JPH0347122A - Antimicrobial composition - Google Patents

Abstract

PURPOSE:To obtain an antimicrobial agent, containing penicillin-based or cephalosporin-based compounds and carbapenem-based compounds as active ingredients and effective against pathogenic germs capable of exhibiting a high level of resistance to beta-lactam agents. CONSTITUTION:The objective substance obtained by mixing one compound selected from the group consisting of penicillin-based compounds (e.g. ampicillin), cephalosporin-based compounds (cefoperazone) and salts thereof and a carbapenem compound (e.g. imipenem) or salts thereof at (1:1)-(600:1) weight ratio as active ingredients, further suitably blending normally used additives for formulation therewith and preparing a pharmaceutical according to a conventional method. The above-substance can be prepared in the form of solutions, such as injection, syrup or emulsion, solid agents, such as tablet, capsule or granule, and drugs for external use, such as ointment or suppository. The resultant pharmaceutical is especially useful for treating microbism caused by Gram- positive bacteria including meticilin-resistant Staphylococcus aureus, meticilin- resistant Staphylococcus epidermis, etc., as phlogogenic germs.

Description

[Detailed Description of the Invention] Good presentation example! The present invention relates to novel antibacterial agents. More specifically, an antibacterial agent containing a compound selected from the group consisting of a penicillin compound, a cephalosporin compound, and their pharmaceutically acceptable salts, and a carbapenem compound or a pharmaceutically acceptable salt thereof as an active ingredient. It is related to.

A large number of antibiotics have been used to treat infections caused by various pathogenic bacteria, but pathogenic bacteria have a tendency to gradually become resistant to antibiotics, and these antibiotics alone are not effective. It is generally known that there are diseases such as Ha that do not exhibit sufficient antibacterial activity.

For example, Staphylococcus aureus (S, aureus)
us), Staphylococcus evidermizois (Kingu idermid country), Enterococcus faecalis (
Durham-positive bacteria such as E, ra6calis); Citrobacter freundii (C, freundii), Escherichia coli (1:, coli), Klebsiella
Pneumoniae (L. eumoniae), Proteus
Durham-negative bacteria such as S. vulgaris (h7) and Serratia marcescens (S. aarcescens);
Pseudomonas cepacia (4), Pseudomonas maltohilia (Ps, maltohilia), Acinetobacter calcoaceticus (A, calcoa)
For the purpose of increasing antibacterial activity against pathogenic bacteria such as non-glucose-fermenting Durham-negative bacilli such as C. cetfcus ), combinations of a plurality of antibacterial agents have 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 strong antibacterial activity, this has become a major clinical problem.

Carbapenem compounds are known to exhibit a broad antibacterial spectrum and strong antibacterial activity. As a known carbapenem compound, imipenem (Japanese Patent Publication No. 61-6081
Publication No. 6), SM-7338 (Japanese Patent Application Laid-open No. 60-104
No. 88), RS-533 (Japanese Unexamined Patent Publication No. 59-5128)
Publication No. 6), etc. However, the above-mentioned known carbapenem compounds alone do not have sufficient antibacterial activity against MRSA, and although imipenem is frequently used to treat MRSA infections, β-lactam agents have a high It has not shown sufficient therapeutic effect against resistant MRSA.

All of the above prior art describes normal Durham-positive bacteria,
References are limited to tests of Durham-negative bacteria and non-glucose-fermenting Durham-negative bacilli.

No antibacterial evaluation has been conducted against MRSA, and there are limitations to the treatment of MRSA infection with a single agent. Examples of combinations of two or more drugs include, for example, aminoglycosides and β-lactams, or fosfomycin and β-lactams. Although attempts have been made to use lactam drugs in combination, the effects of such combination cannot be said to be satisfactory.

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.

