Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/66—Microorganisms or materials therefrom
  • A61K35/74—Bacteria
  • A61K35/741—Probiotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals

Definitions

• the present invention relates to a pharmaceutical composition which can be administered orally, intended to reduce the effects of ⁇ -lactams on the intestinal flora.
• the present invention relates more specifically to a composition containing bacteria which are not pathogenic to humans.
• modifications may relate in particular to the strict anaerobic bacteria which constitute the dominant populations of the intestinal flora and which normally oppose colonization by potentially pathogenic microorganisms such as enterobacteria, Pseudomonas, Staphylococci, yeasts, etc. the dominant flora can therefore lead to the development of infectious germs, which is particularly dangerous in some patients.
• the present invention aims to provide a composition containing non-pathogenic bacteria which is intended not to replace the initial flora but to avoid the disappearance of the natural intestinal flora.
• the subject of the present invention is a pharmaceutical composition, which can be administered orally, intended to reduce the effects of ⁇ -lactams. on the intestinal flora in humans, and characterized in that it comprises strict anaerobic bacteria producing ⁇ -lactamases:
• composition according to the invention is normally administered orally a few hours before or practically at the same time as the treatment with ⁇ -lactamine. Repeated doses may be considered during treatment with ⁇ -lactamine.
• composition according to the invention finds an application during treatment with ⁇ -lactams such as:
• penicillins in particular penicillin G and phenoxymethylpenicillins, methicillin and isoxazolylpenicillins (for example oxacillin and cloxacillin), aminopenicillins (for example ampicillin and amoxicillin), amidinopenicillins
• acylureidopenicillins e.g. Mezlocilline, Azlocilline,
• cephalosporins including cefalotin, cefazolin, cefamandole, cefuroxime, cefotaxime, ceftizoxime, ceftazidime, ceftriaxone. monobactams (with an azetidine ring), for example aztreonam.
• strains of strict anaerobic bacteria which are used in the present invention are in particular strains producing ⁇ -lactamase belonging to the genus Bacteroides.
• the strains producing ⁇ -lactamases can be determined by an in vitro test.
• a method can be used for this purpose which consists in measuring the amount of residual ⁇ -lactam after contact with the solution presumed to contain a ⁇ -lactamase activity (Rolfe RD et al. J. Infect Dis. 147, 227, 1983).
• Strains are selected which have an enzymatic activity of at least 0.02 ⁇ mole of cephaloridine / minute / mg of protein.
• Strains producing ⁇ -lactamases can be isolated from human feces.
• the strict non-pathogenic anaerobic bacteria producing ⁇ -lactamases can be packaged in lyophilized form and added to a drinkable excipient just before administration. They can also be packaged in the form of capsules, tablets, or similar solid forms in admixture with excipients. To avoid any destruction of bacteria during passage through the stomach, provision may in particular be made of forms comprising an anti-acid excipient or an enteric coating.
• the quantity of bacteria producing ⁇ -lactamases which is administered to humans by the oral route is approximately 10 8 to 10 11 viable bacterial cells.
• compositions according to the invention has been demonstrated on the model of the heteroxenic mouse treated with ceftriaxone.
• strains of anaerobic bacteria producing ⁇ -lactamases had been isolated from samples of human faeces and it was the cultures derived from these bacteria that were administered.
• Faeces from healthy subjects were isolated from strict anaerobic bacteria under anaerobic conditions. In each subject, the dominant clones were identified and the ⁇ -lactamase activity of the isolated strains was measured in vitro.
• ⁇ -lactamases are detected using the semi-quantitative microbiological method described by Rolfe RD et al. (J. Infect Dis. 147, 227, 1983). The activity is quantified on a scale of 0+ to 4+. The maximum ⁇ -lactamase activity is represented by 4+. Intermediate activities 3+, 2+, 1+ correspond to partial hydrolysis of the antibiotic. 0 is considered to be the absence of ⁇ -lactamase activity.
• Medium 5 agar medium (Difco) and test strain B. subtilis ATCC6633 were used.
• the activity profile of isolated strains is given in Table I below. The values given are the percentages of hydrolysis of the various ⁇ -lactams.
• strains used must have a ⁇ -lactamase activity ⁇ 0.02 ⁇ mole of cephaloridine / minute / mg of total bacterial proteins.
• mice have also been associated with complex human flora.
• the gavage solution is prepared in an anaerobic chamber, from freshly emitted human faeces.
• the sample is ground using of an Ultraturrax, and diluted 100 times in LCY medium. This dilution is transferred to the isolator where axenic mice are found.
• transport takes place in hermetically sealed tubes inside the anaerobic chamber.
• the previously thirsty animals are force-fed by the gastric and rectal route. The force-feeding is repeated after 24 h. Ten to fifteen days are necessary to obtain equilibria and barrier effects comparable to those observed in the donor.
• mice with human flora are inoculated intragastrically with 1 ml of TGY broth (Trypticase 30 g / l, yeast extract 20
• Enterobacteriaceae sensitive to Ceftriaxone are eliminated. Enterococcal counts are equivalent to those obtained for flora E, untreated control. Resistance to colonization by exogenous microorganisms resistant to Ceftriaxone (Ent.cloacae IGR67, C.albicans IGR66) is maintained in mice in which the strains of active Bacteroides have been previously implanted.
• the anaerobic bacteria persist in the group having received the Bacteroides and the total counts made in anaerobic room are not significantly modified by the presence of these bacteria, compared to the control.
• the MIC 50 and 90 of these bacteria are respectively 512 and> 1024 ⁇ g of ceftriaxone per ml.
• Gram-negative bacilli represent 84% of this flora, there are also 13% of spore-forming Gram-positive bacilli and 3% of cocci.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Mycology (AREA)
• Medicinal Chemistry (AREA)
• Microbiology (AREA)
• Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Molecular Biology (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

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• 1987
  • 1987-04-10 FR FR8705110A patent/FR2613624B1/fr not_active Expired - Fee Related
• 1988
  • 1988-04-07 ZA ZA882426A patent/ZA882426B/xx unknown
  • 1988-04-08 AU AU15786/88A patent/AU604117B2/en not_active Ceased
  • 1988-04-08 EP EP88903277A patent/EP0309532A1/de not_active Withdrawn
  • 1988-04-08 PT PT87190A patent/PT87190B/pt not_active IP Right Cessation
  • 1988-04-08 JP JP63503346A patent/JPH01503537A/ja active Pending
  • 1988-04-08 WO PCT/FR1988/000172 patent/WO1988007865A1/fr not_active Application Discontinuation
  • 1988-12-09 OA OA59487A patent/OA09023A/xx unknown

Non-Patent Citations (1)

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