Aztreonam

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H334：Kann bei Einatmen Allergie, asthmaartige Symptome oder Atembeschwerden verursachen.

  H400：Sehr giftig für Wasserorganismen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P273：Freisetzung in die Umwelt vermeiden.

  P285：Bei unzureichender Belüftung Atemschutz tragen.

  P304+P341：BEI EINATMEN: Bei Atembeschwerden an die frische Luft bringen und in einer Position ruhigstellen, die das Atmen erleichtert

  P342+P311：Bei Symptomen der Atemwege: GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

  P391：Verschüttete Mengen aufnehmen.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Aztreonam Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R20/21/22:Gesundheitsschädlich beim Einatmen,Verschlucken und Berührung mit der Haut.
  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S22:Staub nicht einatmen.
  S24/25:Berührung mit den Augen und der Haut vermeiden.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.

• Beschreibung

  Aztreonam is the first member of the monobactam class of antibiotics to be introduced into the world market. It possesses high β-lactamase stability and moderately good activity against gram negative aerobes such as E. coli, S. marcescens, -9 Proteus Providencia, Salmonella, g. influenzae, E. gonorrhea, and &. pneumonia. While somewhat less potent against Pseudomonas aeruginosa, it is nonetheless one of the better β-lactams against this species. It has poor activity against gram positive organisms.

• Chemische Eigenschaften

  White Crystalline Powder

• Originator

  Squibb (USA)

• History

  Aztreonam was synthesized by the Squibb Institute for Medical Research in 1981 starting with l-threonine. The synthesis was based on findings about bacterial β-lactam compounds of a monocyclic nature . The β-lactam compounds, called monobactams, were isolated from Chromobacterium violaceum, Agrobacterium radiobacter, etc. Such monocyclic βlactams of bacterial origin had previously been found independently in 1981 by Takeda Chemicals Industries in the culture broths of Pseudomonas acidophila and P. mesoacidophila and named sulfazecin and isosulfazecin, respectively. Aztreonam was selected from among hundreds of derivatives as a candidate for clinical trials because of its unique antibacterial spectrum and strong activity. This antibiotic shows excellent activity against a variety of gram-negative aerobic bacteria but no activity against gram-positive bacteria or anaerobes. Its efficacy and safety are now being clinically evaluated.

• Verwenden

  Aztreonam is a synthetic β-lactam antibiotic of the monobactam class. It is effective against Gram-negative bacteria but inactive against Gram-positive bacteria. Its mechanism of action involves the inhibition of mucopeptide synthesis in the bacterial cell wall, thereby blocking peptidoglycan crosslinking. Aztreonam is resistant to hydrolysis by some β-lactamases, but is inactivated by extended-spectrum β-lactamases.

• Verwenden

  antiserotonin

• Verwenden

  The first totally synthetic monocyclic β-lactam antibiotic.

• Verwenden

  The first totally synthetic monocyclic ?lactam antibiotic

• Manufacturing Process

  This mixture was sterilized for 15 minutes at 121°C at 15 lbs/inch2 steam pressure prior to use. The fermentation flasks were incubated at 25°C for 40 to 45 hours on a of rotary shaker. A 250 liter batch of Agrobacterium radiobacter A.T.C.C. No. 31700 is fermented in a 100 gallon steel vessel with a media and operating conditions described below. Culture of Agrobacterium radiobacter grown out on agar slants, pH 7.3 consisted of yeast extract (1 g), beef extract (1 g), NZ amine A (2 g), glucose (10 g), agar (15 g) in 1000 ml distilled water. Loopful of surface growth from agar slant was used as the source of incolumn. Medium of oatmeal (20 g), tomato paste (20 g) tapped water to 1000 ml, pH 7, was sterilized for 15 min at 121°C at 15 lbs/inch2 steam pressure prior to use. 100 ml of the medium, containing incolumn is incubated at 25°C for about 24 hours on a rotary shaker. It was added to a mixture of yeast extract (5 g), glucose (10 g) in 1 L distilled water and incubated for about 42 hours at 25°C in 100 gallon stainless steel fermentation vessel.
  During incubation, the broth is agitated at 155 r.p.m. and aerated at rate of 10.0 cubic feet per minute. An antifoam agent (Ucon LB625, Union Carbide) was added as needed. The fermentation beer was adjusted to pH 4 with aqueous HCl and calls separated by centrifugation. The supernatante (200 L) was extracted with 40 L of 0.05 m cetyldimethylbenzyl ammonium chloride in dichloromethane and extract concentrated in vacuo to 5.5 L. The concentrate was then extracted with solution of 177 g of sodium thiocyanate in 2 L of water, adjusting the mixture of pH 4.35 with phosphoric acid. The aqueous extract was concentrated in vacuo to 465 ml and added to 1840 ml of methanol. Solids are filtrated yielded 194 g of crude solid product. It was dissolved and chromatographed on a 5x106.5 cm column of Sephadex G-10 three times and after concentrating in vacuo gave 3.5 g of crude antibiotic M53 (azetreonam) which was chromatographed at first on QAE Sephadex A- 25 (liner gradient, prepared from 2.5 L of water and 2.5 L of 0.25 M sodium nitrate). Then the residue (fractions 26-75) gave M53 (natrium salt) after evaporation. It was triturated with methanol and the souble fraction, 0.40 g was chromatographed on a 2.5x20 cm column of Diaion HP20AG, eluting at 2 ml per minute with water and collecting 20 ml fractions. Fractions 26-75 gave 51.9 mg of antibiotic M53 (sodium salt).

