JPS59130217A - Drug or animal drug consisting of micronomicin and beta-lactam antibiotic substance - Google Patents

Abstract

PURPOSE:To provide the titled drug containing micronomicin and beta-lactam antibiotic substance, and exhibiting synergistic effect especially to Pseudomonas aeruginosa. CONSTITUTION:The objective drug contains (A) a micronomicin compound (e.g. micronomicin) or its salt and (B) a beta-lactam antibiotic substance (e.g. piperacillin) or its salt, as active components. The micronomicin is an aminoglycoside antibiotic substance having broad antibacterial spectrum to Gram-positive bacteria and Gram-negative bacteria, especially to Pseudomonas aeruginosa. It has been found that the combination of the micronomicin with a beta-lactam antibiotic substance causes remarkable synergistic effect in the antibacterial activity especially to Pseudomonas aeruginosa. The amount of the beta-lactam antibiotic substance depends upon its kind, and is preferably 0.03-2 (W/W) for piperacillin, 0.008-32 (W/W) for cefoperazone and 0.1-16 (W/W) for latamoxef per 1pt. of micronomicin.

Description

[Detailed description of the invention] The present invention provides micronomycins and β-lactam (1) Concerning mixed medicines with antibiotics or veterinary medicines.

For more details, micronomycins or their salts and β
The present invention relates to a pharmaceutical or veterinary drug containing a -2cutam antibiotic or a salt thereof.

Micronomycin is an aminoglycoside antibiotic and exhibits a broad antibacterial spectrum against Durum-positive and Durum-negative bacteria, such as Pseudomonas aeruginosa (Japanese Patent Publication No. 50-39155).

Attempts have been made to use aminoglycoside antibiotics and β-lactam antibiotics in combination to enhance the antibacterial activity of both drugs, particularly against Pseudomonas aeruginosa, and to reduce the side effects of the former.

For example, dibekacin:y (dibekacin *
DKB) and various β-lactam agents [Atsushi Konno, Kotabe Oizumi, Kiyoshi Aonuma: Significance of the combined use of aminoglycosides and β-lactam agents, Pharmaceutical Journal + 17 (12).

1965-1970 (1981)), or the combination of cefoxitin (08fOXitin+ CFX) and various aminoglycoside antibiotics (Unθ+ 'r, ly
, 0sada +H, Ogasa: Cefoxi
tin: 8ynergism with (2) aminoglycoslas in vitro
Ayznerm-Forsch/DrugRes, 31
(1), 761-764 (1981)] has been reported to have a high synergistic effect against Pseudomonas aeruginosa.

The present inventors investigated the combination of micronomycins and β-lactam antibiotics, and as a result found that a remarkable synergistic effect was produced in terms of antibacterial activity percentage and antibacterial activity against Pseudomonas aeruginosa, and the present invention was completed.

Next, the present invention will be explained in more detail.

The micromycins referred to in the present invention are micronomycin t.
Includes micromycin penta-N-methanesulfonic acid, micromycin penta-N-eta/sulfonic acid, and the like. The present applicant has filed an application for micromycin venter N-methanesulfonic acid and micromycin venter N-ethanesulfonic acid (Japanese Patent Application No. 57-136).
No. 610).

β-lactam antibiotics include both penicillins and cephalons. Penicillins include (3) hiheracillin, carbenicillin, sulpenicillin, azlocillin, etc., and cephalosporins include cefoperazone, latamoxes, and cefsulodine.

Examples include cefotaxime and ceftizoxime.

Examples of the salts of micronomycins include sulfates, hydrochlorides, etc.
Examples of salts of β-lactam antibiotics include sodium salts and potassium salts.

The ratio of β-lactam antibiotics to cyclonomycins varies, but for example,
Whereas, piperagiline has 0.03 to 2 (w/w)
, 0,008-32 for cefoperazone (w/w
), 0.1 to 16 (w/w) is suitable for Latamoxes.

The pharmaceutical or veterinary drug may be administered parenterally.

The drug can be administered as an aqueous solution or suspension by intravenous injection (including intravenous drip), intramuscular injection, or subcutaneous administration.

Micronomycins and β-lactam antibiotics can also be prepared by dissolving or suspending them in an aqueous solution or an injectable solvent and then sealed in an ampere (4).1. It may be stored in an ampoule or vial as a crystal, powder, microcrystal, freeze-dried product, etc., and dissolved or suspended before use.

The composition of the present invention can also take the form of eye drops, suppositories, ointments, creams, and the like. In this case, commonly used bases (ointment base, suppository base, etc.).

