Note: Descriptions are shown in the official language in which they were submitted.
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ENHANCEMENT OF THE ACTION OF ANTI-INFECTIVE AGENTS
FIELD OF THE INVENTION
This invention relates to pharmaceutical preparations (which expression is
herein intended to include veterinary preparations) for use in combating
infective organisms afflicting the animal body (which expression is herein
intended to include the human body).
BACKGROUND TO THE INVENTION
In US patent 5,633,284 and their equivalents the applicant disclosed
that dermatological or topical compositions comprising the combination of
nitrous oxide [N20] and at least one fatty acid, or lower alkyl ester
thereof in a dermatologically acceptable carrier medium are useful in the
treatment of a variety of skin, muscle and joint disorders. It also disclosed
therein that such combinations may beneficially also include additional
active ingredients.
Known anti-bacterial, anti-viral or anti-fungal agents were not amongst
the active ingredients specifically mentioned in the patents but mention
was made therein that coal tar solution (also known as Liquor Picis
Carbonis) may be used as a supplementary active ingredient and that the
resultant preparation is suitable for use in the treatment of, inter alia
fever blisters, herpes simplex, shingles and chicken pox. While all of these
conditions are caused by viral infections, the disclosures in these patents
do not refer to that fact.
It is also disclosed in these patents that, in addition to the coal tar
solution the composition may also contain an H1-antagonist antihistamine
(e.g. diphenhydramine hydrochloride) and may in that form be used in
the treatment of atopic and allergic conditions manifesting in skin
irritations such as eczema, dermatitis and ringworm. The latter of these
conditions is caused by a fungal infection. Again the disclosures in issue
do not refer specifically to that fact.
It further disclosed an alternative composition in which the coal tar
solution formulation is further provided with collagen and lanolin and this
formulation was found to be useful in the treatment of persons suffering
from acne vulgaris. Bacteria are involved in the condition but no mention
was made of such involvement in those patents.
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Since coal tar solution is in itself not known to be an anti-viral, anti-
fungal
or antibacterial agent, and has merely been mentioned as being weakly
antiseptic, the aforementioned disclosures would not have been
understood as suggesting that the nitrous oxide and fatty acid
combination has any beneficial effect on the anti-viral or anti-fungal or
anti-bacterial activity of any recognised anti-viral or anti-fungal or anti-
bacterial agent or to have disclosed that such properties are displayed by
coal tar solution. As will appear below the enhancement of the anti-
bacterial, anti-fungal or anti-viral properties of known agents lie at the
very heart of this invention.
Within the context of the disclosure in the abovementioned patent family
the notional addressee most likely would, as did the inventor, have
understood the role of the coal tar solution to sooth the itching and to
assist in the repairing and healing of the skin which was damaged as a
result of the infections/conditions in issue.
In W097/17978 and US Patent 6,221,377 and in corresponding
patents and pending patent applications in other jurisdictions the present
applicant disclosed that the action of analgesic, anti-inflammatory and
anti-pyretic drugs may be enhanced by administering such drugs in
conjunction with a medium which comprises nitrous oxide and at least
one long chain fatty acid selected from the group consisting of oleic acid,
linoleic acid, alpha-linolenic acid, gamma linolenic acid, arachidonic acid,
and any of the C1 to C6 alkyl esters of such long chain fatty acids,
mixtures of such acids and mixtures of such esters. The medium may
comprise the mixture known as Vitamin F Ethyl Ester and may optionally
further comprise eicosapentaenoic acid [C20: 5w3] and decosahexaenoic
acid [C22: 6co3].
It has now surprisingly been found that the aforesaid medium and media
related thereto has the ability remarkably to enhance the action of known
anti-infective agents. The expression "anti-infective agents" as used
herein is intended to have its extended meaning and to include the
antimicrobial agents, the anthelmintic agents and the anti-ectoparasitic
agents, but to exclude coal tar solution and H1-antagonist antihistamines.
The exclusion of coal tar solution and H1-antagonist antihistamines from
the ambit of the present invention is introduced without thereby
conceding that the aforementioned patents and applications contain any
disclosure of any anti-infective agent properties of such excluded
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compounds, or that such properties are obvious in the light of the
disclosures in such patents or applications. Such inferences are
specifically denied. The exclusion is introduced simply to avoid what is
anticipated to be a potential obstacle to the grant of a patent in respect of
an insignificant part of potential subject matter which part in itself is not
considered worth contesting during examination as it might unduly delay
the implementation in practice of the significant features of the present
invention. It is expected that the remaining bulk of the subject matter of
the present invention will greatly contribute to the accessibility of
medicines for the treatment of a large range of infections, including
secondary infections in HIV-compromised patients, at significantly
reduced costs.
The expressions "anthelmintic agents" and "anti-ectoparasitic" agents are
further intended to cover both agents which serve to destroy and those
which serve to inhibit the proliferation of helminths or ecto-parasites.
Those expressions are hence also intended to be understood in the wider
sense of these terms. The expression "antimicrobial agents" is similarly
intended to be understood in the wider sense of that word and hence to
have the meaning ascribed thereto in The McGraw-Hill Dictionary of
Scientific and Technical Terms 2nd Ed 1978, namely all chemical
compounds that either destroy or inhibit the growth of microscopic and
sub microscopic organisms. This term is further specifically intended to
include all the compounds falling within the Pharmacological Classification
20 set out as part of Regulation 5(1) of the General Regulations made in
terms of the South African Medicines and Related Substances Control Act,
Act 101 of 1965, as well as the active ingredients of all products falling
within class 18 of the pharmacological classification employed in the
Monthly Index of Medical Specialities ("MIMS") published by Times Media
in South Africa. It is thus intended to include:
the anti-bacterial agents (including both antibiotics and substances other
than antibiotics such as the sulfonamides, the erythromycins and other
macrolides, the aminoglycocides, the tetracyclines, the chloramphenicols
and the quinolones);
the anti-fungal agents;
the anti-viral agents (including anti-retroviral agents);
the anti-protozoal agents;
the tuberculostatics;
the anti-leprotics;
the germicides;
and
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the spirochaeticides.
The surprising finding of enhancement of action of the anti-infective
agents referred to above is made against the background of the fact that
there appears to be no earlier suggestion in the literature to the effect
that either nitrous oxide or the long chain fatty acids used in the
formulation referred to above, and hence also not the combination of
these, has any effect whatsoever on the sensitivity of any micro-organism
to any anti-infective agent.
The present invention is specifically, though not exclusively aimed at the
enhancement of the action of anti-mycobacterial agents, and particularly
those used in the treatment of patients infected with Mycobacterium
tuberculosis (M.Tb.). This organism is one of the most significant human
pathogens. It is responsible for an estimated seven million new cases of
tuberculosis annually, and an estimated three million deaths worldwide.
Of particular concern is the emergence of tuberculosis (TB) as an
increasing cause of morbidity and mortality among persons compromised
by human immune-deficiency virus (HIV) infection.
Although the prevalence of tuberculosis in developed countries declined in
the first few decades of the 1900's, this trend has reversed and an
increased incidence of tuberculosis has been reported in many countries.
Africa alone is estimated to have approximately 170 million TB patients.
In South Africa the incidence of tuberculosis is also rising and is at
different levels in different population groups.
Re-infection of patients is an ever-increasing problem and has been
shown to be a function of reactivation of TB in patients not completing
their therapy. It is also often associated with the appearance of drug
resistant M.Tb. in the patient. The exact mechanism whereby drug
resistance develops in mycobacteria is not yet fully understood, but the
economic consequences thereof are a reality.
In an attempt to reduce discontinuance of TB-treatments which has been
implicated in reinfections and the development of resistant strains, the
practice of directly observed treatment or DOTS has been resorted to,
with some, but based on the foregoing quotes, not complete success.
Iron, heavy metals, and excessive alcohol consumption (an inherent
feature of some identified high incidence TB communities) generate
harmful reactive oxygen species which have been shown to be involved in
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the auto-oxidation of Rifampicin, an antibiotic anti-mycobacterial agent
used in the treatment of tuberculosis, thereby generating more radical
species. These free radicals have been implicated in the liver toxicity
experienced with use of Rifampicin.
5
These problems associated with TB have led to the investigations
associated with the present invention.
It was pointed out in W097/17978 referred to above that nitrous oxide is
a natural gas which is also produced synthetically, and also known by the
trivial name "laughing gas" which has been in use for many years as an
inhalation anaesthetic and analgesic, particularly in dentistry.
It was further stated that nitrous oxide has been reported to have a
synergistic or potentiating effect on halothane and other gaseous
anaesthetics [See Goodman & Gilman's The Pharmacological Basis of
Therapeutics 8th Ed. 1990 pp. 298-300].
Since such known synergism or potentiation is based on the use of nitrous
oxide administered by inhalation, and since the use of nitrous oxide on its
own as an anaesthetic and analgesic has likewise been in the form of an
inhalation agent, the use of nitrous oxide for all these purposes have been
confined to hospitalised patients or, at best, to treatments carried out by
medical practitioners in their consulting rooms, or treatments carried out
by or under supervision of a nurse in charge of a home-care patient.
Nitrous oxide is known to be soluble in water and it has been reported
that at 20 C and 2 atm pressure one litre of the gas dissolves in 1,5 litres
of water, see The Merck Index 10th Ed. p. 6499.
Nitrous oxide is also known for its use as a propellant gas, mainly as a
substitute for propellant gases such as chlorofluorocarbons, and more
particularly to produce a food product mousse such as whipped cream or
chocolate mousse or quick-breaking foams for hair treatment
preparations. See in this regard U.K. Patent 1033299, U.K. Patent
1105919 and European Patent Application EPA-0123827. None of these
prior publications suggests that the nitrous oxide gas plays any other role
than a physical one, i.e. to expand on being depressurised and thereby to
create a mousse or foam. In fact it is typically regarded as an inert in
these applications and useful due to the fact that it is colourless,
odourless and tasteless but soluble in water and oils.
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There appears to be no suggestion in the literature, other than the
applicants own prior patents and patent applications referred to above,
that aqueous solutions of nitrous oxide might have any effect on man or
animals. As far as the present applicant knows, it has also never been
suggested that nitrous oxide may be used in conjunction with any anti-
infective agent to enhance the known action of such agent.
It is known in the pharmaceutical field to formulate active ingredients in
so-called liposomal formulations. Unlike the present invention which is
based on formulations containing long chain fatty acids and esters thereof
the liposomes are based on a clearly distinguishable group of compounds
namely the phospholipids, and generally also contain cholesterol as a
stabilising agent and may further contain lisolecitein. These compounds or
classes form no part of the present invention and, in case it is necessary
to do so, are specifically excluded from the group of long chain fatty acids
and derivatives thereof incorporated in the method or formulation of the
invention.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a method of enhancing
the known action of anti-infective agents and to provide pharmaceutical
preparations of such anti-infective agents which preparations have
enhanced action compared to the action of known formulations containing
the same agents.
These objects stem from the observations made by present applicant in
respect of a selection of agents falling within the group of anti-infective
agents as herein defined, which can advantageously be formulated with
nitrous oxide and an oil based on long chain fatty acids disclosed herein,
to elicit a more potent response, for each agent according to its own
inherent properties, or to evoke such response more rapidly than it does
when used by conventional administration of the agent in issue.
STATEMENTS OF THE INVENTION
According to the present invention there is provided a method of
enhancing the action of an anti-infective agent characterised in that the
agent is selected from the group comprising antimicrobial agents, the
anthelmintic agents and the anti-ectoparasitic agents, but excluding coal tar
solution and H1-antagonist antihistamines, comprising the step of formulating
the agent with an administration medium which comprises a solution of
nitrous oxide gas in a pharmaceutically acceptable carrier solvent for the
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gas and which administration medium includes at least one fatty acid or
ester or other suitable derivative thereof selected from the group
consisting of oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic
acid, arachidonic acid, eicosapentaenoic acid [C20: 5w3],
decosahexaenoic acid [C22: 6w3], ricinoleic acid and derivatives thereof
selected from the group consisting of the Cl to C6 alkyl esters thereof,
the glycerol-polyethylene glycol esters thereof and the reaction product of
hydrogenated natural oils composed largely of ricinoleic acid based oils,
such as castor oil with ethylene oxide.
According to a further aspect of the present invention there is provided a
pharmaceutical preparation comprising an anti-infective agent
characterised in that it is selected from the group comprising
antimicrobial agents, the anthelmintic agents and the anti-ectoparasitic
agents, but excluding coal tar solution and H1-antagonist antihistamines,
which
agent is formulated with an administration medium which comprises a
solution of nitrous oxide in a pharmaceutically acceptable carrier solvent
for the gas and which includes at least one fatty acid or ester or other
suitable derivative thereof selected from the group consisting of oleic
acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic
acid, eicosapentaenoic acid [C20: 5w3], decosahexaenoic acid [C22:
6w3], ricinoleic acid and the derivatives thereof selected from the group
consisting of the C1 to C6 alkyl esters thereof, the glycerol-polyethylene
glycol esters thereof and the reaction product of hydrogenated natural oils
composed largely of ricinoleic acid based oils, such as castor oil, with
ethylene oxide.
The administration medium preferably includes the eicosapentaenoic acid
[C20: 5w3] and/or decosahexaenoic acid [C22: 6w3] as additional long
chain fatty acids to at least one of the other components of the carrier
medium defined above.
The reaction product of hydrogenated natural oils composed largely of
ricinoleic acid based oils with ethylene oxide is preferably produced from
castor oil of which the fatty acid content is known to be predominantly
composed of ricinoleic acid. This product is known as PEG-n-Hydrogenated
Castor Oil. A range of such products is marketed by BASF under the trade
description of Cremophor RH grades. Glycerol-polyethylene glycol ester
of ricinoleic acid is also marketed by the same company but under the
trade description of Cremophor EL.
The carrier solvent for the nitrous oxide gas may be water or any of the
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pharmaceutically acceptable alcohols, ethers, oils or polymers such as a
polyethylene glycol or the like. The oil may be organic or mineral oil. The
organic oil may be an essential oil based on long chain fatty acids having
between 14 and 22 carbon atoms in the fatty acid. The oil may also be of
either natural or synthetic origin and, if of natural origin, it may be either
plant oil or animal oil. As plant oils those rich in gamma linolenic acid
[GLA] are preferred and as animal oil dairy cream may be used.
In the preferred form of the invention the solution is an aqueous solution
saturated with nitrous oxide. Preferably the water is deionised and
purified to be free of microbes.
When the formulation containing the anti-infective agent to be enhanced
by means of the nitrous oxide is to be in a liquid (including an
encapsulated liquid) presentation for oral administration or in a nasal or
bronchial or pulmonary spray or in the form of an injectable formulation,
such formulation may incorporate, as part of the administration medium,
water or acceptable other liquid into which the nitrous oxide is dissolved
and in which the fatty acid or ester thereof is either dissolved or
suspended or emulsified along with the anti-infective agent to be
enhanced by being formulated therewith.
Likewise, where the anti-infective agent is to be administered to the
patient as a topical, buccal or vaginal cream or ointment, or as a
suppository, the formulation used in making up such cream, ointment, or
suppository may incorporate, along with the anti-infective agent to be
enhanced, a quantity of water or other liquid containing, and preferably
saturated with, nitrous oxide, the long chain fatty acid or ester thereof
and the anti-infective agent formulated therewith, and, further, such
additional excipients and carriers as are conventionally used in the
pharmaceutical trade in making up such dosage forms.
The carrier solvent for the nitrous oxide gas may thus in an alternative
formulation according to the invention be essentially non-aqueous and
composed of least one fatty acid or ester thereof selected from the group
consisting of oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic
acid, arachidonic acid, eicosapentaenoic acid [C20: 5w3],
decosahexaenoic acid [C22: 6w3], ricinoleic acid and derivatives thereof
selected from the group consisting of the C1 to C6 alkyl esters thereof,
the glycerol-polyethylene glycol esters thereof and the reaction product of
hydrogenated natural oils composed largely of ricinoleic acid based oils
with ethylene oxide, required to be part of the formulation.
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A formulation suited to transdermal application whether as an ointment,
cream or lotion or in the form of a skin patch providing a reservoir for the
formulation is also a preferred form of the formulation according to the
invention.
The essential fatty acid, or ester thereof, component of the composition
preferably comprises a mixture of esters of the fatty acids listed above.
Thus, in the most preferred form of the invention the fatty acid
component of the composition is constituted by the complex known as
Vitamin F and in this regard it is preferred to make use of the ester form
of Vitamin F known as Vitamin F Ethyl Ester. This product is commercially
available under the trade description of Vitamin F Ethyl Ester CLR 110 000
Sh.L. U./g from CLR Chemicals Laboratorium Dr.Kurt Richter GmbH of
Berlin, Germany. The typical fatty acid distribution of this product is as
follows:
<C16:0
C16.0 8,3%
C18.o : 3,5 %
C18.1 : 21,7 %
C18.2 : 34,8 %
C18.4 : 28,0 %
> C18: 1,6 %
unknown: 2,1 %
It is further preferred to add to the formulation the long chain fatty acids
known as eicosapentaenoic acid [C20:5w3] and decosahexaenoic acid
[C22:6w3]. Such a product combination is available from Roche Lipid
Technology under the trade name "Ropufa '30' n-3 oil".
It has been found by microscopic studies that the formulation of the anti-
infective agents with a medium as herein described gives rise to the
formation of minute, generally spherical bodies, within which, or attached
to which the active ingredient is contained in a stable form and from
which it is delivered at the site of action namely on or inside the infective
agent.
The anti-infective agent utilised in the method or formulation according to
the present invention may comprise any one or more of the vast
spectrum of anti-infective agents as herein defined.
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In a preferred form of the invention the anti-infective agent is selected
from the group comprising:
the anthelmintics
5 the anti-ectoparasitcides
the anti-bacterial agents (including both antibiotics and substances other
than antibiotics);
the antifungal agents;
the anti-viral agents;
10 the anti-protozoal agents;
the tuberculostatics;
the anti-leprotics;
the germicides;
and
the spirochaeticides.
From amongst these anti-infective agents this invention is particularly
concerned with the anti-bacterials and the tuberculostatics. These classes
of agents overlap to some extent.
The anti-infective agent may in a specific application of the invention
comprise an antimicrobial of the class of compounds known as the
tuberculostatics or anti-mycobacterial compounds and may specifically be
selected from the group consisting of Rifampicin, Isoniazid, Pyrazinamide,
Ethambutol and combinations of any two or more of these.
