Monocyclic Beta-lactam Research Articles

Azthreonam: in vitro activity against urinary pathogens

The in vitro activity of azthreonam, a novel monocyclic beta-lactam antibiotic, was investigated for Gram negative urinary pathogens by determining the susceptibilities of 105 consecutive isolates from specimens submitted to the Auckland Hospital microbiology laboratory. All were sensitive or of intermediate sensitivity by disc diffusion testing. Minimum inhibitory concentrations (MICs) were 0.25 mg/l for 97 per cent of Enterobacteriaceae and ranged from 2-16 mg/l for Pseudomonas aeruginosa. Of antibiotics tested routinely in this laboratory only tobramycin showed comparable potency.

Multiple-dose pharmacokinetics of the monobactam azthreonam (SQ 26,776) in healthy subjects.

Azthreonam, a monocyclic beta-lactam highly active against aerobic gram-negative bacteria in vitro, was administered to four groups of nine healthy male volunteers in the following four regimens: 500 mg intravenously (i.v.) over 2 min every 8 h, 1,000 mg i.v. over 2 min every 8 h, 500 mg intramuscularly (i.m.) every 8 h, and 1,000 mg i.m. every 8 h for 7 days. Serial samples of serum and urine were assayed by microbiological methods, and urine samples collected during the high-dose i.m. regimen were assayed by a high-pressure liquid chromatographic procedure. Mean peak serum levels were 39 and 99 micrograms/ml after the initial i.v. doses and 18 and 39 micrograms/ml after the initial i.m. doses. There was no evidence of drug accumulation. Mean serum trough levels were 1.0 and 2.5 micrograms/ml during the two i.v. regimens and 1.8 and 3.8 micrograms/ml during the two i.m. regimens. The mean difference among Cmax, area under the curve from 0 to 8 h, and urinary recovery at 0 to 8 h on days 1 and 8 was less than 13% for each regimen. From the i.v. study, the mean steady-state volume of distribution was 0.21 liter/kg, the terminal half-life was 1.6 h, serum clearance was 1.7 ml min-1 kg-1, urinary recovery was 60%, and serum protein binding was 56%. An average of about 6% of a 1,000-mg i.m. dose was excreted in the 8-h urine collection on day 8 as the open beta-lactam ring hydrolysis product of azthreonam. The concentrations of azthreonam in serum were within the range required to inhibit growth of susceptible organisms in vitro.

In vitro activity of azthreonam, a monobactam antibiotic.

We studied the activity of azthreonam (SQ 26,776), a novel monocyclic beta-lactam compound, against a variety of clinical isolates. It was more potent than moxalactam, cefoperazone, cefamandole, cefoxitin, ticarcillin, tobramycin, or amikacin against strains of Klebsiella spp., Serratia spp., and the Proteus group. It was highly effective against Escherichia coli and strains of Salmonella spp. The median minimal inhibitory concentration for all species of Enterobacteriaceae was less than or equal to 2 micrograms/ml. Azthreonam was moderately active against Pseudomonas aeruginosa, including tobramycin-resistant strains, and against Pseudomonas cepacia (median minimal inhibitory concentration, 16 to 32 micrograms/ml), but was weakly active against Pseudomonas maltophilia and strains of Acinetobacter spp. and Achromobacter spp. The drug showed little activity against Staphylococcus aureus, enterococci, and anaerobic bacteria, including Bacteroides fragilis, Clostridium spp., and gram-positive cocci. Like moxalactam and cefoperazone, azthreonam exhibited a considerable inoculum effect with strains of Enterobacter spp. and Pseudomonas spp. Combination with clavulanic acid did not increase the activity of azthreonam against S. aureus but was synergistic for 5 of 15 strains of B. fragilis. Azthreonam is about 50% bound to human serum protein. The selective range of activity of this compound could be of clinical benefit.

Mode of action of azthreonam.

