JPH03279329A - Antibiotic comprising cephamycin and cephalosporin - Google Patents

Abstract

PURPOSE:To provide an antibiotic exhibiting a synergistic antibacterial activity and active against pathogenic bacteria exhibiting high resistance to beta-lactam agents by compounding a cephamycin compound, a penicillin compound and a cephalosporin compound as active ingredients. CONSTITUTION:An antibiotic contains as active ingredients (A) a cephamycin compound such as cefoxitin, cefmetazole, flomxef or a pharmaceutically acceptable salt thereof and (B) a compound selected from B1: penicillin compounds such as ampicillin and piperacillin and B2: cephalosporin compounds excluding the cephamycin compounds, such as cefoperazone, cefpiramide, cefatrizine and pharmaceutically acceptable salts thereof in an A:B ratio of 1:1-1:10, preferably 1:1-1:5. The antibiotic exhibits excellent antibiotic activity especially against methicillin-resistant Staphylococcus aureus which is the phlogogenic bacterium of intractable diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION FIELD OF INDUSTRIAL APPLICATION This invention relates to novel antibacterial agents. More specifically, it is selected from the group consisting of cephamycin compounds or their pharmaceutically acceptable salts, penicillin compounds, cephalosporin compounds (excluding cephamycin compounds), and their pharmaceutically acceptable salts. This invention relates to an antibacterial agent whose active ingredient is a type of compound known as phthalate.

A number of antibiotics have been used to treat infections caused by various pathogenic bacteria, but pathogenic bacteria have the property of gradually becoming resistant to antibiotics. It is generally known that there are pathogenic bacteria that do not exhibit sufficient antibacterial activity when used alone.

For example, Staphylococcus aureus (S, aureus)
us), Staphylococcus eidermizois (S,
Durham-positive bacteria such as E. idermidis, Enterococcus faecalis (E. faecalis), and Citrobacter freundii (C. freundii).
, Escherichia coli (E. coli), Klebsiella pneumonia (L.

7), Durham-negative bacteria such as Serratia marcescens (S, w+arcescens); Pseudomonas aeruginosa (Ps, aeru 1no
sa), Pseudomonas cepacia (h), Pseudomonas maltophilia (Ps, malto h
ilia), Acinetobacter calcoaceticus (
For the purpose of increasing antibacterial activity against pathogenic bacteria such as non-glucose-fermenting Durham-negative bacilli such as A. calcoaceticus, the combination of multiple antibacterial agents has been studied.

JP-A-60-126230 and JP-A-61-3
No. 7248 describes an antibacterial agent that is a combination of a penicillin antibiotic and a penicillin or cephalosporin antibiotic. Also, special public service 1986-5044
No. 8 discloses an antibacterial agent that is a combination of a synthetic antibacterial agent and a penicillin or cephalosporin antibiotic, and Japanese Patent Publication No. 63-26732 discloses a combination of a phosphonic acid derivative and various antibacterial substances. Antibacterial agents have been described.

In recent years, there has been an increase in the number of resistant bacteria isolated from patients with intractable diseases. Because there are only a few antibacterial agents that exhibit antibacterial activity, this has become a major clinical problem.

Cephamycin compounds are known to exhibit a broad antibacterial spectrum and strong antibacterial activity. As a known cephamycin compound, cefoxitin (Japanese Patent Publication No. 1986-
46954, Japanese Patent Publication No. 59-46955 and Japanese Patent Publication No. 59-46956), cefmetazole (
Special Publication No. 54-17755 and Special Publication No. 54429
No. 99), flomoxef (Japanese Patent Application Laid-Open No. 59-13938)
Publication No. 5), etc. However, the above-mentioned known cephamycin compounds alone do not have sufficient antibacterial activity against MRSA, and β-lactam agents are frequently used to treat MRSA infections; - It has not shown sufficient therapeutic effects against MRSA, which is highly resistant to lactam drugs.

All of the above prior art describes normal Durham-positive bacteria,
Limited to references based on testing of Durham-negative bacteria and non-glucose-fermenting Durham-negative bacilli, against MRSA.
No antibacterial evaluation has been performed, and MR with a single agent
Since there are limits to the treatment of SA infections, attempts have been made to use two or more drugs in combination, such as aminoglycosides and β-lactams, or fosfomycin and β-lactams, but the combined effects are satisfactory. I can't say it's a thing.

Infectious diseases caused by MRSA are representative of intractable infections, and the lack of effective therapeutic agents is a clinical research issue that should be resolved as soon as possible.

