JPH02250829A - Antibacterial agent - Google Patents

Abstract

PURPOSE:To obtain an antibacterial agent exhibiting synergistic antibacterial action against various pathogenic bacteria, especially Gram-positive bacterium having cephem resistance containing imipenem and cephazolin or ceftizoxime. CONSTITUTION:The aimed antibacterial agent contains (A) imipenem expressed by formula I or salts of said compound allowable as a drug and (B) antibacterial substance selected from cephazolin expressed by formula II and ceftizoxime expressed by formula III or salts of said compounds allowable as drugs in a weight ratio of A:B=1:1-1:20, preferably 1:4-1:10. Dose of active ingredient is in a range of 5-200mg/kg for 1 day.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Application: This invention relates to a novel antibacterial agent, and more particularly to imipenem or its pharmaceutically acceptable salts and an antibacterial substance selected from cefazolin and ceftizoxime. or its pharmaceutically acceptable salts.

Imipenem, cefazolin and ceftizoxime in this invention are the compounds shown below, respectively.

H Cefazolin Ceftizoxime Conventional technology: In recent years, in the treatment of infectious diseases using cephem compounds,
The rate of clinical isolation of bacteria resistant to cephem compounds, especially so-called cephem-resistant bacteria in Gram bacteria such as Staphylococcus, has increased significantly, and this has become a therapeutic problem.
For example, cefmetazole (CMZ) and fosfomycin (FOM
), they act synergistically against the bacteria.
, vol. 5, p. 2683, 1985.

Problems to be solved by the invention: As mentioned above, the isolation rate of bacteria resistant to cephem compounds is increasing, and therefore there is a desire for the emergence of more effective and safer medicines against such resistant bacteria. It is rare.

Means for solving the problem: The inventors have conducted intensive research and found that the combination of imipenem and cefazolin and the combination of imipenem and cefdesixime are effective against various pathogenic bacteria (Gram-negative bacteria, Gram-positive bacteria, and various resistant bacteria). This invention was completed based on the new finding that the present invention exhibits a synergistic antibacterial effect against bacteria (such as bacteria), especially cephem-resistant Gram-positive bacteria (such as Staphylococcus aureus).

Pharmaceutically acceptable salts of imibenem, cefazolin and cefdesixime include, for example, alkali metal salts such as sodium salts and potassium salts, alkaline metal salts such as calcium salts, ammonium salts, ethanolamine salts, triethylamine salts, dicyclohexylamine salts. Salts with organic or inorganic bases such as acetates, triple oloacetates, lactates, maleates, fumarates, tartrates, citrates, methanesulfonates, hydrochlorides, sulfates, nitrates, phosphorus Examples include organic acids such as acid salts or non-am acid addition salts.

In the antibacterial agent of this invention, the mixing ratio of imipenem or its pharmaceutically acceptable salts and cefazolin or cefdesixime or their pharmaceutically acceptable salts is determined by the type of combination, the type of IP4 progenitor bacteria, and the disease. It depends on the degree, usually 1:1 to 1:20
(weight ratio), but generally it is 1
A ratio of :4 to 1:10 is preferable.

The antibacterial agents of the invention may be used, for example, in the form of semisolid or liquid preparations containing the active substances of the invention in admixture with organic or inorganic carriers or excipients suitable for parenteral administration. I can do it.

The active ingredient is usually mixed with a non-toxic, pharmaceutically acceptable carrier and used in a suitable dosage form, such as a suppository, solution, emulsion, or suspension. Carriers herein include water, dextrose, gum acacia, gelatin, mannitol, methylcellulose, polyethylene glycol, keratin, colloidal silica, urea and other substances suitable for use in preparing solid, semisolid, or liquid preparations. is a carrier,
In addition, auxiliaries, stabilizers, thickeners and coloring agents and flavoring agents may also be used; the antimicrobial agent may also be used as a preservative or Bacteriostatic agents can also be included. The amount of active ingredient contained in the antimicrobial agent is sufficient to exert the desired therapeutic effect in preventing or treating disease processes and conditions.

When this antibacterial agent is applied to humans, the dosage of the active ingredient of this invention, which is preferably administered by intravenous injection, subcutaneous injection, intramuscular injection, etc., is determined according to the age of each individual patient to be treated. Although it varies depending on conditions such as the severity of the disease and the severity of the disease, the daily dose of the active ingredient for humans is generally 5 to 2.
00 mg/kg can be administered for prevention or treatment.

[Test example Next, the effects of this invention will be explained using test examples.

(1) Test method Checker board method ('Today's antibiotics', p. 411,
(Refer to Hideyo Yamaguchi (Nanzando)) (a) Test compounds imipenem (abbreviated as IPM), cefazolin sodium (registered trademark: cefamedine, abbreviated as CEZ), cefdesixime sodium (registered trademark 22voserin, abbreviated as C2x) ( b) All strains used were Staphylococcus aureus (5taphylococcus aur@us).

In the table, MS3937 is a methicillin-sensitive bacteria, and the remaining bacteria have a minimum inhibitory concentration (MIC) of 6 for methicillin.
．． 2/al1 or higher resistant bacteria.

(c) Drug Sensitivity Measurement Method The minimum inhibitory concentration (MIC) was measured according to the standard method of the Japanese Society of Chemotherapy using sensitivity measurement broth (manufactured by Tsusui Co., Ltd.) and sensitivity disk medium N (manufactured by Tsui Co., Ltd.). The amount of inoculum is approximately 4 x 10' ce of 37°C overnight culture.
ll/ml! This 54 was inoculated with a stamp using a micro planter (manufactured by Sakuma Seisakusho Co., Ltd.).
The MIC was measured after culturing at 7°C for 18 hours.

BSG, Buff Art Sailine Quiz Gelatin (buffered 5alit+e withgal
(2) Using the test result checker board method, determine the MIC of the two drugs alone and the IllIc of the two drugs when used bilaterally, and calculate the Fractional Inhibitory Concentration Index (fractional inhibitory concentration index) using the following formula.
ncantration 1ndex.

(abbreviated as FIG index) was calculated. The results are shown in Tables 1 and 2.

! , a test for protective activity against systemic infection in mice.
The suspension was suspended in 5% mucin to a concentration of 10' CFυ/ml, and the suspension was inoculated intraperitoneally into mice.

One hour later, the diluted medicine sleeves were subcutaneously administered to 8 mice per group. When using CEZ and IPM together, the ratio is 4.
When using the 21 mixed liquid in combination with CMZ and FOM, it is divided into two parts:
The EDso was calculated from the survival rate 7 days after inoculation, and the fractional effective dose index (
fractional effective dose
1ndex.

The FED index (abbreviated as FED index) was calculated.

The results are shown in Table 3.

CFU: Colony forming unit (col
ony forming unit) Table Cefazolin Sodium 125 rI@
Imi Benem 30! ! @Dissolve the above in bacterial water (2-) to prepare an injection.

Inudo Fake Yuseftizoxime Sodium 300 ■ Imipenem 30a @ Aqueous solution containing lidocaine hydrochloride (0.5 w/v%) (411Q)
) to make an injection.

Claims (1)

[Claims] imipenem or a pharmaceutically acceptable salt thereof;
An antibacterial agent characterized by containing an antibacterial substance selected from cefazolin and ceftizoxime or a pharmaceutically acceptable salt thereof.