Azthreonam (SQ 26,776) is a member of a new class of monocyclic beta-lactam antibiotics. In Escherichia coli, azthreonam caused filamentation at its lowest effective concentration (0.2 microgram/ml), a morphological effect identical to that observed with cephalothin. The penicillin-binding protein (PBP) profile indicated a very high affinity for PBP3 (complete binding at 0.1 microgram/ml), a moderate affinity for PBP1a (complete binding at 10 micrograms/ml), and poor affinities for PBP1b, PBP2, PBP4, and PBP5/6 (complete binding at greater than or equal to 100 micrograms/ml). Accordingly, azthreonam had poor activity against Streptomyces R61 DD-carboxypeptidase (50% inhibition, greater than 100 micrograms/ml) and E. coli peptidoglycan transpeptidase (50% inhibition, 100 micrograms/ml). Azthreonam also showed very high affinity for PBP3 (complete binding at 0.1 microgram/ml) in Proteus vulgaris, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. In all four organisms, its PBP profile was similar to that observed in E. coli. It is concluded that azthreonam, although of novel structure, has a mode of action similar to that of cephalosporins, affecting specifically septation in E. coli and most likely other gram-negative bacteria.

Single-dose pharmacokinetics of the monobactam azthreonam (SQ 26,776) in healthy subjects.

Azthreonam (SQ 26,776) is a new, completely synthetic, monocyclic beta-lactam antimicrobial agent that is highly active in vitro against most gram-negative bacteria. The pharmacokinetics of single intravenous doses of 125 to 4,000 mg, studied in 36 healthy male subjects, were best described by an open, linear, two-compartment kinetic model. The mean peak serum levels at 5 min after completion of 3-min infusions of 500-, 1,000- and 2,000-mg doses were 58, 125, and 242 micrograms/ml, respectively. The mean terminal serum half-life for all doses was 1.66 h, and the apparent volume of distribution was 0.18 liter/kg. The mean serum clearance was 1.27 ml min-1 kg-1, and urinary excretion averaged 68% of the doses administered. The pharmacokinetics of single intramuscular doses of 250 to 1,000 mg, studied in 18 subjects, were best described by a linear, one-compartment model, with first-order absorption and elimination. The mean peak serum levels occurring at 1 h after doses of 250, 500, and 1,000 mg were 12, 22, and 46 micrograms/ml, respectively. Other kinetic parameters were similar to those for intravenous administration. Tolerance of azthreonam was good, with only a mild rash in one subject and with mild to moderate transient elevations in serum transaminases and lactate dehydrogenase in two subjects.

SQ 26,180, a novel monobactam. I Taxonomy, fermentation and biological properties.

Strains of Chromobacterium violaceum, isolated from various environments, were found to produce a novel monocyclic beta-lactam antibiotic. The antibiotic, SQ 26,180 was weakly active against Gram-positive and Gram-negative bacteria with the exception of mutants hypersensitive to beta-lactam antibiotics. The compound was highly stable to beta-lactamases and acted as an inhibitor of the P99 enzyme from Enterobacter cloacae. SQ 26,180 showed affinity for penicillin-binding proteins 1a, 4 and 5/6 of Escherichia coli and inhibited R61 DD-carboxypeptidases.

Azthreonam (SQ 26,776), a synthetic monobactam specifically active against aerobic gram-negative bacteria.

Azthreonam (SQ 26,776) is a synthetic monocyclic beta-lactam antimicrobial agent belonging to the monobactam family (Sykes et al., Nature [London] 291:489-491, 1981), members of which are characterized by having the 2-oxoazetidine-1-sulfonic acid moiety. Azthreonam exhibits a high degree of stability to beta-lactamases and is specifically active against aerobic gram-negative bacteria, including Pseudomonas aeruginosa. Its activity against these organisms was in general equal or superior to that observed with the third-generation cephalosporins, cefotaxime and ceftazidime. Like penicillins and cephalosporins, azthreonam interacts with essential penicillin-binding proteins of gram-negative bacteria. Azthreonam protected mice against experimental infections produced by a range of gram-negative bacteria, exhibiting efficacy comparable to that of cefotaxime and ceftazidime.

ChemInform Abstract: SULFAZECIN AND ISOSULFAZECIN, NOVEL β‐LACTAM ANTIBIOTICS OF BACTERIAL ORIGIN

In the long history of screening for antibiotics, fungi and actinomycetes have been the only producers of beta-lactam antibiotics although several phytopathogenic bacteria have been reported to produce toxins with a beta-lactam structure. We report here the first evidence that novel monocyclic beta-lactam antibiotics, sulfazecin and isosulfazecin, are produced by new species of Pseudomonas.

