HUT69730A - Synergistic combinations of antibiotics - Google Patents

Abstract

The present invention is directed to a synergistic combination of ethambutol and an antibiotic selected from teicoplanin, a teicoplanin amide derivative, an aglycon or pseudoaglycon thereof, antibiotic A40926 complex, a factor, a derivative, aglycon or pseudoaglycon thereof. The synergistic combinations of the invention are particularly effective in the treatment of infections caused or sustained by mycobacteria, particularly M. tuberculosis, including multi-drug resistant strains of M. tuberculosis.

Description

The present invention relates to a synergistic combination of etambutol and an antibiotic selected from the group consisting of etambutol, a teicoplanin amide derivative, an aglycone or pseudoaglyconone, an antibiotic complex A40926, an agent, an aglycone or a pseudoaglyconone thereof.

The synergistic combinations of the present invention are particularly effective for the treatment of infections caused or maintained by mycobacteria, in particular M. tuberculosis, including many drug resistant strains of M. tuberculosis.

Recently, there has been an increase in the incidence of new cases of tuberculosis. The issue is exacerbated by the AIDS epidemic and the emergence of drug resistance. Therefore, there is a need for new agents that can replace or complement existing treatments.

Etambutol is a known drug that is widely used to treat tuberculosis.

Teicoplanin is an antibiotic active ingredient and has been approved in many countries for the treatment of Gram-positive infections.

It has been previously reported that it has no significant activity against M. tuberculosis in vitro (F. Parenti et al., J. Antibiotics, 1978, 21, 276-283).

Teicoplanin and its derivatives and acid addition salts useful in the present invention are represented by formula (I):

Y 'is a hydroxyl group or a group of the formula [mono- or di (C 1 -C 4) alkyl] amino- (CH ₂ ) _n -amino- wherein n is 2,3 or 4,

A 'is hydrogen or N- (C 9 -C 12 aliphatic acyl) -S-2amino-2-deoxyglucopyranosyl,

G 'is hydrogen or N-acetyl-E-2-amino-2-deoxyglucopyranosyl,

Α-hydrogen or α-D-mannopyranosyl.

Teicoplanin is disclosed in U.S. Patent Nos. 4,239,751 and 4,542,018.

Specifically, it is an antibiotic substance produced by Actinoplanes teichomyceticus strain ATCC 31131, which consists essentially of a major component designated TA2-2, with other components distinguished by TA2-1, TA2-3, TA2-4, TA2-5 and TA3-1. can be found. Depending on the specific manufacturing or isolation conditions, one or more of these may only be present in very small or negligible amounts. TA2-2 is a compound of formula (I) wherein A ', G' and M 'are as defined above, Y' is a hydroxy group and the C 9 -C 12 aliphatic acyl group is an 8-methyl nonanoyl group; TA2-1 is a compound of formula (I) wherein A ', G' and M 'are a sugar group as defined above, Y' is a hydroxy group and the C 9 -C 12 aliphatic acyl group is a 4Z-decenoyl group; in the compound of formula (I) TA2-3, A ', G' and M 'are the aforementioned sugar group, Y' is a hydroxy group and the C 9-12 aliphatic acyl group is a decanoyl group; in the compound of formula (I) TA2-4, A ', G' and M 'are as defined above, Y' is a hydroxy group and the C 9 -C 12 aliphatic acyl group is an 8-methyl-decanoyl group; TA2-5 is a compound of Formula (I) wherein A ', G' and M 'are the above sugar group, Y' hydroxy group, and C 9-12 acyl group are 9-methyl-decanoyl; TA3 is a compound of formula (I) wherein A 'is hydrogen and G and M' are a sugar group as defined above.

Teicoplanin aglycone and pseudoaglycones are described in U.S. Patent Nos. 4,650,855, 4,645,827, and 4,629,781.

Teikoplanin amide derivatives are described in European Patent Specification 218,099 and in U.S. Patent Application Serial No. 08/079970.

Preferred are amide derivatives wherein Y 'is 3,3-dimethylaminopropylamino. Most preferred are amides in which A-, G 'and M' are the sugar groups defined above.