It is a further aspect of the invention that the formulation, and
specifically, though not exclusively, the anti-TB formulation of the
invention, may be prepared to be adapted for pulmonary administration.
In the case of the anti-TB formulation it will thereby bring the formulation
into contact with the pathogen at a primary locus thereof and without
passage through, or absorption from the digestive tract and possible
subsequent passage through the liver.
The invention has not yet been demonstrated by empirical work to be
applicable to all the agents listed below. However in respect of such anti-
infective agents which have already been formulated with the
aforementioned administration medium of the invention, and evaluated by
different methods for the anticipated enhancement of anti-infective
action, no negative result has as yet been seen despite the chemical
diversity of the anti-infective agents which has been investigated. The
applicant thus confidently expects, on the basis of the observations in
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respect of products representing a range of classes of such agents, that
the invention will find general application across the entire spectrum of
anti-infective agents embraced by the term as herein defined and of
which some examples are set out below. It is part of the applicant's
present postulations by which it seeks to find an understanding of the
invention and to which it does not wish to be bound at this stage, that
while the administration medium of the present invention serves to
transport the anti-infective agent formulated therewith most efficiently
through the human or animal body, that medium also plays an important
role in transferring, by an as yet unexplained mechanism, the anti-
infective agent through the outer membranes of and into the pathogenic
organism thereby to cause an effective anti-infective dose of the agent
rapidly to be achieved and to be maintained in the organism until it finally
succumbs to the effect of the anti-infective agent.
It is in this respect that the applicant believes that the present invention
will find general application despite the vast list of agents mentioned
below. The following table sets out examples of the specific anti-infective
agents with which this invention is concerned will now be identified with
reference to the broad classes in which they fall and, in some cases, also
with reference the respective indications for which such agents are
indicated and, in some cases, further also with reference to the infective
agent giving rise to the indication to be addressed which products
comprise the following:
A. SULPHONAMIDES
1) Short-acting
SULPHAPYRIDINE-
1) Inflammatory bowel diseases and in rheumatoid arthritis
SULPHADIAZINE-
1) Nocardiosis (Nocardia species)
2) Toxoplasmosis + Pyrimethamine
3) Long term prophylaxis of rheumatic fever
SULPHADIMIDINE-
SULPHAFURAZOLE-
2) Medium-acting:
SULPHAMETHOXAZOLE -
3) Long-acting:
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SULPHADIMETHOXINE -
SULPHAMETHOXYDIAZINE-
SULPHAMETHOXYPYRIDAZINE-
4) Ultra-Long-acting:
SULFADOXINE-
SULFAMETOPYRAZINE-
5) Topical sulphonamide:
SILVER SULPHADIAZINE-
1) Antibacterial in patients with burns
MAFENIDE ACETATE-
1) Antibacterial in patients with burns
SULPHACETAMIDE-
6) Other sulphonamides:
SULPHAGUANIDINE-
1) Gastrointestinal infections
SULPHASALAZINE-
1) Inflammatory bowel diseases and in rheumatoid arthritis
SUCCINYLSULPHATHIAZOLE-
1) Gastrointestinal infections
PHTHALYLSULPHATHIAZOLE-
1) Gastrointestinal infections
7) SULPHONAMIDE COMBINATIONS:
CO-TRIMOXAZOLE (Trimethoprim+ Sulphamethoxazole)-
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other diseases that are
Methicillin-sensitive (Staphylococcus aureus)
2) Pneumonia, Arthritis, Sinusitis, Otitis that are Penicillin-
sensitive (Streptococcus Pneumoniae)
3) Meningitis and Bacteremia (Listeria monocytogenes)
4) Urinary tract infections, Bacteremia, Other infections
(Escherichia coli)
5) Urinary tract and other infections (Enterobacter species)
6) Typhoid fever, Paratyphoid fever, Bacteremia, Acute
gastroenteritis (Salmonella)
7) Acute gastro-enteritis (Shigella)
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8) Otitis media, Sinusitis, Pneumonia, Epiglottitis, Meningitis
(Haemophilus influenzae)
9) Chancroid (Haemophilus ducreyi)
10) Brucellosis (Brucella) Gentamicin
11) Yersiniosis (Yersinia enterocolitica)
12) Cholera (Vibrio cholerae)
13) Meningitis (Flavobacterium meningosepticum)
14) Melioidosis (Pseudomonas pseudomallei)
15) Granuloma inguinale (Calymmatobacterium granulomatis)
16) Legionnaires' disease (Legionella Pneumophila)
17) Pulmonary lesions, Brain abscess, Lesions of other organs
(Nocardia asteroides)
18) Lymphogranuloma venereum, Trachoma, Inclusion
conjunctivitis [blennotthea], Non-specific urethritis,
Cervicitis (Chlamydia trachomatis)
19) Pneumonia in impaired host [Mild or moderate disease,
Moderately severe or severe disease](Pneumocystis
carinii)
B. QUINOLONES
B1 FIRST GENERATION
NALIDIXIC ACID (oxolinic acid)
1) Urinary tract infections
CINOXACIN
1) Urinary tract infections
PIPEMIDIC ACID
PIROMIDIC ACID
ACROSOXACIN
QUINOLONES
B2 SECOND GENERATION
CIPROFLOXACIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and Other infections [Methicillin-
sensitive and Methicillin-resistant] (Staphylococcus
aureus) + Rifampin
2) Urinary tract infection (Enterococcus)
3) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
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4) Penicillin-sensitive and Penicillinase-producing
gonococcus (Neisseria gonorrhoeae (gonococcus))
5) Carrier state (Post-treatment) (Neisseria meningitidis
(meningococcus))
6) Urinary tract infection and other infections, Bacteremia
(Escherichia coli)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract and other infections (Enterobacter species)
9) Urinary tract infection, Pneumonia, Bacteremia
(Pseudomonas aeruginosa)
10) Urinary tract infection (Klebsiella pneumoniae)
11) Typhoid fever, Paratyphoid fever, Bacteremia, Acute
gastroenteritis (Salmonella)
12) Acute gastroenteritis (Shigella)
13) Otitis media, Sinusitis, Pneumonia (Haemophilus
influenze)
14) Chancrois (Hameophilus ducreyi)
15) Plague (Yersinia pestis)
16) Yersomopsis Sepsis (Yersinia enterocolitica)
17) Tualermia (Francisella tularensis)
18) Cholera (Vibrio tularensis)
19) Enteritis (Campulobacter jejuni)
20) Bacteremia, Endocarditis (Campylbacter fetus)
21) Legionnaires' disease (Legionella pneumophila)
22) Disseminated disease in AIDS (Mycobacterium avium -
intracellulare) Clarithromycin; Ethambutol; f
Clofamizine
OFLOXACIN
1) Penicillin-Sensitive and Penicillinase-Producing
gonococcus (Neisseria gonorrhoeae (gonococcus))
2) Urinary tract infection and other infections, Bacteremia
(Escherichia coli)
3) Urinary tract and Other infections (Proteus mirabilis)
4) Urinary tract and Other infections (Enterobacter species)
5) Urinary tract infection (Klebsiella pneumoniae)
6) Typhoid fever, Paratyphoid fever, Bacteremia, Acute
gastroenteritis (Salmonella)
7) Urinary tract infection (Pseudomonas aeruginosa)
8) Yersiniosis, Sepsis (Yersinia enterocolitica)
9) Cholera (Vibrio cholerae)
10) Enteritis (Campylobacter jejuni)
11) Bacteremia, Endocarditis (Campylobacter fetus)
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12) Leprosy (Mycobacterium leprae)
NORFLOXACIN
1) Acute gastroenteritis (Salmonella)
2) Acute gastroenteritis (Shigella)
5 ENOXACIN
LOMEFLOXACIN
PEFLOXACIN
AMIFLOXACIN
FLEROXACIN
10 LEVOFLOXACIN
NADIFLOXACIN
RUFLOXACIN
SPARFLOXACIN
1) Active against Streptococcus pneumoniae and anaerobic
15 bacteria.
TOSUFLOXACIN
ENROFLOXACIN
C. Anti-Septic and Analgesic Agents for Urinary Tract Infections
METHENAMIN
1) Not a primary drug for the treatment of acute urinary
tract infections, but it is of value for chronic suppressive
treatment.
NITROFURANTOIN
1) Urinary tract infection (Escherichia coli)
MENAZOPYRIDINE
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1) Is not a urinary antiseptic but it does have an analgesic
action on the urinary tract and alleviates symptoms of dysuria,
frequency, burning and urgency.
D. PENICILLIN
NARROW SPECTRUM
BENZYLPENICILLIN (Penicillin G) [acid-labile]
1) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and Other systemic infections (Streptococcus
pyogenes [Group A])
2) Endocarditis, Bacteremia (Streptococcus [viridans group])
Gentamicin.
3) Bacteremia, Endocarditis, Meningitis. (Streptococcus
agalactiae [Group B]) Aminoglycoside.
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis [Penicillin - Sensitive
and Penicillin - Resistant] Endocarditis, Meningitis, other
serious infections [Penicillin -Sensitive] (Streptococcus
pneumoniae [pneumococcus])
6) Endocarditis or other serious infections (bacteremia),
Urinary tract infections (Enterococcus) + Gentamicin
7) Penicillin - sensitive gonococcus (Neisseria gonorrhoeae)
+ Probenecid.
8) Meningitis (Neisseria meningitidis [meningococcus])
9) "Malignant pustule", Pneumonia (Bacillus anthracis)
10) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species, aerobic and anaerobic
[diphtheroids]) an Aminoglycoside or + Rifampin
11) Meningitis, Bacteremia (Listeria monocytogenes) f
Gentamicin
12) Erysipeloid (Erysipelothrix rhusiopathiae)
13) Gas gangrene (Clostridium perfringens and other species)
14) Tetanus (Clostridium tetani)
15) Urinary tract infection, Bacteremia, Other infections
(Escherichia coli) + a Penicillinase inhibitor.
16) Urinary tract and other infections (Proteus, other species)
+ a 13 - Lactamase inhibitor
17) Wound infection (animal bites), Abscesses, Bacteremia,
Meningitis (Pasteurella multocida)
18) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
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17
19) Bacteremia, Arthritis, Endocarditis, Abscesses
(Streptobacillus moniliformis)
20) Syphilis (Treponema pallidum)
21) Yaws (Treponema pertenue)
22) Stage 2 - neurological, Cardiac, Arthritis (Borrelia
burgdorferi [Lyme disease])
23) Relapsing fever (Borrelia recurrentis)
24) Weil's disease, Meningitis (Leptospira)
25) Cervicofacial, Abdominal, Thoracic, and other lesions
(Actinomyces israelii)
PHENOXYMETHYL-PENICILLIN
(Penicillin V)
[acid - stable]
1) Pharyngitis, Scarlet Fever, Otitis Media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome, and other systemic infections (Streptococcus
pyogenes [Group A])
2) Pneumonia, Arthritis, Sinusitis, Otitis [Penicillin - Sensitive
and Penicillin - Resistant] Endocarditis, Meningitis, other
serious infections [Penicillin -sensitive] (Streptococcus
pneumoniae [pneumococcus])
3) Urinary tract infections (Enterococccus)
4) Urinary tract infection, Bacteremia, Other infections
(Escherichia coli) + a Peniciliinase-inhibitor.
5) Urinary tract and other infections (Proteus, other species)
+ a (3 - Lactamase inhibitor
E. PENICILLIN
BROAD SPECTRUM
AMOXICILLIN
1) Pharyngitis, Scarlet Fever, Otitis Media, Sinusitis,
Cellulitis, Erysipelas, Pneumonia, Bacteremia, Toxic shock
- like syndrome and other systemic infections
(Streptococcus pyogenes [group A])
2) Pneumonia, Arthritis, Sinusitis, Otitis [Penicillin - Sensitive
and Penicillin - Resistant] (Streptococcus pneumoniae
[Pneumococcus])
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18
3) Urinary tract and other infections (Proteus mirabilis)
4) Otitis Media, Sinusitis, Pneumonia (Haemophilus
influenzae) + Clavulanic acid.
5) Wound - infection (animal bites), Abscesses, Bacteremia,
Meningitis (Pasteurella multocida) + Clavulanic acid
6) Erythema chronica migrans - skin (Borrelia burgdorferi
[Lyme disease])
7) Pulmonary lesions, Brain abscess, Lesions of other organs
(Nocardia asteroides) + Clavulanic acid
8) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis) +
Clavulanic acid
9) Penicillin - Sensitive gonococcus (Neisseria gonorrhoeae)
+ Probenecid
AMPICILLIN
1) Bacteremia, Endocarditis, Meningitis (Streptococcus
agalactiae [Group B])
2) Urinary tract infection, Endocarditis, or Other serious
infections [Bacteremia] (Enterococcus)
3) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis) +
Clavulanic acid
4) Penicillin - Sensitive gonococcus (Neisseria gonorrhoeae)
+ Probenecid
5) Meningitis, Bacteremia (Listeria monocytogenes)
6) Urinary tract infection, Other infections, Bacteremia
(Escherichia coli) + an Amihoglycoside
7) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species, aerobic and anaerobic
[diphtheroids]) + Sulbactam
8) Urinary tract and other infections (Proteus mirabilis)
9) Typhoid Fever, Paratyphoid Fever, Bacteremia, Acute
Gastroenteritis (Salmonella)
10) Acute Gastroenteritis (Shigella)
11) Epiglottitis, Meningitis (Haemophilus influenza) +
Sulbactam
12) Bacteremia, Endocarditis, Meningitis (Campylobacter
fetus)
13) Cervicofacial, Abdominal, Thoracic, an Other lesions
(Actinomyces israelii)
TICARCILLIN
1) Urinary tract and other infections (Enterobacter species)
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2) Pneumonia, Bacteremia (Pseudomonas aeruginosa) an
Aminoglycoside
3) Urinary tract infection (Pseudomonas aeruginosa)
4) Variety of nosocomial and opportunistic infections
(Serratia) + an Aminoglycoside
PIPERACILLIN
1) Urinary tract and other infections (Enterobacter
species)
2) Pneumonia, Bacteremia (Pseudomonas aeruginosa) an
Aminoglycoside
3) Urinary tract infection (Pseudomonas aeruginosa)
4) Variety of nosocomial and opportunistic infections
(Serratia) + an Aminoglycoside
MEZLOCILLIN
1) Urinary tract and other infections (Enterobacter
species)
2) Pneumonia, Bacteremia (Pseudomonas aeruginosa) an
Aminoglycoside
3) Urinary tract infection (Pseudomonas aeruginosa)
4) Variety of nosocomial and opportunistic infections
(Serratia) + an Aminoglycoside
AZLOCILLIN
1) Urinary tract and Other infections (Enterobacter species)
2) Pneumonia, Bacteremia (Pseudomonas aeruginosa) an
Aminoglycoside
3) Urinary tract infection (Pseudomonas aeruginosa)
4) Variety of nosocomial and opportunistic infections
(Serratia) + an Amihoglycoside
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BACAMPICILLIN
TALAMPICILLIN
PIVAMPICILLIN
CARBENICILLIN
5 APALCILLIN
CARINDACILLIN
PIVMECILLINAM
CARFECILLIN
METAAMPICILLIN
10 HETACILLIN
TEMOCILLIN
F. PENICILLIN
PENICILLINASE - RESISTANT PENICILLINS (isoxazoly penicillins)
15 OXACILLIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis, and Other Staphylococcus aureus
infections [methicillin - sensitive] (Staphylococcus
aureus)
CLOXACILLIN
1) Effective against Penicillinase - Producing Staphylococcus
aureus
DICLOXACILLIN
1) Effective against Penicillinase - Producing Staphylococcus
aureus
FLUCLOXACILLIN
1) Effective against Penicillinase - Producing Staphylococcus
aureus
METHICILLIN
1) Effective against Penicillinase - Producing Staphylococcus
aureus
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NAFCILLIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis, and Other Staphylococcus aureus
infections [methicillin-sensitive] (Staphylococcus aureus)
G. CEPHALOSPORINS
G1. FIRST GENERATION
CEPHAZOLIN / CEPHRADINE
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
(Escherichia coli)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
CEPHALORIDINE
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and other systemic infections (Streptococcus
pyogenes [Group A])
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22
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
(Escherichia coli)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) f an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
CEPHRADINE
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
(Escherichia coli)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
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CEFROXADINE
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
(Escherichia coil)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
CEFADROXIL
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
(Escherichia coli)
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7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
CETATRIAZINE
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
(Escherichia coli)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
CEFALEXIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
CA 02416512 2008-07-18
syndrome and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
5 4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
10 (Escherichia coli)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
15 Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
20 PIVCEPHALEXIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
25 2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and other systemic infections
(Streptococcus pyogenes [Group A])
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
(Escherichia coli)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
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26
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
CEFPROZIL
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
infections [Methicillin - Sensitive] (Staphylococcus
aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis (Streptococcus agalactiae
[Group B])
4) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
5) Pneumonia, Arthritis, Sinusitis, Otitis media [Penicillin -
Sensitive] (Streptococcus Pneumoniae [Pneumococcus])
6) Urinary tract infection, other infections, Bacteremia
(Escherichia coli)
7) Urinary tract and other infections (Proteus mirabilis)
8) Urinary tract infection (Klebsiella pneumoniae)
9) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella Multiocida)
11) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
12) "Malignant Pustule" Pneumonia (Bacillus anthracis)
CEPHALOSPORINS
G2 SECOND GENERATION
CEFOXITIN
1) Penicillin - Sensitive and Penicillinase - Producing
gonococcus (Neisseria gonorrhoeae)
2) Gas gangrene (Clostridium perfringens and other species)
3) Variety of nosocomial and opportunistic infections
4) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
