovering the antifungal activity of non-antifungal agents is one way to address these problems. Interestingly, some researchers have demonstrated that several classes of immunosuppressants (calcineurin inhibitors, glucocorticoids, etc) also displayed potent antifungal activity when used alone or in combination with antifungals, especially with FLC. Some of them could increase FLC's susceptibility against resistant Candida albicans significantly reversing fungal resistance to FLC. This article reviews the antifungal activities of immunosuppressants used alone or in combination with antifungals and their potential antifungal mechanisms that have been discovered so far. Although immunosuppressive agents have been identified as risk factors for fungal infection, we believe these findings are very important for overcoming drug resistance and developing new antifungals.     

Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents

Animal infection models in the pharmacokinetic/pharmacodynamic (PK/PD) evaluation of antimicrobial therapy serve an important role in preclinical assessments of new antibiotics, dosing optimization for those that are clinically approved, and setting or confirming susceptibility breakpoints. The goal of animal model studies is to mimic the infectious diseases seen in humans to allow for robust PK/PD studies to find the optimal drug exposures that lead to therapeutic success. The PK/PD index and target drug exposures obtained in validated animal infection models are critical components in optimizing dosing regimen design in order to maximize efficacy while minimize the cost and duration of clinical trials. This review outlines the key components in animal infection models which have been used extensively in antibiotic discovery and development including PK/PD analyses.     

Pros and Cons of Extrapolating Animal Data on Antifungal Pharmacodynamics to Humans

Both the incidence of invasive fungal infections and the number of antifungal agents available to clinicians have expanded significantly over the past two decades. Successes with pharmacokinetic and pharmacodynamic evaluations of other antimicrobial agents in animal models and their clinical correlations with patient outcomes have led to an increased number of studies evaluating both old and new antifungal agents. Recently, animal models have successfully defined target pharmacodynamic indices for many antifungal agents and fungal infections, but validation of these targets in human studies is frequently lacking. This article evaluates the potential pros and cons of extrapolating to humans the animal data on antifungal pharmacodynamics.     

解脲脲原体耐药性研究进展

解脲脲原体是条件致病菌。目前对其耐药性的研究主要包括对喹诺酮类、大环内酯类和四环素类3种抗菌药物相关耐药突变位点的检测,以及生物膜对病原体相关药物敏感性的影响,研究方法和检验手段仍较为传统、局限,研究方案也仅停留在对前人实验的重复。近年来,有学者将多位点序列分型技术用于解脲脲原体耐药序列类型的研究。在完善耐药机制研究的基础上,如何实现对耐药株的快速鉴定,从而指导抗菌药物的合理选择等仍需进一步研究。     

Antimicrobial Susceptibility of Standard Strains of Nontuberculous Mycobacteria by Microplate Alamar Blue Assay

In this study, 24 standard nontuberculous mycobacteria (NTM) species strains including 12 slowly growing mycobacteria strains and 12 rapidly growing mycobacteria strains were subjected to drug susceptibility testing using microplate Alamar Blue assay-based 7H9 broth. The most active antimicrobial agents against the 24 NTM strains were streptomycin, amikacin, the fluoroquinolones, and the tetracyclines. Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium bolletii, and Mycobacterium simiae are resistant to most antimicrobial agents. The susceptibility results of this study from 24 NTM standard strains can be referenced by clinicians before susceptibility testing for clinical isolates is performed or when conditions do not allow for susceptibility testing. The application of broth-based methods is recommended by the Clinical and Laboratory Standards Institute, and the documentation of the susceptibility patterns of standard strains of mycobacteria can improve the international standardization of susceptibility testing methods.     

泊沙康唑药动学-药效学及其治疗药物监测研究进展

泊沙康唑为新一代三唑类广谱抗真菌药,临床主要用于侵袭性曲霉菌病、念珠菌病的预防和难治性口咽念珠菌病的治疗,具有抗菌 活性高、耐受性好、不良反应少等特点,但其口服后生物利用度具有较大的个体差异。综述泊沙康唑混悬液的药动学影响因素、不同患者 人群的药动学特征以及群体药动学特征、药动学 / 药效学特性、治疗药物监测对临床疗效和不良反应的重要影响,以指导临床个体化用药, 提高用药的有效性和安全性。     

Evolving concepts of tumor heterogeneity

Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.     

Treating Addictions: Harm Reduction in Clinical Care and Prevention

This paper examines the role of clinical practitioners and clinical researchers internationally in establishing the utility of harm-reduction approaches to substance use. It thus illustrates the potential for clinicians to play a pivotal role in health promoting structural interventions based on harm-reduction goals and public health models. Popular media images of drug use as uniformly damaging, and abstinence as the only acceptable goal of treatment, threaten to distort clinical care away from a basis in evidence, which shows that some ways of using drugs are far more harmful than others and that punitive approaches and insistence on total abstinence as the only goal of treatment often increases the harms of drug use rather than reducing drug use. Therefore the leadership and scientific authority of clinicians who understand the health impact of harm-reduction strategies is needed. Through a review of harm-reduction interventions in Canada, the United Kingdom, the United States, Australia, Switzerland, and the Netherlands, we identify three ways that clinicians have helped to achieve a paradigm shift from punitive approaches to harm-reduction principles in clinical care and in drug policy: (1) through clinical research to provide data establishing the effectiveness and feasibility of harm-reduction approaches, (2) by developing innovative clinical programmes that employ harm reduction, and thereby (3) changing the standard of care to include routine use of these evidence-based (but often misunderstood) approaches in their practices. We argue that through promotion of harm-reduction goals and methods, clinicians have unique opportunities to improve the health outcomes of vulnerable populations.     

