CA2113614A1 - Antimicrobial treatment methods and compositions - Google Patents

Abstract

Methods for treating patients having infections with antimicrobial agents when the patients are at risk to C. difficile infection comprising concurrently orally administering before the end of about 5 days of antimicrobial therapy a safe and effective amount of bismuth subsalicylate.

Description

WO ~3/018~8 ~ ~ I 3 6 1 ~ P~r/VS92/0584 ANTIMICROBIAL TREATMENT ME~HODS AND COMPOSITIONS

BACKGRO_D OF THE TNVENTIQN
The present invention relates to a method for treating patients having infections with antimicrobial s when the patients are at risk to ~g~m ~ ("~ infection.
This method comprises concurrently orally administering before the end of about 5 days of antimicrob;al therapy a safe and effective amount of bismuth subsal icylate. The present invention also rel ates to compositions useful for the m~thod of the present invention corrprising certain antimicrobials and bismuth subsal i cyl ate .
"A commonly recognized complication of antibiotic therapy is diarrhea ~nd/or pselldomembranous col itis. This is due to bowel overgrowth by C. difficil~ which elaborates an exotoxin ~hat is ~~ responsible for symptoms. Discontinuation of antibio~ic therapy will usually lead to resolution of treatment, but some pa~ients re~uire vancomycin or metronida~ole~ n (5~
Medicine. 1~h ~it10n~ Wyngaarden and Salith editors, copyright 1988 by W.~. Saunders Company; at page 123.) R~por~s have discussed the prev~lence of C. diffieile ;n hospitals [McFarland et al., "Nosooomi~l Aequisition of Clostridium diff;cile Infection", ~ E~gL~L~ ~(4) pages 204-10 (1989)] and in nursing homes tBennett et al., "C. difficile di~rrhea: A conunon - and overlooked - nursing home in~ec~ionH~
Gerial:rics~ 45(9) pages 77-B7 (1990)]. A relationship has been obs~rved between nursing home patients with C. ~f~ fol~owing antibiotic treatment and hiyh mortalil;y rate. [Beltder et al., "Is Çlostrid~um ç~5~ Endemic in Chronic-Care Facilil;ies?~ The h~. July 5, 1986~ pp 11-13; Thomas ~t al . 7 "Postantibiotic Colonization with ~ difficile in Nursing Home Patien~s", ~,, 38, pages 415-420 (1990).] This research concluded that postantibiotic C. diffi~_le infection corre~ates with increased death rate separate from the risk of antibiQtic treatment alone. Other research relating to C difficile infeotion includes: Wilkins, "Role of ~g~Ym ~e Toxins in Disease", Dl~_ , 93 (2), ppO 389-3gl ~1987), W0 ~3~ 18 2 1 1~ 3 6 1 ll - 2 - PCI`~US92/~158'S8 ~yDol~ e~ al . ~ "Prote~n-Losing Enteropathy Associated wi~,.
Clostridium difficile Infectionn, ~,~, June 17, 19899 pp.
1353-1355; Bennett et al., "Evaluation of a Latex Agglutination Test for Clostridium difficile in Two Hursing Home Outbreaksl', J.
~'ln llicrobial, 27 (5), pp. 88g-g93 (1989).
"Th2 most important therapeutic dscision with anti bi oti c-associ ated di arrhea . or col i ti s i s di sconti nuati on of the inoplicated agent. This often results in resolution of symptoms with no necessity for further diagnost~c tests or therapy. Patients with severe or persistent symptoms should undergo erldoscopy to define anatomic ehan~es and stool examination to deteet C. diffi~ile cytotoxin- "
