Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
DOSAGE ADJUSTMENT FOR ANTIBIOTICS
BACKGROUND OF THE INVENTION
This application claims the priority of U.S. Provisional Application No.
60/261,437, filed
January 11, 2001, the disclosure of which is specifically incorporated herein
by reference in its
entirety.
1. Field of the Invention
The present invention relates generally to the fields of infectious diseases
and
administration of antibiotics. More particularly, it concerns the adjustment
of dosage and/or the
adjustment of frequency of administration of antibiotics that are excreted
predominantly through
the biliary tract on the basis of biliary function tests, with the goal of
reducing side effects caused
by the antibiotics.
2. Description of Related Art
The emergence of multidrug-resistant pathogens is a continuing challenge for
the
treatment of infectious diseases. For example, strains of Enterococcus faecium
that are resistant
to vancomycin pose a serious threat to individuals, such as cancer patients
and transplant
recipients, suffering from numerous irnmunosuppressive conditions. As
vancomycin was
considered to be the antibiotic of last resort for several pathogens,
emergence of strains resistant
to vancomycin pose a serious health threat to society. The most serious
complications from
vancomycin-resistant enterococcal (VRE) infections occur in severely
immunocompromised
patients, particularly cancer patients who are either neutropenic or have
underlying hematologic
malignancies (Linden et al., 1996; Edmond et al., 1996; Montecalvo et al.,
1996). Combination
therapies with other known antibiotics have proven futile in treatment of
these infections. A new
drug, Synercid, belonging to the class of streptogramin antibiotics, was FDA
approved in
September 1999, for the treatment of serious or life-threatening infections
associated with
vancomycin-resistant Enterococcus faeciurn (VREF) bacteremia.
Synercid is a combination of two streptogramins: quinupristin and
dalfopristin. It has
successfully been used to treat infections caused by drug-resistant pathogens
such as vancomycin
resistant enterococci, methicillin resistant staphloccocus, penicillin
resistant pneumococci axed
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others. Infections by these pathogens are typically seen in hospitalized and
immunocompromised individuals.
The approval of Synercid was based on clinical studies conducted worldwide in
2,401
Synercid-treated patients enrolled in five Phase III comparative trials and an
Emergency-Use
Program. Synercid was found to be effective and generally well-tolerated.
Success rates were
judged equivalent to the comparator in patients with skin and soft-tissue
infection or with
nosocomial pneumonia. In particular, patients with severe underlying
conditions and a Gram-
positive infection, who were left without any other alternative antibacterial
treatment due to in
vitro resistance of infecting bacteria, previous failure, allergy or
intolerance to commercially
available antibiotics, were successfully treated with Synercid.
A major side effect of Synercid is the occurrence of arthralgias and myalgias.
These
were reported with an overall incidence of 9.5 percent in the Emergency-Use
Program. In cancer
patients at least 36% of the patients treated with Synercid develop
arthralgias and myalgias.
Often the arthralgia and myalgia leads to discontinuation of the drug in these
patients. Since the
patients treated with Synercid have life-threatening infections there is an
urgent need for
development of methods that will reduce and/or alleviate the side effects of
Synercid that lead to
drug discontinuation.
In addition to Synercid, it is also desirable to minimize or alleviate side
effects caused by
other antibiotics. Thus, there is a need for methods of dosage adjustments
that minimize side
effects caused by antibiotics.
SUMMARY OF THE INVENTION
The present invention provides methods that overcome existing defects in the
art.
Provided herein are methods for determining the necessity of and the amount of
adjustment of
dosage for antibiotics that are predominantly excreted through the biliary
tract. These methods
reduce or alleviate side effects caused by the antibiotics in individuals in
need of the antibiotics.
One example of such an antibiotic is Synercid and the major side-effects of
Synercid are
arthralgias and myalgias.
Synercid is used in patients that have resistant infections. So far, no dosage
adjustment is
performed for Synercid. For example, no dose adjustment has been required for
patients with
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renal impairment and/or patients undergoing peritoneal dialysis; patients with
hepatic
insufficiencies; patients that are older or pediatric; and/or on basis of
patient gender. Thus, all
types of patients are typically given the same dosage of this drug regardless
of other conditions
that may exist. The side effects of Synercid result in the discontinuation of
therapy in some
patients with acute adverse effects. As most patients that require Synercid
therapy are
immunocompromised patients, Synercid constitutes a life-saving therapy for
these individuals.
Discontinuation of the drug due to side effects offers very limited
alternative options and is thus
often fatal for the patient.
The present invention provides methods for reducing side effects in an
individual to be
treated with an antibiotic that is predominantly excreted through the biliary
tract comprising, a)
performing a liver function test on the individual; and b) administering to
the individual an
amount of the antibiotic based on the liver function test. The term
"predominantly excreted
through the biliary tract" is defined here as an antibiotic that is excreted
at about 60% or more
through the biliary tract. Thus, an antibiotic that is excreted at about 60%,
61%, 62%, 63%,
64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,
79%,
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, or even about 99%, including all percentages between the listed
percentages,
through the biliary tract may be dosage adjusted by the methods of the present
invention. The
term "about" used in the sentence above is defined to include fractional
values of ~ 0.1 to ~ 0.5
of each value for example, ~ 0.1, ~ 0.2, ~ 0.3, ~ 0.4 and ~ 0.5 as well as the
values in between
these numbers. For example, the term "about 60%" includes, 59.5%, 59.6%,
59.7%, 59.8%,
59.9%, 60%, 60.1%, 60.2%, 60.3%, 60.4%, and 60.5%, and the values in between
these
numbers; and the term "about 61%" includes 60.5%, 60.6%, 60.7%, 60.8%, 60.9%,
61%, 61.1%,
61.2%, 61.3%, 61.4%, and 61.5% as well as the values in between these numbers.
In one embodiment of the present invention the antibiotic is a streptogramin
antibiotic.
In a more specific embodiment the streptogramin antibiotic is Synercid. Some
antibiotics that
may be dosage and/or frequency adjusted using the methods of the present
invention include
those that are predominantly excreted through the biliary tract such as
Synercid, Nascillin,
Cefoperzone, Doxycycline, macrolide antibiotics such as Erythromycin,
Clarithromycin,
Azithromycin (administered by LV.), Amphoterecin B and lipid formulations of
Arnphoterecin
B, Clofazimine and the like. However, the skilled artisan will understand that
the methods of the
invention are not limited to the listed antibiotics and that any antibiotic
that is predominantly
excreted by the biliary tract may be dosage adjusted by the methods taught
herein.
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In some embodiments, the antibiotic is used in combination with other
antibiotics. For
example, Synercid may be used in conjunction with other antibiotic drugs such
as minocycline.
In one embodiment of the present invention the liver function tests measures
the function
and/or metabolic ability of the liver of the individual. In another
embodiment, the liver function
test measures the metabolism of the antibiotic. In other embodiments the liver
function test
measures the extent of biliary tract dysfunction. In specific embodiments the
liver function test
measures the activity of an enzyme. The enzyme activity measured can be the
activity of
alkaline phosphatase and/or the activity of gamma-glutamyl transpeptidase
(gamma GT). Other
liver enzyme activities may also be measured.
In one embodiment of this invention the amount of antibiotic comprises a dose
of the
antibiotic. In another embodiment the amount comprises the frequency of
administering the
antibiotic.
In other embodiments, the methods of the present invention may be used to
reduce and/or
prevent side effects in an individual being treated with the antibiotic. In
some embodiments the
individual can also be further afflicted with cancer, and/or is neutropenic,
and/or is
immunocompromised and/or is a transplant recipient and/or is. a HIV patient.
The individuals
being treated with the antibiotic may be afflicted with an infection. The
infections may be
bacteremia, urinary tract infection (UTI), pneumonia, wound infections, bone &
joint infections,
endocarditis etc. The infection can further be mufti-drug resistant. The
skilled artisan will
recognize that the practice of the methods of the invention are not limited by
the type of
infection.
In other aspects, the infection may be bacterial. Examples of bacterial
infection include
enteroccocal infections that may further be vancomycin-resistant. For example,
the infection
may be caused by Erater~ococcus faecium or Enterococcus aviurn. Other examples
of bacterial
infection are staphylococcal infections. Fox example the infection may be
caused by methicillin-
resistant Staphylococcus aureus or Staphylococcus pyogenes.
The invention also provides a method for dosaging an antibiotic that is
predominantly
excreted by the biliary tract comprising, a) measuring liver function; and b)
adjusting the
dosage of the antibiotic based on the liver function measurements. In some
embodiments of the
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present invention adjusting the dosage comprises the frequency of
administering the antibiotic
and/or adjusting the amount of antibiotic administered.
The invention further provides an improved method for reducing side effects in
an
individual to be treated with an antibiotic that is predominantly excreted
through the biliary tract
by determining the appropriate dosage amount of antibiotics administered to an
individual
wherein the improvement comprises, a) performing a liver function test on the
individual; and b)
adjusting the dosage of the antibiotic based on the liver function test.
As used herein the specification and claim(s), the words "a" or "an" when used
in
conjunction with the word "comprising" may mean one or more.
Other objects, features and advantages of the present invention will become
apparent
from the following detailed description. It should be understood, however,
that the detailed
description and the specific examples, while indicating preferred embodiments
of the invention,
are given by way of illustration only, since various changes and modifications
within the spirit
and scope of the invention will become apparent to those skilled in the art
from this detailed
description.
DETAILED DESCRIPTION OF THE INVENTION
1. The Present Invention
Side effects caused by antibiotics often pose major problems and may include
myalgias,
arthralgias, cardiotoxicity, hepatotoxicity, nephrotoxicity, anemia and the
like. One of the goals
for effective therapy with antibiotics is to find methods that allow
administration of antibiotics in
dosages and frequencies that minimize or prevent side effects. The present
invention provides
methods for minimizing side effects of antibiotics that are predominantly
excreted by the biliary
tract by adjusting their dosage and/or frequency of administration. These
methods involve
performing a biliary function test to analyze the ability of a patient to
handle the excretion of an
antibiotic and formulating a dosage regimen for administration of the
antibiotic based on the
biliary function of the patient. The inventors contemplate that the methods
taught herein can be
used to minimize side effects of any antibiotic that is predominantly excreted
by the biliary tract.
