Note: Descriptions are shown in the official language in which they were submitted.
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I
COMh~lU..~ CO~ff wsnNG B~hnrrH ~ND ONE OR MORB ~NmMncRoBLuLs~poR THE
TRE~l~n3NT ~NDPREVE~n~ON OF GASTRO~ ALl~-O~r~-c
BACKGROUND OF THE INVENTION
While bacteria and viruses have long been recognized as a leading
cause of diarrhea throughout the world, it was not until about twenty years
ago that parasites were considered in the etiology. The importance of
diarrhea associated with parasitic protozoa was not re~li7~d in the United
States, as it was generally believed that this was an illness of impoverished,
developing countries. Since that time, parasites such as Cryptosporidium,
Giardia, and Entamoeba among others, have been implicated with diarrhea
and other gastrointestinal disorders at high incidence rates outside the
United States and at an increasing frequency within the United States. For
example, in a recent survey of drinking water supplies in fourteen states of
the U. S., investigators found one in four to be tainted with Cryptosporidium
parvum. Health, July/August 1993, p. 14. Therefore, diarrhea and other
gastrointestinal disorders associated with parasitic protozoa represent a
serious health concern and the need for effective anti-parasitic treatment
therapies continues to grow.
It has been discovered by the present invention that the
adminisl, dliGI, of bismuth salts and one or more antimicrobials may be
effective for the prevention and/or treatment of gastrointestinal disorders
caused or mediated by parasitic p~uto~oan. Thus, an object of the present
invention is to provide safe and effective compositions and methods for
preventing and/or treating gastroi"leslinal disorders c~l~sed or n,edidled by
pd,dsilic protozoa. A further object of the invention is to provide such a
method comprising the administration of bismuth and one or more
anlil "ic~ obials.
These and other objects of the present invention will become readily
apparent from the det~iled description which follows.
SUMMARY OF THE INVENTION
The present invention relates to a method for treatment of a human
or lower animal subject having a gastrointestinal disorder caused or
mediated by one or more parasitic protozoa comprising administering to the
sl~bject from about 50 milligrams to about 5000 milligrams of bismuth, per
day, for from about 1 to 56 days; and from about 100 milligrams to about
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10,000 milligrams of each of one or more antimicrobiais, per day, for from
about 1 to about 21 days.
The present invention also relates to a method of prevention in a
human or lower animal for a gastrointestinal disorder caused or mediated by
one or more parasitic protozoa comprising administering to the subject from
about 50 milligrams to about 5000 milligrams of bismuth, per day, for from
about 1 to 21 days; and from about 100 milligrams to about 10,000
milligrams of each of one or more antimicrobials, per day, for from about 1 to
about 14 days.
DETAILED DESCRIPTION OF THE INVENTION
The methods of the present invention comprise the prevention and/or
treatment of gastrointestinal disorder caused or mediated by one or more
parasitic protozoa. Such gastrointestinal disorders are prevented and/or
treated by the administration of bismuth and one or more a"lil~icrobials.
The components of the present invention are more fully defined below.
Gastrointestinal Disorder
The term ''gasl,ui,,lesli,,al disorder", as used herein, encorrlp~sses
any infection, disease or other disorder of body, typically the upper and/or
iower gasfro~,~LesG"al tract, caused or mediafed by one or rnore parasitic
proto,oa. Such disorders include one or more of the following conditions:
diarrhea, abdominal pain and/or cramping, flatulence, nausea, abdominal
distention, fever, constipation, blood, mucus and/or pus present in feces,
vomiting, gastroenteritis, weight loss, anorexia, malaise, and any other
condition commonly :~sso~ i~ted with infection by parasitic protozoa.
In immunocompromised subjects and children, gastroi"teslinal
disorders c~ secl or medi~ted by parasitic protozoa may be more severe
and life threatening than the common disorders listed above. Therefore, the
term "ga~L,ui"leslinal disorder" also includes any condition commonly
associated with protozoa infection in immunocompromised subjects and
children, including but not limited to, acute diarrhea, dehydration, electrolyteimbalance, colitis, and fatal necrosis of the i, lleslil ,e.
