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PubMed1990

Synthesis and antimicrobial properties of substituted 3-aminoxypropionyl and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams.

The substituted 3-aminoxyproprionyl (VII) and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams (VIII) which possess the monocyclic beta-lactam nucleus of aztreonam (IX) were synthesized by reaction of triethylammonium (3S, 4S)-3-amino-4-methyl-2-oxo-1-azetidinsulfonate with the aminoxy acids X and XI, respectively. Compounds VII and VIII were assayed in vitro for their antimicrobial properties against Gram-positive and Gram-negative bacteria, whether producers of beta-lactamases or otherwise. Both types of compounds (VII and VIII) exhibited a poor antibacterial activity towards Gram-positive bacteria, comparable to that of aztreonam. On the contrary VII and VIII proved to be practically inactive against Gram-negative microorganisms, towards which aztreonam exhibits a high degree of activity.

Anti-Bacterial Agents↗
PubMed1989

Antibacterial activity in vitro of tigemonam, a new oral monobactam.

Using a broth microdilution method, the antibacterial activity of tigemonam, a novel oral monobactam, was evaluated against 217 gram-negative aerobes freshly isolated from clinical specimens. Reference antibiotics were amoxicillin, amoxicillin-sulbactam, cephalexin, cefaclor, norfloxacin, and co-trimoxazole. At a concentration of less than or equal to 8 mg/L, tigemonam inhibited 88% of the members of the Enterobacteriaceae family. Its activity was poor against the nonfermenter pathogens. In comparison with the other drugs, tigemonam generally exhibited superior antibacterial activity (with the exception of norfloxacin, which showed similar potency against the strains tested). Minimum bactericidal concentrations and time-kill determinations indicated that tigemonam showed remarkable bactericidal activity, with a 9% reduction in colony-forming units after 2 h at a dose corresponding to fourfold its minimum inhibitory concentration. When tigemonam was used in combination with netilmicin and amikacin against susceptible representative isolates of Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Escherichia coli, a synergistic effect was obtained.

Amikacin↗
PubMed1988

New antibiotics: carbapenems, monobactams and quinolones.

New beta lactams and the quinolone class of antibiotics represent major improvements in the therapy of moderate to severe infections. These newer antibiotics have an extended spectrum of antimicrobial activity, excellent pharmacokinetic properties and low toxicity. The beta lactams include carbapenems, represented by imipenem-cilastatin, and monobactams, represented by aztreonam. Norfloxacin and ciprofloxacin are potent quinolones.

4-Quinolones↗
PubMed1988

[Influence of human albumin on bactericidal or antibacterial activities of cephems and monobactams].

Influence of human albumin on bactericidal or antibacterial activities of 11 beta-lactams were examined. The 11 beta-lactams included second generation cephems (cefsulodin, cefotiam and cefmetazole), third generation cephems (ceftazidime, latamoxef, cefmenoxime, cefoperazone, cefotetan and cefpiramide) and monobactams (carumonam and aztreonam). The micro-broth-dilution method was used to determine antibacterial activities. Bactericidal activities were determined using the time-kill method. Used in the broth-dilution method were 2 media, MUELLER-HINTON broth (MHB) and the same medium supplemented with 5 g human albumin/d1 (MHB-A). The first experiment was to compare minimum inhibitory concentrations (MICs) determined in MHB were compared with those in MHB-A of 6 antibiotics against Staphylococcus aureus FDA 209P JC-1, of 7 antibiotics against Escherichia coli ATCC 25922 and of 5 antibiotics against Pseudomonas aeruginosa NCTC 10490. MICs using MHB-A were higher than MIC using MHB for 2 of the 6 antibiotics against S. aureus, and for all the 7 antibiotics against E. coli, and for 3 of the 5 antibiotics against P. aeruginosa. The second experiment was done to compare MICs of 5 antibiotics determined in MHB-A with those determined in MHB against 10 clinical isolates of S. aureus, of 6 antibiotics against 10 clinical isolates of Klebsiella pneumoniae and of 6 antibiotics against 10 clinical isolates of P. aeruginosa. The results obtained in the second experiment were varied for different antibiotics and different strains of organisms, and same antibiotics produced different results for different strains. MICs determined in MHB-A were lower than those in MHB for antibiotics with relatively low protein binding rates against 22 of 170 isolates tested (12.9%), whereas the former was higher than the latter against 103 out of 170 isolates tested (60.6%). MICs of antibiotics with relatively high protein binding rates showed an opposite trend. In the third experiment, time-kill curves were determined in the 2 media for 5 antibiotics against S. aureus FDA 209P JC-1, for 6 drugs against E. coli ATCC 25922 and for 5 drugs against P. aeruginosa NCTC 10490. The concentrations of these antibiotics used were 1/2 x MIC, 1 x MIC and 2 x MIC. MICs determined in the first experiment were used here. Time-kill curves determined in MHB-A didn't reflect MICs determined in MHB. Using MHB-A, antibiotics with lower MICs determined in MHB-A showed bactericidal activities in lower concentrations. Human albumin influenced antibacterial or bactericidal activities of beta-lactams.(ABSTRACT TRUNCATED AT 400 WORDS)