The antibiotic A 40926 and its derivatives and their acid addition salts are represented by the formula (II) in which

R ^{2 is C} 9 -C 12 alkyl;

M is hydrogen, α-D-mannopyranosyl or 6-O-acetyl-α-Dmannopyranosyl;

Y is a carboxyl group, (C1-C4) alkoxycarbonyl group, aminocarbonyl group, (C1-C4) alkylaminocarbonyl group, di (C1-C4) alkylaminocarbonyl group in which the alkyl group is hydroxy, amino,

It may be substituted by one of C 1-4 alkylamino and di (C 1-4) alkylamino or hydroxymethyl;

X is hydroxy or -NR ³ -alk ¹ - (NR ⁴ -alk ² ) p - (NR ³ -alk ³ ) gW in which

R ^{3 is} hydrogen or C 1-4 alkyl;

alk ¹ , alk ² and alk ³ are independently straight or branched C 2 -C 10 alkylene;

p and q are independently 0 or 1:

R ⁴ and R ³ are each independently hydrogen, C 1-4 alkyl, or

R ³ and R ⁴ together are C 2 -C ⁴ alkylene linking the two nitrogen atoms, with the proviso that p is 1; obsession

R ⁴ and R ^{3 taken} together are C 2 -C 4 alkylene groups linking the two nitrogen atoms, with the proviso that both p and q are 1:

W is hydrogen, C 1-4 alkyl, amino, C 1-4 alkylamino, di (C 1-4) alkylamino, one or two amino (C 2-4) alkyl or one or an amino group substituted by two (C 1 -C 4) alkylamino (C 2 -C 4) alkyl groups or by one or two di (C 1 -C 4) alkylamino (C 2 -C 4) alkyl groups;

or if p and q is both 0, the NR - ^ - alk ¹ - group together piperazino obsession 4-methyl-piperazino-group can also create, with the proviso that if X hydroxy, Y hidr-

pivaloyloxymethyl group,

Z is a hydrogen atom or a group (a) wherein A ^- a mineral or organic acid anion or carboxylic acid group present in the molecule of antibiotic other, represent the internal anion, which can be derived from the above carboxylic acid group.

Antibiotic A 40926 and factors thereof, i.e. compounds of formula II wherein X is hydroxy, are disclosed in U.S. Patent 4,935,238.

In particular, the antibiotic A 40921 antibiotic A is a compound of formula II wherein X is hydroxy, Y is carboxyl, R ^{2 is} n-decyl and M is α-D-mannopyranosyl.

A 40926 factor Bq labeled antibiotic A 40926 factor B material, satisfies the formula (II) compound of general formula wherein wherein X is hydroxy, Y is carboxy, R ² 9-methyl-decyl, and M ct-D- mannopyranosyl.

Factor A 40926 Bj differs only in factor A

Bg to include R ² n-undecyl [E. Riva et al., Chromatography, 24, 295 (1987)].

The A 40926 factor PA and factor PB antibiotics differ from the corresponding factor A and B in that the mannose unit is replaced by a 6-O-acetyl-α-D-mannopyranose unit.

U.S. Pat. No. 4,782,042 discloses an antibiotic A 40925, a mannosyl aglycone, a compound of formula II wherein X is a hydroxy group and a sugar group at position 56 is replaced by a hydroxy group. Antibiotic A 40926 is a pseudoaglycone and magic icon, i.e., a compound of formula II wherein X is hydroxy and M is hydrogen, and a compound of formula II wherein X is hydroxy, the sugar at position 56 is hydroxy and M is hydrogen, U.S. Patent No. 4,868,171. The aforementioned compounds wherein X is other than hydroxy are described in International Patent Application No. PCT / EP92 / 01594, which is incorporated by reference, inter alia, in the United States, and is disclosed in WO 93/03060. Other derivatives which are also suitable for their preparation are disclosed in WO 92/17495, PCT / EP92 / 00374, in which one of the designated states is the United States.

A group of preferred compounds of formula II is those wherein X is mono- or dialkylaminoalkyl, most preferably 3,3-dimethylaminopropyl. Another preferred group of compounds of formula (II) compounds can be classified into, wherein R ² 9-methyl-decyl group. Most preferred are compounds of formula II wherein X is 3,3-dimethylaminopropyl and Y is hydroxymethyl.

Methods for preparing these compounds can be found in the above literature, which are incorporated herein by reference and are known in the art by analogy.

According to the present invention, any of the compounds of formula (I) or (II) above may be used in the combination or methods of the invention, either alone or in any ratio.

For the sake of brevity, a compound of formula (I) above is hereinafter referred to as teicoplanin or a derivative thereof, and a compound of formula (II) is referred to as antibiotic A 40926 or a derivative thereof.

Teicoplanin or a derivative thereof and antibiotic A 40926 or a derivative thereof are a component of the synergistic combination of the invention. These are hereinafter referred to as the glycopeptide component of the combination according to the invention. The other component of this combination is ethambutol, referred to as the etambutol component of the synergistic combination.

The term "treatment" is used in the present application to include prevention, therapy and cure, and each is individually described.

