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Rescuing The Last-line Therapy Colistin Against Gram-negative ‘superbugs’: Increasing The Therapeutic Index By Attenuation Of Nephrotoxicity
Funder
National Health and Medical Research Council
Funding Amount
$498,631.00
Summary
Antibiotic resistance in Gram-negative ‘superbugs’ is presenting a significant global medical challenge. Colistin (polymyxin E) is increasingly used as the last treatment option even though the current use is suboptimal. Simply increasing the daily dose is not an option due to kidney toxicity. This project focuses on a new approach using antioxidants to ameliorate the potential for colistin-induced kidney toxicity, thereby allowing higher doses to achieve adequate bacterial kill in patients.
Targeting The Achilles' Heel Of Polymyxins: Eliminating The Nephrotoxicity
Funder
National Health and Medical Research Council
Funding Amount
$673,420.00
Summary
The world is facing a growing threat from the emergence of bacterial 'superbugs' that are resistant to all current antibiotics except the polymyxins. However, kidney toxicity occurs in up to 60% of patients receiving intravenous polymyxins. In this project, we will examine how polymyxins cause kidney toxicity then employ the obtained mechanistic information to decrease this adverse effect. Our study targets the urgent global unmet medical need, lack of new antibiotics for bacterial ‘superbugs’.
Optimisation Of Antimicrobial Therapy For Severe Bacterial Infections In Neonates And Young Children In Papua New Guinea
Funder
National Health and Medical Research Council
Funding Amount
$943,865.00
Summary
This study aims to provide important information on the way young Papua New Guinean children with serious bacterial infections handle antibiotics, including newer agents that may be required if bacterial resistance is confirmed or increases. The data will be used to optimise treatment, thus reducing mortality and potential adverse drug effects, in PNG nad other tropical countries, and may have implications for the developed world as well.
Targeting Hypermutable ‘superbugs’ In Chronic Respiratory Infections By Optimised Antibiotic Combination Dosage Regimens
Funder
National Health and Medical Research Council
Funding Amount
$697,731.00
Summary
Many bacterial ‘superbugs’ can increase their mutation rate, i.e. become hypermutable, and thus rapidly become resistant to multiple antibiotics. Chronic lung infections with hypermutable bacteria cause increased ill-health and death in patients and current treatments do not work well. We will develop improved treatments using combinations of available antibiotics. This project will provide guidance to doctors on how to treat infections more effectively and minimise emergence of resistance.
A Prospective, Randomised, Double-blind Trial Of Extended- Versus Bolus-infusion ?-lactam Therapy In Infective Exacerbations Of Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$148,431.00
Summary
I am an infectious diseases physician focused on the most effective way to use antibiotics to treat infections. People with cystic fibrosis often get lung infections and the bacteria that causes this, Pseudomonas aeruginosa, can be difficult to treat. I will be investigating whether infusing antibiotics over a prolonged period of time is more effective than standard therapy in treatment of Pseudomonas aeruginosa lung infections in patients with cystic fibrosis.
Targeting The Unmet Global Medical Need Caused By Gram-negative 'superbugs': From Antibiotic Discovery To Novel Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$697,209.00
Summary
Bacterial ‘superbugs’ present a significant global medical challenge. ‘Old’ polymyxins are the only antibiotics against Gram-negative ‘superbugs’ but with limited pharmacological information available. In the next 5 years, as a pharmacologist I will continue re-developing polymyxins and discovering novel antibiotics against these problematic bacteria. My research targets the “Bad Bugs, No Drugs” disaster highlighted by the Infectious Diseases Society of America and the World Health Organization.
