Antimicrobial-resistant ESKAPE ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens represent a global threat to human health. The acquisition of antimicrobial resistance genes by ESKAPE pathogens has reduced the treatment options for serious infections, increased the burden of disease, and increased death rates due to treatment failure and requires a coordinated global response for antimicrobial resistance surveillance. This looming health threat has restimulated interest in the development of new antimicrobial therapies, has demanded the need for better patient care, and has facilitated heightened governance over stewardship practices.

Antimicrobial resistance in ESKAPE pathogens

Klebsiella pneumoniae is a common cause of antimicrobial-resistant opportunistic infections in hospitalized patients. The species is naturally resistant to penicillins, and members of the population often carry acquired resistance to multiple antimicrobials. However, knowledge of K. pneumoniae ecology, population structure or pathogenicity is relatively limited. Over the past decade, K. pneumoniae has emerged as a major clinical and public health threat owing to increasing prevalence of healthcare-associated infections caused by multidrug-resistant strains producing extended-spectrum β-lactamases and/or carbapenemases. A parallel phenomenon of severe community-acquired infections caused by 'hypervirulent' K. pneumoniae has also emerged, associated with strains expressing acquired virulence factors. These distinct clinical concerns have stimulated renewed interest in K. pneumoniae research and particularly the application of genomics. In this Review, we discuss how genomics approaches have advanced our understanding of K. pneumoniae taxonomy, ecology and evolution as well as the diversity and distribution of clinically relevant determinants of pathogenicity and antimicrobial resistance. A deeper understanding of K. pneumoniae population structure and diversity will be important for the proper design and interpretation of experimental studies, for interpreting clinical and public health surveillance data and for the design and implementation of novel control strategies against this important pathogen.

Population genomics of Klebsiella pneumoniae.

The evolution of Staphylococcus aureus during the modern antibiotic era has been delineated by distinct strain emergence events, many of which include acquisition of antibiotic resistance. The relative high burden of methicillin-resistant S. aureus (MRSA) in healthcare and community settings is a major concern worldwide. Vancomycin, a glycopeptide antibiotic that inhibits cell wall biosynthesis, remains a drug of choice for treatment of severe MRSA infections. S. aureus strains exhibiting increased resistance to vancomycin, known as vancomycin intermediate-resistant S. aureus (VISA) (MIC = 4-8 µg/mL), were discovered in the 1990s. The molecular basis of resistance in VISA is polygenic and involves stepwise mutations in genes encoding molecules predominantly involved in cell envelope biosynthesis. S. aureus isolates with complete resistance to vancomycin (MIC ≥ 16 µg/mL) are termed vancomycin-resistant S. aureus (VRSA)-they were first reported in the U.S. in 2002. Resistance in VRSA is conferred by the vanA gene and operon, which is present on a plasmid. Although treatment of VRSA infections is challenging, the total number of human VRSA infections to date is limited (14 in the U.S.). By comparison, the burden of VISA is relatively high and the molecular mechanisms of resistance are less well-defined. VISA are associated with persistent infections, vancomycin treatment failure, and poor clinical outcomes. Here, we review in brief progress made toward understanding the acquisition of antibiotic resistance in S. aureus, with an emphasis on the molecular mechanisms underlying vancomycin resistance.

Vancomycin Resistance in Staphylococcus aureus .

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds3,4. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s2. We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.

A new antibiotic selectively kills Gram-negative pathogens

SUMMARY New Delhi metallo-β-lactamase (NDM) is a metallo-β-lactamase able to hydrolyze almost all β-lactams. Twenty-four NDM variants have been identified in >60 species of 11 bacterial families, and several variants have enhanced carbapenemase activity. Klebsiella pneumoniae and Escherichia coli are the predominant carriers of blaNDM, with certain sequence types (STs) (for K. pneumoniae, ST11, ST14, ST15, or ST147; for E. coli, ST167, ST410, or ST617) being the most prevalent. NDM-positive strains have been identified worldwide, with the highest prevalence in the Indian subcontinent, the Middle East, and the Balkans. Most blaNDM-carrying plasmids belong to limited replicon types (IncX3, IncFII, or IncC). Commonly used phenotypic tests cannot specifically identify NDM. Lateral flow immunoassays specifically detect NDM, and molecular approaches remain the reference methods for detecting blaNDM. Polymyxins combined with other agents remain the mainstream options of antimicrobial treatment. Compounds able to inhibit NDM have been found, but none have been approved for clinical use. Outbreaks caused by NDM-positive strains have been reported worldwide, attributable to sources such as contaminated devices. Evidence-based guidelines on prevention and control of carbapenem-resistant Gram-negative bacteria are available, although none are specific for NDM-positive strains. NDM will remain a severe challenge in health care settings, and more studies on appropriate countermeasures are required.