Parasitic Protozoa
Protozoa are unicellular, eucaryotic organisms which contain a
nucleus, or nuclei, and cytoplasm. Four groups of Protozoa contain
parasites which are contemplated in the present invention. These
organisms are fully described in Zinsser Microbioloqv. 20th Edition, 1992,
pp. 1 163-1 173, and T. L. Kuhls, M.D., "P, oto~oal Infections of the Intestinal
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Tract in Children", Advances In Pediatric Infectious Diseases, vol. 8, 177-
202, (1993), both of which are incorporated herein by reference. The term
"parasitic protozoa", as used herein, refers to Protozoa of the phyla
Sarcomastigophora such as Entamoeba, Giardia, Dientamoeba, and
Blastocystis; Ciliophora (ciliates) such as Balantidium; Apicomplexa such as
Isospora and Clyptosporidium; and Microspora such as Enterocytozoon.
Preferred parasitic protozoa are Entamoeba, Cryptosporidium, Giardia,
Isospora, and combinations thereof. Most preferred parasitic protozoa are
Entamoeba, Cryptosporidium, Giardia, and combinations thereof.
Diagnosis of gastrointestinal disorders caused or mediated by
parasitic protozoa may be accomplished by any method commonly used in
the medical community. Such methods are fully described in Zinsser
Microbiology, and T.L. Kuhls, M.D. "Protozoal Infections of the Intestinal
Tract in Children", as referenced above.
Bismuth
The methods of treatment and/or prevention in the present invention
involve administration of bismuth. As used herein, the quantity of bismuth is
by weight of elemental bismuth.
The preferred duration of bismuth administration will vary according
to the specific gastrointestinal disorder to be treated and the physical
condition of the subject being treated. In general, as a method of treatment,
bismuth may be administered in an amount of from about 50 milligrams to
about 5000 milligrams, and preferably from about 50 milligrams to about
2500 milligrams, per day, for from about 1 to about 56 days, preferably for
from about 2 to about 28 days, and most preferably for from about 7 to
about 21 days.
In general, as a method of prevention, bismuth may be administered
in an amount of from about 50 milligrams to about 5000 milligrari,s, and
preferably from about 50 milligrams to about 2500 milligrams, per day, for
from about 1 to about 21 days, and preferably for from about 1 to about 14
days. In a method of prevention, bismuth may be administered prior to
potential exposure to parasilic proLo,oa. Such administration of bismuth
may vary depending on the likelihood of parasitic protozoa exposure and
condition of the subject and may be commenced at any time deemed
beneficial by the l"edical community including from about 1 to about 7 days,
from about 2 to about 5 days, and from about 3 to about 4 days, prior to
potential exposure.
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In the present methods, bismuth may be in the form of a
pharmaceutically-acceptable salt or may be in the form of an organic
complex which contains bismuth as an active ingredient. Such organic
complexes include 2,2'-spirobi[1"32-benzodoxabismole]. Preferably,
bismuth is administered in the present methods as a pharmaceutically-
acceptable salt. Such bismuth salts include bismuth aluminate, bismuth
subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato
bismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate,
bismuth subsalicylate, and mixtures thereof. Bismuth citrate, bismuth
subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth
subsalicyiate, and mixtures thereof are preferred bismuth salts for use in this
invention.
The bismuth useful herein may be administered alone, or in
combination with other pharmaceutically-acceptable components in a
bismuth-containing composition. A variety of such compositions containing
bismuth salts are commercially available. Such compositions include DeNol,
containing tripotassium dicitrato bismuthate (by Brocades); Bislumina,
containing bismuth aluminate (by Mazuelos); Roter, containing bismuth
subnitrate (by Roterpharma); Devroma~, containing bismuth subgallate (by
The Parthenon Co., Inc.); and Pepto-Bismol~, containing bismuth
subsalicylate (by The Procter & Gamble Company).
As used herein, the term "administering" refers to any method which,
in sound medical practice delivers the compounds or compositions used in
this invention to the subject to be treated in such a manner so as to be
effective in the treatment of the gastroinleslinal disorder. P,~ferably, the
bismuth is administered orally.
