EP0309532A1 - Phamaceutical composition, for oral administration, designed to attenuate the effects of -lactamines - Google Patents

Phamaceutical composition, for oral administration, designed to attenuate the effects of -lactamines

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Publication number
EP0309532A1
EP0309532A1 EP88903277A EP88903277A EP0309532A1 EP 0309532 A1 EP0309532 A1 EP 0309532A1 EP 88903277 A EP88903277 A EP 88903277A EP 88903277 A EP88903277 A EP 88903277A EP 0309532 A1 EP0309532 A1 EP 0309532A1
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Prior art keywords
bacteria
lactamases
strains
producing
composition according
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EP88903277A
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German (de)
French (fr)
Inventor
Cyrille Tancrede
Antoine Andremont
Roger Labia
Florence Leonard
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Institut Gustave Roussy (IGR)
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Institut Gustave Roussy (IGR)
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    • 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)
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  • Mycology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

La présente invention a pour objet une composition pharmaceutique, administrable par voie orale, destinée à réduire les effets des ss-lactamines sur la flore intestinale chez l'homme, et caractérisée en ce qu'elle comprend des bacteries anaérobies strictes non pathogènes pour l'homme et productrices de ss-lactamases.The subject of the present invention is a pharmaceutical composition, which can be administered orally, intended to reduce the effects of ss-lactams on the intestinal flora in humans, and characterized in that it comprises strict anaerobic bacteria which are not pathogenic for man and producers of ss-lactamases.

Description

COMPOSITION PHARMACEUTIQUE, ADMINISTRABLE PAR VOIE ORALE, PHARMACEUTICAL COMPOSITION, ORAL ADMINISTRATIVE,
DESTINEE A REDUIRE LES EFFETS DES β-LACTAMINESTO REDUCE THE EFFECTS OF β-LACTAMINES
La présente invention concerne une composition pharmaceutique administrable par voie orale, destinée à réduire les effets des β-lactamines sur la flore intestinale. La présente invention concerne plus spécialement une composi tion contenant des bactéries non pathogènes pour l'homme.The present invention relates to a pharmaceutical composition which can be administered orally, intended to reduce the effects of β-lactams on the intestinal flora. The present invention relates more specifically to a composition containing bacteria which are not pathogenic to humans.
On sait que le traitement par des β-lactamines à large spectre entraîne des modifications importantes de la flore microbienne normale et en particulier de la flore intestinale dans le cas d'un traitement par des β-lactamines à élimination biliaire notable.It is known that treatment with broad-spectrum β-lactams leads to significant modifications of the normal microbial flora and in particular of the intestinal flora in the case of treatment with β-lactams with notable bile elimination.
Ces modifications peuvent concerner en particulier les bactéries anaérobies strictes qui constituent les populations dominantes de la flore intestinale et qui s'opposent normalement à la colonisation par des microorganismes potentiellement pathogènes tels que entérobactéries, Pseudomonas, Staphylocoques, levures, etc... La diminution de la flore dominante peut donc conduire au développement de germes infectieux, ce qui est particulièrement dangereux chez certains patients.These 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.
Par le passé, on a déjà proposé d'administrer par voie orale diverses bactéries ou levures. Il s'agissait toutefois de suppléer aux bactéries constituant initialement la flore intestinale.In the past, it has already been proposed to administer various bacteria or yeasts orally. However, it was a question of supplementing the bacteria initially constituting the intestinal flora.
La présente invention vise à fournir une composition contenant des bactéries non pathogènes qui est destinée non pas à remplacer la flore initiale mais à éviter la disparition de la flore intestinale naturelle.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.
