key: cord-286574-t9z2ynt5
authors: nan
title: Speaker presentations
date: 2017-09-30
journal: International Journal of Antimicrobial Agents
DOI: 10.1016/s0924-8579(17)30340-0
sha: 
doc_id: 286574
cord_uid: t9z2ynt5

nan

Increased mortality rates in patients infected with major resistant pathogens are as follows;

• MRSA: MRSA can cause almost 2-fold higher mortality (OR 1.93) compared with MSSA strains according to a meta-analysis (Cosgrove et al. 2003) . MRSA kills more American people every year (∼19,000) than emphysema, HIV/AIDS, Parkinson's disease and homicide combined (Klevens et al. 2007 ). • ESBL-producing Gram-negative bacilli: A meta-analysis showed that crude RRs were significantly higher mortality in ESBL-associated bacteremia ( pooled RR 1.85) (Schwaber et al. 2007 ). • Carbapenem-resistant K.pneumoniae: In patients with carbapenem-resistant K.pneumoniae bacteremia, the crude mortality rate was 71.9%, while it was 21.9% in control subjects (Borer et al. 2009 ). A mortality risk ratio was 3.3 for patients with carbapenem-resistant K. pneumoniae bacteremia.

Increased mortality and morbidity in resistant infections is due to treatment failure of antibiotic therapy which is associated with bacterial fitness, greater severity of underlying illness, delays in initiating effective therapy and lack of effective therapy (Friedman et al. 2016) . Due to mismatch between choice of empirical antibiotics and in vitro susceptibility test results, administration of effective antibiotics was delayed by 6-times in the case of antibiotic-resistant E.coli and K.pneumoniae infections compared with susceptible strains (72 hours vs 11 hours) (Lautenbach et al. 2001) . Also, patients infected with resistant strains are more frequently associated with more severe underlying illness requiring longer hospitalization. For example, patients with CRE infections are more likely to be a transplant recipient, require mechanical ventilation, a prolonged hospitalization, ICU stays, or use of central venous catheters (Borer et al. 2009 ). Patients infected with resistant strains are more likely to develop complications and long-term sequelae. For example, MRSA infection caused higher incidence of complications by 69% compared with MSSA infection. The most frequent complications are a progression of the local infection (RR 3.25) and pneumonia (RR 2.28) (Cecchini et al. 2015) .

Once AMR emerges in the hospital, resistant pathogens can cause additional cases of bacterial infections that affect more patients. Emergence of AMR in major human pathogens also affects safety and efficacy of surgical procedures, cancer chemotherapy, organ transplantation, and intensive care. Therefore, AMR is not just an infectious disease issue, but rather an issue in surgery, cancer care, organ transplantation and whole health system. AMR can also negatively affect the daily hospital activities such as total closure of an affected ward or unit or cancellation of elective surgery.

Economic impact of AMR is difficult to quantify, which consists of direct costs associated with use of more expensive antibiotics, special equipments, longer hospital stay, and isolation procedures etc., and indirect costs mainly due to loss of productivity of the patients. According to the World Bank report to estimate the AMR impact on global GDP in -2050 (World Bank, 2016 , in the optimistic "low-AMR" scenario, global economic output is projected to be 1% lower by 2030 ($1 trillion) and 1.1% lower by 2050 than in the base case. In the pessimistic "high-AMR impact" scenario, global economic output would be 3.2% lower in 2030 ($3.4 trillion) and 3.8% lower by 2050 than in the base case. It means that in the "high-AMR" scenario, economic damage will be greater than that in 2008-2009 global financial crisis which caused 3.6% drop in the global GDP. Economic impact of AMR differs by countries with different economic level. Low-income and lower middle-income countries would have greater impact of economic loss (5.6% loss of GDP) due to AMR compared with high-income countries (3.1% loss of GDP), particularly in the "high-AMR" scenario. Global economy is negatively affected by AMR in various aspects such as international trade, livestock production, and healthcare expenditures. By 2050, the volume of global real exports may decrease by 1.1% in the "low-AMR" scenario and by 3.8% in the "high-AMR" scenario. In the "high-AMR" scenario, healthcare expenditures in 2050 would be as 25% higher than the baseline values for low-income countries, 15% higher for middle-income countries, and 6% higher for high-income countries. The additional expenditures in 2050 would be $1.2 trillion annually in the "high-AMR" scenario. In the US, CDC estimated the cost of AMR as a total of $55 billion per year : $20 billion in excess for direct healthcare costs and $35 billion for indirect societal costs due to loss of productivity (CDC, 2013) . In Europe, the overall economic burden of AMR was estimated to be at least 1.5 billion euros; 60 % for direct costs and 40% for indirect costs (ECDC/EMEA, 2009 ). Data on the economic impact of AMR in major pathogens showed that healthcare costs significantly increase in the treatment of infections caused by antibiotic-resistant strains (Maragakis et al. 2008) ; MRSA bacteremia (US$ 6,916), MRSA surgical site infection (US$ 13, 901) , VRE infection (US$ 12, 766) , and ESBL or KPC-producing E.coli or Klebsiella infection (1.7fold increase).

AMR is obviously one the most serious and urgent issues with devastating impact on clinical medicine, economic growth and societal system and function. G20 Leaders' Declaration which was announced in July 2017 also underlined the importance of combating AMR through international collaboration. For more effective and robust implementation of global action plan to combat AMR, appropriate evaluation of impact of AMR should be performed, particularly in developing world which would have greater damage due to AMR.

School of Public Health, The University of Hong Kong, China

The development, large-scale production and widespread use of antimicrobial drugs in the twentieth century was a turning point in human history, resulting in dramatic improvements in medical care and reduction of deaths. Over time, however, rising levels of antimicrobial resistance (AMR) among a wide range of pathogens has placed such gains at risk of being lost. Reducing AMR is now a top-level global public health priority. In principle, the major high-level goals consist of optimizing the use of such drugs in health and agriculture and minimizing environmental contamination; sustaining the development of new classes of antimicrobials drugs and other medicines and making them affordable and accessible to all who need them; and much more effective application of infection control and prevention principles. For decades, technical solutions have been the primary approach used for addressing AMR. More recently, FAO, OIE and WHO in combination with like-mined champions have embarked upon a more political and broader "one health" approach to increase awareness and engagement beyond scientific and medical groups. This change is the basis for the 2015 Global Action for AMR, the 2016 High Level Meeting on AMR held at the UN General Assembly and attention to AMR by groups such as the G20. While such results have been instrumental in broadening the awareness and attention paid to AMR, it is now critical to adopt concrete and focused activities to consolidate and build upon these gains. The fundamental building blocks will be proposed and discussed.

Murdoch University, Australia

Methicillin-resistant Staphylococcus aureus (MRSA) was initially a healthcare associated pathogen limited to distinct lineages often associated with multi-drug resistance. However, in the late 1980s MRSA began to emerge in the community. In the beginning, this was mostly confined to closed communities, i.e. Australian aboriginals, but around the late 1990s community-associated MRSA (CA-MRSA) emerged worldwide in the general population. The CA-MRSA clones evolved independently of the HA-MRSA clones, and typically, possessed type IV or V SCCmec elements, were non multi-drug resistant, and were positive for the Panton Valentine leucocidin (PVL) toxin.

Whilst regionally many unique CA-MRSA clones have emerged, only a few clones predominate within a region, and even fewer clones have a global distribution. The reasons for the variation in the prevalence and dominance of CA-MRSA clones between different geographical niches remains unclear.

Although the epidemiology of CA-MRSA varies considerably, four major global CA-MRSA clones have been described: ST8-MRSA-IV (USA300) and ST30-MRSA-IV (South West Pacific Clone) which and are considered pandemic; ST80-MRSA-IV (European clone) which predominates in Europe, Africa and the Middle East; and ST59-MRSA-IV/V T (Taiwan/Asia Pacific Clone) in Asia. However, using whole genome sequencing analysis, at least two of the clones have different clades that have evolved independently of each other. In clonal complex 8 nine phylogenetic clades with at least eight independent events of methicillin-resistance acquisition have been identified. Subsequently, it has been hypothesised USA300 did not evolve from the healthcare-associated ST8-IV USA500 clone, the historic CA-MRSA from Western Australia, or the PVL-positive MSSA clone from Trinidad and Tobago or Western Africa, but most likely from PVL-positive MSSA circulating within the USA. The ancestor of the USA300 clade emerged in central Europe in the mid-19 th century and exported to North America in the early 20 th century. Once in North America the clone progressively acquired the USA300 characteristic genetic specifications, diversified and spread globally including Africa. Within the USA300 clade two closely related ST8-IV clones are recognised: USA300, primarily isolated in North America (ST8-MRSA-IVa, spa t008 lukS-PV/lukF-PV, ACME positive, msrA-mediated macrolide resistance genes) and the USA300 Latin American Variant, primarily isolated in South America (ST8-MRSA-IVc, spa t008, lukS-PV/lukF-PV, ACME negative, tetK, copper and mercury resistance genes). Similarly, ST59 MRSA is also not a single clone but consists of two major clades, one originating in the USA and the other in East Asia. Furthermore, two distinct subclades within the East Asia clade have been identified: PVLnegative ST59-MRSA-IV (Asia Pacific clone) and the multi-resistant PVL positive ST59-MRSA-V T (Taiwan clone) which possesses two distinct ccrC genes.

Recently three newly described PVL-positive CA-MRSA clones have been reported in multiple countries: ST93-MRSA-IV (Queensland CA-MRSA) from Australia, and ST772-MRSA-V T (Bengal Bay) and ST22-MRSA-IV from the Indian subcontinent. ST22-MRSA-IV, first reported in India in 2010, is genetically distinct from the healthcare associated ST22-MRSA-IV (EMRSA-15) having acquired different SCCmec types and sub types. Of concern, ST772-MRSA-V T and ST22-MRSA-IV are multi-resistant hyper-virulent CA-MRSA that have recently been associated with nosocomial transmission.