Ar~ ~,icrobial
The processes of the present invention also include administration of
a safe and effective amount of one or more antil,,i~;,ubials, per day. As used
herein, the term "aoli",ic,ubial(s)" refers to one or more a"li",icrobials.
Typically, according to the present Ill~lhods for prevention and
dl",ent, each of the one or more a"li")icrobials is adr"i,-istered at a level
of from about 100 milligrams to about 10,000 milligrams, per day, for from
about 1 to about 28 days. Preferably, each of the one or more
anli",icrobials is adnlinistered at a level of from about 100 Illilligrdllls to
about 8000 milligrams per day, and more preferdbly at from about 100
",illi$~rd"~s to about 5000 milligran,s per day. It is also preferred that each of
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the antimicrobials is administered for from about 1 to about 7 to 10 days,
more preferably for from about 1 to about 14 days, and most preferably for
from about 1 to about 21 days. In the methods for prevention, it is further
preferred that each of the one or more antimicrobials is administered for
from about 1 to about 14 days, and preferably for from about 1 to about 7 to
10 days.
The specific dosage of antimicrobial(s) to be administered, as well as
the duration of antimicrobial(s) treatment, are mutually dependent, and will
also depend upon such factors as the specific anli"~icrobial used, the
number of antimicrobials used in the treatment, the resistance pattern of the
infecting organism to the antimicrobial used, the ability of the antimicrobial to
reach minimum inhibitory concentrations at the site of the infection, the
nature and extent of other infections (if any), the personal attributes of the
subject, compliance with the treatment regimen, and the presence and
severity of any side effects of the treatment. Therefore, in the case of
prevention or treatment with more than one a"li,~icrobial, the duration of
administration should depend on the type of antimicrobial rather than the
administration of the antimicrobials for the same number of days.
A wide variety of antimicrobials are useful in this invention. As used
herein, the term "anlimicrobial" refers to any naturally-occurring, synthetic orsemi-synthetic compound or composition or mixture thereof, which is safe
for human use as used in the methods of this invention, and is effective in
killing or substantially inhibiting the parasitic protozoa when used in the
methods of this invention. Antiprotozoal agents, antiparasitic agents and
antibiotics are among the preferred antimicrobials useful herein.
Antiprotozoal and antiparasitic agents suitable for use in the present
invention include any of the agents recognized in the medical community as
acceptable for treating protozoal infection. Such antiprotozoal and
antiparasitic agents include atovaquone, chloroquine phosphate, quinacrine
hydrochloride, iodoquinol, pyrimethamine, and mefloquine hydrochloride.
Antibiotics can be generally classified by chemical composition, into
the following principal groups: the aminoglycosides, such as gentamicin,
neomycin, kanamycin, and streptomycin; the macrolides, such as
erythromycin, clindamycin, and rifampin; the penicillins, such as penicillin G,
penicillin V, ampicillin and amoxycillin; the polypeptides such as bacitracin
and polymyxin; the tetracyclines such as tetracycline, chlortetracycline,
oxytetracycline and doxycycline; the cephalosporins such as cephalexin and
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cephalothin; quinolones such as ciprofloxacin, norf oxacin and ofloxacin;
and such miscellaneous antibiotics as chloramphenicol and clindamycin.
These antibiotics can generally be said to function in one of four ways:
inhibition of cell wall synthesis, alteration of cell wall permeability, inhibition
of protein synthesis or inhibition of nucleic acid synthesis. -'
Other antimicrobials useful herein include the sulfonamides;
nitrofurans, such nitrofurazon, nitrofurantoin, and furozolidone;
metronidazole, tinidazole, and nimorazole. Antimicrobials among those
useful herein are described in Remington's Pharmaceutical Sciences. 18th
Edition, pp. 1173-1232 (1990), which is incorporated herein by reference.
While any of these antimicrobials may be used, penicillin,
erythromycin, metronidazole, doxycycline, tinidazole, amoxycillin, ampicillin,
nitrofurantoin, and atovaquone are among the preferred antimicrobials for
use in the present invention.