A cet effet, la présente invention a pour objet une composition pharmaceutique, administrable par voie orale, destinée à réduire les effets des β-lactamines. sur la flore intestinale chez l'homme, et caractérisée en ce qu'elle comprend des bactéries anaércbies strictes productrices de β-lactamases :To this end, the subject of the present invention is a pharmaceutical composition, which can be administered orally, intended to reduce the effects of β-lactams. on the intestinal flora in humans, and characterized in that it comprises strict anaerobic bacteria producing β-lactamases:
- Bactéroides fragilis- Bacteroides fragilis
- Bactéroides mélaninogenicus - Bactéroides intermedius - Bactéroides nonfragilis- Bacteroides melaninogenicus - Bacteroides intermedius - Bacteroides nonfragilis
- Bactéroides asaccharolyticus- Asaccharolyticus bacteria
- Bactéroides bivius- Bivius bacteria
- Bactéroides disiens - Bactéroides oralis- Bacteroides say - Bacteroides oralis
- Bactéroides ruminicola- Ruminicola bacteria
- Bactéroides capillosus- Bacteroides capillosus
- Bactéroides uniformis- Bacteroides uniformis
- Clostridium butyricum - Fusobacterium nucleatum- Clostridium butyricum - Fusobacterium nucleatum
(Nord CE. 1986 Rev. Infect Dis.8-5 543, 548).(Nord CE. 1986 Rev. Infect Dis. 8-5 543, 548).
Ces bactéries font partie de la flore intestinale de sujets normaux et leur introduction dans l'intestin de sujets qui en sont dépourvus ne présente pas d'inconvénients.These bacteria are part of the intestinal flora of normal subjects and their introduction into the intestine of subjects who lack them does not present any disadvantages.
La composition selon l'invention est normalement administrée par voie orale quelques heures avant ou pratiquement en même temps que le traitement par la β-lactamine. Des prises répétées peuvent être envisagées pendant le traitement par la β-lactamine.The composition according to the invention is normally administered orally a few hours before or practically at the same time as the treatment with β-lactamine. Repeated doses may be considered during treatment with β-lactamine.
La composition selon l'invention trouve une application lors du traitement par des β-lactamines telles que :The composition according to the invention finds an application during treatment with β-lactams such as:
- des pénicillines notamment la pénicilline G et les phénoxyméthylpénicillines, la méthicilline et les isoxazolylpénicillines (par exemple oxacilline et cloxacilline), des aminopénicillines (par exemple ampicilline et amoxicilline), des amidinopénicillines- penicillins, in particular penicillin G and phenoxymethylpenicillins, methicillin and isoxazolylpenicillins (for example oxacillin and cloxacillin), aminopenicillins (for example ampicillin and amoxicillin), amidinopenicillins
(par exemple pivmecillinam), des carboxypénicillines (par exemple carbénicilline, ticarcilline), des méthoxycarboxypénicillines (par exemple témocilline), des acylureidopénicillines (par exemple Mezlocilline, Azlocilline,(e.g. pivmecillinam), carboxypenicillins (e.g. carbenicillin, ticarcillin), methoxycarboxypénicillines (e.g. temocillin), acylureidopenicillins (e.g. Mezlocilline, Azlocilline,
Pipéracilline), des acylpénicillines (par exemplePiperacillin), acylpenicillins (e.g.
Apalcilline).Apalcillin).
- des céphalosporines notamment la céfalotine, la céfazoline, le céfamandole, le céfuroxime, le céfotaxime, le ceftizoxime, la ceftazidime, la ceftriaxone. des monobactames (à noyau azétidine), par exemple l'aztréonam.- cephalosporins including cefalotin, cefazolin, cefamandole, cefuroxime, cefotaxime, ceftizoxime, ceftazidime, ceftriaxone. monobactams (with an azetidine ring), for example aztreonam.
Les souches de bactéries anaérobies strictes que l'on utilise dans la présente invention sont notamment des souches productrices de β-lactamase appartenant au genre Bactéroides.The strains of strict anaerobic bacteria which are used in the present invention are in particular strains producing β-lactamase belonging to the genus Bacteroides.