Means for Solving the Problem The present inventors have developed MRS that is highly resistant to β-lactam drugs.
As a result of intensive research aimed at increasing the antibacterial activity of penicillin antibiotics and cephalosporin antibiotics against A. By combining a compound selected from the group consisting of phosphorus compounds (excluding cephamycin compounds) and their pharmaceutically acceptable salts, a remarkable synergistic antibacterial effect against MRSA has been observed. The antibacterial activity can be sufficiently increased against MRSA, for which penicillin antibiotics or cephalosporin antibiotics alone have little or very weak antibacterial activity. With this new knowledge, we have completed the present invention.

The present invention provides compounds selected from the group consisting of cephamycin compounds or their pharmaceutically acceptable salts, penicillin compounds, cephalosporin compounds (excluding cephamycin compounds), and their pharmaceutically acceptable salts. The present invention relates to an antibacterial agent containing a type of compound as an active ingredient. Moreover, an antibacterial agent using a combination of a cephamycin compound and a cephalosporin antibiotic or a penicillin antibiotic has not been known so far, and the antibacterial agent of the present invention is novel.

The penicillin compounds and cephalosporin compounds (excluding cephamycin compounds) used in the present invention have synergistic antibacterial activity when combined with cephamycin compounds or their pharmaceutically acceptable salts. There are no particular limitations as long as the compound exhibits the following, and examples include cephalosporin compounds other than known penicillin compounds and cephamycin compounds.

Specific examples of the penicillin compounds include:

For example, Benicilli:>G, ampicillin, amoxicillin,
Mecillinum, bivmecillinum, carbenicillin, carbenicillin, calindacillin, sulpenicillin, tarambicillin, vacambicillin, ticarcillin, piperacillin, cyclacillin, hetacillin, and the like. Suitable examples include ampicillin and piperacillin, among which piperacillin is preferred.

Specific examples of the cephalosporin compounds include cefatridine, cefamandole, cefzonam,
Cefubimizole, cefapirin, cephalozin, cephalozin, cefotiam, cefoperazone, ceftesol, cefoxitin, cefoperazone, cephaloglycin, cephalexin, cefadroxil, cephalozin,
Examples include cephradine, cefaclor, cefoperazone, and the like.

Suitable examples include cefoperazone, cefoperazone, cefatridine, cefapirin, cefotiam, and cefaclor, among which cefatridine, cefapirin,
Cefothiam, cefoperazone and cefoperazone are preferred.

Cephamycin compounds refer to the penicillin compounds,
There is no particular restriction as long as it exhibits synergistic antibacterial activity when combined with the cephalosporin compound or their pharmaceutically acceptable salts, and examples include known cephamycin compounds, such as latamoxef and flomoxef. , cefmetazole and cefotetan.

Specific examples of the cephamycin compounds include cefoxitin; 3-[[(7minocarbonyl)oxy]methyl]-7-medoxy8-
Oxo-7-[(2-thienylacetyl)aminoco-5
-thia-1-azabicyclo[4,2,0]octa-2-
ene-2-carboxylic acid], cefmetazole (cefme
tazole; 7-[[[(cyanomethyl)thiocoacetyl]amino]-7-medoxy3-[[(1-methyl-IH-tetrazol-5-yl)thio]methyl]
-8-oxo5-thia-1-7zabicic O[4,2,
O]oct-2-ene-2-carboxylic acid] and flomoxef [flomo-xef: (-)-(6R,7
R)-7-[2-[(difluoromethyl)thiocoacetamide]-3-1[1-(2-hydroxyethyl)-1H
-tetrazol-5-ylcothiomethyl]-7-medoxy8-orquin-5-oxa-1-azabicyclo[4
,2,0]oft-2-ene-2-carboxylic acid], and among them, cefoxitin is preferred.

Pharmaceutically acceptable salts of the above cephamycin compounds, penicillin compounds and cephalosporin compounds (excluding cephamycin compounds) include the cephamycin compounds, penicillin compounds and cephalosporin compounds. Means the customary non-toxic salts or solvates of phosphorous compounds. Such salts include, for example, metal salts with sodium, potassium, calcium, magnesium, aluminum, etc.; organic amine salts with N,N''-dibenzylethylenediamine, brocaine, etc.; for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, etc. , inorganic acid salts with perchloric acid, etc.; organic acid salts with acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, etc.;
Examples include sulfonic acid salts with methanesulfonic acid, isethionic acid, p-toluenesulfonic acid, etc.; amino acid salts with glutamic acid, aspartic acid, lysine, arginine, etc. Among them, metal salts, inorganic acid salts, and organic acid salts. Preferred examples of the solvate include hydrates, ethanolates, acetonates, propylene glycolates, and the like, with hydrates and propylene glycolates being preferred.