The term co-treatment refers to the simultaneous or sequential administration of the components of the combination of the invention to a patient in need of such treatment. That is, the effect of the first compound to be administered is still present when the second is administered.

It is therefore an object of the present invention to provide a combination for the combined treatment of tuberculosis comprising synergistically effective doses of the glycopeptide component and the ethambutol component.

The synergistically effective dose of each component for each combination of the invention may be determined by one of ordinary skill in the art from the general and detailed description, assays, and results thereof, or by the use of conventional techniques well known in the art. can be inferred.

For use in the combination according to the invention, it is not necessary that the above compounds be included in a single formulation, and on the contrary, it is preferable that both the glycopeptide component and the ethambutol component are used in the preferred pharmaceutical formulation and dosage form.

Conventional formulations containing the glycopeptide component or the ethambutol component are generally those that are • 9

- ίο - '* **' * ^: can be prepared based on general knowledge in the art, for example in some professional books on Remington's Pharmaceutical Sciences (Alfonso R. Gennaro Editor, 17th Edition, Mack Publishing Co., Easton, Pennsylvania, 1985). reference may be made. .

Particularly advantageous formulations are, of course, those already authorized by the Health Authorities and currently commercially available.

For use in the combination according to the invention, the glycopeptide component is preferably formulated in a dosage form suitable for parenteral administration, particularly intramuscular (i.m.) or intravenous (i.v.) administration. A preferred dosage range is from 1 to 15 mg / kg body weight / day and most preferably from 3 to 6 mg / kg body weight / day. For use in the combination according to the invention, the preferred dosage form of the glycopeptide component is intramuscularly administered, containing 100-600 mg, preferably 200-400 mg of such active ingredient.

For use in the combination according to the invention, the etambutol component is preferably formulated in an oral dosage form, such as a tablet or capsule.

The preferred dosage range is in this case 5 to 25 mg / kg / day, and preferably 10 to 20 mg / kg / day. For use in the combination according to the invention, a pharmaceutical composition comprising ethambutol for oral administration and in an amount of 50-500 mg, preferably 100-400 mg, is preferred.

The combination according to the invention has the advantage that it is particularly effective in treating M. tuberculosis infections, including multi-drug resistant M. tuberculosis, at a dose of the etambutol component which is generally significantly lower than the dose, currently used or considered necessary to treat the infection when ethambutol is used alone. The effective dose of Teicoplanin in the combination according to the invention is also in the lower range of the hitherto used doses for the treatment of Gram-positive infections and is significantly lower than any dose expected to be effective against M. tubercolis when Teicoplanin is used alone.

Administration of the combination of the invention to a patient in need of such treatment includes administration of the glycopeptide component and the ethambutol component, each using the preferred or suspected preferred mode of administration, or simultaneously or sequentially, according to the combination treatment of the invention.

Preferably, the glycopeptide component is administered first, by the preferred route of administration for this component, i.e. intramuscularly, and then the etambutol component is administered when the glycopeptide component is still high in blood.

More preferably, the etambutol component is administered orally 1 to 3 hours after intramuscular administration of the glycopeptide.

If the glycopeptide component is teicoplanin or another member of this group with a similarly long half-life, it is sufficient to administer the glycopeptide component of the invention two or three times a week while the etambutol component is still administered once daily.

This dosage regimen is particularly convenient for routine treatment of tuberculosis maintained by presumed many drug-resistant strains, where multiple drug treatments are required, and the combination of the invention can be performed with standard treatments with rifampicin, isoniazid and / or pyrazinamide and / or streptomycin. In these treatments, the combination according to the invention is preferably intended to replace streptomycin, the toxicity of which is known.

The combination of the invention may also be used alone or in combination with isoniazid to prevent tuberculosis in vulnerable communities such as hospital staff, patient families, and others.

Although it is generally preferable to administer ethambutol in the most convenient manner, i.e., oral administration, a single formulation for intramuscular administration can be readily prepared from the etambutol component and the glycopeptide component of the combination of the invention, especially when oral administration is not possible.

According to the present invention, a patient is defined as an individual in need of treatment with a composition of the invention

refers to and includes warm-blooded animals such as birds, such as poultry, mammals such as rodents, sheep, dogs, cats, cows, primates, and especially humans.

References to effective doses, preferred dosage ranges, compositions, routes and route of administration of the composition of the present invention are considered to be accurate, however, since the conditions of use of the combination according to the invention are definitively determined by the attending physician. general medical condition, associated pathologies, and specific drug resistance or hypersensitivity.

