Antibiotics new:

The rapidly increasing resistance of
bacteria to antibiotics is a global issue,
which can cause longer recovery times
and hospitalizations, increased costs
and rising mortality. It is estimated that
each year about 25,000 people in the
European Union die as a result of
infections cause by multi-drug resistant
bacteria.

A study from the US estimated that
patients with infections due to
antimicrobial-resistant organisms
increase the costs of care by between
$6,000 and $30,000 per patient
compared with patients with infections
that are caused by bacteria
susceptible to antimicrobials.  

Gram-negative bacteria are common
causes of hospital-acquired infections
like pneumonia and septic shock and
are increasingly developing resistance
to available antibiotics.  



ACHAOGEN DEVELOPING  NEW
ANTIBIOTIC  AGAINST PLAGUE AND
TULAREMIA
Achaogen, a biopharmaceutical
company in South San Francisco is
developing innovative antibiotics to
treat life-threatening, multi-drug
resistant (MDR) bacterial infections.
Achaogen  has a contract with the
Biomedical Advanced Research and
Development Authority (BARDA),  in
the U.S. Department of Health and
Human Services.
The contract covers development of  
Achaogen’s lead antibiotic candidate
ACHN-490 for the treatment of certain
biothreat agents, including Yersinia
pestis, which causes bubonic plague,
and Francisella tularensis, which
causes tularemia.
Other  life-threatening conditions
included  such as complicated urinary
tract infections and hospital-acquired
pneumonia.

ACHN-490 has been chemically
engineered to retain activity against
bacteria resistant to carbapenems,
cephalosporins, fluoroquinolones,
tetracyclines, and legacy
aminoglycosides.

ACHN-490 Injection is being
investigated in a randomized, double-
blind, comparator-controlled Phase 2
clinical study for the treatment of
complicated urinary tract infection
(cUTI), the most commonly treated
hospital infections in the U.S., and
acute pyelonephritis. Subsequent
clinical studies are being considered to
evaluate ACHN-490 Injection for
hospital-acquired pneumonia (HAP),
ventilator-associated pneumonia
(VAP), complicated intra-abdominal
infections (cIAI) and blood stream
infections (BSI).


ANTIBIOTIC  PTK0796 FROM
PARATEK PHARMA/NOVARTIS
Paratek Pharmaceuticals’ PTK0796, a
broad spectrum antibiotic that Novartis
licensed in October in a deal worth up
to $485 million. A modification at the C-
9 position of tetracycline endowed
PTK0796 with the ability to be given
both intravenously and orally—
desirable properties when you want to
transition a patient from the hospital to
home. It just shows that even small
changes make different properties in
terms of pharmacokinetics, efficacy,
and spectrum.

PTK 0796, a first-in-class
aminomethylcycline, has shown broad-
spectrum activity against a wide range
of bacteria, including both Gram-
positive and Gram-negative strains - a
basic classification derived from the
staining process used to analyze the
cell wall - as well as atypical and
anaerobic bacteria, which grow with
little or no oxygen.

In addition, PTK 0796 has shown
activity against multi-drug resistant
bacteria such as MRSA, vancomycin-
resistant enterococci (VRE) and Gram-
negatives producing ESBL (extended-
spectrum beta-lactamase). These
bacteria have developed resistance
during decades of antibiotic use, so
many of the standard therapies are no
longer effective. Studies have
estimated there were nearly 100,000
deaths from hospital-acquired
infections in the US in 2002[1], and
around 50,000 deaths a year in the EU

Clinical studies involving a total of
more than 500 patients have shown
that PTK 0796 has a favorable safety
and tolerability profile. A Phase II study
in cSSSI ( Complicated Skin and Skin
Structure Infections) found that clinical
success rates among evaluable
patients  were 98% for PTK 0796 and
93% for Zyvox. In this study PTK 0796
was used as a single agent, whereas
Zyvox was used for Gram-positive
infections only and an additional
antibiotic had to be given for Gram-
negative cases.  In this study,
approximately 50% of the infecting
bacteria were MRSA.



ANTIBIOTIC THURICIN FROM
TEAGASC
Scientists from University College Cork
and Teagasc have, together with
Canadian colleagues, identified a new
antibiotic which combats the potentially
fatal hospital-acquired superbug,
Clostridium difficile.

