JPS606617A - Antibacterial agent - Google Patents

Abstract

PURPOSE:To provide an antibacterial agent containing a specific pyridonecarboxylic acid drug and a beta-lactam antibiotic substance as active components. CONSTITUTION:The objective antibacterial agent contains (A) the compound of formula (R is H or methyl; R<1> is ethyl, 2-fluoroethyl or cyclopropyl; A is -CH=, -CF=, =N-, etc.) (e.g. norfloxacin), its acid addition salt or its hydrate and (B) a beta-lactam antibiotic substance (e.g. ampicillin, cephalexin, piperacillin, cefotaxime, cefoperazone, cefsulodin, etc.) as active components. The above components exhibit remarkable synergistic effect. There is no antagonistic effect to certain kind of pathogenic microorganisms in contrast to nalidixic acid, pipemidic acid, etc.

Description

Detailed Description of the Invention: '-+ +-R1 [In the formula, R is hydrogen or a methyl group, R1 is an ethyl group, 2
- A combination of a compound represented by a fluoroethyl group or a cycloflovyl group, or a di-c-CH, CHs-cH-CH, or an addition salt or hydrate thereof, and a β-lactam antibiotic. The present invention relates to an antibacterial composition containing the composition as an active ingredient.

In general, the combined effects of drugs have been known for a long time, and with regard to antibacterial agents, there are various effects such as synergistic effects, prevention of the appearance of heat-resistant 1', expansion of the antibacterial spectrum, reduction of side effects, and inhibition of drug inactivating enzymes. Senboku continues to be the goal.

However, when all drugs are used together, there are cases where they show synergistic or additive effects, and cases where they show antagonistic effects. . Furthermore, aminoglycoside drugs and macrolide drugs only exhibit additive effects.

The combination drugs that have been put into practical use are penicillin G and streptomycin (or kanaicin), but trimetrim and flufamethoxanol, which have attracted attention in recent years, or ampicillin and clapranic acid (or similar drugs) ). However, these methods face the following problems. That is, due to the increase in the number of internally resistant bacteria, the combination of Veniacillin G and Streptomycin is no longer meaningful except for subacute endocarditis. Additionally, excessive doses of Zulfa and trimethoprim combination drugs are avoided due to damage to blood-forming organs. Furthermore, even when ampicillin is used in combination with a β-lactamase inhibitor, the inhibition is fundamentally variable and the clinical effect is not stable.

Today, although various antibiotics are being developed one after another, they still meet the requirements for being a first-choice drug, that is, they have strong bactericidal properties. No drug has yet been found that satisfies all the conditions, such as high potency.

In the course of a series of antibacterial agent development research, the present inventors found that the above conditions were satisfied by a combination of pyridone carboxylic acid drugs such as nalidixic acid '1f-tit and β-lactam antibiotics. I have been thinking about this and have conducted a lot of basic research.

As a result, it was found that there was a significant synergistic effect with internal cutting. However, on the other hand, it has also been found that it exhibits antagonistic effects against certain pathogenic bacteria1-. Therefore, it was judged that it lacked practicality as a mixture. However, the present inventors conducted further intensive research and found that among pyridonecarboxylic acid-based drugs, the compound represented by the general formula (1), especially norfloxacin, was surprisingly effective against other pyridonecarboxylic acid-based drugs, such as nalidixic acid. It was discovered that this compound did not have an antagonistic effect on certain pathogenic bacteria, unlike pipemic acid and pipemidic acid, and this was the first time that the present inventors completed a practical combination drug.

Examples of the β-lactam antibiotic as a component of the composition of the present invention include ampicillin, cephalexin, cephalexin, cefoperazone, cefsulozin, and the like.

Examples of dosage forms include oral dosage forms such as tablets, capsules, suspensions, solutions, and syrups; external dosage forms such as ointments, solutions, and sprays; and injection forms.

The present invention will be explained in more detail with reference to experimental examples below.

Experimental example 1゜Measurement of synergistic effect in vitro A series of combinations of two drugs was prepared and investigated by the agar plate dilution chessboard method using the Japanese Society of Chemotherapy standard method [
Also. A two-fold θ dilution series of the drugs to be used in combination was prepared, and each concentration level was combined in a total pressure range and impregnated in Mueller-Hinton medium to prepare an agar plate. The test strain All Mueller-Hinton Broth was cultured at 37°C in one fume, and a 100-fold dilution thereof was inoculated onto an agar plate prepared previously using a whole micro planter.

After inoculation with the bacterial solution, culture was performed at 37°C for 20 hours, and sensitivity was determined by observing the presence or absence of colony growth on the agar. I-de? ,,,(¥,<,,). ? 186E To Rushoho Z.

Agents & Chemother, Volume 11,
225, 1977). Test results are in Tables 1-4
summarized in.

The following abbreviations were used in the table.

ABPC: Ampicillin PIPC: Viperacillin CEX: Cephalexin CTX: Cephalexin cpz: Cefoperazone CFS: Cefsulodine NFLX: Norfloxacin, 1-ethyl-6-fluoro-1,4-dihydro-4-oxy-7-(1-piperazinyl)quinoline 3-carvone Acid NA: nalidixic acid PPA: pipemidic acid DL The combined effect of Nio70xazine has been shown.

When nalidixic acid is used in combination with cephalexin, cephalexin, cefoverazone, and cefsulodin, it has an antagonistic effect on 2 of 6 strains, 6 of 122 strains, and 4 of 7.9 strains of 122 strains, respectively. It was done.

A combined effect against F. has been shown. Norfloxacin had an additive or synergistic effect on Zenrin for all bacterial species. Some strains showed antagonistic effects with nalidixic acid and pipemidic acid.

Table 1 Combination effect on Nis marsetus sevenans strain Table 1
Continued a): Number of stocks with FIC index <0.5 b): FI
C index jlka Q, i%<<; number of shares s of 0.75)
:Number of stocks with FIC index of 0.7F+<<;l d)
: Number of strains with FfC index of 2 Table 2 Table 2 of combination effect on B. aeruginosa strains Continued a): Number of strains with FIC index of <0.5 b): FI
Number of stocks with C index OJ<<0.76 e): FIC
Number of stocks with an index of 0.75 << 1 d): Number of stocks with an FIC index of 2 Table 3 Table 3 of combination effect on Acinetobacter 5 strains Continued): Number of stocks with an FIc index of <: 0.5 b):
Number of stocks with FIc index OyR<rio, 7s e):
FIC index is 0.75 (number of shares in Kui d): FI
Number of stocks with a C index of 2 (Table 4)
′(Concomitant effect table 3 continued)

Claims (1)

[Claims] [In the formula, R is hydrogen or a methyl group, R1 is an ethyl group, 2
-Fluoroethyl group or cyclopropyl group or -C
An antibacterial composition comprising a compound represented by -CM, c1rsn-CH,e] or an addition salt or hydrate thereof as an active ingredient of a β-lactam antibiotic. [In the formula, R is hydrogen or a methyl group 'k, R'' is an ethyl group,
2-fluoroethylene or cyclopropyl group, A is \
CHg, represents C+ or ζN/, and then A and R together represent 10-0-CH・-an-CH・Also Fi, :c-CH, CHkuCH-CH,] 2. The antibacterial composition according to claim 1, which comprises a compound represented by the above formula or an addition salt or hydrate thereof, an effective amount of a β-lactam antibiotic, and excipients necessary for formulation.