CEFOTETAN
1) Gas gangrene (Clostridium perfringens and other species)
2) Variety of nosocomial and opportunistic infections
CEFUROXIME AXETIL
1) Otitis media, Sinusitis, Pneumonia (Haemophilus
influenza)
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CEPHAMANDOLE
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus mirabilis)
3) Urinary tract infection (Klebsiella Pneumoniae)
4) Pneumonia (Klebsiella Pneumoniae) an Aminoglycoside
CEFUROXIME
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus mirabilis)
3) Urinary tract infection (Klebsiella Pneumoniae)
4) Pneumonia (Klebsiella Pneumoniae) an Aminoglycoside
CEFONICID
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus mirabilis)
3) Urinary tract infection (Klebsiella Pneumoniae)
4) Pneumonia (Klebsiella Pneumoniae) an Aminoglycoside
CEFORANIDE
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus mirabilis)
3) Urinary tract infection (Klebsiella Pneumoniae)
4) Pneumonia (Klebsiella Pneumoniae) an Aminoglycoside
CEFOTIAM
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus mirabilis)
3) Urinary tract infection (Klebsiella Pneumoniae)
4) Pneumonia (Klebsiella Pneumoniae) an Aminoglycoside
CEFAMYCINS
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus mirabilis)
3) Urinary tract infection (Klebsiella Pneumoniae)
4) Pneumonia (Klebsiella Pneumoniae) an Aminoglycoside
CEFACLOR
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus mirabilis)
3) Urinary tract infection (Klebsiella Pneumoniae)
4) Pneumonia (Kiebsiella Pneumoniae) an Aminoglycoside
LORACARBEF
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus mirabilis)
3) Urinary tract infection (Klebsiella Pneumoniae)
4) Pneumonia (Klebsiella Pneumoniae) an Aminoglycoside
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28
CEPHALOSPORINS
G3 THIRD GENERATION
CEFTRIAXONE
1) Endocarditis, Bacteremia (Streptococcus [Viridans Group])
2) Meningitis (Streptococcus agalactiae [Group B])
3) Pneumonia, Arthritis, Sinusitis, Otitis [Penicillin -
Resistant] (Streptococcus pneumoniae
[Pneumonococcus])
4) Endocarditis, Meningitis, Other serious infections
[Penicillin intermediate- resistant and Penicillin -
Sensitive] (Streptococcus Pneumoniae)
5) Penicillin - Sensitive and Penicillin Producing gonococcus
(Neisseria gonorrhoeae [gonococcus])
6) Meningitis (Neisseria meningitidis [meningococcus])
7) Typhoid fever, Paratyphoid fever, Bacteremia
(Salmonella)
8) Epiglottis, Meningitis (Haemophilus influenzae)
9) Chancroid (Haemophilus ducreyi)
10) Wound infection (animal bite), Abscesses, Bacteremia,
Meningitis (Pasteurella multocida)
11) Melioidosis (Pseudomonas pseudomallei)
12) Bacteremia, Endocarditis, Meningitis (Campylobacter
fetus)
13) Syphilis (Treponema pallidum)
14) Erythema chronica migrans - skin, Stage 2 - neurological,
Cardiac, Arthritis (Borrelia burgdorferi [Lyme disease])
15) Pulmonary lesions, Brain abscess, Lesions of other organs
(Nocardia asteroides)
CEFOTAXIME
1) Meningitis (Streptococcus agalactiae [Group B])
2) Pneumonia, Arthritis, Sinusitis, Otitis [Penicillin -
Resistant] (Streptococcus pneumoniae
[Pneumonococcus])
3) Endocarditis, Meningitis, Other serious infections
[Penicillin intermediately- Resistant and Penicillin -
Sensitive] (Streptococcus Pneumoniae)
4) Endocarditis, Meningitis, Other serious infection [Penicillin
G - Resistant] (Streptococcus pneumoniae) + Rifampin or
+ Vancomycin
5) Meningitis (Neisseria meningitidis [meningococcus])
6) Epiglottits, Meningitis (Haemophilus influenzae)
CEFTIZOXIME
CA 02416512 2008-07-18
29
1) Gas gangrene (Clostridium perfringens and other species)
CEFIXIME
1) Penicillin - Sensitive and Penicillinase - Producing
gonococcus (Neisseria gonorrhoeae)
CEFTAZIDIME
1) Urinary tract infection (Pseudomas aeruginosa)
2) Pneumonia, Bacteremia Pseudomonas aeruginosa + an
Aminoglycoside
3) Melioidosis (Pseudomonas pseudomallei)
CEFMENOXIME
1) Otitis, Sinusitis, Pneumonia (Moraxella Catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
3) Urinary tract and other infections (Proteus mirabilis)
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
8) Variety of nosocomial and opportunistic infections
(Serratia)
CEFODIZIME
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
3) Urinary tract and other infections (Proteus mirabilis)
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
8) Variety of nosocomial and opportunistic infections
(Serratia)
CEFDINIR
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
3) Urinary tract and other infections (Proteus mirabilis)
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
8) Variety of nosocomial and opportunistic infections
(Serratia)
CEFETAMET PIVOXIL
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
3) Urinary tract and other infections (Proteus mirabilis)
CA 02416512 2008-07-18
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
5 8) Variety of nosocomial and opportunistic infections
(Serratia)
CEFTIBUTEN
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
10 3) Urinary tract and other infections (Proteus mirabilis)
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
15 8) Variety of nosocomial and opportunistic infections
(Serratia)
LATAMOXEF (OXACEPHALOSPORIN)
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
20 3) Urinary tract and other infections (Proteus mirabilis)
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
25 8) Variety of nosocomial and opportunistic infections
(Serratia)
CEFPIRAMIDE
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
30 3) Urinary tract and other infections (Proteus mirabilis)
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
8) Variety of nosocomial and opportunistic infections
(Serratia)
CEFSULODIN
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
3) Urinary tract and other infections (Proteus mirabilis)
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
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31
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
8) Variety of nosocomial and opportunistic infections
(Serratia)
CEFOPERAZONE
1) Otitis, Sinusitis, Pneumonia (Moraxella catarrhalis)
2) Urinary tract and other infections (Proteus, other species)
3) Urinary tract and other infections (Proteus mirabilis)
4) Urinary tract infection (Klebsiella pneumoniae)
5) Pneumonia (Klebsiella pneumoniae) an Aminoglycoside
6) Various nosocomial infections (Acinetobacter)
7) Yersiniosis, Sepsis (Yersinia enterocolitica)
8) Variety of nosocomial and opportunistic infections
(Serratia)
CEPHALOSPORINS
G4 FOURTH GENERATION
CEFEPIME
1) Active against many Enterobacteriaceae that are resistant
to other cephalosporins
2) Active against H. influenzae, N. gonorrhoeae and N.
meningitidis
3) High activity for streptococci and Methicillin-Sensitive
Staphylococcus aureus
4) Also active against P. aeruginosa and Xanthomonas
maltophilia
H. OTHER LACTAM ANTIBIOTICS CARBAPENEMS
IMIPENEM
1) Gas gangrene (Clostridium perfringens and other species)
2) Urinary tract and other infections (Enterobacter species)
3) Urinary tract and other infections (Proteus, other species)
4) Urinary tract infection (Pseudomonas aeruginosa)
5) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + an
Aminoglycoside
6) Pneumonia (Klebsiella pneumoniae)
7) Variety of nosocomial and opportunistic infections
(Serratia)
8) Various nosocomial infections (Acinetobacter)
9) Bacteremia, Endocarditis (Campylobacter fetus)
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32
10) Pulmonary lesions, Brain abscess, Lesions of other organs
(Nocardia asteroides)
MEROPENEM
1) Active against some Imipenem - Resistant Pseudomonas
aeruginosa
2) Urinary tract infection (Pseudomonas aeruginosa)
I. OTHER R - LACTAM ANTIBIOTICS
MONOBAKTAMS
AZTREONAM
1) Urinary tract infection, Other infections, Bacteremia
(Escherichia coil)
2) Urinary tract and Other infections (Proteus, other species)
3) Urinary tract infection (Pseudomonas aeruginosa)
4) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + an
Aminoglycoside
5) Pneumonia (Klebsiella pneumoniae)
6) Variety of nosocomial and opportunistic infections
(Serratia)
J. AMINOGLYCOSIDE
STREPTOMYCIN
1) Urinary tract infection, other infections, Bacteremia.
(Escherichia coli) Ampicillin
2) Urinary tract infection and other infections (Enterobacter
species)
3) Urinary tract infection and other infections (Proteus
mirabilis)
4) Urinary tract infection and other infections (Proteus, other
species)
5) Urinary tract infection (Pseudomonas aeruginosa)
6) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + A
broad-spectrum Penicillin; + Ciprofloxacin; + Ceftazidime;
+ Aztreonam; + Imipenem
7) Urinary tract infection (Klebsiella pneumoniae)
8) Pneumonia (Klebsiella pneumoniae) + Mezlocillin or
Piperacillin
9) Variety of nosocomial and opportunistic infections
(Serratia) + A broad-spectrum Penicillin
10) Various nosocomial infections (Acinetobacter)
11) Sepsis (Yersinia enterocolitica)
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33
12) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species; aerobic and anaerobic
[diptheroids]) + Penicillin G
13) Bacteremia, Arthritis, Endocarditis, Abscesses
(Streptobacillus moniliformis)
14) Pulmonary, Milary, Renal, Meningeal, and other
tuberculous infections (Mycobacterium tuberculosis) +
Rifampin or Ethambutol
15) Yaws (Treponema pertenue)
16) Plague (Yersinia pestis) Tetracycline
17) Tularemia (Francisella tularensis)
18) Glanders (Pseudomonas mallei) + a Tetracycline or +
Chloramphenicol
19) Occasionally administrate for tuberculosis (Mycobacterium
tuberculosis)
GENTAMICIN
1) Urinary tract infection, other infections, Bacteremia.
(Escherichia coli) Ampicillin
2) Urinary tract infection and other infections (Enterobacter
species)
3) Urinary tract infection and other infections (Proteus
mirabilis)
4) Urinary tract infection and other infections (Proteus, other
species)
5) Urinary tract infection (Pseudomonas aeruginosa)
6) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + A
broad-spectrum Penicillin; + Ciprofloxacin; + Ceftazidime;
+ Aztreonam; + Imipenem
7) Urinary tract infection (Klebsiella pneumoniae)
8) Pneumonia (Klebsiella pneumoniae) + Mezlocillin or
Piperacillin
9) Variety of nosocomial and opportunistic infections
(Serratia) + A broad-spectrum Penicillin
10) Various nosocomial infections (Acinetobacter)
11) Sepsis (Yersinia enterocolitica)
12) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species; aerobic and anaerobic
[diptheroids]) + Penicillin G
13) Endocarditis or other serious infection [bacteremia]
(Enterococcus) +Penicillin G or Ampicillin; +Vancomycin
14) Meningitis, Bacteremia (Listeria monocytogenes) +
Ampicillin or Penicillin G
15) Brucellosis (Brucella) + Doxycycline
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34
16) Tularemia (Francisella tularensis)
17) Bacteremia, Endocarditis (Campylobacter fetus)
TOBRAMYCIN
1) Urinary tract infection, other infections, Bacteremia.
(Escherichia coil) Ampicillin
2) Urinary tract infection and other infections (Enterobacter
species)
3) Urinary tract infection and other infections (Proteus
mirabilis)
4) Urinary tract infection and other infections (Proteus, other
species)
5) Urinary tract infection (Pseudomonas aeruginosa)
6) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + A
broad-spectrum Penicillin; + Ciprofloxacin; + Ceftazidime;
+ Aztreonam; + Imipenem
7) Urinary tract infection (Kiebsiella pneumoniae)
8) Pneumonia (Klebsiella pneumoniae) + Mezlocillin or
Piperacillin
9) Variety of nosocomial and opportunistic infections
(Serratia) + A broad-spectrum Penicillin
10) Various nosocomial infections (Acinetobacter)
11) Sepsis (Yersinia enterocolitica)
12) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species; aerobic and anaerobic
[diptheroids]) + Penicillin G
AMICACIN
1) Urinary tract infection, other infections, Bacteremia.
(Escherichia coil) Ampicillin
2) Urinary tract infection and other infections (Enterobacter
species)
3) Urinary tract infection and other infections (Proteus
mirabilis)
4) Urinary tract infection and other infections (Proteus, other
species)
5) Urinary tract infection (Pseudomonas aeruginosa)
6) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + A
broad-spectrum Penicillin; + Ciprofloxacin; + Ceftazidime;
+ Aztreonam; + Imipenem
7) Urinary tract infection (Klebsiella pneumoniae)
8) Pneumonia (Klebsiella pneumoniae) + Mezlocillin or
Piperacillin
9) Variety of nosocomial and opportunistic infections
(Serratia) + A broad-spectrum Penicillin
CA 02416512 2008-07-18
10) Various nosocomial infections (Acinetobacter)
11) Sepsis (Yersinia enterocolitica)
12) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species; aerobic and anaerobic
5 [diptheroids]) + Penicillin G
13) Disseminated disease in AIDS (Mycobacterium avium -
intracellulare)
14) Pulmonary lesions, Brain abscess, Lesions of the other
organs
10 NETILMICIN
1) Urinary tract infection, other infections, Bacteremia.
(Escherichia coli) Ampicillin
2) Urinary tract infection and other infections (Enterobacter
species)
15 3) Urinary tract infection and other infections (Proteus
mirabilis)
4) Urinary tract infection and other infections (Proteus, other
species)
5) Urinary tract infection (Pseudomonas aeruginosa)
20 6) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + A
broad-spectrum Penicillin; + Ciprofloxacin; + Ceftazidime;
+ Aztreonam; + Imipenem
7) Urinary tract infection (Klebsiella pneumoniae)
8) Pneumonia (Klebsiella pneumoniae) + Meziocillin or
25 Piperacillin
9) Variety of nosocomial and opportunistic infections
(Serratia) + A broad-spectrum Penicillin
10) Various nosocomial infections (Acinetobacter)
11) Sepsis (Yersinia enterocolitica)
30 12) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species; aerobic and anaerobic
[diptheroids]) + Penicillin G
13) Effective against certain gentamicin-resistant pathogens,
except enterococci
35 KANAMYCIN
1) Urinary tract infection, other infections, Bacteremia.
(Escherichia coli) Ampicillin
2) Urinary tract infection and other infections (Enterobacter
species)
3) Urinary tract infection and other infections (Proteus
mirabilis)
4) Urinary tract infection and other infections (Proteus, other
species)
CA 02416512 2008-07-18
36
5) Urinary tract infection (Pseudomonas aeruginosa)
6) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + A
broad-spectrum Penicillin; + Ciprofloxacin; + Ceftazidime;
+ Aztreonam; + Imipenem
7) Urinary tract infection (Klebsiella pneumoniae)
8) Pneumonia (Klebsiella pneumoniae) + Mezlocillin or
Piperacillin
9) Variety of nosocomial and opportunistic infections
(Serratia) + A broad-spectrum Penicillin
10) Various nosocomial infections (Acinetobacter)
11) Sepsis (Yersinia enterocolitica)
12) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species; aerobic and anaerobic
[diptheroids]) + Penicillin G
13) Orally for the prophylactic use as adjunctive therapy in
cases of hepatic coma
NEOMYCIN
1) Urinary tract infection, other infections, Bacteremia.
(Escherichia coli) Ampicillin
2) Urinary tract infection and other infections (Enterobacter
species)
3) Urinary tract infection and other infections (Proteus
mirabilis)
4) Urinary tract infection and other infections (Proteus, other
species)
5) Urinary tract infection (Pseudomonas aeruginosa)
6) Pneumonia, Bacteremia (Pseudomonas aeruginosa) + A
broad-spectrum Penicillin; + Ciprofloxacin; + Ceftazidime;
+ Aztreonam; + Imipenem
7) Urinary tract infection (Klebsiella pneumoniae)
8) Pneumonia (Klebsiella pneumoniae) + Mezlocillin or
Piperacillin
9) Variety of nosocomial and opportunistic infections
(Serratia) + A broad-spectrum Penicillin
10) Various nosocomial infections (Acinetobacter)
11) Sepsis (Yersinia enterocolitica)
12) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species; aerobic and anaerobic
[diptheroids]) + Penicillin G
13) For bladder irrigation + Polymyxin B
14) Variety of infections of the skin and mucous membranes
caused by microorganisms susceptible to the drug. These
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37
include infections associated with burns, wounds, ulcers,
and infection dermatoses.
K. TETRACYCLINE
TETRACYCLINE
1) Sinusitis (Moraxella catarrhalis)
2) Plague (Yersinia pestis) Streptomycin
3) Glanders (Pseudomonas mallei) + Streptomycin
4) Stage 2 - Neurological, cardiac, arthritis (Borrelia
burgdorferi [Lyme disease])
CHLORTETRACYCLINE
OXYTETRACYCLINE
DOXYCYCLINE
1) Erysipeloid (Erysipelothrix rhusiopathiae)
2) Gas gangrene (Clostridium perfringens & other species)
3) Tetanus (Clostridium tetani)
4) Urinary tract infection (Escherichia coli)
5) Brucellosis (Brucella) + Gentamicin or Rifampin
6) Chancriod (Haemophilus ducreyi)
7) Plague (Yersinia pestis)
8) Wound infection-animal bite (Pasteurella multocida)
9) Cholera (Vibrio cholerae)
10) Lung abscess, empyema (Fusobacterium nucleatum)
11) Arthritis (Streptobacillus moniliformis)
12) Syphilis (Treponema pallidum)
13) Yaws (Treponema pertenue)
14) Erythema chronica migrans-skin (Borrelia
burgdorferi[Lyme disease])
15) Relapsing fever (Borrelia recurrentis)
16) Weil's disease and meningitis (Leptospira)
17) Cervicofacial, abdominal, thoracic, and other lesions
(Actinomyces israelii)
18) Non-specific urethritis (Ureaplasma urealyticum)
19) "Atypical pneumonia" (Mycoplasma pneumoniae)
20) Typhus fever, Murine typhus, Brill's disease, Rocky
Mountain spotted fever, Q fever, and Rickettsialpox
(Rickettsia)
21) Psittacosis (Chlamydia psittaci)
22) Lymphogranuloma venereum, Trachoma, Inclusion
conjunctivitis (blennorrhea), Non-specific urethritis,
Cervicitis (Chlamydia trachomatis)
23) Pneumonia (Chlamydia pneumoniae)
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38
MINOCYCLINE
DEMECLOCYCLINE
METHACYCLINE
L. CHLORAMPHENICOL
CHLORAMPHENICOL
1) Meningitis (Streptococcus agalactiae [Group B])
2) Bacteremia, Endocarditis, Brain and other abscesses, and
Sinusitis (Streptococcus [anaerobic species])
3) Pneumonia, Arthritis, Sinusitis, Otitis, Endocarditis,
Meningitis, Other serious infections (Streptococcus
pneumoniae [pneumonococcus]).
