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At least 19 recordsLinked to original sources
PubMed1986

Enhanced bactericidal action of mouse macrophages by subinhibitory concentrations of monobactams.

The effects of sub-minimum inhibitory concentrations (sub-MICs) of monobactams (aztreonam and AMA1080) on the host-parasite relationship were studied in an in vitro system using an established mouse macrophage cell line. The presence of sub-MICs aztreonam or AMA1080 enhanced significantly the macrophage bactericidal activity against Escherichia coli S615, Pseudomonas aeruginosa K1, Klebsiella pneumoniae 12 and Serratia marcescens US5. Even four times the MIC of monobactams had no direct effect on macrophages. A synergistic bactericidal effect against E. coli was also observed with sub-MICs of monobactams and lysozyme or macrophage lysate. Furthermore, E. coli treated with sub-MICs of aztreonam was more sensitive to two bactericidal macrophage products, hydrogen peroxide and superoxide anion. These results suggest that the effects of monobactams are exerted on bacteria and not on macrophages; sub-inhibitory levels of monobactams may alter the bacterial cell rendering it more susceptible to bactericidal substances released by macrophages, thus favouring phagocytosis and killing by macrophages. Electron microscopic observations support these conclusions. This study provides evidence that monobactams at sub-MICs may work in partnership with host defenses against Gram-negative bacterial infections.

Animals↗
PubMed1991

Preferential hydrolysis of cis configuration compounds at the 3,4 position of monobactams by beta-lactamase from Morganella morganii.

Carumonam and BO-1166 (cis configuration) were inactivated by beta-lactamase of Morganella morganii more rapidly than were aztreonam and BO-1165 (trans configuration), as demonstrated by spectrophotometric analysis and microbiological assay. An active enzyme was recovered more rapidly from the inactivated enzyme-monobactam complex derived from the cis form of monobactams than from the complex derived from the trans form of monobactams. This result suggests that the configuration at the 3,4 position on the azetidinone ring of monobactams, together with the chemical structure of the side chains attached to the azetidinone ring, may play an important role in the stability of monobactams to the beta-lactamase of M. morganii.

Aztreonam↗
PubMed1988

[Antibacterial activities of monobactams against fresh clinical isolates].

Antibacterial activities of monobactam antibiotics (carumonam (CRMN) and aztreonam (AZT] against Gram-negative bacilli isolated from inpatients in the latter half of 1987 were investigated using penicillin (PC: piperacillin (PIPC], cephems (CEPs: ceftazidime (CAZ), cefotaxime (CTX), latamoxef (LMOX), cefsulodin (CFS], carbapenem (imipenem (IPM] and pyridonecarboxylic acids (norfloxacin (NFLX) and ofloxacin (OFLX] as reference antibiotics. A total of 400 strains of 13 species, i.e. Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Pseudomonas aeruginosa and Haemophilus influenzae, were used as test strains. 1. CRMN and AZT, both monobactam antibiotics, were roughly comparable in their activities and no resistant strain to these antibiotics were found among isolates of E. coli, Klebsiella spp., Proteus spp., M. morganii, P. rettgeri or H. influenzae and few resistant strains were observed among isolates of S. marcescens. On the other hand, isolates of C. freundii, Enterobacter spp. and P. aeruginosa included rather numerous strains resistant to the monobactam antibiotics. Among these cases, whereas R strains, i.e. resistant strains showing MICs greater than or equal to 50 micrograms/ml, accounted for a large proportion of strains resistant to PC and CEPs, I strains, i.e. intermediately resistant strains showing MICs between 12.5 and 25 micrograms/ml, accounted for a large proportion of strains resistant to the monobactam antibiotics. 2. Strains resistant to PIPC, a PC, were detected with high and more or less uniform frequencies over the entire spectrum of the isolates examined. 3. Antibacterial activities of CEPs varied against different bacterial species. While strains resistant to CTX, CAZ and LMOX were commonly detected with high frequencies among isolates of C. freundii, Enterobacter spp. and S. marcescens, large percentages of LMOX-resistant strains of C. freundii and Enterobacter spp. were of the I type. CTX-resistant strains were also found among isolates of P. vulgaris and M. morganii. Proportions of CEP-resistant strains of P. aeruginosa were 28% for CFS and 12% for CAZ. 4. No or few strains among the isolates of 13 species investigated were resistant to IPM, a carbapenem antibiotic, which showed the most stable antibacterial activity, but it was less active than monobactam antibiotics and CEPs against Klebsiella spp., P. mirabilis and H. influenzae.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Quinolones↗
PubMed1988

Monobactam antibiotics in subinhibitory concentrations enhance opsonophagocytosis and serum bacteriolysis in certain Escherichia coli strains.

