Description
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.
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).
Brand name
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.
General Description
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.
Pharmacokinetics
Cmax 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
Side effects
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.
Safety Profile
Moderately toxic by severalroutes. An experimental teratogen. Other experimentalreproductive effects. When heated to decomposition itemits toxic fumes of NOx and SOx.
Synthesis
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.
Drug interactions
Potentially hazardous interactions with other drugs
Possibly enhanced anticoagulant effect of coumarins.
Metabolism
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.