Thus, dosage adjustment for any antibiotic that is excreted at about 60% or
more by the biliary
tract axe contemplated.
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One such drug is Synercid, which is a streptogramin antibiotic. Synercid-based
treatments are currently the only effective treatment for Vancomycin-resistant
enterococci
(VRE), especially, Enterococcur faecium (VREF) infections. VRE infections
occur in seriously
immunocompromised patients, such as cancer patients, HIV patients, transplant
patients etc. A
Synercid-based therapy comprising a combination of Synercid
(quinupristin/dalfopristin) with
minocycline, was found to be either synergistic or additive against VREF in
vitro in a study by
the present inventors. Thus, the efficacy and the tolerability of this regimen
against VRE
infections in cancer patients in a prospective, open-label study was
evaluated. Fifty-six
evaluable patients with VRE infection were entered on
quinupristin/dalfopristin 7.5 mg/kg every
8 hours plus minocycline 100 mg every 12 hours for a mean duration of 12 days
(range, 2-52
days).
. Fifty-one (91%) infections were caused by VREF. Liver functions tests were
performed
on all patients before, during and after the end of therapy. All patients were
followed until one
month after completion of therapy. Thirty-eight (68%) of the 56 patients
responded. Ninety
percent of them had hematological malignancies, 40 (71%) were neutropenic (<
500 cells/mm3).
The types of infections were bacteremia (71%), urinary tract infection (14%),
pneumonia (5%)
and wound infection (5%). There were no significant differences in responses
related to site of
infection or presence of neutropenia. Adverse events included
arthralgia/myalgia in 36% of
patients, liver ftmction abnormalities in 7%, and leukopenia in 5%. Patients
with
arthralgia/myalgia had significantly higher levels of alkaline phosphatase
during therapy than
patients without this adverse event (P = 0.05). Higher levels of alkaline
phosphatase are
therefore indicators of biliary dysfunction. Other enzymes that are tested for
biliary function
tests include gamma glutamyl transpeptidase (gamma GT).
In this high risk patient population, treatment of serious VRE infections with
quinupristin/dalfopristin and minocycline was effective. The present inventors
have shown
herein that the associated side effects of arthralgias/myalgias which occurred
at a substantial
frequency are related to biliary tract dysfunction. The invention also
describes that performing
liver function tests that specifically evaluate biliary function on patients
treated with Synercid
(alone or in combination with other drugs) allows the determination of an
amount and dosage of
Synercid to be administered so as to decrease or prevent the occurrence of the
associated side
effects. Some examples of such liver ftinction tests are gamma GT
measurements, alkaline
phosphatase measurements etc. This is important as many patients have to
discontinue Synercid
based therapy due to the side effects. As these patients are severely
immunocompromised, the
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infections they have can be fatal, and therefore there is need to continue the
Synercid-based
therapy. The present invention provides methods that reduce or alleviate the
side effects which
mainly manifest as arthralgias and myalgias in individuals being treated with
Synercid, thereby,
allowing the continuation of this life saving therapy.
2. Infections
Vancomycin was a drug of last resort for resistant gram positive infections.
The
emergence of vancomycin resistance in the 1980's has been a cause of high
concern. It has been
demonstrated that vancomycin resistance is a significant independent predictor
of increased
morbidity and mortality in enterococcal bacteremia (Vergis et al., 1997;
Linden et al., 1996).
The most serious complications from VRE infections occur in severely
immunocomprornised
patients, particularly cancer patients who are either neutropenic or have
underlying hematologic
malignancies (Linden et al., 1996; Edmond et al., 1996; Montecalvo et al.,
1996). Edmond et al.
(1996), studied the outcome of VRE bacteremia in a population consisting of
mostly (70%) of
patients with underlying hematologic malignancy. In that subgroup of patients,
VRE bacteremia
was associated with an attributable mortality of 37%, and 81% of the patients
developed
hypoperfusion abnormalities and/or organ dysfwction. Montecalvo et al.,
(1996), determined
that neutropenia is a risk factor for the persistence of VRE bacteremia in
irnmunocompromised
patients. Similarly, Linden et al., (1996) found that VRE bacteremia in
immunocompromised
liver transplant patients is associated with a persistence of the infection,
more frequent recurrent
bacteremia and the need for multiple invasive interventions. In that same
study, Linden et al.
attributed the serious morbidity and attributable death in patients with VREF
bacteremia to be
partially mediated by the lack of effective antimicrobial therapy.
Among the conventional antimicrobial agents there are no effective regimens
available
for the treatment of VRE infections. Various regimens have been tried, such as
oral novobiocin
plus intravenous ciprofloxacin (Linden et al., 1996), doxycycline
(Papanicolaou et al., 1996),
continuous high dose ampicillin or ampicillin-sulbactam (Mekonen et al.,
1995), or
chloramphenicol. The results of these studies have been inconclusive in terms
of efficacy. In a
study involving 100 patients with VRE bacteremia, there was no significant
difference in
mortality between treated and untreated patients (Lautenbach et al., 1998).
The treatment in that
study included the use of ampicillin, imipenem, ciprofloxacin, doxycycline,
and
chloramphenicol. Chloramphenicol has been proposed as an alternative agent
(Horns et al.,
1995); however, more recently it was shown to have no significant impact on
mortality, even in
uncomplicated cases with catheter-related VRE bacteremia (Lautenbach et al.,
1998).
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3. Streptogramin antibiotics
Streptogramins comprise a homogenous group of antibiotics, consisting of a
combination
of two types of chemically different molecules; the A-group components which
are
polyunsaturated macrolactones and the B-group components which are
depsipeptides. Several
streptogramin antibiotics are known (Table 1), which are known by different
names in
accordance with their origin, including pristinamycins, mikamycins and
virginiamycins.
TAELE 1
MICROORGANISM ANTIBIOTIC
FUNGI
Micromonospora sp. Vernamycin
STREPTOMYCES
S. alborectus Virginiamycin
S. griseus (NRRL2426) Viridogrisein
S. lavendulae Etamycin
S. loidensis (ATCC11415) Vernamycin
~' mitakaensis (ATCC15297)Mikamycin
S. ostreogf~iseus (ATCC27455)Ostreogrycin
S. p~istinaespiralis(ATCC25486)Pristinamycin
S. virginiae (ATCC13161) Virginiamycin
ACT1NOMYCES
A. daghestanicus Etamycin
The A and B components have a synergistic antibacterial activity which can be
as much
as 100 times that of each separate component. The bactericidal activity is
more effective against
Gram-positive bacteria such as staphylococci and streptococci. The A and B
components inhibit
protein synthesis by binding to the SOS subunit of the ribosome.
Streptogramins axe mainly produced by actinomycetes, including many
streptomycetes
for example, Streptom~ces alborectus, Str~eptornyces mitakaensis, Streptomyces
pristinaespiralis,
Streptorrtyces ostreogriseus and Streptomyces virginiae. In addition,
streptogramins are also
synthesized by eukaryotes such as Micromonospora which synthesizes
vernamycins. Some
examples are listed in Table 1 above.
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Among known streptogramins, pristinamycin (RP 7293), an antibacterial of
natural origin
produced by Sty~eptornyces pristizzaespiralis, was isolated for the first time
in 1955.
Pristinamycin is used in Europe as an oral antibiotic and is marketed under
the name
Pyostacine~ and consists mainly of pristinamycin IA and pristinamycin IIA.
Another
antibacterial of the streptogramin class, namely virginiamycin, has been
prepared from
StYeptomyces vizginiae, ATCC 13161 and is also known as Staphylomycine~.
Virginiamycin is
used in animal feed to protect animals from infections. Yet other examples of
streptogramins
include mikamycin, ostreogrycin, viridogrisein, vernamycin and etamycin. The
group A and
group B components are also used for the treatment of acne.
4. S nercid
Synercid~ (also called RP 59500 or RP 57669/RP 54476) is an antibacterial
agent that
belongs to the class of macrolides-lincosamides-streptogramins. This
injectable streptogramin is
approved for the treatment of patients with serious or life-threatening
infections, for example,
those associated with vancomycin-resistant Enterococcus faecium (VREF)
bacteremia; and
complicated skin and skin structure infections caused by Staphylococcus aureus
(methicillin
susceptible) or Streptococcus pyogenes. Synercid has been approved for
marketing in the United
States for this indication under FDA's accelerated approval regulations that
allow marketing of
products for use in life-threatening conditions when other therapies are not
available.
Synercid has been shown both in vitro and in clinical infections to be active
against most
strains of the following microorganisms:
Aerobic grant positive microorga~zisms:
Enterococcus faecium (Vancomycin-resistant and multidrug-resistant strains
only)
Staphylococcus aureus (methicillin-susceptible strains only)
Stf~eptococcus pyogerzes
In addition irz vitf°o data shows that Synercid exhibits a minimum
inhibitory
concentrations (MIC's) of <l .0m g/mL against >90% isolates of the following
microorganisms:
Aerobic grain positive nzicroorgahisyrzs:
Cozynebacter ium jeikeiuzn
Staphylococcus aur~eus (methicillin-resistant strains)
Staphylococcus epidermidis (including methicillin-resistant strains)
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Streptococcus agalactiae
Pharmacology: Synercid is a sterile lyophilized formulation of two
semisynthetic
pristinamycin (streptogramin) derivatives, quinupristin (derived from
pristinamycin I) and
S dalfopristin (derived from pristinamycin IIA) in the ratio of 30:70 (w/w).
These two components
act synergistically, therefore, Synercid's ifa vitro microbiologic activity is
greater than that of the
individual components. The metabolites of quinupristin and dalfopristin also
contribute to the
antimicrobial activity of Synercid. The site of action of quinupristin and
dalfopristin is the
bacterial ribosome. Dalfopristin has been shown to inhibit the early phase of
protein synthesis
while quinupristin inhibits the late phase of protein synthesis.