Albumins↗
PubMed1993

Effects of granulocyte colony stimulating factor and monobactam antibiotics (Aztreonam) on neutrophil functions in sepsis.

Possible clinical use of a recombinant human granulocyte colony stimulating factor (rG-CSF) and a newly developed monobactam antibiotics (Aztreonam) for the treatment of gram-negative sepsis was investigated. Gram-negative sepsis was induced in male WKA rats by cecal ligation and puncture (CLP). Untreated CLP rats all died by septicemia with severe peripheral blood leukocytopenia within 5 days after the operation. When we administered 2.0 micrograms/kg of rG-CSF and/or 20 mg/kg of Aztreonam intravenously just after the operation, the rats survived longer than the untreated CLP rats. These drugs were found to be more effective when used in combination. Since these rats showed an increase in leukocyte counts, we next examined the changes in the functions of polymorphonuclear leukocytes (PMNs, mainly neutrophils) after the treatment. PMNs from untreated CLP rats at 24 hr after the operation exhibited enhanced plastic-dish adherence, suppressed chemotaxis, and depressed O2 production when compared with PMNs from control animals. A single injection of rG-CSF restored both the depressed chemotaxis and the O2 production to levels greater than those of controls. Although a single injection of Aztreonam could not improve the suppressed O2 production, it could restore the depressed chemotaxis. Interestingly, simultaneous injection of Aztreonam with rG-CSF significantly enhanced the effect of rG-CSF on the PMN functions. These data suggest that the Aztreonam and rG-CSF may be useful for the treatment of gram-negative sepsis, especially when used in combination.

Animals↗
PubMed1985

Review of the clinical pharmacology of the monobactam antibiotic aztreonam.

Serum and urine levels of aztreonam after 0.5, 1, and 2 g doses are potentially therapeutic for susceptible gram-negative organisms. Aztreonam is widely distributed in body fluids and tissues, and concentrations exceeding the minimal inhibitory concentrations of important gram-negative pathogens are attained in those compartments in which infections are most common. Aztreonam is eliminated primarily in the urine in unchanged form, although it is also secreted into the bile and is metabolized to a minor extent. Renal insufficiency may significantly impair the elimination of aztreonam, thus requiring modification of the dosage regimen. The monobactam can be cleared by hemodialysis but is only minimally cleared by peritoneal dialysis. Parenterally and orally administered aztreonam can selectively reduce the population of aerobic gram-negative bacteria in the gut without notably altering the number of anaerobic organisms.

Anti-Bacterial Agents↗
PubMed1991

Substitution of lysine at position 104 or 240 of TEM-1pTZ18R beta-lactamase enhances the effect of serine-164 substitution on hydrolysis or affinity for cephalosporins and the monobactam aztreonam.

