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PubMed2000

High incidence of Klebsiella pneumoniae clinical isolates to extended-spectrum B-lactam drugs in intensive care units.

A prospective study conducted among Jordanian ICU patients in 1997 using Etest identified resistance rates among isolates of E. coli (25%-44%), Enterobacter spp. (54%-62%), and Klebsiella spp. (30%-80%) to extended-spectrum B-lactams (ESBLs): ceftazidime, cefotaxime, ceftriaxone, and aztreonam. All these isolates were susceptible to imipenem and showed low resistance rate to ciprofloxacin (5%-19%) and amikacin (13%-18%). Higher and significant resistance rates of Klebsiella isolates to ceftazidime (80%) and aztreonam (65%) were observed in 1997 compared with a previous study performed in 1994. The majority of Klebsiella pneumoniae (70%) express different ESBL phenotypes that were almost resistant to aztreonam and ceftazidime but susceptible or resistant to cefotaxime and/or ceftriaxone. This prospective study strongly suggests that ESBL production of Klebsiella pneumoniae isolates have been highly disseminated among ICU patients during 1997.

Aztreonam↗

PubMed2006

Molecular dynamics simulations of class C beta-lactamase from Citrobacter freundii: insights into the base catalyst for acylation.

Herein, we present results from molecular dynamics (MD) simulations of the class C beta-lactamase from Citrobacter freundii and its Michaelis complex with aztreonam. Four different configurations of the active site were modeled in aqueous solution, and their relative stability was estimated by means of quantum mechanical energy calculations. For the free enzyme, the energetically most stable configurations present a neutral Lys67 residue or an anionic Tyr150 side chain. Our calculations predict that these two configurations are quite close in terms of free energy, the anionic Tyr150 state being favored by approximately 1 kcal/mol. In contrast, for the noncovalent complex formed between the C. freundii enzyme and aztreonam, the energetic analyses predict that the configuration with the neutral Lys67 residue is much more stable than the anionic Tyr150 one (approximately 20 kcal/mol). Moreover, the MD simulations reveal that the neutral Lys67 state results in a proper enzyme-aztreonam orientation for nucleophilic attack and in a very stable contact between the nucleophilic hydroxyl group of Ser64 and the neutral amino side chain of Lys67. Thus, both the computed free energies and the structural analyses support the assignation of Lys67 as the base catalyst for the acylation step in the native form of the C. freundii enzyme.

Acylation↗

PubMed1991

Interaction of metronidazole with antibiotics containing the 2-aminothiazole moiety.

The mechanism of possible incompatibility between commercially available metronidazole parenteral solutions and the injectable aztreonam leading to the development of pink color in their intravenous admixtures was studied. It was demonstrated that nitrite ions may be produced in metronidazole solutions at the time of preparation or during storage by the effects of temperature and light. Under acidic pH conditions of admixtures the aminothiazole moiety of aztreonam was diazotized by the nitrite ion contributed by metronidazole solutions. The diazotized molecule, in turn, reacted with another aztreonam molecule by diazo-coupling. The resultant pink-colored product was isolated by chromatography and its structure was determined by mass spectral and NMR analyses. Other beta-lactam antibiotics containing the 2-aminothiazole moiety also react in acidic media in a similar manner.

Aztreonam↗

PubMed2001

The effect of acetazolamide on the kinetics of four newer beta-lactams in the aqueous humor.

OBJECTIVE: To evaluate whether the effect of acetazolamide on piperacillin's aqueous humor concentrations observed in animals exists also in humans for ceftazidime, cefotaxime, ceftriaxone and aztreonam. METHODS: One hundred and eighty-eight patients undergoing eye cataract surgery were randomly allocated to receive intravenous ceftazidime, cefotaxime, aztreonam or ceftriaxone with (subgroup A) or without (subgroup B) concomitant oral administration of acetazolamide. Antibiotic concentrations in serum and the aqueous humor, simultaneously sampled during the operation, were measured using an agar well diffusion technique, and the ratios of the concentrations of aqueous humor to serum were calculated and compared. Statistical analysis was performed by using the paired t-test. RESULTS: Mean aqueous humor ceftazidime concentrations at 2, 4 and 6 h were 24.65, 16.4 and 8.6 mg/L (subgroup A), and 4.26, 8.66 and 5.61 mg/L (subgroup B). Corresponding concentrations of cefotaxime were 1.75, 1.0 and 0.77 mg/L (subgroup A), and 1.11, 0.81 and 0.58 mg/L (subgroup B), and of aztreonam 6.9, 5.84 and 3.61 mg/L (subgroup A), and 3.38, 2.57 and 1.48 mg/L (subgroup B). Ceftriaxone concentrations at 2, 4, 6 and 12 h were 1.78, 1.49, 1.57 and 1.41 mg/L (subgroup A), and 1.35, 0.95, 1.08 and 0.85 mg/L (subgroup B). The differences in aqueous humor concentrations when acetazolamide was administered were statistically significant (P < 0.05), with the exception of ceftazidime 6 h, cefotaxime 6 h and ceftriaxone 2 h. CONCLUSIONS: Although acetazolamide resulted in statistically significant increases in the aqueous humor concentrations of all the antibiotics tested, this effect was most marked for ceftazidime.