Quinupristin is a white to very slightly yellow, hygroscopic powder. It is a
combination
of three peptide macrolactones. The main component of quinupristin (>88.0%)
has the following
chemical name: N-[(6R,9S,lOR,13S,1SaS,18R,22S,24aS)-22-[p-
(dimethylamino)benzyl]-6
1S ethyldocosahydro-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyl-18-
[[(3S)-3
quinuclidinyithio]methyl]-12H-pyrido [2,1-fJpyrrolo-[2,1-1] [ 1,4,7,10,13,16]
oxapentaazacyclononadecin-9-yl]-3-hydroxypicolinamide. The main component of
quinupristin
has an empirical formula of CS3H67N9010S, a molecular weight of 1022.24.
Dalfopristin is a slightly yellow to yellow, hygroscopic, powder. The chemical
name for
dalfopristin is: (3R,4R,SE,l0E,12E,14S,26R,26aS)-26-[[2-
(diethylamino)ethyl]sulfonyl]-
8,9,14,15,24,25,26,26a-octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3H-21,18-
nitrilo-
1 H,22H-pyrrolo [2,1-c] [ 1, 8,4,19]-dioxadia zacyclotetracosine-1,
7,16,22(4H,17H)-tetrone.
Dalfopristin has an empirical formula of C34HSON409S, a molecular weight of
690.85.
2S
Pharmacokinetics: Quinupristin and dalfopristin are the main active components
circulating in plasma in human subjects. Quinupristin and dalfopristin are
converted to several
active major metabolites: two conjugated metabolites for quinupristin (one
with glutathione and
one with cysteine) and one non-conjugated metabolite for dalfopristin (formed
by drug
hydrolysis). Pharmacokinetic profiles of quinupristin and dalfopristin in
combination with their
metabolites provide doses of 7.S mg/kg of Synercid intravenously ql2h or q8h
for a total of 9 or
10 doses, respectively. In vitro, the transformation of the parent drugs into
their major active
metabolites occurs by non-enzymatic reactions and is not dependent on
cytochrome-P4S0 or
glutathione-transferase enzyme activities.
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Synercid is a major inhibitor of cytochrome P450 3A4 isoenzyme. Synercid can
also
interfere with the metabolism of other drug products that are associated with
QTc prolongation.
However, electrophysiologic studies show that Synercid does not itself induce
QTc prolongation.
Fecal excretion constitutes the main elimination route for both parent drugs
and their
metabolites (75 to 77% of dose). Urinary excretion accounts for approximately
15% of the
quinupristin and 19% of the dalfopristin dose. Preclinical data in rats have
demonstrated that
approximately 80% of the dose is excreted in the bile and in man, biliary
excretion is probably
the principal route for fecal elimination. ~ The pharmacokinetics of the
Synercid were not
modified in older individuals or by gender differences.
In patients with renal insufficiency, i.e., creatinine clearance 6 to 28
mL/min, the AUC of
quinupristin and dalfopristin in combination with their major metabolites
increased about 40%
and 30%, respectively. In patients undergoing Continuous Ambulatory Peritoneal
Dialysis,
dialysis clearance for quinupristin, dalfopristin and their metabolites is
negligible. The plasma
AUC of unchanged quinupristin and dalfopristin increased about 20% and 30%,
respectively.
The high molecular wVeight of both components of Synercid indicates that it is
unlikely to be
removed by hemodialysis.
In patients with hepatic dysfunction (Child-Pugh scores A and B), the terminal
half life
of quinupristin and dalfopristin was not modified. However, the AUC of
quinupristin and
dalfopristin in combination with their major metabolites increased about 180%
and 50%,
respectively.
I~r vitro combination testing of Synercid with aztreonam, cefotaxime,
ciprofloxacin, and
gentamicin against Entef°obacteriaceae and Pseudomonas aerugifzosa does
not show
antagonism. In vitro combination testing of Synercid with prototype drugs of
the following
classes: aminoglycosides (gentamicin), -lactams (cefepime, ampicillin, and
amoxicillin),
glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines
(doxycycline) and also
chloramphenicol against enterococci and staphylococci also does not show
antagonism. The
mode of action differs from that of other classes of antibacterial agents such
as -lactams,
aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and
tetracyclines. No
cross resistance was seen between Synercid and these agents when tested by the
minimum
inhibitory concentration (MIC) method.
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Indications for Use: Use of Synercid for treating resistant infections such as
in VREF-
infected patients has been allowed under an investigator sponsored-IND program
("compassionate use program') in the US (Cerwinka et al., 1995) and under a
similar
Compassionate Use Program in other countries including France, Israel and the
UK (Lynn et al.,
1994). Patients are treated for a variety of infections, including post-
operative wounds, intra-
abdominal infections, peritonitis, urinary tract infection, suppurative
phlebitis, osteomyelitis,
bacteremia of unknown origin and endocarditis. Listed below are some of the
different types of
patients and infections that may be treated with Synercid and therefore be
amenable to dosage
adjustment to reduce or alleviate side effects by the methods of this
inventions. Thus, liver
function tests in accordance to methods of the present invention can be
performed on all these
patient types prior to the appropriate dosage adjustment.
The following criteria are used as general indications for Synercid based
treatments due
to the Emergency/Compassionate Use clause of Synercid, however, it will be
understood that
this is just a guideline and that the Synercid based therapy may be performed
on any patient
regardless of the guidelines if determined essential by a trained physician:
i. Microbiological Criteria:
Patients that are treated with Synercid generally have a culture of the
infection site which
is positive for the causative pathogen prior to treatment. Treatment is
generally not initiated
without positive cultures. In general, the patient must meet at least one of
the following
inclusion criteria; the infection must be caused by a pathogen with resistant
or intermediate ih
vitro susceptibility to all clinically appropriate antibiotics. One example of
this is
Vancomycin-resistant Ehterococcus faecium (VREF) which has been shown to have
a
vancomycin sensitivity of intermediate or resistant via one of the following
inclusion criteria: 1.
Disk Diffusion zone size of 16 mm or less and/or 2. MIC of S ~g/ml or higher.
Patients with an
infection due to a non-VREF organism including infections with but not limited
to staphylococci
(MRSA, MRSE), streptococci, other enterococci and Legionella sp. may also be
treated with
Synercid. Another inclusion criteria is documented intolerance or absolute
contraindication of a
patient to all available clinically appropriate antibiotics. Yet another
inclusion criteria is a
documented treatment failure with all available clinically appropriate
antibiotics of the patient.
Generally, all types of infection can be treated with Synercid and hence all
such patients
are amenable to dosage adjustment using methods of the invention. The
infection type includes
intra-abdominal infections, skin and skin-structure infections, urinary tract
infections, central
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catheter related bacteremia, endocarditis, bone and joint infections,
bacteremia with an unknown
source, respiratory tract infections, and all other types of infections.
ii. Site-specific Infection Criteria:
Patients with infra-abdominal infections can be treated with Synercid and the
following
three criteria are generally considered, at least one of the following:
radiological evidence (such
as a CT scan or ultrasound) of infra-abdominal infection, abdominal wall
rigidity (localized or
diffuse), mass or ileus; evidence of systemic inflammatory response (except if
patient is
neutropenic), i.e. at least one of the following: fever*, elevated white blood
cell count,
hypotension, tacliycardia, tachypnea, hypoxia or altered mental status; and
culture of
infra-abdominal fluid or abdominal soft tissue positive for the causative
pathogen.
*Fever is defined herein as rectal temperature > 3S°C or oral
temperature > 37.5°C on
two or more occasions during a 12-hour period.
Patients with skin and skin-structure infections generally have the following
criteria:.
seropurulent drainage or at least three of the following: tenderness to
palpation, erythema,
induration, fluctuance; and/or properly collected culture of drainage or
material biopsied or
aspirated from the site of infection positive for the causative pathogen.
Patients with urinary tract infections (IJTI) generally fit into one of the
following four
UTI groups: (1) Acute Uncomplicated LM, wherein patients meet four of the
following criteria:
at least two of the following symptoms: dysuria, urgency, frequency,
suprapubic pain; no urinary
symptoms in the four weeks prior to this episode; pyuria: which is dipstick
positive for leukocyte
esterase or WBC in microscopic examination > 10 leukocytes/nima (unspun urine)
unless
neutropenic; and midstream urine culture growing at least 103 cfu/mL of the
causative pathogen
of unspun urine; (2) Acute Uncomplicated Pyelonephritis, wherein patients
generally meet
some of the following criteria: fever, chills, flank pain, other diagnosis
excluded, no history or
clinical evidence of urological abnormalities; pyuria which is dipstick
positive for leukocyte
esterase or WBC in microscopic examination > 10 leukocytes/mm~ (unspun urine)
unless
neutropenic; and/or midstream urine culture growing at least 104 cfu/mL of the
causative
pathogen of unspun urine; (3) Complicated UTI and (4) UTI in men, wherein
patients with
complicated UTI may have four of the following criteria or UTI in men may have
at least one of
the following factors associated with complicated UTI including: presence of
an indwelling or
intermittent urinary catheter > 100 mL of residual urine retained after
voiding, obstructive
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uropathy due to bladder outlet obstruction, a calculus or, other causes,
vesico-ureteral reflux or
other urologic abnormalities including, surgically created ileal loops,
azotemia due to intrinsic
renal disease, renal transplantation. Further UTI patients may also have some
of the following
symptoms: dysuria, urgency, frequency, suprapubic pain, fever, chills, flank
pain. The patients
may also have pyuria which is dipstick positive for leukocyte esterase or WBC
in microscopic
examination > 10 leukocytes/mm3 (unspun urine) unless neutropenic. The
midstream urine
culture growing at least 105 cfu/ml of the causative pathogen in unspun urine
for a Complicated
LM patient or 104 cfu/ml of the causative pathogen for a patient in the LM in
Men category or
for catheter associated LM, a specimen taken directly from the catheter
growing at least 10z
cfu/ml of the causative pathogen.