The co-emergence of multiple CA-MRSA lineages that have risen independently in most parts of the world has been striking. To date no single genetic or epidemiological factor has been identified that accounts for the extraordinary success of some genetically distinct CA-MRSA clones. Over time, some CA-MRSA clones will replace HA-MRSA clones, which will have significant clinical and public health implications. Along the way they will become increasing antibiotic resistant making the distinctions between HA-MRSA and CA-MRSA blurred and antimicrobial treatment difficult. Methicillin-resistant Staphylococcus aureus (MRSA) has been a major cause of healthcare-associated infections with significant morbidity and mortality, and it has become one of the most important nosocomial pathogens in many countries worldwide since 1980s. In particular, several MRSA clones have been successful in spreading and causing infections in the hospitalized patients. The prevalence rates of MRSA in S. aureus isolates from the hospitalized patients have become high enough to spread into the community. Interestingly, during the past two decades, the emergence of community-associated (CA-) MRSA clones has greatly affected the global epidemiology of S. aureus infection. Circulating CA-MRSA clone varies according to the region, and it includes ST8 (USA300), ST80, ST30, ST59, ST72, ST772 and ST22 which mostly belong to SCCmec type IV or V. As a result, the proportion of MRSA in community-acquired S. aureus infections has been significantly increasing in many countries. Furthermore, many reports have shown that CA-MRSA clones have replaced traditional hospital-endemic MRSA clones. Such an influx of dominant CA-MRSA clones into the hospitals has been making the 'search and destroy' policy which have contributed to maintain low MRSA rates in some countries difficult to maintain. In addition, there has been concern that healthcareassociated infections such as surgical site infection caused by CA-MRSA may increase. In this talk, an update on CA-MRSA epidemiology in healthcare-associated infection and concerns on infection prevention and control will be discussed. The newly emerging Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (∼35%), and has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea, and resulted in 186 confirmed cases with 38 deaths (case-fatality rate: 20.4%). Here, we show the rapid emergence and spreading of a mutant MERS-CoV with reduced affinity to the human receptor, CD26, during the Korean outbreak. We isolated thirteen new viral genomes from fourteen infected patients treated at a hospital and found that twelve of them possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. We also analyzed clinical data and specimens from fourteen MERS patients treated in a hospital who collectively represent a wide spectrum of disease severity, ranging from mild febrile illness to fatal pneumonia. Comparative and kinetic analyses revealed that high viral loads, weak antibody responses, and lymphopenia accompanying thrombocytopenia were associated with disease mortality, whereas persistent and gradual increases in lymphocyte responses might be required for effective immunity against MERS-CoV infection. The correlation of the virological and immunological responses with disease severity and mortality, as well as their responses to current antiviral therapy, may have prognostic significance during the early phase of MERS. Severe fever with thrombocytopenia syndrome (SFTS) was discovered as an infectious disease caused by a novel bunyavirus in China in 2011 (N Engl J Med, 2011 . The causative agent for SFTS is named SFTS virus (SFTSV), which is a tick-borne virus and belongs to the Family Buniyaviridae, Genus Phlebovirus. The virus infection causes generalized infections with a high case fatality rate. In late 2012, it was discovered that SFTS was also endemic to Japan (Takahashi T, et al., JID, 2014) . SFTS is endemic to China, South Korea, and Japan. Since the discovery of SFTS endemic to Japan in January 2013, approximately 240 patients with SFTS have been reported to the National Institute of Infectious Diseases. The case fatality is about 25%. Most of the patients were aged over 40's.

The pathophysiology of SFTS has been studied through the pathological examination of SFTS patients, who died. Through the pathological studies on SFTS, SFTSV is present in the lymph node tissues. There are two pathological types, SFTSV-positive lymph node-localized type and SFTSV-positive lymph node-generalized types. All the patients, in whom bone marrow aspiration test was performed, showed hemophagocytic syndrome, indicating that cytokine storm plays an important role in pathogenesis of SFTS. Most fatal SFTS patients showed symptoms of hemorrhage and deterioration in consciousness. One of the patients showed a symptom of bloody vomit. Real time imaging of the stomach by endoscopic examination revealed the presence of ulcerative lesions with whoozing hemorrhage (Kaneyuki S, et al., JJID, 2017) . The pathophysiological features behind the high case fatality rate in SFTS are hemophagocytosis, hemorrhagic tendencies due to thrombocytopenia, disseminated intravascular coagulation, and ulcerative lesions appeared in the gastrointestinal tracts, and multi-organ failure.

The efficacy of antiviral agent, favipiravir, which was developed by Dr. Furuta Y and his colleagues (Toyama Chemical Co., Ltd, Japan), in the treatment of SFTS was evaluated using mice lacking the type I interferon alpha receptor (IFNAR −/− ) (Tani H, et al., mSphere, 2016) . Favipiravir inhibited replication of SFTSV in Vero cells by 5 log units, with a 50% inhibitory concentration (IC 50 ) and IC 90 of 6.0 and 22 µM, respectively. Intraperitoneal or oral administration of favipiravir for 5 days to IFNAR−/− mice infected with lethal SFTSV significantly improved survival rates (100% survival) without causing body weight loss and reduced the viral load in the serum. Although ribavirin also inhibited SFTSV replication, it was quite less effective than favipiravir both in vitro and in vivo. A time-of-drug-addition study revealed that therapeutic favipiravir treatment of SFTSV infection in IFNAR−/− mice was effective. These results suggest that favipiravir might be a promising candidate as antiviral drug against SFTS. The study suggested that favipiravir is a candidate drug for the treatment of SFTS.

In the presentation, I will present the overview of the epidemiology and pathophysiology evaluated through pathological autopsy, and the development strategy of antiviral drug therapy for SFTS. This disease, SFTS, continues to be endemic to China, Korea, and Japan for the future. We can not escape from the risk being infected with SFTSV. On the other hand, there is a potential that favipiravir has a therapeutic effect in the treatment of SFTS. Safe and efficacious vaccine against SFTS should be developed. Furthermore, I will discuss the issues to be addressed to reduce the SFTS disease burden. The challenges posed by infectious diseases in the 21 st century are forever growing more complex and numerous. There are no magic bullets or simple solutions that we can employ in our battle against the array of pathogens that every day attack humans, animals and plants. But there is much that we can do to mitigate the changing landscape of infectious diseases threats. This presentation will expand upon Dr. Osterholm's previous plenary session lecture. It will go into detail describing the major steps we can and must take to tip the balance between the growing threat of infectious diseases and our ability to anticipate these threats and prevent and control them before they can result in increased morbidity and mortality. The polymyxins, colistin ( polymyxin E) and polymyxin B, are effective antibiotics against most multidrug-resistant (MDR) Gram-negatives and are currently considered as the last-line drugs for treating severe bacterial infections. Polymyxin resistance among Gram-negatives has increased gradually for the last few years, and knowledge of its multifaceted resistance mechanisms is expanding. Typically, colistin resistance is due to chromosomally mediated modulation of two-component regulatory systems leading to modification of lipid A that resulted in reduced affinity to polymyxins. Clones of polymyxin-resistant Gram-negatives have spread in some hospitals, but have not significantly affected the use of polymyxins. These resistance genes are generally not transmissible between bacteria and so have not disseminated widely. However, a newly discovered plasmid-mediated polymyxin resistance gene mcr-1 has been detected in many countries in different geographical regions of the world since its first report in 2016. Therefore, it seems inevitable that plasmid-mediated transfer of polymyxin resistance will seriously reduce the lifespan of the polymyxins as the backbone of regimens against infections due to MDR Gram-negatives. This review provides an update on epidemiology and mechanisms of polymyxin resistance among different commonly encountered MDR Gram-negative bacilli. Some unresolved questions with respect to polymyxin resistance are also discussed. One of the few remaining options for the infectious disease caused by multiple-drug resistant Gram-negative bacilli is colistin. Accordingly, emerging mobile colistin resistance mcr-1 for phosphoethanolamine transferase became a death threat to public health. Various Enterobacteriaceae carrying mcr-1-plasmids from human beings, animals, and environments were reported in Asia, Europe, Africa, and North and South America. In South Korea, by the retrospective screening for the animal-oriented Escherichia coli strains, the mcr-1 positive isolates have been identified. To evaluate mcr-1-positive clinical strains, a total of 9396 Enterobacteriaceae isolates collected between 2010 and 2015 were screened and, finally, three strains, two Escherichia coli belonging to either ST1011 or ST101 and one Enterobacter aerogenes, harboring the gene were identified. All possessed IncI2 mcr-1-plasmids and colistin MICs were 4 g/ml in E. coli strains and 32 g/ml in E. aerogenes. The bla CTX-M-55 gene for extended-spectrum beta-lactamase was co-carried in the mcr-1-plasmid of E. aerogenes and extra plasmids carrying bla CTX-M-55 , bla CTX-M-27 , and bla NDM-9 were co-harbored by E. coli strains. One of the E. coli strains produced complete conjugal machinery presenting the best efficiency of plasmid transfer while E. aerogenes having a truncated prepilin peptidase PilU resulting in complete loss of conjugal activity. The plasmid in E. coli transferred efficiently to E. coli recipients compared to K. pneumoniae and to Enterobacter cloacae probably due to the species-specificity allowed by rearranged shufflon. Previously identified 11 mcr-1-positive E. coli strains of animal-origin from South Korea also possessed IncI2 mcr-1-plasmid and the non-self-transferable mcr-1-plasmid in E. aerogenes was closely associated to those, while the self-transferable mcr-1-plasmid in E. coli strains were alike to each other. The plasmid carrying the gene, or the bacterial host harboring the plasmid, has come from animals as the previous reports illustrated. Better stewardship for the proper usage of antimicrobials as well as a collaborating surveillance study as a concept of one-health is needed.

What to use in the clinical practice?

Yohei Doi MD, PhD

University of Pittsburgh, USA While colistin resistance in Enterobacteriaceae due to the plasmid-mediated mcr genes has drawn much attention, the threat of colistin resistance that impacts patient care most currently exists in extensively drug-resistant (XDR) bacteria which have acquired colistin resistance through chromosomal mutations in species such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii.