By site-directed mutagenesis, TEM-1 beta-lactamase was altered to contain single amino acid changes of E104K, R164S, and E240K, in addition to double changes of E104K/R164S or R164S/E240K and the triple change of E104K/R164S/E240K. Hydrolysis rates for cephaloridine and benzylpenicillin were lowered at least 1 order of magnitude for all enzymes containing R164S substitutions. All mutant enzymes exhibited increased kcat values for beta-lactam antibiotics containing an aminothiazole oxime side chain. Hydrolysis of ceftazidime was most affected, with kcat values increased 3-4 orders of magnitude in all enzymes with the substituted R164S moiety. Km values decreased for all substrates except ceftazidime in the enzymes with multiple mutations. Aztreonam was most affected, with Km values lowered 23-56-fold in the enzymes bearing multiple mutations. When the crystal structures of aztreonam and related monobactams were studied and projected into an active-site model of the PC1 beta-lactamase, it became apparent that the two lysine residues might serve equivalent roles by interacting with the carboxylate of the aminothiazole oxime side chain. Hydrogen-bonding interactions involving the oxime and N7 of the lysine, particularly Lys-104, may also be important in some antibiotics. Ser-164 apparently serves an indirect role, since it is somewhat distant from the active-site cleft.

Aztreonam↗
PubMed1986

The anti-microbial activity, beta-lactamase stability, and disk diffusion susceptibility testing of carumonam (RO 17-2301, AMA-1080), a new monobactam.

Carumonam, a new monobactam, was found to have an anti-microbial spectrum similar to aztreonam. Its spectrum includes Enterobacteriaceae, Haemophilus influenzae, pathogenic Neisseria species, Pseudomonas aeruginosa, and some streptococci. Staphylococcus species, enterococci, and many other nonenteric gram-negative bacilli were not inhibited. Enterobacteriaceae resistant to cefoperazone (minimum inhibitory concentrations [MICs] greater than or equal to 32 mg/L) were more likely inhibited by carumonam (52% at less than or equal to 8.0 mg/L) than aztreonam (39%) or ceftazidime (35%). Dilution test methods on agar or in Mueller-Hinton broth produced similar results. Carumonam minimum bactericidal concentrations were usually the same or one dilution above the MIC. Carumonam and aztreonam were very stable to most chromosomal (P99, K1, K14) and plasmid-mediated beta-lactamases (TEM, OXA, PSE). The Klebsiella oxytoca enzymes hydrolyzed aztreonam at rates greater than or equal to fivefold higher than carumonam but at a rate less than 1% that of cephaloridine. The aztreonam MICs for these Klebsiella stains were greater than or equal to 32 mg/L, but the hydrolysis rates do not fully explain the high-grade resistance to aztreonam. In vitro susceptibility tests with 30-micrograms carumonam disks were found to be very predictive. Similar regression statistics were observed for aztreonam and cefotaxime. Recommendations for carumonam susceptibility testing are susceptible greater than or equal to 21 mm (less than or equal to 8.0 mg/L) and resistant less than or equal to 14 mm (greater than or equal to 32 mg/L). Cross-resistance analysis favors the independent testing of carumonam or aztreonam against gram-negative species other than Enterobacteriaceae and P. aeruginosa.

Anti-Bacterial Agents↗
PubMed1983

Effectiveness of aztreonam, a new monobactam antibiotic, against penicillin-resistant gonococci.

