ANTIMICROBIAL TREATMENT METHODS AND COMPOSITIONS

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: ANTIMICROBIAL TREATMENT METHODS AND COMPOSITIONS BACKGROUND OF THE INVENTION The present invention relates to a method for treating patients having infections with antimicrobials when the patients are at risk to Clostridium difficile ("L. difficile", infection. This method comprises concurrently orally administering before the end of about 5 days of antimicrobial therapy a safe and effective amount of bismuth subsalicylate. The present invention also relates to compositions useful for the method of the present invention comprising certain antimicrobials and bismuth subsalicylate. "A commonly recognized complication of antibiotic therapy is diarrhea and/or pseudome branous colitis. This is due to bowel overgrowth by difficile, which elaborates an exotoxin that is responsible for symptoms. Discontinuation of antibiotic therapy will usually lead to resolution of treatment, but some patients require vancomycin or metronidazole." (Cecil Textbook of Medicine. 18th Edition. Wyngaarden and Smith editors, copyright 1988 by W.B. Saunders Company; at page 123.) Reports have discussed the prevalence of C difficile in hospitals [McFarland et al., "Nosoco ial Acquisition of Clostridium difficile Infection", N. Enol . J. Med.. 320(4) pages 204-10 (1989)] and in nursing homes [Bennett et al., "C. difficile diarrhea: A common - and overlooked - nursing home infection", Geriatrics. 45(9) pages 77-87 (1990)]. A relationship has been observed between nursing home patients with C^ difficile following antibiotic treatment and high mortality rate. [Bender et al., "Is Clostridium difficile Endemic in Chronic-Care Facilities?", The Lancet. July 5, 1986, pp 11-13; Thomas et al., "Postantibiotic Colonization with Clostridium difficile in Nursing Home Patients", J. Am. Geriatr. Soc. 38. pages 415-420 (1990).] This research concluded that postantibiotic (____. difficile infection correlates with increased death rate separate from the risk of antibiotic treatment alone. Other research relating to C^ difficile infection includes: ilkins, "Role of Clostridium difficile Toxins in Disease", Gastroenterolo g v. 93 (2), pp. 389-391 (1987); Kyooit et al., "Protein-Losing Enteropathy Associated with Clostridium difficile Infection", The Lancet. June 17, 1989, pp. 1353-1355; Bennett et al., "Evaluation of a Latex Agglutination Test for Clostridium difficile in Two Nursing Home Outbreaks", jL. Clin. Microbial, 27 (5), pp. 889-893 (1989). "The most important therapeutic decision with antibiotic-associated diarrhea or colitis is discontinuation of the implicated agent. This often results in resolution of symptoms with no necessity for further diagnostic tests or therapy. Patients with severe or persistent symptoms should undergo endoscopy to define anatomic changes and stool examination to detect j_ difficile cytotoxin." (Cecil Textbook of Medicine. supra, at page 1632). Specific therapies for £___. difficile infection include cholestyra ine to bind the toxin or antimicrobials (such as metronidazole or preferably vancomycin) to inhibit the pathogen. Bismuth subsalicylate has been investigated for its effectiveness in treating C_j. difficile colitis in hamsters [Chang et al., "Effect of Bismuth Subsalicylate on Clostridium difficile Colitis in Hamsters", Rev. Infect. Pis.. 12 (Supplement 1), pages S57-S58 (1990)]. Further, bismuth subsalicylate has been used to treat (_____ difficile diarrhea in nursing homes (Bennett et al., Geriatrics, supra) and chronic diarrhea due to C difficile in children (Gryboski et al., "Effect of bismuth subsalicylate on chronic diarrhea in childhood: a preliminary report", Rev. Infect. Pis.. \2 (Supplement 1), pages S36-S40 (1990)]. Clearly, there is a need for treatment methods which improve the safety and/or effectiveness of antimicrobial treatment for patients at risk to ]____. difficile infection. It has been surprisingly discovered by the present invention that when bismuth subsalicylate therapy is concurrently administered with a course of antimicrobial therapy, there is a significant reduction in the death rate of this patient population versus similar patients receiving only antimicrobial therapy. Further, because the deaths associated with antimicrobial treatment alone can occur very suddenly and within about 5 days after the start of the treatment regimen, it is also important for xne purposes and the present method to concurrently orally administer the bismuth subsalicylate before the end of about 5 days of antimicrobial treatment. Thus, an object of the present invention is to provide compositions and methods for treating patients at risk to Cj. difficile infection with antimicrobials. A further objective is to improve the chances of successful completion of an antimicrobial treatment regimen in patients at risk to C^. difficile infection. A further object is to reduce the mortality rate for patients being treated with antimicrobials who are at risk to ______ difficile infection. These and other objects of the present invention will become readily apparent