sll~ra9 at page 1632). Speci~i~ therapies ~or C. g~
infection include cholestyramine to bind the toxin or alltimicr4bials (such ~s metronidazole or preferably vancomycin) to inhibit the pa~hogen.
Bismuth subsalicylate has been investigated for itc effectiveness in t~eating C. g~icile colitis in hanlsters ~Chang et al., "Effect of ~ismuth S~bsalicylate on ~ s~l~
2û Colitis in HamstQrsn, ~~, 12 (Supplemsnt 1), pages S57-S58 (1990)~ . Further, bismuth subsal icylate has been used to treat C. 5~5~ diarrhea in nursing homes (Bennett et al., Geriatrics, ~3) and chronic diarrhea due to C. ~.~ in chiidren (Gryboski et al ~, "Effect of bismuth subsal icylate on chronic diarrhea in childhood: a prel iminary reportN, Rev.
Infect. Dis., 12 ~Supplement 1), pages S36-S40 (199OJ~.
Clearlyg there is a need for treatment methods which improYe the safety and~or effect7veness of antimicrobial treatment for pat i ents at ri sk to C~ s~ i nfecti on .
It has been surprisingly discovered by the present imention that when bi smuth subsal i cyl ate therapy i s ç~
administered wi th a course of antimicrohial therapy, there is a significant reduction in the death rate QP this ,~atient population versus similar patients receiving only antimicrobial therapy.
Further, because the deaths associated with antimicrobi~l treatment alone can occur very suddenly and within about 5 days after the start of the treatment regimen" it is also important for WO 93/01X18 3 21~ 3 ~ 14 PCT/US92/05848 ne purposes and the ps~esent method to coneurrently oral ly administer the bismuth subsalicylate before the end of about 5 days of antimi crobi al treatment .
Thus, an object of the pre~ent invention is to provide compositîons and meth~ds for treating patients at risk to C
in~ection with antimicrobials. A flJrther objective is to improve the chances of successful conlpletion of an antimicrobial treat~ent regimen in patients at risk to C.
g~ inf~ction. A further object is to reduce the mortality lû rate for patients being treated with antimicrobials whs are at risk to C. ~f~.~ infection.
These and other objects of the pre5ent invesltion will become readily apparent from the detailed description which fol~ows.
All percentages and ratios used herein are by weight~ and all measurements made at 25-C~ unless otherwise specified.
SUMM~RY OF TIIE INV~NTION
The present invention rel ates to a method lFor treating with antimicrobials patients at risk to C. ~ infection, said metho~ comprising administering to a patient at risk to C.
5~~ infection who needs antimicrobial treat~ent ~or infection a safe and effectiYe amount of an antimicrobial agent and concurrently orally administering before the end of about 5 days of antimicrobial treatment a safe and effeotive aalount of bismuth subsal ioylate.
The present inventioll also relates~ to oral antimicrobial compositions useful for treating patients at risk to C. difficilç
infection comprising~ (a) an orally administrable anti~icrobial agent in an amolJnt safe and effectiYe for treat1ng inf@ctions other than infections of the upper yastrointestinal tract; ~b) a 30 safe and effectiYe amount of bismuth subsalicylate; and (c~
pharmacQutic~lly-acceptable carrier material suitable for oral admi ni strati on .
.~_~