Targeting NDM-producing ‘superbugs’: Optimising Novel Combinations With ‘old’ Polymyxins Using Pharmacological, Molecular Imaging And Systems Biology Approaches
Funder
National Health and Medical Research Council
Funding Amount
$582,732.00
Summary
Rapid global spread of so-called NDM-producing bacterial ‘superbugs’ is presenting a major medical challenge. Without new antibiotics under development, polymyxin is becoming the only effective antibiotic. Unfortunately we recently revealed that treatment with polymyxin alone can rapidly lead to resistance in NDM-producing ‘superbugs’. This project will employ new tools to optimise rational polymyxin combinations, thereby providing urgently needed information to clinicians for treating these ver ....Rapid global spread of so-called NDM-producing bacterial ‘superbugs’ is presenting a major medical challenge. Without new antibiotics under development, polymyxin is becoming the only effective antibiotic. Unfortunately we recently revealed that treatment with polymyxin alone can rapidly lead to resistance in NDM-producing ‘superbugs’. This project will employ new tools to optimise rational polymyxin combinations, thereby providing urgently needed information to clinicians for treating these very problematic infections.Read moreRead less
Development Of An In Vivo Pharmacokinetic-pharmacodynamic Model For Evaluation Of Antimalarial Drug Therapy Combinations
Funder
National Health and Medical Research Council
Funding Amount
$120,604.00
Summary
The World Health Organization currently estimates that there are 300-500 million cases of malaria annually, with 1.5-2.7 million deaths. These are staggering data, given that almost 20 antimalarial drugs are now in regular clinical use. Multi-drug resistance is present in most tropical countries where malaria is endemic and there has been a rapid escalation in cases of malaria in developed countries over recent decades (imported by travellers). Clearly, there is a need to ensure that current and ....The World Health Organization currently estimates that there are 300-500 million cases of malaria annually, with 1.5-2.7 million deaths. These are staggering data, given that almost 20 antimalarial drugs are now in regular clinical use. Multi-drug resistance is present in most tropical countries where malaria is endemic and there has been a rapid escalation in cases of malaria in developed countries over recent decades (imported by travellers). Clearly, there is a need to ensure that current and new treatment and prevention strategies are rational and effective. This project is based on the premise that improvements can be made in the in vitro testing process of antimalarial drugs. The experiments will be conducted using mice and a form of malaria that is specific to mice but closely resembles human malaria. In the first stage, the relationship between the amount of a new antimalarial drug (dihydroartemisinin) in the body and the effectiveness of the dose will be tested. These experiments will be repeated using conventional antimalarial drugs such as mefloquine. Information from these studies will subsequently be used to evaluate combinations of antimalarials. The results will be used as the basis of extensive, collaborative clinical studies in South-East Asia that are beyond the scope of this project. The methods used for this research will be important for future testing of new antimalarial drugs or combinations of drugs for the treatment and prophylaxis of malaria.Read moreRead less
Novel Therapeutic Strategy Against Multidrug-resistant Gram-negative Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$349,823.00
Summary
In the past two decades, there has been a marked decline in discovery and development of new antibiotics while there has been a remarkable increase in resistance to the currently available antibiotics. The growth in the number of resistant bacteria and lack of antibiotics available for treatment is very significant with gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Colistin, an old antibiotic that has been used little over the l ....In the past two decades, there has been a marked decline in discovery and development of new antibiotics while there has been a remarkable increase in resistance to the currently available antibiotics. The growth in the number of resistant bacteria and lack of antibiotics available for treatment is very significant with gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Colistin, an old antibiotic that has been used little over the last 40-50 years, has been 'taken off the shelf' and is now being used as a last line of defence to treat people with infections caused by these bacteria. Clearly, doctors and their infected patients will be in an even more precarious position than currently exists if resistance to colistin increases. We have discovered a novel therapeutic strategy that is able to reverse colistin resistance in P. aeruginosa. The studies proposed in this project will investigate this novel strategy across a range of multidrug-resistant bacteria and provide the information essential for rational use in patients. We propose that such a novel therapeutic strategy will provide a powerful weapon for the war on these 'superbugs'.Read moreRead less
Towards Optimising Dosing Of The 'old' Antibiotic Colistin Methanesulphonate: Enhancing Efficacy And Reducing Resistance
Funder
National Health and Medical Research Council
Funding Amount
$266,500.00
Summary
The global problem of multidrug-resistant bacteria is a major clinical challenge. In cystic fibrosis (CF) patients, the bacteria pseudomonas shows significantly high resistance to the commonly used antibiotics and is a major cause of death. As a consequence, interest in an old antibiotic, colistin, has been rekindled after 40 years on the shelf. The safety of intravenous colistin has been demonstrated in several clinical trials. However, based on our preliminary studies in CF patients, the curre ....The global problem of multidrug-resistant bacteria is a major clinical challenge. In cystic fibrosis (CF) patients, the bacteria pseudomonas shows significantly high resistance to the commonly used antibiotics and is a major cause of death. As a consequence, interest in an old antibiotic, colistin, has been rekindled after 40 years on the shelf. The safety of intravenous colistin has been demonstrated in several clinical trials. However, based on our preliminary studies in CF patients, the current dosage regimen where colistin is given three times a day does not achieve high enough concentrations to kill the bacteria. The studies proposed in this project will address the safety, effectivenss and impact on development of resistance of larger doses of intravenous colistin given once or twice daily. We propose that such dosing strategies will yield more effective usage of this promising 'old' antibiotic.Read moreRead less