4) Meningitis (Neisseria meningitidis [meningococcus])
5) "Malignant pustule", Pneumonia (Bacillus anthracis)
6) Bacteremia (Listeria monocytogenes)
7) Erysipeloid (Erysipelothrix rhusiophathiae)
8) Gas gangrene (Clostridium perfringens and other species)
9) Typhoid fever, Paratyphoid fever, Bacteremia
(Salmonella)
10) Epiglottitis, Meningitis (Haemophilus influenza)
11) Brucellosis (Brucella)
12) Plague (Yersinia pestis)
13) Sepsis (Yersinia enterocolitica)
14) Tularemia (Francisella tularensis)
15) Cholera (Vibrio cholerae)
16) Glanders (Pseudomonas mallei) + Streptomycin
17) Melioidosis (Pseudomonas pseudomallei)
18) Meningitis (Campylobacter fetus)
19) Ulcerative pharyngitis, Lung abscess and Empyema,
Genital infections, Gingivitis (Fusobacterium nucleatum)
20) Bacteremia, Arthritis, Endocarditis, Abscesses
(Streptobacillus moniliformis)
21) Typhus fever, Murine typhus, Brill's disease, Rocky
mountain spotted fever, Q fever, Rickettsialpox
(Rickettsia)
22) Psittacosis [ornithosis] (Chiamydia psittaci)
THIAMPHENICOL
AZIDAMPHENICOL
M. ERYTHROMYCIN AND OTHERS
MACROLIDES:
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39
ERYTHROMYCIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia
Osteomyelitis, Cellulitis and other Staph. aureus
infections [Methicillin - Sensitive] (Staphylococcus
s aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, toxic shock - like
syndrome, and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
4) Penicillin - Sensitive gonococcus (Neisseria gonorrhoeae)
5) "Malignant pustule", Pneumonia (Bacillus anthracis)
6) Pharyngitis, Laryngotracheitis, Pneumonia, and other local
lesions, Carrier state (Corynebacterium diptheriae)
7) Bacteremia (Listeria monocytogenes)
8) Chancroid (Haemophilus ducreyi)
9) Enteritis (Campylobacter jejuni)
10) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis (Fusobacterium nucleatum)
11) Bacteremia, Arthritis, Endocarditis, Abscesses
(Streptobacillus moniliformis)
12) Legionnaires' disease (Legionella pneumophila) rifampin
13) Relapsing fever (Borrelia recurrentis)
14) Cervicofacial, Abdominal, Thoracic and other lesions
(Actinomyces israelii).
15) Non-specific Urethritis (Ureaplasma Urealyticum)
16) "Atypical pneumonia" (Mycoplasma pneumoniae)
17) Lymphogranuloma venereum, Trachoma, Inclusion
conjunctivitis [blennorrhea], Non-specific urethritis,
Cervicitis (Chlamydia trachomatis)
18) Pneumonia (Chlamydia pneumoniae)
19) Erysipeloid (Erysipelothrix rhusiopathiae)
20) Bordetella pertussis disease and for post-exposure
prophylaxis of all household member and other close
contacts.
21) Tetanus in patients who are allergic to penicillin
(Clostridium tetani)
CLARITHROMYCIN
1) Legionnaires' disease (Legionella pneumophila)
2) "Atypical pneumonia" (Mycoplasma pneumoniae)
3) Pneumonia (Chlamydia pneumoniae)
CA 02416512 2008-07-18
4) Enteritis (Campylobacter jejuni)
5) Disseminated disease in AIDS (Mycobacterium avium --
intracellulare) + Ethambutol; t Clofazimine; f
Ciprofloxacin
5 6) Erythema chronica migrans - skin (Borrelia burgdorferi
[Lyme disease])
7) Modest activity against H. influenzae and N. gonorrhoeae
8) Good activity against M. catarrhalis
9) Enhanced activity against some protozoa (e.g.,
10 Toxoplasma gondii, Cryptoporidium and Plasmodium spp.
10) Regimens for the treatment of peptic ulcers related to H.
pylori infection
11) Lepromatous leprosy (Mycobacterium leprae) +
minocycline
15 AZITHROMYCIN
1) Otitis media, Sinusitis, Pneumonia (Haemophilus
influenzae)
2) Enteritis (Campylobacter jejuni)
3) Legionnaires' disease (Legionella pneumophila)
20 4) Erythema chronica migrans - skin (Borrelia burgdorferi
[Lyme disease])
5) "Atypical pneumonia" (Mycoplasma pneumoniae)
6) Lymphogranuloma venereum, Trachoma, Inclusion
conjunctivitis [blennorrhea], Non-specific urethritis,
25 Cervicitis (Chlamydia trachomatis)
7) Pneumonia (Chlamydia pneumoniae)
8) Less active against Streptococcus spp. And Enterococci
9) Active against M. catarrhals, Pasteurella multocida,
Fusobacterium spp., N. gonorrhoeae
30 10) Enhanced activity against Mycobacterium avium-
intracellulare, as well as against protozoa (e.g.
Toxoplasma gondii, Crytosporidium and Plasmodium spp.
11) Toxoplasmosis encephalitis and diarrhoea due to
Cryptosporidium
ROXITHROMYCIN
N. LINCOMYCIN
CLINDAMYCIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
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41
infections [Methicillin - Sensitive] (Staphylococcus
aureus).
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome, and other systemic infections (Streptococcus
pyogenes [Group A])
3) Bacteremia, Endocarditis, Brain and other abscesses,
Sinusitis (Streptococcus [anaerobic species])
4) Pneumonia, Arthritis, Sinusitis, Otitis [Penicillin - Sensitive
and Penicillin - Resistant] (Streptococcus pneumoniae)
5) Pharyngitis, Laryngotracheitis, Pneumonia, Other local
lesions (Corynebacterium diphteriae)
6) Gas gangrene (Clostridium perfringens and other species)
7) Tetanus (Clostridium tetani)
8) Enteritis (Campylobacter jejuni)
9) Ulcerative pharyngitis, Lung abscess, Empyema, Genital
infections, Gingivitis
10) Pneumonia in impaired host [Mild or moderate disease
and moderately severe or severe disease] (Pneumocystis
carinii) + Primaquin
11) Treatment of infections with anaerobes, especially those
due to B. fragilis
12) Intra-abdominal or pelvic abscesses and peritonitis + an
Aminoglycoside or + Penicillin or + Cephalothin
13) Topically or orally for acne vulgaris and for bacterial
vagionosis
SPECTINOMYCIN
1) Penicillin - Sensitive and Penicillinase-Producing
gonococcus (Neisseria gonorrhoeae)
2) In pregnancy when patients are intolerant to 3-Lactams
and when quinolones are contraindicated
3) Recommended as an alternative regimen in patients who
are intolerant or allergic to [3-Lactam antibiotics and
quinolones
POLYMYXIN B (Polymyxin B Sulfate)
1) Available for ophthalmic, otic and topical use in
combination with a variety of other compounds.
2) Infections of the skin, mucous membranes, eye, and ear
due to polymyxin B - sensitive microorganisms
3) External otitis, frequently due to pseudomonas
4) Infection of corneal ulcers (Pseudomonas aeruginosa)
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42
5) Pneumonia (Pseudomonas)
COLISTIN (Colisten Sulfate)
1) Diarrhoea caused by bacteria susceptible to the drug in
infants and children
RAMOPLANIN (glycopeptide)
1) Treatment of acne and skin infections, and to reduce
nasal carriage of staphylococci
Active against Bacteroides spp.
TEICOPLANIN (glycopeptide)
1) Osteomyelitis, Endocarditis caused by Methicillin -
Resistant and Methicillin - Susceptible Staphylococci,
Streptococci and Enterococci
2) Bacteremia, Endocarditis [methicillin - susceptible]
(Staphylococcus aureus) + an Aminoglycoside
[gentamycin]
3) Enterococcal endocarditis + Gentamicin
4) Endocarditis + Vancomycin
BACITRACIN
1) Infected eczema, Infected dermal ulcers
2) Suppurative conjunctivitis and infected corneal ulcer when
they are cause by susceptible bacteria
3) Eradication of nasal carriage of Staphylococci
4) Antibiotic - associated diarrhoea (Clostridium difficile)
RP 59500
1) Is a good inducer of the methylase enzyme that mediates
MLS resistance
2) Are synergistic and therefore, erythromycin-resistant
organisms frequently are susceptible to RP 59500 in vitro
GLYCYLCYCLINES (Tetracycline Antibiotic derivatives)
1) They inhibit some tetracycline-resistant organisms
2) Also appear to be active against multiply drug-resistant
strains of Staphylococci, pneumacocci and vancomycin-
resistant enterococci
GLYCOPEPTIDE AND OTHER:
VANCOMYCIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis and other Staphylococcus aureus
CA 02416512 2008-07-18
43
infections [Methicillin - Sensitive and Methicillin Resistant]
(Staphylococcus aureus)
2) Pharyngitis, Scarlet fever, Otitis media, Sinusitis, Cellulitis,
Erysipelas, Pneumonia, Bacteremia, Toxic shock - like
syndrome, and other systemic infections (Streptococcus
pyogenes [Group A])
3) Endocarditis, Bacteremia (Streptococcus [Viridans Group])
4) Bacteremia, Endocarditis (Streptococcus agalactiae [
Group B])
5) Pneumonia, Arthritis, Sinusitis, Otitis [Penicillin -
Resistant] (Streptococcus pneumoniae).
6) Endocarditis, Meningitis, Other serious infections
[Penicillin - intermediately Resistant] (Streptococcus
pneumoniae) + Rifampin
7) Endocarditis, Meningitis, Other serious infections
[Penicillin G - Resistant] (Streptococcus pneumoniae) +
Rifampin or + Cefotaxime
8) Endocarditis or other serious infection [bacteremia]
(Enterococcus) + Gentamincin
9) Urinary tract infection (Enterococcus)
10) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species, aerobic and anaerobic
[diptheroids])
11) Tetanus (Clostridium tetani)
12) Antibiotic - associated colitis (Clostridium difficile)
13) Meningitis (Flavobacterium meningosepticum)
14) Pseudomembranous colitis
15) Staphylococcal infections in patients who are allergic to
penicillins and cephalosporins
0. Drugs Used in the Treatment of Tuberculosis, Mycobacterium avium
Complex, and Leprosy
AMIKACIN
AMINOSALICYCLIC ACID
AZITHROMYCIN
CAPREOMYCIN
CEFOXITIN
CIPOFLOXACIN
CLARITHROMYCIN
CLOFAZIMINE
DAPSONE
DOXYCYCLIN E
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ETHAMBUTOL
ETHIONAMIDE
IMIPENEM
ISONIAZID
KANAMYCIN
MINOCYCLINE
OFLOXACIN
OFLOXACIN
PYRAZINAMIDE
RIAMPIN
RIFABUTIN
RIFAMPIN
STREPTOMYCIN
SULFONAMIDE
TRIM ETHOPRIM-SULFAMETHOXAZOLE,
P. OTHER TREATMENTS
RIFAMPIN
1) Abscesses, Bacteremia, Endocarditis, Pneumonia,
Osteomyelitis, Cellulitis, Other [Methicillin-Sensitive
Methicillin-Resistant] (Staphylococcus aureus) +
Ciprofloxacin or [+ Trimethoprim-sulfumethoxazole when
methicillin-resistant]
2) Endocarditis, Meningitis, Other serious infection
[Penicillin-Intermediately resistant] (Streptococcus
pneumonia (pneumonococcus)) + Vancomycin
3) Endocarditis, Meningitis, Other serious infection [Penicillin
G-resistant] (Streptococcus pneumoniae
(pneumonococcus)) + Cefotaxime or + Vancomycin
4) Carrier state (post-treatment) (Neisseria meningitidis
(meningoccoccus))
5) Pharyngitis, Laryngotracheitis, Pneumonia, Other local
lesions (Corynebacterium diphtheriae)
6) Endocarditis, Infected foreign bodies, Bacteremia
(Corynebacterium species, aerobic and anaerobic
(diphtheroids)) + Penicillin G
7) Brucellosis (Brucella) + Doxycycline or + Trimethoprim
8) Meningitis (Flavobacterium meningosepticum)
9) Legionnaires' disease (Legionella pneumophila) +
Erythromycin
Q. ANTI-FUNGAL AGENTS
AMPHOTERICIN B
AMPHOTERICIN B
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AMPHOTERICIN B
AMPHOTERICIN B
AMPHOTERICIN B
AMPHOTERICIN B
5 AMPHOTERICIN B
AMPHOTERICIN B,
BUTOCONAZOLE
CICLOPIROX
CICLOPIROX
10 CLOTRIMAZOLE
CLOTRIMAZOLE
CUTANEOUS
ECONAZOLE
ECONAZOLE
15 EXTRACUTANEOUS
FLUCONAZOLE
FLUCONAZOLE
FLUCONAZOLE
FLUCONAZOLE
20 FLUCONAZOLE,
FLUCYTOSINE
GRISEOFULVIN
HALOPROGIN
INTRATHECAL
25 IODIDE, ITRACONAZOLE
ITRACONAZOLE
ITRACONAZOLE
ITRACONAZOLE,
ITRACONAZOLE,
30 ITRACONAZOLE,
IV MICONAZOLE
KETOCONAZOLE
KETO-CONAZOLE
KETO-CONAZOLE
35 KETO-CONAZOLE
KETOCONAZOLE,
MICONAZOLE
MICONAZOLE
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46
MICONAZOLE NYSTATIN
NAFTIFINE
NYSTATIN
NYSTATIN
SPOROTRICHOSIS
SYSTEMIC
TERBINAFINE
TERBINAFINE
TERCONAZOLE
TIOCONAZOLE
TOPICAL CLOTRIMAZOLE
UNDECYLENATE
R. OTHER TREATMENTS
POLIEEN ANTIBIOTICS
AMPHOTERICIN B
1) Deep infection (Candida species) f Flucytosine
2) Disseminated (non-meningeal), Meningitis (Coccidioides
immitis)
3) Chronic Pulmonary disease, Disseminated (Histoplasma
capsulatum)
4) All the Blastomyces brasiliensis infections
5) All the paracocidioides brasiliensis infections followed up
by a sulfonamide
6) Extracutaneous (Sporothrix schenckii)
7) Invasive (Aspergillus species)
8) All the infections of the mucormycosis Agents
9) Pulmonary (Cryptococcus neoformans)
10) Meningitis (Cryptococcus neoformans) Flucytosine
NYSTATIN
1) Cutaneous or vaginal thrush, oral thrush (Candida
species)
FLUCYTOSINE
1) Deep infections (Candida species) + Amphotericin B
2) Meningitis (Cryptococcus neoformans) + Amphotericin B
POVIDONE IODINE
Povidone-iodine is an iodophore which is used as a disinfectant
and antiseptic mainly for the treatment of contaminated wounds
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and pre-operative preparation of the skin and mucous
membranes as well as for the disinfection of equipment.
S. IMIDAZOLES AND TRIAZOLES
KETOCONAZOLE
1) Cutaneous or vaginal thrush, Oral thrush, (Candida
species)
2) Chronic pulmonary disease (Histoplasma capsulatum)
3) All Blastomyces dermatitidis infections.
4) All Paracoccidioides brasiliensis infections
ITRACONAZOLE
1) Cutaneous or vaginal thrush, Oral thrush (Candida
species)
2) Disseminated (non-meningeal), Meningitis (Coccidioides
immitis)
3) Disseminated (Histoplasma capsulatum)
4) Cutaneous, Extracutaneous (Sporothrix schenckii)
5) Invasive (Aspergillus species)
6) Chronic pulmonary disease (Histoplasma capsulatum)
7) All paracoccidioides brasiliensis infections
8) All Blastomyces dermatitidis infections
FLUXONAZOLE
1) Cutaneous or vaginal thrush, Oral thrush, Deep infection
(Candida Species)
2) Disseminated (non-meningeal), Meningitis (Coccidioides
immitis)
3) Chronic pulmonary disease (Histoplasma capsulatum)
4) Meningitis (Cryptococcus neoformans)
CLOTRIMAZOLE
1) Oral thrush (Candida Species)
GRISEOFULVIN
1) Mycotic disease of the skin, hair and nails due to
Microsporum, Trichophyton or Epidermophyton
2) Tinea capitis (M. canis, M. audouini; T. schoenleinii and T.
verrucosum)
3) "Ringworm" of the glabrous skin, Tinea cruris and tinea
corporis (M. canis, T. rubrum, T. verrucosum and E.
floccosum)
4) Tinea of the hands (T. rubrum, T. mentagraphytes)
5) Tinea of the beard (Trichopyton species)
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6) "Athlete's foot" or epidermophytosis involving the skin
and nails (T. mentagraphytes and the hyperkeratotic type
to T. rubrum).