Unlike the mcr mechanisms that readily spread horizontally via plasmids, colistin resistance in these XDR species usually arises through selective pressure in patients upon treatment with colistin, though outbreaks have also been reported on occasions. Development of colistin resistance in these strains means few or even no remaining active agents. However, patients who are affected by these bacteria are medically complex, heterogenous, and difficult to enroll into clinical trials for many reasons. Consequently, clinical data associating colistin resistance, antimicrobial therapy given and patient outcome are scarce and retrospective in nature for the most part. For K. pneumoniae, limited data suggest that mortality of infection from colistin-resistant strains may be lower when treated with gentamicin-containing regimens than those without gentamicin, but this approach is only applicable when the infecting strain is susceptible to this agent. Fortunately, the approval of ceftazidime-avibactam has ameliorated concerns over colistin resistance in K. pneumoniae at least for the time being, as therapy with ceftazidime-avibactam appears to improve clinical outcome of infected patients over those treated with colistin-based regimens. Interestingly, gastrointestinal decolonization with gentamicin may reduce infections and mortality in those known to be colonized with colistin-resistant K. pneumoniae, but the recent spread of mcr genes in humans brings into question the long-term viability of this approach. There are even less clinical data regarding the treatment of infections caused by colistin-resistant P. aeruginosa and A. baumannii. In vitro data variably support colistin-based combinations with partner agents including carbapenems, rifampicin, fosfomycin, and even gram-positive agents like vancomycin in the case of A. baumannii, but without accompanying robust clinical data. There are several novel agents with activity against colistin-resistant strains in late-stage clinical development. They include novel beta-lactam-beta-lactamase inhibitor combinations, a siderophore cephalosporin, an aminoglycoside and tetracyclines. Most of them target carbapenem-resistant Enterobacteriaceae, while some are also active against P. aeruginosa and A. baumannii. These new agents are bound to change the paradigm for the treatment of infections caused by colistin-resistant Gram-negatives, but uncertainties are still likely to remain, including which agent to use, how to optimize dosing in to maximize efficacy and minimize toxicity as well as potential for development of resistance, and whether use of more than one agent would still be needed.

Analyte Health, USA

In the United States, telehealth represents a rapid, convenient, and cost-effective solution for non-life threatening conditions, including acute respiratory infections, urinary tract infection (UTI), and sexually transmitted infections (STIs). Over 1.25 billion outpatient "bricks and mortar" visits occur annually in the US, and it is estimated that one third of these visits (417 million) can be handled through telehealth. Furthermore, one third of this subgroup of consults (140 million) are related to infectious disease causes. Until recently, the provision of diagnostic testing, in conjunction with telemedicine physician consults, was difficult due to diverse geo-locations of patients, physicians and testing laboratories. For example, in the virtual world of telehealth, a patient can be located in California, with the physician licensed to practice in California located three time zones away in New York. Linkage of the physician and patient is now easily accomplished by electronic means (e.g., video conferencing, phone calls, text messaging). However, obtaining specimens from the patient and then transporting the specimen to the appropriate testing laboratory has been a challenge, such that most telemedicine consults are performed without diagnostic testing and empiric treatment is provided. This approach, especially with acute respiratory infection, could result in overuse or underuse of antibiotics. This lecture will describe new approaches to diagnostic testing for infectious diseases in the telehealth ecosystem. Included is a description of the infrastructure requirements required and/or recently developed to accommodate specimen acquisition and testing through aggregation ("uber"-ization), of both physicians and laboratory patient service centers, provision of "round the clock" mobile collection (in-home collection) services and self-collection and self-testing. Also, the cost-savings of these approaches, in contrast to traditional bricks and mortar approaches will be discussed. Rapid molecular, point of care testing instruments are now available for the accurate and complete (no confirmation testing required) testing for Group A Streptococcus for throat swab specimens, and Influenza and RSV for nasopharyngeal swab specimens; future testing capabilities include sexually transmitted diseases like Neisseria gonorrhoeae, Chlamydia trachomatis and human papilloma virus (HPV). These new devices will accommodate the next inflection point in virtual medicine: point of patient testing, including testing the patients in their homes. The World Bank estimates that epidemics will cost $6 trillion dollars in the 21 st centuryroughly $60 billion per year. The $6 billion cost of the Ebola epidemic was its economic impact (in countries that can least afford it); however the impact of Ebola on families, social customs, and health infrastructure will have long term consequences. In addition, funding for epidemic diseases waxes and wanes with the passage of the epidemic, and as a consequence longer term preventive solutions, such as vaccines, have little means for progressing. In 2016 several nations and charitable foundations launched a new enterprise known as CEPI, the Coalition for Epidemic Preparedness Innovations. CEPI will fund the development of vaccine candidates for diseases of epidemic potential, the initial candidates are MERS, Nipah and Lassa fever. We will review product development activities in these diseases and also detail attempts by international organizations to try to develop a framework around responses to public health emergencies of international concern.

Carbapenemases, from KPC to NDM to OXA-48: diverse enzymes in diverse clones David M. Livermore

Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK Carbapenemase-producing Enterobacteriaceae present a growing problem. The predominant enzymes are members of the KPC, NDM, IMP, VIM and OXA-48 families. Rarer types include IMI, SME and FRI enzymes, also some members of the GES family. KPC, IMI, SME, FRI and GES enzymes belong to Class A; NDM, IMP and VIM are Class B metallo carbapenemases, whilst OXA-48 and its relatives, e.g. OXA-181, belong to Class D. This diversity of enzymes is reflected in a diversity of properties. KPC carbapenemases hydrolyse all widely available β-lactams and are inhibited by avibactam and vaborbactam. By contrast the metallo types evade avibactam and vaborbactam and attack all β-lactams except monobactams, which are often compromised by co-produced ESBL and AmpC enzymes. OXA-48, which is inhibited by avibactam but not vaborbactam, has little activity against oxyimino-cephalosporins but, again, is often accompanied by cephalosporin-hydrolysing ESBLs.

The origins of most clinically-important carbapenemases are obscure; the exception is OXA-48, which is a chromosomal escape from Shewenella spp. It is assumed that other carbapenemase genes similarly escaped from unknown environmental organisms. Escape often entails gene mobilisation by insertion sequences, followed by capture by transposons and plasmids, which then facilitate dissemination. bla KPC , regardless of geographic origin, is generally carried by Tn4401, often within pKpQIL plasmids, whilst bla OXA-48 is often encoded by Tn1999-related elements, carried on a small range of plasmids. bla OXA-181 differs only slightly from bla OXA-48 but appears to be a separate escape from Shewenella, being associated with an ISEcp1 element on Tn2013, a quite different transposon; moreover bla OXA-181 is epidemiologically linked to India, whereas classical bla OXA-48 links to Turkey and the Middle East. bla IMP and bla VIM metallo-carbapenemases occur as cassettes within Class I integrons. bla NDM is generally linked to ISAba125, carried by a wide diversity of different plasmids and may have arisen as a chimera between aphA6, encoding its first six amino acids but otherwise deleted, and a pre-existing metallocarbapenemase gene of unknown origin.

The plasmids encoding OXA-48-like enzymes and all the major metallo types (i.e. IMP, NDM and VIM) spread among strains and species. These enzymes all have a predilection for Klebsiella pneumoniae, but frequently occur also in Escherichia coli, Enterobacter and other Enterobacteriaceae species. Individual producer strains cause local outbreaks but no single strain has become nationally or globally widespread. Rather, when producers became prevalent, the common pattern is one of small clusters within a wider epidemiology of plasmid transfer among strains. By contrast, KPC carbapenemases (carried by Tn4401 transposons within pKpQIL plasmids) are strongly associated with K. pneumoniae ST258. This lineage, along with its variants (e.g. ST512), has become internationally widespread and is responsible for the major expansion of 'Carbapenemase-producing Enterobacteriaceae' in e.g. Greece, Italy, Brazil and Israel. Only in the last of these countries has it been brought under control, achieved by a determined and centrally mandated infection control effort.

Not all KPC problems are linked to ST258. In Manchester, England, the problem is more akin to that with other carbapenemase types, entailing plasmid transfer among strains and species. The plasmids responsible are pKpQIL variants with large substitutions resulting in the replacement of the partitioning and replication functions, potentially explaining their spread.

The diversity of carbapenemase types and hosts exacerbates the problem of resistance. Self-evidently, it harder to devise new pharmaceuticals that inhibit or evade multiple carbapenemase families than to develop those that inhibit or evade single or closely related enzyme types. What is more, experience suggests that it is harder to mobilise infection control staff and efforts against 'plasmid epidemics,' as with most carbapenemases, than against single strains epidemics. Carbapenem-resistant Enterobacteriaceae (CRE) has been increasingly reported worldwide in the past 10 years, which represents a serious threat to public health. Invasive CRE infections are associated with high mortality, and CRE has the potential to spread widely.

Carbapenem resistance in Enterobacteriaceae can mainly result from two different mechanisms. Some CRE, which possess either AmpC or extended-spectrum β-lactamase (ESBL) with concomitant porin mutations, can render the organism non-susceptible to carbapenems. More importantly, some CRE may result from production of carbapenemases that break down carbapenems. Carbapenemases belong to heterogenous group of β-lactamases: molecular class A ( penicillinases), class B (metalloenzymes), and class D (oxacillinases).

In 2011, CLSI and EUCAST updated the carbapenem clinical breakpoints for Enterobacteriaceae, in order to better predict treatment outcomes and to provide therapeutic alternatives for carbapenem-resistant bacteria. These breakpoints were based on patient response, pharmacokinetic/pharmacodynamic information, and in vitro minimal inhibitory concentration data. With the new lower breakpoints, routine testing for carbapenemase in clinical laboratory became not required for patient care.

However, by these updated breakpoints, not all carbapenemase producing CRE were non-susceptible to carbapenems. Using the updated breakpoints, a study identified that occasional isolates of Klebsiella pneumoniae with KPC or VIM carbapenemases were susceptible to one or more carbapenem. As of now, few clinical data are available to support that MIC is more important than presence of carbapenemase when predicting carbapenem treatment outcome. The different breakpoints for imipenem and meropenem in CLSI and EUCAST may need evaluation for optimal patient care as well as epidemiologic study.

Carbapenemase detection and characterization are recommended for public health and infection control. Currently, there are a variety of the phenotypic assays such as modified Hodge test, the Carba NP test, modified Carbapenemase inactivation method, and molecular assays. None of the currently described phenotypic test can detect all carbapenemases. Molecular tests are often used as the golden standard, but they have inherent limitations such as missing novel variants and/or previously undescribed enzymes.