from the detailed description which follows. All percentages and ratios used herein are by weight, and all measurements made at 25*C, unless otherwise specified. SUMMARY OF THE INVENTION The present invention relates to a method for treating with antimicrobials patients at risk to £__. difficile infection, said method comprising administering to a patient at risk to £__. difficile infection who needs antimicrobial treatment for infection a safe and effective amount of an antimicrobial agent and concurrently orally administering before the end of about 5 days of antimicrobial treatment a safe and effective amount of bismuth subsalicylate. The present invention also relates to oral antimicrobial compositions useful for treating patients at risk to Z difficile infection 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. DETAILED PESCRIPTION OF THE INVENTION Antimicrobial Treatment Methods: The present invention relates to a method for treating with antimicrobials patients at risk to £__. difficile infection who need antimicrobial treatment for infection. This method comprises administering to such patients a safe and effective amount of an antimicrobial agent and concurrently orally administering 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 infections of humans. Such infections are typically other than infections of the upper gastrointestinal tract (e.g., Helicobacter pylori, a.k.a. Campy!obacter pyloridis. infection of the stomach which results in gastritis and ulcers as taught for example by European Patent Application Publication Number 206,625 published December 30, 1986 by Marshall), and preferably the present invention involves treating infections not involving gastrointestinal tract infection. Examples of infections treatable according to the present invention include, but are not limited to, upper and lower respiratory tract infections, sepsis, and wound infections including surgical wound infections. The term "patient at risk to C^. difficile infection", as used herein, means a human subject in need of antimicrobial treatment for infection and this subject is either infected with £__. difficile or deemed to be at risk to becoming infected with C difficile within the scope of sound medical judgment. Patients at risk to £__. difficile infection therefore include patients already diagnosed as being colonized by C__. difficile (but preferably not exhibiting £___ difficile diarrhea), as well as those patients in an environment wherein C^ difficile infection is known to be present or is reasonably believed by the attending medical expert to potentially be a hazard. Such environments include institutional settings such as hospitals and long term care facilities such as nursing homes. The risk factors and incidence of C___ difficile are known, and are described in more detail in (1) McFarland et al., "Nosocomial Acquisition of Clostridium difficile Infection", N^ Enol. J. Med.. 320(4) pages 204-10 (1989); (2) Bennett et al., "£,. difficile diarrhea: A co mon-and overlooked-nursing home infection", Geriatrics. 45(9) pages 77-87 (1990); (3) Thomas et al., "Postantibiotic Colonization with Clostridium difficile in Nursing Home Patients", J. Am. Geriatr. Soc. 38, pages 415-420 (1990); and (4) Cecil Textbook of Medicine. 18th Edition. Wyngaarden and Smith editors, copyright 1988 by W.B. Saunders Company; at pages 123, 727, 757, and 1632-1633, the disclosures of all these documents being incorporated by reference herein in their entirety. The term "safe and effective amount", as used herein, means an amount of a compound or composition high enough to significantly positively modify the infectious condition being treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of the antimicrobial agent and bismuth subsalicylate will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of other therapy, the specific antimicrobial agent employed, the particular pharmaceutically-acceptable carrier utilized, the method of administration used, and like factors within the knowledge and expertise of the attending physician. However, typical dosages of the antimicrobial agents and bismuth subsalicylate are also described hereinafter. The terms "concurrently" and "concurrent", as used herein, mean that the safe and effective amount of bismuth subsalicylate is orally administered within 24 hours of administration of the antimicrobial agent. As noted hereinbefore, this concurrent administration of the bismuth subsalicylate should occur or commence before the end of about 5 days of antimicrobial treatment. Bismuth subsalicylate administration may therefore begin before commencement of the antimicrobial treatment, at the same time, or even after commencement of the antimicrobial treatment but before about 5 days of antimicrobial treatment have been completed. Further, the concurrent bismuth subsalicylate administration may be terminated on or before the end of about 10 days of antimicrobial 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. Preferably, concurrent bismuth subsalicylate admin stration is commenced prior to, or more preferably within two days after, the