Capsular polysaccharides are known to protect Gram-negative bacteria from complement-mediated killing and opsonophagocytosis. Monobactam antibiotics selectively inhibit penicillin-binding protein 3 (PBP3), resulting in abnormally structured peptidoglycan, causing defective cell surface structures. The authors studied the influence of subinhibitory concentrations of the monobactam antibiotics aztreonam and carumonam on serum bacteriolysis and opsonophagocytosis of four K-encapsulated and five non-K-encapsulated Escherichia coli strains. It was observed that monobactam antibiotics in subinhibitory concentrations enhanced opsonophagocytosis of the four K-encapsulated and one non-K-encapsulated E. coli strains tested. Opsonophagocytosis of the other four non-K-encapsulated E. coli strains was not enhanced. Serum bacteriolysis studies revealed that of the four K-encapsulated strains tested only one strain showed a significant enhancement of bacteriolysis after treatment with subinhibitory concentrations of monobactam antibiotics. None of the unencapsulated strains showed a significant change in percentage lysis after treatment with either aztreonam or carumonam.

Anti-Bacterial Agents↗
PubMed1991

The monobactams.

The monobactam antibiotics are synthetic compounds, although monocyclic beta-lactam compounds have been found in nature in various soil bacteria. Although additional orally and parenterally administered monobactams are under investigation, the first marketed monobactam was aztreonam. This agent has an antimicrobial spectrum similar to that of gentamicin and tobramycin, aminoglycoside antibiotics. Aztreonam, however, is not nephrotoxic, is weakly immunogenic, and has not been associated with disorders of coagulation. Aztreonam may be administered intramuscularly or intravenously; absorption after oral administration is poor. The primary route of elimination is the urine. The serum half-life of the drug in patients with normal renal function is 1.5 to 2.1 hours; the recommended dosing interval in patients with normal renal function is every 8 hours. Dosage adjustment is necessary in patients with renal impairment. The strictly gram-negative aerobic spectrum of aztreonam limits its use as a single empiric agent. Approved indications for its use include infections of the urinary tract or lower respiratory tract, intra-abdominal and gynecologic infections, septicemia, and cutaneous infections caused by susceptible organisms. Concurrent initial therapy with other antimicrobial agents is recommended before the causative organism (or organisms) has been determined in patients who are seriously ill and at risk for gram-positive or anaerobic infections.

Humans↗
PubMed1988

Synthesis and in vitro antibacterial activity of a new series of monobactam derivatives.

Using as a model monobactams with a substituted alpha-oxyimino moiety in the side chain (aztreonam), a series of 2-(2-aminothiazol-4-yl)-2-hydrazono-acetamido monobactam (II a, f) were prepared by condensation of the hydrazones (I a, e) (Z form) with tetrabutylammonium 3-amino-4-methyl-2-oxo-1-azetidin-sulphonate. Isomerization occurred during this synthesis and gave the E form of all compounds. Monobactams (II a, f) showed no significant in vitro antibacterial activity when compared with aztreonam and with some cephalosporins bearing the same E-hydrazono side chain.

Anti-Bacterial Agents↗
PubMed1988

The new monobactams: chemistry and biology.

The discovery of the monobactams led to the successful development of aztreonam as the first of this novel class of beta-lactam antibiotics to enter the clinical field. Continued structural modification on the monobactam nucleus has resulted in two additional compounds from this class that show interesting biologic properties. The first, SQ 83,360, is like aztreonam in exhibiting high activity against members of the Enterobacteriaceae but has the added characteristic of being exceptionally active against strains of Pseudomonas aeruginosa. Also, significant gains are made with SQ 83,360 in activity against Pseudomonas spp. and Acinetobacter. The second compound, tigemonam, is also like aztreonam, having good activity against Enterobacteriaceae, Haemophilus influenzae, and Neisseria gonorrhoeae and showing good beta-lactam stability. Tigemonam differs from aztreonam in being well absorbed orally by experimental laboratory animals.