Minimum Inhibitory Concentrations (MICs) and checkerboard titrations to determine synergistic activity were measured in final volumes of 2.0 ml in Middlebrook 7H9 (Difco) medium containing 0.2% glycerol and 10% ADC in the base medium. The inoculum was obtained from a 21-day Lowenstein-Jensen culture (Sclavo) from which a suspension of 0.8 optical density was prepared at 540 nm. This was incubated at 37 ° C for 48 hours and an additional suspension was prepared in 7H9 medium (see above) supplemented with glycerol and ADC with an optical density of 0.12 and used as a 2% final inoculum. Inhibition was determined as the absence of visible growth after incubation for 21 days at 37 ° C.

The interaction coefficient, called the Fractional Inhlbitory Concentration Index (FIC Index), was calculated from the results to determine whether the combined effect of the two drugs is synergistic (FIC Index <0.5), additive ( FIC Index = 1.0) or antagonistic (FIC Index> 4.0) as originally described by MC Berenbaum (J. Infectious Diseases, 1978, 137, 122-130) and cited in detail by GM Eliopoulos and RC Moellering (Antibiotics). in Laboratory Medicine, V. Lorian et al., Ed., Baltimore, 1991, 432-492):

Ethambutol ^combination teicoplanin ^{MIC MIC Koin} b ·

FIC Index =

M ^ Cetambutol ^e s ^{ed by MIC} teicoplan ^e s ^ed

The results of these experiments are shown in Table I.

• · ·

- 15 Table I

Minimum inhibitory concentration of etambutol and teicoplanin (g / ml) alone and in combination

Tribe ethambutol teicoplanin FIC Index alone combinations Cioban alone combinations Cioban M. tuberculosis 1 0.25 64 8 0.38 L1901 M. tuberculosis 4 1 > 64 0.25 0.25 L1904 M.tuberculosis 4 1 > 64 1 0.27 L1905 M. tuberculosis 2 0.25 32 4 0.25 L1908 M. tuberculosis 2 0.5 > 64 1 0.27 L1909 M. tuberculosis 2 0.5 32 1 0.28 L1910A M.tuberculosis 2 0.5 64 1 0.27 L1912 M.tuberculosis 2 1 64 2 0, 53 L1913 M.tuberculosis 2 0, 5 64 2 0, 16

Based on these results, 8 of the 9 strains tested showed a synergistic effect of teicoplanin and ethambutol. The result for the different strain can be called autonomy according to the above summary by G. M. Eliopoulos and E. C. Moellering.

These results were also demonstrated in strains of Mvcobacterium tuberculosis which are resistant to various antibiotics. No synergism was observed for an ethambutol resistant strain (L 1966, ATCC 35837).

These experiments were performed in accordance with methods known in the art using BACTEC 12B tubes (Becton and Dickinson), which were stained with M. tuberculosis strain at ca. 10 µl of live cells were inoculated. Various amounts of antibacterial agents were added alone or in combination to the different tubes. Concentrations of teicoplanin were prepared by two-fold serial dilutions ranging from 128-0.25 mg / L. Ethambutol was tested at concentrations ranging from 0.06 to 4 mg / L. For each strain, a control tube was inoculated with a 1: 100 dilution of inoculum used for tubes containing antibacterial agents. Tubes were incubated at 37 ° C and the Growth Index (GI) was measured daily with a BACTEC 460 (Becton & Dickinson). DeltaGI was calculated when the control culture had a GI of 30 or greater. For each culture, deltaGI was obtained by subtracting the penultimate daily GI from the last day. An antibacterial agent • ·:

concentration was considered to be inhibitory to a particular bacterial strain when the deltaGI value was less than or equal to untreated control.

After the lowest inhibitory concentration was determined for each agent and for different combinations, the criteria for synergistic effect were identical to those described for the MIC assay (see above).

The results of these experiments are shown in Table II. are summarized in Table.

II. spreadsheet

Minimum inhibitory concentration (mg / ml)

Tribe ethambutol teicoplanin FIC index alone combinations Cioban alone combinations Cioban M. tuberculosis L 1906 (Isoniazid- resistant, clinical Kai isolate) 0.5 0.25 64 <0.25 0.5 M. tuberculosis L 1909 (Pyrazinamide resistant clinical isolate) 0.5 0.25 128 <0.25 0.5

M. tuberculosis

L 1959 (ATCC 35820, streptomycin resistant) 0.5 0.25> 128 0.5

0.5

M. tuberculosis

L 1967 (ATCC 35838, rifampicin0.5 resistant)> 128

Claims (13)