• Trademarks

  Azactam (Bristol-Myers Squibb);PRIMBACTAM.

• Therapeutic Function

  Antibiotic

• Antimicrobial activity

  Concentrations (mg/L) inhibiting 50% of other organisms are: Aeromonas spp., 0.1;Acinetobacter spp., 16; Mor. catarrhalis, 0.1; Burkholderia cepacia, 2; and Yersinia spp., 0.1. Synergy has been shown with gentamicin, tobramycin and amikacin against 52–89% of strains of Ps. aeruginosa and gentamicin-resistant Gram-negative bacteria.

• Allgemeine Beschreibung

  Azactam (aztreonam for injection, intravenous or intramascular)contains the active ingredient aztreonam, which is amember of the monobactam class of antibiotics. A true antibiotic,aztreonam was originally isolated from cultures ofthe bacterium Chromobacterium violaceum. Now, the antibioticis prepared by total synthesis. Monobactams possessa unique monocyclic β-lactam nucleus, and are structurallyunlike other β-lactams like the penicillins, cephalosporins,carbapenems, and cephamycins. The β-lactam arrangementof aztreonam is unique, possessing an N-sulfonic acid functionality.This group activates the β-lactam ring towardattack. The side chain (3-position) aminothiazolyl oximemoiety and the 4-methyl group specify the antibacterialspectrum and β-lactamase resistance.
  The mechanism of action of aztreonam is essentially identicalto that of other β-lactam antibiotics. The action of aztreonamis inhibition of cell wall biosynthesis resulting from ahigh affinity of the antibiotic for penicillin binding protein 3(PBP-3). Unlike other β-lactam antibiotics, aztreonam doesnot induce bacterial synthesis of β-lactamases. The structureof aztreonam confers resistance to hydrolysis by penicillinasesand cephalosporinases synthesized by most Gramnegativeand Gram-positive pathogens. Because of theseproperties, aztreonam is typically active against Gram-negativeaerobic microorganisms that resist antibiotics hydrolyzedby -lactamases. Aztreonam is active against strains that aremultiply-resistant to antibiotics such as cephalosporins, penicillins,and aminoglycosides. The antibacterial activity ismaintained over a broad pH range (6–8) in vitro, as well as inthe presence of human serum and under anaerobic conditions.
  Aztreonam for injection is indicated for the treatment ofinfections caused by susceptible Gram-negative microorganism,such as urinary tract infections (complicated and uncomplicated),including pyelonephritis and cystitis(initial and recurrent) caused by E. coli, K. pneumoniae, P.mirabilis, P. aeruginosa, E. cloacae, K. oxytoca, Citrobactersp., and S. marcescens. Aztreonam is also indicated for lowerrespiratory tract infections, including pneumonia and bronchitiscaused by E. coli, K. pneumoniae, P. aeruginosa, H.influenzae, P. mirabilis, S. marcescens, and Enterobacterspecies. Aztreonam is also indicated for septicemia causedby E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, S.marcescens, and Enterobacter spp. Other infections respondingto aztreonam include skin and skin structure infections,including those associated with postoperative wounds andulcers and burns. These may be caused by E. coli, P.mirabilis, S. marcescens, Enterobacter species, P. aeruginosa,K. pneumoniae, and Citrobacter species. Intra-abdominalinfections, including peritonitis caused by E. coli,Klebsiella species including K. pneumoniae, Enterobacterspecies including E. cloacae, P. aeruginosa, Citrobacterspecies including C. freundii, and Serratia species includingS. marcescens. Some gynecologic infections, including endometritisand pelvic cellulitis caused by E. coli, K. pneumoniae,Enterobacter species including E. cloacae, and P.mirabilis also respond to aztreonam.

• Biochem/physiol Actions

  Aztreonam is a monobactam antibiotic used primarily to treat gram-negative bacterial infections. It is an older compound being re-examined as a therapeutic agent because of increasing carbapenem resistance in aerobic Gram-negative bacilli and because aztreonam is stable to Ambler class B metallo-β-lactamases. It is used alone or more commonly in combination with β-lactamase inhibitors such as avibactim.