start of an antimicrobial treatment regimen and continues at least until the antimicrobial treatment regimen is concluded. Most preferred is administering the bismuth subsalicylate concurrently with the entire antimicrobial treatment regimen. Bismuth subsalicylate is a known therapeutic agent, having been sold for many years as the active ingredient in Pepto-Bismol ® (sold by The Procter & Gamble Company). Preferred methods according to the present invention comprise administering from about 0.25g to about 8.5g of bismuth subsalicylate per day, preferably from about 0.5g to about 5g per day, and most preferably from about lg to about 3g per day. Preferred is from about 0.25g to about 1.5g per dose for from about 1 dose to about 10 doses per day; more preferred is administering from about 0.5g to about l.lg of bismuth subsalicylate per dose or from about 2 doses to about 8 doses per day; and most preferred is from about 0.5g to about l.lg of bismuth subsalicylate given per dose by 4 doses per day. Administration of the bismuth subsalicylate according to the present invention is by oral administration, which may be by any form, including liquids, suspensions, chewable tablets, swallowable capsules, swallowable caplets, etc. Preferred bismuth subsalicylate-containing compositions useful for the methods of the present invention are in liquid form comprising from about 1.75% to about 3.5% of bismuth subsalicylate. Such compositions typically comprise magnesium aluminum silicate (e.g., Veegum ® sold by R. T. Vanderbilt Company, Inc.), methyl salicylate, sodium salicylate, salicylic acid, and/or methyl cellulose (e.g., as present in Pepto-Bismol ® liquid and Maximum Strength Pepto-Bismol® liquid, sold by The Procter & Gamble Company). Bismuth subsalicylate-containing pharmaceutical compositions and their method of preparation are also described in detail in U.S. Patent 4,801,454, to Coveney, issued January 31, 1989; U.S. Patent 4,940,695, to Coveney et al., issued July 10, 1990; and U.S. Patent 5,013,560, to Stentz et al., issued May 7, 1991, the disclosures of all these patents being incorporated herein by reference in their entirety. Antimicrobial agents useful herein are those safe and effective for treating the infectious diseases for which the present method is useful, and which are compatible with concurrent bismuth subsalicylate administration. More preferred are those antimicrobials which are administered to treat infections other than infections of the gastrointestinal tract. A wide variety of antimicrobial agents are therefore useful in this invention. The term "antimicrobial agents", 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 is effective in killing or substantially inhibiting the growth of the microorganism desired to be treated when used in the processes of this invention. Antibiotics are among the preferred antimicrobials useful herein. Such antibiotics can be generally classified by chemical composition, into the following principle groups: the aminoglycosides, such as gentamicin, neomycin, kanamycin, and streptomycin; the macrolides, such as erythromycin, clindamycin, and rifa pin; 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, cefaclor, and cephalothin; and such miscellaneous antibiotics as chloramphenicol . These antibiotics can be generally 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 as nitrofurazone, nitrofurantoin, and furozolidone; fluoroquinolones, such as ciprofloxacin and norfloxacin; and etronidazole, tinidazole, and nimorazole. Antimicrobials among those useful herein are described in the following publications, incorporated by reference herein: Remington's Pharmaceutical Sciences (15th edition 1975); F. H. Meyers, et al., Review of Medical Pharmacology (7th edition 1980); Gaddum's Pharmocoloqy (8th edition 1978); and A. Goodman, A. G. Goodman and L. S. Gilman, The Pharmacolo g ical Basis of Therapeutics (6th edition 1980). While any of these antimicrobials may be used, penicillin, erythromycin, doxycycline, metronidazole, tinidazole, clindamycin, amoxycillin, ampicillin, cefaclor, ciprofloxacin, norfloxacin, and nitrofurantoin 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 to other factors, depend upon the particular antimicrobial used and its pharmacology. In general, though, the tetracycl nes are preferably administered at a level of from about 100 milligrams to about 2000 milligrams, per day. Macrolides (such as erythromycin) are preferably administered at a level of from about 1000 milligrams to about 4000 milligrams, per day. Penicillins are preferably administered at a level of from about 500 milligrams to about 3000 milligrams, per day. The aminoglycosides (such as neomycin) are, preferably, administered at a level of from about 100 milligrams to about 8000 milligrams, per day. Nitrofurans (such as nitrofurantoin) are administered preferably at levels of from about 100 milligrams to about 800 milligrams, per day. Preferably, metronidazole is administered at a level of from about 500 to about 2000 milligrams, per day. Antimicrobials, such as tetracycline, which are known not to be compatible with bismuth subsalicylate when the two agents are dosed at about the same time, are to be administered using sound medical judgement to avoid incompatibility, and antimicrobial agents which are not suited for concurrent administration with bismuth subsalicylate are not useful according to the present invention. See, for example, CD. 