CRE continue to present challenges related to both treatment decisions by physicians and detection methods applied at laboratories. Continued efforts to improve detection methods, by making them rapid, sensitive, and unbiased for specific carbapenemase, will hopefully allow for better patient care and prevention of further CRE dissemination.

Ami Neuberger, M.D.

Infections caused by carbapenem-resistant enterobacteriacea (CRE) are more difficult to treat both because our current arsenal of antibiotics is limited and because some of the available antibiotics are less efficacious or have not been rigorously studied. The presentation will provide a brief overview of the future of treatment of CRE infections.

There are a number of controversies regarding the modes of administration of antibotics for CRE infections: high versus lower dose, continuous or prolonged versus intermittent administration, duration of antibiotic treatment, and mono versus dual therapy. Current evidence supports prolonged or continuous administration of β-lactam antibiotics. New randomized controlled trials of mono versus dual antimicrobial therapy, and short versus long duration of treatment for Gram-negative bacteremia are ongoing, with results expected to be available in 2018.

Older antibiotics, such as colistin, aminoglycosides, fosfomycin, and tigecycline are increasingly used together with newly approved drugs such as ceftazidime-avibactam. Some new antibiotics in advanced stages of development ( phase 2 or 3 trials) will be reviewed. These drugs will include combinations of carbapenems or aztreonam with β-lactamses inhibitors, new combinations of cephalosporins with β-lactamses inhibitors, cefiderecola novel cephalosporin, plazomicinan aminoglycoside, and eravacyclinea new fluorocycline. The advantages and disadvantages of these drugs will be discussed.

Novel approaches to antibiotic development include the use of antibacterials produced from previously "non-culturable" bacteria, and development of new entry mechanisms of antibiotics into Gram-negative bacilli.

Treatment of CRE infections is likely to undergo rapid changes in the upcoming years, but any such change will have to be accompanied by comprehensive infection-control programs, antibiotic stewardship programs in hospitals and in the community, and judicious use of new antibiotics. One health approaches, 'One hdealth, one medicine', have been globally recognized to control zoonotic diseases. World Organization of Animal Health (OIE) has reported 60% of human pathogens are animal origin and more than 75% of emerging animal diseases are zoonoses. This means collaboration and cooperation between animal and human medicine together can only solve the problem. Recent huge outbreaks of Highly Pathogenic Avian Influenza (HPAI) and Middle East Respiratory Syndrome (MERS) in Korea have been more pay attention to implement one health approaches in practice. We experienced several HPAI epidemics past ten years and the MERS in 2015 and had to bear huge damages. One health becomes a key approach to control zoonotic diseases systemically and effectively. A 'One health' approach to minimize the antimicrobial resistance in humans and animals need collaboration among the responsibility of all three parts; human health, animal health and environmental health-communities. Surveillance of antimicrobial usage and resistance provides important data for the identification of resistance problems and contributing factors for the development and spread of resistance at a national and local level. Through the painful Korean experience of these zoonotic diseases and global challenge to AMR brings us to establish the effective preventive method and early diagnosis as critical control strategies. Prevention and control of infections is essential in fighting antimicrobial resistance. Thus, to minimize infections in animal and human and to decrease the volume of antimicrobials used, collaborative efforts should be implemented to improve animal and human health.

One health activities on Nipah in Bangladesh: a high risk country for zoonotic disease spillover to man Epidemiological investigations in Bangladesh implicated consumption of date palm sap as the major route of transmission of the virus from bats to humans. In Bangladesh date palm sap is collected from date palm trees for consumption either as fresh or as fermented beverage. The sap is collected in clay pots attached to the top portion of the tree, where the tree has been denuded of bar, so that the sap can ooze overnight into the collection pots. Outbreaks of disease typically occur in the winter months, the interval in which date palm sap is collected. As well, case-control studies have identified consumption of date palm sap beverage as a risk factor at the individual level. Videos using infrared cameras have documented that fruit bats visit date palm trees at night and contaminate the collection pots by licking the oozing sap and by urinating in the collection pots. Ethnographic studies of affected populations has enabled development of a behavior change intervention to reduce consumption of date palm sap. In addition, bamboo skirts placed around the denuded bark area of the date palm trees and collection pots have been developed to obstruct contamination of collected date palm sap by bat saliva and urine.

Of great concern, epidemiological studies in Bangladesh have also identified person-to-person transmission of the virus between patients and persons who are in close contact with patient secretions, often in hospital settings. A study of Nipah outbreaks between 2001 and 2007 attributed 51% of all cases to person-to-person transmission, though only 7% of patients were assessed as having transmitted their infection onward via this route. Importantly, handwashing seemed to be effective in reducing person-to-person transmission.

In aggregate, these studies illustrate the power of multidisciplinary collaborations under the rubric of one health, and, in view of the documented person-to-person transmission in Bangladesh and the potential for emergence of new genetic variants of Nipah that are capable of sustained human-to-human transmission, underscore the need for continued surveillance and control efforts, including development of effective vaccines. Mycoplasma pneumoniae (MP) is one of the most common causes of community-acquired pneumonia in children and young adults. Emerging resistance to macrolides among MP is of great concern since a macrolide-resistant MP strain was first reported in 1997, most notably in Japan, China, and Korea. Although macrolides are recommended for the first-line treatment for MP pneumonia, the efficacy of macrolides in the treatment of M. pneumoniae infection remains unclear. In addition, with the increase in macrolide resistance, concerns about the efficacy of macrolides for the treatment of MP pneumonia in children have been raised.

Given the versatile features of MP pneumonia, which are determined by the patient's age, the immunologic response of the host, and extrapulmonary manifestations, a more comprehensive approach must be established to analyze the clinical outcome of MP pneumonia according to the presence of macrolide resistance. Initially, treatment of MP pneumonia with antimicrobials was supported by a randomized trial of 290 marine recruits that showed a shortening of fever duration, alleviation of cough, and improvement of chest x-rays. A recent systematic review that evaluated the effect of treating MP pneumonia demonstrated that there was no significant clinical benefit of antimicrobial therapy in children with MP pneumonia.

Although much is not known about clinical impact of macrolide resistance on the severity of MP pneumonia, macrolide resistance alone does not seem to explain the severity of MP pneumonia. Some studies have reported that patients infected with macrolide-resistant strains had more febrile days and a longer duration of persistent cough than those infected with macrolide-susceptible strains, suggesting poorer response to macrolide treatment in macrolide-resistant strains. The results highlight the need for well-designed prospective studies to assess a therapeutic benefit from macrolides and an adjunctive therapeutic strategy in the treatment of children with macrolide-resistant MP pneumonia.

Mayo Clinic, USA Mycoplasma pneumoniae (MP) can cause upper and lower respiratory tract infections in children and adolescents, with communityacquired pneumonia (CAP) comprising the major burden of the disease. MP infections are generally mild and self-limiting. Some patients, of any age, may develop severe and fulminant infection with pulmonary complications and/or extrapulmonary manifestations that may affect almost every organ. This presentation will focus on pulmonary infections due to MP.

It is estimated that 3-10% of children with MP respiratory infection develop CAP and less than 5% are severe enough to require hospitalization, although this may change with increasing prevalence of MRMP. Children with MP CAP present with a longer duration of fever compared with children with CAP due to other organisms. Complicating the diagnosis of MP has been the insensitivity of testing as the organism does not grow well in culture, the inability to perform reliable and sequential serologic testing or PCR testing; the co-existence of MP with other pathogens; and asymptomatic carriage of MP in 21-56% of patients.

Pathogenic effects on the respiratory tract may be direct by active infection, indirect by infection-induced immune mechanisms, or both. The immunopathology is poorly understood, in particular the role of cell-mediated immunity (CMI). Studies have demonstrated increased concentrations in IL-8 and IL-18 in acute phase serum and pleural fluid samples and INF gamma, IL-6 and IP-10 in patients with MRMP and that severity of CAP correlated positively with the size of cutaneous induration following intradermal injection of MP antigens. It's been postulated that cytoadherence of MP to the respiratory epithelium initiates an immune response with progression to an excessive inflammatory response and a vigorous CMI response leading to pulmonary injury and severe clinical illness.

Macrolides have been and remain the drugs of choice for treatment of MP infections in children. Alternative drugs such as tetracyclines and fluoroquinolones are not first line due to age-related adverse effects. Macrolide resistant M. pneumoniae (MRMP) have been reported as early as the 1970s in Japan with rates now greater than 90% in areas of Japan and China. Korea reported MRMP in 2010. MRMP in North America was reported in 2008 with a prevalence now of approximately 13%. Europe has reported rates of 2-26% and Israel as high as 30%.

Many countries have unreported rates likely due to the lack of susceptibility testing.

The mechanism of resistance is genetic with point mutations in a few positions of the domain V of the peptides transferase loop of the 23S rRNA where macrolides bind the 50S rRNA subunit. MP pneumonia was more prevalent throughout Korea in 2011 and caused more severe clinical features than at any other time, which led to an unpublished observation that it may be associated with MRMP. Despite the increasing prevalence of resistance, macrolides remain the drugs of choice for treatment of MP infections in children, but require antimicrobial stewardship.

With increasing clinical severity of MP pneumonia and growing evidence for the role of an overreactive host defense, the role of corticosteroids has been investigated. In a study of 12 healthy patients followed retrospectively all had either severe pneumonia (high fever, respiratory distress or initial lobar pneumonic consolidation with or without pleural effusion) or refractory pneumonia ( prolonged fever of >7 days or persistent consolidation of more than one lobe of the lung despite appropriate antimicrobial therapy), were diagnosed serologically, had no viral co-infection, received appropriate antimicrobials (macrolide or beta-lactam) and methylprednisolone at 30 mg/kg/day × 3 days. All improved. Although MRMP may cause severe refractory MP, susceptibility testing was not performed in the above study.

Most often, MP causes a benign respiratory illness that may involve both upper and lower respiratory tracts. But MP has the potential to cause severe disease. The emergence of MRMP has led to severe MP pneumonia. But macrolide resistance is only one potential cause of severe disease. An exuberant host inflammatory response with release of cytokines and, perhaps mediated largely by CMI, appears to play a role in some children and adolescents. In the latter situation, corticosteroids may prove beneficial but more research needs to be done.