The present invention relates to a method for treating with antimicrobials patients at risk to C. diff~cile infection who need antimicrobial treatment for infectioTl. This method comprises 81X Pcr/vss2/os8~8 w~s3/ol 211361ll - 4 -administering to such patients a safe and effect1Ye amount of a,.
antimicrobial agent and concurrently orally administerillg before the end of about 5 days of antimicrobial treatment a safe and effective amount of bismuth subsalicylate.
The present invention methods are useful for treating with antimicrobial agents infeetions of humans. Suoh infections are typically other than infections of the upper gastrointestinal tract (e.g., Helicobacter p~lori, a.k.a. Camp~Lobacter ~g~, infection of the stomach which results in gastritis and ulcers as lû ~augh~ for example by European Patent Appl kation Publ ication Number 206~625 published December 3Q9 1986 by Marshall), and preferably the present invention involves treating infections not involving gastrointestinal tract infect~on~ Examples of infe~tions treatable according t~ the present invention include, but are not limited to9 upper and lower res~iratory tract infections, sepsis, and wollnd infections including surgical woun~
i nfecti ons .
The terln "patient at risk to C. ~ infectionn1 as used herein, means a hum~n subjeet in need of as~timiGrobial treatment for infection and this sub~ect is either infected with C
difficile or deemed to be at risk to becoming infected with C.
difficile within the scope of sound medical judgment. Patients at risk to C. ~ 5 ~ infection therefore include patients already diagn~sPd as being colonized by C. diffic;le (but preferably not exhibiting C. dif~icile diarrhea)~ as well as those patients in an environment wherein C. ~ ~1~ infection is known to be presÆnt .
or is reasonably b~lieved by the attending med kal expert to potentially be a hazard. Such environments include institutioral settings such as hospitals and long term care facilities such as nursing homes. The risk factors and incidence of C. ~ S~g are known, and are described in more detail in (1) Mc~arland et al., "Nosocomial Acquisition of Clostridium diffic_le Infectionn, N
Enql. J. Med., 320(4) pages 204-10 (1989); (2) Bennett et al., "C.
difficile diarrhea: A common-and overlooked-nursing home infPetion", Ceriatrics, 45(93 pages 77-87 (1990); (3) Thomas et al., "Postantibiotic Colonization with ~19~ Ym qiffioile in Nursing Home Patients", ~ f~_.LaC~_5nL~. 38, pages 415-420 WO g3/01818 ~ PCT/~S92/05848 (1990); and (4) Ççy~ g Wyngaarden and Sm~th e~itors, copyright 1938 by ~.B. Saunders Company; at payes 123, 727, 757, and 1632-1633, the dlsclosures of all these documents being incorporated by reference herein in ~heir entirety.
The term "safe and ef~ective amount'l, as used herein, means an amount o~ a compound or composition high enough to significantly positively modi~y the infectious cond~tion being treated, but low enough to avoid serious side effects ~at a reasonable benef~t/risk ratio~, with;n the scope of sound medical judgment. The safe and effec~ive amount of the antimicrobi~l a~ent and bismuth subsalicylate will vary with thc particular condi~ion being treated, the age and physical cond~tion of the patient being treated, the severity of the condition, the durat~on of the treatment, th~ nature of other therapy, the sp2cjfic ~ . .
antimicrobial agent employed, the particular pharmaceutieally-acceptable carrier utilized, the method of administration used, and like factors withtn the knowledge and expertise of the attending physician. However, typical dos:ages of the antimicrob~al agents and bismuth subsa~icylate are also described hereinaFt~r.
The terms "concurre~tly" and "concurrent", as used herein, mean that the safe and effective amourt of bismuth subsalicylate is orally administered within 24 h w rs of administration of the antimicrsbial agent. As not d hereinbefore, this concurrent administration of the bismuth subsalicylate should occur or commence before the end of ab~ut 5 days of antimicrobial treatm~nt. B;smuth subsalicylate administration may therefore begin before eommencement of the antimicrobial treatment, at the same time, or even aftQr commencement of the antimicrobial treatment bl~t before about 5 days of antimicrobial treatment have been completcd. Further, the concurrent bismuth subs~al~cylate administration may be terminated on or before the end of about 10 days of antimierobial treatment, but preferably it continues at least through the end of the antimicrobial treatment regimen, typically for from about 10 to about 30 days, and more preferably for about 2 to about 3 weeks.