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 antimicrobials that are subject to adverse interaction with bismuth subsalicylate by methods that minimize such interactions, i.e., by minimizing the simultaneous presence or antimicrobial and bismuth subsalicylate in the stomach. Such methods include one or more of the following: staggered oral dosing of the bismuth subsalicylate and antimicrobial, through discrete administration 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 antimicrobial which prevents dissolution of the antimicrobial in the stomach; and administering the antimicrobial by a non-oral route, e.g., by intraveneous or intramuscular injection. When treating the identified infection, administration of the antimicrobial agent may be by any route as generally recognized for the particular antimicrobial being administered, the site of infection, the amount of antimicrobial agent to be administered per day, the presence of any adverse side effects, and the interaction (if any) between the antimicrobial agent and the bismuth subsalicylate. Therefore, various modes of administration include, without limitation, oral, transdermal, mucosal, sublingual, intramuscular, intravenous, intraperitoneal and subcutaneous administration, as well as topical application. Antimicrobial Compositions: The present invention also relates to oral antimicrobial compositions useful for treating patients at risk to (λ. difficile infection according to the present invention. These compositions comprise: (1) an orally administrable antimicrobial agent in an amount safe and effective for treating infections other than infections of the upper gastrointestinal tract (more preferred are those orally administrable antimicrobial agents in an amount safe and effective to be useful for treating infections other than 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, including liquids, suspensions, capsules, tablets, chewable tablets, caplets, etc. The term "pharmaceutically-acceptable carrier material", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for oral administration to a human. The term "compatible", as used herein, means that the components of the pharmaceutical composition are capable of being commingled with the antimicrobial agent and the bismuth subsalicylate, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations. Pharmaceutically-acceptable carrier materials must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human subject being treated. Some examples of substances which can serve as pharmaceutically-acceptable carrier materials are sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; magnesium aluminum silicate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar, alginic acid; and water and/or ethanol, as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabilizers, antioxidants, and preservatives, can also be present. Other compatible pharmaceutical additives 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-acceptable carrier to be used in the present composition is basically determined by the form of the composition. The preferred form is liquids, suspensions, capsules, tablets and the like. Pharmaceutically- acceptable carrier materials suitable for the preparation of dosage forms for oral administration are well-known in the art. Their selection will depend on secondary considerations like tαa e, uuj>L, sπeif stability, etc which are not critical τor tne purposes of the present invention, and can be made without difficulty by a person skilled in the art. The pharmaceutically-acceptable carrier materials employed in the compositions of the present invention are used at a concentration sufficient to provide a practical size to dosage relationship. The pharmaceutically-acceptable carrier materials, in total, may comprise from about 0.1% to about 99.8% by weight of the pharmaceutical compostions of the present invention. The "orally administrable antimicrobial agents" useful in the present compostions are those as described in detail hereinbefore which 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 weight of the antimicrobial composition of the present invention, typically from about 1 mg to about 2g per dose safe and effective for treating infections other than infections of the upper gastrointestinal tract. Also, the bismuth subsalicylate may comprise from about 0.1% to about 99.8% by weight of the antimicrobial composition of the present invention, typically from about 0.25g to about 1.5g per dose. The following example further describes and demonstrates an embodiment within 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 many variations thereof are possible without departing from its spirit and scope. Exa ole An elderly nursing home patient suffering from a respiratory tract