Over the last three decades, many studies have investigated the best approaches to promote hand hygiene practices and improve hand hygiene indicators, in particular healthcare workers' (HCWs) compliance. Early studies on hand hygiene improvement in healthcare were focused on single interventions promoting the importance of handwashing and introducing the use of antimicrobial soaps. In 1994, our group in Geneva conducted the first large-scale epidemiological research on hand hygiene, identifying major risk factors for noncompliance and demonstrating the critical role of alcohol-based handrubs (ABHRs) as major system change to replace handwashing with soap and water, while included in a multimodal strategy to change HCW behavior. The strategy combines easy access to ABHR ( proven to bypass the time constraint on HCWs), HCW education, performance monitoring and feedback, reminders in the workplace and institutional safety climate. The strategy (referenced as the "Geneva Model of hand hygiene promotion) was proven successful, and hand hygiene improvement was associated with significant reduction in healthcare-associated infections (HAIs) and spread of multi-resistant organisms. Between 2000 and 2006, the "Geneva Model of hand hygiene promotion" was replicated in single, as well as multiple healthcare institutions, at local, regional and national level, with success. Since 2005, the World Health Organization (WHO) mandated our group to lead the First Global Patient Safety Challenge (Clean Care is Safer Care) with the main objectives to raise awareness about HAI worldwide, mobilize nations toward IPC activities and promote best IPC practices, in particular hand hygiene. The recent meta-analysis by Luangasanatip et al. demonstrates the critical role of the WHO multimodal approach in successful hand hygiene promotion.

Nevertheless, several knowledge gaps in hand hygiene monitoring and efficacy remain. In my lecture I will focus on the following topic areas related to key questions in the hand hygiene research agenda:

• Studies on direct and indirect monitoring of hand hygiene compliance, including new devices for observation and feedback;

• Studies of the influence of i) handrubbing duration; ii) volume of ABHR used, and iii) the optimal sequence of the handrubbing steps within the "How to Handrub" 6-step technique, in the reduction of bacterial counts on HCWs hands; • Studies on the burden of disease and implementation of infection prevention and control strategies worldwide; • Studies of the possible role of patient participation and empowerment in hand hygiene promotion. Hepatitis C virus (HCV) infection is one of the most common chronic liver disease. Globally, it was estimated that in 2005, more than 185 million people had HCV antibodies ( prevalence of 2.8%). Most patients infected with HCV acquired the disease through intravenous drug use or blood transfusion, the latter of which has become rare since routine testing of the blood supply for HCV began in 1990.

Nosocomial transmission of HCV has been documented in several health care settings. Where there are stringent infection control protocols to prevent transmission, particularly through unsafe medication injection practices, nosocomial transmission has still been reported, generally because of breaches in protocol. Rare sources of transmission of HCV include contaminated equipment used during the performance of procedures and other breakdowns of infection control procedures or aseptic techniques leading to person-to-person transmission. Screening for hepatitis C virus (HCV) infection is an important component of successful control of HCV for the infected individual and for public health purposes.

Diagnostic tests for hepatitis C virus (HCV) are serologic assays that detect antibodies to hepatitis C, and molecular assays that detect or quantify HCV RNA, Other investigations such as genotype testing, serum fibrosis panels and liver biopsy may help to predict the response to treatment and prognosis. Most cases of acute HCV infection are anicteric and asymptomatic, with fewer than 25% being clinically apparent. Fulminant hepatitis C is rare. Of those who go on to have chronic infection, a substantial proportion will develop cirrhosis, and a subset of those develop hepatocellular carcinoma.

Active surveillance based on MDR gram-negative pathogens?

Anucha Apisarnthanarak MD

Active surveillance is one of the common strategies employed to control MDR-gram negative pathogens. Although listed in the guideline, the true value of active surveillance for MDR gram-negative pathogens has never been demonstrated. Several considerations should be made when Infection Preventionists implement active surveillance as part of control measures. These include the specific reservoir of each specific MDR gram-negative pathogens, resource availability for isolation precaution, the turn-around time of active surveillance culture, whether institution is able to implement other infection prevention strategies together with active surveillance culture. In this session, I will address the pro-and con-for active surveillance culture for MDR gram-negative pathogens. Application of active surveillance culture in resource-limited settings will also be discussed. Also, rates of catheter associated urinary tract infection (CAUTI) and C-line associated blood stream infection (CLBSI) significantly decreased from 1.85 to 0.88 ( per 1000 catheter-days, F = 10.14, p < 0.0001) and from 3.40 to 2.20 ( per 1,000 catheter-days, F = 14.17, p < 0.0001). In subgroup analysis, rates of VAP, CAUTI and CLBSI were significantly decreased regardless of organizational and institutional characteristics of ICUs.

In summary, all of the DA-HAIs have shown a significant reduction in the last 10 years, however V-UR has year-wise significantly increased trend for past 10-years, also UC-UR and CL-UR have not decreased trend significantly. We need effort to make reduction of device utilization ratios and associated infections. Invasive fungal infections (IFI) are primary causes of mortality, and rapid and accurate diagnostic laboratory tests are required to improve patient outcomes. Although histopathologic examinations of tissues can detect IFIs, tissue morphology alone is insufficient to distinguish between Aspergillus and other fungi, including Fusarium, Scedosporium, or Mucorales. Therefore, species identification using culture and non-culture methods is necessary. Recently, assays targeting ribosomal DNA have been used to identify infectious fungi in tissues. Notably, analyses using frozen tissues were superior to those using formalin-fixed paraffin-embedded tissues. Because pan-fungal primers hybridized DNA from other eukaryotes, the pan-fungal approach was limited in tissues that primarily contained human DNA and little fungal DNA.

Diagnostic tests that rely on fungal cultures are common for IFIs. Recently, however, DNA sequencing and matrix-assisted laser desorption/ ionization time-of-fight mass spectrometry (MALDI-TOF MS) have been used to rapidly and accurately identify fungal pathogens recovered from cultures. Sequence-based identifications have been particularly useful for identifying cryptic species that were misidentified by microscopic analyses or were identified only to the complex level. Some cryptic species are resistant to azole antifungal agents, and molecular methods have been developed to detect azole-and echinocandin-resistant Candida species as well as azole-resistant Aspergillus species.

Blood cultures are the gold standard for diagnosing candidemia; however, cultures require 1-3 days of growth followed by an additional 1-2 days for identification and antifungal susceptibility testing. Such timeframes lead to delays in treatment initiation. Additionally, up to onethird of patients with invasive candidiasis fail to test positive in blood cultures.

PCR and the 1,3-β-D-glucan (BDG) assay are more sensitive than blood cultures for patients with deep-seated candidiasis. BDG is a cell wall component in Candida and other fungal species, except Mucorales and Cryptococcus, and is included in the EORTIC/MSG revised diagnostic criteria for invasive fungal diseases. However, BDG assays are expensive and labor-intensive, making them unavailable in most developing countries. The BDG assay is highly sensitive but lacks specificity; thus, it is typically suitable only for ruling out the causes of candidiasis.

Serum galactomannan (GM) is a cell wall component of Aspergillus, and can be detected in serum using a commercial test (Platelia™ Aspergillus EIA; BioRad, USA). The serum GM test is considered Aspergillus-specific, and multiple studies demonstrated high sensitivities (∼70%) in sera from patients with hematological malignancies or allogeneic hematopoietic stem cell transplantations. However, GM sensitivity is low in non-neutropenic patients and recipients of solid organ transplants. Additionally, the GM test is associated with poor predictive values in patients receiving mold-active antifungal prophylaxis. However, the detection of GM in BAL fluid is high (>70%) even among patients receiving mold-active antifungal therapies.

Multiple studies have shown that PCR was more sensitive than culture methods at detecting Aspergillus in blood and respiratory fluids. Multiple PCR assays are commercially available for the detection of Aspergillus spp.; however, none is FDA-approved. Moreover, Aspergillusspecific PCR is not recommended for clinical use as only few assays are standardized and validated. The T2Candida assay (T2 Biosystems, USA) was recently introduced for the detection of five common Candida species from whole-blood samples. The T2Candida assay is the only FDA-approved diagnostic test that offers rapid diagnosis (3-5 hours) and specific organism identification with detection limits of 1 CFU/ml. The development of additional diagnostic tests will facilitate the early diagnosis and management of IFIs in high-risk patients.

The newest treatment strategies for candidemia Thomas F. Patterson Professor of Medicine, UT Health San Antonio, San Antonio, Texas USA Candidemia is an important cause of morbidity and mortality especially in hospitalized and immunocompromised patients. Despite advances in antifungal therapy, the number antifungal drugs and drug classes for treating these serious infectious remains limited. Management is further complicated by the fact that it remains difficult to establish an accurate diagnosis which is compounded by the need for early therapy. Fluconazole remains a useful antifungal agent especially for follow-on therapy after stabilization of infection but resistance is high for some species including C. glabrata. Thus, the echinocandins have become recommended as primary therapy in most patients. However, development of echinocandin drug resistant strains has been reported worldwide. The development of drug resistance has often been tied to antifungal drug use, particularly for some species like Candida glabrata. While multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. New agents are under development for candidemia, including echinocandins improved pharmacokinetic profiles and those available for oral use. In addition, other agents with new targets of action are also undergoing preclinical development. Diagnosis of infection and detection of antifungal resistance is critical to the successful management of patients with these infections. New therapies are aimed at improving outcomes in candidemia.

Epidemiology and management of mucormycosis and invasive aspergillosis: are there lessons to be learned?

Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR, Westmead Hospital, University of Sydney, New South Wales, Australia

The epidemiology of Aspergillus and Mucorales infections may be changing. Although invasive aspergillosis (IA) remains a substantive cause of morbidity in patients with neutropenia, hematologic malignancy and organ transplants, there is an expansion in the spectrum of at risk patients. Patients in the intensive care unit (ICU), with chronic lung disease, HIV/AIDS and those on immunomodulating drugs are amongst relatively understudied populations. Diagnostic difficulties including the interpretation of Aspergillus cultures contribute to this limitation.

Other than the expansion in host risk groups, is the shift in etiology of IA, with cryptic or uncommon species emergent. In addition, azoleresistant A. fumigatus infections pose an increasing dilemma in regions of Europe and Asia (<5-30% resistance rates).