W~ 93/01818 21 13 ~ 1 ~1 6 ~ PCI/US92/OS848 ~re~era~ly, concurrent bismuth subsalicylate administratl~,n is cw~nenced prior to, or more preferably within two days after, the start of an antimicrobial trea~ment regimen and contlnues at least un~il the antimicrobial treatment regimen is concludled.
Most preferred is ad~ninisterin~ the bismuth subsalicylate concurrently with the entire ~ntimicrobial treatment regimen.
5ismuth subsalisylate is a known therapeutic agent, having been sold for mary years as the active ingredient in Pepto-Bis~ol~D
(sold by The Procter & Gamble Company). Pref~rred methods ~ccording to the present invention comprise administerin~ from about û.25g to about l3.5~ of bismllth subsalicylate per day, preferably from about 0.5~ to about 5g ~er day, and most preferably from about 19 to about 39 per day. Preferred is from about 0.25g to about 1.59 per dose for from about 1 dose to about 10 doses p~r day; more preferred ~s administering from about 0.59 to about 1 .19 of bi smuth subsal i cyl ate per d~se or from about 2 doses to about 8 doses per day; ~nd most preferred is from about 0.5g to about 1.19 of bismuth subsalicylate given per dose by 4 doses per day.
Administration of the bismukh subsalicylate according to the present in~ention is by oral administration, wh kh may be by any form, ineluding liquids, suspensions,- chewable tablets, swal~owable capsules, swa1lowable caplets, etc. Preferrsd bismuth subsalicylate-cont~ining compositions useful ~or the methods uf the present lnvention are in liquid form comprising ~rom about I.7~% to about 3.5% of bismu~h sub5alicylate. Such compositions typically comprise magnesium aluminum silicate le.~., Yeegum~;sold by R. T. Vanderbilt ~ompany, Inc.), mlsthyl salie~1ate, sodium salicylate, salieylic acid, and/or methyl cellu1Ose ~e.g., as present in Pepto-Bismol~ uid an~ Maxi~u~ Strength Pep~o-~ismol~
liguid, sold by The Procter & Gamble ~ompany~. Bismuth subsalicylate-containing pharmaceutical compositions and their method of preparation are also described in detail in U.S. Patent 4,801,454, tu Coveney, issued January 31, 1989; U.S. Patent 4,g4~,695, to Coveney et al., issued July 10, 1990; and U.S.
Patent 5~013,$6Q, to Stentz Qt al., issued May 7, I99I, the WO 93/01$l8 2 1 1 3 6 1 ~ PcrtUsg2/05848 - :7l -~lsclosures of a11 these patents being incorporated herein by reference in their entirety.
Antimicro~ial agents use~ul herein are those safe dnd effective for treating the infectiGus diseases for which the present method is useful, and which are eompatible with concurrent bismuth subsalicylate administration. More preferred are those ant~microb~als which are administerad to treat infections other than infeet~ons of the gastrointestinal tract.
A wide variety of antimicro~ial agents are therefore useful ;n this in~ention. The term "antimicrobial agentsN, as used herein~ refers to any naturally-occurring, synthetic or semi-synthetic compound or composition, or mixture thereof~ which is safe for human use as used in the processes of this invention, and i~ ~ffec~ve in killing or substantially inhibiting the growth of the microorganis~ desired tQ be treated when used in the processes of this invention. Antibiotics are among the preferred antimicrobials useful herein. Such antibiotics can be generally classified ~y chemical composition, into the following prin~iple groups: the aminoglyeosides, such as genta~icin~ neomycin, kanamycin, ~nd streptomycin; the macrolides~ such as erythromycin, clindamycin, and rifampin; the penicillins, such as penicillin G, penicillin V, ampicillin and amoxycillin; the polypeptides, such as ba~itracin and polymyxin; the te~racyclines, such as tetracycline, chlortetracycline, oxytetracycline, and doxycycline;
the eephalosporins, such as cephalexin, cefaclor, and cephalothin;
and such miscellaneous antibiotics ~s chloramphenicol. ~hese antibiotics can be generally said to ~unction in one of four ways~
inhibition of cell wall synthesis~ alteration of cell wall permcability1 inhibition of protein synthesis, or inhibition o~
nucleic ac~d synthesis.
Other anti~icrobials useful herein include the sulfonamides;
nitrofurans, such as nitrofuraz~ne, nitrofurantoin, and furozolidone, fluoro~uinolones, such as c~profloxacin and norfloxaein; and metronidazole, tinidazole, and nimorazole.
Antimicrobials among those useful herein are deseribed in the following publications. incorporated by reference herein:
R.emin~ton's Ph_rmaceutical Sciences ~15th edit~on 1975); F. H.

