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The United Nations General Assembly debate on antimicrobial resistance (AMR) recognizes the global significance of AMR. Much work needs to be done on technology capability and capacity to convert the strategic intent of the debate into operational plans and tangible outcomes. Enhancement of the biomedical science–clinician interface requires better exploitation of systems biology tools for in-laboratory and point of care methods that detect sepsis and characterize AMR. These need to link sepsis and AMR data with responsive, real-time surveillance. We propose an AMR sepsis register, similar in concept to a cancer registry, to aid coordination of AMR countermeasures.
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February 2017 | Volume 5 | Article 61
published: 06 February 2017
doi: 10.3389/fpubh.2017.00006
Frontiers in Public Health |
Edited by:
Matthew Bellgard,
Murdoch University, Australia
Reviewed by:
Arnold Bosman,
Transmissible, Netherlands
Gregory Dore,
University of New South Wales,
Timothy J. J. Inglis
Specialty section:
This article was submitted
to Public Health Policy,
a section of the journal
Frontiers in Public Health
Received: 14November2016
Accepted: 17January2017
Published: 06February2017
InglisTJJ and UrosevicN (2017)
Where Sepsis and Antimicrobial
Resistance Countermeasures
Front. Public Health 5:6.
doi: 10.3389/fpubh.2017.00006
Where Sepsis and Antimicrobial
Resistance Countermeasures
Timothy J. J. Inglis1,2* and Nadia Urosevic1,2
1 The Marshall Centre for Infectious Diseases Training and Research, School of Biomedical Sciences, University of Western
Australia, Perth, WA, Australia, 2 Department of Microbiology, PathWest Laboratory Medicine WA, Queen Elizabeth II Medical
Centre, Nedlands, WA, Australia
The United Nations General Assembly debate on antimicrobial resistance (AMR) rec-
ognizes the global signicance of AMR. Much work needs to be done on technology
capability and capacity to convert the strategic intent of the debate into operational plans
and tangible outcomes. Enhancement of the biomedical science–clinician interface
requires better exploitation of systems biology tools for in-laboratory and point of care
methods that detect sepsis and characterize AMR. These need to link sepsis and AMR
data with responsive, real-time surveillance. We propose an AMR sepsis register, similar
in concept to a cancer registry, to aid coordination of AMR countermeasures.
Keywords: antimicrobial resistance, sepsis, integrated systems biology, biocomplexity, microbial forensics,
infection control
e United Nations high-level meeting on antimicrobial resistance (AMR) was calculated to
thrust the issue of AMR into public view (1) and represents the latest milestone in a global
awareness-raising campaign by public health authorities. At rst glance, this appears to be the
antithesis of precision public health, which places an emphasis on targeted multidisciplinary
application of emerging biotechnology to the specic health needs of individuals (2). However,
this onslaught against a leading global health challenge is built on a foundation of laboratory
AMR surveillance and powered by similar multidisciplinary application of emerging high-
throughput biotechnologies (3). e big data outputs obtained in such a way are attractive to
public health precisely because they are amenable to mathematical modeling of the ecological
and evolutionary processes that lead to AMR (4). ese dynamic aspects of infection are complex
and have led to a widening comprehension gap. Consequently, the growing public recognition
of AMR has yet to acquire a more sophisticated understanding of its personal implications (5,
6). Health professionals who share our concern about escalating AMR support the translation
of global policy into action at local, national, and international levels (7). A global campaign
to contain and control AMR needs translation from strategic policy into day-to-day health-care
practice. Strategy; the practice of the art of war by the strategos or general, includes the broader
considerations of game theory, complexity, business, and management strategy (8). Biocomplexity
provides an attractive framework for placing the cell and molecular biology or biomedical end
of the AMR scale in a broader context that includes the clinical pathology of tissues and organs,
and ultimately population health including all professional, social, and government regulation
(9). So, to understand the mechanistic workings of an emerging public health phenomenon
Inglis and Urosevic Antimicrobial Resistance Countermeasures
Frontiers in Public Health | February 2017 | Volume 5 | Article 6
such as the rise in AMR infections, it is necessary to descend
the scale of biological organization from population health
to the molecular and cellular mechanisms of multiple-drug
resistance in dierent bacterial species (10). A robust assess-
ment of the broad consequences of AMR requires the converse;
an ascent from a specic AMR phenotype to multinational
surveillance review (11, 12). An unavoidable feature of AMR
is its capacity for unpredictable double transmission: the ability
to not only enhance case-clusters of transmissible disease, but
also for transmission between resistant and previously sensitive
bacteria contributing to novel disease case-clusters, as seen in
the dissemination and proliferation of multiple mechanisms
of carbapenem resistance (13). Both specic mechanisms and
means of AMR transmission need consideration, since both the
AMR mechanism and its transmission will impact on the ecol-
ogy and epidemiology of AMR infection and have implications
for the measures needed to control AMR (14). New analytical
systems biology tools provide scope for evidence-based design
of AMR surveillance and control (15). e complex picture that
emerges can be used to develop an AMR narrative that covers
the wide range of AMR molecular signatures, multiple bacterial
species, and AMR mechanism combinations across the broad
scale of biological organization (3). However, other emerging
systems biology methods such as proteomics, metabolomics,
and bacterial cytomics have yet to be integrated in a holistic
AMR analysis that forms a more compelling argument for
a specic causal eect (16). Practical use of this approach
to attribution of causality has been explored in the eld of
microbial forensics and has wider application in linking the
dierent tiers of analysis up to a strategic level (17). e O’Neill
Review identied critical vulnerabilities that could be exploited
in control of the global AMR problem and made a series of
recommendations (18):
1. A massive global public awareness campaign,
2. Improve hygiene and prevent the spread of infection,
3. Reduce unnecessary use of antimicrobials in agriculture and
their dissemination into the environment,
4. Improve global surveillance of drug resistance and antimicro-
bial consumption in humans and animals,
5. Promote new, rapid diagnostics to cut unnecessary use of
6. Promote development and use of vaccines and alternatives,
7. Improve the numbers, pay and recognition of people working
in infectious disease,
8. Establish a Global Innovation Fund for early-stage and non-
commercial research,
9. Better incentives to promote investment for new drugs and
improving existing ones.