In general, voriconazole is recommended for the primary treatment of IA regardless of site of infection. Other azoles, the echinocandins or amphotericin B compounds may be used as second line or salvage therapy. Primary combination therapy is not routinely advised. Surgical derbridement or resection is an important adjunct where feasible. In the presence of azole resistance, either liposomal amphotericin B (L-AMB) or a voriconazole-echinocandin combination is preferred. In vitro susceptibility testing is recommended for all IA cases. Isavuconazole has good activity against Aspergillus and new antifungal drugs with anti-Aspergillus activity are in development.

Many cases of mucormycosis affect hosts with malignancy and stem cell transplantation, but organ transplantation, diabetes mellitus and iron overload are also important underlying conditions although the use of certain calcineurin inhibitors may be associated with lower risk. Emerging risks include underlying rheumatological/autoimmune conditions. Trauma-related cases may also be increasing and outbreaks of infection following natural disasters and iatrogenic exposure described. Pathogen epidemiology varies with region with emergence of uncommon genera such as Apophysomyces.

Despite best practice management and reversal of risks, mortality is up to 80%. Treatment is based on case series and expert opinion. Surgical debridement/resection combined with antifungals improves outcomes. Initial treatment with L-AMB is preferred agent although optimal dosage is uncertain. Isavuconazole appears to be as efficacious as L-AMB. Combination polyene-echinocandin can be considered for extensive disease or salvage therapy, with posaconazole typically employed as step-down therapy. Treatment algorithms may change with wider availability of IV posaconazole; other new drugs are in the pipeline.

Endemic fungal infection in the Asia-Pacific region (in the context of altered immunity)

National University Health System, Singapore

Less is known about the incidence and characterization of deep mycoses in the Asia Pacific region. Geoclimatic conditions, population demographics and health resource accessibility vary within the respective Asian countries and also differ from West. Invasive fungal diseases (IFD) encountered in the region will be discussed with specific highlights on the unique challenges faced pertaining to host immune susceptibility and in the management of these diseases.

Candidemia and candidiasis constitute the highest proportion of the IFDs. In particular, the contribution by Candida tropicalis in tropical Asia Pacific is not to be overlooked. Candida tropicalis infection, linked to more severe disease, is seen in patients with weakened immunity such as hematological malignancies and in neonates. The host immune factors recently identified as predisposing to oro-esophageal candidiasis will also be discussed. Chronic (cavitatory) pulmonary aspergillosis (CPA) in Asia is often a sequelae to old tuberculosis as well as aspergillosis in the critically ill is under-recognized. The immune interplay between the ubiquitous mold and the host defense during severe illness will be explored. Cryptococcosis and penicilliosis have traditionally been seen in patients infected with the human immunodeficiency virus (HIV). While Cryptococcus infections have been recognized to occur beyond the context of HIV and even in apparently immunocompetent subjects, it is only recently that the immune susceptibility of such patients to Cryptococcus are being dissected. Similarly the notable predilection of Talaormyces marneffei (and other rare fungi) in the Asia Pacific region is being linked to other non-HIV-attributed host immune defects including a novel disease trait seemingly distinct to Asians.

Pre-exposure prophylaxis: from science to implementation Rossana A. Ditangco MD

PrEP for HIV refers to the preventive strategy of taking a medical agent prior to HIV exposure. This method specifically involves the oral intake of an antiretroviral drug (ARV) by HIV-negative individuals who are at high risk of acquiring the virus in order to prevent HIV infection.

Recent studies have demonstrated safety and efficacy of dual antiretroviral (ARV) oral pre-exposure prophylaxis (PrEP) in preventing sexual and parenteral transmission of HIV infection. The IPrEX study, a randomized controlled efficacy trial in men who have sex with men (MSM) and a small contingent of male-to-female transgender women (TGW) is particularly relevant to Asia and the Pacific. In this study, emticitrabine/tenofovir disoproxil fumarate (FTC/TDF or Truvada ® ) safely achieved a 44% per-protocol reduction in new HIV infections. However, risk reduction was 92% in FTC/TDF recipients having detectable study-drug blood levels, indicative of much greater efficacy associated with increased adherence. Subsequent pharmacologic modeling and follow-up studies demonstrated daily use of these agents not being required for achieving optimal protection, declining on a gradual scale associated with decreased frequency of use . This research showed a reduction of HIV infection risk of 99% for 7 doses, 96% for 4 doses and 76% for 2 doses of FTC/TDF per week. The protective efficacy of non-daily dosing (89% risk reduction) was subsequently confirmed in a placebo-controlled trial of intermittent (on-demand) FTC/TDF PrEP among MSM in France and Canada. Mathematical modeling using IPrEX findings demonstrated substantial reductions in new HIV infection associated with modest PrEP program coverage in MSM, while increased PrEP adherence was shown to have the largest population level preventive impact with greatest cost-effectiveness .

PrEP implementation has been shown feasible in open-label extensions and project sites with research and program capacity. Despite its excellent safety and efficacy profile, the proof of implementation of PrEP in resource-limited settings outside of these situations still needs to be delivered.

Applications of PrEP in resource limited situations must be grounded in the reality of existing health systems and the interface between community-level primary care clinic-and hospital-based services. A number of unknowns remain with respect to the delivery of HIV PrEP for MSM/TGW in these environments. Among others, access, uptake and adherence, effectiveness and behavioral and social impact effects are not described. Taking part in a PrEP project or using ARV drugs may disclose same-sex behavior and HIV risk. These in turn may provoke negative reactions or undue pressures in the social, professional and family environment. Participants may see certain services or privileges being revoked or denied. In a worst case scenario, disclosure may lead to denial or termination of health or life-insurance, rental agreements, employment or promotion. These negative repercussions constitute violations of individual rights and may adversely impact project participation and PrEP access, uptake and adherence. Of particular concern are poor adherence and increases in sexual risk behavior, the latter potentially accelerating sexually transmitted infections (STI) followed by increased HIV acquisition and transmission in the non-PrEP serviced portion of at risk population.

At present countries are at varying stages of introducing daily oral PrEP using TDF/FTC, which is now recommended by WHO as an option for people at substantial risk of HIV.

Some countries have national programs; others have smaller-scale programs; others aren't offering PrEP at all. The benefit of PrEP as a prevention strategy goes beyond its clinical efficacy. PrEP programs could increase HIV testing uptake and contact with health care provider for HIV counseling and education services and early diagnosis and treatment of sexually transmitted infection. Scientific evidence of efficacy and safety of PrEP, mathematical models for cost effectiveness and potential elimination of new HIV infection and projected benefit beyond clinical effectiveness provide rationale for making PrEP available as additional layer of HIV prevention strategy.

Center for AIDS Research, Kumamoto University, Kumamoto, Japan

Despite the significant reduction in morbidity and mortality following combination antiretroviral therapy (ART) there is emerging evidence that people with successfully treated HIV infection by ART age prematurely, leading to progressive multi-organ disease referred as comorbidities. One of the major factors involved in this pathogenic process is residual viral replication by persistently infected cells surviving in vivo and subsequent chronic inflammation. In contrast to the current ART that only targets viral replication neutralizing or nonneutralizing antibodies against the envelope proteins of HIV-1 have been reported to have an ADCC (antibody-mediated cellular cytotoxicity) activity that eliminate HIV-1 infected cells in vitro.

The discovery of potent and broadly neutralizing antibodies (bNAbs) against HIV has made passive immunization a potential strategy for the prevention and treatment of HIV infection. The bNAbs 3BNC117 and VRC01 targeting the HIV CD4-binding site has been tested in treatment naïve patients and on treatment patients for the delay in plasma viral rebound after the discontinuation of ART. Monoclonal antibody 10-1074 targets the V3 glycan supersite was used at the highest dose of 30 mg/kg and showed a rapid decline in viremia. However, virologic analyses revealed the emergence of multiple independent neutralization resistant mutants in every case.

We conducted a phase 1b clinical trial of passive transfer of neutralizing monoclonal antibody KD-247, which is reactive against the tip of the V3 region. Eligible subjects were randomized to receive one of the 3 doses of KD-247 and the treatment was found safe and well tolerated. We observed significant decrease in HIV-RNA in the 16 mg/kg cohort of KD-247 with two in six cases who achieved >1 log reduction of HIV-RNA. Long-term suppression of viral load was observed for one patient despite significant decrease in plasma concentration of KD-247, suggesting effects of antibody other than neutralization. We previously reported that the neutralization escape mutants to KD-247 became sensitive to chemokine CC receptor (CCR)5 inhibitors such as maraviroc or cenicriviroc. Conversely, resistance mutants to CCR5 inhibitors became sensitive to several neutralizing antibodies including KD-247. Furthermore, a series of in vitro experiments suggested synergistic effects of the combination of KD-247 and CCR5 antagonists including maraviroc (Figure) . These results taken together, suggest that the combination of neutralizing antibodies with CCR5-inhibitors would be a promising candidate of intensification therapy added onto the current suppressive ART aiming toward functional cure of the disease. Programmable nucleasesincluding zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and RNA-guided engineered nucleases (RGENs) derived from the bacterial clustered regularly interspaced short palindromic repeat (CRISPR)-Cas (CRISPRassociated) systemenable targeted genetic modifications in cultured cells, as well as in whole animals and plants. The value of these enzymes in research, medicine and biotechnology arises from their ability to induce site-specific DNA cleavage in the genome, the repair (through endogenous mechanisms) of which allows high-precision genome editing. However, these nucleases differ in several respects, including their composition, targetable sites, specificities and mutation signatures, among other characteristics. Knowledge of nucleasespecific features, as well as of their pros and cons, is essential for researchers to choose the most appropriate tool for a range of applications.