As stated above, the specific preferred quantity of antimicrobial and
duration of treatment used in the methods of this invention will, in addition toother factors, depend upon the particular a"lin,i-robial used and its
pharmacology. In general, though, the tetracyclines are preferably
administered at a level of from about 100 milligrams to about 2,000
milligrams per day. Macrolides (such as erythromycin) are preferably
administered at a level of from about 1,000 milligrams to about 4,000
milligrams per day. Penicillins are preferably administered at a level of from
about 500 milligralos to about 3,000 milligrams per day. The
aminoglycosides (such as neomycin) are preferably administered at a level
of from about 100 milligrams to about 8,000 milligrams per day. Nitrofurans
(such as nitrofurantoin) are administered preferably at levels of from about
100 milligrams to about 800 Illilli5~ldms per day. Preferably, metronidazole
is ad",i.,istered at a level of from about 500 to about 2,000 milligrams per
day. P,eft:ral)ly, atovaquone is administered at a level of from about 750 to
about 2250 milliyrar"s, per day.
The specific method of ad",i"istering the a"li",icrobial, according to
the processes of this invention, may depend upon such factors as the
particular antimicrobial(s) used, the site of infection, the amount of
anli",icrobial(s) to be administered per day, the presence of any adverse
side effects, and the interactions (if any) between the antimicrobial(s) and
the bismuth. Thus, the a"li",ic~obial(s) may be administered under the
process of this invention by single daily doses, or by administration in two,
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three, four, or more doses per day. One factor, in particular, in potential
interaction between the antimicrobial(s) and the bismuth administered under
~ these processes. For example, the presence of bismuth is known to
adversely affect the efficacy of the tetracyclines. See, for example, C. D.
Ericsson, et al., "Influence of Subsalicylate Bismuth on Absorption of
Doxycycline", 247 J. of American Medical Assoc. 2266 (1982). Hence, it is
preferred to administer those a"li",icrobials that are subject to adverse
bismuth interaction by methods that minimize such interactions, i.e., by
minimizing the simultaneous presence of antimicrobial and bismuth in the
stomach. Such methods include one or more of the following: staggered
oral dosing of the bismuth and antimicrobial, through discreet
administrations of each compound or composition separated by at least
preferably two hours between dosages; oral administration of the
antimicrobial in an enterically coated form, i.e., coating of the a"li",icrobialwhich prevents dissolution of the anli" ,icrobial in the stomach; use of
optional processes of this invention, wherein the step of administering the
bismuth is terminated prior to commencing the step of orally administering
the antimicrobial; and administering the anli",icrobial by a non-oral route,
e.g., by intravenous or intramuscular injection.
Bismuth/Antimicrobial ComPositions:
The present invention also provides compositions for the treatment of
gasl,oi"testinal disorders comprising a safe and effective amount of bismuth
and a safe and effective amount of one or more al,li",icrobials. Typically,
these compositions comprise a safe and effective amount one or more
a"li" ,icr(,l,ials; a safe and effective amount of bismuth; and
pl,al",aceutically-accepl~ble carrier materials; wherein the safe and
effective amount of the one or more antimicrobials and the bismuth is
effective for preventing and/or treating a gastrGinLes~li"al disorder caused or
me-Ji~led by one or more parasitic protozoa.
A preferred composition comprises:
(a) from about 50 milligrams to about 5,000 milliyrdms of bismuth;
and
(b) from about 100 milligrams to about 10,000 milligrams of each of
one or more a"li",icrobials.
Preferably, the bismuth salt is present at a level of from about 50 milligrams
to about 2500 milligrams. Also, preferably each of the one or more
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antimicrobials is present at a level of from about 100 milligrams to about
8000 milligrams.
The compositions of the present invention may contain optional
components which affect the physical and therapeutic characteristics of the
present compositions. In particular, a variety of pharmaceutically-
acceptable carriers and excipients may be included, depending upon the
particular dosage form to be used. Various oral dosage forms can be used,
including such solid forms as tablets, capsules, granules and bulk powders.
Tablets can be compressed, tablet triturates, enteric-coated, sugar coated,
film-coated or multiple compressed, containing suitable binders, lubricants,
diluents, disintegrating agents, coloring agents, flavoring agents, flow-
inducing agents and melting agents. Liquid oral dosage forms include
aqueous solutions, emulsions, suspensions, solutions, and/or suspensions
reconstituted from non-effervescent granules and effervescent preparations
reconstituted from effervescent granules, containing suitable solvents,
preservatives, emulsifying agents, suspending agents, diluents, sweeteners,
melting agents, coloring, and flavoring agents.