infection and in a facility know to further increase this patient's risk to C... difficile infection is treated as follows. Ten days of orally administered amoxycillin (500 mg; three times per day) and concurrently for the same 10 days, and continuing thereafter for a total of 3 weeks, orally administered bismuth subsalicylate (525 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: CLAIMS 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 subsa icylate according to Claim 1 or 2 wherein the bismuth subsalicylate is administered concurrently within two days after the start of the antimicrobial treatment. L The use of bismuth subsalicylate according to any of Claims 1-3 wherein the bismuth subsalicylate is administered concurrently at least until the antimicrobial treatment is concluded. i. The use of bismuth subsalicylate according to any of Claims 1-4 wherein the antimicrobial agent is selected from the group consisting of aminoglycosides, macrolides, penicillins, polypep- tides, tetracyclines, cephalosporins, chloramphenicol, sulfona- ides, nitrofurans, fl oroquinolones, metronidazole, tinidazole, nimorazole, and mixtures thereof. 6. The use of bismuth subsalicylate according to any of Claims 1-5 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 1-6 wherein the bismuth subsalicylate is administered in an amount of from 0.25g to 8.5g per day, for from 10 to 30 days. 8. The use of bismuth subsalicylate according to any of Claims 1-7 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 1.5g of bismuth subsalicylate per dose. 11. The oral antimicrobial composition according to Claim 9 or 10 in unit dose form. 12. A method for treating with antimicrobials patients at risk to C. difficile infection, said method comprising administering to a patient at risk to C. difficile infection who needs antimicrobial treatment for infection a safe and effective amount of an antimicrobial agent and concurrently orally administering before the end of about 5 days of antimicrobial treatment a safe and effective amount of bismuth subsalicylate. 13. The method according to Claim 12 wherein the bismuth subsalicylate is administered concurrently within two days after the start of the antimicrobial treatment. 14. The method according to Claim 13 wherein the bismuth subsalicylate is administered concurrently at least until the antimicrobial treatment is concluded. 15. The method according to Claim 12 wherein the antimicrobial agent is selected from the group consisting of aminoglycosides, macrolides, penicillins, polypeptides, tetracyclines, cephalosporins, chloramphenicol , sulfonamides, nitrofurans, fluoroquinolones, metronidazole, tinidazole, nimorazole, and mixtures thereof. 16. The method according to Claim 15 wherein the antimicrobial agent is selected from penicillin, erythromycin, doxycycline, metronidazole, tinidazole, clindamycin, amoxycillin, ampicillin, cefaclor, ciprofloxacin, norfloxacin, nitrofurantoin, and mixtures thereof. 17. The method according to Claim 13 wherein the bismuth subsalicylate is administered in an amount of from about 0.25g to about 8.5g per day, for from about 10 to about 30 days. 18. The method according to Claim 15 wherein the bismuth subsalicylate is administered in an amount of from about 0.5g to about 5g per day. 19. A method for treating with antimicrobials patients at risk to C. difficile infection, said method 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 about 5 days of antimicrobial treatment a safe and effective amount of bismuth subsalicylate. 20. The method according to Claim 19 wherein the antimicrobial agent is selected from the group consisting of aminoglycosides, macrolides, penicillins, polypeptides, tetracyclines, cephalosporins, chloramphenicol , sulfonamides, nitrofurans, fluoroquinolones, metronidazole, tinidazole, nimorazole, and mixtures thereof., 21. The method according to Claim 19 wherein the bismuth subsalicylate is administered concurrently within 2 days after the start of the antimicrobial treatment in an amount of from about 0.25g to about 8.5g per day. 22. The method according to Claim 21 wherein the bismuth subsalicylate is administered concurrently at least until the antimicrobial treatment is concluded. 23. The method according to Claim 22 wherein the antimicrobial agent is selected from the group consisting of penicillin, erythromycin, doxycycline, metronidazole, tinidazole, clindamycin, amoxycillin, ampicillin, cefaclor, ciprofloxacin, norfloxacin, nitrofurantoin, and mixtures thereof. 24. The method according to Claim 19 wherein the patient being treated is selected from patients having upper respiratory tract infections, lower respiratory tract infections, sepsis, or wound infections, and the antimicrobial agent is administered in an amount safe and effective for treating one or more of these infections. 25. The method according to Claim 21 wherein the bismuth subsalicylate is administered for from about 2 to about 3 weeks.

Inventors: WHALEN SCOTT DONALD, WHALEN, SCOTT, DONALD
Applicants: PROCTER & GAMBLE, THE PROCTER & GAMBLE COMPANY
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P31