W~ 93/01~18 PCT/U!~92/05~4~

2~I-361~ ~-Meyers, et al., Review of Medical Pharmacoloqy (7th edition 1~8~"
(8th edition 1978); and A. Goodman, A. G.
Goodman and L. S. Gi1man, ~_ Thera~eut;cs (6th edition 1g~0).
While any of these antimkrobials may be used, penieillin, erythromycin, doxycycline, metronidazole, tinidazole, olindamycin, amoxyoillin, ampicillin, cefaclor, ciprofloxacin, norfloxacin, and nitrofurantoin ar~ among the preferred antimicrobials for use in the present inventicn.
~s stated above, the speoiflc preferred quantity of antimiorobial, and duration of treatment used in the methods of this invention will, in addition to other f~c~ors, dep~nd upon the particular antimkrobial used and its pharmacology. In general, though, the tetraeycl ines are preferably ad~inister~d at a leYel of from about 100 milligrams to abollt 2000 milligrams~ per day.
Macrolides ~such as erythromycin) are preferably administered at a level oF from about 1ûOû millig~ams to about 40ûO milligrams, per day. Penicillins are preferably administerQd at a levet olP from about 500 milligrams to about 3000 milligrams, per day. Th~
2û aminoglyc~sides (sueh as neomy~in) are, preferably~ administered a~ ~ level of from about 10Q milligrams to about 8000 milligranls, per day Nitrofurans (such as nitrofurantoin) are administersd pref~rably at levels of from about 100 millîgrams to about 800 milligrams, per day. Prefe~ably, metronidazol~ is admillis~.ered at a level of from about 50~ to ~bout 2000 milligrams, per day.
Antimicrobials, such as tetracycl ine, which are known not to be comp~tible with bismuth subsalicylate when the two agents are dosed at about the same time, are to be administered using sound medic~l judgement to aYoid incompatibi~ity, and antimicro6ial 3û agents which are not suited for conc~lrrent administration with bismuth subsalieylate are not use~ul according to the present inYention. See, for example, C.D. Ericsson, et~ al., "Influence of Subsalicylate Bismuth on Absorption of Doxycycline" 247 American Medi~al~Assoc.. 2266 ~1982). Hence, it is pref~rred to administer those antimicrobials that are subject to adverse interaction with bismuth subsalicylate by methods that mirlimize such interactions, i.e., by minimizing the simultaneous presence wo 93/0~8~g 2 1 1 3 ~ 1 Jl PCI/~JS92/05848 ot an~imicrobia~ and bismuth subsal ~cylate in the stomach. Such methods i ncl ude one or more of the ~ol 1 owi n9 . staggered oral dosing Qf the bismuth subsalicylate and antimicrobial, through discrete administration of each compound or composition separated by at least (preferably) two hours between dosages; oral administration o~ the antimicroblal in an enterically coated form, i.e. coating of the antimicrobial which prevents dissolution of the antimicrobial in the stomach; and administering ths antimkrobial by a non-oral route, e.g., by intraveneous or intramuscular injection.
When treating the identified infection, administral;ion of the antimicrobial agent may be by any route as generally recognized for the particular antimicrobial being administered, ~he site of infection~ the amount of antimicrob~al agent to b~ administered per day, the presence of any adverse side ef~ects, and the ~- interaction (if any) between the antimicrobial agent and the bismuth subsalicylate. Therefore, v~rious modes of admillistratisn inelude, without 1 imitation, oral 9 l:ransdermal, mucosal, subl i ngual, i ntramuscul ar , i nl~ravenous , i ntraperi toneal and subcutaneous administration, as well as topical appl ication.