Antimicrobial activity of mupirocin, daptomycin, linezolid, quinupristin/dalfopristin and tigecycline against vancomycin-resistant enterococci (VRE) from clinical isolates in Korea (1998 and 2005)

It is a hot clinical issue whether newly approved antimicrobial agents such as daptomycin, linezolid, quinupristin/dalfopristin (synercid) and tigecycline are active enough to be used for infections caused by vancomycin resistant bacteria. We performed susceptibility tests for mupirocin, which is in widespread clinical use in Korea, and four new antimicrobials, daptomycin, linezolid, quinupristin/dalfopristin and tigecycline, against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium isolated from Korean patients in 1998 and 2005 to evaluate and compare the in vitro activity of these antimicrobials. Among these agents, quinupristin/dalfopristin, which is rarely used in hospitals in Korea, showed relatively high resistance to several vancomycin-resistant enterococci (VRE) isolated in 2005. Likewise, daptomycin, linezolid and tigecycline have not yet been in clinical use in Korea. However, our results showed that most of the 2005 VRE isolates were already resistant to linezolid and daptomycin (highest minimum inhibitory concentration (MIC) value >100 microg/ml). Compared with the other four antimicrobial agents tested in this study, tigecycline generally showed the greatest activity against VRE. However, four strains of 2005 isolates exhibited resistance against tigecycline (MIC >12.5 microg/ml). Almost all VRE were resistant to mupirocin, whereas all E. faecium isolated in 1998 were inhibited at concentrations between 0.8 to approximately 1.6 microg/ml. In conclusion, resistances to these new antimicrobial agents were exhibited in most of VRE strains even though these new antibiotics have been rarely used in Korean hospitals.     

LARaLink 2.0: a comprehensive aid to basic and clinical cytogenetic research

LARaLink 2.0 (Loci Analysis for Rearrangement Link) is an enabling web technology that permits the rapid retrieval of clinical cytogenetic and molecular data. New data mining capabilities have been incorporated into version 2.0, building upon LARaLink 1.0, to extend the utility of the system for applications in both the clinical and basic sciences. These include access to the Chromosomal Variation in Man database and the GEO database. Together these new resources enhance the user's ability to associate genotype with phenotype to identify potential gene candidates. Unlimited access for researchers exploring disease-gene relationships and for clinicians extending practice in patient care is available at LARaLink.bioinformatics.wayne.edu:8080/ unigene.     

Synergism between plant extract and antimicrobial drugs used on Staphylococcus aureus diseases

Searches for substances with antimicrobial activity are frequent, and medicinal plants have been considered interesting by some researchers since they are frequently used in popular medicine as remedies for many infectious diseases. The aim of this study was to verify the synergism between 13 antimicrobial drugs and 8 plant extracts--"guaco" (Mikania glomerata), guava (Psidium guajava), clove (Syzygium aromaticum), garlic (Allium sativum), lemongrass (Cymbopogon citratus), ginger (Zingiber officinale), "carqueja" (Baccharis trimera), and mint (Mentha piperita)--against Staphylococcus aureus strains, and for this purpose, the disk method was the antimicrobial susceptibility test performed. Petri dishes were prepared with or without dilution of plant extracts at sub-inhibitory concentrations in Mueller-Hinton Agar (MHA), and the inhibitory zones were recorded in millimeters. In vitro anti-Staphylococcus aureus activities of the extracts were confirmed, and synergism was verified for all the extracts; clove, guava, and lemongrass presented the highest synergism rate with antimicrobial drugs, while ginger and garlic showed limited synergistic capacity.     

Insights in the antibacterial action of poly(methyloxazoline)s with a biocidal end group and varying satellite groups

The antimicrobial activity of poly(2-methyl-1,3-oxazoline)s (PMOX) with the antimicrobial N,N-dimethyldodecylammonium (DDA) end group is greatly dependent on the nature of the group at the distal end of the polymer, the satellite group. Three comparable PMOX with a DDA end group and different satellite groups (methyl, decyl, hexadecyl) were investigated with respect to the reasons for the huge differences in their biocidal behavior. Static light scattering (SLS) and pulsed field gradient diffusion NMR measurements revealed that the samples show comparable aggregation conduct, thus, not being responsible for the varying biological activity. Experiments using different liposomal systems as models for bacterial cell membranes have been performed. It was found that differential interactions between the respective polymers and the phospholipid membranes constitute the reason for the varying effectiveness observed in antimicrobial susceptibility determinations.     