They screened more than 30,000
bacteria isolated from the human gut
and discovered that the new antibiotic
consists of two distinct peptides that
act together to kill a wide range of
clinical C difficile.

“This specificity of thuricin towards
Clostridium difficile is a key advantage
that it has over other antibiotic
treatments,” said Prof Hill, adding that
tests have shown it doesn’t have an
impact on other bacteria in the gut.


ANTIBIOTIC FIDAXOMICIN FROM
OPTIMER
Optimer Pharmaceuticals, Inc.  has two
late-stage anti-infective product
candidates under development.
Fidaxomicin is a narrow spectrum
antibiotic being developed for the
treatment of Clostridium difficile
infection.  In two Phase 3 trials
completed by Optimer to study the
safety and efficacy of fidaxomicin for
the treatment of CDI, fidaxomicin was
statistically superior to vancomycin in
global cure rate (defined as cure with
no recurrence within four weeks of
completing therapy) as well as
statistically superior in reducing
recurrences of CDI by up to 50% when
compared with vancomycin, the only
FDA approved product for CDI.

Decision Resources, an advisory firm
for pharmaceutical and healthcare
issues, finds that, in first- and second-
line treatment of Clostridium difficile
infection (CDI), nearly 70 percent of
surveyed infectious disease specialists
and internists will use Optimer's
fidaxomicin one year after the launch
of the agent.

Pruvel is a prodrug in the
fluoroquinolone class of antibiotics
being developed as a treatment for
infectious diarrhea.  Optimer has also
successfully completed two Phase 3
trials with Pruvel.
Prodrug: A class of drugs, initially in
inactive form, that are converted into
active form in the body by normal
metabolic processes.



OTHER  DEVELOPMENTS
A new compound is being developed
by GlaxoSmithKline, called GSK
299423, against antibiotic-resistant
strains of bacteria such as
Staphylococus aureus, including
methicillin resistance S. aureus
(MRSA), and against gramnegative
bacteria like E. coli, Pseudomonas,
Klebsiella and Acinetobacter.
Gram-negative bacteria are
particularly difficult to attack as they
have an outer membrane surrounding
the bacterial cell wall, which interferes
with drug penetration. New medicines
must not only be toxic to the pathogen,
but must first overcome the barriers to
entry into the cell.



Tygacil by Wyeth;

Doribax (Doripenem) by Janssen-Cilag;

Ceftobiprole by Johnson&Johnson and
Basilea;

Zyvox by Pfizer;
Dalbavancin by Pfizer (trial);
Telavancin by Theravance Inc;

Iclaprim by Arpida trial;

Oritavancin by Targanta;

Cubicin (daptomycin for injection) by
Cubist;
Primaxin by Merck;
Merrem by Astrazeneca;


OVERVIEW

The Gram Negative
bacterial challenge

There are several drugs, including
some approved in the last few
years, that can treat MRSA. But for
a combination of business and
scientific reasons, the
pharmaceuticals industry is
pursuing very few drugs for
Acinetobacter and other
organisms of its type, known as
Gram-negative bacteria.

Meanwhile, the germs are
evolving and becoming ever more
immune to existing antibiotics.

NDM-1 is a  new superbug  that
makes an enzyme called NDM-1
which probably travelled back to
the UK in patients who went over
to India and Pakistan for surgical
treatments.
This superbug is resistant to
virtually all antibiotics, even the
most powerful ones. So far, only 50
cases have been reported in Great
Britain but it is feared that it will
spread worldwide.

Two types of bacteria have been
host to NDM-1: the gut bacterium E.
coli and another that can invade
the lungs called Klebsiella
pneumonia. Both can lead to
urinary tract infections and blood
poisoning.

While there is a great deal of
investment in research to find new
antibiotics, most of the drugs
currently in the pipeline will be
useless for treating NDM-1
patients.
This is because the bacteria that
carry NDM-1 are Gram-negative,
while most of the work is being
carried out for Gram-positive bugs
like MRSA.

