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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↗
PubMed1996

Comparative epileptogenic properties of two monobactam derivatives in C57, Swiss and DBA/2 mice.

The behavioural and electrocortical effects of two monobactam derivatives were studied after intraperitoneal (ip) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures, and in C57 and Swiss mice, two strains not prone to seizure. DBA/2 mice were more susceptible than Swiss and C57 mice to seizures induced by aztreonam or carumonam. No significant differences were observed between seizures elicited by aztreonam and carumonam in animals (DBA/2 only) administered intracerebroventricularly or ip. Although the main mechanism for seizure-like activity of monobactams cannot be easily determined, we believe that several mechanisms may be involved. An increased excitation of the central nervous system (CNS) by inhibition of GABA binding to receptors and a slow clearance of aztreonam and carumonam from the CNS may be postulated.

Acoustic Stimulation↗
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↗
PubMed1995

Extended-spectrum beta-lactamases conferring resistance to monobactams and oxyimino-cephalosporins in clinical isolates of Serratia marcescens.

We studied antibiotic resistance patterns and extended-spectrum beta-lactamases (ES beta Ls) production in Serratia marcescens strains isolated in our hospital during 1993. We examined 210 S. marcescens isolates. Of these, 172 were obtained from 49 patients admitted to an intensive care ward; 157 out of 172 were obtained from February to October and presented the same pattern of antibiotic resistance, including monobactams and oxyimino-cephalosporins. The remaining 15 out of 172 isolates (obtained from September to December) were susceptible to all drugs tested, with the exception of first generation cephalosporins. Thirty-eight additional isolates were recovered, during the same period, from 28 patients admitted to wards other than the intensive care unit; also these strains showed the high susceptibility pattern reported above. Epidemic strains of S. marcescens produced three different types of beta-lactamase with pI 5.4, 5.5, and 8.4. In contrast, non-epidemic strains produced only one type of beta-lactamase with pI 8.4. Conjugation experiments showed that the beta-lactamases having a pI of 5.4 and 5.5 (but not the one with pI 8.4) were plasmid-mediated. Since the beta-lactamase with pI 5.5 was capable of hydrolyzing monobactams and oxyimino-cephalosporins it was classified as ES beta L. Electrophoretic analysis showed that plasmids obtained from multiresistant strains were of about 54 kb; these plasmids appeared also to code for aminoglycoside resistance. Our data indicate that the plasmid-mediated production of ES beta Ls may contribute to the epidemic spread of Serratia marcescens in high-risk wards.

Aztreonam↗
PubMed1995

Adverse effects of monobactams and carbapenems.

Monobactams and carbapenems are 2 classes of beta-lactam antibiotics that were introduced in the 1980s. This review considers the monobactam aztreonam and the carbapenems imipenem and meropenem. Imipenem is administered together with cilastatin, which inhibits the enzymatic breakdown of imipenem in the kidney. The antibacterial activities of these drugs are quite different from older beta-lactams. Aztreonam is directed towards aerobic Gram-negative bacteria, especially Pseudomonas aeruginosa, while imipenem and meropenem are active against both aerobic and anaerobic Gram-positive and Gram-negative bacteria. Thus, these drugs should be reserved for patients who have a special need for them. They are also structurally different from older beta-lactams and possess different adverse drug reaction profiles. It was initially suggested that aztreonam would be less immunogenic than previous beta-lactams because reactive breakdown products acting as haptens are less likely to be formed. Clinical reports now support this assumption, and, in particular, cross hypersensitivity between aztreonam and other beta-lactams seems to be rare which makes the drug a useful therapeutic alternative. However, hypersensitivity to aztreonam does occur. The predominant concern in terms of adverse reactions to imipenem/cilastatin is the increased tendency to cause seizures compared with other beta-lactams. The risk of producing a seizure is highly associated with inadequate dose adjustment in relation to kidney function. If appropriate care is taken, seizures occur in less than 1% of patients treated. However, it is possible that concomitant administration of other drugs with neurotoxic profiles (e.g. theophylline and cyclosporin) given in overdose, may increase the risk of seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
PubMed1982

Interaction between monobactams and Streptomyces R61 DD-carboxypeptidase.

The monobactams are a novel family of monocyclic beta-lactam antibiotics characterized by the 2-oxoazetidine-1-sulfonic acid moiety. A series of monobactams bind covalently to the Streptomyces R61 DD-carboxypeptidase in a manner similar to that for bicyclic beta-lactams, especially cephalosporins. The similarity of interaction was established by the following criteria: inhibition of binding by diisopropylfluorophosphate and alpha-dicarbonyls; stoichiometry of binding; similarity of partial proteolysis products of radiolabelled enzyme; rates of release of bound beta-lactams; nature of hydrolysis and hydroxylaminolysis products.