e O’Neill Review recognizes that no single measure will solve
the problem of AMR and only seeks to lay out a broad agenda. e
review’s introduction emphasizes the inability of current diag-
nostic procedures to provide rapid and comprehensive answers,
noting that it is
incredible that doctors must still prescribe antibiotics
based only on their immediate assessment of a patient’s
symptoms, just like they used to when antibiotics rst
entered common use in the 1950s.
Antibiotic prescribers face three major obstacles: (a) AMR is
an abstract concept for all but its victims and their physicians;
(b) detection of specic forms of AMR does not conclusively
determine the best choice of anti-infective therapy; and (c) in
severe infections, the wait for laboratory evidence on which to
base a choice of antibiotic can have fatal consequences. is
last consideration remains a key promoter of emerging AMR
and could be described as poorly targeted personal medicine;
the antithesis of precision public health. Half a millennium ago,
Machiavelli observed that the increase in diagnostic certainty
with the passage of time leads to reduced treatment success
(19). is makes the physician reluctant to wait for the deni-
tive culture results and subsequent antimicrobial susceptibility
before commencing treatment. e clinical laboratory still
relies on culture-based methods (20), despite continued interest
in sepsis biomarker and other culture-independent technolo-
gies. e denition of sepsis has been a point of debate, since it
rests on a range of non-specic clinical features and laboratory
indicators. e most recent consensus statement on sepsis rec-
ognizes only two clinical categories (sepsis and septic shock)
and recommends preliminary patient assessment with an easily
applied clinical scoring method (qSOFA) (21). e three criti-
cal decision steps in the early stages of clinical management of
sepsis occur before-, at-, and immediately aer hospital admis-
sion, which approximate to determination of illness severity,
its etiology and the choice of denitive therapy (Figure 1).
From a precision public health perspective, these correspond
to pre-hospital point of care tests that distinguish viral from
bacterial infection, rapid hospital biomarker tests for sepsis, or
culture-independent tests for severe viral infection and bacte-
remia and rapid determination of antimicrobial susceptibility.
e greatest benet is most likely to be a pre-hospital, rule-out
test that distinguishes possible bacterial from viral infection
(22). Improved speed and accuracy of bacterial detection and
antimicrobial susceptibility testing has thus become apriority
in managing the subsequent stages of sepsis and demands a
culture-independent approach (23).
e mechanisms of AMR are numerous, increasing in variety,
prevalence, and geographic distribution (24), but the ecological
inevitability of AMR should not have caught us by surprise.
Many antimicrobial agents are derivatives of naturally occur-
ring compounds, whose corresponding AMR has its origins in
the environment in which the antimicrobial compound evolved
(25). However, the global success of a small number of mul-
tiresistant species such as Klebsiella pneumoniae (26) happened
faster than predicted. e invisible, abstract nature of this public
health threat is one of the more dicult aspects of the challenge
we now face. It is unfortunate that the clinical laboratory mark-
ers of AMR do not translate into specic infectious diseases like
FIGURE 1 | The sepsis management continuum, showing alignment of time-critical clinical decision points with clinical microbiology laboratory data
Inglis and Urosevic Antimicrobial Resistance Countermeasures
Frontiers in Public Health | February 2017 | Volume 5 | Article 6
septicemia, pneumonia, or meningitis. e bacterial species
names that appear on public health notication lists are not
by themselves notiable diseases. Despite its limitations, the
international standard method of antimicrobial susceptibility
testing; broth microdilution minimum inhibitory concentra-
tion (MIC), converts the susceptibility of a particular bacterial
isolate into a comprehensible measurement (27). e widely
performed disc diusion susceptibility test converts antimicro-
bial susceptibility into a visible and qualitative approximation to
clinical outcome; sensitive or resistant. Disc diusion and MIC
tests, therefore, generate measurable and clinically valuable
indicators of the antimicrobial eect against named bacteria,
whereas resistance mechanism detection by nucleic acid ampli-
cation, gene sequencing, or other molecular means is not a
reliable quantitative measure of antimicrobial sensitivity. e
guidance these susceptibility tests give the prescriber in their
choice of antimicrobial agent relies on a second growth step,
which adds a further delay to the clinical laboratory process.