T. TOPICAL ANTI-FUNGAL AGENTS
Imidazoles and Triazoles for Topical Use
CLOTRIMAZOLE
1) Dermatophyte infections, Cutaneous candidiasis,
Vulvovaginal candidiasis
ECONAZOLE
MICONAZOLE
1) Tinea pedis, Tinea cruris, Tinea versicolor
2) Vulvovaginal candidiasis
3) Some vaginal infections caused by Candida glabrata
TERCONAZOLE
1) Vaginal Candidiasis
BUTOCONAZOLE
1) Vaginal Candidiasis
TIOCONAZOLE
1) Candida Vulvovaginitis
OXICONAZOLE
1) Infections caused by the common pathogenic
dermatophytes
SULCONAZOLE
1) Infections caused by the common pathogenic
dermatophytes
U. OTHER ANTI-FUNGAL AGENTS FOR TOPICAL USE
CICLOPIROX OLAMINE
1) Cutaneous candidiasis, Tinea corporis, Tinea cruris, Tinea
pedis, Tinea versicolor
2) Dermatomycoses and candidal infections
HALOPROGIN
1) Tinea pedis, Tinea cruris, Tinea corporis, Tinea manuum
and Tinea versicolor
TOLNAFTATE
1) Tinea pedis
NAFTIFINE
1) Treatment of Tinea cruris and Tinea corporis
2) Cutaneous candidiasis and Tinea versicolor
TERBINAFINE
1) Tinea corporis, Tinea cruris, Tinea pedis
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2) Cutaneous candidiasis and Tinea versicolor
3) Treatment of ringworm and in some cases of
onychomycosis
V. MISCELLANEOUS ANTI-FUNGAL AGENTS
UNDECYLENIC ACID
1) Treatment of various dermatomycoses, especially Tinea
pedis
2) Treatment of diaper rash, Tinea cruris and other minor
dermatologic conditions
BENZOIC ACID AND SALICYLIC ACID
1) Treatment of Tinea pedis and sometimes used to treat
Tinea capitis
PROPIONIC ACID AND CAPRYLIC ACID
1) Treatment of the dermatomycoses
POTASSIUM IODIDE
1) Cutaneous (Sporothrix schenckii)
W. ANTI-FUNGAL AGENTS FOR OPHTHALMIC USE
NATAMYCIN
Fungal blepharitis, conjunctivitis, keratitis
IMIDAZOLES CLOTRIMAZOLE
Fungal keratitis
ECONAZOLE
Fungal keratitis
FLUCONAZOLE
Fungal keratitis
KETOCONAZOLE
Fungal keratitis
MICONAZOLE
Fungal keratitis, endophthalmitis
PYRIMIDINES
FLUCYTOSINE
Fungal keratitis
POLYENES
AMPHOTERICIN B
Fungal keratitis, endophthalmitis
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X. ANTI-VIRAL AGENTS
ANTI-HERPESVIRUS AGENTS:
ACYCLOVIR
1) Genital disease, Keratoconjunctivitis, Encephalitis,
5 Neonatal HSV, Mucocutaneous HSV in immuno-
compromised host (Herpes simplex virus)
2) Herpes zoster or varicella in immuno-compromised host,
pregnancy, Varicella or herpes zoster in normal host
(Varicella zoster virus)
10 VALACYCLOVIR
1) Genital herpes or localised herpes zoster
FAMCICLOVIR
1) Varicella or herpes zoster in normal host (Varicella zoster
virus)
15 PENCICLOVIR
1) It is inhibitory for hepatitis B virus
FOSCARNET
1) Retinitis in patients with AIDS (Cytomegalovirus)
2) Mucocutaneous HSV in immuno-compromised host
20 (Herpes simplex virus)
3) Herpes zoster or varicella in immuno-compromised host,
pregnancy (Varicella zoster virus)
GANCICLOVIR
1) Retinitis in patients with AIDS (Cytomegalovirus)
25 IDOXURIDINE
1) Keratoconjunctivitis (Herpes simplex virus)
SORIVUDINE
1) Herpes zoster in HIV - infected adults
30 TRIFLURIDINE
1) Keratoconjunctivitis (Herpes simplex virus)
VIDARABINE
1) Encephalitis, neonatal herpes (Herpes simplex virus)
2) Zoster or varicella in immuno-compromised patients
Y. ANTI-RETROVIRAL AGENTS
ZIDOVUDINE
1) AIDS, HIV antibody positive and CD4 count less than
500/mm3 (Human immuno-deficiency virus)
DIDANOSINE
1) Advanced HIV infections in adults and children over 6
months
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STAVUDINE
1) AIDS, HIV antibody positive and CD4 count less than
400/mm3 (Human immuno-deficiency virus)
ZALCITABINE
1) AIDS
2) HIV infection and CD4 count less than 300/mm3
Z. OTHER ANTI-VIRAL AGENTS
AMANTADINE
1) Influenza (Influenza A)
RIMANTADINE
1) Influenza (Influenza A)
INTERFERONS ALFA
1) Genital papilloma (Human papilloma virus)
RIBAVIRIN
1) Pneumonia and bronchiolitis of infancy (Respiratory
syncytial virus)
AA. NEWER AGENTS UNDER CLINICAL DEVELOPMENT
LAMIVUDINE
PROTEASE INHIBITORS
ACYCLIC NUCLEOSIDE PHOSPHONATES
AB. ANTI-VIRAL AGENTS FOR OPHTHALMIC USE
IDOXURIDINE (HERPLEX )
1) Herpes simplex keratitis
TRIFLURIDINE (VIROPTIC )
1) Herpes simplex keratitis
VIDARABINE (VIRA-A )
1) Herpes simplex keratitis
2) Herpes simplex conjunctivitis
ACYCLOVIR (ZOVIRAX )
1) Herpes zoster ophthalmicus
2) Herpes simplex keratitis
FOSCARNET (FOSCAVIR )
1) Cytomegaloviris retinitis
GANCICLOVIR (CYTOVENE )
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52
1) Cytomegaloviris retinitis
AC. Topical Antibacterial Agents Commercially Available for Ophthalmic
Use
BACITRACIN ZINC (AK-TRACIN )
1) Conjunctivitis, blepharitis
CHLORAMPHENICOL (AK-CHLOR , CHLOROMYCETIN ,
CHLOROPTIC , OCU-CHLOR )
1) Conjunctivitis, keratitis
CHLORTETRACYCLINE HYDROCHLORIDE
(AUREOMYCIN )
1) Conjunctivitis, blepharitis
CIPROFLOXACIN HYDROCHLORIDE (CILOXAN )
1) Conjunctivitis, keratitis
ERYTHROMYCIN (AK-MYCIN , ILOTYCIN )
1) Blepharitis, conjunctivitis
GENTAMICIN SULFATE (GARAMYCIN , GENOTIC , GENT-AK,
GENTACIDIN )
1) Conjunctivitis, blepharitis, keratitis
NORFLOXACIN (CHIBROXIN )
1) Conjunctivitis
SULFACETAMIDE SODIUM
(AK-SULF , BLEPH-10 , CETAMIDE , SULF-10 , ISOPTO
CETAMIDE , OPHTHACET , SULAMYD SODIUM )
1) Conjunctivitis, blepharitis, keratitis
SULFISOXAZOLE DIOLAMINE (GANTRISIN )
1) Conjunctivitis, blepharitis, keratitis
POLYMYXIN B COMBINATIONS
1) Conjunctivitis, blepharitis, keratitis
TETRACYCLINE HYDROCHLORIDE (ACHROMYCIN )
1) Conjunctivitis, blepharitis
TOBRAMYCIN SULFATE (TOBREX )
1) Conjunctivitis, blepharitis, keratitis
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54
PRELIMINARY HYPOTHESES OF MECHANISM OF OPERATION
The mechanism by which the enhancement of action of anti-infective
drugs is achieved by the present invention, is currently under
investigation. Some observations in this regard have been recorded
above. In addition it is recorded that preliminary observations point to
some additional possible explanations. The applicant again does not wish
to be bound to any of the tentative explanations it may put forward at
this time. It is recorded, however, that it would appear that the long chain
fatty acids used in the formulation of the preparation according to the
invention, or at least some of these components, form, during the
manufacturing process of the medicinal formulation, very small spherical
bodies, hereinafter referred to as "nanolipid vesicles". These nanolipid
vesicles have dynamic characteristics in respect of the encapsulation and
subsequent delivery of compounds at predicted areas in cells and
organisms where the optimal utilisation of these compounds occur with
resultant maximised modes of actions.
The present model for the understanding of the invention is that the
dynamic delivery characteristics of the nanolipid vesicles are utilised
efficiently to transport compounds to locations where maintenance of
optimal concentrations in the organisms is beneficial in combating specific
infective diseases.
Infectious diseases, especially those which are known to develop
resistance to compounds are known to be difficult to treat due to
insufficient penetration of the compound into the causative
microorganisms. These, or at least some of these appear to be
particularly suited for the benefits of the present invention.
The composition of the invention has thus been found to have beneficial
drug delivery effects when exposed to cells and causative organisms
harboured by such cells.
These beneficial effects are believed to be attributable to the dynamic
characteristics of the nanolipid vesicles. The current hypothesis is that
these characteristics include:
1. The structural characteristics of the formulation of the
preparation:
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Nitrous oxide and the unsaturated long chain fatty acids forming
part of the administration medium are formulated by being mixed
with designated anti-infective agents or compounds to form the
nanolipid vesicles containing the compound or anti-infective agent.
5 Two important observations have been made in this regard:
a) It was found that when the unsaturated long chain fatty acids used
are 20 carbons or more, the nanolipid vesicles form spherical
structures with sub-compartments similar to those seen in a
10 sponge.
These structures are stable and it is our belief that antibodies or
other ligands would fit ideally in these sub-compartments so that
the nanolipid vesicles bind to specific epitopes or receptors at the
15 target cell surface.
b) When unsaturated long chain fatty acids of 16 to 20 carbons are
used, the form of the nanolipid vesicles is spherical with a dynamic
field of moving autofluorescent particles surrounding the vesicles.
When nitrous oxide is omitted from the process the moving particles
surrounding the nanolipid vesicles move erratically and
asymmetrical movements are then detected.
It is believed that nitrous oxide is essential in stabilising the moving
autofluorescent particles surrounding the nanolipid- vesicles, which
is an essential characteristic to efficient compound delivery.
2. Stability:
The nanolipid vesicles appear to remain structurally intact after 24
months at room temperature. Any encapsulated active compounds
remain encapsulated during this time. This stability feature is
believed to be of substantial significance and one of the contributing
factors for the enhancement observed.
3. Absence of cytotoxicity:
The nanolipid vesicles have no apparent cytotoxicity. When applied
to cells in culture, at applicable concentrations they appear rather to
have a beneficial effect on normal cell growth.
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56
4. Mechanism of action:
4.1 Loading efficiency:
The high loading efficiency of nanolipid vesicles has been
demonstrated by achieving a high degree of encapsulation of
a wide range of active drugs.
4.2 Transport:
The nanolipid vesicles behave as a transport mechanism to
carry molecules such as active compounds.
4.3 Release:
It has been shown that the nanolipid vesicles have very high
delivery efficiencies. The high delivery efficiency relates to
tissue penetration, cell adsorption, internalisation of nanolipid
vesicles by cells, parasites and bacteria, intra-cellular
stability, and subsequent sub-cellular organelle delivery.
The result of high delivery efficiency is the release of active
compounds not only at membrane sites, but also at
intracellular sites including the nuclei of viable cells or
microorganisms. The result is an enhanced efficacy of said
active compound. The nanolipid vesicles and active compound
appear to act synergistically in attaining enhanced efficacy.
5. Elasticity:
Confocal laser scanning microscopy (CLSM) shows that the
conformation of nanolipid vesicles can be changed while in
movement.
When the vesicles move through membranes, the conformation
changes so that the intracellular nanolipid vesicles may have other
morphological characteristics.
While moving through membranes the nanolipid vesicles 'feed' the
membranes with unsaturated long chain fatty acids which in its turn
will have a positive effect on membrane bound processes. This
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57
process has a positive effect on the metabolism of the cell and thus
the survival of the cells.
6. Dynamic inter-lipid vesicle relationships:
It has been shown that vesicle inter-lipid relationships do exist. The
lipid vesicles can interchange the compounds they respectively
carry.
They can also combine to resize themselves continuously without
detriment to their stability. The inter-lipid relationship is also
revealed when moving through the cellular membrane.
These interactive membrane characteristics make the movement of
the vesicles through the cells optimal.
Although inter-relationships of the dynamic nanolipid vesicles are
continuously present, it has also been shown that the particles are
stable in blood and body fluids for up to 5 hours.
EXAMPLES OF THE INVENTION
Without thereby limiting the scope of the invention some examples will
now be described to illustrate the invention. Preparations which do not as
such form part of the claimed subject matter of this application, being
preparations first disclosed in the applicant's own prior patents referred to
above, are first restated.
PREPARATION 1
Preparing an aqueous nitrous oxide solution
A pressure vessel is charged to its operating volume with water at 20 C
[ambient temperature]. The vessel is connected to a supply of nitrous
oxide via a flow control valve and pressure regulator. The closed vessel is
supplied with nitrous oxide at a pressure of 2 bar for a period of 48 hours,
it having been determined that at the aforementioned temperature the
water is saturated with nitrous oxide over such period of time under the
above-mentioned pressure.
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58
A resultant solution is bottled as stock solution for use in the formulations
and applications set out below.
PREPARATION 2
Preparation of nitrous oxide/Vitamin F aqueous emulsion
30g Vitamin F ethyl ester as identified and described above was mixed
with 10g Cremophor RH40 (which is the trade name used by BASF for a
product which it describes as the reaction product of hydrogenated castor
oil with ethylene oxide which product is also known by the INCI name as PEG-
n-Hydrogenated Castor Oil), 2,2g methyl paraben, 0,08g butyl
hydroxyanisole, 0,23g butyl hydroxytoluene with stirring at 800 C.
Into 942,5g of the stock nitrous oxide solution was dissolved 2,5g sodium
propyl paraben and 2,5g Germall 115 [Imidurea] with stirring at room
temperature.
The oily composition first described was emulsified into the aqueous
solution with stirring to constitute a stock nitrous oxide/Vitamin F
emulsion. It is herein referred to as "Lindil", ~'MZL" or "nanolipid-vesicle"
formulation.
PREPARATION 3
Preparation of a non-aqueous solution of nitrous oxide in carrier
formulation.
The Manufacturing Process for producing a non-aqueous formulation of an
anti-infective agent according to the invention will now be described with
reference to the manufacture of a first anti-TB medicament containing
Pyrazinamide as active ingredient and a second anti-TB medicament
containing the combination of Rifampicin, Isoniazid and Ethambutol as
active ingredients. These products are respectively designated as
"Preparation P" and "Preparation RIE" herein.
Preparation P was made up according to the following protocol:
Step 1: Weigh off the Pyrazinamide 5,00Kg and reduce the particle
size to less than 40pm.
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Step 2: Weigh off and add together the Poloxyl hydrogenated castor
oil 1,15Kg, Vitamin F ethyl ester 2,35Kg, dl-a-Tocopherol
150,Og and Polyethylene glycol 400 1,295Kg into mixing pot 2
and heat to approximately 40 C until all the oil has melted.
Step 3: Gas the oil mixture with nitrous oxide for 3 hours at 2 bar in
the stainless steel pressure vessel in the manner described in
Preparation 1 above.
Step 4: Transfer the gased mixture to mixing pot 1 and heat to
approximately 70 C .
Step 5: Weigh off and add the Methyl paraben 50,00g and the
Butylated hydroxytoluene 5,00g to mixing pot 1, while
continuously mixing ensuring each solid is dissolved before
adding the next while still maintaining the temperature at
70 C.
Step 6: Remove from the heat and allow to cool down to
approximately 40 C.-
Step 7: Add the Pyrazinamide 5,00 Kg stepwise while continuously
mixing.
Step 8: Gas the mixture from step 7 with nitrous oxide at 20kPa for
minutes with mixing until the mixture has reached room
temperature.
30 Preparation RIE was made up according to the following protocol:
Step 1: Weigh off the Rifampicin 1,467Kg, Isoniazid 733,00g and
Ethambutol 2,20Kg and reduce the particle size to less than
40pm. Ensure that the raw material is protected from
exposure to light at all times.
Step 2: Weigh off and add together the Poloxyl hydrogenated castor
oil 1,33Kg, Vitamin F ethyl ester 3,11Kg and Polyethylene
glycol 400 1,30Kg into mixing pot 2 and heat to
approximately 40 C until all the oil has melted.
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Step 3: Gas the oil mixture with nitrous oxide for 3 hours at 2 bar in
the stainless steel pressure vessel in the manner as described
above.
5 Step 4: Transfer to mixing pot 1 and continue to mix.
Step 5: Weigh off and add the Methyl paraben 50,00g, Ascorbyl
palmitate 10,00g and the Butylated hydroxytoluene 5,00g to
mixing pot 1, while continuously mixing ensuring each solid is
10 dissolved before adding the next.
Step 6: Remove from the heat and allow to cool down to
approximately 40 C.
15 Step 7: Check the pH and add Potassium hydroxide while continuously
mixing until the pH reads 7.
Step 8: Add the Rifampicin 1,467Kg, Isoniazid 733,00g and
Ethambutol 2,20Kg, respectively, each stepwise allowing
20 mixing after each addition.
Step 9: Gas with nitrous oxide at 20kPa for 30 minutes with mixing
until the mixture has reached room temperature.
25 The Preparation P and Preparation RIE formulations were encapsulated in
soft gel capsules in the manner well known in the pharmaceutical trade as
oral capsules for use as described below.
EXAMPLE 1
30 ENHANCEMENT OF ANTI-BACTERIAL ACTION
This example pertains to the enhancement of current treatment
modalities of infectious bacterial diseases.
35 The increased efficacy of antibiotics carried by nanolipid-vesicle in the
treatment of bacterial infectious diseases was demonstrated by:
(a)
and (b) Bacterial culture studies (Bactec studies and confocal laser
40 scanning microscopy CLSM);
(c) Infection studies involving live confocal laser scanning microscopy
(CLSM) studies; and
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(d) Zone of Inhibition studies according to the USP XXIII zone inhibition
method.
The following organisms considered to be representative and hence
demonstrative albeit not exhaustive of the range of organisms to which
the invention relates, were used in the above studies to confirm the
invention:
Mycobacteria Tuberculosis (ref strain H37RV)
Mycobacteria Tuberculosis (MDR strains V79 & V25)
Bacillus of Calmette and Guerin (BCG)
E Coli
S Aureus
P Aeruginosa
B.Cereus
A. Niger
C. Albicans
The anti-infective agents in the form of anti-bacterials used in these
studies, and again considered to be representative and illustrative of the
wide application of the invention, albeit not exhaustive, were Rifampicin,
Ethambutol, Izoniazid, Pyrazinimide and Povidone-iodine, Cloxacillin,
Erythromycin E, Ciprofloxacin, Co-trimoxazole (Sulfamethoxazole and
Trimethoprim combination) and Itraconazole.
As will appear from the results discussed below the tests conducted on
formulations involving the association of the active ingredient with the
carrier prepared as set out in Preparation 2 above, showed a 10 to 40-fold
enhancement of the efficacy of selected anti-infective agents compared to
conventional formulations thereof.
A. Bacterial culture studies:
(a) The effect of the nanolipid vesicle encapsulation on the
action of known anti-mycobacterials in BACTEC
determinations.