Anti-Bacterial Agents↗
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↗
PubMed1983

[Comparative in vitro activity of 6 recent beta-lactams against hospital strains of Acinetobacter calcoaceticus: role of the monobactam SQ 26,776].

Acinetobacter calcoaceticus is recognized as one of the most resistant nosocomial pathogens. Clinical isolates of Acinetobacter are usually resistant to most beta-lactam antibiotics and even to carbenicillin; 50% of the strains isolated in 1981-82 at the Bichat hospital were inhibited only at a concentration of 180 micrograms/ml. Recently several new molecules belonging to the beta-lactam group were discovered. Among them, monobactam SQ 26 776, a new broad spectrum highly potent monocyclic beta-lactam antibiotic, is resistant to beta-lactamase degradation and is able to inhibit especially Pseudomonas aeruginosa and Providencia. Its activity against 110 clinical strains of Acinetobacter was compared to that of 5 recent beta-lactam antibiotics which are resistant to beta-lactamase degradation (N-formimidoyl-thienamycin, cefotaxime, moxalactam, ceftriaxone, cefoperazone). 50% of the strains were inhibited at a concentration of 25 micrograms/ml and 90% at a concentration of 58 micrograms/ml of monobactam. The geometric mean was 27 micrograms/ml. For the other beta-lactam antibiotics, the MIC values (except for thienamycin), were superior to the critical values of bacterial susceptibility. N-formimidoyl-thienamycin is the most active compound against clinical isolates of Acinetobacter, with MIC 50 and MIC 90% being respectively of 0,4 and 0,8 micrograms/ml.

Acinetobacter↗
PubMed2002

Water-assisted alkaline hydrolysis of monobactams: a theoretical study.

A theoretical study of the water-assisted alkaline hydrolysis of 2-azetidinone, 3-formylamino-2-azetidinone and 3-formylamino-2-azetidine-1-sulfonate ion is carried out at the B3LYP/6-31+G* level. The effect of bulk solvent is taken into account using the PCM solvation model while specific solvent effects are represented by the inclusion of an ancillary water molecule along the reaction profile. The calculated free energy barriers in solution are in reasonable agreement with experimental values. The observed substituent effects due to the presence of the 3-formylamino and the SO(3) groups attached to the beta-lactam ring are crucial factors determining the hydrolysis of monobactam antibiotics.

Azetidines↗
PubMedDate not supplied

Monobactams and carbapenems for treatment of intraabdominal infections.

During the last decade improved clinical and microbiological methods have resulted in the realization that most intraabdominal infections involve both aerobic and anaerobic bacteria. Papers on the use of different antimicrobial agents directed against the polymicrobial flora of the infected site have been published. In this paper the use of monobactams and carbapenems for treatment of intraabdominal infections is reviewed. The review is based on data published since 1990. Three hundred forty-four patients participated in three trials where aztreonam combined with clindamycin was compared with other antimicrobial agents for treatment of intraabdominal infections. Eighty-six percent of the patients receiving aztreonam plus clindamycin were cured/improved, while 83% of the patients receiving the comparative drugs had favorable outcomes. Eleven trials compared imipenem/cilastatin versus other antimicrobial combinations for therapy of intraabdominal infections. One thousand three hundred seventy-five patients were evaluated in the trials. Eighty percent of patients treated with imipenem/cilastatin had favorable outcomes, while 81% of the patients receiving the comparative drugs were cured/improved. Nine studies including 1,205 patients for evaluation of meropenem versus other antimicrobial agents in the treatment of intraabdominal infections have been published. Cure/improvement was seen in 96% of the patients treated with meropenem and in 91% receiving the comparative drugs. One trial has been published comparing biapenem with imipenem/cilastatin for treatment of intraabdominal infections. Eighty-three patients participated, 65% of the patients in the biapenem group were cured/improved and 68% in the imipenem/cilastatin group.

Abdomen↗
PubMed2005

Synthesis and reactivity with beta-lactamases of a monobactam bearing a retro-amide side chain.

The monobactam sodium 3-benzylcarbamoyl-2-oxo-1-azetidinesulfonate, bearing a retro (vs classical beta-lactam)-amide side chain, has been synthesized and the kinetics of its reaction with typical beta-lactamases studied. The new compound is generally a poorer substrate than the analogous compound with a normal side chain but its formation of a transiently stable complex with a class C beta-lactamase sustains the retro-amide side-chain concept.

Amides↗