Bacteria↗
PubMed1986

Intramolecular nucleophilic amino attack in a monobactam: synthesis and stability of (2S,3S)- 3-[(2R)-2-amino-2-phenylacetamido]-2-methyl-4-oxo-1- azetidinesulfo nic acid.

The potentially orally bioavailable arylglycine-substituted monobactam, (2S,3S)- 3-[(2R)-2-amino-2-phenylacetamido]-2-methyl-4-oxo-1- azetidinesulfonic acid, was prepared as a crystalline solid. No significant antibacterial activity [i.e., MICs were greater than 128 (micrograms/mL)] was found when the monobactam was tested against Gram positive and Gram negative bacteria. Solution instability (greater than 2,000 times less stable than aztreonam) due to intramolecular nucleophilic amine attack on the beta-lactam is believed to be a contributing factor to the poor microbiological activity.

Aztreonam↗
PubMedDate not supplied

Discovery and development of the monobactams.

A novel procedure designed to detect naturally occurring beta-lactam-containing molecules led to isolation of the monobactams - structurally unique, bacterially produced, monocyclic beta-lactam antibiotics. Although none of these monobactams exhibited impressive antimicrobial activity, side-chain variation - as with the penicillins and cephalosporins - resulted in potently active compounds. Aztreonam was chosen from hundreds of compounds for extended laboratory studies. In addition to a unique chemical structure, aztreonam has biologic properties that are unique in comparison with those of the classical penicillins and cephalosporins. Aztreonam is relatively inactive against gram-positive bacteria and anaerobes but is extremely effective against aerobic gram-negative bacteria, including Pseudomonas aeruginosa. The drug is highly resistant to enzymatic hydrolysis by beta-lactamases, particularly those known to be mediated by R plasmids, and is a poor inducer of chromosomal beta-lactamases. In the majority of drug combinations tested, aztreonam exhibits additive or synergistic activity. In a series of animal-model infections, the drug showed a high degree of efficacy that was consistent with findings in studies in vitro. In a hamster model for Clostridium difficile-induced pseudomembranous colitis, aztreonam did not induce any significant changes.

Animals↗
PubMed1987

Structure-activity relations of 4-fluoromethyl monobactams.

New monobactam compounds with fluoromethyl side chains at the 4-position were synthesized. These compounds showed strong antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa and good stability to various beta-lactamases. The effect of replacement of the 1-carboxy-1-methylethoxyimino residue of aztreonam with various substituted groups, and of the configuration of the 3- and 4-position were examined. Substitution of a carboxycyclopropoxy group in the oxyimino moiety effected the most potent antibacterial activity. The cis congeners were not hydrolysed by any types of beta-lactamases including the oxyiminocephalosporin hydrolysing enzyme. Introduction of a fluorine atom in the methyl group at the 4-position increased the beta-lactamase stability of monobactams.

Bacteria↗
PubMed1987

In vitro activity and beta-lactamase stability of a new monobactam, B0-1165.

B0-1165 is a 1-carboxy-1-cyclopropoxyamino,4-fluoromethyl monobactam. It inhibited the majority of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter diversus, Aeromonas hydrophila, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Yersinia enterocolitica, Haemophilus influenzae, Neisseria gonorrhoeae, and Salmonella and Shigella species at less than or equal to 0.125 microgram/ml. Overall, its in vitro activity was similar to that of aztreonam, cefotaxime, and ceftazidime, with minor differences in the MICs for individual isolates. Enterobacter species and Citrobacter freundii which were derepressed for beta-lactamase production and had higher MICs of aztreonam and ceftazidime had MICs that ranged from 4 to 32 micrograms/ml. B0-1165 had activity against Pseudomonas aeruginosa similar to that of aztreonam but lower than that of ceftazidime and carumonam. Pseudomonas maltophilia and other Pseudomonas species were resistant or had MICs of 32 micrograms/ml, as did Acinetobacter species. B0-1165 did not inhibit streptococcal, staphylococcal, or anaerobic species, such as Clostridium and Bacteroides species. B0-1165 was not hydrolyzed to any appreciable extent by common plasmid- and chromosomally Richmond-Sykes type 1a-, 1c-, and 1d-mediated beta-lactamases. It inhibited the Enterobacter cloacae P99 and inducible Pseudomonas aeruginosa beta-lactamases. B0-1165 was a poor inducer of beta-lactamase, but exposing E. cloacae and C. freundii to B0-1165 selected for resistant isolates. Overall, B0-1165 had in vitro properties similar to those of other monobactams currently available or under investigation.