(i) General Methodology of Collection and cultivation of
Samples and Evaluation
Clinical isolates of M.tuberculosis banked at the Medical School at
Tygerberg Hospital were cultured on L-J slant cultures and used for
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BACTEC analysis. Drug sensitivity determinations in respect of the
strains were done. M.tuberculosis strains were selected from a bank
of 1800 clinical isolates genotyped according to their IS6110
insertion sequence profiles. The insertion sequence ranges from 1 to
23 copies per strain. These strains have been clustered into families
according to their genetic patterns and represent recent
transmission clusters because of their most frequent appearance in
the community. These strains may also represent more virulent
strains although virulence factors in M.Tb. have not yet been
clarified.
The mycobacterial strains were carefully selected according to their
genetic and epidemiological type. Multi drug resistant (MDR) strains
were selected over a wide range from mildly resistant to highly
resistant for Isoniazid, Rifampicin, Ethambutol and Pyrazinamide.
Clinical and laboratory strains of M.tuberculosis were cultured in a
medium enriched with ADC enrichment medium with continuous
stirring to ensure homogenous bacterial distribution and uniform
aeration as described by Middlebrook, G. (1977) in ""Automatable
radiometric detection in growth of mycobacterium tuberculosis in
selective media." Ann. Rev. Respir. Dis. 115:1066-1069. Under
these conditions, cultures grow reproducibly (<1.0% difference).
This technique was established in the Medical Biochemistry
laboratory at Tygerberg Hospital.
At a culture density of approximately A600nm=0.16 (1x
McFarland), (Siddiqui, S. H. (1995). BACTEC 460 MTB system.
Product and procedure manual.) M.Tb. strain cultures were
inoculated into BACTEC vials. Cultures in BACTEC were grown until
a growth index (GI) of 500( 50) was reached. This culture was
used as starter culture for BACTEC evaluation of carrier
encapsulated antimycobacterial drugs. BACTEC growth of cultures
was monitored over a period of 6-10 days and the AGI value for
every 24-hour doubling period determined. Every series of
experiments were repeated at least 4 times to allow for accurate
statistical analyses. Controls, with no drugs, were brought to the
same concentrations. Sterility of mycobacterial cultures were
monitored by Ziehl-Nielsen staining.
All experiments with infectious material should be carried out in a
category 3 bio-safety laboratory. All experiments should be carried
CA 02416512 2008-07-18
63
out in such a way as to ensure maximum safety for all other
laboratory co-workers.
(ii) Evaluation in respect of Rifampicin
Lindil, also referred to as the nanolipid vesicle formulation was
prepared as described in Preparation 2 above and Rifampicin
dissolved at a concentration of 80 micrograms per ml, was used in
an initial evaluation of the effect of the preparation on
M.tuberculosis cultures in BACTEC. This Lindil/Rif preparation was
sterilized by filtration through 0.45 micron filters so as not to give
background contamination by other bacteria.
M.tuberculosis Rifampicin resistant patient isolates were acquired
from the South African Institute for Medical Research (SAIMR).
Strains TV25 and TV79 were acquired from the strain bank at
Tygerberg Hospital. Both were determined to be resistant to
Rifampicin, Isoniazid an also streptomycin. The catalase activity of
TV79 was found to be negative and that of TV25 to be 5mM.
Rifampicin was made up in 50% ethanol at a concentration of
10pg/ml. Eight pl were added to 1ml Lindil to give a concentration
of 80pg/ml Lindil. Of this, 0.1 ml was added to a BACTEC vial to
give a final concentration of 2pg/ml Rifampicin in Lindil. This is the
cut-off value at which M.tuberculosis strains are evaluated for drug
resistance or drug sensitivity for Rifampicin.
Results: It was found that Rifampicin in Lindil kills drug sensitive
strains of M.tuberculosis to a much greater extent than Rifampicin
alone at concentrations below 2pg/ml. Microscopy illustrated
delivery of Rifampicin by Lindil into the interior of the bacillus, and
these results show that the Rifampicin does not stay encapsulated
in the bacillus, but is released from the nanolipid vesicle to the
bacilli internal environment for biological activity. Lindil alone has
no bactericidal effect at the concentration employed in this
determination.
It was further found that the Rifampicin resistant strain used
displayed increased Rifampicin sensitivity when Rifampicin is
delivered to the bacilli via Lindil.
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64
These results were considered to be very important. It has now
been shown that Lindil by itself has anti-mycobacterial activity. The
observation that Lindil may have an effect on M.Tb. alone could only
be extrapolated from results over the first 24 hours. It would
appear that only after a 1:128 dilution of Lindil, growth of M.Tb. is
the same as for the untreated control.
It was further found that the application of Lindil/Rifampicin
combinations to the Rifampicin resistant strain TV79 resulted in an
inhibition of the same order as was observed with the Rifampicin
resistant patient isolates which displayed inhibition by
Lindil/Rifampicin at a concentration of 0.5pg /ml Lindil.
(iii) Evaluation in respect of Isoniazid ""INH"
A quantity of MZL as prepared in Preparation 2 was filter sterilized
through a 0.22uM syringe filter (Millipore). MZL was diluted in the
ratios of 1:2, 1:8, and 1:32. These dilutions ranged from an
inhibitory effect on the viability of M.Tb. to slight inhibition on the
viability of M.Tb.. These effects were observed with serial dilutions
of M.Tb. in BACTEC.
INH was reconstituted with MZL dilutions in two ways: First,
dilutions of MZL were made as described before, and INH was
added to the dilutions to give a final concentration of 0.lpg INH/ml
MZL per BACTEC vial (4m1 content). Secondly, INH was
reconstituted with undiluted MZL to give a final concentration of 0.1
pg INH per ml MZL. The viability of drug resistant strain TV25 was
evaluated in the presence of the INH/MZL combinations in BACTEC.
The Delta Growth Index (dGI) was calculated for each combination.
The dGI is an indicator of Mycobacterial growth over a period of
time and is determined: dGI = GI (day+1) - GI (day).
Results
The results are set out in Figure 1. It shows that after 6 days
incubation in BACTEC (dG5), the dGI for M.Tb. strain TV25 was still
below 10 in the presence of MZL and INH reconstituted prior to 1:2
dilution, whereas the sample subjected to the formulation in which
the 1:2 dilution of MZL was made prior to INH dilution already
showed strong positive growth with a dGI = 28.
CA 02416512 2008-07-18
TABLE 1
H37Rv reference strain treated with Ethambutol. Consecutive
treatment of H37Rv with MZL carrier.
Day 1 2 4 6 7 8 9
Eth/MZL 8 /ml 7 5 3. 2 2 1
Eth/MZL 4 /ml 5 4 3 3 3 3
Eth/MZL 2 /ml 6 4 4 6 6
Eth/MZL 1 /ml 6 5 4 10 1 2 31 4 5
Eth/MZL.5 /ml 5 5 5 10 2 3 6 10 15
Eth/MZL.25 /ml 5 5 4 7 1 3 7 13 20
Eth/MZL .125 /ml 5 4 4 8 1 4 8 142-199
Eth/MZL.0625 /ml 5 4 7 14 31 6 12 171 210
Eth/MZL.03125 /ml 5 5 7 15 3 6 12 182 21
Eth 8 /ml 16 18 1 18 1 1 1 1 1
Eth 4 /ml 21 2 2 28 2 2 2 2523
Eth 2 /ml 21 2 2 32 3 3 3 4 5
Eth 1 /ml 15 1 2 29 31 4 4 5 6
Eth .5 /ml 15 21 2 48 6 10 13 16 20
Eth .25 /ml 21 3 62 110 160 26 34 42 48
Eth .125 /ml 21 4 92 200 30 60 78 87 93
Eth .0625 /ml 20 4 9 211 33 63 84 99 99
Eth .03125 /ml 20 4 9 218 37 65 90 99 99
Control 1 4 91 220 33 54 53 561 52
Control + MZL 71 N 8, 21, 44, 95, 18 280 41
This represented an increased inhibition of 78% compared to the
effect of MZL dilution prior to INH addition. The effect of MZL alone
was 50% relative to the control for strain TV25. Relative to the
5 control, the effect of MZL combined with INH followed by dilution,
was 91%. This gave an additional effectiveness of 41.5% of INH
(INH alone showed no effect) in the presence of MZL.
(iv) Evaluation in respect of Ethambutol
Ethambutol was prepared in sterile deionized water and dissolved in
MZL at appropriate concentrations and the mixtures then sonicated
in a cup-horn sonicator for one minute at frequency setting 7. It
was brought into contact with a culture of M.tuberculosis H37Rv
known to be resistant to Ethambutol. GI was determined every 24
hours one hour. The observations are recorded in Table 1.
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66
Calculations:
Figures in the highlighted column (6) were used to calculate the
effect of Ethambutol on mycobacterial growth in the absence of
MZL. At this point the untreated TB control is GI=540. This is also
the point where the TB growth becomes stationary (decline in
growth). All GI values in this column were calculated relative to the
control value of 415 to give % inhibition of growth. Column (9)
shows the MZL treated control at approximately GI=415. All GI
values in this column (Ethambutol in the presence of MZL) were
calculated relative to the control value of 415 to give % inhibition of
growth. The untreated control value was normalized to 415 to make
results comparable. The results of the calculations are set out in
Table 2.
Table 2
Plus MZL Minus MZL
% Inhibition % Inhibition
1.0 pg/ml Ethambutol 86 92
0.5 pg/ml Ethambutol 62 81
0.25 pg/ml Ethambutol 51 51
0.125 pg/ml Ethambutol 52 -12
0.0625 pg /ml Ethambutol 49 -16
0.0325 pg /ml Ethambutol 48 -21
Results:
The results show that the MIC for Ethambutol in M.tuberculosis
H37Rv strain is around 1.0 pg/ml. Results clearly show that from
0.125pg/ml Ethambutol, MZL presence still maintains a strong
inhibitory effect on mycobacterial growth compared to MZL
untreated bacteria whereas there was no growth inhibition. In fact,
a slight stimulation of growth (negative values) is observed. This is
usually observed with very low antibiotic manipulations. At the
higher Ethambutol concentrations (0.25-1.Opg/ml) there does not
appear to be much difference in growth inhibition between MZL
treated and untreated. The very high concentrations appear to have
a better effect in the untreated M.Tb. This effect could be a dose
response because of the very high presence of Ethambutol at the
high concentrations. In the MZL treated experiments it appears as
though MZL captures Ethambutol in its structure making less
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67
Ethambutol freely available for diffusion over the mycobacterial
membrane. However as the concentrations become lower it
appears that MZL gives a steady delivery of Ethambutol to the
M.Tb. with the result that inhibition is steadily maintained (approx
50% inhibition over the range of 0.03125pg/ml-0.125pg/ml).
From these results it appears that MZL maintains steady state
delivery of Ethambutol to the M.Tb. over the spectrum of
concentrations used and this effect is most prominent in the low
concentration range of MZL that is the concentration range
significant for therapeutic efficacy.
(b) The effect of nanolipid-vesicle encapsulation of the antibiotic
Pyrazinamide on the resistance of BCG (Bacillus of Calmette
and Guerin) to Pyrazinamide:
The encapsulation of antibiotics Izoniazid, Ethambutol and
Rifampicin into the nanolipid vesicles formulation of Preparation 2
described above resulted in a product suitable for use in the
inhibition of Mycobacterium Tuberculosis in bacterial isolates from
patients infected with both drug-sensitive and multidrug resistant
strains. The results were obtained with the Bactec system, with no
human cell involvement.
The significance of the following result stems from the fact that the
BCG vaccine is extensively used for vaccination against infection by
Mycobacterium Tuberculosis (M.Tb.). BCG vaccine is classified as a
non-pathogenic mycobacterial strain and is therefore a widely used
investigative model of infection by (M.Tb.). All BCG strains are
resistant to Pyrazinamide (see Morbidity and Mortality Weekly
Report; 1996, vol 45, No RR-4). The effect of encapsulation of this
antibiotic by nanolipid vesicles according to the invention and its
delivery in that form to BCG was investigated.
In this investigation which was performed by confocal laser
scanning microscopy (CLSM), use was made of a live/dead
fluorescent stain known as Baclight. It stains live bacteria green and
dead bacteria red. General viability of the BCG's was determined by
the green/red ratio of the bacteria. The effect of equal amounts
and concentrations of free and nanolipid-vesicle encapsulated
Pyrazinamide on BCG viability was investigated.
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68
Bacterial viability: The general viability of the BCG 's before any
addition of antibiotics was between 85 - 95%. The BCG-viability
after a two-hour incubation of the applicable dosage of free
Pyrazinamide was 68 -72%.
Bacterial growth characteristics: BCG generally grows in
clumps. Incubation with free Pyrazinamide resulted in the
appearance of single live bacteria with a few granuloma-type
clumps, which gradually secrete single live bacteria. The single live
bacteria were mobile. Encapsulation of Pyrazinamide in nanolipid-
vesicles led to a 65-75% decrease in BCG viability within a two-hour
incubation. No moving BCG was observed.
Accordingly, BCG prelabelled with live/dead Baclight bacterial stain
and then treated with nanolipid-vesicle encapsulated Pyrazinamide
was observed by confocal laser scanning microscopy. It was found
that, after an hour, most of the bacteria were labelled red, and were
therefore dead. No granuloma-type clumps or single bacteria were
observed. Such clumps and single bacteria, all coloured green, were
seen in the control in which the same quantity of Pyrazinamide in
water alone was brought into contact with BCG also prelabelled with
live/dead bacterial stain.
The study thus yielded the most surprising result that bacterial
resistance to Pyrazinamide may be overcome by encapsulation of
the antibiotic into the nanolipid vesicles composition of Preparation
2.
(c) Infection studies (Live confocal laser scanning microscopy
studies)
In this study the aim was to determine whether encapsulation of an
antibiotic by nanolipid vesicles gives rise to a product by which one
could overcome resistance of intracellular bacteria, using infection
of human macrophages by BCG in culture as a cell model.
The THP1 macrophage cell line (ATCC) was used for the infection
study. RPMI 1640 with L glutamine cell culture medium, Foetal
Bovine Serum and phosphate buffered solution (Gibco BRL), were
used for cell growth according to general cell culture methods.
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69
THP1 macrophage cells were cultured and infected with pre-treated
labelled BCG bacteria. Treatment consisted of equal concentrations
namely 0.075 Ng/ml of free and nanolipid-vesicle encapsulated
Pyrazinamide. CLSM was used to determine infection by and
survival of the bacteria.
The viability of BCG's after infection in macrophages reflects that
BCG's inside macrophages treated with nanolipid-vesicle associated
Pyrazinamide is effectively killed by the antibiotic Pyrazinamide,
even though the bacteria are generally recognised to be resistant to
the antibiotic used.
(d) Zone of Inhibition Studies:
(i) Enhancement of Povidone iodide against two bacterial
organisms as evidenced by zone of inhibition studies.
Inhibition of bacterial growth of two types of bacteria by the
active ingredient known as Povidone iodine in formulated form
with the nanolipid vesicles of Preparation 2, and so used at a
concentration of 6.30g Povidone iodine equivalent to 0.75g
available Iodine in 100g of product, was compared with the
effect of the same amount and concentration of the free
active ingredient. The bacteria were S. Aureus and
P.Aeruginosa. The control used was saline.
The results obtained in the study are graphically represented
in the graph which is Figure 2 hereto. It is clear that inhibition
of bacterial growth in both types of bacteria is dramatically
increased when the active is associated with the nanolipid
vesicles.
(ii) Enhancement of five anti-infective agents against five
different bacterial organisms
Five commercially available antibacterial compositions containing the
active ingredients set out in Table 3 below were compared in zone
inhibition studies with saline as control with compositions of the same
active ingredients made up in a carrier according to the invention. These
are designated "MZL" formulations in the case of aqueous made according
to preparation Z above and "MZLA" formulations in the case of non-
aqueous formulations prepared according to Preparation 3 above. This
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convention is also followed in other examples below as opposed to the
commercial formulations (COM) of particular active agents. The compared
formulations were diluted where necessary to achieve the same
concentrations.
5
It is evident from the results set out below that the organisms were more
sensitive to the active agents when encountered in the carrier formulation
according to the invention.
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71
TABLE 3
ZONE OF INHIBITION STUDY: FIVE COMMERCIAL ANTI-INFECTIVE
FORMULATIONS AGAINST FORMULATIONS ACCORDING TO THE
INVENTION FOR DIFERENT INFECTIVE AGENTS
ACTIVE MZLA/ Dose
AGENT Com mg/ cn
cn ui C
5m1 = a, L
0 0
L
Q) 0
Q Q U U z
cn a m w Q U
Cloxacillin MZL 125 30.74 23.96
Cloxacillin COM 125 29.45 19.86
Erythromycin MZL 250 26.7 29.89
Erythromycin COM 250 25.84 27.78
Ciprofloxacin MZL 250 33.05 35.78
Ciprofloxacin COM 250 30.14 33.4
Cotrimoxazole MZL 240 13.95 24.64
Cotrimoxazole COM 240 11 22.83
Itraconazole MZLA 50 16.03 14.28
Itraconazole COM 50 10.21 11.47
Control 9 9 9 9 9 9
Example 2
ENHANCEMENT OF ANTI-VIRAL AGENTS
In this study AZT at different dosages was associated with the nanolipid
vesicles to test the efficacy of such association on the viral growth in
CD4+ Helper T-cells.
The rationale for this investigation is that AZT is cytotoxic and long-term
use is associated with loss of muscle. Other side effects can be nausea,
anaemia, white blood cell depression, mouth sores, bone marrow
damage, and headaches. It would therefore be desirable from both a
side effect and cost perspective to be able to lower the dosage of AZT
administered to an HIV-infected patient, provided that such lowering of
dosage does not compromise the effect of the administration. It was thus
decided to investigate the dose/effect relationship of AZT when
formulated with the administration medium of Preparation 2.
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Although it was the result the applicant had hoped for, it was
nevertheless a surprise to find that these objects may be accomplished by
increasing the effective delivery of AZT to HIV-infected cells, thereby
maintaining a therapeutic intracellular concentration at lower dosages.
From the observations made it is presently postulated:
a) That the AZT-loaded nanolipid vesicles significantly increase the
kinetics of intracellular and intranuclear AZT delivery, with the
result that AZT therapeutic dosages can be decreased;
b) That nanolipid vesicle-associated AZT appears to assume the
pharmacokinetics of the vesicles until such time as it is released
and;
c) That the optimal loading concentration for AZT-loading into
nanolipid vesicles can be determined with regard to the
applicable cell types.