Les souches productrices de β-lactamases peuvent être déterminées par un test in vitro. On peut utiliser à cet effet une méthode qui consiste à doser la quantité de β-lactamine résiduelle après contact avec la solution présumée contenir une activité β-lactamase (Rolfe RD et coll.J. Infect Dis. 147, 227, 1983).The strains producing β-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 β-lactam after contact with the solution presumed to contain a β-lactamase activity (Rolfe RD et al. J. Infect Dis. 147, 227, 1983).
On sélectionne les souches qui ont une activité enzymatique d'au moins 0,02 μmole de céphaloridine/minute/mg de protéine.Strains are selected which have an enzymatic activity of at least 0.02 μmole of cephaloridine / minute / mg of protein.
Des souches productrices de β-lactamases peuvent être isolées de fèces humaines. Les bactéries anaérobies strictes non pathogènes productrices de β-lactamases peuvent être conditionnées sous forme lyophilisée et ajoutées à un excipient buvable juste avant l'administration. Elles peuvent être également conditionnées sous forme de gélules, comprimés, ou formes solides analogues en mélange avec des excipients. Pour éviter toute destruction des bactéries lors du passage dans l'estomac, on peut notamment prévoir des formes comportant un excipient anti-acide ou un revêtement entérique.Strains producing β-lactamases can be isolated from human feces. The strict non-pathogenic anaerobic bacteria producing β-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.
La quantité de bactéries productrices de β-lactamases qui est administrée chez l'homme par voie orale est d'environ 108 à 1011 cellules bactériennes viables.The quantity of bacteria producing β-lactamases which is administered to humans by the oral route is approximately 10 8 to 10 11 viable bacterial cells.
L'activité des compositions selon l'invention a été mise en évidence sur le modèle de la souris hétéroxénique traitée par la ceftriaxone. Préalablement, des souches de bactéries anaérobies productrices de β-lactamases avaient été isolées d'échantillons de fèces humaines et ce sont les cultures tirées de ces bactéries qui ont été administrées.The activity of the compositions according to the invention has been demonstrated on the model of the heteroxenic mouse treated with ceftriaxone. Previously, strains of anaerobic bacteria producing β-lactamases had been isolated from samples of human faeces and it was the cultures derived from these bacteria that were administered.
1.- Isolement de souches de bactéries anaérobies strictes productrices de β-lactamase.1.- Isolation of strains of strict anaerobic bacteria producing β-lactamase.
On a isolé des fèces de sujets sains des bactéries anaérobies strictes dans des conditions d'anaérobiose. Chez chaque sujet, on a identifié les clones dominants et on a mesuré in vitro l'activité β-lactamase des souches isolées.Faeces from healthy subjects were isolated from strict anaerobic bacteria under anaerobic conditions. In each subject, the dominant clones were identified and the β-lactamase activity of the isolated strains was measured in vitro.
Les β-lactamases sont détectées grâce à la méthode microbiologique semi-quantitative décrite par Rolfe RD et coll. (J. Infect Dis. 147, 227, 1983). L'activité est quantifiée sur une échelle de 0+ à 4+. Le maximum d'activité β-lactamase est représenté par 4+. Les activités intermédiaires 3+, 2+, 1+ correspondent à une hydrolyse partielle de l'antibiotique. 0 est considéré comme l'absence d'activité β-lactamase. Le milieu gélose Médium 5 (Difco) et la souche test B. subtilis ATCC6633 ont été utilisés.Β-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 β-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 β-lactamase activity. Medium 5 agar medium (Difco) and test strain B. subtilis ATCC6633 were used.
Les échantillons de fèces sont incubés pendantFaecal samples are incubated for
30 minutes à 37 °C, avec une concentration connue d'antibiotique : Amoxicilline, Amoxicilline + acide clavulanique, Ticarcilline, Cefotaxime, Ceftriaxone ou Cefoperazone; l'activité antibiotique résiduelle est dosée.30 minutes at 37 ° C, with a known concentration of antibiotic: Amoxicillin, Amoxicillin + clavulanic acid, Ticarcillin, Cefotaxime, Ceftriaxone or Cefoperazone; the residual antibiotic activity is assayed.