The present invention also relates to oral antimicrobial composit~on useflll for treating patients at risk to C 5~1 infection accordin~ to the present invention. These compos~tions comprise: ~1) an orally administrable antlmicrobial agent in an amount sa~e and effectiYe for treating infections other than infections ~f the upper gastrointestinal tract (more preferredl are those orally administrable ant;microbial agents in an amount safs and effective to be useful for treating infections other th~n infections of the gastrointestinal tract~; ~2) a safe and effective amount of bismuth subsalicylate, and (3) pharmaceutically-acceptable carrier material suitable for oral administration. Compositions according to the present invention may be in any form, inclu~ing liquids~ suspensions, capsules9 tablets~ chewable tablets, caplets, etc.
- The term "pharmaceutically-acceptable carrier materi~l", asused herein, means one or more compatible solid or liquid filler WO g3/Ol~lX PCI/US92105~48 211361'1 a~ luents or encap~ulating substances which are suitable for o~.
administration to a human. The term "compatiblen, as used herein, means that the ~omponents of the pharmaceutical composition are capable of being connningled with the antimicrobial agent and the bismuth subs~licylate, and with each other, in a manner such that there is no ;nter~ction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations, Pharmaceutkally-acceptable carrier materials must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administraîion to the human subjact being ltreated.
Some examples of substances which can serve as pharmaceutically-acceptable carrier materials are sugars such as laetose, glucose and sucrose; starches such as cornstarch and 15~ potato starch; cellulose and its deriYatives such as sodium carboxymethylcellulose, ethy k ellulose~ methylcellulose, cellulose acetate; powdered tragacanth; malt; getatin; talc; stearic acid;
magnesium stearate; magnesium alumin~m silicate; calcium sulfate;
vegetable oils such as peanut oil, cottonseed oil~ sesame 9i 1, olive oil, corn oil and oil of theobroma; polyols such as propylene glyeol~ glycerine~ sorbitol~ mannitol, and polyethylene glycol; agar, a~ginic aeid; and water and/or ethanol, as well as other non-toxic compat~ble substances used in pharl.laceutical formulations. Wetting agents and lubricants such as sodium lauryl : 25 sulfate, as well as coloring agentst flavoring agents, excipients, tableting agents~ stabilizers, antioxidants, and preservat~ves, can also be present. Other ~ompatible pharmaceut k ~l additiv~s and actives may be included in the pharmaceutically-acceptable carrier material for use in the compositions of the present invention.
The choice of a pharmaceutically-acce~table carrier to be used in the present composition is bas;ically determined by the form ~f the composition. The preferred ~orm is li~uids, suspensions, capsules, tablets and the like. Ph~rmaceutically-aceeptable carrier materials suitable for the preparation of dosage forms for oral administration are well-known in the art.
Thcir selection ~ill depend on secondary considQrations like WO 9~/01~18 2 1 ~ 3 6 i l1 P~;'r/USg2/~)5848 I,a~ U~L~ ~in~lf stability, etc. which are no~ crl~lcal ror ~ne purposes of the present invention, and can be made without difficulty by a person skilled in the art.
The pharmaceutically-acceptable oarrier materials employed in the compositions of the present inYention are used at a coneentration sufficient to provide a practical size to dosage relationship. The pharmaceut kally acceptable ~arrier materials, in total, m~y comprise from about 0.1% to about 99.8X by weight of the pharmaceutical compvstions of the present invention.
The "nrally administrable antimisrobial agentsn useful in the present compostions are those as desoribed in detail hereinbefore whieh are safe and effective when administered orally for treating the identified infection. The antimicrobial agent may comprise from about 0.1% to about 99~8% by wei~ht of the antim krobial composition of the present invention, typically from about 1 mg to about ?g per dose safe and effective for treating infections other than infections of the upper gastrointestinal traet~ Also, the bismuth subsalicylate may comprise fram about 0.1% to about 99.8%
by weight of ~he antim krobial cQmposition o~ th~ present 29 invention, typically from about 0.259 to about 1.59 per dose.
The following example further describes and demonstrates an embodiment withih the scope of the present invention. The example is given solely for the purpose of illustration, and is not to be ~ construed as limitations of the present invention since mary variations tbereof are pvssible without dep~rting ~rom its spirit and scope.
ExamDl~e An elderly nursing home patient suffering from a respiratory tract infection and in a ~acility know to further increase this patient's risk to C. di~fficile inFection is treated as follows.
Ten days of orally administered amoxycillin (500 mg; three times per day~ and concurrently for the same 10 da~s, and continuing thereafter for a total of 3 weeks, orally administered bismuth subsalicylate (S25 mg; four times per day; Pepto-Bismol~ liquid, sold by The Procter & Gamble Company~. The course of treatment is completed with resolution of the infection.

