News

MSD in the UK launches new

antibiotic to treat complicated
intra-abdominal and urinary tract
infections, and acute
pyelonephritis
21 November 2015

MSD (Merck & Co., Inc., Kenilworth, NJ, USA)

today announces the availability of Zerbaxa?
(ceftolozane/tazobactam) in the UK, a new
intravenous antibiotic for the treatment of
complicated intra-abdominal infections (cIAI),
acute pyelonephritis and complicated urinary tract
infections (cUTI) in hospital settings.
Ceftolozane /tazobactam offers an alternative to
carbapenems, currently a standard treatment for
ESBL-producing organisms which have been
linked to the emergence of carbapenem-resistant
bacteria contributing to global antimicrobial
resistance (AMR)
Professor David Livermore, Professor in Medical Microbiology at University of East
Anglia, said: Ceftolozane/tazobactam is very important because its a new antibiotic
that treats Gram-negative infections, where a lot of resistance problems are now
accumulating. Its activity against Pseudomonas is especially important. It overcomes
both the major mechanisms efflux and inactivation that often compromise other
cephalosporins against this difficult species. As always, theres more to be done, more

clinical trials are needed in further settings particularly those where you find most of
the difficult Pseudomonas strains.
Ceftolozane/tazobactam (1g/0.5g) is a combination product consisting of the
cephalosporin antibacterial drug ceftolozane sulfate and the beta-lactamase inhibitor
tazobactam sodium. It is administered
every 8 hours by an intravenous
infusion lasting one hour with thetreatment
length normally lasting 4 14
days. Consideration should always be
given to official guidance on the
appropriate use of antibacterial agents.
The licensing of ceftolozane/tazobactam
was supported by positive data from two
pivotal Phase 3 clinical trials
demonstrating non-inferiority to their comparator; one in patients with cIAI and the other
in patients with cUTI. Both trials met the pre-specified primary endpoints agreed with the
European Medicines Agency (EMA).
Dr Ron Daniels, Chief Executive at Sepsis Trust, said: Antimicrobial resistance is one of
the biggest threats facing public health in the 21st century and every stakeholder involved
from pharmaceutical companies to healthcare professionals to the general public must
work together to combat it. The development of new antimicrobial agents like this one
and an increased awareness about the appropriate use of antibiotics will help us to
continue moving in the right direction towards reducing AMR.
Ceftolozane/tazobactam represents a new option in the fight against AMR in the gramnegative cIAI, cUTI and acute pyelonephritis space. Recent research from the Department
of Health notes that AMR costs the European Union (EU) at least 1.5 billion per year
and claims an estimated 25,000 lives an estimated 3,000 in the UK. A governmentcommissioned AMR Review Team (chaired by economist Lord Jim ONeill) has
projected this to increase to 390,000 deaths per annum by 2050 in Europe and globally
from an estimated 700,000 to 10 million.7
Mike Nally, Managing Director, MSD UK and Ireland, said: In the face of the
increasing threat posed by antimicrobial resistance, MSD continues to advocate for
improvements in regulatory guidance and financial incentives to support and accelerate
innovation in the development of new antimicrobials, services and solutions.

MSDs work in AMR

In January of this year, MSD invested $9.5 billion acquiring Cubist Pharmaceuticals and
their innovative pipeline of medicines, to complement MSDs existing and growing antiinfectives portfolio. This acquisition will continue MSDs heritage in providing new antiinfective treatments to patients, which includes its work in developing one of first
methods of mass producing penicillin during the Second World War.

Reference:
Nally, Mike. "MSD in the UK Launches New Antibiotic to Treat Complicated
Intra-abdominal and Urinary Tract Infections, and Acute Pyelonephritis."
DrugsDiscoveryToday.com. N.p., 21 Nov. 2015. Web. 25 Nov. 2015.
<http://www.drugdiscoverytoday.com/view/43286/msd-in-the-uk-launches-newantibiotic-to-treat-complicated-intra-abdominal-and-urinary-tract-infections-andacute-pyelonephritis/>.