Le profil d'activité de souches isolées est donné dans le tableau I suivant. Les valeurs données sont les pourcentages d'hydrolyse des différentes β-lactamines. The activity profile of isolated strains is given in Table I below. The values given are the percentages of hydrolysis of the various β-lactams.
L'activité β-lactamase a en outre été testée selon une méthode spectrophométrique (O'Callaghan et coll. Antimicrobial Agents Chemotherapy 1, 283, 1972). Les résultats sont reportés dans le tableau II ci-dessous.The β-lactamase activity has also been tested according to a spectrophometric method (O'Callaghan et al. Antimicrobial Agents Chemotherapy 1, 283, 1972). The results are reported in Table II below.
On considère que les souches utilisées doivent avoir une activité β-lactamase ≥0,02 μmole de céphaloridine/minute/mg de protéines bactériennes totales. 2. - Mise en évidence chez la souris des propriétés des souches isolées chez la souris,It is considered that the strains used must have a β-lactamase activity ≥0.02 μmole of cephaloridine / minute / mg of total bacterial proteins. 2. - Demonstration in mice of the properties of strains isolated in mice,
a) Association de quatre souches d'anaérobies productrices de β-lactamase et traitement par la ceftriaxone : Des souris sans germe (axéniques) C3H (Centre dea) Association of four strains of anaerobes producing β-lactamase and treatment with ceftriaxone: Mice without germ (axenic) C3H (Center for
Sélection des Animaux de Laboratoires, Orléans, Trance), sont maintenues en isolateur de plastique souple de type Texler. Elles reçoivent de l'eau de boisson à pH 3, stérilisée par la chaleur. La nourriture est préparée commercialement (RO3, Villemoisson/Orge, France) et stérilisée par irradiation à 4 mégarads.Selection of Laboratory Animals, Orleans, Trance), are kept in Texler-type flexible plastic insulator. They receive drinking water at pH 3, sterilized by heat. The food is commercially prepared (RO3, Villemoisson / Orge, France) and sterilized by irradiation at 4 megadads.
De tels animaux sont associés à quatre souches de bactéries anaérobies :Such animals are associated with four strains of anaerobic bacteria:
- C1 : B.thétaiotaomicron - C6 : C.clostridiformis- C1: B. thétaiotaomicron - C6: C. clostridiformis
- E9 : B.uniformis- E9: B.uniformis
- V4E3 : B.thétaiotaomicron- V4E3: B. thétaiotaomicron
Avant le traitement par la ceftriaxone, l'activité β-lactamase n'est pas détectable (0+), alors que les souches bactériennes s'implantent à 10(10,02 ± 0,31)ufc/g de fèces. Lorsque ces mêmes souris recoivent la ceftriaxone per os (ajouté à l'eau de boisson à raison de 2 mg/ml), les comptes totaux ne sont pas modifiés, l'activité enzymatique reste non détectable mais l'antibiotique n'est pas retrouvé dans les fèces.Before treatment with ceftriaxone, the β-lactamase activity is not detectable (0+), while the bacterial strains are implanted at 10 (10.02 ± 0.31) cfu / g of feces. When these same mice receive ceftriaxone per os (added to drinking water at a rate of 2 mg / ml), the total counts are not modified, the enzymatic activity remains undetectable but the antibiotic is not found in faeces.