The following protocols were followed in this investigation:
a) Several cultures of CD4 helper T-cells (CEM-SS cell line; NIH
AIDS Research and Reference Reagent Program) were infected
with HIV subtype D viruses at applicable cell seeding densities
and viral loads. Cells were maintained in tissue culture under
standard culturing conditions.
b) The viral load in cultured cells were determined every day for 7
consecutive days after infection by measuring the p24 core
antigen of HIV-1 in the supernatant culturing fluid by ELISA. This
assay is based on a colour change after addition of substrate that
is proportionate to the viral replication in each culture. The
colour change is monitored by absorbance spectrophotometry at
450 nm. Negative control absorbance readings were used to
calculate the absorbance/cut-off for each culture.
c) Determination of the optimal concentration of nanolipid-vesicle
containing base formulation was done by cytotoxicity assays and
cell growth curves. The cytotoxicity assay used was the standard
MTT assay and spectrophotometry was once again used to
determine cell viability for the CEM-SS cell line. Growth curves
were used to determine the optimal concentration of base
formulation for human macrophage cells (THP-1 cell line).
The results obtained are graphically presented in Figure 3 hereto. It
shows the following:
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73
a) The delivery and transport function of the nanolipid-
vesicles increase the therapeutic efficacy of AZT ten fold at
a dilution of 1:512 base formulation, thereby creating the
possibility of decreasing the AZT dosage 10 fold, as is
shown by the relative effect of 1nM free AZT versus 0.1 nM
nanolipid-vesicle formulated AZT. The results clearly show
that the addition of 0.1nM free AZT inhibited viral growth
and replication by 44% by day 7 and 8, when compared to
the control (no AZT added). However, the addition of
0.1nM nanolipid vesicle-associated AZT inhibited viral
growth by between 70 - 80% on day 8. This is comparable
to the inhibition observed by 1nM free AZT (i.e. 10 times
the concentration). Furthermore, addition of 0.1nM
nanolipid vesicle-associated AZT showed a continued
decrease in viral load over 8 days, whereas the addition of
even 10x that amount of free AZT resulted in a decrease in
viral load up to day 6, after which the viral growth
increased slightly.
b) The graphs in Figure 2 show that the association of AZT
with nanolipid vesicles changes the pharmacokinetics and
possibly the intra-cellular biodistribution of AZT.
c) The effective delivery of the basic nanolipid vesicle
formulation has been established for CD4 T-cells and
macrophages to be a dilution of between 1:512 and 1:1024
of the concentrated unfiltered formulation. Higher content
of nanolipid vesicles appears to favour viral growth in the
cells. At a dilution of base-formulation (1:256), viral
inhibition is optimal at a higher concentration of AZT (0.5 -
1nM).
Note that no correction has been made in the above evaluation
for the contribution of the cells itself to the Absorbance/cut-off
ratio. It was considered to be negligible (>0.4).
Conclusions:
a) The administration medium of Preparation 2 at the correct
dilution may be used to decrease the effective therapeutic dosage
of AZT by as much as 10 fold. It would considerably decrease the
cytotoxicity of the AZT treatment. At such low dosages, it may
CA 02416512 2008-07-18
74
be more attractive to treat expecting mothers for HIV infection,
without any long-term side effects on the foetus.
b) Optimisation of nanolipid vesicle concentration for AZT-delivery is
essential, as unloaded nanolipid vesicles can favour the
multiplication of HIV viruses by supplying components for viral
membranes synthesis and energy for viral metabolism, as the
metabolism of nanolipid vesicle essential fatty acids (EFAs) may
increase the energy status of the cell, and therefore also the
energy available to the HIV virus for its replication. The nanolipid
vesicle concentration must therefore be sufficient to serve only
its transport function, without supplying either membrane
components or energy for viral multiplication.
The changed pharmacokinetics and intracellular biodistribution of AZT
transported by nanolipid vesicles are probably the result of the following
two mechanisms:
a) the change in environment with regards to charge and
hydrophobicity when nanolipid vesicles move from the extracellular
to the intracellular environment, and
b) the normal cellular pathways of the EFAs, which include its
metabolism in the mitochondria. The release of AZT is therefore
most probably in the region of the mitochondria.
Example 3
Yeasts and fungi: The enhancement of agents used in the
treatment of Infectious Diseases caused by Yeasts and Fungi.
The use of this invention for the enhancement of agents used in the
treatment of yeasts and fungi (moulds) was investigated and established
by the following studies described in greater detail below, namely:
Comparative culture studies
Infection studies (Live CLSM imaging)
Zone inhibition.
(a) Comparative culture studies:
Fungi of the mycosis type was grown in culture medium (RPMI 1640 with
L glutamine cell culture medium) at 37 C at 90% humidity, 5% CO2 for a
week. Equal aliquots of grown fungi were exposed to nanolipid vesicles
loaded with a commercially available antifungal agent containing 2%
Miconazole nitrate. Comparison was made with free Miconazole nitrate
CA 02416512 2008-07-18
i.e. the commercially available form of that active ingredient. In both
instances the exposure was at a final concentration of 0.4% over similar
time periods (30 minutes to 18 days), using a single initial dosage.
5 Results:
The nanolipid-vesicle delivery system can be used for the efficient
delivery of antifungal agents to fungi.
10 Miconazole nitrate association with nanolipid vesicles, but not free
Miconazole nitrate caused a fast and unexpectedly dramatic decrease of
the fungi as illustrated in Table 4.
TABLE 4
15 VIABILITY OF FUNGI AGAINST TIME ELAPSED AFTER SINGLE
EXPOSURE TO MICONAZOLE NITRATE
Nanolipid-vesicle Free
Time encapsulated Miconazole Miconazole
30 min 5% 80%
4 hours 0% 70%
11 days 0% 30%
18 days 1% 15%
20 (b) Infection studies:
Two equal aliquots of melanoma cells (UCT Mel 1 cell line) were
incubated for 4 hours with fungi and 0.2% of either free Miconazole
nitrate or Miconazole nitrate formulated with the administration
25 medium of Preparation 2 in order to test the effect of the
formulation in terms of the invention on the efficacy of fungal
treatment of human cells.
The viability of both human melanoma and human macrophages
30 was found to decline dramatically in the presence of free Miconazole
nitrate but not when the Miconazole is encapsulated in nanolipid
vesicles. The result is graphically presented in Figure 4 hereto.
Figure 4 shows the viability of both the human melanoma and fungi 4
35 hours after the addition of the therapeutic agents in a petri dish.
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Using a macrophage cell line, the same result was obtained.
Melanoma cells were healthy after 4 hours incubation with nanolipid-
vesicle encapsulated Miconazole nitrate and no fungi was present. In the
presence of free Miconazole nitrate, cells were no longer attached to the
petri dish and fungi were still present in large numbers.
(c) Zone of inhibition studies:
Zone of inhibition studies on yeasts and moulds namely C. Albicans,
T. Mentagrophytes and E. Flocossum were also carried out.
Inhibition of yeast and mould growth by the active ingredient
Miconazole nitrate in association with nanolipid vesicles was
observed. The control used was saline.
The result of this study is reflected in Figure 5 hereto
Conclusion:
It is quite clear from the results presented in Figure 5 that the active
Miconazole nitrate in association with the nanolipid vesicles inhibits the
growth of both yeasts and moulds and does so to a greatly enhanced
extent.
Example 4
Parisitology: The treatment of Infectious Diseases caused by
parasites:
Summary:
The effect of free and non-aqueous nanolipid formulated chloroquin made
according to the process described in Preparation 3 against a resistant
Falciparum strain (the reference strain W2 for drug resistant malaria) was
preliminarily determined in the conventional manner. The strain is known
to have a 50% Inhibition concentration value (IC50) of between 200-300
nmolar Chloroquine. The determined IC50 value for nanolipid formulated
Chloroquine was about one tenth of the value for free chloroquine,
namely 25-30 nmolar. This most surprising result holds substantial
promise for further research as its utilisation in practice means that
malaria would be capable of being treated with greatly reduced
cytotoxicity and resulting lower incidence of side effects. In addition drug
cost will also be lower.
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Approach and general Method
The specific parasite investigated was the reference drug resistant strain
W2 of the species Plasmodium Falciparum. Plasmodium Falciparum is the
most commonly occurring as well as the most virulent malaria parasite
currently known in man.
The system used in this investigation aims to mimic the live situation as
closely as possible. For that reason, the parasites were infected into fresh
primary erythrocytes isolated from 0+ or A+ blood donors.
Furthermore, human serum prepared from the same donors was used as
an adjuvant instead of foetal calf serum. Parasite growth was maintained
by the addition of freshly prepared erythrocytes from the same donors.
The growth of the parasites was determined by visualization of the
parasite DNA on thin smears of the infected cultures. Since mature
erythrocytes contain no nucleus, and therefore no DNA, the only DNA
present was of parasitic origin. Only intracellular parasites were included
in determining the percentage parasitaemia, as extracellular parasites are
no longer viable.
Protocol:
The protocol was typical for work of this nature and included the following
steps as will be readily apparent to those skilled in the art.
A. Culturing of malaria parasites:
1. Preparation of fresh human erythrocytes
2. Preparation of human serum from the same donor.
3. Quality control of human serum.
4. Infection of erythrocyte cultures with parasites. Initial infection
load was 0.5% parasitaemia.
5. Maintenance of parasite blood cultures
6. The parasite percentage in the blood cultures was determined after
36 or 48 hours, depending on the level of infection of the freshly
added erythrocytes.
B Basic toxicology:
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Determination of possible toxic effect of nanolipid formulations on
erythrocytes and parasite growth.
The following nanolipid formulation concentrations were investigated:
0. 1:1500, 1:1000; 1:750; 1:500; 1:250; 1:100; undiluted.
C Loading of nanolipid formulation with chloroquine:
A stock solution of 10mM chloroquine solution in a 1:250 dilution of
nanolipid formulation was made by vortexing and sonication. All
concurrent dilutions were from this stock.
D Drug delivery by MZL nanolipid formulations:
1. Penetrance of nanolipid formulations in red blood cells was
determined by microscopic visualization, as were the penetrance
of chloroquine-carrying nanolipid formulations.
2. The drug concentration series used centred around the known
IC50 concentration of chloroquine in the W2 strain.
3. Typically 48-well plates or 96-well plates were used. 200ul or
100ul total culture volumes were used respectively, of which
90% of the volume was infected erythrocyte culture. 10%
volume was used for the treatment, be it chloroquine in
Nanolipid formulation, chloroquine in water, or for the controls
1:250 pure Nanolipid formulation, pure culturing media or water
only.
4. All series were in duplicate.
E Visualization of intracellular parasites:
Parasitic DNA was visualised by Giemsa staining of thin smears.
Ethidium bromide or acridine orange may be used for fluorescent staining.
F % Parasitaemia:
The % infection after applicable incubation periods was determined as
follows:
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Total parasite count per 10 microscopic fields
----------------------------------------------------x 100%
Total cell count per 10 microscopic fields
G Quality assurance of counting:
All counts of the first series were undertaken by two scientists. The
results correlated very well. The second series was spot-checked by a
second scientist, especially around crucial concentrations. Once again no
significant deviations were found between the two sets of results.
Results:
The counts of the cultures are reflected in the table 5 below:
TABLE 5
CLQL CLQ
Chloroquin
e % Parasit
concentrati Cells/ Total Para- + Cells/ Total Para- %
on field cells sites MZL field cells sites Parasit
0 nM 95 950 17 1.8 73 730 16 2.19
1nM 87 870 18 2.06 127 1270 34 2.67
5nM 127 1270 29 2.88 60 600 14 2.33
10nM 130 1300 37 2.84 135 1350 40 2.96
25nM 120 1200 23 1.91 130 1300 37 2.84
50nM 90 900 13 1.41 111 1110 30 2.7
75nM 54 540 5 0.9 129 1290 43 3.33
100nM 125 1250 14 1.1 64 640 18 2.81
200nM 106 1060 4 0.3 108 1080 31 2.87
300nM 88 880 13 1.41 105 1050 19 1.8
500nM 63 630 7 1.1 76 760 0.15 1.5
1000nM 87 870, 12 1.3 71 710, 10 1.4
CA 02416512 2008-07-18
W2= Chloroquine resistant strain internationally recognized and used.
CLQL = Chloroquine in 1:250 dilution MZL nanolipid carrier; concentrations of
chloroquine as indicated.
CLQ= Chloroquine in medium at the specified concentrations.
Resistant strains become sensitive only at very high Chloroquine
concentrations.
Association of chioroquine with nanolipid formulation results in a similar
susceptibility as sensitive strains.
Statistical analysis of the results was by Chi-square analysis between the
two sets of data. A combination of the 3 repeats of the two sets of data
5 gives a Chi-square value of 7.6. According to the probability tables, the
difference between pure chloroquine and MZL-associated chloroquine is
highly significant, with only a 0.0001 probability that the difference
observed between the two treatments is due to chance.
10 Conclusions:
1. The association of chioroquine with MZL nanolipid formulation
significantly decreases the IC50 of chloroquine (by 6x to 10x).
2. Primary human cells show high tolerance for the MZL nanolipid
15 formulation, with cytotoxicity only observed at high extremely
high concentrations.
3. MZL formulations may be used in the prophylaxis of drug
resistant malaria.
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Example 5
Comparative release properties as determined by Membrane Diffusion of
Anti-infective agents formulated in accordance with the present invention
and commercially available formulations of the same anti-infective agents.
1. OBJECTIVE
The scope of this study was to establish whether the Test Anti-infectives
Acyclovir and Miconazole Nitrate are released from the dosage form of the
invention at a satisfactorily rate and extent in comparison to the
commercially available Comparators.
The applicability of the test method for release out of the dosage forms
was confirmed by Handbook of Dissolution Testing: Dissolution Testing of
Transdermal Delivery Systems, page 61. The small receptor volume to be
used, in this case 12 mt, is confirmed in the same reference on page 63,
which refers to 5 - 25 mt.
2. METHOD
The in vitro release from the dosage forms was determined by a Hanson
Model 57-6M, Manual Start-Up, Diffusion Cell Test System bought from
Hanson Research with the following main parts:
CELL DRIVE CONTROL
6-CELL DRIVE WITH CELLS
VERTICAL CELLS
3. PARTS NEEDED
1. Diffusion cell assembly, including donor top and receptor
chamber (set of 6). The donor top includes a drug dosage
wafer (Teflon washer), an acrylic top plate, and a clamp to
connect top to bottom.
2. Pig skin used within 24 hours from being slaughtered kept in
Ringer Solution between 2 C - 8 C.
3. Davies Gold Series Dermatone, Simplex GS 102.
4. Application squeegee and tweezers.
5. Drug dosage form.
6. Absorbent paper towels and tissues.
4. TECHNIQUE
1. Obtain skin from pig heads (jawbone skin). Use Dermatome
according to the Operation standard operating procedure for
the Dermatone, setting it to size the skin to a thickness of
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82
0.33mm. The diameter of the skin should be in excess of the
drug dosage wafer.
2. Prepare receptor chamber of diffusion cells with slight
overflow of medium (pH 5 buffer with glacial acetic acid for
the Test Product Acyclovir and 6.8 phosphate buffer for the
test product Miconazole) with temperature controlled at 32 C.
3. Prepare each piece of skin with the relevant products one at a
time as follows:
3.1. Lift skin with tweezers, place on tissue and blot excess
of solution, invert and blot.
3.2. Place skin in centered position on drug dosage wafer.
3.3. Place relevant products on top of skin in dosage wafer
cavity - 0.5 ml by means of a Gilman pipette - weighed
and averaged to obtain dosage applied.
3.4. Use squeegee to carefully smooth product over
membrane, filling entire cavity.
3.5. Wipe excess dosage water with squeegee.
3.6. Lift loaded dosage wafer with skin and place on top of
receptor cell with skin side towards cell medium.
Exclude bubbles during process. Place on top of donor
cell assembly, pressing down with finger, squeezing out
bubbles between top plate and dosage form. Apply
clamp to lock down top donor and bottom receptor
halves of diffusion cell.
5. OPERATION OF APPARATUS
The apparatus must be set to 150 rpm. Samples of 150pl are withdrawn
with a micropipette at 2', 5', 8' and 10' and 15 minutes. The samples
after being withdrawn are analysed for Acyclovir and Miconazole Nitrate
respectively by means of HPLC according to the parameters set out in
Table 6 below.
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Table 6
Acyclovir Miconazole Nitrate
Injection volume 20 I 20 I
Column Zorbax SB C18 Zorbax SB C18
250mm x 4.6mm 250mm x 4.6mm
Mobile Phase 0.02M GAA in H2O 70% Methanol
pH 3.5 30% H20+1% GAA
Detector HPLC at 254nm HPLC at 224 nm
Temperature Ambient 22 C) Ambient 22 C)
Flow Rate 1.5 ml per min 1.5 ml per min
Retention Time 20.8 - 21.9 min 9.4 -9.9 min
Solvent MP adjusted to pH 5 Methanol
Cells used 3 (1 for Comparator) 6
Time at which total 15 60
release determined
Min
6. RESULTS
The release experiment was performed in the number of cells indicated
above for each product and the mean release is reported for each analysis
point. The results are tabulated and graphically presented. The results as
a percentage of the active released per label claim per cell at the different
time intervals is also tabulated.
In Table 7 below is shown a summary of the release rate and percentage
release per label claim for the products determined according to
calculations, reporting the mean values of the utilised number of cells of
each product after the effluxion of the time indicated above.
Table 7
Table indicating release rates and percentage release per label
claim for product tested.
Active Agent % Active Release Rate % Release per
/product (pg/CM2 label claim
Ac clovir MZL 0.5 69.1533 0.1214
Acyclovir COM 0.5 54.0942 0.0952
Miconazole 2 389.9238 6.8155
Nitrate MZL
Miconazole 2 111.2222 1.9466
Nitrate
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84
7. CALCULATIONS
The Release Rate was calculated as follows:
7.1. pg Active Released at time (min.)