Sulfazecin and isosulfazecin, novel beta-lactam antibiotics of bacterial origin.

In the long history of screening for antibiotics, fungi and actinomycetes have been the only producers of beta-lactam antibiotics although several phytopathogenic bacteria have been reported to produce toxins with a beta-lactam structure. We report here the first evidence that novel monocyclic beta-lactam antibiotics, sulfazecin and isosulfazecin, are produced by new species of Pseudomonas.

Studies on the biosynthesis of isopenicillin N with a cell-free preparation of Penicillium chrysogenum.

When delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine was added to a cell-free system prepared by lysis of Penicillium chrysogenum protoplasts, "compounds X and Y" were detected after analysis on a cation-exchange column. The chromatographic position as well as results of experiments with double labelled tripeptides showed "compound X" to be the penicilloic acid of isopenicillin N. LLD-Tripeptide labelled with tritium at carbon-2 of th valine part was incorporated into isopenicillin N with retention of label. "Compound Y" retained all hydrogens on the valine part of the peptide, but lost half of the tritium on carbon-3 of the cysteine part. The results are consistent with the hypothesis that the LLD-tripeptide is converted into isopenicillin N via a monocyclic beta-lactam and without a dehydrovalinyl intermediate. Extensive transacylase activity was observed between isopenicillin N and 6-aminopenicillanic acid.

Nocardicin A, a new monocyclic .BETA.-lactam antibiotic. V. in vivo evaluation.

Nocardicin A is a new monocyclic beta-lactam antibiotic which provides a potent therapeutic effect in mice experimentally infected with gram-negative bacilli. When given subcutaneously to mice, the therapeutic effect of the drug was stronger than had been anticipated from in vitro studies. Nocardicin A was more potent in therapeutic effect than carbenicillin against infections due to Pseudomonas aeruginosa, Proteus mirabilis, Pr. vulgaris, Pr. rettgeri and Pr. inconstans, and was similar in effect to carbenicillin against infections due to Escherichia coli in mice. In addition, nocardicin A proved to be active against infections due to Serratia marcescens and other organisms resistant to beta-lactam antibiotics. When nocardicin A was given subcutaneously to mice, blood and hepatic levels of the drug were higher than those of carbenicillin.

Letter: Nocardicin A and B, novel monocyclic beta-lactam antibiotics from a Nocardia species.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNocardicin A and B, monocyclic .beta.-lactam antibiotics from a Nocardia speciesMasashi Hashimoto, Tadaaki Komori, and Takashi KamiyaCite this: J. Am. Chem. Soc. 1976, 98, 10, 3023–3025Publication Date (Print):May 1, 1976Publication History Published online1 May 2002Published inissue 1 May 1976https://doi.org/10.1021/ja00426a063RIGHTS & PERMISSIONSArticle Views276Altmetric-Citations83LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (380 KB) Get e-Alerts Get e-Alerts

Nocardicin A, a new monocyclic beta-lactam antibiotic II. Structure determination of nocardicins A and B.

The structures of nocardicins A and B, novel monocyclic beta-lactam antibiotics produced by a strain of Nocardia, have been established as 1 and 2, respectively, on the basis of spectroscopic and chemical evidence. They are the first examples of monocyclic beta-lactam antibiotics possessing relatively high antimicrobial activity, and are stereochemically and biologically related to penicillins and cephalosporins.

Nocardicin A, a new monocyclic beta-lactam antibiotic. I. Discovery, isolation and characterization.

Nocardicin A is a new monocyclic beta-lactam antibiotic obtained from the fermentation broth of a strain of actinomycetes. The producing organism, strain WS 1571, was identified as Nocardia uniformis subsp. tsuyamanensis ATCC 21806. The antibiotic, obtained as colorless crystals, exhibits moderate in vitro antibacterial activity against a broad-spectrum of Gram-negative bacteria including Proteus and Pseudomonas. It has low toxicity in laboratory animals.