Aztreonam↗
PubMed1988

MM 42842, a new member of the monobactam family produced by Pseudomonas cocovenenans. I. Identification of the producing organism.

A bacterial soil isolate designated 326-32B produces a new member of the monobactam series of antibiotics, MM 42842, and the bulgecins. Identification studies show isolate 326-32B to be a strain of Pseudomonas cocoveneans which is a species previously noted for the production of toxoflavin. A description of P. cocovenenans does not appear to have been previously published and the identify of strain 326-32B was established by means of a direct comparison with the deposited organism P. cocovenenans NCIB 9450. The properties of strain 326-32B, and P. cocovenenans NCIB 9450 were compared with those of the monobactam and bulgecin producing organisms Pseudomonas acidophila ATCC 31363 and Pseudomonas mesoacidophila ATCC 31433. The four organisms were found to share certain properties, including the ability to grow at pH 4.0.

Monobactams↗
PubMed1985

Aztreonam: the first monobactam.

A novel screening procedure led to isolation of the structurally unique, bacterially produced, monocyclic beta-lactam antibiotics early in 1979. These naturally occurring "monobactams" were not clinically useful as antibiotics because of their poor antibacterial properties. They were, however, found to interact with certain penicillin-binding proteins of bacteria and thus to interfere with the biosynthesis of bacterial cell walls. The focus of monobactam development then turned toward increasing the binding activity of the beta-lactam ring of the molecule. Aztreonam was the first compound to emerge that fulfilled the objectives of the program. It is relatively inactive against gram-positive and anaerobic bacteria but is extremely effective against aerobic gram-negative bacteria, even in low concentrations. In addition, it is highly resistant to enzymatic hydrolysis by beta-lactamases and demonstrates a high degree of stability against plasmid-mediated gram-negative lactamases. With the chromosomally mediated beta-lactamases, on the other hand, aztreonam can act either as an inhibitor or as a poor substrate. It is unique in that it does not induce production of chromosomally mediated enzymes. Interference with normal gut flora by the use of broad-spectrum antibiotics can result in decreased defense capacity and can lead to intestinal colonization by resistant pathogenic organisms. Therapy directed specifically against the invading pathogen is thus preferred. Such directed therapy is provided by aztreonam. Its narrow spectrum can, if necessary, be broadened by combining it with other antibiotics while continuing to maintain an alternative to the more generalized "shotgun" therapy with its attendant side effects such as disturbances of the natural gut flora, diarrhea, and the emergence of resistant bacteria.

Animals↗
PubMed1989

A comparison of monobactam antibiotics in surgical infections.

The introduction of gentamicin almost 20 years ago provided an effective option for the treatment of gram-negative bacillary infections. During the past few years, the availability of aztreonam (a monobactam), imipenem (a carbapenem), and newer cephalosporins within vitro activities comparable with aminoglycosides against many gram-negative bacilli, has stimulated a reassessment of the role of aminoglycosides in treating these infections. When determining the role of new antimicrobials as potential replacements for more established agents, the clinical focus should be on three factors: comparative efficacy, safety, and cost. Consideration of cost is relevant only when efficacy and safety are equivalent. Other factors, such as comparative in vitro antimicrobial activity, pharmacokinetics, and effect on normal flora can also influence the selection of an antimicrobial regimen. A new class of antimicrobials, the monobactams, is the focus of this review. The only member of this class currently in clinical use is aztreonam. A comparison with aminoglycosides is particularly relevant because aztreonam is active against aerobic gram-negative bacilli. This review will discuss the acknowledged concerns with aminoglycoside use and compare the characteristics of aztreonam and currently marketed aminoglycosides.

Aminoglycosides↗
PubMedDate not supplied

Aztreonam, a new monobactam antimicrobial.