Next, a method for formulating the antibacterial agent of the present invention will be explained.

The antibacterial agent of the present invention contains, as its active ingredients, a cephamycin compound or a pharmaceutically acceptable salt thereof, a penicillin compound, a cephalosporin compound (excluding cephamycin compounds), and a pharmaceutically acceptable salt thereof. It can be produced by appropriately combining with one kind of compound selected from the group consisting of salts containing water.

When producing the antibacterial agent of the present invention, cephamycin compounds or their pharmaceutically acceptable salts, penicillin compounds, cephalosporin compounds (excluding cephamycin compounds), and their pharmaceutically acceptable salts are used. The mixing ratio (weight ratio) with a type of compound selected from the group consisting of can be changed freely,
Usually carried out within the range of 1:1 to 1:10, 1:1 to 1:
A range of 5 is preferred.

The antibacterial agent of the present invention can be used by mixing it with a solid or liquid excipient carrier known in the art and formulating it, similarly to known β-lactam antibiotics.

Pharmaceutical preparations include liquid preparations such as injections, syrups, and emulsions;
Examples include solid forms such as tablets, capsules, and granules; external preparations such as ointments and halved forms. These preparations may also contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants, etc., as necessary. Additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter,
Examples include ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.

The administration form of the antibacterial agent of the present invention includes parenteral administration, oral administration, or external administration, as in the case of ordinary β-lactam antibiotic preparations. Generally, administration by injection is preferred. In this case, the injection is mixed with the above-mentioned solid or liquid carrier additives and prepared by a conventional method. Furthermore, it also includes the case where it is dissolved in an appropriate vehicle such as sterilized distilled water, physiological saline, etc. immediately before use as an injection form.

The compound of the present invention can be used as an antibacterial agent, particularly in the treatment of human bacterial infections caused by Durham-positive bacteria, including methicillin-resistant Streptococcus aureus, methicillin-resistant Staphylococcus epidermidis, and the like. The dosage varies depending on the condition of the patient, such as age and gender, but in general, it is 5 to 5 times a day.
200mg/kg, preferably 10-100I100I
I1 is suitable, but it is not necessarily limited to this, and if necessary, it can be administered in divided doses 2 to 5 times a day.

Next, the effects of the antibacterial agent of the present invention will be shown and the usefulness of the present invention will be explained in detail.

The synergistic effect of antibacterial agents can be evaluated using common methods, such as the disk method,
fractional inhibitory concentration
(hereinafter abbreviated as FIC) coefficient and fractional effective dose (fr
It can be expressed by an active effective dose (hereinafter abbreviated as FED) coefficient.

Note that the FIC coefficient is an index indicating the enhancement of antibacterial activity when an antibacterial agent is used in combination, and the FED coefficient is an index indicating the enhancement of antibacterial activity in an infection prevention experiment.

1) By disk (test method) A predetermined amount of MRSA is smeared with a cotton swab onto a Mueller-Hinton agar plate containing 4% NaCl (Deifco Group, USA), and the test plate is straightened. A paper disk with a diameter of 8 mm containing 6Itg of a cephamycin compound or its pharmaceutically acceptable salt (hereinafter abbreviated as cephamycin), a penicillin compound, and a cephalosporin compound (however, excluding cephamycin compounds) and a kind of compound selected from the group consisting of salts thereof (hereinafter referred to as
Diameter 8I containing 100g of other antibacterial compounds
Place the paper disk of II11 on the test plate.
After culturing at 30°C for 18 hours at intervals of lIm,
The zone of inhibition formed around the disc containing other antimicrobial compounds is measured. If there is a synergistic effect between cephamycin and other antimicrobial compounds, the zone of inhibition around the disk containing the other antimicrobial compound will usually increase on the side of the disk containing the cephamycin. Therefore, the ratio of the size (radius) of the increased inhibition zone to the size (radius) of the inhibition zone in the opposite direction, which is not affected by cephamycin, is determined, and a value of 1.1 or more is considered to be synergistic. I judged it. Table 1 uses cefoxitin sodium, cefmetazole sodium, and flomoxef as cephamycins, and other antibacterial compounds include ampicillin sodium, piperacillin sodium, cephaloridine,
MRS with Cefazolin Sodium, Cefapirin Sodium, Cefamandole Sodium, Cefothiam Hydrochloride, Cefzonam and Cefoperazone Sodium
AB Shows the results of a synergistic effect test against the B85719 strain.