• Pharmakokinetik

  C_max 1 g intravenous: 90 mg/L end infusion
  1 g intramuscular: 46 mg/L after 1 h
  Plasma half-life: 1.7 h
  Volume of distribution: 0.18 L/kg
  Plasma protein binding: 56%
  Absorption and distribution
  Oral bioavailability is less than 1%. Peak concentrations above the median MIC for most Gram-negative pathogens are achieved in most tissues and body fluids after 1 g intramuscular or intravenous doses.
  Metabolism and excretion
  It is not extensively metabolized, the most prominent product, resulting from opening the β-lactam ring, being scarcely detectable in the serum and accounting for about 6% of the dose in the urine and 3% in the feces.
  It is predominantly eliminated in the urine, where 58–72% appears within 8 h. Less than 12% is eliminated unchanged in the feces, suggesting low biliary excretion.

• Clinical Use

  Urinary tract infections, including pyelonephritis and cystitis
  Lower respiratory tract infections, including pneumonia and bronchitis
  caused by Gram-negative bacilli
  Septicemia
  Skin and skin structure infections, including postoperative wounds, ulcers
  and burns
  Intra-abdominal infections, including peritonitis
  Gynecological infections, including endometritis and pelvic cellulitis

• Nebenwirkungen

  Local reactions occasionally occur at the injection site. Systemic reactions include diarrhea, nausea and/or vomiting and rash (1–1.3%). Neutropenia was seen in 11.3% of the pediatric patients younger than 2 years. Pseudomembranous colitis has been reported.
  There are no reactions in patients with immunoglobulin E (IgE) antibodies to benzylpenicillin or penicillin moieties. It is rarely cross-reactive with other β-lactam antibiotics and is weakly immunogenic.

• Sicherheitsprofil

  Moderately toxic by severalroutes. An experimental teratogen. Other experimentalreproductive effects. When heated to decomposition itemits toxic fumes of NOx and SOx.

• Synthese

  Aztreonam, (Z)-2[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]cabamoyl]methylen]amino]oxy]-2-methylpropionoic acid (32.1.4.9), is synthesized from tert-butyloxycarbonylthreonine, which is reacted with O-benzylhydroxylamine in the presence of dicyclohexylcarbodimide and 1-hydroxybenzotriazole, to form the benzyl hydroxamide derivative (32.1.4.1). This product undergoes a reaction with triphenylphosphine and ethyl azodicarboxylate, which results in the cyclodehydration of the product to (3S-trans)-N-benzyloxy-3-tert-butyloxycarbonylamino-4-methyl-azetidinone (32.1.4.2). Debenzylating this by hydrogen reduction using a palladium on carbon catalyst forms (3S-trans)-N-hydroxy-3-tertbutyloxycarbonyl-amino-4-methyl-azetidinone (32.1.4.3). The hydroxyl group in this compound is removed by reducing it with titanium trichloride, which forms azetidinone (32.1.4.4). Removing the tert-butyloxycarbonyl protection using trifluoroacetic acid and subsequent acylation of the resulting product with the benzyl chloroformate gives (3S-trans)-benzyloxycarbonylamino-4-methylazetidinone (32.1.4.5). Sulfonating this product with a mixture of sulfur trioxide and dimethylformamide gives the corresponding N-sulfonic acid. Turning the resulting Nsulfonic acid into a potassium salt by reacting it with potassium hydrophosphate, followed by replacing the potassium cation with a tetrabutylammonium cation by reacting it with tetrabutylammonium sulfate gives the product (32.1.4.6). Reducing this with hydrogen using a palladium on carbon catalyst gives 3-amino-4-methyl-monobactamic acid (32.1.4.7). Acylating this with (Z) 2-amino-|á-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino] 4-thiazoleacetic acid in the presence of dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole gives the diphenylmethyl ester of the desired aztreonam (32.1.4.8), which is hydrolyzed to aztreonam (32.1.4.9) using trifluoroacetic acid.

  

  
  It is believed that the methyl group at position 4 increases the stability of the beta-lactam ring with respect to most beta-lactamases, and at the same time it does not induce formation of beta-lactamase as cephalosporins and imipenems do.

• Veterinary Drugs and Treatments

  Aztreonam is a monobactam antibiotic that may be considered for use in small animals for treating serious infections caused by a wide variety of aerobic and facultative gram-negative bacteria, including strains of Citrobacter, Enterobacter, E. coli, Klebsiella, Proteus, Pseudomonas and Serratia. The drug exhibits good penetration into most tissues and low toxic potential and may be of benefit in treating infections when an aminoglycoside or a fluoroquinolone are either ineffective or are relatively contraindicated. Any consideration for using aztreonam must be tempered with the knowledge that little clinical experience or research findings have been published with regard to target species.
  Aztreonam has also been used to treat pet fish (koi) infected with Aeromonas salmonocida.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs Possibly enhanced anticoagulant effect of coumarins.

• Stoffwechsel

  Aztreonam is not extensively metabolised. The principal metabolite, SQ-26992, is inactive and is formed by opening of the beta-lactam ring; it has a much longer half-life than the parent compound. Aztreonam is excreted as unchanged drug with only small quantities of metabolites, mainly in the urine, by renal tubular secretion and glomerular filtration. Only small amounts of unchanged drug and metabolites are excreted in the faeces.

Aztreonam Upstream-Materialien And Downstream Produkte

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