Since the recognition of penicillinase-producing strains of N gonorrhoeae (PPNG) in 1976, these organisms have attained a worldwide distribution. The treatment of choice for infection due to PPNG has generally been spectinomycin administered im. In 1981, however, an infection from California was reported to be due to a strain of PPNG that was also resistant to spectinomycin (MIC, greater than 2,048 micrograms/ml) [1]. Throughout 1982, seven such isolates were reported worldwide [2], and in January 1983 an epidemiologically linked series of 27 cases of infection due to spectinomycin-resistant PPNG occurred in Korea. Because of the apparent declining utility of spectinomycin, we studied the efficacy and safety of aztreonam, a synthetic monobactam antibiotic from the Squibb Institute for Medical Research (Princeton, NJ) [3], in the treatment of acute uncomplicated gonococcal urethritis in men. Men with gonococcal urethritis were randomly treated with either 1 g of aztreonam or 2 g of spectinomycin im. Of the 112 men so treated, 93 could ultimately be evaluated: 51 who received aztreonam and 42 who received spectinomycin. Both drugs were 100% effective in the treatment of urethritis produced by both penicillin-sensitive and penicillin-resistant strains of gonococci. Furthermore, there were no reported side effects in either group and no laboratory abnormalities attributable to the aztreonam, with the exception of one patient with a minimally elevated level of serum glutamic oxaloacetic transaminase (serum glutamic pyruvic transaminase and alkaline phosphatase levels were normal).(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMed1985

In-vitro activity of the monobactam Ro 17-2301 against clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa.

Ro 17-2301 is a monobactam antibiotic. Its in-vitro activity was compared with those of aztreonam, ampicillin, cefuroxime, ceftriaxone, ceftazidime, and gentamicin. Ro 17-2301 had qualitatively similar activity to aztreonam and activity superior to that all the other antibiotics against the Enterobacteriaceae, but against Pseudomonas aeruginosa ceftazidime had equal or marginally better activity.

Anti-Bacterial Agents↗
PubMed1991

Aztreonam: a review of the first monobactam.

Aztreonam represents the first synthetic monobactam marketed in the United States and is being viewed as a nontoxic alternative to the aminoglycosides. Advantages of aztreonam over the aminoglycosides include lack of ototoxicity and nephrotoxicity and better penetration into the CSF. Additional advantages include its use in penicillin and cephalosporin allergic patients. Disadvantages of aztreonam compared to the aminoglycosides include the cost of the drug (50 times more expensive than gentamicin), the lack of post antibiotic effect, resistance to P. aeruginosa, and lack of significant activity against Enterobacter cloacae and E. aerogenes. There are insufficient clinical trials to document the superiority of aztreonam over the "gold standard" therapy for gram-negative infections--the aminoglycosides. The restricted anti-microbial spectrum of aztreonam has been proposed as an advantage. Theoretically, this would permit targeting of a gram-negative pathogen with minimal disruption of the (largely anaerobic) intestinal flora. In fact, use of this drug has been associated with colonization of gram-positive organism, especially enterococci. Although aztreonam appears to be an excellent antibiotic, its use has been limited by its relatively high cost, narrow spectrum of activity, and the availability of numerous alternative agents.

Aztreonam↗
PubMed1982

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.

Animals↗
PubMed1983

Oral bioavailability of the monobactam aztreonam (SQ 26,776) in healthy subjects.

To investigate the oral bioavailability of aztreonam (SQ 26,776), we administered single 500-mg doses of this monobactam as an oral solution, as two 250-mg capsules, and as a 3-min intravenous infusion to 15 healthy male subjects at 1-week intervals according to a three-way crossover study design. Serum and urine samples were assayed by microbiological methods. The absolute systemic bioavailability of each oral formulation, defined as the ratio of areas under the serum concentration-time curves after oral and intravenous administration, was less than 1%. Peak serum levels achieved with oral solution, capsule, and intravenous infusion were 0.15, 0.14, and 56.7 micrograms/ml, respectively, and cumulative urinary excretion was 0.7, 0.6, and 68% of the administered dose, respectively.

Administration, Oral↗
PubMed1983

In vitro activity and beta-lactamase stability of a monobactam, SQ 26,917, compared with those of aztreonam and other agents.