The present inventors have investigated MRS, which 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 a carbapenem compound or a pharmaceutically acceptable salt thereof, a remarkable synergistic antibacterial effect against MRSA has been observed, and it has been shown to be effective against penicillin antibiotics or cephalosporin antibiotics. Substances alone have little antibacterial effect, or
The present invention was completed based on new knowledge that it is possible to sufficiently enhance antibacterial activity against MRSA, which exhibits only a very weak antibacterial effect.

The present invention provides an antibacterial agent containing as active ingredients a compound selected from the group consisting of penicillin compounds, cephalosporin compounds, and their pharmaceutically acceptable salts, and a carbapenem compound or their pharmaceutically acceptable salts. Regarding. Moreover, an antibacterial agent using a combination of a carbapenem 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 used in the present invention are not particularly limited as long as they exhibit synergistic antibacterial activity when combined with carbapenem compounds or their pharmaceutically acceptable salts. , known penicillin compounds and cephalosporin compounds.

Specific examples of the penicillin compounds include penicillin G, ampicillin, amoxicillin, mecillinum, bivmecillinum, carbenicillin, carbenicillin,
Examples include calindacillin, sulpenicillin, tarambicillin, bacanbicillin, 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, cephaloridine, cefsulodine, cefothiam, ceforanid, ceftezole, cefoxitin, latamoxef, flomoxef, cefmetazole, cefazolin, cefotetane, ceraviramide, cephaloglycine, cephalexin, cefadroxil, cefuroxazine, cefradine, cefaclor,
Examples include cefpiramide. Suitable examples include cefpiramide, cefpiramide, cefazolin, cefapirin, cefothiam, flomoxef, cefaclor, etc.
Among them, cefatridine, cefapirin, cefothiam,
Cefpiramide and cefpiramide are preferred.

The carbapenem compound is not particularly limited as long as it exhibits synergistic antibacterial activity when combined with the penicillin compound, the cephalosporin compound, or their pharmaceutically acceptable salts, and any known known compound can be used. Examples include carbapenem compounds.

Specific examples of the carbapenem compounds include imipenem (1-i panes * (5R+ 6 S +
8 R)-3-([2-(formimidoylamino)
ethyl)thio]-6-(1-hydroxyethyl)-7-
Buta-2- to oxo-1-azabicyclo(3,2,0)
ene-2-carboxylic acid l hydrate], SM-7338;
(4R, 5S, 6S, 8R, 2″S, 4' 5)-6
-(1-hydroxyethyl)-4-methyl-3-[2-
(dimethylaminocarbonyl)pyrrolidin-4-ylthio]-7-oxo-1-azabicyclo[3,2,0]but-2-ene-2-carboxylic acid and RS-533
; (5R,6S,8R,4' 5)-3-(1-acetimidoylpyrrolidin-4-ylthio]-6-(1-
hydroxyethyl)-7-oxo-1-azabicyclo(
Among them, imipenem is preferred.

Pharmaceutically acceptable salts of carbapenem compounds, penicillin compounds and cephalosporin compounds include conventional non-toxic salts or solvates of the carbapenem compounds, penicillin compounds and cephalosporin compounds. means something Such salts include, for example, metal salts with sodium, potassium, calcium, magnesium, aluminum, etc.; organic amine salts with N,N'-dibenzylethylenediamine, propylene, etc.; for example, hydrochloric acid, hydrobromic acid, nitric acid. , sulfuric acid, 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. preferable.

Examples of the solvate include hydrates, ethanolates,
Examples include acetone hydrate and propylene glycol hydrate, with hydrates and propylene glycol hydrate 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, one compound selected from the group consisting of penicillin compounds, cephalosporin compounds, and their pharmaceutically acceptable salts, and carbapenem compounds or their pharmaceutically acceptable salts. It can be manufactured by appropriately combining with.

When producing the antibacterial agent of the present invention, a compound selected from the group consisting of penicillin compounds, cephalosporin compounds, and their pharmaceutically acceptable salts is combined with a carbapenem compound or its pharmaceutically acceptable salts. The mixing ratio (weight ratio) can be freely changed, but is usually in the range of 1:1 to 600:1, preferably in the range of 1:1 to 200:1.