Patients with Asymptornatic l3acteriuria generally meet three of the following
criteria: no
symptoms of UTI infection; pyuria which is dipstick positive for leukocyte
esterase or VrBC in
microscopic examination > 10 leukocytes/mm3 (unspun urine) unless neutropenic
and two
consecutive midstream urine cultures growing at least 105 cfu/ml of the
causative pathogen of
unspun urine > 24 hours apart.
Patients with Catheter-Related Bacteremia generally meet the following four
criteria:
presence of a percutaneous inserted or tunneled central venous or arterial
catheter; at least one of
the following three criteria of no other apparent origin than. a catheter
infection: fever or
hypothermia (<35.6°C) observed on two or more occasions over a 12-hour
period, chills,
leukocytosis with > 101° PMN/L (10,000 PMN/mm3), unless neutropenic;
one or more blood
cultures positive for the causative pathogen with no-apparent source other
than the catheter; and
if catheter is removed prior to treatment, semi-quantitative catheter culture
positive (> 15 cfu,
'Maki technique") with isolation of an identical causative pathogen from the
catheter and from
the bloodstream.
Patients with Endocarditis generally have the following criteria for either
definite,
probable or possible endocarditis ("Von Reyn" criteria modified by E.A.
Blumberg et al, 1992).
Patients with definite endocarditis have culture of a valvular vegetation, of
a vegetation that has
embolized, or of an intracardiac abscess positive for the causative pathogen.
Patients with
probable endocarditis have either, persistently positive blood counts, and one
of the following: a
new murmur due to vascular insufficiency, or predisposing heart disease and
vascular
phenomena; or they may have all of the following: intermittently positive
blood cultures (i.e. not
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meeting definition for persistently positive); fever; new regurgitant murmur
or
echocardiographic evidence of endocarditis; and vascular phenomena.
Patients with possible endocarditis can have either, persistently positive
blood cultures,
and one of the following: predisposing heart disease, or vascular phenomena or
all of the
following: intermittently positive blood cultures (i.e. not meeting definition
for persistently
positive); fever, predisposing heart disease, vascular phenomena.
5. Definition of terms
Blood cultures: at least 2 cultures of samples of > 0 mL of blood each, drawn
from two
different access sites following application of antiseptic solution, with at
least 5 minutes
(preferably 15-30 minutes) intervals between drawings.
Persistently positive blood cultures: all of 2, all of 3, or more than 66% of
> 3 cultures
of separate blood cultures positive for the causative pathogen.
T~asczzlar plzenofnena: petechiae, conjunctival hemorrhages, Roth's spots,
Osler's nodes,
Janeway lesions, aseptic meningitis, glomerulonephritis, pulmonary, coronary
or peripheral
emboli.
Predisposing heart disease: definite valvular or congenital heart disease or a
cardiac
prosthesis excluding permanent pacemakers.
Patients with Bone and Joint infections include those with the following types
of bone
and joint infections: (1) Osteomyelitis. These patients generally meet one of
the following two
criteria: positive bone biopsy culture for the causative pathogen, or
radiological evidence of
osteomyelitis plus positive blood cultures for the causative pathogen. The
following may
conditions also be present: focal pain, swelling, erythema, induration,
draining sinus fever,
chills, increased WBC (>10,000/mm3 or > 15% bands). (2) Septic arthritis.
These patient
generally have: painful / tender joint or loss of joint function; Fever;
and/or positive synovial
fluid culture for the causative pathogen from the infected joint. (3)
Prosthetic joint infections.
These patients generally have fever; pain, dysfunction or weakening of the
joint; and/or positive
culture of needle aspirate from the joint space or intraoperative culture for
the causative
pathogen. (4) Mediastinitis. These patients generally have: pathogens isolated
from blood
culture and/or culture of mediastinal tissue or fluid obtained during surgery
or needle aspiration;
fever; chest pain or sternal instability or mediastinal widening on x-ray
examination.
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Patients with bacteremia of unknown source can be those where bacteremia
includes as at
least one positive blood culture for the causative pathogen, bacteremia of an
unknown source is
defined as bacteremia without an identifiable primary source of infection at
the time of study
entry.
Patients with respiratory infections that are treated with Synercid include
the following
types of conditions: (1) Pneumonia. These patients normally have infiltrate on
chest x-ray; at
least one of the following: new or worsening cough, sputum changes, fever,
auscultatory
findings such as rales or evidence of consolidation, leukocytosis; (WBC>
10,000/mm3 or > 15%
bands); and/or positive sputum culture for the causative pathogen or one
positive blood culture
for the causative pathogen in the absence of another source of bacteremia. (2)
Pleurisy. These
patients can have positive pleural fluid culture for the causative pathogen
and/or radiological
evidence of purulent collection in the pleural cavity.
Patients who do not qualify for any of the above categories default into the
other
infections category. These types of infections include but are not limited to
intravascular, deep
wound other than abdominal or CNS infections.
Uses of Other Drugs with Synercid: Some selected drugs that are predicted to
have
plasma concentrations increased by Synercid are:
Antihistamines: astemizole, terfenadine
Anti-HIV (NNRTIs and Protease inhibitors): delavirdine, nevirapine, indinavir,
ritonavir
Antineoplastic agents: vinca alkaloids (e.g., vinblastine), docetaxel,
paclitaxel
Benzodiazepines: midazolam, diazepam
Calcium channel blockers: dihydropyridines (e.g., nifedipine), verapamil,
diltiazem
Cholesterol-lowering agents: HMG-CoA reductase inhibitors (e.g., lovastatin)
GI motility agents: cisapride
Immunosuppressive agents: cyclosporine, tacrolimus
Steroids: methylprednisolone
Other: carbamazepine, quinidine, lidocaine, disopyramide
Arthralgias/Myalgias: Episodes of arthralgia and myalgia, some of which tend
to be
severe, are the major side effects seen in patients treated with Synercid. In
several of these
patients, treatment discontinuation resolves these symptoms. The etiology of
the myalgias and
arthralgias are not very well understood.
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Dosage and Administration: Synercid is generally administered by intravenous
infusion in 5% Dextrose in Water solution over a 60-minute period. The
recommended dosage
for the treatment of infections is described in Table 2. An infusion pump or
device may be used
to control the rate of infusion. If necessary, central venous access (e.g.,
PICC) can be used to
administer Synercid to decrease the incidence of venous irritation.
TABLE 2
Infection Dose
Vancomycin-Resistant 7.5 mg/kg q8h
EnterococcuS faecium
Complicated Skin and 7.5 mg/kg ql2h
Skin
Structure Infection
The minimum recommended treatment duration for Complicated Skin and Skin
Structure
Infections is seven days. For Vancomycin-Resistant En.te~ococcus faecium
infection, the
treatment duration varies and is determined based on the site and severity of
the infection.
6. Liver Function Tests
Liver Function tests (LFTs) are among the most commonly used investigations in
clinical
medicine. The standard LFTs include an analysis of serum aminotransferase,
alkaline
phosphatase and bilirubin. These tests reflect activities of liver enzymes in
liver injury. In
context of this invention, liver function test results are used to determine
the dose an antibiotic
that is predominantly excreted through the biliary tract administered to a
patient in need thereof.
This adjustment of dosage reduces and/or alleviates side effects caused by the
antibiotics. One
example of such an antibiotic is Synercid.
Transaminases, or aminotransferases, catalyze the transfer of an amino group
from an
amino acid to ketoacid thereby forming a new amino acid. They are present in
highest
concentrations in cells from the liver, heart, skeletal muscle and
erythrocytes. In hepatocytes,
alanine transaminase (ALT) is present in higher concentrations than aspartate
transaminase
(AST) and therefore with liver injury, ALT exceeds AST (alcoholic liver
disease is a notable
exception). These enzymes become elevated as hepatocytes become necrotic or
partially
damaged; however, the magnitude of elevation correlates poorly with disease
severity. For
example, patients with mild viral hepatitis may have transaminase levels
measured in the
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thousands for several weeks, yet there may be insufficient cellular injury to
cause jaundice or
prolongation of the prothrombin time. Alternatively, patients with severe
alcoholic hepatitis or
autoimmune chronic active hepatitis rarely have transaminase values in excess
of 500 despite the
presence of life-threatening disease.
Patients whose LFTs show a predominant rise in the transaminases have liver
diseases
which are characterized by hepatocellular damage. Examples include viral
hepatitis, drug or
toxin induced injury, or hepatic ischemia. Transaminases are useful as a
screening test for the
presence of many liver diseases, however notable exceptions are methotrexate
induced damage,
and alcoholic liver disease which may progress with little change in the LFTs.
The AST or ALT
are also useful to follow the activity of certain diseases to help judge the
need for therapy or the
response to therapy (e.g. steroids for autoimmune chronic active hepatitis or
interferon for
chronic HCV). The transaminases are not useful indicators of prognosis since
viable cells may
leak transaminases and because it is the extent of hepatic regeneration that
more accurately
reflects outcome.
Alkaline phosphatase represents a group of membrane associated enzymes which
become
elevated in response to increased intracellular concentrations of bile acids.
This is secondary to
increased pressures within the biliary ductal system as a result of either
cholestasis or
obstruction. Since alkaline phosphatase is present in other cells outside the
liver, a hepatic origin
can be confirmed by demonstrating an associated increase in the 5'
nucleotidase or gamma-
glutamyl transpeptidase (GGT). An elevation of the alkaline phosphatase is a
sensitive indicator
of intrahepatic cholestasis/obstruction or extrahepatic obstruction, whereas
bilirubin will become
elevated only when the process is advanced. Conditions commonly associated
with a
predominant elevation of the alkaline phosphatase include: extrahepatic
obstruction, infiltrative
liver diseases such as amyloidosis or neoplasia, granulomatous hepatitis
(especially TB and
sarcoid), certain drug reactions, and other chronic cholestatic conditions
such as primary biliary
cirrhosis and primary sclerosing cholangitis.