b) Influence de l'introduction des souches d'anaérobies productrices de β-lactamases chez les souris à flore humaine traitées avec la ceftriaxone :b) Influence of the introduction of anaerobic strains producing β-lactamases in mice with human flora treated with ceftriaxone:
- Des souris axéniques ont été également associées à une flore complexe humaine. La préparation de la solution de gavage est réalisée en chambre anaérobie, à partir de fèces humaines fraîchement émises. L'échantillon est broyé à l'aide d'un Ultraturrax, et dilué 100 fois en milieu LCY. Cette dilution est transférée jusqu'à l'isolateur où se trouvent des souris axéniques. Afin de protéger cette solution bactérienne du contact avec l'oxygène, le transport se fait dans des tubes fermés hermétiquement à l'intérieur de la chambre anaérobie. Comme dans le cas précédent, les animaux préalablement assoiffés sont gavés par voie gastrique et rectale. Le gavage est répété après 24 h. Dix à quinze jours sont nécessaires pour obtenir des équilibres et des effets de barrières comparables à ceux observés chez le donneur.- Axenic 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. In order to protect this bacterial solution from contact with oxygen, transport takes place in hermetically sealed tubes inside the anaerobic chamber. As in the previous case, 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.
Les souris à flore humaine sont inoculées par voie intragastrique avec 1 ml de bouillon TGY (Trypticase 30 g/l, extrait de levure 20 g/l, glucose 5 g/l, Thioglycolate de sodium 1 g/l, pH = 7,4) contenant 5.108ufc/ml de 4 souches d'anaérobies productrices de β-lactamase (C1, C6, E9, V4E3) avant l'administration orale de Ceftriaxone (2 mg/ml dans l'eau de boisson). Les résultats sont présentés dans le tableau III.Mice with human flora are inoculated intragastrically with 1 ml of TGY broth (Trypticase 30 g / l, yeast extract 20 g / l, glucose 5 g / l, Sodium thioglycolate 1 g / l, pH = 7.4 ) containing 5.10 8 cfu / ml of 4 strains of anaerobes producing β-lactamase (C1, C6, E9, V4E3) before the oral administration of Ceftriaxone (2 mg / ml in drinking water). The results are presented in Table III.
Pendant la période de traitement, aucune concentration antibiotique n'est détectée dans les fèces. Une activité β-lactamase sur la ceftriaxone est décelée après 14 jours de traitement, elle varie entre 1+ et 4+.During the treatment period, no antibiotic concentration is detected in the feces. A β-lactamase activity on ceftriaxone is detected after 14 days of treatment, it varies between 1+ and 4+.
Les entérobactéries sensibles à la Ceftriaxone sont éliminées. Les comptes d'entérocoques sont équivalents à ceux obtenus pour la flore E, témoin non traitée. La résistance à la colonisation par des microorganismes exogènes résistants à la Ceftriaxone (Ent.cloacae IGR67, C.albicans IGR66) est maintenue chez les souris chez lesquelles les souches de Bactéroides actives ont été implantées précédemment.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.
Les bactéries anaérobies persistent dans le groupe ayant reçu les Bactéroides et les comptes totaux effectués en chambre anaérobie ne sont pas significativement modifiés par la présence de ces bactéries, par rapport au témoin. Les CMI 50 et 90 de ces bactéries sont respectivement de 512 et >1024 μg de ceftriaxone par ml. Les bacilles à Gram négatif représentent alors 84 % de cette flore, il y a également 13 % de bacilles à Gram positif sporulés et 3 % de cocci.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 μg 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.
L'identification par le système Api 20A permet de retrouver parmi ces souches des C.clostridiformis et B.uniformis ayant les mêmes caractères que ceux administrés juste avant le début du traitement par Ceftriaxone. Identification by the Api 20A system makes it possible to find among these strains C.clostridiformis and B.uniformis having the same characteristics as those administered just before the start of treatment with Ceftriaxone.
Moyenne ± SEM ufc/g de fèces (10 g) sur 6 prélèvementsAverage ± SEM cfu / g of faeces (10 g) on 6 samples
Résultats soulignés : différences significatives p > 0,5Results underlined: significant differences p> 0.5
* Valeurs extrêmes s = nombre de souris testées n ≈ nombre d'échantillons fécaux étudiés* Extreme values s = number of mice tested n ≈ number of faecal samples studied
En thérapeutique humaine, on administre 108 à 1011 de bactéries par jour de traitement antibiotique sous forme de gélules gastroresistantes à debitement enterique (gélules 5.109 de bactéroides). In human therapy, 10 8 to 10 11 bacteria are administered per day of antibiotic treatment in the form of enteric capsules with enteric flow (5.10 9 capsules of bacteroides).