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 preparations such as tablets, capsules, and granules; external preparations such as ointments and suppositories. In addition, these preparations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants, etc. as necessary. Distilled water for injection, Ringer's solution, glucose.

Sugar syrup, gelatin, edible oil, cocoa butter.

Examples include ethylene glycol, sucrose, corn starch, magnesium stearate, and talc. It is generally known that carbapenem compounds are metabolized by dehydropeptidases (E, C, 3, 4, 13, 11), which are in vivo enzymes.1 For example, imibenem, R5-533, which is metabolized by in vivo enzymes. When using carbapenems such as carbapenems as active ingredients of the present antibacterial agent, dehydropeptidase inhibitors that selectively inhibit this metabolism, such as cilastatin [C11astatin;
7-(R-amino-2-carboxyethylthio)-2
-(2,2-dimethylcyclopropanecarboxamide)
-2-sodium heptenoate] and the like can be appropriately included in the antibacterial agent of the present invention. Further, the dehydropeptidase inhibitor can be administered separately at the time of administration of the antibacterial agent of the present invention without being mixed with the antibacterial agent.

When using a carbapenem compound that does not undergo the above-mentioned metabolism, it is not necessary to specifically include the inhibitor.

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 compounds of the present invention can be used as antibacterial agents, particularly in the treatment of human bacterial infections caused by Durham-positive bacteria, including methicillin-resistant Staphylococcus 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 2 doses per day.
00 mg/kg, preferably 10 to 10 mg/kg, but is not necessarily limited to this, and can also be administered in divided doses 2 to 5 times a day if necessary.

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.

l) Disk size ≦ffl (Test method) A predetermined amount of MRSA is smeared onto a Mueller-Hinton agar (American Difco type) plate with a cotton swab, and a test plate is prepared. A paper disk with a diameter of 8M containing 6/4 of a carbapenem compound or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as carbapenem), a penicillin compound, a cephalosporin compound, and a salt thereof. 8-diameter paper discs containing 100 ug of one type of compound (hereinafter referred to as "other antibacterial compound") were placed on a test plate at a distance of 17 am.

After 18 hours of incubation at 30° C., the zone of inhibition formed around the disks containing other antimicrobial compounds is measured.

When there is a synergistic effect between a carbapenem and another antimicrobial compound, there is usually an increase in the zone of inhibition around the disk containing the other antimicrobial compound on the side of the disk containing the carbapenem. 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 carbapenems, is calculated, and the value is 1.
．． 1 or more, it was determined that there was a synergistic effect. Table 1 shows imipenem, SM-7338 and R3- as carbapenems.
533 and other antibacterial compounds such as penicillin G,
MRSA B85 using ampicillin, carbenicillin, piperacillin, cephalolidine, cefazolin, cefapirin, cefamandole, cefothiam, cefaclor, cefadroxil, cefzonam, cefoperazone, cefubimizole, cefpiramide, cefoxitin
The results of a synergistic effect test against the 918 strain are shown.

Table 1 MR3AB of carbapenems and other antibacterial compounds
Synergistic action against strain B5918 Ampicillin 1.2 1.2
1.2 Carbenicillin 1.1
1.0 1.0 Piperacillin 1.
5 1.4 1.5 Cephaloridine
1.2 1.2 0.6 Cefazoline 1.5 1.3 1.
5 Cefavirin 1.3 1.3
1.3 Sefa Mandor 1.2
1.7 1.2 Cefuothium 1.
6 1.6 1.5 Cefaclor
1.4 1.3 1.5 Cephadroxil 1.3 1.0 1.
0 Cefzonam 1.6 1.0
1.4 Cefoberazone 2.1
2.3 2.1 Cefubimizole 3.
6 1.3 2.7 Cefpiramide
1.4 1.4 1.5 Cefoxitin 1.1 1.0 1
．． 1 (Results) When we investigated the synergistic effect of the combination of carbapenems and other antibacterial compounds against MRSA B85918 strain, we found that
Synergism was seen with penicillin G, ampicillin, piperacillin, cefazolin, cefapirin, cefamandole, cefothiam, cefaclor, cefpiramide, cefazolin, and in combination with both cefpiramide and carbapenems.