= A sam x Mass Std x Vol Receptor x Mass of Active Applied for Z cells x C
A std x Vol Std x Label Claim x Mass of Product Applied for 1 cell x Z x 100
WHERE:
A sam = Area of peak sample solution
A std = Area of peak of standard solution
Mass std = Mass of standard taken to prepare the
standard solution expressed in fag
Vol Std = Volume to which the standard solution is
made up, expressed in mf
Label Claim = Amount of active present per 100g of
product
Mass of Product
Applied for 1 cell = Specific amount of product applied for a
specific cell
Mass of Active
Applied for Z cells = Amount of active applied in total for all Z
cells utilised per one study
C = potency of the standard, expressed as a
percentage
7.2. Accumulative Dose (pg) released /square cm at time (min)
_ pg Active Released
(Surface Area of Exposed Skin)
= uq Active Released
1.767 cm2
7.3. Release Rate
= Accumulative Dose (fag) released / square cm
Time (hours)
CA 02416512 2008-07-18
7.4. Percentage of Active Released at time (min.)
jig Active Released x 100
5 pg Active Applied
8. CONCLUSION
From the aforegoing test it was concluded that the formulation according
to the invention
10 (a) releases Acyclovir 1.28 faster than the Comparator Acyclovir
formulation at 15 minutes, and continues to release higher quantities
throughout the duration of the test;
(b) releases Miconazole Nitrate 3.51 times faster than the commercial
Comparator at 60 minutes.
Example 6
DEMONSTRATION OF THE EQUIVALENT OR IMPROVED
BIOAVAILABILITY OF ANTI-TB DRUGS IN THE FORMULATION
ACCORDING TO THE INVENTION COMPARED TO A COMMERCIALLY
AVAILABLE PRODUCT
1. BACKGROUND:
Anti-tuberculosis treatment presents with two major problems- the
development of drug resistance and compliance. The nanolipid based
delivery system provides a system for single or combination tuberculosis
drug treatment with a significantly increased therapeutic index, using
currently prescribed anti-tuberculosis drugs, with a resultant decrease in
the development of drug resistance. The delivery system contains the
same therapeutic moieties but differs in chemical form, and dosage of
those moieties and can therefore regarded as a pharmaceutical
alternative. Furthermore, the higher therapeutic index of the drug
facilitates lower dosage, which limits the side effects, which may in its
turn be expected to improve compliance. Using this delivery system,
delivery of the drugs may also be expanded to tissues usually not easily
reachable by current therapeutic regimes.
The formulated delivery system contains components that have been
recognized as pharmaceutically safe. The public health authority of South
Africa in concert with many other health authorities, advise the same
actives as used in this investigation as initial treatment regime for all
tuberculosis patients. This protocol describes the delivery of the
CA 02416512 2008-07-18
86
prescribed anti-TB drugs in 4 single daily doses by way of the delivery
system at a reduced dosage level to 1 healthy volunteer.
In an open crossover design, pharmacokinetic parameters of the four
drugs delivered by the test formulations in reduced doses were compared
to those achieved when the same drugs were administered in the
reference formulations of established quality and in the standard
treatment doses. The volunteer was monitored daily during the study.
The protocol below describes the dosage level, the specific drug, the time
period of the study, the parameters investigated and the combinations of
drugs used.
2. STUDY OBJECTIVES
Primary Objectives
The first primary objective of this investigation was to determine the
bioavailability of generally used anti tuberculosis treatment agents, i.e.
Rifampicin (R), Izoniazid (H), Ethambutol (E) and Pyrazinamide (Z), each
packaged into the MZL drug delivery system in the form of the capsules
produced in the manner as described in Preparation 3 above.
Secondly, it was to determine changes in patient global assessment, i.e.
significant change from baseline of the following pharmacokinetic
parameters:
a) peak plasma concentration (Cmax),
b) the time needed to reach this concentration (Tmax),
c) exposure (the area under the plasma curve (AUC 0-9
hours), and
d) coverage.
The pharmacokinetic results were compared with those of reference
formulations. The packaged drugs were administered at an equal or a
decreased dosage of that in the commercially available combination
antituberculosis drugs.
2.2 Secondary objectives
The secondary objectives of the investigation were
firstly, to determine whether bioequivalence exists for drugs packaged
into the delivery system by comparison to reference agents;
CA 02416512 2008-07-18
87
secondly, to determine whether there are changes in the status of side
effects caused by the actives;
thirdly, to determine the relative safety levels of the comparative
products;
fourthly, to determine possible partitioning of the MZL nanolipid delivered
drugs to cells and possible cytotoxicity as a result; and
finally, to note the possible advantages to the volunteer's well-being (i.e.
malaise, bone ache, nausea etc) when using the delivery system of the
invention for the administration of anti-tuberculosis drugs.
3. STUDY DESIGN
The treatment was based on the Standard Treatment Guidelines and
Essential Drugs List (1998). The study design was an open crossover
bioavailability design of tuberculosis drugs [Rifampicin (R), Izoniazid (H);
Ethambutol(E) and Pyrazinamide(Z)] delivered by a formulated drug
delivery system. Bioavailability is understood to be the rate and extent to
which the active substance or therapeutic moiety is absorbed and
delivered from a pharmaceutical form
a) into the general circulation and
b) becomes available at the site of action.
As in other bioavailability studies, the kinetics of the therapeutic moiety in
the general circulation was monitored in this study.
The study was conducted over two periods of 4 days each, interrupted by
a two week wash out period. During the last day (day 4) of each period,
blood samples will be taken at the times specified below to determine
several pharmacokinetic parameters. Blood samples (10ml each) were
taken at the following intervals after administration of the drugs: 30
minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours.
3.1 Rifampicin:
The volunteer received the currently commercially available prescribed
Rifampicin, namely Rifampin, treatment for 4 consecutive days, followed
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by a wash out period of 2 weeks. Rifampin contains Rifampicin as active
ingredient. The volunteer then received pure Rifampicin packaged into
the nanolipid delivery system of the invention as described above at two
thirds of the prescribed dosage, again for 4 consecutive days. This
nanolipid formulation of Rifampicin is herein also referred to as
Rifemzaloid. The volunteer took the medication in the morning before a
meal with 200m1 of tea, as food has been shown to influence absorption.
Meals were standardized and supplied a couple of hours after first
administration of the medication.
3.2 Combination Drugs:
The volunteer started with two third dosage of all four drugs packaged
into the nanolipid delivery system of the invention, followed by the same
scenario with the commercially available treatment regime, namely
Rifafour, after a two week wash out period. The volunteer took the
medication in the morning before a meal with 200ml of tea, as food has
been shown to influence absorption. Meals were standardized and
supplied a couple of hours after first administration of the medication.
3.3 General Protocol Requirements:
a) The subject volunteered for participation in the study. The
volunteer was a Caucasian middle-aged female and was clinically
healthy i.e. blood chemistry, full blood count and liver function tests
of subjects fell within the normal ranges. The volunteer granted
written informed consent before participating in the study.
b) All drugs were orally administered in Soft Gel capsule form at
applicable doses. The volunteer did not take any other chronic
medication during the study.
c) The study was single blind for laboratory procedures. Plasma level
assays of the actives were performed in the conventional manner.
d) Blood and liver function assays were undertaken in the conventional
manner.
e) The safety of the treatments was assessed according to the ICH
Clinical Trial Guidelines. No serious adverse events (AE) occurred
during the study.
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4 TREATMENT REGIME:
4.1 Pharmaceutics
The nanolipid delivery system formulated as described above was
used as a base for the active drugs used when comparing the
pharmaceutical efficacy of drugs delivered by a delivery system with
the generally prescribed drugs containing identical actives.
4.2 Dosing:
Rifampicin:
Commercially available Rifampin tablets (600mg) were taken daily
for four consecutive days, followed by sample collection on day 4.
Nanolipid formulated Rifampicin was taken in the same manner but
at two thirds of the above dosage, i.e. 400mg Rifampicin
encapsulated in the delivery system. Dosing was again followed by
a sample collection in order to determine the comparative
pharmacodynamic profile of the active.
Combination treatment:
The generally prescribed drug regime, consisting of 5 combination
tablets Rifafour RHZE (120 /60 / 300/200 mg) were taken daily for
4 consecutive days, after which blood samples were collected for
plasma concentration analysis.
In the nanolipid combination formulation, 5 capsules containing a
two third dosage of each of the actives i.e. RHZE
100/40/200/132mg were taken and analysed in the same manner.
4.3 Study Supplies
The drugs used in the study were packaged into the nanolipid delivery
system, manufactured according to Preparation 3 above and labelled
in accordance with Good Laboratory and Manufacturing Practice (GLP
and GMP) Guidelines for the labelling of study medication as set out in
Table 8 below.
CA 02416512 2008-07-18
Table 8
4.4 Sample Collection and Preparation
5
Blood (10ml) was collected at specified times for HPLC determination
of the plasma concentrations of Rifampicin. Blood was also collected
for liver function determinations and full blood cell counts.
10 Samples were collected in heparinized tubes and placed immediately
on ice. Plasma was extracted by centrifugation within 15 minutes of
collection and stored at a minimum of minus 80 C.
Prescribed treatment: RHZE combination tablet
Dosage RHZE mg/tablet RHZE mg/day RHZE mg/week
Less than 50 kg 120/60/300/200 480/240/1200/800 2400/1200/6000/40(
more than 50 kg 120/60/300/200 600/300/1500/10003000/15.00/7500/50(
Drugs administered b drug delivery system
Drug mg/week
y
Drug delivered treatment Dru mg/capsule Dru m /da
Rifam icin; R 100mg 400mg 2000mg
Isoniazid; H 100mg 200mg 1000mg
Pyrazinamide; Z 250mg 1000mg 5000m
Ethambutol; E 132mg 660mg 3300mg_
Prescribed treatment: RHZE combination tablet
Dosage RHZE mg/tablet RHZE mg/day RHZE mg/week
Less than 50 kg 120/60/300/200 480/240/1200/800 2400/1200/6000/40(
more than 50 kg 120/60/300/200 600/300/1500/1000 3000/1500/7500/50(
Drugs administered b drug delivery system
Drug delivered treatment Dru mg/ca sule Dru mg/day Drug mg/week
Rifam icin R 100mg 400mg 2000mg
Isoniazid; H 100mg 200mg 1000mg
Pyrazinamide; Z 250mg 1000mg 5000mg
Ethambutol; E 132m 1660mg 13300mg
Blood samples were collected and handled in accordance with Good
15 Clinical Procedures (GCP) Guidelines.
4.5 Plasma concentration determination
The concentrations of Rifampicin(RIF), Izoniazid(INH) and
20 Pyrazinamide(PZA) and their active metabolites were determined by
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high performance liquid chromatography after their simultaneous
extraction from plasma. The materials used were INH, RIF, PZA and
pyrazynoic acid; HPLC - grade acetonitrile, methanol and
trifluoroacetic acid (TFA) and C18 Bondelut extraction columns,
200mg, 3 ml 40 microns.
The plasma concentrations of RIF were determined using a mobile
phase of 80% acetonitrile in 0.1% trifluoracetic acid. A reversed phase
C8 analytical column (Spherisorb, 250 X 4.6 mm ID, 5um) linked to a
C8 precolumn, with flow rate at 2.0 ml per minute and detection at
270 nm was used.
For the determination of INH and PZA, the mobile phase was 3%
acetonitrile in 0.06%. TFA. A reversed phase C8 analytical column
(Spherisorb, 150 x 4.6 mm ID, 5um) linked to a C8 pre-column with
flow rate at 1.5 ml per minute and detection at 254 nm was used.
Stock standards
A stock standard solution of Rifampicin (0.5mg/ml), PZA(0.5 mg/ml)
and INH(0.5 mg/ml) and pyrazynoic acid were prepared (0.5 mg/ml)
is prepared in Methanol.
Relative retention times were established by spiking and comparing
peak area ratio of RIF.
INH and PZA.
All stock solutions are kept at a minimum of 4 C and protected from
light.
Specificity
Analyses of blank samples of the appropriate biological matrix were
tested for endogenous interferences in the reference standard region
for RIF, INH and PZA.
Calibration graphs (peak areas vs concentration) were constructed for
RIF and INH in the range 0.1-20pg/ml and for PZA in the range 0.1-
60pg/ml. INH, RIF and PZA and pyrazynoic acid analysis were done in
triplicate.
Intra- and inter-assay coefficients of variation were determined.
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Five replicate samples of four concentrations were run through the
procedure with exactly controlled volumes, as described for the
extraction of the samples. To verify recovery/quality control, precision
and accuracy, the peak areas obtained for the extracted samples were
be compared to those of fresh standards of the analytes in mobile
phase with respect to the volumes handled during extraction.
C18 Bondelut extraction cartridges were washed sequentially with 2 x
2 ml of methanol, 2 x 2 ml of water and 2ml of 0.05 M potassium
phosphate, pH 4.5 (phosphate buffer) prior to application of the
sample to the columns.
A 0.5 ml quantity of plasma were thawed and drawn slowly onto the
column and allowed to stand for 5 minutes, after which time unbound
material were discarded. The columns were washed with 1 ml of
phosphate buffer to be discarded, and the drugs eluted with 0.5 ml of
acetonitrile, followed by 0.5 ml of methanol with these elutes being
pooled.
60 l of the pooled eluates were injected immediately onto the HPLC
column to assay for RIF.
INH, PZA and pyrazynoic acid:
0.5m1 of the combined eluates were dried by vacuum centrifugation
and taken up in 0.5 ml of 3% acetonitrile in 0.06% TFA.
60p1 of this were injected onto the autosampler HPLC to assay for INH
and PZA, which were detected together on the same column.
Acceptance criteria:
A validated analytical method meets the following criteria:
Precision and accuracy: The between batch CVs for low, medium and
high concentrations should be <15%, and 20% for the LOQ QC.
Sensitivity: The lowest standard should be accepted as the LOQ if the
%CV is <20%
Specificity: The responses of interfering peaks at the retention time of
the analyte should be less than 20% of the response of an LOQ
standard.
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Stability: Stock solution stability should meet the criteria specified in
the SOP.
5. RESULTS
5.1 Comparative bioavailability of Rifampicin
The first part of the study concerned only Rifampicin
and the nanolipid-formulated Rifamzaloid. The plasma
levels determined for the indicated times are reflected
in Table 9.
TABLE 9
Plasma levels of Rifampicin
MZLA
Rifamzaloid Rifampicin
( g Rif /ml ( g/ml
Time(min) plasma) plasma)
0 0 0
30 10.31 0
60 12.93 7.46
90 11.23 10.23
120 11.22 9.3
150 10.16 8.43
210 8.82 9.03
240 10.03 7.39
370 9.27 6.32
300 7.22 4.84
330 6 4.1
360 5.77 3.45
Increased Cmax
The maximum plasma concentration (Cmax) of Rifampicin was
determined to be 12.93 g/ml and was reached 60 minutes (Tmax)
after oral administration of the active in the nanolipid delivery
system. The Cmax obtained for the Rifampin (10.23 g/ml) was
reached 90 minutes after administration. The delivery of Rifampicin
to the plasma was therefore increased by at least 21% at Tmax by
the nanolipid carrier. Furthermore, only two thirds of the normal
CA 02416512 2008-07-18
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dosage was taken in the MZL formula. Therefore, the increased
delivery of Rifampicin to plasma by the Nanolipid delivery system
at Tmax was 181% that of its comparator at equal dosages.
Decreased Tmax
The minimum effective concentration of Rifampicin in plasma is
7 g/ml. It is clear from the results that Rifampicin reaches its
effective concentration much quicker when delivered by the
Nanolipid delivery system. This is especially important in the case
of unstable drugs such as Rifampicin, as increased gastric exposure
may lead to increased loss of activity.
Increased Coverage
Coverage can be regarded as the time period during which the
effective concentration is maintained. Figure 6 illustrates that the
coverage afforded by using the nanolipid delivery system is
increased by 180% (270 minutes vs 150 minutes). It is therefore
possible to the increase the time intervals between sequential
dosages.
The above parameters reflect the comparative bioavailability
dynamics of the Nanolipid delivery system. The total average
increase in bioavailability by Nanolipid delivery system was 227%,
while using only two thirds of the dosage of the comparator.
Differences in the above pharmacodynamic and pharmacokinetic
parameters were statistically significant (see Table 10), with a p-
value of 0.0157. The statistical method for analysis used was
Analysis of Variance with a single factor variant.
TABLE 10
SUMMARY OF STATISTICAL ANALYSIS
Groups Count Sum Average Variance
Column 1 11 103.16 9.378182 4.944216
Column 2 11 70.45 6.404545 9.408267
ANOVA
Source of Variation SS df MS F P-value F crit
Between Groups 48.63382273 1 48.63382 6.77706 0.017005894 4.351250027
Within Groups 143.5248364 20 7.176242
CA 02416512 2008-07-18
Figure 6 hereto records the observed bioavailability of Rifampicin in the
MZL formulated Rifamzaloid vs its comparator Rifampin. The comparative
daily Rifampicin dosages were 400mg/ day in the case of Rifamzaloid and
5 600mg/day in the case of Rifampin.
5.2 Bioavailability of Combination Drugs
Similar results were obtained with Isoniazid and
10 Pyrazinamide. Figure 7 hereto illustrates the enhancement in
bioavailability of INH, using the nanolipid delivery system,
and Figure 8 that of Pyrazinamide (PZA).
Figure 7 shows the enhanced bioavailability of Izoniazid when
encapsulated in the MZL delivery system, even though the daily
15 dosage of the INH in the MZL formula was only two thirds of that of
the comparator, Rifafour.
Figure 8 illustrates the enhanced bioavailability of Pyrazinamide in
the MZL formulation. Again the daily dosage of the PZA in the MZL
formula was only two thirds of the PZA in Rifafour, the comparator.
5.3 Side effects:
No significant side effects were found with the MZL formulated
liver function analysis. None of the liver enzymes showed
levels higher than the normal range. The S-unconjugated
bilirubin, which did show levels elevated above the normal
range was nearly back to normal 8 hours after drug
administration, and was normal on the following day.
5.4 Volunteer's assessment:
The only adverse reaction to either of the MZL formulas
(Rifampicin or Combination) was nausea, whereas the
comparator Rifafour led to serious headache, jitters and
nausea.
5.5 Partitioning of nanolipid formulated Rifampicin:
Between 5-10% of the Rifampicin encapsulated in the
nanolipid partitioned to blood cells rather than to plasma.
This partitioning should increase the effective dosage
CA 02416512 2008-07-18
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delivered to the cells, but the partitioning is not so high as to
be cytotoxic.
The study was repeated for Rifampicin and Pyrazinamide with
s similar results.
Many modifications of the invention may be devised without departing
from the spirit and general scope of the invention.
