BUFFALO, N.Y. – Scientists at the University at Buffalo
are turning to an old class of antibiotics to fight new superbugs
resistant to modern medicine.
A $4.4 million grant from the National Institutes of Health will
allow UB researchers to develop new dosing regimens for polymyxin
Developed more than 50 years ago, polymyxins were not subject to
modern antibiotic drug development standards. And they have proved
to be toxic to both the kidneys and nervous system.
But they’re also effective against superbugs such as
Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella
pneumoniae and other gram-negative bacteria that are resistant
to all current antibiotics and which can cause a variety of
diseases, ranging from pneumonia and other respiratory infections,
to serious blood or wound infections.
The grant is the largest NIH grant in the history of the UB
School of Pharmacy and Pharmaceutical Sciences, and the largest
active R01 at UB and among departments of clinical pharmacy in the
U.S. The research is led by Brian Tsuji, PharmD, associate
professor and director of clinical research in the Department of
The aim of the project is to evaluate novel dosing regimens for
polymyxin combinations to maximize antibacterial activity and to
minimize the emergence of resistance and toxicity, says Tsuji,
principal investigator on the grant.
Tsuji and his team will then translate this knowledge back to
the bedside by proposing new, optimal regimens that can be utilized
Gram-negative bacteria, which do not retain a gram-staining
process used in the laboratory to differentiate bacteria, are
causing a global health crisis, Tsuji explains.
“This is a massive public health problem because the
emergence of these new highly resistant strains has been coupled
with a dwindling pipeline of development and approval for new
drugs,” he says.
Polymyxins remain a viable option, but there is mounting
evidence that resistance even to polymyxins is also increasing,
Tsuji notes, and no new antibiotics will be available for these
superbugs for many years to come.
Because of this, clinicians often are left with little or no
option but to use polymyxins (polymyxin B and colistin, i.e.
polymyxin E). Resistance to polymyxins is increasing because plasma
concentrations at recommended daily doses are not effective in
reducing infection in critically ill patients. Increasing the dose
is not an option because they may cause kidney toxicity at higher
“Therefore,” Tsuji says, “we needed to think
innovatively and differently about how to attack this
Researchers will use an innovative Hollow Fiber Model System in
Tsuji’s lab to mimic the concentrations of antibiotics in
patients against bacteria from critically ill patients.
“We want to mimic conditions seen in real patients who are
infected with these deadly strains by using model systems that
mirror exact drug concentrations in the body,” he says.
“In the lab, we can study these combination regimens very
intensely over the same time frame that we would treat a patient
with bacterial pneumonia (14 days) to understand the fundamental
basis for drug resistance.
“This will allow us to address the public health disaster
of antimicrobial resistance and to fight these deadly infections in
severely ill patients where no traditional treatments
Tsuji has put together a team of world-renowned experts in
polymyxin pharmacology, genomics, animal models and
The international, interdisciplinary team is also co-led by Jian
Li, PhD, PI, and includes Roger Nation, PhD, and John Boyce, PhD,
all from Monash University, Melbourne, Australia; and Thomas Walsh,
MD, and Vidmantas Petraitis, MD, from Weill Cornell Medical
College, New York City.
The research team also includes experts in PK/PD, including Alan
Forrest, PharmD, and Gauri Rao, PharmD, from the UB Department of
Pharmacy Practice, and former UB postdocs Juergen Bulitta, PhD, and
Cornelia Landersdorfer, PhD, both now of Monash University.
The team of Forrest, Bulitta, Landersdorfer and Rao, which will
develop mathematical models to perform computer simulations that
propose optimal doses of polymyxin combinations for patients in the
study, was critical for the success of the grant, Tsuji says.
Technicians and students in his lab, including Patricia Holden
and Neang Ly, generated key preliminary data to make the grant