Specific examples of pharmaceutically-acceptable carriers and
excipients that may be used to formulate oral dosage forms of the present
invention are described in U. S. Patent 3,903,297, Robert, issued
Septel"ber 2, 1975, incorporated by reference herein. Techniques and
compositions for making dosage forms useful herein are described in the
following references, all incorporated by reference herein: 7 Modern
Pharmaceutics. Chapters 9 and 10 (Banker and Rhodes, editors, 1979); an
Lieberman, et al., Pharmaceutical Dosaqe Forms: Tablets (1981); and
Ansel, Introduction to Pharmaceutical Dosage Forms (2d edition,1976).
As ~iscusseri above, care must be taken in avoiding any interactions
between the bismuth compound or composition and the particular
anli",ic,~bial(s) used in these cornrositions. Accordingly, in prefe"ed
compositions of this invention, one or more of the al,li",icrobials is physically
separated from the bismuth in such a manner so that the antimicrobial(s)
and the bismuth are not simultaneously dissolved in the sLolllach. Hence, a
preferred composition of this invention comprises a capsule containing
bismuth particles and enterically-coated antimicrobial particles.
The compositions of this invention may be used according to the
methods of this invention by administering the composition from 1 to 7 times
per day, and p~ferably from 1 to 4 times per day; for from 1 to 21 days,
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preferably for from about 1 to about 14 days. The specific frequency of
administration will depend upon such factors as the specific bismuth
compound or composition and antimicrobial(s) used, the levels at which the
components are incorporated in the composition, the nature and severity of
the condition to be treated, and the nature of any concurrent therapy, if any.
The present invention comprises methods wherein the administration
of bismuth and the administration of one or more arlLi",ic,obials are
performed simultaneously (beginning and ending on the same day),
concurrently (overlapping), or consecutively (sequential, but wherein the
course of the treatment is substantially continuous). Preferably, the step of
administeri"g the antimicrobial(s) is not commenced prior to commencing
the step of administering bismuth.
As used herein, the term "administering" refers to any method which,
in sound medical practice delivers the compounds or compositions used in
this invention to the subject to be treated in such a manner so as to be
effective in the treatment of the gastrointestinal disorder. Frer~rdbly, the
bismuth is administered orally. Also preferably, the a"li",icrobial(s) is
administered either orally, intravenously, or any other method which effects
systemic distribution, or local distribution to the site of the gastroi"le~li"aldisorder, of the anlil "ic, ~,bial(s) in the subject. Oral ingestion of the
anli",i obial(s) is a preferred method of administering the antimicrobial(s) in
the methods of this invention.
The following non-limiting examples illustrate the methods and uses
of the present invention.
EXAMPLE I
A human subject, suffering from severe diarrhea, is treated by a
lod of the present invention. Fecal samples are taken from the subject
and analyzed for the presence of i"lesli"al parasites, including organism
eggs, cysts, sporozoites, etc. Clinical parasitology specimens reveal the
presence of Cryptosporidium parvum. The subject is then treated by
admir,isteri"g a composition containing bismuth 5l~hs~licylate~ sold by The
Procter & Gamble Company under the name "Pepto-Bismol~". The
composition, in liquid form, is administered four times daily in equal doses
delivering approximately 2500 milligrams of bismuth per day, for 21 days.
Atovaquone tablets (750 milligrams per tablet) is concurrently administered
three times a day for 21 days, delivering a total of 2250 Illilligldllls of
atovaquone per day. Thereafter, fecal samples from the s~bject are
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analyzed again, finding no trace of parasitic infection. The subject remains
asymptomatic, and another fecal analysis performed 5 months later is
normal.
In the above example, tripotassium dicitrato bismuthate, bismuth
tartrate, bismuth citrate, and bismuth subnitrate are substituted, J
respectively, for bismuth subsalicylate, with substantially similar results.