Many prescribers are not interested in the specic identity of
AMR mechanisms, particularly if the overall AMR phenotype
is a combination of multiple molecular mechanisms, with var-
ied invivo expression and an unpredictable impact on clinical
outcome. A carbapenem-resistant K. pneumoniae septicemia
cannot be treated with a carbapenem, whether the mechanism
of resistance is NDM-1, OXA-48, VIM, or IMP. e antimi-
crobial susceptibility phenotype is, therefore, a critical decider
in the sepsis management continuum, even if the laboratory
result comes 24–48 h aer the initial choice of presumptive
antimicrobial therapy. e susceptibility phenotype currently
determines denitive therapy and ultimately informs the
wider public health community. At present, surveillance data
on antimicrobial susceptibility vary with laboratory capability,
capacity, and locally determined public health priorities. ese
are all under-resourced, particularly in remote regional settings
and in low-income countries (28). Nevertheless, multinational
networks such as EARSS and CAESAR collect regional AMR
data and interest is growing in standardizing the susceptibility
tests on which surveillance relies (2931). e monitoring task
is easier when centers that combine a longstanding interest in
sepsis and AMR collect prospective data from invasive infec-
tions (32).
Rapid, culture-independent phenotypic tests are needed
that improve precision in antimicrobial prescribing (17, 18).
In particular, tests are needed that measure antimicrobial
susceptibility, indicate eective treatment choices and deliver
their results closer to the point of care. e wide diversity of
molecular mechanisms of AMR limits the value of nucleic acid
amplication (PCR assays) as a guide to antibiotic selection in
acute clinical settings, particularly for carbapenem-resistant
Gram-negative bacteria, which require supplementary tests to
improve test sensitivity and overall coverage (33). Much eort
has been devoted to detection of AMR mechanisms by rapid
whole bacterial genome sequencing (3). ough this approach
is not yet feasible as a routine service in the clinical laboratory,
bacterial genome sequencing has clear application to public
health investigations of AMR infection (3, 11, 26, 34), where
decision triggers and task selection procedures can be applied
to avoid overloading reference laboratory capacity. Clinical
microbiologists who have to cope with the practical scientic
challenge of detecting AMR while patients are still under
treatment concentrate their eort on standardizing accurate
measurement of the AMR phenotype (29). Faster methods of
antimicrobial susceptibility testing are now a high priority, as
noted in one of the O’Neill Review’s technical reports (35).
It is here that systems biology applications are beginning to
bear fruit (36). However, careful validation is necessary before
FIGURE 2 | Technical progression in support of AMR/sepsis countermeasures.
Inglis and Urosevic Antimicrobial Resistance Countermeasures
Frontiers in Public Health | February 2017 | Volume 5 | Article 6
emerging technologies can be used in the clinical laboratory.
is requires test verication and harmonization to maximize
analytical value and avoid poorly coordinated proliferation (29,
30). Systematic validation of new antimicrobial susceptibility
test methods against agreed reference standards is a necessary
step to delivering sucient condence in emerging laboratory
methods before they can be used for surveillance and control
purposes. High prole incentives such as the UK Longitude
Prize are being used to attract new candidate tests for this
lengthy development process (37).
Countermeasures need purpose, intent, direction, and evidence
for their ecacy. An understanding of the complex intersection
of laboratory, clinical, and public health insights will improve
their benecial eect (16). AMR-specic countermeasures,
therefore, operate at three levels (Figure2) beginning with faster
and more accurate phenotypic laboratory assays that use agreed
international standards (29, 30, 36). e O’Neill Review expects
new laboratory technology to enable recognition of sepsis, its
etiology and antimicrobial susceptibility faster than current
culture-dependent methods (35). At the clinical level, prescrib-
ing physicians need incentives such as faster conrmation of the
etiology of infection and its antimicrobial susceptibility to use the
evidence-based antimicrobial therapy advocated in the O’Neill
Review (18). In addition to the recommended clinical sepsis score
(21), prescribing physicians need a bacterial infection rule-out
test to support their initial sepsis triage (22) and innovative
methods of rapid antimicrobial susceptibility testing to support
their decision-making at the point of care. However, a clearer
picture of the global burden of AMR and the measures to control
it will not emerge until variations in regional AMR notication
have been harmonized through introduction of a sepsis/AMR
registry (Figure2). Other elds of medicine, such as oncology,
use case registries to develop and rene their disease-specic
countermeasures (38, 39). A sepsis registry could be used in
similar manner as a precision public health tool to stratify sepsis
by syndrome, etiology, AMR phenotype, and resistance mecha-
nism, and, therefore, to coordinate AMR countermeasures. e
recent consensus denition of sepsis is a helpful starting point
for discussion of a sepsis registry (21), but requires a stronger
laboratory-based emphasis on bacterial etiology and AMR.
Precision is measurable, particularly when supported by archival
material in bacterial culture collections and registered clinical
biobanks. Claims for the increased accuracy of new methods
should thus be veriable and linked with the clinical laboratory,
where the precision of antimicrobial susceptibility tests is already
monitored against reference standards and veried by regulatory
agencies (29, 30).