Bilirubin is a breakdown product of heme which is released as senescent
erythrocytes are
hemolyzed by the reticuloendothelial system. After uptake by the liver,
bilirubin is conjugated
with UDPG which enhances its water solubility and enables biliary excretion.
The capacity of
the liver to take up, conjugate and excrete bilirubin is large and a
considerable increase in
bilirubin load is required before this hepatic reserve is exceeded. Similarly,
extensive
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parenchymal injury, widespread canalicular dysfunction or almost complete
obstruction must be
present before the serum bilirubin rises.
From the above discussion, it is clear that bilirubin is a true liver function
test, but is
insensitive in that it becomes increased only with advanced hepatocellular
disease or high grade
obstruction. Other true liver function tests include the serum albumin and the
prothrombin time.
They serve as a measure of the liver's synthetic function and are particularly
useful in
determining the extent of damage in acute or chronic hepatocellular injury.
In relation to the present invention the inventors have demonstrated that
recognition of
the pattern of abnormal liver function tests permits the diagnosis of the
hepatic capability of the
individuals liver to handle Synercid or any antibiotic that is secreted at 60%
or more through the
biliany tract. Thus, an accurate dosage scheme for the administration of an
antibiotic that is
primarily excreted by the biliary tract can be formulated based on the liver
function test. The
inventors contemplate that adjustment of the dosage of Synercid to the
individuals will help
reduce or alleviate side effects such as arthralgias and myalgias.
From the art, as practiced so far, no dosage adjustment of Synercid is
performed for
different patient types. For example, the same dosage of Synercid is
prescribed currently for in
patients, with renal impairment and/or patients undergoing peritoneal
dialysis; in patients with
hepatic insufficiencies; in patients that are older; in pediatric patients;
and/or on basis of patient
gender. The present inventors have shown that Synercid is mainly metabolized
and cleared by
the liver. Performing a liver function test on patients that are undergoing
therapy with Synercid
reveals hepatic insufficiencies such as biliary dysfunction. Based on the
results of these liver
function tests, especially biliany function tests such as alkaline phosphatase
or gamma glutamyl
transpeptidase (gamma GT), the methods of the present invention may be used to
adjust the
dosage of Synercid and to decrease or alleviate the serious side effects such
as arthralgias and
myalgias associated with its used that often lead to discontinuation of the
Synercid therapy.
Listed below in Table 3 is a list of dosages of Synercid depending on the
severity of the biliary
tract dysfunction as determined by the present invention. However, one of
skill in the art will
recognize that while Table 3 is a general indicator of the dosage range and
adjustment a
determination of the exact dose of Synercid or any other antibiotic that is
predominantly excreted
by the biliary tract, will be made by a trained physician at the time of drug
administration to an
individual taking into consideration factors such as disease, age, gender and
other similar
criteria.
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TABLE 3
Biliary Dysfunction Adjusted Dose of Synercid
1. Normal biliary function 7.Smg/kg Q8h
(alkaline
phosphatase or gamma GT within
1.5X
normal limit)
2. Mild biliary function 7.Smg/kg Ql2h OR Smg/kg Q8h
(alkaline
phosphatase or gamma GT within(maintaining a daily dose
1.5- of l5mg/kg)
3X normal levels)
3. Moderate biliary functionSmg/kg IV Ql2h
(alkaline
phosphatase or gamma GT within
3-SX
normal levels)
4. Severe biliary function Smg/kg IV; Q24h or use alternate
(alkaline
phosphatase or gamma GT withintherapy with other drugs,
>5X for example,
normal levels) Linezolid
7. Examples
The following examples are included to demonstrate preferred embodiments of
the
invention. It should be appreciated by those of skill in the art that the
techniques disclosed in the
examples which follow represent techniques discovered by the inventor to
function well in the
practice of the invention, and thus can be considered to constitute preferred
modes for its
practice. However, those of skill in the art should, in light of the present
disclosure, appreciate
that many changes can be made in the specific embodiments which are disclosed
and still obtain
a like or similar result without departing from the spirit and scope of the
invention.
EXAMPLE 1
1. Patients and Methods
Patients: Between February 1994 and November 1998, 56 cancer patients with
proven
VRE infections were entered on the study. Patients known to have
hypersensitivity to
streptogramin antibiotics were excluded. All subjects gave written informed
consent to
participate in the study which was approved by the Institutional Review Board
of MD Anderson
Cancer Center. To be eligible for the study, the patient had to have VRE
isolated from at least
one culture specimen from the site of infection. Infections were defined
according to the criteria
of the Centers for Disease Control and Prevention (Garner et al., 1988).
Catheter-related
bacteremia was defined as the isolation of >_ 15 colony-forming units of VRE
from the
intravasculax catheter segment and also isolated from a blood culture
collected from a peripheral
vein, without any other obvious site of infection (Raad and Bodey, 1992).
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The patients' history and physical examination were reviewed prior to entry on
the study.
Quinupristin/dalfopristin was administered at a dose of 7.5 mg/kg every 8
hours, and
minocycline at a dose of 100 mg every 12 hours, for a period ranging from 2-52
days (mean, 12
days). Therapy was administered via a central venous catheter in most
patients. Liver function
tests including bilirubin, alkaline phosphatase, alanine aminotransferase, and
albumin were
determine on all patients within one week before therapy, midterm during
therapy, and within
one week after completion of therapy. Patients were followed daily until the
end of therapy and
re-evaluated one month after completion of therapy.
Microbiologic Methods: Enterococci were identified initially from culture
specimens
based on colony morphology and gram stain morphology. They were subcultured
for final
identification on Vitek GPI medium (BioMeriuex Vitek, Hazelwood, MD).
Susceptibility
testing to gentamicin, streptomycin, ampicillin, penicillin, chloramphenicol,
minocycline,
quinupristinldalfopristin, and vancomycin was performed by the I~irby/Bauer
disk diffusion
method and the microdilution method in Mueller-Hinton broth at an inoculum
size of 5 x 105
cfu/mL (National Committee for Clinical Laboratory Standards, 1993). The MIC9o
was
determined after incubation for 24 hours at 35°C using the
interpretations of the National
Committee for Clinical Laboratory Standards (National Committee for Clinical
Laboratory
Standards, 1993). Resistance to vancomycin was defined as a zone size of > 16
mm by the
I~irby-Bauer method and a MIC > 8 ~g/mL by the microdilution method. Central
venous
catheters were cultured upon removal by the roll plate semiquantitative
culture technique (Maki,
et al, . 1977).
Definitions: A clinical response to treatment is defined as resolution of all
signs and
symptoms relating to the original infection. A microbiological response is
defined as the
eradication of VRE from the site of infection at the end of treatment. Relapse
is defined as the
return of signs and symptoms of infection and isolation of VRE from the site
of infection within
one month of follow-up from the end of treatment. Treatment failure is defined
as no resolution
or worsening of signs and symptoms of infection during treatment, coupled with
persistent
positive cultures for VRE. Neutropenia is defined as an absolute neutrophil
count of < 500
cells/mm3.
Statistical Analysis: Either the X2 test of Fisher's Exact Test was used to
determine
differences in categorical data. Statistical significance was defined as P <
0.05.
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2. Results
The majority of patients (71%) had bacteremia (Table 4). Fifty-six patients
with VRE
were included in the study, 90% of whom had hematological malignancies (Table
5).. The mean
age of the patients was 51 years (range, 7-86 years). VREF accounted for 91%
of the infections;
E. faecalis and E. aviuna were each responsible for one infection Three
patients were infected
with a mixed infection caused by both E. faecium and E. faecalis.
TABLE 4
Characteristics of Patients Enrolled in the Study
Age, mean (range) (years)51 (7-86)
Male/female (n) 28/28
Underlying disease:
Leukemia 43 (77%)
Lymphoma/Myeloma 7 ( 13 %)
Solid Tumor 6 (11%)
Type of infection
Bacteremia 40 (71%)
Urinary Tract Infection 8 (14%)
Pneumonia 3 (5%)
Wound Infection 3 (5%)
Other 2 (4%)
Bone marrow transplant* 15 (27%)
(within
a year prior to culture)
Mean APACHE Score (range)16 (6-25)
* Or pure blood stem cell transplant.
TABLE 5
Outcome of Quinupristin/Dalfopristin Plus Minocyline Therapy in Neutropenic
versus
Non-neutropenic Patients
NeutropenicNon-neutropenicTotal P value
n=40 n= 16 n=56
Clinical and 26(65%) 12 (75%) 36 (68%) 0.47
microbiological
response
Relapse (% of 4(10%) 3 (25%) 7 (18%) 0.65
respondents)
* Neutropenic patients were defined as those with <_500 neutrophils/mm' at the
onset of
treatment.
The overall response rate to quinupristin/dalfopristin with minocycline was
68% (38/56
patients). The response rate was similar for the 40 neutropenic patients
(neutropenic at the onset
of treatment) and the 16 patients with adequate neutrophil counts (65% vs 75%,
P = 0.47, Table
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5). The relapse rates were 10% and 19%, respectively (P = 0.65). Thirty-two
(80%) of the
neutropenic patients had bacteremia compared to 8 (50%) of the patients with
adequate
neutrophils (P = 0.025). As expected, the response rate for the 21 patients
with persistent
neutropenia during the treatment course was lower (57%) than the response rate
for the 35
patients who were non-neutropenic or recovered their neutrophil count (74%; P
= 0.18).
Twenty-six (65%) of the 40 patients with bacteremia responded, 7 of the 8 with
urinary
tract infections, 2 of the 3 with pneumonia, and 3 of the 5 patients with
other sites of infection.
Hence, the response rates were similar for bacteremias compared to other sites
of infection (65%
vs 75%, P = 0.417). Four patients had catheter-related bacteremias. Three
neutropenic patients
responded to therapy and catheter removal, whereas one patient who was not
neutropenic failed
to respond. In this latter patient, the catheter was exchanged over a guide
wire, which may
account for the failure.