Gram-positive bacteria are those
that are stained dark blue or violet
by Gram staining. This is in
contrast to Gram-negative
bacteria, that is appearing red or
pink.
But the real difference is in their
structure.

Gram-negative bacteria are
practically built to withstand drugs.

The bacteria have a double cell
membrane to shield them,
compared with Gram-positive
organisms, which have a single
membrane. They can make various
enzymes that break down
antibiotics. And some, particularly
Pseudomonas aeruginosa, have
powerful pumps that can expel the
drugs.
The bacteria also readily exchange
genes, even across different
species, that confer drug
resistance.
Acinetobacter baumannii, an
increasingly common drug-
resistant  bacteria found in health
care settings across the United
States  and globally.
Acinetobacter is multidrug-
resistant, and is extremely difficult
to kill once it enters the
body.  As a result, Acinetobacter
now often is treatable only with a
highly toxic  drug, colistin, which
was abandoned in the 1960s
because it causes kidney damage.

Of note, Acinetobacter has
become a particular problem for U.
S. soldiers who have served in
Iraq and Afghanistan.
A 2006 study  conducted at Walter
Reed Army Medical Center found
that of 75  patients who tested
positive for the bacteria, 89
percent were resistant to at least
three classes of antibiotics and 15
percent were resistant to five
classes.

Another resistant infection
receiving increased scrutiny is
Clostridium difficile (C. Diff).
C. diff. is an HAI or Hospital
Associated Infection that can lead
to severe diarrhea, rupture of the
colon, kidney failure, blood
poisoning, and death. CDC
estimates there are 500,000 cases
of C. diff. infection annually in the
U.S., contributing to between
15,000 and 30,000 deaths.

Meanwhile, New York City
hospitals, perhaps because of the
large numbers of patients they
treat, have become the global
breeding ground for another drug-
resistant Gram-negative germ,
Klebsiella pneumoniae.
According to researchers at SUNY
Downstate Medical Center, more
than 20 percent of the Klebsiella
infections in Brooklyn hospitals
are now resistant to virtually all
modern antibiotics.
Stark choices have to be taken
sometimes.
Last year doctors at St. Vincent's
Hospital in Manhattan published a
paper describing two cases of
"pan-resistant" Klebsiella,
untreatable by even the kidney-
damaging older antibiotics. One of
the patients died and the other
eventually recovered on her own,
after the antibiotics were stopped.

Health authorities do not have
good figures on how many
infections and deaths in the United
States are caused by Gram-
negative bacteria. The Centers for
Disease Control and Prevention
estimates that roughly 1.7 million
hospital-associated infections,
from all types of bacteria
combined, cause or contribute to
99,000 deaths each year.
But in Europe, where hospital
surveys have been conducted,
Gram-negative infections are
estimated to account for two-thirds
of the 25,000 deaths each year.

It is likely to be several years
before new drugs to treat Gram-
negative infections are available.
A report last September by
European health authorities found
only six novel drugs in clinical
trials that might work against at
least one Gram-negative organism,
compared with 13 for Gram-
positive bacteria.
A separate study released about a
year ago by the Infectious
Diseases Society of America found
no drugs in middle- or late-stage
clinical trials directed specifically
at Gram-negative organisms.
There were eight drugs in those
trials that developers hoped might
work against both Gram-negative
and Gram-positive microbes.
The thin pipeline has raised the
value of the few drugs under
development for Gram-negative
infections.
Novexel was acquired by
AstraZeneca.
Novexel's  NXL104, a novel beta-
lactamase inhibitor is  currently in
two Phase II clinical trials in
patients with complicated intra-
abdominal infections and patients
with complicated urinary tract
infections.
NXL103, an oral Streptogramin
antibiotic is currently in a Phase II
clinical trial in adults with acute
bacterial skin infections.

Cubist Pharma has acquired Calixa
mainly for its Phase 2 CXA-201
antibiotic candidate, which is
being developed as a first line
intravenous therapy for the
treatment of certain serious Gram-
negative bacterial infections,
including those caused by multi-
drug resistant Pseudomonas
aeruginosa.
Assuming successful clinical
development, Cubist expects to
file a New Drug Application for
CXA201 in complicated urinary
tract infections and complicated
intra-abdominal infections in 2013.