Antimicrobial resistance has become a global tragedy of the
commons, driven by a complex bacterial survival trade-o at
a cellular level (40). Now that AMR is recognized as a global
priority, it is time to learn to use additional systems biology tools
to improve the speed and accuracy of antimicrobial prescribing
at an individual patient level and simultaneously increase the
precision of AMR sepsis surveillance. Improved condence
in the recognition of early sepsis, faster determination of its
etiology, and antimicrobial susceptibility phenotype, and real
time surveillance through an AMR sepsis registry will lead to
more eective coordination of clinical, laboratory and public
health AMR countermeasures. Given the speed with which
antimicrobial agents have been compromised by AMR, there
is no time to lose introducing these laboratory and surveillance
tools into wider use.
e authors are working together on culture-independent pathol-
ogy test development. TI prepared the initial dra. NU reviewed,
edited, and supplemented the rst dra with an emphasis on
sepsis. Subsequent versions of the manuscript were exchanged
between the authors who both approved the nal version.
Inglis and Urosevic Antimicrobial Resistance Countermeasures
Frontiers in Public Health | February 2017 | Volume 5 | Article 6
e authors’ work on AMR and sepsis countermeasures is
supported by translational research project grants from the
Department of Health, Government of Western Australia, a
Grand Challenges Award from the Bill and Melinda Gates
Foundation (OPP 1150984), the NATO SPS Programme
(project grant 984835), philanthropic donations from Rotary
Clubs and Lab Without Walls Inc., and in-kind contributions
from ermo Fisher Scientic and Biomerieux Australia. is
research is conducted in accordance with the Government
of Western Australia’s governance requirements and super-
vised by the Department of Health’s Research Development
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Conict of Interest Statement: e authors are supported by a Grand Challenges
award from the Bill and Melinda Gates Foundation, as stated in the acknowl-
edgments above. is and research translation grants from the Government of
Western Australia are being used to develop culture-independent pathology tests
for sepsis and AMR countermeasures. ermo Fisher Scientic and Biomerieux
have provided in-kind support to the authors’ research group, under supervision
of the WA Health Department’s Research Development Unit. Neither author
has received funding from these companies for any purpose. No supporting
organization or its members had any role in the preparation of this manuscript,
which is the opinion of the two authors.
Copyright © 2017 Inglis and Urosevic. is is an open-access article distributed
under the terms of the Creative Commons Attribution License (CC BY). e use,
distribution or reproduction in other forums is permitted, provided the original
author(s) or licensor are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
... A growing number of public health experts are highlighting this highly complex problem and demanding more accurate language and effective advocacy for the issue as drug-resistant infection escalates [3], instead of relegating AMR to a back-room laboratory. A matter of grave concern is the convergence of AMR and serious infection, since the time-critical urgency of sepsis treatment is a potent force for excessive antibiotic prescribing and subsequent resistance development [4]. ...
... Progress from our current slow, methodical, AST-dependent laboratory capability to a high-speed, evidence-driven sepsis management pathway is a work in progress [4,7,8,25,26]. There have been encouraging developments in methods to distinguish viral and bacterial infection by both rapid pointof-care tests and detailed analysis of haemocytometer data [21,22]. ...
... At present, we are working on improvement to clinical laboratory workflow, starting at the right-hand end of thetimeline with the definitive microbiology laboratory AST result, and progressing towards the initial consideration of sepsis by the diagnosing physician. Prior to performance of the AST, widespread use of MALDI-TOF MS has reduced the time to bacterial identification in larger clinical laboratories by around 24 h [34], but it does alter the primary incubation period required for blood and other liquid cultures [4]. More sensitive nucleic acid amplification techniques, such as multiplex PCR array for blood culture isolate identification, can be as effective as MALDI-TOF MS for referred regional blood cultures [8], and when deployed close to the point of care, reduce reporting delays by over 24 h [8,25]. ...
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Current methods for antimicrobial susceptibility testing (AST) are too slow to affect initial treatment decisions in the early stages of sepsis, when the prescriber is most concerned to select effective therapy immediately, rather than finding out what will not work 1 or 2 days later. There is a clear need for much faster differentiation between viral and bacterial infection, and AST, linked to earlier aetiological diagnosis, without sacrificing either the accuracy of quantitative AST or the low cost of qualitative AST. Truly rapid AST methods are eagerly awaited, and there are several candidate technologies that aim to improve the targeting of our limited stock of effective antimicrobial agents. However, none of these technologies are approaching the point of care and nor can they be described as truly culture-independent diagnostic tests. Rapid chemical and genomic methods of resistance detection are not yet reliable predictors of antimicrobial susceptibility and often rely on prior bacterial isolation. In order to resolve the trade-off between diagnostic confidence and therapeutic efficacy in increasingly antimicrobial-resistant sepsis, we propose a series of three linked decision milestones: initial clinical assessment (e.g. qSOFA score) within 10 min, initial laboratory tests and presumptive antimicrobial therapy within 1 h, and definitive AST with corresponding antimicrobial amendment within an 8 h window (i.e. the same working day). Truly rapid AST methods therefore must be integrated into the clinical laboratory workflow to ensure maximum impact on clinical outcomes of sepsis, and diagnostic and antimicrobial stewardship. The requisite series of development stages come with a substantial regulatory burden that hinders the translation of innovation into practice. The regulatory hurdles for the adoption of rapid AST technology emphasize technical accuracy, but progress will also rely on the effect rapid AST has on prescribing behaviour by physicians managing the care of patients with sepsis. Early adopters in well-equipped teaching centres in close proximity to large clinical laboratories are likely to be early beneficiaries of rapid AST, while simplified and lower-cost technology is needed to support poorly resourced hospitals in developing countries, with their higher burden of AMR. If we really want the clinical laboratory to deliver a specific, same-day diagnosis underpinned by definitive AST results, we are going to have to advocate more effectively for the clinical benefits of bacterial detection and susceptibility testing at critical decision points in the sepsis management pathway.