Most of the organisms causing infection were fully susceptible to
quinupristin/dalfopristin (86%) and/or minocycline (82%) (Table 6). Five
organisms had
intermediate susceptibility to quinupristinldalfopristin and 3 were resistant.
Eight organisms had
only intermediate susceptibility to minocycline and two were resistant.
TABLE 6
MIC Susceptibility Profiles of Quinupristin/Dalfopristin and Minocycline and
Response to
Therapy
Susceptible Intermediate Resistant
Quinupristin/dalfopristin:
MIC9o (pg/mL) _< 1 2 . >_ 4
Number of patients (% of total) 48 (86) 5 (9) 3 (5)
Number of responses (% of patients 32 (67) 4 (80) 2 (67)
in category)
Minocycline:
MIC~o (p.g/mL) < 4 8 >_ 16
Number of patients (% of total) 46 (82) 8 (14) 2 (4)
Number of responses (% of patients 32 (70) 5 (63) 1 (50)
in category)
*Breakpoints are defined by the National Committee for Clinical Laboratory
Standards (8, 34).
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The response rate for the 39 infections caused by organisms susceptible to
both
quinupristin/dalfopristin and minocycline was 60% compared to 63% for the 16
infections
caused by organisms susceptible to only one drug. One patient had infection
caused by an
organism that was intermediately susceptible to both drugs and responded to
therapy. One
patient with E. faecalis bacteremia responded to the combination of
quinupristin/dalfopristin
with minocycline even though the organism was resistant to
quinupristin/dalfopristin but
susceptible to minocycline. The patient with E. aviufyz bacteremia failed to
respond. The E.
aviuna was susceptible to quinupristin/dalfopristin but not to minocycline.
Finally, all 3 patients
with mixed E. faeciufya and E. faecalis bacteremias responded to the
combination therapy.
Myalgia and arthralgia were reported. in 36% of patients (Table 7). Myalgias
and
arthralgias occurred in 40% of leukemic patients but in only 23% of other
patients (P = 0.23).
However, patients with arthralgias/myalgias had significantly higher levels of
alkaline
phosphatase (mean 318.7 IU/1) during midterm therapy cycle as compared to
patients without
any joint or muscular pain (mean 216.3 IU/1, P = 0.05). In addition, 16.6% of
patients with
arthralgias/myalgias had more than fivefold the normal levels of alkaline
phosphatase which did
not occux in any of the other patients who did not develop this adverse event
(P = 0.04). Other
toxicities were abnormalities in liver function tests of four patients (7%),
leukopenia in three
(5%) and phlebitis in one (2%). VRE infection was considered as the primary
cause of death in
4 (7%) patients and was a contributing cause of death in another 13 (23%).
TABLE 7
Incidence of Adverse Events Associated with Quinupristin/Dalfopristin Therapy
Adverse event Number of patients (%)
n=56
Myalgia/arthralgia 20 (36%)
Increased liver function 4 (7%)
tests
Leukopeiua 3 (5%)
Phlebitis 1 (2%)
3. Discussion
Lack of effective therapy for VRE bacteremia: It has been demonstrated that
vancomycin resistance is a significant independent predictor of increased
morbidity and
mortality in enterococcal bacteremia (Vergis et al., 1997; Linden et al.,
1996). The most serious
24
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complications from VRE infections occur in severely irmnunocompromised
patients, particularly
cancer patients who are either neutropenic or have underlying hematologic
malignancies (Linden
et al., 1996; Edmond et al., 1996; Montecalvo et al., 1996). Edmond et al.
(1996), studied the
outcome of VRE bacteremia in a population consisting of mostly (70%) of
patients with
underlying hematologic malignancy. In that subgroup of patients, VRE
bacteremia was
associated with an attributable mortality of 37%, and 81% of the patients
developed
hypoperfusion abnormalities and/or organ dysfunction. Montecalvo et al.
(1996), determined
that neutropenia is a risk factor for the persistence of VRE bacteremia in
immunocompromised
patients. Similarly, Linden et al. (1996) found that VRE bacteremia in
immunocompromised
liver transplant patients is associated with a persistence of the infection,
more frequent recurrent
bacteremia and the need for multiple invasive interventions. In that same
study, Linden et al.
(1996) attributed the serious morbidity and attributable death in patients
with VREF bacteremia
to be partially mediated by the lack of effective antimicrobial therapy.
15. Among the conventional antimicrobial agents there are no effective
regimens available
for the treatment of VRE infections. Various regimens have been tried, such as
oral novobiocin
plus intravenous ciprofloxacin (Linden et al., 1996), doxycycline
(Papanicolaou et al., 1996),
continuous high dose ampicillin or ampicillin-sulbactam (Mekonen et al.,
1995), or
chloramphenicol (Lautenbach et al., 1998). The results of these studies have
been inconclusive
in terms of efficacy. In a study involving 100 patients with VRE bacteremia,
there was no
significant difference in mortality between treated and untreated patients
(Lautenbach et al.,
1998). The treatment in that study included the use of ampicillin, imipenem,
ciprofloxacin,
doxycycline, and chloramphenicol. Chloramphenicol has been proposed as an
alternative agent
(Morris et al., 1995); however, more recently it was shown to have no
significant impact on
mortality, even in uncomplicated cases with catheter-related VRE bacteremia
(Lautenbach et al.,
1998).
Efficacy of quinupristin/dalfopristin: Quinupristin/dalfopristin is a novel
streptogramin antibiotic composed of two-semi-synthetic pristinamycin
components
(quinupristin/dalfopristin). The two components act synergistically to inhibit
protein synthesis
for most gram-positive pathogens, including vancomycin-resistant E. faecimra
(VREF)
(Rubinstein and Bompart, 1997). Although highly active ifa vitro, clinical
studies have shown
that quinupristin/dalfopristin when used alone is associated with limited
efficacy in
immunocompromised patients. Dever et al. (1996), have studied
quinupristindalfopristin in the
treatment of VREF infections in 15 patients, most of whom were
immunocompromised; 80% of
CA 02434046 2003-07-08
WO 02/055731 PCT/US02/00775
the patients had liver transplant, AIDS, or underlying malignancy. Clinical
cure was reported in
38% of the eight evaluable patients. More recently, Wood et al. (1998a),
treated 70 patients with
VRE infections using quinupristin/dalfopristin. Among the evaluable patients
(n = 65), 38%
were neutropenic and 35% had leulcemia. The overall response rate was 49%.
Wood et al.
(1998b), also reported a 14% rate of emergence of resistance to
quinupristin/dalfopristin.
Emergence of resistance was associated with clinical and bacteriologic
failure.
A clinical and microbiologic cure, at a frequency of 65% in neutropenic
patients, was
observed in the present invention, including those with associated VRE
bloodstream infections.
Neutropenic febrile patients with a documented bacteremia are usually
associated with a lower
response rate to active antimicrobial combination therapy than neutropenic
febrile patients
without bloodstream infections. For example, in a recent analysis of
prospective randomized
studies of antimicrobial treatment of neutropenic febrile patients the present
inventors observed
an overall response rate of 76% to the combination of imipenem plus amikacin,
whereas those
patients with associated bacteremia had a response rate of 59% to the same
regimens (Raad et
al., 1998). A response rate for VRE bacteremia of 65% to the combination of
minocycline and
quinupristin/dalfopristin in a patient population consisting mostly of
leukemia and bone marrow
transplant patients therefore seems favorable, especially when compared to a
response rate of
less than 50% to quinupristin/dalfopristin previously reported by Dever et al.
(1996) and Wood
et al. (1998a). In addition, there was no evidence of emergence of resistance
to either
quinupristin/dalfopristin or minocycline among those patients with recurrence
of the VRE
infection.
Rationale for combination therapy: The improved outcome resulting .from the
use of
the combination of quinupristinldalfopristin and minocycline compared to
quinupristin/dalfopristin without minocycline could be related to several
factors, for example,
Moreno et al. (1994), suggests that tetracyclines could play a role in the
treatment of VREF
infections. Minocycline is a tetracycline with superior activity against
resistant gram-positive
organisms when compared to other tetracyclines because it is less prone to the
efflux by these
resistant organisms (Minuth et al., 1974; Robertson et al., 1972). Most of the
vancomycin
resistant enterococcal organisms at the MD Anderson Cancer Center (82%) were
found to be
susceptible to minocycline. The ira vitro combination of minocycline and
quinupristinldalfopristin was found to be either additive or synergistic
against VREF organisms,
without any evidence of antagonism. Howe et al. (1997), reported that the
addition of
tetracycline to quinupristin/dalfopristin improved the outcome in a leukemia
patient with
26
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neutropenia during bone marrow transplant in the immediate post-
transplantation period.
Recently, a report by Aeschlimann et al. (1998), showed that the addition of
doxycycline to
quinupristin/dalfopristin prevented the emergence of resistance to
quinupristin/dalfopristin.
Thus, explaining the lack of emergence of resistance to
quinupristin/dalfopristin in the present
study. Almost all VRE infections (91 %) in the present study were caused by
vancomycin-
resistant E. faeciuna which, unlike E. faecalis, are highly susceptible to
quinupristin/dalfopristin
(Williams et al., 1997). However, the addition of minocycline most likely
improved the
outcome in those patients with VRE infections resistant to
quinupristin/dalfopristin. In the
present study, 67% of the patients with quinupristin/dalfopristin-resistant E.
faeciunz and all of
the patients with quinupristin/dalfopristin-resistant E. faecalis responded to
the combination
therapy, probably due to the fact that all of the quinupristin/dalfopristin-
resistant VRE organisms
were susceptible to minocycline. The inventors contemplate evaluation of
quinupristin/dalfopristin with and without minocycline in immunocompromised
cancer patients
and comparing its efficacy and safety with other promising agents such as the
oxazolidinones
(Jones et al., 1996).
Role of the catheter: With respect to patients with catheter-related
bloodstream
infections, the data shows that the catheter needs to be removed in such
patients, as it may act as
a source of -reinfection. This observation is consistent with the study of Lai
(1996), who
determined that VRE catheter-related bacteremia should be treated by catheter
removal .