NDM Metallo-β-Lactamases and Their Bacterial Producers in Health Care Settings.

Carbapenem resistant K. pneumoniae (CRKP) has aroused widespread attention owing to its very limited therapeutic options, and this strain has increased rapidly in recent years. Although it is accepted that drug resistance is associated with increased mortality in general, but some other studies found no such relationship. To estimate mortality of patients infected with CRKP in general and analyze factors for mortality of this infection, thus, we conducted this systematic review and meta-analysis. A systematic literature review of relevant studies published until December 2015 was conducted. We selected and assessed articles reporting mortality of patients infected with CRKP. Pooled mortality was 42.14% among 2462 patients infected with CRKP versus 21.16% in those infected with carbapenem-susceptible K. pneumoniae (CSKP). The mortality of patients with bloodstream infection (BSI) or urinary tract infection was 54.30 and 13.52%, respectively, and 48.9 and 43.13% in patients admitted to the intensive care unit (ICU) or who underwent solid organ transplantation (SOT). Mortality was 47.66% in patients infected with K. pneumoniae carbapenemase-producing K. pneumoniae and 46.71% in those infected with VIM-producing K. pneumoniae. Geographically, mortality reported in studies from North America, South America, Europe, and Asia was 33.24, 46.71, 50.06, and 44.82%, respectively. Our study suggests that patients infected with CRKP have higher mortality than those infected with CSKP, especially in association with BSI, ICU admission, or SOT. We also considered that patients’ survival has a close relationship with their physical condition. Our results imply that attention should be paid to CRKP infection, and that strict infection control measures and new antibiotics are required to protect against CRKP infection.

/pdf/systematic-review-and-meta-analysis-of-mortality-of-patients-fe0h4si87c.pdf

Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae

Background 
Vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are associated with vancomycin treatment failure, and are becoming an increasing public health problem. Therefore, we undertook this study of 91 published studies and made subgroup comparisons of hVISA/VISA incidence in different study years, locations, and types of clinical samples. We also analyzed the genetic backgrounds of these strains.


Methods 
A systematic literature review of relevant articles published in PubMed and EMBASE from January 1997 to August 2014 was conducted. We selected and assessed journal articles reporting the prevalence rates of hVISA/VISA.


Results 
The pooled prevalence of hVISA was 6.05% in 99,042 methicillin-resistant S. aureus (MRSA) strains and that of VISA was 3.01% in 68,792 MRSA strains. The prevalence of hVISA was 4.68% before 2006, 5.38% in 2006–2009, and 7.01% in 2010–2014. VISA prevalence was 2.05%, 2.63%, and 7.93%, respectively. In a subgroup analysis of different isolation locations, the prevalence of hVISA strains was 6.81% in Asia and 5.60% in Europe/America, and that of VISA was 3.42% and 2.75%, respectively. The frequencies of hVISA isolated from blood culture samples and from all clinical samples were 9.81% and 4.68%, respectively, and those of VISA were 2.00% and 3.07%, respectively. The most prevalent genotype was staphylococcal cassette chromosome mec (SCCmec) II, which accounted for 48.16% and 37.74% of hVISA and VISA, respectively. Sequence Type (ST) 239 was most prevalent.


Conclusion 
The prevalence of hVISA/VISA has been increasing in recent years, but has been grossly underestimated. Its incidence is higher in Asia than in Europe/America. hVISA is isolated from blood culture samples more often than from other samples. These strains are highly prevalent in epidemic MRSA strains. This study clarifies the epidemiology of hVISA/VISA and indicates that the detection of these strains and the control of nosocomial infections must be strengthened.

Systematic Review and Meta-Analysis of the Epidemiology of Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Isolates

Background: While many studies have concluded that local traffic density is positively associated with childhood leukemia, the results are inconsistent. We therefore performed a meta-analysis to assess the relationship between traffic density and the risk of childhood leukemia. Methods: A systematic literature review was carried out using PubMed, EMBASE, and the Cochrane Library from January 1979 to December 2013. We selected and assessed journal articles evaluating the relationship between local traffic density and the risk of leukemia in children. The analysis was carried out using STATA version 12.0. Results: A total of 11 articles, including 12 estimates of effect, were included in our meta-analysis. The summary effect size from the random-effects model, expressed as an odds ratio, was 1.03 (95% CI: 0.98-1.09, p=0.002). No significant association between traffic density and the risk of childhood leukemia was found. Similar conclusions were found on subgroup analysis. Conclusions: The results of our meta-analysis suggested no association between traffic density and the risk of childhood leukemia. This implies that living in close proximity to roads with heavy traffic may not increase the risk of childhood leukemia. However, further high-quality prospective trials are needed to support these results.