Table 1 MR5ABB57 of Cephamycin and other antibacterial compounds
Synergistic effect against 19 strains (results) When we investigated the synergistic effect of the combination of cephamycin and other antibacterial compounds against MRSA B85719 strain, we found that
Synergy was observed with ampicillin sodium, piperacillin sodium, cephalolidine, cefazolin sodium, cefapirin sodium, cefamandole sodium, cefotiam hydrochloride, cefzonam, and with any combination of cefoperazone sodium and cefoxitin sodium.

2) FIC, according to the method (test method) 4% NaC1-containing muller containing a predetermined amount of an antibacterial agent that is a combination of cephamycin and other antibacterial compounds in a predetermined ratio (1: 1012 to 1012: 1; weight ratio)・
Prepare Hinton agar (Deifco family, USA). MRSA
One platinum loopful (approximately 5 μQ) of each fraction prepared so that the final concentration was 10" cells/mQ was inoculated and incubated at 35°C.
After culturing for 8 hours, the minimum growth inhibitory concentration (hereinafter abbreviated as ?lTC) is measured.

(FIC coefficient calculation method) The FIC coefficient is calculated by the following formula. (Checker board method) B A: MIC of cephamycin alone B2 MIC of other antibacterial compounds alone C: MIC of cephamycin when used in combination: MIC of other antibacterial compounds when used in combination Usually, l-IC coefficient ≦0.5 indicates synergistic effect, 0.5 (FIC coefficient≦1.0
It has been determined that there is partial synergism.

Table 2 shows cefmetazole sodium and cefoperazone hydrochloride, cefoxitin sodium and cefociam hydrochloride, cefoxitin sodium and cefoperazone sodium, cefoxitin sodium and piperacillin sodium, cefoxitin sodium and cefoxitin sodium, and The results of a test of the synergistic effect of flomoxef and cefoperazone sodium on MR5A (Kikan 25 strain) using various combinations of dilution series are shown.

(Left below) Table 2 Synergistic effect of cephamycin and other antibacterial compounds on MR5A (25 planned strains) (Results) 25 MR5A strains (MIC for methicillin is 400μ
We investigated the synergistic effects of the combination of cephamycin and other antibacterial compounds against the antibacterial agents (e.g., gem A synergistic effect was observed for all strains in combination, flomoxef and cefoperazone sodium.

The results in Table 2 also show that in all cases of tested antibiotics there is a significant synergistic effect between cephamycin and other antibacterial compounds.

3FED, according to method (test method) Cefoxitin sodium and other antibacterial compounds are dissolved in sterile distilled water for injection in a predetermined ratio to prepare an injectable antibacterial agent. Suspend a predetermined amount of MR5A in 5% mucin solution and perform ICR
Strain male mice (4 weeks old, weight 19-21 g, n = 10
) was inoculated intraperitoneally with 0.5vrQ.

One hour after the inoculation, 0.2 Q of the injectable antibacterial agent was subcutaneously injected, and the dose required for 50% survival (hereinafter abbreviated as ED) was determined from the surviving mice after 5 days.

(Calculation method of FED coefficient) The FED coefficient is calculated by the following formula.

a: ED of cefoxitin alone, value b = ED of other antibacterial compounds, value C: ED of cefoxitin in combination, value d: ED of other antibacterial compounds in combination.

value Generally, an FED coefficient ≦0.5 was determined to be synergistic.

Table 3 shows the prescribed mixing ratio of cefoxitin sodium and cefoperazone sodium (weight ratio = 2:1 to 1:4).
MR5A in mice conducted using an antibacterial agent formulated in
The results of an infection prevention experiment for strain B85924 (6,9X 10'CFU/mouse) are shown.

Table 3: Synergistic effects of cefoxitin and another antibacterial agent (cefviramide) in infection prevention experiments (results) From the results in Table 3, the antibacterial action of cefoxitin sodium and cefoperazone sodium against mouse MR5A BB5924 strain In infection prevention experiments using the agent, a significant synergistic effect was observed at any predetermined mixing ratio.

The following examples show specific formulation examples of the present invention and explain the present invention in more detail.

Example 1 A sterile mixture consisting of 500 mg of cefotiam hydrochloride and 500 mg of cefoxitin sodium is placed in a sterile vial and sealed. At the time of use, this mixture is dissolved in physiological saline to form an injection.

Example 2 A sterile mixture consisting of 400 mg of cefoperazone sodium and 400 a+g of cefoxitin sodium was dissolved in 2 (1 m Q) of physiological saline, filtered through a 0.22 μl Millipore filter, and then placed in a glass bottle that had been sterilized in advance. Pack it, seal it, and use it as an injection.

Example 3 A sterile mixture consisting of 500 mg of cefapirin sodium and 500 g of cefoxitin sodium is placed in a sterile vial and sealed. At the time of use, this mixture is dissolved in physiological saline to form an injection.