Evaluation based on the 2FIC method (test method) Mueller-Hinton agar containing a predetermined amount of an antibacterial agent that is a combination of carbapenem and other antibacterial compounds in a predetermined ratio (1: 1012 to 1012: 1, weight ratio). ). One platinum loop (approximately 5 μQ) of MRSA prepared so that the final concentration of each fraction was 10 cells/sQ was inoculated, and after culturing at 30°C for 18 hours, the minimum growth inhibitory concentration (hereinafter abbreviated as MIC) was inoculated. ) to measure.

(FIC coefficient calculation method) The FIC coefficient is calculated by the following formula. (Checker board method) A: MIC of carbabenem alone B: MIC of other antibacterial compounds alone C: MIC of carbapenem when used in combination; MIC of other antibacterial compounds when used in combination Usually, FIC coefficient ≦0
．． 5 is determined to be a synergistic effect, and 0.5<FIC coefficient≦1.0 is determined to be a partial synergistic effect.

Table 2 shows SM-7338 and cefotiam hydrochloride, imipenem and cefotiam hydrochloride, imibenem and cefpiramide sodium, imipenem and piperacillin sodium,
Various combinations of dilution series of imipenem and cefatridine propylene glycol, imibenem and cefapirin sodium, and imipenem and cefapirin sodium were used.
The test results of synergy against MR5A (Kikan 25 strain) are shown.

(Left below) Table 2 MRSA of carbapenems and other antibacterial compounds (
Synergistic effect (results) on MR5A25 strain (MIC for methicillin is 400μ)
When we investigated the synergistic effect of the combination of carbapenems and other antibacterial compounds on the antibacterial effects (more than A synergistic effect was observed in 24 strains in combination.

Furthermore, from the results in Table 2, significant synergistic effects with carbapenems are seen in all cases of the tested antibiotics.

3FED Method (Test Method) An antibacterial agent for injection is prepared by dissolving imibenem and other antibacterial compounds mixed with cilastatin in a predetermined amount in a predetermined ratio in sterile distilled water for injection. A predetermined amount of MRSA was suspended in 5% mucin solution, and a male ICR mouse (4 weeks old, body weight 19-21
g%n=1o) was inoculated intraperitoneally with 0.5aQ. Inoculation 1
After an hour, 0.2 mm of the injectable antibacterial agent was subcutaneously injected, and the dose required for 50% survival (hereinafter abbreviated as ED) was determined from the low number of surviving mice after 5 days.

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

a: ED of imipenem alone, value b: ED of other antibacterial compounds, value C; ED of imipenem when used together, value d: ED of other antibacterial compounds when used together.

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

Tables 3-1 and 3-2 show that imipenem (a mixture of cilastatin and imibenem in the same weight) and cefotiam hydrochloride are mixed at a predetermined mixing ratio (weight ratio = 1:5 to 1:6).
The test was carried out using the antibacterial agent formulated in 00). Mouse MR
SA B85918 strain (2,7X10”CFU/mouse) and MRSA pMS 520/Smlth strain (
1,4×10′CFtl/mouse).