No association between traffic density and risk of childhood leukemia: a meta-analysis.

Background/aims LukS-PV is a component of Panton-Valentine leukocidin (PVL). We have previously demonstrated that LukS-PV potently promoted differentiation and induced apoptosis in THP-1 cells. However, the precise mechanisms of these actions remain unknown. MicroRNAs (miRs) play important roles in cellular differentiation and apoptosis. This study aimed to investigate the role of miR-125a-3p in LukS-PV-regulated differentiation and apoptosis and its underlying mechanism in THP-1 cells. Methods MicroRNA profiling analyses were conducted to determine differential miRNA expression levels in THP-1 cells treated with LukS-PV. Cell differentiation and apoptosis were measured in THP-1 cells by gain-of-function and loss-of-function experiments. Bioinformatics analysis and luciferase reporter assays were used to confirm the targets of miR-125a-3p. The effects of the miR-125a-3p targets on cellular differentiation were determined by knocking them down. Results MiR-125a-3p was up-regulated after treating the human monocytic leukaemia cell line THP-1 with LukS-PV. In addition, miR-125a-3p positively regulated apoptosis and differentiation in THP-1 cells treated with LukS-PV. Concordantly, luciferase reporter assays confirmed that neurofibromatosis type 1 (NF1) and B-cell lymphoma 2 (Bcl-2) were direct target genes of miR-125a-3p. Moreover, NF1 knockdown in THP-1 cells significantly promoted differentiation in vitro. Finally, the extracellular signal-regulated kinase (ERK) pathway, a downstream target of NF1, was activated after NF1 knockdown. Conclusions These findings confirm that miR-125a-3p is involved in LukS-PV-mediated cell differentiation and apoptosis in THP-1 cells.

/pdf/luks-pv-regulated-microrna-125a-3p-promotes-thp-1-92dqqcw1wm.pdf

LukS-PV-Regulated MicroRNA-125a-3p Promotes THP-1 Macrophages Differentiation and Apoptosis by Down-Regulating NF1 and Bcl-2.

Background To date, many studies have reported that microRNAs participate in human carcinogenesis as tumor suppressors or oncogenes and may play important roles as prognostic biomarkers of cancer. The aim of this meta-analysis was to assess the prognostic value of circulating miR-125 in human malignant neoplasms by summarizing the results from all available studies. Methods A systematic literature review was carried out using PubMed and Embase. We extracted and estimated the hazard ratios (HRs) for overall survival, which enabled comparison of the high and low expression levels of miR-125 in patients included in the available studies. The analysis was carried out using Stata version 12.0. Results A total of 15 articles including 1,606 patients were included in this meta-analysis. For overall survival, the pooled HR of higher miR-125 expression in human malignant neoplasms was 0.90 (95% confidence interval [CI]: 0.58 - 1.38, p = 0.000). Subgroup analysis showed that higher miR-125a expression may predict better survival in patients with cancer (HR = 0.56, 95% CI: 0.41 - 0.76, p = 0.226). However, higher miR-125b expression may predict poorer survival in colorectal cancer (HR = 2.32, 95% CI: 1.35 - 3.99, p = 0.513), non-small cell lung cancer (HR = 2.33, 95% CI: 1.78 - 3.03, p = 0.519), and prostate cancer (HR = 1.60, 95% CI: 1.01 - 2.54, p = 0.292), but better survival in hepatocellular carcinoma (HR = 0.52, 95% CI: 0.34 - 0.81, p = 0.696). Conclusions These results suggest that different members of the miR-125 family may have different functions in various cancers. Furthermore, miR-125a or miR-125b may be important clinical prognostic biomarkers for cancer patients.

Xiaoxi Sun

Papers

Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae

Systematic Review and Meta-Analysis of the Epidemiology of Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Isolates

No association between traffic density and risk of childhood leukemia: a meta-analysis.

LukS-PV-Regulated MicroRNA-125a-3p Promotes THP-1 Macrophages Differentiation and Apoptosis by Down-Regulating NF1 and Bcl-2.

Prognostic Value of MicroRNA-125 in Various Human Malignant Neoplasms: a Meta-Analysis.