PATENT CLAIMS A combination for the treatment of tuberculosis, which a) one of the compounds of the formula I or their acid addition salts thereof Y 'is a hydroxy group or a group of the formula [mono- or di (C 1 -C 4) alkyl] amino- (CH ₂ ) _n -amino- wherein n is 2, 3 or 4, A 'is hydrogen or N- (C 9 -C 12 aliphatic acyl) -β-2amino-2-deoxyglucopyranosyl, G 'is hydrogen or N-acetyl-E-2-amino-2-deoxyglucopyranosyl, M 'is hydrogen or an α-D-mannopyranosyl group, or a compound of formula II or an acid addition salt thereof, wherein R ^{2 is C} 9 -C 12 alkyl; M is hydrogen, α-D-mannopyranosyl or 6-O-acetyl-α-Dmannopyranosyl; Y is a carboxyl group, (C1-C4) alkoxycarbonyl group, aminocarbonyl group, (C1-C4) alkylaminocarbonyl group, di (C1-C4) alkylaminocarbonyl group in which alkyl may be substituted by hydroxy, amino, C 1-4 alkylamino, and di (C 1-4) alkylamino, or hydroxymethyl; X is hydroxy or -NR 4 -alk - * - (NR ⁴ -alk ² ) p - (NR ⁴ -alk ³ ) q W _ · · · · · * - an amino group of the formula 20 in which R ^{3 is} hydrogen or C 1-4 alkyl; alk ¹ , alk ² and alk ³ are independently straight or branched C 2 -C 10 alkylene; p and q are independently 0 or 1: R ⁴ and R ⁵ are each independently hydrogen, C 1-4 alkyl, or R ³ and R ⁴ together are C 2 -C ⁴ alkylene linking the two nitrogen atoms, with the proviso that p is 1; obsession R ⁴ and R 4 taken together form a C 2 -C 4 alkylene group linking the two nitrogen atoms, with the proviso that both p and q are 1; W is hydrogen, C 1-4 alkyl, amino, C 1-4 alkylamino, di (C 1-4) alkylamino, one or two amino (C 2-4) alkyl or one or amino substituted with two (C 1 -C 4) alkylamino (C 2 -C 4) alkyl groups or one or two di (C 1 -C 4) alkylamino (C 2 -C 4) alkyl groups, or p and q are both 0, together with the group -NR ³ -alk ¹ - is piperazino It may also form a 4-methylpiperazino group, provided that when X is hydroxy, Y is hydroxymethyl, Z is a hydrogen atom or a group of formula (a) in which ·· • · ·· A ^- an anion of a mineral or organic acid or, if a carboxylic acid moiety is present on another molecule of the antibiotic, it may also represent an internal anion derived from the above carboxylic acid moiety, a selected glycopeptide component, and b) containing ethambutol in a dose that is synergistic to a strain of Mvcobacterium tuberculosis. A combination according to claim 1, wherein the glycopeptide component is selected from the group consisting of compounds of formula I wherein Y 'is hydroxy or 3,3-dimethylaminopropyl and G' and M 'are as defined above and It is selected from compounds of Formula II wherein X is 3,3-dimethylaminopropyl, Y is hydroxymethyl and M is aD-mannopyranosyl. The combination according to claim 1 or 2, wherein the glycopeptide component is present in an amount of from 1 to 15 mg / kg body weight. The combination according to claim 1 or 2, wherein the glycopeptide component is present in an amount of from 3 to 6 mg / kg body weight. 5. A combination according to any one of claims 1 to 5, wherein the amount of ethambutol is between 5 and 25 mg / kg body weight. 6. A method of treating tuberculosis infections comprising the steps of claims 1-5. An effective amount of a combination according to any one of claims 1 to 6, for administration to a patient in need of such treatment. * ··; ···· '· ........ * ·. * · _ _ »» _{Λ Λ} »» »» »» · A method of preventing tuberculosis infections, comprising the steps of: 1-5. An effective amount of a composition according to any one of claims 1 to 6, to a patient in need of such treatment. The method of claim 6 or 7, wherein the glycopeptide component is in a form suitable for intramuscular administration and ethambutol for oral administration. The method of claim 6 or 7, wherein the glycopeptide component and the ethambutol are in a form for intramuscular administration containing the two components together. The method of claim 8, wherein the glycopeptide component is administered 1 to 3 hours prior to administration of ethambutol. The method of claim 8, wherein the glycopeptide component is first administered and the ethambutol is added within 1 hour of the glycopeptide component administration. The method of claim 8, 9, 10 or 11, wherein the glycopeptide component and ethambutol are administered once daily. 13. The method of claim 8, 10 or 11, wherein the glycopeptide component is administered twice or three times a week and etambutol is administered once daily.