EXAMPLE ll
A three-year-old child with diabetes and in a day care center is
suffering from chronic diarrhea, and abdominal distention. Analysis of fecal
specimens shows the presence of Giardia lamblia. The infection is
diagnosed and treated by orally administering approximately 400 milligrams
of bismuth in the form of bismuth subcitrate ("DeNol", sold by Brocades), in
four equal doses daily, for about 28 days and 100 milligrams of
furolzolidone, four times daily, for about 10 days. Thereafter, fecal samples
from the subject are analyzed again, finding no trace of parasitic infection.
EXAMPLE lll
A Peace Corps volunteer preparing to travel to a developing country
with sub-standard sanitation and water purification systems has a fecal
sample clinically analyzed for the presence of Giardia lamblia,
Cryptosporidium parvum, and Entamoeba hisfolyfica. Clinical results show
no evidence of the parasites. The subject is given approximately 1200
milligrams of bismuth, (administered as bismuth subsalicylate in the
composition Pepto-Bismol~, sold by The Procter & Gamble Company), in
four equal doses daily, and 750 milligrams of metronir~a~ , three times
daily, for about 21 days. Upon return to the U.S., approxi"lately 30 days
after the initial clinical analysis, the subject remains asymptomatic. Fecal
samples from the subject are analyzed and no evidence of parasitic
inr~ctiol, is found.
EXAMPLE IV
Four young Boy Scouts, having enjoyed a week of primitive camping
and fishing in the bayous of Louisiana, reported flulike symptoms, including
nausea, vomiting, anorexia, weight loss, and explosive diarrhea one week
following their trip return. Fecal bacterial isolates and immunodiagnostics
fail to identify the offending pathogen. Direct wet mount exan,i"dlion of the
boys' diarrheic fecal specimens reveal the presence of the trophozoite stage
of Dientamoeba fragilis. Following the diagnosis, the pdlienls are treated by
administering 500 milligra,.,s of bismuth subgallate per day (two doses per
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11
day) for 21 days. After the second day (commencing on the third day) of
bismuth treatment, the patients are aiso treated by administering 750
milligrams of nitrofurantoin, per day, for 10 days. (Hence, bismuth treatment
continues for 9 days after the last antimicrobial treatment). Fecal specimens
~ are then collected from the patients and wet mount examinations are
performed. There is no indication of parasitic infection.
In the above example, nitrofurazone, metronidazole, and tinidazole
are substituted, respectively, for nitrofurantoin, with substantially-similar
results.
EXAMPLE V
A pig farmer reports chronic abdominal pain, severe cramps, n~l-se~,
vomiting, tenesmus, and frequent watery, mucoid diarrhea. Examination of
saline mounts of sigmoidoscopic aspirates reveal the presence of numerous
ciliated trophozoites of Balanfidium co/i, readily recognized by their
characteristic large size (50-200 micrometers), shape, and rapid rotating
motion. The subject is treated, according to the present invention, by
concurrent ad."i.,istration of 500 milligrams of tetracycline four times a day
(for a daily total of 2 grams) and 650 milligrams of iodoquinol three times a
day (for a daily total of 1850 milligrams) for 20 days. After five days
(commencing on the sixth day), a composition containing tripotassium
dicitrato bismuthate manufactured by Gist Brocades,. and sold under the
name "De-Nol") is administered four times a day (for a daily total of 480
milligrams) for 15 days. Sigmoidoscopic aspirates were taken following the
conclusion of treatment and ev~ t~ci for parasitic presence. The
specimens were normal and the patient was asy""~to",dLic.
In the above example, bismuth citrate, bismuth tartrate, bismuth
suL,cil, dle~ bismuth alu" ,i, ldte and bismuth subsalicylate are substituted,
respsctively, for tripotassium dicitrato bismuthate, with substantially similar
results. Similarly, penicillin, erythromycin, metronid~ - ~ l o, doxycycline,
tinidazole, amoxycillin, ampicillin, nitrofurantoin, and atovaquone are
substituted respectively for tetracycline or iodoquinol, with substantially
similar results. In addition, either a"liLiJIic can be eliminated from the
regimen (e.g. due to hypersensitivity) and maintain therapeutic efficacy.