Group Cpf1 is a recently reported effector endonuclease protein of the class 2 CRISPR-Cas system. Cpf1 has several differences from Cas9: cleavage with 5' overhangs, shorter guide RNA, and a longer distance between the seed sequence and cleavage site, which could provide potential advantages for some cases of genome editing such as nonhomologous end joining-based gene insertion and efficient genome editing using homology-directed repair. However, limited information is available about Cpf1 activity profiles in mammalian cells, precluding its wide use for genome editing. Furthermore, both selection of highly efficient guide RNAs and collection of big data for determination of parameters of RNA-programmable nucleases are currently laborious and costly due to lack of a reliable high-throughput approach to determine RNAprogrammable nuclease activity in mammalian cells. Here, we performed en masse evaluation of guide RNA and Cpf1 activity using synthetic target sequences and deep sequencing. Using this in vivo high-throughput approach, we determined on-and off-target activity profiles and protospacer adjacent motif (PAM) sequences of Cpf1. We found that sequence features of high activity AsCpf1 guide RNAs are distinct from those of SpCas9 and that the PAM of As and LbCpf1 in mammalian cells is TTTV, rather than TTTN, which was previously determined using an in vitro system. Evaluation of off-target activity showed that Cpf1 target sequences can be divided into three regions: a 6 base pair (bp) seed, a 13 bp trunk, and a 6 bp promiscuous region. These results should serve as a useful guide to select Cpf1 as a genome editing tool. More importantly, our in vivo high-throughput evaluation system will greatly facilitate both the selection of efficient and precise guide RNAs and the generation of big data for the development of advanced prediction programs for on-and off-target activities. TasP works if an infected person knows his/her HIV status. A diagnosis should have been made as early as possible, and treatment offered promptly, so that the time gap between infection and viral suppression can be narrowed. Around the world, late diagnosis is still common. Early diagnosis often hinges not just on easy access to voluntary testing, freedom from stigma, but also the availability of screening. Selftesting and the submission of specimens (urine, saliva, dried blood spots) for laboratory testing are some solutions, albeit the existence of technical problems, and the need for establishing linkage to care. Periodic testing campaigns could impact HIV epidemiology, as illustrated in our modelling study parametrized by Hong Kong's surveillance data. For patients enrolled in treatment programs, optimization of regimen is crucial to ensure lifelong maintenance of HAART without adverse reactions. In the developed world, integrase inhibitor is now used in first-line regimens, which has the capacity of reducing viral load to undetectable range within weeks. Their access and that of single tablet regimens, are however limited in places where most HIV patients are. For some antiretrovirals, for example abacavir and efavirenz, knowledge of the host genotype (HLA-B5701 and CYP2B6-516GT respectively) could minimize the occurrence of adverse reactions which might otherwise compromise adherence. Notably adherence is the key to lifelong maintenance of virus suppression, and there is no simple solution to guarantee adherence over years, or tens of years.

Whereas all efforts could be made to promote testing and improve treatment coverage, the underdiagnosed interval is often where the Achilles heel is. Except for a small number of cases presenting as acute infection, the seroconversion time is often unknown. Using modified back calculation methods to estimate the seroconversion year of over 3,000 patients in Hong Kong, we found that the interquartile range of their underdiagnosed intervals was 1-4 years with a range between 0 and 10 years. The lengths of undiagnosed intervals were associated with age and the routes of HIV transmission. Obviously people with low perceived risk of HIV infection had longer undiagnosed interval and were more likely to be late for diagnosis. From mathematical modelling, increase of undiagnosed intervals would offset infections averted by TasP even if good coverage and high adherence were assumed. Apparently, TasP is a necessary yet insufficient intervention to achieve HIV elimination. TasP targets people infected with HIV, whereas interventions for non-infected individuals would contribute to the reduction of the size of populations requiring TasP. One good example of the latter is pre-exposure prophylaxis, but it's only accessible to handfuls of people at risk around the world. Effective protocols are needed, and risk compensation is a new concern. Let's not forget promotion of protected sex, provision of methadone maintenance (and other harm reduction measures) for injection drug users, and community-level behavioral interventions. They continue to be powerful components of the armamentarium of measures to combat HIV, complementing TasP to achieve HIV elimination.

Stephan Harbarth

Health care-associated infection (HCAI) is a major global issue in patient safety. It affects hundreds of millions of people worldwide, complicates the delivery of patient care, contributes to patient deaths and disability, promotes resistance to antibiotics, and generates additional expenditure to that already incurred by the patients' underlying disease. Indeed, HCAI is a growing international problem.

Patients are becoming more susceptible to infections because of more serious underlying illnesses. Poor compliance with hand hygiene by health care staff, increased recourse to invasive medical devices, and care of the critically ill as well as lack of access to safe water and unclean instruments and environmental surfaces all play a role. The environment of patient care is also important. Factors such as understaffing, high bed occupancy, and increased patient transfers all create new risks of infection. The first Global Patient Safety Challenge created a worldwide focus on reducing HCAI as a vital element of the safety of patient care.

The last two years provided important and clinically relevant research data for prevention of HCAI in different patient populations. My presentation will summarise the results of clinical trials and systematic reviews for the reduction of various types of HCAI, and will discuss them in the context of the current relevant scientific and clinical background. In particular, I will discuss recent data on the epidemiology and prevention of nosocomial infections in intensive care units, present new approaches to prevention of surgical site infections as well as catheter-related bloodstream infections, describe recent advances in hand hygiene research and attempt to briefly summarise specific challenges related to the management of infections caused by multidrugresistant microorganisms. Overall, HCAIs remain one of the key challenges of hospital care and significantly contributes to morbidity and mortality. Papers published in the last 2 years remind us that further reductions of HCAI rates are possibleoften with the help of simple and rather inexpensive interventions. Rapid and accurate diagnosis is critical for the effective treatment of life threatening infections, such as bloodstream, respiratory tract and complicated urinary tract infections (UTIs). These clinical syndromes are difficult to diagnose due to complex aetiology and challenging clinical sample types (e.g. blood, sputum). Current culture based diagnosis often has sub-optimal specificity and sensitivity and is too slow to impact on patient management. Shotgun metagenomics sequencing has the potential to change the way we diagnose infection, combining rapidity with comprehensiveness beyond that of current methods. Real-time nanopore sequencing technology provides the rapid turnaround necessary for infectious diseases diagnostics applications at point-of-care.

There are challenges in applying sequencing to infection diagnosis, however, including high human:pathogen nucleic acid ratios, low pathogen numbers and low quality nucleic acid, depending on the disease and the clinical sample type. It is, therefore, vital to carefully design, develop, and optimise diagnostics pipelines before attempting to apply them to clinical samples. I will describe how we develop our MinION based infectious diseases diagnostics pipelines with examples from our ongoing research on pneumonia, sepsis and UTIs.

Protein synthesis enzymes as primary defense system against infection Aminoacyl-tRNA synthetases (ARSs) are essential protein synthesis enzymes, making a covalent linkage of their cognate amino acids to tRNAs. Since the catalytic activities of ARSs are always required for the viability of organisms, they are constitutively expressed and ubiquitously present. Due to these features, ARSs are the first to be exposed to broad spectrum of stresses and challenges. In fact, they have shown diverse roles as rapid responding signal mediators beyond protein synthesis. Here we show our recent findings on ARSs as primary defense system against bacterial and viral infections. For instance, tryptophanyl-tRNA synthetase (WRS), is rapidly secreted out from monocytes upon bacterial infection and primes innate immune responses. The secretion was far more rapid than the induction of innate immune system. In another case, glutamyl-prolyl-tRNA synthetase (EPRS) plays a unique role in viral clearance. EPRS blocks PCBP2mediated ubiquitination of MAVS (mitochondrial antiviral signaling protein), leading to the inhibition of viral replication. Based on these findings, other ARSs are expected to play unique roles against infection, thereby collectively serve as a primary shielding system.

Victor Lim

International Medical University, Kuala Lumpur, Malaysia

The world is facing a crisis in antimicrobial resistance (AMR). It has been projected that if nothing is done 10 million people will die from antimicrobial-resistant infections annually by 2050 and the economic cost will also be correspondingly high at one hundred trillion US dollars.

The overuse of antimicrobial agents is a major driver for the emergence of resistance. Improving antibiotic stewardship is therefore crucial in meeting the challenges posed by AMR. To do so would require recognition of the problem by all stakeholders at all levels and the political will to solve. Adequate planning and provision of resources (including legislation) are essential. Most importantly however, it would require a behaviour change among all stakeholders.

There is increasing recognition that providing evidence from health research while necessary is insufficient for the delivery of optimal health care. There is a need to translate knowledge into action. The field of Knowledge Translation (KT) is the scientific study of methods for closing the knowledge-to-practice gap, and of the barriers and facilitators inherent in this process and such methods must be employed if we are to enjoy any success in antibiotic stewardship. The ESRC Working Group on AMR Report 2014 stated that although AMR involves biological processes, the context which determines the operation of these biological mechanisms is shaped by social, cultural, political, and economic processes. 1

Behavioural Science is a multidisciplinary study of human (and animal) behavior and encompasses the disciplines of psychology, anthropology, sociology and economics. The contribution of behavioural science in improving antibiotic stewardship is crucial but has only been recognized lately. 2 Antibiotic prescribing is a complex behaviour, carried out by an informed individual often making a subjectively rational choice. A recent report by the Department of Health and Public Health England summarised the evidence on behavioural change and antibiotic prescribing in healthcare settings. It pointed out the lack of underpinning psychological theory and behavioural science in most of the studies which have been done so far. 3 As a result interventions may not be effective in changing behavior.

To change behavior we need to understand the drivers of behavior. Drivers of prescriber behavior may be intrinsic or extrinsic. Intrinsic factors include an altruistic motivation to do one's best for the patient, ignorance, duration of practice, the tendency to yield to patient demands, fear (both of progression of disease and losing the patient), and a lack of understanding of the resistance problem.

Extrinsic factors would include patient demands, the influence of the pharmaceutical industry, diagnostic uncertainty, patient comorbidities and social class, workload and time pressures, role modelling by senior colleagues and financial incentives.

Interventions to improve antibiotic stewardship had included prescriber education and training, the issuance of Antibiotic Guidelines, the use of electronic decision support systems, audit and feedback, rapid and near patient testing to reduce diagnostic uncertainty, restriction strategies (pharmacy and laboratory) as well as financial strategies. To increase awareness of the problem of AMR among the public social marketing strategies have been employed including the use of the mass media.

Although a variety of interventions have been employed over the last 5 decades; their overall effectiveness is subject to question. Results have been variable. What works in one setting may not work in another as behavior change is a complex process and influenced by social, economic, ethnic and cultural beliefs. Many studies are cross-sectional in nature and the sustainability of the intervention is not measured.