The chemistry, in vitro activity, pharmacokinetics, adverse reactions, and clinical use of the monobactam antimicrobial aztreonam are reviewed. Aztreonam, an investigational agent nearing approval in the United States and Canada, is the first in a class of monobactam antimicrobials to be evaluated extensively in vitro and in vivo. It has a narrow spectrum of activity, encompassing only aerobic gram-negative microorganisms including Pseudomonas aeruginosa and most multiply resistant Enterobacteriaceae. Aztreonam has no useful activity against gram-positive or anaerobic microorganisms. In preliminary studies, aztreonam achieved high tissue concentrations and was usually well tolerated. Approximately 65-75% of an administered dose is excreted unchanged into the urine, and the elimination half-life is 1.6-2.2 hours in subjects with normal renal function. Dosage should be adjusted in patients with renal impairment. Aztreonam was shown equivalent to gentamicin and cefamandole for treating serious urinary-tract infections and produced cure rates greater than 85% in gonococcal, lower respiratory tract, orthopedic, serious urinary tract, acute uncomplicated lower urinary-tract, gynecologic, and intraabdominal infections. Development of resistance during therapy may be less likely with aztreonam than with other new cephalosporins. Aztreonam will probably have an important role in antimicrobial therapy, but much further study is necessary to assess clinical efficacy and toxicity. The clinical importance of aztreonam's superior activity under anaerobic conditions compared with aminoglycosides and the theoretical reduced alteration in GI colonization resistance must be assessed in controlled trials. Evaluation of aztreonam versus ceftazidime, the carbapenems, and the carboxyquinolones is needed, and the likelihood of gram-positive superinfection, especially with enterococci, must be further assessed.

Animals↗
PubMed1985

[Comparative in vitro activity of 2 monobactams (RO 172301 (AMA 1080)and aztreonam), ceftazidime and cefotaxime on Gram-negative bacilli].

In vitro activities of two monobactams (RO 172301 and aztreonam), ceftazidime and cefotaxime against 739 bacterial strains belonging to different species of Gram negative aero-anaerobic bacilli were studied comparatively. Strains were studied according to their resistance phenotype to beta-lactams. Minimal inhibitory concentrations (MIC) of the four antibiotics were determined using the agar dilution method. RO 172301 and aztreonam exhibited a similar activity against P. aeruginosa with a MIC around 2 mg/l for 50% of strains and around 4 mg/l for 90% of strains. As compared to the two monobactams, ceftazidime was more active and cefotaxime less active (one halving dilution either way). Activity of antibiotics was not dependent upon the mechanism of resistance to beta-lactams, except for strains producing a constitutive cephalosporinase. Against Enterobacteriaceae, RO 172301 proved slightly more active than aztreonam and cefotaxime; ceftazidime was the least active drug. Only 12 of the 739 strains tested (1.6%) had a MIC for RO 172301 above 32 mg/l. The percentage of resistant strains was 2.4% for aztreonam and ceftazidime and 8.8% for cefotaxime.

Acinetobacter↗
PubMed1987

Cephalosporin, carbapenem, and monobactam antibiotics.

Cephalosporin and related antibiotics are highly effective bactericidal agents of relatively low toxicity. The spectrum of activity varies with the drug but is usually broad. The first-generation cephalosporins, and especially cefazolin, are most active against sensitive staphylococci and streptococci. Most second-generation (except cefoxitin) and third-generation cephalosporins show substantial activity against Haemophilus influenzae. All cephalosporins (except cefsulodin) are active against Klebsiella, Escherichia coli, and Proteus mirabilis, whereas only the third-generation agents have pronounced activity against the other Enterobacteriaceae. Imipenem (a carbapenem) is active against essentially all pathogenic organisms, but aztreonam (a monobactam) is active against only aerobic gram-negative bacilli. Advantages associated with some of the new cephalosporins are once-daily administration and high cerebrospinal fluid levels. With the development of new cephalosporins, however, new toxicities have become apparent, and superinfections and induction of resistance have become greater problems. The cephalosporins are among the most expensive antibiotics in use today; thus, use of these expensive agents must be justified by lower toxicity, greater efficacy, or both in comparison with drugs of more reasonable cost.

Bacteria↗