... Sepsis is a life-threatening infectious disease and a leading cause of death in hospitals (1). Upon pathogen infection, the host immune system elicits an appropriate inflammatory response to eliminate the invading microbe, followed by active resolution of the inflammation to maintain tissue homeostasis (2). ...
... Immunocompromised patients are at a higher risk of sepsis partially due to an impaired capability of clearing pathogens, leading to the continued activation of inflammatory cells (4,5). Antibiotics are currently used to treat sepsis (6); however, antimicrobial resistance has become a major global healthcare problem (1). The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA), for which multiple antibiotic resistances are conferred by mutations in a penicillin-binding protein, has been one of the serious threats (7). ...
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Macrophages are important for the first line of defense against microbial pathogens. Integrin CD11b, which is encoded by Itgam, is expressed on the surface of macrophages and has been implicated in adhesion, migration, and cell-mediated cytotoxicity. However, the functional impact of CD11b on the inflammatory responses of macrophages upon microbial infection remains unclear. Here, we show that CD11b deficiency resulted in increased susceptibility to sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection by enhancing the pro-inflammatory activities of macrophages. Upon infection with MRSA, the mortality of Itgam knockout mice was significantly higher than that of control mice, which is associated with increased production of TNF-α and IL-6. In response to MRSA, both bone marrow-derived macrophages and peritoneal macrophages lacking CD11b produced elevated amounts of pro-inflammatory cytokines and nitric oxide. Moreover, CD11b deficiency upregulated IL-4-induced expression of anti-inflammatory mediators such as IL-10 and arginase-1, and an immunomodulatory function of macrophages to restrain T cell activation. Biochemical and confocal microscopy data revealed that CD11b deficiency augmented the activation of NF-κB signaling and phosphorylation of Akt, which promotes the functional activation of macrophages with pro-inflammatory and immunoregulatory phenotypes, respectively. Overall, our experimental evidence suggests that CD11b is a critical modulator of macrophages in response to microbial infection.
... Secondly, if reducing mortality attributed to GN-ARB BSI is the focus, increasing healthcare access and quality (enhanced accessibility and active surveillance) and improving treatment success rates for BSIs within the hospital are critical. In particular, early-stage identification (and testing capability) through a rapid response from healthcare facilities might favour the early prediction of the clinical progression of BSIs in communities at high risk right before the disease burden is aggravated 71,72 . The risk of BSIs is notably greater in low-andmiddle-income communities due to under-resourced infrastructure to diagnose and quantify these complications. ...
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Exposure to community reservoirs of gram-negative antibiotic-resistant bacteria (GN-ARB) genes poses substantial health risks to individuals, complicating potential infections. Transmission networks and population dynamics remain unclear, particularly in resource-poor communities. We use a dynamic compartment model to assess GN-ARB transmission quantitatively, including the susceptible, colonised, infected, and removed populations at the community-hospital interface. We used two side streams to distinguish between individuals at high- and low-risk exposure to community ARB reservoirs. The model was calibrated using data from a cross-sectional cohort study (N = 357) in Chile and supplemented by existing literature. Most individuals acquired ARB from the community reservoirs (98%) rather than the hospital. High exposure to GN-ARB reservoirs was associated with 17% and 16% greater prevalence for GN-ARB carriage in the hospital and community settings, respectively. The higher exposure has led to 16% more infections and attributed mortality. Our results highlight the need for early-stage identification and testing capability of bloodstream infections caused by GN-ARB through a faster response at the community level, where most GN-ARB are likely to be acquired. Increasing treatment rates for individuals colonised or infected by GN-ARB and controlling the exposure to antibiotic consumption and GN-ARB reservoirs, is crucial to curve GN-ABR transmission.
... Escalating antibiotic resistance in the most commonly encountered bacterial causes reduces the efficacy of sepsis treatment and patient survival [1][2][3]. The best means of preventing sepsis progression is by stopping its progression by early detection and treatment of the bloodstream infection [4,5]. Despite improved methods that confirm bacteraemia, culture-based microbiology methods are cumbersome and do not deliver actionable results early enough in bacteraemic infection to intervene with effective antimicrobial therapy. ...