To design any strategy or intervention there is a need to understand both prescriber and patient/public behavior and the factors that drive it using methodologies that are established in the behavioural sciences. Any intervention has to be specific to the local context and the target population. A combination of strategies may be necessary to modify behavior for desired outcomes.

Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore

Antimicrobial resistance in hospitals is characterized by widespread dissemination of multidrug-resistant and extensively drug resistant bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase and carbapenemase producing Enterobacteriaceae, and pandrug-resistant Acinetobacter baumannii. A combination of enhanced infection control and antimicrobial stewardship is often recommended to combat antimicrobial resistance in hospitals. Multiple strategies are recommended by professional societies for antimicrobial stewardship, with differing levels of evidence and effectiveness. Several recent well conducted systematic reviews and meta-analyses have shown that antimicrobial stewardship is effective in reducing broadspectrum antibiotic use and antimicrobial resistance without increasing adverse clinical outcomes. Restrictive strategies produce more immediate effects but persuasive strategies are associated with more sustained impact. In addition to commonly adopted strategies of pre-authorization and prospective review and feedback, a greater variety of antimicrobial stewardship interventions are now recommended. In particular, evidence-based clinical care paths for common infections are associated with improved mortality. However antimicrobial use in hospitals is part of the greater context of antimicrobial use and resistance within the One Health continuum. Increasingly national and regional antimicrobial stewardship efforts must move outside of hospitals.

DAMPs: Neutrophil dysfunction in experimental sepsis and post-septic complications related to immunosuppression Jaroslaw Zmijewski University of Alabama at Birmingham, USA DAMPs: Neutrophil dysfunction in experimental sepsis and post-septic complications related to immunosuppression Bone

Using a murine model of polymicrobial septic peritonitis, we demonstrated that treatment with anti-HMGB1 Ab significantly diminished sepsis-induced dysfunction of neutrophil NADPH oxidase activity. Importantly, confirmatory experiments revealed that blocking HMGB1 prevents neutrophils dysfunction. In summary, these results suggest that HMGB1 accumulation in the late phase of sepsis plays a specific role in the development of immunosuppression and specifically affects neutrophil-dependent antibacterial function in sepsis survivors. Epidemiology of extensively-resistant Gram-negative in Mainland China Hui Wang Peking University People's Hospital, PR China Multidrug resistance in gram-negative bacteria, especially carbapenem-resistant Enterobacteriaceae (CRE), is a critical public health threat in China

Advances in next-generation sequencing (NGS) platforms and microbial bioinformatics have positioned NGS to play an increasing role in clinical microbiology laboratories. Next-generation sequencing is being applied to microbial isolates as well as directly to clinical specimens

Benchtop sequencers suitable for use in clinical microbiology laboratories are now available. Sequences may be generated with various approaches (e.g., paired-end, mate-pair) and either aligned against a reference strain or assembled de novo with subsequent analytic strategies including single nucleotide polymorphism (SNP) analysis and core genome multilocus sequence typing (cgMLST), among others. These approaches impact turnaround time, cost, technical difficulty, and accuracy. How results compare to those of historical methods

Not only does it allow for pathogen identification, but gene content information can also be used for resistance prediction, typing, and assessment for other relevant genes, such as those encoding virulence factors. Our experience applying this approach to the diagnosis of prosthetic joint infection will be presented

We found that loss of Parkin, ubiquitin ligase implicated in autophagy and mitophagy occurs several hours after pro-inflammatory engagement in macrophages and lungs of mice subjected to intratracheal instillation of endotoxin. Parkin dissipation was also accompanied with diminished activity in AMPactivated protein kinase (AMPK), a major sensor and metabolic regulator of immune homeostasis. We hypothesize that AMPK activation will overcome loss in Parkin-mediated autophagy and thus, diminish severity of ALI. We found that AMPK activators metformin or AICAR did not recover the amounts of Parkin. However, AMPK activation promoted autophagy and improved bacterial clearance. In summary, our results show that Parkin deficiency increased macrophage pro-inflammatory activation and the severity of ALI

Mayo Clinic, USA Infectious diseases diagnostic testing is currently in a revolution vis-à-vis delivering new technologies. A myriad of new technologies are in use or under development, including matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS), rapid multiplex (i.e., panel) nucleic acid amplification tests (NAATs), point-of-care microbiology NAATs, and rapid phenotypic bacterial susceptibility testing, to name a few. These technologies provide new tools to combat antimicrobial resistance, which is especially important in an era of rising resistance. Today, there is increased use of unneeded broad spectrum therapy because of the need to address the possibility of resistance until such a time as results of conventional diagnostic tests are available. This situation can potentially be ameliorated by more rapid diagnostics. In addition, over-prescription of antibacterial agents in general can potentially be addressed by rapid tests which exclude the need to prescribe antibacterial agents in the first place. An overview of new rapid diagnostics for infectious diseases that can potentially help combat antimicrobial resistance will be presented.Ideal new diagnostics are more rapid, less expensive, and more accurate than existing diagnostics. Unfortunately, not all new diagnostics meet all these criteria, with cost often being high. To address this situation, outcomes studies evaluating new diagnostics have assumed an important role. Outcomes that should be addressed include antibiotic and further test avoidance, patient outcomes (e.g., length of stay, morbidity, mortality), patient and provider satisfaction, and infection transmission. Results of outcomes studies then need to be used to inform the development of practice guidelines for use of these tests (which may vary from practice-to-practice) and also to inform ideal reconfiguration/development of tests by diagnostics companies. Our experience with a recent randomized controlled clinical trial evaluating a rapid multiplex NAAT for testing positive blood culture bottles will be presented.It is an exciting time for diagnostics, with new technologies and opportunities for studies to determine how best to use these technologies in patient care.

Div. Infectious Diseases, Dept. Internal Medicine, The Catholic University of Korea, KoreaSepsis is a significant syndrome in medicine and one of a major contributing cause of death world-widely.Prompt recognition and aggressive management is the key element of improving survival from this brutal disease. Unfortunately, sepsis is very complex immunologic event according to etiology and individuals' characteristics. As a result, a degree of organ dysfunction result from sepsis, an effect of protocolized treatment, and outcome could not be same.Resuscitation with fluid and vasopressors is an initial and essential treatment of severe sepsis and septic shock. Surviving Sepsis Campaign (SSC) continues to revise the treatment guideline and the initial steps for treatment are converged to use crystalloid fluid and use norepinephrine to whom do not respond to fluid therapy. In 2001, Rivers et al suggested protocolized quantitative resuscitation method, otherwise known as early goal-directed therapy (EGDT). This method was attractive in hospital settings because of clear notification of parameters, target, and drugs. The uncertainty of the effect of the individual component of bundle approach in treating severe sepsis/septic shock has been debated and EGDT has been challenged following the failure to show a mortality reduction in subsequent large multicenter randomized controlled trials. Effective fluid resuscitation means an effective restoration of tissue perfusion. Although mean arterial pressure (MAP) can be a representative marker of tissue perfusion, central venous pressure (CVP) and serum lactic acid do not. As you already know, we do not have precise parameters of individual patient's hemodynamic status and also evaluating an effect of therapy we do. What is the proper volume of resuscitating fluid and how to monitor are also important issues we should have interest? Although the crystalloid fluid is recommended as an initial therapy of resuscitation, the benefit, and harm of colloidal fluid, and alternative fluid is still evaluating.Vasopressor therapy is needed to who do not respond fluid resuscitation. But there are many unresolved questions such as target MAP, optimal timing, and duration. Norepinephrine has been recommended since the first SSC guideline, because more potent and effective at reversing hypotension, and less adverse events compared to dopamine. Epinephrine and vasopressin are regarded as next-line or partner drug with norepinephrine. The effect of other vasopressors such as angiotensin II and endothelin-1 are evaluating.Medical experience clearly says that fluid resuscitation and vasopressor are very essential and initial element to improve the survival of the sepsis and septic shock patients. But we do not exactly know how to do accurately and properly. I will briefly present the current consensus and controversies about fluid resuscitation, monitoring of patient's hemodynamics, and use of vasopressors in septic patients in this lecture. The antimicrobial stewardship program (ASP) is recognized as the most important tool for proper use of antibiotics. However, in order to properly implement ASP, systematic training and tools are needed for medical staff prescribing antibiotics.Basic education consists of face-to-face training for medical staffs. However, face-to-face education alone is difficult to maximize its effectiveness. When medical staffs prescribe, a variety of tools are being used to prescribe antibiotics properly.The most basic program is the antibiotic prescription restriction program. This program is a system that antibiotics which can only be used for certain resistant strains in hospitals are used with the permission of an antibiotic manager (usually an infectious diseases specialist).Most hospitals in Korea with infectious diseases specialists have this system. The Infectious disease division of Hallym Universuty Kangnam Sacred Heart Hospital have a list of restricted antibiotics that contain vancomycin, linezolid, carbapenem, piperacillin/tazobactam, tigecycline, liposomal amphotericin B, echinocandin, voriconazole as restricted antibiotics.Since the 2000s, antibiotic prescription programs have been introduced in Korea and used in various hospitals. The purpose of this program is to recommend appropriate antibiotics according to the impression at the time of admission to the patient. When the causative bacteria are cultured, they help to prescribe appropriate antimicrobial agents according to the cultures. Advanced programs automatically adjust the antibiotic dose according to the renal function. The number of antibiotic doses is also automatically recommended. When antibiotics need to be mixed with other solutions, it is automatically recommended that the solutions be mixed.Currently, these antibiotic prescription programs have begun to apply the learning function of artificial intelligence and recommend antibiotics that frequently used depending on the name of diagnosis. If you are using antibiotics which could be expected to be drug interactions, you can also show alarms via pop-ups.In 2016, the Korean Society for Chemotherapy developed a mobile app to help prescribe antibiotics. From 2017 to 2018, the Korean Society of Chemotherapy and Korea CDC (Center for Disease Control and Prevention) are conducting this project together. The antibiotic program is a collaborative project with hospital and clinic antibiotic prescription programs.This lecture will discuss antibiotic prescription programs used in Korea and discuss the developmental direction of this program.