Molecular epidemiology of clinically high-risk Pseudomonas aeruginosa strains: Practical overview

In recent years, numerous outbreaks of multidrug-resistant Pseudomonas aeruginosa have been reported across the world. Once an outbreak occurs, besides routinely testing isolates for susceptibility to antimicrobials, it is required to check their virulence genotypes and clonality profiles. Replacing pulsed-field gel electrophoresis DNA fingerprinting are faster, easier-to-use, and less expensive polymerase chain reaction (PCR)-based methods for characterizing hospital isolates. P. aeruginosa possesses a mosaic genome structure and a highly conserved core genome displaying low sequence diversity and a highly variable accessory genome that communicates with other Pseudomonas species via horizontal gene transfer. Multiple-locus variable-number tandem-repeat analysis and multilocus sequence typing methods allow for phylogenetic analysis of isolates by PCR amplification of target genes with the support of Internet-based services. The target genes located in the core genome regions usually contain low-frequency mutations, allowing the resulting phylogenetic trees to infer evolutionary processes. The multiplex PCR-based open reading frame typing (POT) method, integron PCR, and exoenzyme genotyping can determine a genotype by PCR amplifying a specific insertion gene in the accessory genome region using a single or a multiple primer set. Thus, analyzing P. aeruginosa isolates for their clonality, virulence factors, and resistance characteristics is achievable by combining the clonality evaluation of the core genome based on multiple-locus targeting methods with other methods that can identify specific virulence and antimicrobial genes. Software packages such as eBURST, R, and Dendroscope, which are powerful tools for phylogenetic analyses, enable researchers and clinicians to visualize clonality associations in clinical isolates.     

艰难梭菌耐药性及耐药机制研究进展

艰难梭菌(Clostridium difficile)是医疗保健相关性腹泻最主要的病原菌。2002年起欧美地区艰难梭菌感染发病率和病死率均明显增高,耐药艰难梭菌的出现和传播更给临床治疗和预防带来了挑战。绝大多数临床分离菌对甲硝唑及万古霉素仍呈高度敏感,但已有异质性耐药或最低抑菌浓度上升的报道;对红霉素和莫西沙星等其他抗菌药物的耐药率在不同国家和地区则有较大差异。艰难梭菌对甲硝唑或万古霉素敏感性下降产生的耐药机制尚不明确,而对红霉素、氟喹诺酮类、四环素和利福霉素形成的耐药机制主要是因为作用靶点发生了改变。文章简述了近年来国际上艰难梭菌耐药性及耐药机制方面的研究进展。     

Microbial environments confound antibiotic efficacy

The increasing prevalence of bacteria that are insensitive to our current antibiotics emphasizes the need for new antimicrobial therapies. Conventional approaches to antibacterial development that are based on the inhibition of essential processes seem to have reached the point of diminishing returns. The discovery that diverse antibiotics stimulate a common oxidative cell-death pathway represents a fundamental shift in our understanding of bactericidal antibiotic modes of action. A number of studies, as discussed above, also provide hints about how intra- and extracellular metabolism can enable antibiotic resistance and tolerance. We have, nonetheless, just begun to understand the repertoire of tactics that bacteria use to evade antibiotics. Biosynthetic pathways for natural antibiotics are ancient, and numerous mechanisms for antibiotic resistance and tolerance are likely to have evolved over the past few million years. Unraveling these mechanisms will require concerted efforts by chemical biologists, microbiologists and clinicians. These efforts will benefit from the use of metabolic models and other network-biology approaches to guide investigation of processes that modulate antibiotic susceptibility. Importantly, by helping to identify common points of vulnerability as well as key differences between pathogens, these models may lead to the development of effective adjuvants, novel antibiotics and new antimicrobial strategies. There is also a crucial need to better understand how bacteria within a population cooperate to overcome antibiotic treatments. Such investigations may benefit from the use of novel chemical probes and experimental techniques to interrogate the physiology and functional dynamics of natural microbial communities. Insights gained from these studies will augment metagenomic models that can be used to identify biomolecules responsible for these cooperative strategies. Leveraging chemical biology methodologies and systems-biology approaches for further studies of microbial environments may reveal a wealth of untapped targets for the development of novel compounds to counter the growing threat of resistant and tolerant bacterial infections.     

Radiopharmaceuticals: new antimicrobial agents

Small antimicrobial peptides are good candidates for new antimicrobial agents. A scintigraphic approach to studying the pharmacokinetics of antimicrobial peptides in animals has been developed. The peptides were safely and reproducibly labelled with technetium-99m and, after intravenous injection of the radiolabelled peptides into infected animals, scintigraphy allowed real-time quantification of the peptide in the various body compartments. Antimicrobial peptides rapidly accumulated at sites of infection but not at sites of sterile inflammation, indicating that radiolabelled antimicrobial peptides could be used in detection of infection. These radiopharmaceuticals enabled the efficacy of antibacterial therapy in animals to be monitored. The scintigraphic approach provides a useful method for investigating the pharmacokinetics of small peptides in animals.