Current research projects

For study opportunities, please also check Research Supervisor Connect (in critical infection).

Antimicrobial resistance

GNT 1145914 Plasmid specialisation modules, microbial husbandry and microbiome resilience

Synopsis: The two bacterial species most responsible for septic shock acquire antimicrobial resistance (AMR) via a mobile gene pool. The most important vectors of this AMR are self-transmissible (conjugative) plasmids, the ‘vessels of the communal gene pool’. Specific genetic modules on plasmids seem to be primary determinants of plasmid-plasmid/plasmid-host relationships - that is, of AMR epidemiology in E. coli and K. pneumoniae. Plasmid-borne AMR is acquired very quickly and, once acquired, becomes fixed in the bacterial accessory genome by ‘addiction systems’ that poison cells from which the AMR plasmid is lost. Modular systems that protect cells from repeated entries by the same plasmid (entry exclusion systems) and that promote plasmid stability and host antibiotic tolerance/persistence (addiction systems) are ill-defined, even for the most important AMR plasmids. In project 1084672 (ends 2017), we have shown for the first time that a bacterial population can be restored to an antibiotic susceptible state in vivo by manipulating addiction and replication modules of specific AMR plasmids (PLoS One 2017 12:e0172913). Here we examine the impact of these modules on AMR plasmid epidemiology and their capacity for manipulation to protect the microbiome from invasive plasmids, including after problem plasmids have been eradicated.

Research team: Jon Iredell, Muhammad Kamruzzaman, Sally Partridge, Alicia Farjaro-Lubian, Nouri Ben Zakour, Qi Qin, Alma Wu, Ali Khalid


Bacteriophage

GNT1107322 Eradication of high-risk bacterial clones using bacteriophages

Synopsis: Antibiotic resistance and pathogenicity are partner attributes in E. coli and K. pneumoniae, the dominant pathogens that cause serious sepsis in adults and children in developed and developing countries alike. The epidemiology of serious infections is dominated by successful bacterial clonal types within these species. Often cited are E. coli sequence type (ST) 131 with extended spectrum beta-lactamase (ESBL)-type resistance encoded by blaCTX-M-15 and highly resistant K. pneumoniae ST 258 with the blaKPC gene. Once colonised, humans commonly remain so for at least 6-12 months.

Lytic viruses (bacteriophages) are effective against a range of bacterial species but clinical utility is limited by poor understanding of clinical applicability, penetration (e.g. into the gut), and resistance. We hypothesise that tools available to clinical laboratories can be used to define predictably susceptible populations of bacteria for given lytic phages, that the evolution of resistant populations can be effectively managed, and that we can develop and test an effective strategy to decolonise humans.

We propose to define target populations from a prospective global set in our lab, characterise diversity within these populations using practicable tools such as high throughput multiple locus variable number tandem repeat analysis (MLVA) typing, purify high-titre lytic phages and study the kinetics of bacterial killing in vitro and in vivo. We will conduct these studies with a focus on E. coli ST131 and K. pneumoniae CC292 (ST258, ST512 etc) in vitro and in mice. We will define multiple phage cocktails of optimal efficacy and optimal administration protocols. The best cocktail/s will be offered to colonised humans in an open clinical trial with informed consent. At the end of this proposal we will have optimised bacteriophage therapy against signature pathogens and defined the most important parameters that remain as barriers to its effective deployment.

Summary: Nature offers remedies to the spread of dangerous antibiotic resistant bacteria in the form of predatory viruses (bacteriophages). In this project, we will define optimal mixtures of these for killing problem bacterial types, the mechanisms by which bacterial resistance develops, the best approach to identifying susceptible bacteria and to using these viruses to eradicate them, and we will test a carefully optimised bacteriophage therapy in humans colonised by the dangerous E. coli ST131 strain.

Research team: Jon Iredell, Carola Venturini, Nouri Ben Zakour, Bethany Bowring

Treatment of severe Staphylococcus aureus infections with bacteriophage therapy

This is an investigator-led research project sanctioned by FDA, TGA and Western Sydney Local Health District (WSLHD) HREC to investigate phage and bacterial kinetics as well as the possibility of beneficial clinical outcomes of phage therapy. This is a collaborative project between WSLHD, Westmead Institute for Medical Research and AmpliPhi BioSciences led by Prof Jon Iredell and managed by A/P Ruby Lin. The treatment plan is in conjunction with the prescribed antibiotics treatment regime, involving intravenous bacteriophage (AB-SA01) administration for 14 days, with 90 days follow-up for patients with severe S. aureus infections. Data (such as markers of inflammation) are prospectively collected starting with patient’s admission and consent. Patients are offered therapy before in vitro susceptibility data is known if the treating physicians believe the delay is not in the patient’s interests. The aim is to test whether AB-SA01 is safe and well tolerated when administered via intravenous infection in critically ill patients with staphylococcal infection. We also aim to address whether staphylococcal bacteraemic burden declines after bacteriophage administration.