Because the majority of VRE bacteremias (90%) in the present study were non-
catheter-related,
the inventors contemplate determining whether the bacteremia is catheter-
related prior to
removal of the catheter. Simultaneous blood cultures drawn through the
catheter and peripheral
vein would be useful in determining whether the catheter is the source of the
infection prior to
catheter removal. A recent study shows that a catheter infection is suggested
if the blood culture
drawn through the central line becomes positive at least 2 hours before a
blood culture drawn
simultaneously through the peripheral vein (Blot et al., 1999).
Occurrence of adverse events: Myalgias and arthralgias were the leading
adverse
events associated with the use of quinupristin/dalfopristin and minocycline in
the present study,
occurring at a frequency of 36%. In a large prospective study by Moellering et
al. (1999),
quinupristin/dalfopristin was used to treat VREF infections in 396 patients.
Myalgias and
arthralgias were the leading adverse events, occurnng at a rate of 6.6 % and
9.1%, respectively.
However, the population studied by Moellering et al. (1999) was mostly non-
oncologic, with
only 19% of the patients having an underlying malignancy. In a study by
Mandler et al.,
27
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involving 65 patients treated with quinupristin/dalfopristin,
arthralgialmyalgia occurred at rate of
26% and was found to be significantly associated with leukemia as a risk
factor
In the present study, myalgia/arthralgia was associated with high levels of
alkaline
phosphatase. Since quinupristin/dalfopristin is primarily eliminated through
the bile into the
feces (Bergeron and Montay, 1997), biliary tract dysfunction as manifested by
high alkaline
phosphatase may lead to accumulation of this drug and its metabolites
resulting in arthralgias
and myalgias. Cancer patients, particularly leukemia patients, tend to have
metastatic and
infiltrative liver disease with intrahepatic cholestasis resulting in higher
frequency of arthralgias
and myalgias. This might explain why arthralgias and myalgias improve with the
reduction of
the quinupristin/dalfopristin dose to a frequency of every 12 hours. In
addition, when
quinupristin/dalfopristin was administered at a dose of 7.5 mg/kg every 12
hours to 450 patients
none developed arthralgias and myalgias (Nichols et al., 1999) Therefore,
given the association
between quinupristin/dalfopristin and arthralgia/myalgia in cancer patients
with biliary
dysfunction and the discomfort produced by it, it would be desirable adjust
the dose in
accordance with the degree of biliary dysfunction in order to prevent the
occurrence of such
adverse effects. Quinupristinldalfopristin is also associated with a high
frequency of phlebitis if
administered through a small peripheral vein. However, as the present
invention used the central
venous catheters for drug delivery, only one patient, who received the drug
through a small
peripheral catheter, developed phlebitis.
4. Conclusion
Quinupristin/dalfopristin, 7.5 mg/kg every hours administered intravenously in
combination with minacycline, 100 mg every 12 hours, was found to be
efficacious in the
treatment of VRE infections in cancer patients. The efficacy was maintained in
neutropenic
patients with VREF bloodstream infections. Arthralgia/myalgia was reported in
more than one-
third of the patients, occurring mostly in patients with biliary dysfunction,
but resolved upon
completion of therapy.
EXAMPLE 2
Treatment with Synercid: Improvement of Safety in Comparison with Zyvox in a
Prospective, Randomized Trial
Resistant gram positive infections, including vancomycin-resistant enterococci
(VREF),
have become the leading cause of infections in cancer patients. Synercid
(quinupristin/dalfopristin) is a novel antibiotic which is active and
efficacious in the treatment of
28
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WO 02/055731 PCT/US02/00775
these resistant gram positive infections, particularly VREF. However, the use
of this drug is
limited by a frequent adverse event which is arthralgias/myalgias. In a study
of cancer patients
at MDACC, 36% of the patients developed arthralgias/myalgias, often
necessitating analgesic
treatment.
The present inventors contemplate a prospective, randomized trial with the
following
objectives:
1. To establish the relationship between arthralgias/myalgias and biliary
dysfunction
through the determination of a more specific blood test for biliary function,
which is the gamma
GT;
2. To alleviate the adverse events by adjusting the dose of Synercid in
accordance to the
biliary function test.
3. To compare the adverse events and efficacy of Synercid to another agent
active
against VRE, Zyvox, which does not cause arthralgias/myalgias. The patients
who receive
Zyvox would serve as the control group.
Methods: Patients with VRE infections will be randomized to either Synercid or
Zyvox.
Biliary Function tests, including gamma GT, will be obtained at the initiation
of antibiotic
therapy, midcourse, and at the end of therapy. Those patients who develop
arthralgias/myalgias
will have their dose adjusted in accordance with their biliary function status
and gamma GT
levels. Synercid serum levels will be obtained on all patients who receive
this agent and will be
repeated after adjusting the dose. Patients receiving Zyvox will serve as
controls.
Statistics: Reports of Synercid study conducted at MDACC show that adverse
events of
myalgias and arthralgias occur due to the use of Synercid at a rate of about
36%. Results from
early Zyvox clinical trials indicate that adverse events associated with the
drug are much lower
than those reported with Synercid (8% definitely related). A sample size of 33
in each arm is
needed to be able to detect a difference of 36% for Synercid vs. 8% for Zyvox
with 80% power
and 95% confidence.
If arthralgias/myalgias are shown to resolve with dose adjustment based on
biliary
function tests, this will have a wide impact on the use of this antibiotic in
cancer patients and all
hospitalized patients with VRE infection.
29
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********************=x********************
All of the compositions and methods disclosed and claimed herein can be made
and
executed without undue experimentation in light of the present disclosure.
While the
compositions and methods of this invention have been described in terms of
preferred
embodiments, it will be apparent to those of skill in the art that variations
may be applied to the
compositions and methods and in the steps or in the sequence of steps of the
method described
herein without departing from the concept, spirit and scope of the invention.
More specifically,
it will be apparent that certain agents which are both chemically and
physiologically related may
be substituted for the agents described herein while the same or similar
results would be
achieved. All such similar substitutes and modifications apparent to those
skilled in the art are
deemed to be within the spirit, scope and concept of the invention as defined
by the appended
claims. . .
CA 02434046 2003-07-08
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REFERENCES
The following references, to the extent that they provide exemplary procedural
or other
details supplementary to those set forth herein, are specifically incorporated
herein by reference.
Aeschlimann, J.R., M. J. Zervos, M. J. Rybak. 1998. Treatment of vancomycin-
resistant
Enterocaccus faecium with RP 59500 (quinupristin-dalfopristin) administered by
intermittent or continuous infusion, alone or in combination with doxycycline,
in an in
vitro pharmocodynamic infection model with simulated endocardial vegetations.
0 Antimicrob. Agents Chemother. 47:2710-2717.
American Thoracic Society. Official Statement. Hospital-acquired pneumonia in
adults:
diagnosis, assessment of severity, initial antimicrobial therapy and
preventative
strategies. A consensus statement. Respir. Crit. Care Med., 153:1711-1725,
1996.
Aumercier, M., S. Bouhallab, and M. L. Capmau. 1992. P59500: A proposed
mechanism for its
5 bactericidal activity. J. Antimicrob. Chemother. 30:9-14.
Baquero, F. 1997. Gram-positive resistance: challenge for the development of
new antibiotics. J.
Antimicrob. Chemother. 39:1-6, (suppl A).
Bergeron, M., G. Montay. 1997. The pharmacokinetics of
quinupristin/dalfopristin in laboratory
animals and in humans. J. Antimicrob. Chemoter. 39: 129-138.
0 Blot, F., G. Nitenberg, E. Chachaty, B. Raynard, N. Germann, S. Antoun, A.
Laplanche, C.
Brun-Buisson, C. Tancrede C. 1999. Diagnosis of catheter-related bacteremia: a
prospective comparison of the time to positivity of hub-blood versus
peripheral-blood
cultures. Lancet 354: 1072-1977.
Blumberg, E.A. et al, Clin. Infect. Dis. 1992; 15:983-90.
5 Centers for Disease Control and Prevention. Morbidity and Mortality Weekly
Report CDC
Surveillance, 46:891, 1993.
Cerwinka S., Bornpart F., Kreter B. and Savarese J. . Abstract. IBC Bacterial
Multidrug
Resistance
Civetta Jm, Taylor Rw, Kirby Rr. Critical Care, 3rd ed. Philadelphia, Pa:
Lippincott-Raven;
0 1997:2259.
Curbelo, D. E., B. S. Doll, I. Wilets, et al. 1997. Treatment and outcome in
100 patients with
vancomycin-resistant enterococcal (VRE) bacteremia. Abstr. J-7. Izz Program
and
abstracts of the 37th Interscience Conference on Antimicrobial Agents and
Chemotherapy, Washington, DC.
31
CA 02434046 2003-07-08
WO 02/055731 PCT/US02/00775
Delden and Iglewski, Cell-to-cell signaling and Pseudonaonas aeruginosa
infections, Emerging
Infectious Diseases, 4:551-560, 1998.
Dever, L. L., S. M. Smith, D. Dejesus, et al. 1996. Treatment of vancomycin-
resistant
Enterococcus faeciuna infections with an investigational streptogramin
antibiotic
(quinupristin/dalfopristin): A report of fifteen cases. Microb. Drug Resist.
2:407-413
Edmond, M.B., J. F. Ober, J. D. Dawson, et al. 1996. Vancomycin-resistant
enterococcal
bacteremia: Natural history and attributable mortality. Clin. Infect. Dis.
23:1234-1239
Garner, J. S., W. R. Jarvis, G. T. Emori, et al. 1988. CDC Definitions for
nosocomial infections.
Am. J. Infect. Control 16: 128-140.
0 Gonzalez, Venzon, Lee, Mueller, Pizzo, Walsh, Risk factors for fungemia in
children infected
with h~.unan immunodeficiency virus: a case control study, Clin. Infect. Dis.,
23:515-521,
1996.