Claims (11)

1. The use of bismuth subsalicylate for the manufacture of a medica-ment for the treatment with antimicrobials of patients at risk to C. difficile infection, said treatment comprising administering to a patient at risk to C. difficile infection who needs antimi-crobial treatment for infection a safe and effective amount of an antimicrobial agent and concurrently orally administering before the end of 5 days of antimicrobial treatment a safe and effective amount of bismuth subsalicylate.

2. The use of bismuth subsalicylate for the manufacture of a medica-ment for the treatment with antimicrobials of patients at risk to C. difficile infection, said treatment comprising administering to a patient at risk to C. difficile infection, in order to treat an infection other than an infection of the gastrointestinal tract, a safe and effective amount of an antimicrobial agent and concurrently orally administering before the end of 5 days of antimicrobial treatment a safe and effective amount of bismuth subsalicylate.

3. The use of bismuth subsalicylate according to Claim 1 or 2 wherein the bismuth subsalicylate is administered concurrently within two days after the start of the antimicrobial treatment.

4. The use of bismuth subsalicylate according to any of Claims 1 or 2 wherein the bismuth subsalicylate is administered concurrently at least until the antimicrobial treatment is concluded.

5. The use of bismuth subsalicylate according to any of Claims 1 or 2 wherein the antimicrobial agent is selected from the group consisting of aminoglycosides, macrolides, penicillins, polypep-tides; tetracyclines, cephalosporins, chloramphenicol, sulfona-mides, nitrofurans, fluoroquinolones, metronidazole, tinidazole, nimorazole, and mixtures thereof.

6. The use of bismuth subsalicylate according to any of Claims 1 or 2 wherein the antimicrobial agent is selected from penicillin, erythromycin, doxycycline, metronidazole, tinidazole, clinda-mycin, amoxycillin, ampicillin, cefaclor, ciprofloxacin, norflox-acin, nitrofurantoin, and mixtures thereof.

7. The use of bismuth subsalicylate according to any of Claims 1 or 2 wherein the bismuth subsalicylate is administered in an amount of from 0.259 to 8.59 per day, for from 10 to 30 days.

8. The use of bismuth subsalicylate according to any of Claims 1 or 2 wherein the bismuth subsalicylate is administered for from 2 to 3 weeks.

9. An oral antimicrobial composition comprising:
(a) an orally administrable antimicrobial agent in an amount safe and effective for treating infections other than infections of the upper gastrointestinal tract;
(b) a safe and effective amount of bismuth subsalicylate; and (c) pharmaceutically-acceptable carrier material suitable for oral administration.

10. The oral antimicrobial composition according to Claim 9 com-prising from 0.25g to 1.59 of bismuth subsalicylate per dose.

11. The oral antimicrobial composition according to Claim 9 or 10 in unit dose form.