Bactericidal agents, preservatives, etc. can be used, and surfactants can also be added. .

The appropriate dosage for this composition is 60-240 mg per day for an adult (60 Kp) as a micromycin and 0.5-41 mg per day as a β-lactam antibiotic.

Next, examples showing the effects of the combination of micronomycins and β-lactam antibiotics are shown in Examples.

Example 1 Test reagents: Micronomycin sulfate (Kyowa Hakko Kogyo ■, Sagamicin, 12011g titer), piperagiline Na salt (Toyamaka School District, Bentocillin, (5) 12 titer), cefoperazone NatM ( Toyama Chemical 1, cefoberazine, 0°5f titer), and Latamoxes Na salt (Shionogi Seiyaku bottle, Geomarin, 0.5v titer) were used.

Test strain: A clinical isolate of Pseudomonas aeruginosa recently isolated from the clinic and stored in the applicant's laboratory was used to test the effectiveness of the combination.

Medium: Mueller Hlnton B for pre-culture of test bacteria
roth (MHB) medium (Difco La, bs)
was used.

Mueller for determining the minimum inhibitory concentration (MIC)
Hlnton Agar ('kA HA) medium (D
ifc.

Lab8) was used.

Measurement of in vitro antibacterial activity: According to the standard method of the Japanese Society of Chemotherapy, prepare MHA medium containing multiple dilutions of each drug, and add test bacteria that have been pre-cultured overnight in MHB on top of it so that it has a 106Cθ11B shoulder. After inoculating the bacterial solution and culturing at 37°C for 8 hours, MI
CCmQ? ,,4d)(6) was obtained.

Judgment of synergy: Judgment of synergy is Tt'raclonal Inhib
Itory Concentration (F I C
) The method was used to calculate the Index.

FIC' was determined according to the following criteria.

FICIndex≦0.5 Synergistic effect 0.5<FI
CIndex<1 Partial synergy FICIndex
=1 Additive effect FICIndex > 1
Invalid results: As shown in Table 1.

Table 1 8train/46FICInclexP, aer F
3465 0.38 F3440 0.38 F3443 0.63 (7) F3420'''0.75 F3398 0.31 F3378 0.27 F3375 0.53 1?3376 0.63 F3365 0.50 P, aer F3465 0.53F
3440 0.25 F3395 0.52 F3393 0.52 F3365 0.28 F3361 0.50 F3354 0.51 F3349 0.38 F3340, 0.5 Example for MCR-LMOX (LMOX: Rutter e
8train4 F'ICIncle
xP, aer A-10,31 A-40,5 A-80,38 people-100,63 A-180,50 people-200,38 A-250,31 B-30,75 E-150,19 Patent application Person (102) Kyowa Hakko Kogyo Co., Ltd. Procedural Amendment January 13, 1980 Patent Application No. 4720 of 1982 2, Name of Invention Pharmaceutical or veterinary drug consisting of micromycins and β-lactam antibiotics 3; Relationship with the case of the person making the amendment Patent applicant Postal code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name (102) Kyowa Hakko Kogyo Co., Ltd. Claims column of the specification and the invention Detailed Explanation Column 5, Contents of Amendment (1, 1 The description of the claims is corrected as shown in the attached sheet.

(1,) do.

(3) Correct "Latamokises" on page 4, line 3, page 6, line 3, and page 8, line 18 to "Latamokisev."

(4) On page 4, lines 10 to 14, “For example, it is appropriate.” was changed to “Generally, 2 to 7
(W/W) is appropriate. ” is corrected.

(2) Claims (11) Pharmaceutical or veterinary drug containing micronomycins or a salt thereof and a β-lactam antibiotic or a salt thereof (2) Micronomycins include micronomycin, micronomycin penta N-methanesulfonic acid or micromycin penta-N-ethanesulfonic acid, β
-The lactam antibiotic is piperagiline.

carbenicillin, sulpenicillin, azlocillin.

Cefoperazone, Latamoxef, Cefsulozin.

The pharmaceutical or veterinary drug according to claim 1, which is cefotaxime or ceftizoxime.

(3) 114-

Claims (2)

[Claims] (1) Pharmaceuticals or veterinary drugs containing micronomycins or their salts and β-lactam antibiotics or their salts (2) Micronomycin is micronomycin. micromycin penta-N-methanesulfonic acid or micromycin venta-N-ethanesulfonic acid,
The pharmaceutical or veterinary drug according to claim 1, which is a β-lactam antibiotic kahiheracillin, carbenicillin, sulpenicillin, tazulocilin, cefoperazone, latamoxes, cefsulodin, cefotaxime or cefoxitin.