SQ 26,917 is a monobactam antibiotic. Its in vitro activity was compared with those of aztreonam, cefotaxime, ceftazidime, and moxalactam. SQ 26,917, which contains a beta-methyl configuration on the beta-lactam ring, was similar in activity to aztreonam with the exception of greater activity against Pseudomonas aeruginosa isolates. SQ 26,917 had no activity against gram-positive isolates or anaerobic bacteria. It was not hydrolyzed by common plasmid and chromosomal beta-lactamases.

Anti-Bacterial Agents↗
PubMed1984

Immunology of the monobactam aztreonam.

To assess the immunological cross-reactivity of the monobactam antibiotic aztreonam (AZ), rabbits were immunized with protein conjugates of benzylpenicillin, cephalothin (CEPH), and AZ. The resulting antibenzylpenicilloyl (BPO) and anti-CEPH rabbit antibodies showed negligible cross-reactivity with AZ conjugated to human serum albumin (AZ-HSA), whereas anti-AZ showed negligible cross-reactivity with BPO-HSA and CEPH-HSA. Unlike benzylpenicillin and CEPH, unconjugated AZ was as effective as AZ conjugated to epsilon aminocaproic acid (AZ-EACA) in inhibiting the binding of homologous antibody. Studies with various analogs of AZ confirmed that immunoglobulin G (IgG) anti-AZ was entirely side-chain specific. The inhibition of the binding of human IgE anti-penicilloyl to BPO-HSA was studied in the presence of AZ-EACA, BPO-formyl lysine, and CEPH-EACA. Whereas CEPH-EACA displayed 3% cross-reactivity with BPO-lysine, AZ-EACA showed little or no cross-reactivity (much less than 0.9%). To assess the immunogenicity of AZ in humans, IgE and IgG antibodies were measured in sera from 36 healthy male volunteers receiving 0.5 or 1 g intravenously or intramuscularly every 8 h for 7 days. None of the subjects had detectable preexisting IgE reactive with AZ or demonstrated an IgE response to antibiotic administration. Four subjects gave evidence for naturally occurring IgG cross-reactive with AZ, but only one subject demonstrated a rise in IgG levels after exposure to AZ. This anti-AZ IgG did not cross-react with BPO or CEPH conjugates of bovine thyroglobulin and was completely side-chain specific. These studies suggest that AZ displays very low immunological cross-reactivity with other beta-lactam antibiotics and may be only weakly immunogenic in humans.

Animals↗
PubMed1985

Forecasting cephalosporin and monobactam antibiotic half-lives in humans from data collected in laboratory animals.

The postdistribution half-lives of 10 cephalosporin and 2 monobactam antibiotics in humans were predicted from data obtained in other mammals. This forecasting was accomplished with the allometric equation t1/2 = aWb, where a is the y intercept and b is the slope obtained from the log-log plot of antibiotic half-life (t1/2) versus body weight (W). Dimensionless similarity criteria were used to produce a biological clock for ceftizoxime elimination. The creation of the biological clock, which measured physiologic time (heartbeats) rather than chronologic time (minutes), demonstrated that ceftizoxime half-life was identical in five mammals. This methodology will contribute to infectious disease research through a greater understanding of pharmacokinetic scaling in mammals.

Animals↗
PubMed1985

Pharmacokinetics and tissue penetration of carumonam, a new synthetic monobactam.

The pharmacokinetics of the monobactam carumonam (Ro 17-2301) as derived from serial measurement of the concentrations of this agent in serum, blister fluid, and urine were studied in six male volunteers subsequent to intravenous infusion of a single 2-g dose. Drug levels in serum in excess of 75 micrograms/ml were achieved 0.5 h after the end of infusion, declining to 2.9 micrograms/ml at 8 h. The mean serum and blister fluid elimination half-lives were 1.68 and 1.7 h, respectively. The urinary recovery of the drug by 24 h was 80.6% (range, 68.3 to 91.1%). Carumonam penetrated blister fluid well, the mean percentage penetration (as measured by the ratio of areas under curves) being 101.6%.

Adult↗