EP0595890A1 - Procedes et compositions de traitement antimicrobien - Google Patents

Procedes et compositions de traitement antimicrobien

Info

Publication number
EP0595890A1
EP0595890A1 EP92915528A EP92915528A EP0595890A1 EP 0595890 A1 EP0595890 A1 EP 0595890A1 EP 92915528 A EP92915528 A EP 92915528A EP 92915528 A EP92915528 A EP 92915528A EP 0595890 A1 EP0595890 A1 EP 0595890A1
Authority
EP
European Patent Office
Prior art keywords
bismuth subsalicylate
antimicrobial
treatment
safe
infection
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92915528A
Other languages
German (de)
English (en)
Inventor
Scott Donald Whalen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Procter and Gamble Co
Original Assignee
Procter and Gamble Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Procter and Gamble Co filed Critical Procter and Gamble Co
Publication of EP0595890A1 publication Critical patent/EP0595890A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • 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.
  • 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)].
  • 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.
  • 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.
  • 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.
  • 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.
  • patient at risk to C ⁇ . difficile infection 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.
  • environments include institutional settings such as hospitals and long term care facilities such as nursing homes.
  • C___ difficile 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.
  • safe and effective amount 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 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.
  • 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).
  • magnesium aluminum silicate e.g., Veegum ® sold by R. T. Vanderbilt Company, Inc.
  • methyl salicylate sodium salicylate
  • salicylic acid e.g., sodium salicylate, salicylic acid
  • methyl cellulose e.g., as present in Pepto-Bismol ® liquid and Maximum Strength Pepto-Bismol® liquid,
  • 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.
  • antimicrobial agents 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.
  • 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.
  • 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.
  • the tetracycl nes are preferably administered at a level of from about 100 milligrams to about 2000 milligrams, per day.
  • Macrolides such as erythromycin
  • 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 are administered preferably at levels of from about 100 milligrams to about 800 milligrams, per day.
  • 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).
  • 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.
  • 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.
  • the present invention also relates to oral antimicrobial compositions useful for treating patients at risk to ( ⁇ . 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.
  • pharmaceutically-acceptable carrier material means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for oral administration to a human.
  • compatible 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.
  • 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.
  • sugars such as lactose, glucose and sucrose
  • starches such as cornstarch and potato starch
  • cellulose and its derivatives such as sodium carboxy
  • 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.
  • 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 t ⁇ a e, uuj>L, s ⁇ eif stability, etc which are not critical ⁇ or 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.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédés de traitement de patients soumis à des infections provoquées par des agents antimicrobiens, dans le cas d'un risque d'infection par C. difficile, comprenant l'administration orale simultanée effectuée avant le terme d'une durée de 5 jours environ de thérapie antimicrobienne, d'une quantité efficace de sous-salicylate de bismuth.
EP92915528A 1991-07-24 1992-07-15 Procedes et compositions de traitement antimicrobien Withdrawn EP0595890A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US735400 1985-05-17
US73540091A 1991-07-24 1991-07-24
PCT/US1992/005848 WO1993001818A1 (fr) 1991-07-24 1992-07-15 Procedes et compositions de traitement antimicrobien

Publications (1)

Publication Number Publication Date
EP0595890A1 true EP0595890A1 (fr) 1994-05-11

Family

ID=24955626

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92915528A Withdrawn EP0595890A1 (fr) 1991-07-24 1992-07-15 Procedes et compositions de traitement antimicrobien

Country Status (10)

Country Link
EP (1) EP0595890A1 (fr)
JP (1) JPH06509340A (fr)
AU (1) AU2324392A (fr)
BR (1) BR9206300A (fr)
CA (1) CA2113614A1 (fr)
IE (1) IE922403A1 (fr)
MA (1) MA22597A1 (fr)
MX (1) MX9204338A (fr)
PT (1) PT100729A (fr)
WO (1) WO1993001818A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPN771596A0 (en) * 1996-01-25 1996-02-15 Mclean, Allan Joseph Methods of and compositions for potentiating the action of agents active on cell-wall sites of susceptible bacteria
DE10236347A1 (de) † 2002-08-08 2004-02-19 Basf Coatings Ag Wäßrige Elektrotauchlacke, ihre Verwendung in Verfahren zur Beschichtung elektrisch leitfähiger Substrate sowie die Verwendung von Bismutverbindungen in diesen wäßrigen Elektrotauchlacken
WO2005014567A1 (fr) * 2003-08-12 2005-02-17 Biocon Limited Sel de bismuth a acide mycophenolique
WO2017165729A1 (fr) * 2016-03-24 2017-09-28 Paratek Pharmaceuticals, Inc. Méthodes de traitement et de prévention d'une infection à c. difficile

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3686836T2 (de) * 1985-06-13 1993-03-04 Marshall Barry James Zusammensetzungen zur behandlung von magen-darmstoerungen.
DE3887353T2 (de) * 1987-10-12 1994-05-05 Capability Services Pty Ltd Behandlungsverfahren für magen-darm-krankheiten.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9301818A1 *

Also Published As

Publication number Publication date
MA22597A1 (fr) 1993-04-01
AU2324392A (en) 1993-02-23
MX9204338A (es) 1993-03-01
BR9206300A (pt) 1994-08-02
IE922403A1 (en) 1993-01-27
CA2113614A1 (fr) 1993-02-04
WO1993001818A1 (fr) 1993-02-04
JPH06509340A (ja) 1994-10-20
PT100729A (pt) 1993-10-29

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