Breast Cancer Drug Beats Superbug

13 October 2015

Tamoxifen helps white blood cells clear multidrug-resistant

bacteria in lab and mouse studies
Researchers at University of California, San Diego School of Medicine and
Skaggs School of Pharmacy and Pharmaceutical Sciences have found that
the breast cancer drug tamoxifen gives white blood cells a boost, better
enabling them to respond to, ensnare and kill bacteria in laboratory
experiments. Tamoxifen treatment in mice
also enhances clearance of the antibioticresistant bacterial pathogen MRSA and
reduces mortality.
The study is published October 13
by Nature Communications.
The threat of multidrug-resistant bacterial
pathogens is growing, yet the pipeline of
new antibiotics is drying up. We need to
open the medicine cabinet and take a closer look at the potential infectionfighting properties of other drugs that we
The team also tested Tamoxifens
already know are safe for patients, said
immune-boosting effect in a
mouse model
senior author Victor Nizet, MD, professor of
pediatrics and pharmacy. Through this
approach, we discovered that tamoxifen has pharmacological properties that
could aid the immune system in cases where a patient is
immunocompromised or where traditional antibiotics have otherwise failed.
Tamoxifen targets the estrogen receptor, making it particularly effective
against breast cancers that display the molecule abundantly. But some
evidence suggests that tamoxifen has other cellular effects that contribute to
its effectiveness, too. For example, tamoxifen influences the way cells
produce fatty molecules, known as sphingolipids, independent of the
estrogen receptor. Sphingolipids, and especially one in particular, ceramide,

play a role in regulating the activities of white blood cells known as

neutrophils.
Tamoxifens effect on ceramides led us to wonder if, when it is administered
in patients, the drug would also affect neutrophil behavior, said first author
Ross Corriden, PhD, project scientist in the UC San Diego School of Medicine
Department of Pharmacology.
To test their theory, the researchers incubated human neutrophils with
tamoxifen. Compared to untreated neutrophils, they found that tamoxifentreated neutrophils were better at moving toward and phagocytosing, or
engulfing, bacteria. Tamoxifen-treated neutrophils also produced
approximately three-fold more neutrophil extracellular traps (NETs), a mesh
of DNA, antimicrobial peptides, enzymes and other proteins that neutrophils
spew out to ensnare and kill pathogens. Treating neutrophils with other
molecules that target the estrogen receptor had no effect, suggesting that
tamoxifen enhances NET production in a way unrelated to the estrogen
receptor. Further studies linked the tamoxifen effect to its ability to influence
neutrophil ceramide levels.
The team also tested Tamoxifens immune-boosting effect in a mouse model.
One hour after treatment with tamoxifen or a control, the researchers
infected mice with MRSA (methicillin-resistant Staphylococcus aureus), a
superbug of great concern to human health. They treated the mice again
with tamoxifen or the control one and eight hours after infection and
monitored them for five days.
Tamoxifen significantly protected mice none of the control mice survived
longer than one day after infection, while about 35 percent of the tamoxifentreated mice survived five days. Approximately five times fewer MRSA were
collected from the peritoneal fluid of the tamoxifen-treated mice, as
compared to control mice.
There are two caveats, the researchers said. First, while tamoxifen was
effective against MRSA in this study, the outcome may vary with other
pathogens. Thats because several bacterial species have evolved methods
for evading NET capture. Second, in the absence of infection, too many NETs
could be harmful. Some studies have linked excessive NET production to
inflammatory disease, such as vasculitis and bronchial asthma.

While known for its efficacy against breast cancer cells, many other cell
types are also exposed to tamoxifen. The off-target effects we identified in
this study could have critical clinical implications given the large number of
patients who take tamoxifen, often every day for years, Nizet said.
Tamoxifen is taken daily by hundreds of thousands of patients worldwide for
the treatment of estrogen receptor-positive breast cancer. The World Health
Organization considers tamoxifen an essential medicine, due to its costeffectiveness and safety profile. According to the breast cancer organization
Susan G. Komen, generic tamoxifen cost patients about $100 per month in
2010.
Tamoxifen is not the only drug prescribed for other indications that just
happen to also boost neutrophil activity. In 2010, Nizet and team reported
that cholesterol-lowering statins also enhance NET formation.
Co-authors of this study include Andrew Hollands, Joshua Olson, Jaclyn
Derieux, Justine Lopez, John T. Chang, David J. Gonzalez, all of UC San Diego.
This research was funded, in part, by the National Institutes of Health (grants
HD071600, AI057153, AI052453 and OD008469).
Reference:
Hollands, A., Olson, J., Derieux, J., Lopez, J., Chang, J., Gonzalez, D.(2015, October
13). Breast Cancer Drug Beats Superbug. Retrieved November 25, 2015, from
http://www.drugdiscoverytoday.com/view/43080/breast-cancer-drug-beats-superbug/