Example 4 Ampicillin sodium 200m5. A mixture consisting of 200 mg of cefoxitin sodium was added to 201 mg of physiological saline.
The solution is dissolved in Ilα, filtered through a 0.22μ Millipore filter, and then packed into a previously sterilized glass bottle and sealed to give an injection.

Example 5 A sterile mixture consisting of 500 mg of cefapirin sodium and 500 a+g of cefoxitin sodium is placed in a sterile vial and sealed. At the time of use, this mixture is dissolved in physiological saline to form an injection.

Example 6 Cefotiam hydrochloride 500 mg and flomoxef 50
A sterile mixture consisting of 1 g of 0II is placed in a sterile vial and sealed. At the time of use, dissolve this mixture in saline;
As an injection.

Example 7 A mixture consisting of 400 mg of cefoperazone sodium and flomoxef 400a+g was added to 20 m of physiological saline.
After filtration with a 0.22μl Millipore filter, it was packed in a previously sterilized glass bottle and sealed.
As an injection.

Example 8 A sterile mixture consisting of 1 g of cefapirin sodium 500II and 500 mg of cefmetazole sodium is placed in a sterile vial and sealed. At the time of use, this mixture is dissolved in physiological saline to form an injection.

Example 9 A mixture consisting of 400 o+g of cefoperazone sodium and 400 mg of cefmetazole sodium was added to 2 ml of physiological saline.
After dissolving in 0taQ and filtering through a 0.22 μm Millipore filter, the solution is packed in a previously sterilized glass bottle and sealed to give an injection.

Example 10 A sterile mixture consisting of 500 mg of cefapirin sodium and 500 mg of cefmetazole sodium is placed in a sterile vial and sealed. At the time of use, this mixture is dissolved in physiological saline to form an injection.

Example 11 A mixture consisting of 225 mg of ampicillin sodium and 1 g of cefmetazole sodium 225 II was dissolved in physiological saline.
Dissolved in 0IDQ and filtered with 0.22μ Millipore filter.
After filtration, the solution is packed into a previously sterilized glass bottle and sealed to make an injection.

Example 12 A sterile mixture consisting of 900 Il 1 g of cefoperazone sodium and 900 mg of cefmetazole sodium is placed in a sterile vial and sealed. At the time of use, this mixture is dissolved in physiological saline to form an injection.

x Riji shy! The antibacterial agent according to the present invention is effective against MR, which is a pathogenic bacterium that causes intractable diseases.
Shows particularly excellent antibacterial activity against 5A.

Therefore, the present invention provides an antibacterial agent that is effective against pathogenic bacteria that are highly resistant to β-lactam agents.

Claims (11)

[Claims] (1) A type of compound selected from the group consisting of cefamycin compounds or their pharmaceutically acceptable salts, penicillin compounds, cephalosporin compounds (excluding cefamycin compounds), and their pharmaceutically acceptable salts. Antibacterial agent as an active ingredient. (2) The antibacterial agent according to claim 1, which contains a cefamycin compound or a pharmaceutically acceptable salt thereof and a penicillin compound or a pharmaceutically acceptable salt thereof as active ingredients. (3) The antibacterial agent according to claim 1, which contains a cephamycin compound or a pharmaceutically acceptable salt thereof and a cephalosporin compound (excluding cephamycin compounds) or a pharmaceutically acceptable salt thereof as an active ingredient. (4) The compound according to claim 2, wherein the penicillin compound is ampicillin or piperacillin. (5) The compound according to claim 2 or 4, wherein the penicillin compound is piperacillin. (6) The antibacterial agent according to claim 3, wherein the cephalosporin compound is cefoperazone, cefpiramide, cefatridine, cefotiam, cefapirin, or cefacrol. (7) The antibacterial agent according to claim 3 or 6, wherein the cephalosporin compound is cefoperazone, cefpiramide, cefatridine, cefapirin, or cefothiam. (8) The antibacterial agent according to any one of claims 1 to 3, wherein the cefamycin compound is cefoxitin, cefmetazole, or flomoxef. (9) The antibacterial agent according to any one of claims 1 to 3 or 8, wherein the cefamycin compound is cefoxitin. (10) A type of compound selected from the group consisting of cefamycin compounds or their pharmaceutically acceptable salts, penicillin compounds, cephalosporin compounds (excluding cephamycin compounds), and their pharmaceutically acceptable salts. Mixing ratio (weight ratio)
The antibacterial agent according to claim 1, wherein is from 1:1 to 1:10. (11) The antibacterial agent according to claim 10, wherein the mixing ratio is 1:1 to 1:5.