3
BioTech Navigator, March 1998
of the other aminoglycosides, makes it
difficult for even gram-negative bacte-
ria to develop resistance to this antibi-
otic as they can with other aminogly-
cosides. To date, the therapeutic use
of aminoglycosides has been limited
by significant dose-limiting toxicities
specifically, kidney damage and hear-
ing loss. The target product profile for
MiKasome, as compared to free
amikacin, includes significantly im-
proved safety, extended circulation
times, increased penetration to sites of
infection and a broader range of an-
timicrobial activity. A Phase l clini-
cal trial of MiKasome was initiated in
February 1997. But will this new for-
mulation of an antibiotic that bacteria
may already be resistant to be of use?
Not necessarily.
PathoGenesis on the other hand
may have a winner. PathoGenesis
recently received FDA approval
(12/97) to market Tobi, an inhalant
form of tobramycin to treat bacterial
infections in cystic fibrosis patients.
Cystic fibrosis causes severe lung in-
fections that are generally treated with
an intravenous tobramycin, and re-
quire hospital stays of 16 days on av-
erage annually. Tobi delivers a
higher dose of the antibiotic directly
into the lungs through inhalation to
the site of infection, thereby reducing
the infection. Additionally, it can be
taken at home. The result is fewer
patients in the hospital, reducing av-
erage annual visits to just 10 days and
saving up to $14,000 in health-care
costs per episode. Although the mar-
ket size is not very large for cystic
fibrosis, the fact that this drug can
improve the quality of life for cystic
fibrosis patients is significant. Physi-
cians should begin prescribing the
drug, which will translate into in-
creased revenues for PathoGenesis.
BioTech Navigator (BTN) likes Ptho-
Genesis.
New directions: Inhibiting the
resistance
antibiotics are generally variations on
old themes -- beta-lactam (penicillin
and cephalosporins), macrolide,
quinolone, tetracyclic (tetracyclines),
aminoglycoside (kanamycin and gen-
tamicin) -- and antibiotic resistance
develops ever more rapidly as soon as
new agents are in clinical use. De-
spite the ability to become resistant to
antibiotic, researchers continue to tin-
ker with the structure of certain an-
tibiotics, the beta-lactams in particu-
lar, in an attempt to circumvent resis-
tance mechanisms. Beta-lactams
have the largest share of the multi-
billion dollar worldwide antibiotic
market. Because there are so many of
these compounds, they are now
grouped into 10 classes based on the
parent beta-lactam skeleton. Peni-
cillin and cephalosporins are now
classified as penams and cephems,
respectively. Other categories include
penems, oxycephems, clavams,
clavems, azetidinones, carbapenams,
carbapenems, and cabacephems.
The carbapenems are one of the
most promising classes of beta-lactam
antibiotics. These compounds have a
wide spectrum of activity against
Gram-positive, Gram-negative, aero-
bic, and anaerobic bacteria, including
strains resistant to multiple drugs. In
1995, the Food and Drug Administra-
tion (FDA) approved a new broad-
spectrum parental antibiotic of the
carbapenem for the treatment of com-
plicated intra-abdominal infections in
adults and children, and for pediatric
bacterial meningitis. Meropenem
(Merrem/Zeneca) has an antimicro-
bial profile similar to the carbapenem
imipenem (Primaxin/Merck), al-
though it is relatively resistant to in-
activation by renal dehydropeptidase
(DHP) so does not require co-
administration with a DHP inhibitor
such as cilastatin. As with the peni-
cillin's, meropenem binds to proteins
involved in bacterial cell wall synthe-
sis, causing cell death. The drug is
resistant to beta-lactams and has a
high affinity for penicillin-binding
proteins in important pathogens such
as Staphylococcus aureus, Escherichia
coli, and Pseudomonas aeruginosa.
More recently, a FDA advisory
panel approved a new type of antibi-
otic to treat potentially fatal infections
that are resistant to all available an-
tibiotics. The drug, referred to as
Synercid (Rhone-Poulenc Rorer), was
recommended for approval to treat
vancomycin-resistant Enterococcus
faecium, complicated skin and skin-
structured infections, and hospital-
acquired (nosocomial) pneumonia.
Enterococcus faecium is the second
most frequently acquired hospital in-
fection in the US, and like Staph, is
becoming increasingly resistant to
vancomycin. Synercid is composed of
two distinct compounds that work
synergistically at up to 16 times the
power of either agent alone to kill sus-
ceptible bacteria through a two-
pronged attack on protein synthesis in
bacterial cells. However, the advisory
panel voted 7 to 3 that the data did
not necessary prove the drug was safe
and effective for treatment. Side ef-
fects were observed in a significant
percentage of the patients, which in-
cluded muscle and joint pain, nausea,
diarrha, vomiting, and rash.
Repackaging antibiotics or
improving delivery:
NeXstar is currently developing
MiKasome, a liposomal formulation
of amikacin, which is a member of a
class of antibiotic compounds called
aminoglycosides. Aminoglycosides
kill bacteria by inhibiting protein syn-
thesis, an activity necessary for life.
Aminoglycosides are particularly ef-
fective against gram-negative bacte-
ria, a large group of organisms resis-
tant to most other types of antibiotics,
although amikacin is also active
against certain important gram-
positive bacteria that are resistant to
other antibiotics. Amikacin's unusual
chemical structure, compared to that