Introduction . Increased plasma cell-free DNA (cfDNA) has been reported for various diseases in which cell death and tissue/organ damage contribute to pathogenesis, including sepsis. Gap Statement . While several studies report a rise in plasma cfDNA in bacteraemia and sepsis, the main source of cfDNA has not been identified. Aim . In this study, we wanted to determine which of nuclear, mitochondrial or bacterial cfDNA is the major contributor to raised plasma cfDNA in hospital subjects with bloodstream infections and could therefore serve as a predictor of bacteraemic disease severity. Methodology . The total plasma concentration of double-stranded cfDNA was determined using a fluorometric assay. The presence of bacterial DNA was identified by PCR and DNA sequencing. The copy numbers of human genes, nuclear β globin and mitochondrial MTATP8 , were determined by droplet digital PCR. The presence, size and concentration of apoptotic DNA from human cells were established using lab-on-a-chip technology. Results . We observed a significant difference in total plasma cfDNA from a median of 75 ng ml ⁻¹ in hospitalised subjects without bacteraemia to a median of 370 ng ml ⁻¹ ( P =0.0003) in bacteraemic subjects. The copy numbers of nuclear DNA in bacteraemic also differed between a median of 1.6 copies µl ⁻¹ and 7.3 copies µl ⁻¹ ( P =0.0004), respectively. In contrast, increased mitochondrial cfDNA was not specific for bacteraemic subjects, as shown by median values of 58 copies µl ⁻¹ in bacteraemic subjects, 55 copies µl ⁻¹ in other hospitalised subjects and 5.4 copies µl ⁻¹ in healthy controls. Apoptotic nucleosomal cfDNA was detected only in a subpopulation of bacteraemic subjects with documented comorbidities, consistent with elevated plasma C-reactive protein (CRP) levels in these subjects. No bacterial cfDNA was reliably detected by PCR in plasma of bacteraemic subjects over the course of infection with several bacterial pathogens. Conclusions . Our data revealed distinctive plasma cfDNA signatures in different groups of hospital subjects. The total cfDNA was significantly increased in hospital subjects with laboratory-confirmed bloodstream infections comprising nuclear and apoptotic, but not mitochondrial or bacterial cfDNAs. The apoptotic cfDNA, potentially derived from blood cells, predicted established bacteraemia. These findings deserve further investigation in different hospital settings, where cfDNA measurement could provide simple and quantifiable parameters for monitoring a disease progression.
... A number of culture-independent laboratory methods are now available that promise faster, more sensitive, and more specific aetiological diagnoses across a broad spectrum of pathogen and specimen types. 20 Examples include nucleic acid-based approaches to detect bacteriaspecific DNA or RNA, and protein-based assays, such as matrix assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry (MS), which identifies organism-unique protein signatures. 21,22 These techniques are relatively rapid, leading to faster reporting times and the detection of organisms that may be difficult to culture. ...
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Peritoneal dialysis (PD) is a cost-effective, home-based treatment option for patients with end-stage renal disease; however, PD is declining in many countries. A major reason for this is peritonitis, which commonly leads to technique failure and has led to negative perceptions of PD by clinicians and patients. To restore confidence in PD, better diagnostics are required to enable appropriate treatment to be started earlier; this needs to be coupled with improved understanding of the biology of peritonitis. Advances in culture-independent microbiological methods, in particular the use of bacterial flow cytometry and immune fingerprinting techniques, can enable organism detection and antimicrobial susceptibility testing to be performed in as little as 3 hours after samples are received. At the same time, improved understanding of peritoneal mesothelial cell responses to infection is providing insights into pathways that may be targeted to dampen deleterious elementsof the host immune response, promote healing, and preserve membrane function.
... 17,18 Antibiotic susceptibility pattern of bacteria causing sepsis show multi-drug resistance which increases the morbidity and mortality in sepsis patients. 13,19,20 Inappropriate antibiotic selection is an important determinant of multi-drug resistance. 21 Colistin, imipenem, showed the highest sensitivity toward gram-negative isolates. ...
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Biofilms are arguably the root cause of most human infections, imposing a high level of public health concern. Biofilm growth is a lifestyle characterized by co-aggregation of organisms and secretion of an extracellular matrix (ECM) that facilitates attachment to a surface. They are responsible for up to 80% of all healthcare-acquired infections (National Institutes of Health) with the majority being diagnosed as device associated. They are multi-compositional structures that are influenced by surrounding biological, mechanical and chemical variation in their microenvironment. Within the confines of biofilms, microorganisms are capable of promoting increased rates of antimicrobial resistance. When observing biofilm physiology in the presence of a biomaterial, the attachment process and intermolecular activity, contribute to significant genotypic responses. When utilized as part of medical devices, antimicrobial biomaterials seek to prevent biofilm infections, however, the complexity of biofilms make it difficult to extract useful results necessary to improve material properties without consideration of bacterial molecular processes. This interdisciplinary article emphasizes molecular mechanisms as a pertinent consideration in evaluating biofilm growth on biomaterials. It also advocates for standardizing in vitro biofilm models as opposed to animal models. Such models include microfluidic systems, that can be engineered to scale and mimic infection-relevant microenvironments. The connection of advances in antibiofilm surface modifications and high-throughput sequencing make way for new and important biomaterial assessments. We endeavor to establish a gold standard model for in vitro biomaterials testing that incorporates the complexity of healthcare-associated infections in order to guide medical device design and improve disease outcomes.
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Purpose. Antimicrobial susceptibility is slow to determine, taking several days to fully impact treatment. This proof-of-concept study assessed the feasibility of using machine-learning techniques for analysis of data produced by the flow cytometer-assisted antimicrobial susceptibility test (FAST) method we developed.Methods. We used machine learning to assess the effect of antimicrobial agents on bacteria, comparing FAST results with broth microdilution (BMD) antimicrobial susceptibility tests (ASTs). We used Escherichia coli (1), Klebsiella pneumoniae (1) and Staphylococcus aureus (2) strains to develop the machine-learning algorithm, an expanded panel including these plus E. coli (2), K. pneumoniae (3), Proteus mirabilis (1), Pseudomonas aeruginosa (1), S. aureus (2) and Enterococcus faecalis (1), tested against FAST and BMD (Sensititre, Oxoid), then two representative isolates directly from blood cultures.Results. Our data machines defined an antibiotic-unexposed population (AUP) of bacteria, classified the FAST result by antimicrobial concentration range, and determined a concentration-dependent antimicrobial effect (CDE) to establish a predicted inhibitory concentration (PIC). Reference strains of E. coli, K. pneumoniae and S. aureus tested with different antimicrobial agents demonstrated concordance between BMD results and machine-learning analysis (CA, categoric agreement of 91 %; EA, essential agreement of 100 %). CA was achieved in 35 (83 %) and EA in 28 (67 %) by machine learning on first pass in a challenge panel of 27 Gram-negative and 15 Gram-positive ASTs. Same-day AST results were obtained from clinical E. coli (1) and S. aureus (1) isolates.Conclusions. The combination of machine learning with the FAST method generated same-day AST results and has the potential to aid early antimicrobial treatment decisions, stewardship and detection of resistance.