Table 3-2 Table 3-1 Imipenem and other antibacterial agents (cefotiam)
Synergistic effect in infection prevention experiments (see margin below) (Results) From the results in Tables 3-1 and 3-2, MR of mice
SA B85918 strain and MR5Ap M S 52
In an infection prevention experiment using an antibacterial agent containing imipenem and cefotiam against the 0/Sm1th strain, 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 Cefotiam hydrochloride 475 mg, imibenem 25I 1 g
A sterile mixture consisting of 25 mg of Cilastatin and Cilastatin 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 Cefpiramide sodium 400mg, imipenem 80m
A sterile mixture consisting of 80 mg of cilastatin and 80 mg of cilastatin is dissolved in 20 s Q of physiological saline, filtered through a 0.22 µm Millipore filter, and sealed in a previously sterilized glass bottle to prepare an injection.

Example 3 Cefapirin sodium 500mg, imibenem 50f
A sterile mixture consisting of fig and 50 mg of cilastatin 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 225 mg, imipenem 25+
A mixture of 25 mg of cilastatin and 25 mg of cilastatin is dissolved in 20 s Q of physiological saline, filtered through a 0.22 μm Millipore filter, and then sealed in a glass bottle that has been sterilized in advance to prepare an injection.

Example 5 Cefapirin sodium 900II 1 g, Imibenem 1
A sterile mixture consisting of 00 g and 100 g of cilastatin 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 475+*g and SM-7338
Place 25 μg of the sterile mixture into a sterile vial and seal. At the time of use, this mixture is dissolved in physiological saline to form an injection.

Example 7 Cefpiramide sodium 4005g and SM-733
A mixture consisting of 880 mg is dissolved in 20 ra Q of physiological saline, filtered through a 0.22 μm Millipore filter, and then packed in a glass bottle that has been sterilized in advance and sealed to give an injection.

Example 8 Cefapirin Sodium 500B, SM-733
A sterile mixture consisting of 850 mg and 50 mg of cilastatin 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 Cefpiramide sodium 400 mg, RS-5338
A mixture consisting of 0 mg of cilastatin and 80 mg of cilastatin is dissolved in 20 ta Q of physiological saline, filtered through a 0.22 μI Millipore filter, and then sealed in a glass bottle that has been sterilized in advance to prepare an injection.

Example 1O Cefapirin Sodium 500 mg, RS-533
A sterile mixture consisting of 501 g and 50 mg of cilastatin 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 Ampicillin sodium 225 mg, RS-53
A mixture consisting of 325 mg of cilastatin and 25 mg of cilastatin is dissolved in 20 am of physiological saline, filtered through a 0.22 μm Millipore filter, and then sealed in a glass bottle that has been sterilized in advance to prepare an injection.

Example 12 Cefapirin sodium 900 mg, RS-53
A sterile mixture consisting of 3100 mg and Cilastatin 100B 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 change liquid! 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 3A.

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) An antibacterial agent containing as active ingredients a compound selected from the group consisting of penicillin compounds, cephalosporin compounds, and their pharmaceutically acceptable salts, and a carbapenem compound or their pharmaceutically acceptable salts. (2) The antibacterial agent according to claim 1, which contains a penicillin compound or a pharmaceutically acceptable salt thereof and a carbapenem compound or a pharmaceutically acceptable salt thereof as active ingredients. (3) The antibacterial agent according to claim 1, which contains a cephalosporin compound or a pharmaceutically acceptable salt thereof and a carbapenem compound or a pharmaceutically acceptable salt thereof as active ingredients. (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, cefuotiam, cefapirin, flomoxef, 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 carbapenem compound is imipenem, SM-73
3. The antibacterial agent according to any one of claims 1 to 3, which is RS-533 or RS-533. (9) The antibacterial agent according to any one of claims 1 to 3 or 8, wherein the carbapenem compound is imipenem. (10) Mixing ratio of one compound selected from the group consisting of penicillin compounds, cephalosporin compounds, and their pharmaceutically acceptable salts and carbapenem compounds or their pharmaceutically acceptable salts (
The antibacterial agent according to claim 1, wherein the weight ratio) is 1:1 to 600:1. (11) The antibacterial agent according to claim 10, wherein the mixing ratio is 1:1 to 200:1.