Research team Jon Iredell, Ruby Lin, Aleksandra Petrovic Fabijan, Josephine Ho


eSuDDICU

GNT1127292 Antibiotic resistance and the ecological effects of selective decontamination of the digestive tract in Intensive Care Units

Synopsis: Control of spread of antibiotic resistance (‘infection control’) and of inappropriate antibiotic use (‘antimicrobial stewardship’) are two pillars of the public health response to global antibiotic resistance. The first requires accurate early recognition of the need for containment and the latter requires a clear understanding of the effects of antibiotics in causing resistance. An opportunity to address these issues arises in a study of selective decontamination of the digestive tract (SDD), which includes the administration of antibiotics to an uninfected individual in order to prevent later infection. This approach has been widely rejected by the clinical community because of concern about development of antibiotic resistance. Antibiotics with similar value in treatment of severe infection have different outcomes in terms of development of antibiotic resistance. Although clinical trials indicate reduced antibiotic use, reduced antibiotic resistance and reduced death rates in Intensive Care patients on life support who are treated with SDD, it may not work here in Australia - or SDD may only work here with different antibiotics. A definitive Australian RCT (the SuDDICU study) will be conducted in 2017 to answer this question.
We propose a substudy within this large trial to determine whether this protocol can be safely taken up in Australia, whether the protocol needs to be modified (by changing antibiotics), to explore mechanisms by which antibiotic resistance arises and to test whether we can predict the increased risk of acquisition of resistant infection in patients on life support using simple clinical samples. This will provide important scientific data to directly inform our approaches to infection control and to antibiotic stewardship, develop infection risk prediction and true personalised medicine in the critically ill, and potentially validate a life-saving intervention broadly applicable in Australia and comparable countries.

Summary: We will study patients within a large trial of gut decontamination, in which antibiotics are given in advance to reduce the risk of infection.Specifically, we will determine whether there is any increased antibiotic resistance and even biodiversity loss, as some fear. This is a one-off chance to provide essential data that can help us design better national policies for antibiotic resistance control and a true personalised medicine approach to resistance and infection in ICU.

Research team: Jon Iredell, Sally Partridge, Belinda Roychoudhry, Lee Thomas and Josephine Ho

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Severe sepsis and septic shock

Comparative mortality benefit

In 2004, an Australia-wide study reported that hospital admissions associated with life-threatening infection “septic shock” may have a mortality of 37.5%.

The hospital care of this group alone costs > $60 million annually (1), and the added yearly load of deaths from severe sepsis and septic shock exceeds that attributable to breast and colo-rectal cancer (2) and is three times higher than the national road toll (3).

A reduction of mortality in severe sepsis is dependent on early appropriate antibiotic treatment
Available data suggest a critical 6-12 hour window for maximum impact of antibiotic therapy on survival.

CRE researchers are now studying the impact of bacterial load on outcomes in septic shock (the BLISS study), in research linked to the Australasian Resuscitation in Sepsis Evaluation (ARISE) study of patients presenting to hospital with severe sepsis.

At the moment, even with the best available treatment, identification of the pathogen takes about 12 hours and antibiotic susceptibility results can take another 24 hours.

Can we predict antibiotic resistance when a patient first develops septic shock
We have recently shown that the resistance gene pool is naturally limited in Sydney, and that we can accurately predict susceptibility to aminoglycosides and third generation cephalosporins (NPV for resistance >99.5% in E. coli and K pneumoniae). An international consortium is now examining this in other parts of the world.

Publications

Surviving Sepsis Campaign
International guidelines for management of severe sepsis and septic shock 2015

  1. Rechner IJ, Lipman J. The costs of caring for patients in a tertiary referral Australian Intensive Care Unit, 2005.
  2. Australian Bureau of Statistics. Cancer in Australia: A Snapshot, 2004-2005.
  3. Bureau ATS. Road deaths in Australia: 2005 Statistical summary. 2005.

BioBank

Coming soon


Research with us

Researchers and postgraduate students

Infectious diseases are a leading cause of death worldwide with new infectious agents emerging each year. Our researchers seek to understand the body’s immune responses to infectious agents such as bacteria, viruses, parasites and fungi. The study of infectious diseases and immunology at Sydney Medical School covers laboratory, clinic and population studies, and involves all organ systems and crosses all medical specialties.

PhD and MSc candidates: visit Sydney Medical School for prospective research student enquiries.
Post Doctoral research candidates: need to have excellent English skills and a strong research background relevant to one or more of our current research projects. Please your CV, referee list and research outline, this information will help us to try and link you with suitable research groups.