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The emergence of carbapenem-resistant Gram-negative pathogens poses a serious threat to public health worldwide. In particular, the increasing prevalence of carbapenem-resistant Klebsiella pneumoniae is a major source of concern. K. pneumoniae carbapenemases (KPCs) and carbapenemases of the oxacillinase-48 (OXA-48) type have been reported worldwide. New Delhi metallo-β-lactamase (NDM) carbapenemases were originally identified in Sweden in 2008 and have spread worldwide rapidly. In this review, we summarize the epidemiology of K. pneumoniae producing three carbapenemases (KPCs, NDMs, and OXA-48-like). Although the prevalence of each resistant strain varies geographically, K. pneumoniae producing KPCs, NDMs, and OXA-48-like carbapenemases have become rapidly disseminated. In addition, we used recently published molecular and genetic studies to analyze the mechanisms by which these three carbapenemases, and major K. pneumoniae clones, such as ST258 and ST11, have become globally prevalent. Because carbapenemase-producing K. pneumoniae are often resistant to most β-lactam antibiotics and many other non-β-lactam molecules, the therapeutic options available to treat infection with these strains are limited to colistin, polymyxin B, fosfomycin, tigecycline, and selected aminoglycosides. Although, combination therapy has been recommended for the treatment of severe carbapenemase-producing K. pneumoniae infections, the clinical evidence for this strategy is currently limited, and more accurate randomized controlled trials will be required to establish the most effective treatment regimen. Moreover, because rapid and accurate identification of the carbapenemase type found in K. pneumoniae may be difficult to achieve through phenotypic antibiotic susceptibility tests, novel molecular detection techniques are currently being developed.
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Recent advances in whole genome sequencing have made the technology available for routine use in microbiological laboratories. However, a major obstacle for using this technology is the availability of simple and automatic bioinformatics tools. Based on previously published and already available web-based tools we developed a single pipeline for batch uploading of whole genome sequencing data from multiple bacterial isolates. The pipeline will automatically identify the bacterial species and, if applicable, assemble the genome, identify the multilocus sequence type, plasmids, virulence genes and antimicrobial resistance genes. A short printable report for each sample will be provided and an Excel spreadsheet containing all the metadata and a summary of the results for all submitted samples can be downloaded. The pipeline was benchmarked using datasets previously used to test the individual services. The reported results enable a rapid overview of the major results, and comparing that to the previously found results showed that the platform is reliable and able to correctly predict the species and find most of the expected genes automatically. In conclusion, a combined bioinformatics platform was developed and made publicly available, providing easy-to-use automated analysis of bacterial whole genome sequencing data. The platform may be of immediate relevance as a guide for investigators using whole genome sequencing for clinical diagnostics and surveillance. The platform is freely available at: and it is the intention that it will continue to be expanded with new features as these become available.
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A challenge panel of bacterial strains useful for clinical laboratories to validate their European Committee on Antimicrobial Susceptibility Testing (EUCAST) antimicrobial susceptibility test (AST) system was established. A total of 117 strains, obtained from Belgian Reference Centers (n=57) and from routine clinical samples (n=60) was selected based on resistance pattern. These strains were analyzed in 7 different laboratories by 3 different automated AST systems (Vitek (n=2), Phoenix (n=2) and Microscan (n=2)) and by disk diffusion from 5 different manufacturers (Rosco (n=2), Becton-Dickinson (n=2), Biomérieux (n=1), Bio-rad (n=1) and i2a (n=1)). To select the challenge panel, selection criteria were set for categorical agreement (CA) between the different systems and the number of very major errors (VME), major errors (ME) and minor errors (MI). VMEs or MEs for at least 2 antibiotics were observed in 43% of all strains, leading to the exclusion of these strains to be selected in the panel. In only 10% of all tested strains there was a 100% CA for all antibiotics. Finally, 28 strains (14 Gram-positive and 14 Gram-negative) covering a wide spectrum of resistance mechanisms were selected. Pilot-testing of this challenge panel in 20 laboratories mainly confirmed the results of the validation study. Only 6 strains withheld for the pilot-study could not be used as challenge strain due to an overall (very) major error rate of more than 5% for a particular antibiotic (n=5) or for two antibiotics (n=1). To conclude, this challenge panel should facilitate the implementation and use of EUCAST breakpoints in laboratories.