Griswold, M.W., B. M. Lamestro, L. L. Briceland. 1996. Quinupristin-
dalfopristin (RP 59500):
An injectable streptogramin combination. Am. J. Health Syst. Pharm. 53:2045-
53.
5 Heir, Sundheim, Holck, Resistance to quaternary ammonium compounds in
Staphylococcus spp.
Isolated from the food industry and nucleotide sequence fo the resistance
plasmid
pST827, .T. Appl. Bacteriol., 79:149-156, 1995.
Howe, R. A., M. Robson, A. Oakhill, et al. 1997. Successful use of
tetracycline as therapy of an
immunocompromised patient with septicaemia caused by a vancomycin-resistant
~.0 enterococcus. J. Antimicrob. Chemother. 40:144-145.
Jones, R, N, D. Johnson, M. E. Erwin. 1996. In vitro antimicrobial activities
and spectra of
U100592 and U100766, two novel fluorinated oxazolidinones. Antimicrob. Agents
Chemother. 40:720-726
Klempner, Lorber, Bartlett, Hospital infections and health-care epidemiology,
In: INFECTIOUS
!,5 DISEASES: MEDICAL KNOWLEDGE SELF-ASSESSMENT PROGRAM, 2ND EDITION, American
College of Physicians, Philadelphia, PA, pp. 210, 1998.
Koll, B.S., and A. E. Brown. 1993. Then changing epidemiology of infections at
cancer
hospitals. Clin. Infect. Dis. 17: 5322, (suppl 2).
Lai, K. K. 1996. Treatment of vancomycin-resistant Enterococcus faeciurn
infections. Arch.
0 Intern. Med. 156: 2579-2584.
Lautenbach, E., M. G. Schuster, W. B. Bilker, et al. 1998. The role of
chloramphenicol in the
treatment of bloodstream infection due to vancomycin-resistant enterococcus.
Clin.
Infect. Dis. 27:1259-65
Lecciones, Lee, Navarro, Vascular catheter-associated fungemia in patients
with cancer:
5 analysis of 155 episodes, Clin. Infect. Dis. 14:875-883, 1992.
32
CA 02434046 2003-07-08
WO 02/055731 PCT/US02/00775
Leu, Kaiser, Mori, Hospital-acquired pneumonia: attributable mortality and
morbidity, Ana. J.
Epidemiol., 129:1258-1267, 1989.
Linden, P, K, A. W. Pasculle, R. Manez, et al. 1996. Differences in outcomes
for patients with
bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-
susceptible E. faeciuna. Clin. Infect. Dis. 22:663-670.
Maki, D. G., C. E. Weise, and H. W. Sarafin. 1977. A semi quantitative culture
method for
identifying intravenous catheter infection. N. Engl. J. Med. 296:1305-1309.
Mandler, H. D., E. A. Blumberg, A. E. Fuchs, et al. Arthralgias and myalgias
associated with
quinupristin/dalfopristin (Synercid) treatment of infections caused by
vancomycin
0 resistant Eraterococcus faecium (VREF). abstr. 608 Fr. IrZ Program and
abstracts of the
36th annual meeting of the Infectious Diseases Society of America, Denver, Co.
Mekonen, E. T., G. A. Noskin, D. M. Hacekm et al. 1995. Successful treatment
of persistent
bacteremia due to vancomycin-resistant, ampicillin-resistant Enterococcus
faecium.
Microbiol. Drug Resistance 1:249-253.
5 Minuth, J. N., T. M. Holmes, D. M. Musher. 1974. Activity of tetracycline,
doxycycline, and
minocycline against methicillin-susceptible and resistant staphylococci.
Antimicrob.
Agents Chemother. 6:411-414.
Moellering, R. C., P. K. Linden, J. Reinhardt, et al. 1999. The efficacy and
safety of
quinupristin/dalfopristin for the treatment of infections caused by vancomycin-
resistant
0 Ente~ococcus faecium. J. Antimicrob. Chemother. 44:251-261.
Montecalvo, M. A., D. K. Shay, P. Patel, et al. 1996. Bloodstream infections
with vancomycin-
resistant enterococci. Arch. Intern. Med. 156:1458-1462.
Moreno, F., J. H. Jorgensen , M. H. Weiner. 1994. An old antibiotic for a new
multiple-resistant
Eyaterococcus faecium? Diagn. Microbiol. Infect. Dis. 20:41=43.
5 National Committee for Clinical Laboratory Standards. 1993. Methods for
dilution antimicrobial
susceptibility tests for bacteria that grow aerobically. 3rd ed. Approved
standard M7-43.
National Committee for Clinical Laboratory Standards, Villanova, Pa.
National Committee for Clinical Laboratory Standards. 1998. Subcommittee on
Antimicrobial
Susceptibility Testing. Minutes of June 1998 meeting. National Clinical
Laboratory
0 Standards, Reston, Va.
Nichols, R. L., D. R. Graham, S. L. Barnere, A. Rodgers, S. E. Wilson, M.
Zervos, D. L. Dunn,
B. Kreter for the Synercid Skin and Structure Infection Group. 1999. Treatment
of
hospitalized patients with complicated Gram-positive skin and skin structure
infections:
two randomized, multicentre studies of quinupristin/dalfopristin versus
cefazolin,
5 oxacillin or vancomycin. J. Antimicrob. Chemother. 44: 263-273.
33
CA 02434046 2003-07-08
WO 02/055731 PCT/US02/00775
Norris, A.H., J. P. Reilly, P. H. Edelstein, Chloramphenicol for the treatment
of vancomycin-
resistant enterococcal infections. 1995. Clin. Infect. Dis. 20: 1137-44.
Papanicolaou, G. A, B. R. Meyers, and J. Meyers. 1996. Nosocomial infections
with
vancomycin-resistant Enterococcus faecimn in liver transplant recipients: risk
factors for
acquisition and mortality. Clin. Infect. Dis. 23:760-766.
Platt, Bucknall, MIC tests are not suitable for assessing antiseptic
handwashes, J. Hosp. Infect.,
11:396-397, 1988.
Raad, Darouiche, Dupuis, Central venous catheters coated with minocycline and
rifampin for~the
prevention of catheter-related colonization and bloodstream infections: a
randomized,
0 double-blind trial, Ann. Intern. Med., 127:267-274, 1997.
Raad, I. I. and G. P. Bodey. 1992. Infectious complications of indwelling
vascular catheters.
Clin. Infect. Dis. 15:197-210.
Raad, I. L, D. Abi-Said, I~. V. Rolston , et al. 1998. How should imipenem-
cilastatin be used in
the treatment of fever and infection in neutropenic cancer patients? Cancer
82:2449-58.
5 Raad, Intravascular-catheter-related infections, Lancet, 351:893-898, 1998.
Reiselman, Tarara, Wenzel, Nosocomial bloodstream infections in the critically
ill, JAMA,
272:1578-1601, 1994.
Reverdy, Bes, Nervi, Martra, Fleurette, Activity of four antiseptics
(acriflavin, benzalkonium
chloride, chlorhexidine diglnconate and hexamidine di-isethionate) and of
ethidium
~,0 bromide on 392 strains representing 26 Staphylococcus species, Med.
Microbiol. Lett.,
1:56-63, 1992.
Robertson, J. M., E. C. R. Reeve. 1972 Analysis of the resistance mediated by
several R-factors
to tetracycline and minocycline. Genetical Research, 20:239-252
Rubinstein, E, F. Bompart. 1997. Activity of quinupristin/dalfopristin against
gram-positive
I',5 bacteria: clinical applications and therapeutic potential. J. Antimicrob.
Chemother. 39
(suppl A):139-143
Russell, Plasmids and bacterial resistance to biocides, J. App. Microbiol.,
82:157-161, 1997.
Tacconelli, Tumbarello, Pittiruti, Central venous catheter-related sepsis in a
cohort of 366
hospitalized patients, Eur. J. Clin. Microbiol. Infect. Dis., 16:203-209,1997.
0 Townsend, Ashdown, Momoh, Grubb, Distribution of plasmid-born resistance to
nucleic acid
hinging compounds in methicillin resistant Staphylococcus aureus, J. acid
hinging
compounds in methicillin resistant Staphylococcus aureus, J. Antimicrob.
Claemother.
15:417-434, 1985.
34
CA 02434046 2003-07-08
WO 02/055731 PCT/US02/00775
Tumbarello, Tacconelli, Danati, Nosocomial bloodstream infections in HIV-
infected patients:
attributable mortality and extension of hospital stay, J. Acquir. Imrnun.
Defic. Syndr-.
Hum. Retrovir~ol., 19:490-497, 1998.
Vergis, E. N., J. W. Chow, M. K, and Haydn, et al. Vancomycin resistance
predicts mortality in
enterococcal bacteremia. A prospective, multicenter study of 375 patients.
Program and
Abstracts of the 37th Interscience Conference on Antimicrobial Agents and
Chemotherapy. Toronto, Canada. September 28-October 1, 1997, p 289 (Abstract #
J-6)
Wey, Mori, Pfaller, Woolson, Wenzel, Risk factors for hospital-acquired
candidemia, Af°clz.
Intern. lVled. 149:2349-2353, 1989.
0 Williams, J. D., J. P. Maskell, A.C. Whiley, et al. 1997. Comparative in-
vitro activity of
quinupristin/dalfopristin against Enterococcus spp. J. Antimicrob. Chemother.
39 (suppl
A):41-46.
Wood CA, Blumberg EA, Fuchs AE, et al. 1998a. Quinupristin/dalfopristin
(Synercid) treatment
of infections caused by vancomycin-resistant Enterococcus faecium. abstr. 606
Fr. In
5 Program and abstracts of the 36th annual meeting of the Infectious Diseases
Society of
America, Denver, Ca.
Wood CA, Blumberg EA, Fuchs AE, et al. 1998b. Emergence of resistance to
quinupristin/dalfopristin (Synercid) during treatment of infections caused by
vancomycin-resistant Enterococcus faecium. abstr. 607 Fr. In Program and
abstracts of
~;0 the 36th annual meeting of the Infectious Diseases Society of America,
Denver, Co.