Claims

REVENDICATIONS
1) Composition pharmaceutique, administrable par voie orale, destinée à réduire les effets des β-lactamines sur la flore intestinale chez l'homme, et caractérisée en ce qu'elle comprend des bactéries anaérobies strictes non pathogènes pour l'homme et productrices de β-lactamases.1) Pharmaceutical composition, administered orally, intended to reduce the effects of β-lactams on the intestinal flora in humans, and characterized in that it comprises strict anaerobic bacteria which are non-pathogenic for humans and which produce β -lactamases.
2) Composition selon la revendication 1, caractérisée en ce que les bactéries sont choisies parmi les souches de Clostridium et de Bactéroides productrices de β-lactamases.2) Composition according to claim 1, characterized in that the bacteria are chosen from the strains of Clostridium and of Bacteroides producing β-lactamases.
3) Composition selon la revendication 2, caractérisée en ce que les bactéries sont choisies parmi les souches de3) Composition according to claim 2, characterized in that the bacteria are chosen from strains of
Clostridium productrices de β-lactamases.Clostridium producing β-lactamases.
4) Composition selon la revendication 2, caractérisée en ce que les bactéries sont choisies parmi les souches de Bactéroides uniformis productrices de β-lactamases.4) Composition according to claim 2, characterized in that the bacteria are chosen from strains of Bacteroides uniformis producing β-lactamases.
5) Composition selon la revendication 2, caractérisée en ce que les bactéries sont choisies parmi les souches de Bactéroides thétaiotaomicron productrices de β-lactamases.5) Composition according to claim 2, characterized in that the bacteria are chosen from strains of thetaiotaomicron Bacteroides producing β-lactamases.
6) Composition selon l'une quelconque des revendications 1 a 5, caractérisée en ce que les bactéries choisies ont une activité β-lactamase d'au moins 0,02 μmole de céphaloridine/minute/mg de protéines bactériennes totales.6) Composition according to any one of claims 1 to 5, characterized in that the bacteria chosen have a β-lactamase activity of at least 0.02 μmole of cephaloridine / minute / mg of total bacterial proteins.
7) Composition selon l'une quelconque des revendications7) Composition according to any one of claims
1 à 6, caractérisée en ce qu'elle contient d'environ 108 à 10 11 bactéries anaérobies strictes non pathogènes productrices de β-lactamases. A B R E G E1 to 6, characterized in that it contains approximately 10 8 to 10 11 strict non-pathogenic anaerobic bacteria producing β-lactamases. SHORT
La présente invention a pour objet une composition pharmaceutique, administrable par voie orale, destinée à réduire les effets des β-lactamines sur la flore intestinale chez l'homme, et caractérisée en ce qu'elle comprend des bactéries anaérobies strictes non pathogènes pour l'homme et productrices de β-lactamases. The subject of the present invention is a pharmaceutical composition, which can be administered orally, intended to reduce the effects of β-lactams on the intestinal flora in humans, and characterized in that it comprises strict anaerobic bacteria which are not pathogenic for humans and producers of β-lactamases.
EP88903277A 1987-04-10 1988-04-08 Phamaceutical composition, for oral administration, designed to attenuate the effects of -lactamines Withdrawn EP0309532A1 (en)

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FR8705110A FR2613624B1 (en) 1987-04-10 1987-04-10 ORAL ADMINISTRATIVE PHARMACEUTICAL COMPOSITION FOR REDUCING THE EFFECTS OF B-LACTAMINES
FR8705110 1987-04-10

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FR2613624A1 (en) 1988-10-14
WO1988007865A1 (en) 1988-10-20
JPH01503537A (en) 1989-11-30
OA09023A (en) 1991-03-31
FR2613624B1 (en) 1990-11-23

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