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Resistance developed by microbes is challenging success stories of treatment of infectious diseases with anti-microbials. Developing new antimicrobials against these resistant organisms does not progress at the same speed. In an effort to address this key issue, this work overviews the role of different stakeholders and discusses preventative and control measures for effective management of available resources. Roles and concerns of physicians, pharmacists and the public are also discussed. More than anything, this situation requires immediate action to establish antimicrobial stewardship program, control over the counter sale and promote public awareness. The paper also confronts the idea of curbing the use of antimicrobials using mass media, while detailing the consequences of non-therapeutic use. The role of policy makers in taking global action is essential to establishing authority or agency for formulating national guidelines and regulations for prudently using antimicrobials. To do this, this paper recommend the establishment of a global fund. In conclusion, the race against resistance is a collective responsibility requiring coordinated action at local, national, regional and international levels to ensure sustained utilization of antimicrobials.
The Australian Group on Antimicrobial Resistance performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric Gram-negative pathogens. The 2014 survey was the second year to focus on blood stream infections. During 2014, 5,798 Enterobacteriaceae species isolates were tested using commercial automated methods (Vitek 2, BioMérieux; Phoenix, BD) and results were analysed using the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (January 2015). Of the key resistances, non-susceptibility to the third-generation cephalosporin, ceftriaxone, was found in 9.0%/9.0% of Escherichia coli (CLSI/EUCAST criteria) and 7.8%/7.8% of Klebsiella pneumoniae, and 8.0%/8.0% K. oxytoca. Non-susceptibility rates to ciprofloxacin were 10.4%/11.6% for E. coli, 5.0%/7.7% for K. pneumoniae, 0.4%/0.4% for K. oxytoca, and 3.5%/6.5% in Enterobacter cloacae. Resistance rates to piperacillin-tazobactam were 3.2%/6.8%, 4.8%/7.2%, 11.1%/11.5%, and 19.0%/24.7% for the same 4 species respectively. Fourteen isolates were shown to harbour a carbapenemase gene, 7 blaIMP-4, 3 blaKPC-2, 3 blaVIM-1, 1 blaNDM-4, and 1 blaOXA-181-lke.
Background. Little is known about the American public's perceptions or knowledge about antibiotic-resistant bacteria or antibiotic misuse. We hypothesized that although many people recognize antibiotic resistance as a problem, they may not understand the relationship between antibiotic consumption and selection of resistant bacteria. Methods. We developed and tested a survey asking respondents about their perceptions and knowledge regarding appropriate antibiotic use. Respondents were recruited with the Amazon Mechanical Turk crowdsourcing platform. The survey, carefully designed to assess a crowd-sourced population, asked respondents to explain “antibiotic resistance” in their own words. Subsequent questions were multiple choice. Results. Of 215 respondents, the vast majority agreed that inappropriate antibiotic use contributes to antibiotic resistance (92%), whereas a notable proportion (70%) responded neutrally or disagreed with the statement that antibiotic resistance is a problem. Over 40% of respondents indicated that antibiotics were the best choice to treat a fever or a runny nose and sore throat. Major themes from the free-text responses included that antibiotic resistance develops by bacteria, or by the infection, or the body (ie, an immune response). Minor themes included antibiotic overuse and antibiotic resistance caused by bacterial adaptation or an immune response. Conclusions. Our findings indicate that the public is aware that antibiotic misuse contributes to antibiotic resistance, but many do not consider it to be an important problem. The free-text responses suggest specific educational targets, including the difference between an immune response and bacterial adaptation, to increase awareness and understanding of antibiotic resistance.
Importance Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.Objective To evaluate and, as needed, update definitions for sepsis and septic shock.Process A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment).Key Findings From Evidence Synthesis Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant.Recommendations Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.Conclusions and Relevance These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.
The increasing use of carbapenems for treating multidrug resistant (MDR) gram-negative infections has contributed to the global dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Serine and metallo-β-lactamases (MBL) that hydrolyze carbapenems have become prevalent and endemic in some countries necessitating the use of older class agents such as colistin. 19,719 isolates of Enterobacteriaceae (excluding Proteeae and Serratia spp. that have innate resistance to colistin) were collected from patient infections during 2012-2013 in a global surveillance program and tested for antimicrobial susceptibility using CLSI methods. Isolates of CRE were characterized for carbapenemases and extended-spectrum β-lactamases (ESBLs) by PCR and sequencing. Using EUCAST breakpoints, colistin susceptibility was 98.4% overall, but was reduced to 88.0% among 482 carbapenemase-positive isolates. Colistin susceptibility was higher among MBL-positive isolates (92.6%) compared to those positive for KPC (87.9%) or OXA-48 (84.2%). Of the agents tested, only tigecycline (MIC90, 2 - 4 μg/ml) and aztreonam-avibactam (MIC90, 0.5 - 1 μg/ml) consistently tested with low MIC values against colistin-resistant, ESBL-positive, and carbapenemase-positive isolates. Among the 309 (1.6%) colistin-resistant isolates from 10 species collected in 38 countries, 58 carried a carbapenemase that included KPCs (38 isolates), MBLs (6), and OXA-48 (12). These isolates were distributed globally (16 countries) and 95% were K. pneumoniae. Thirty-nine (67.2%) isolates carried additional ESBL variants of CTX-M, SHV, and VEB. This sample of Enterobacteriaceae demonstrated a low prevalence of colistin resistance overall. However, the wide geographic dispersion of colistin resistance within diverse genus and species groups and the higher incidence observed among carbapenemase-producing MDR pathogens is concerning.