Acetazolamide↗

PubMed2001

beta-Lactam-susceptibility patterns of Plesiomonas shigelloides strains: importance of inoculum and medium.

The susceptibility of 10 Plesiomonas shigelloides strains to 30 beta-lactam antibiotics was examined. Susceptibility testing was carried out with a microdilution procedure using 3 media (Isosensitest broth, Mueller-Hinton broth and cation-adjusted Mueller-Hinton broth) and 4 inocula [1 x 10(4), 1 x 10(5), 1 x 10(6) and 1 x 10(7) colony-forming units (CFU)/ml]. A high inoculum dependency of MIC values was found for numerous beta-lactams. Each strain showed 2 completely different susceptibility patterns to several cephalosporins and aztreonam, but the same patterns were found with little variation in each strain. Using an inoculum of 1 x 10(4) CFU/ml the strains showed a high susceptibility to aztreonam and to all cephalosporins in all media (pattern 1), whereas they showed a decreased susceptibility to aztreonam and numerous cephalosporins with an inoculum of 1 x 10(7) CFU/ml (pattern 2). Using an inoculum of 1 x 10(6) CFU/ml, 4/10 strains in lsosensitest broth and 2/10 strains in Mueller-Hinton media showed pattern 1. Susceptibility testing of numerous penicillins revealed a medium-independent inoculum dependency, characterized by a step-to-step correlation between MICs and inocula. The beta-lactam susceptibility patterns arising from different inocula point to new beta-lactamase expression and regulation mechanisms in Plesiomonas. The potential to be resistant to a variety of beta-lactams under conceivable testing conditions should question the use of numerous beta-lactams for the treatment of Plesiomonas infections.

Animals↗

PubMed1986

Bactericidal and bacteriolytic activities of carumonam and its effect on bacterial morphology.

The in-vitro bactericidal and bacteriolytic activities and the effect on bacterial morphology of carumonam, a new N-sulfonated monocyclic beta-lactam antibiotic, against aerobic Gram-negative bacilli were compared with those of aztreonam. Both antibiotics, at their minimal inhibitory concentration (MIC) levels, were strongly bactericidal against species of Enterobacteriaceae, but weakly bactericidal against Pseudomonas aeruginosa. Their bactericidal activity was not increased by increasing the antibiotic concentration above the MICs. In contrast to this potent bactericidal activity, the bacteriolytic activity of carumonam and aztreonam was low and limited to enteric bacterial species like Escherichia coli. Filamentation was the major morphological change of Gram-negative bacilli after exposure to carumonam and aztreonam. E. coli and Serratia marcescens, but not P. aeruginosa, were converted to ghosts after prolonged incubation with carumonam.

Anti-Bacterial Agents↗

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↗

PubMed1987

Comparative bactericidal activity of cefixime, carumonam, enoxacin and roxithromycin with those of other antibiotics against resistant Haemophilus influenzae including beta-lactam tolerant strains.

One hundred isolates of Haemophilus influenzae including 50 beta-lactamase producing, five ampicillin-resistant non-beta-lactamase producing and five beta-lactam tolerant strains were tested for susceptibility (MICs and MBCs) to ampicillin, aztreonam, carumonam, cefixime, cefaclor, cefamandole, cefotaxime, imipenem, enoxacin, ciprofloxacin, roxithromycin, erythromycin, chloramphenicol, and co-trimoxazole, by a microdilution broth method. Cefotaxime, enoxacin and ciprofloxacin with MIC90 and MBC90 of less than 0.03 mg/l) were the most active antimicrobial agents tested. Cefixime, carumonam, aztreonam, and co-trimoxazole (MIC90 and MBC90 less than 0.25 mg/l) showed good activity against most strains. Roxithromycin and erythromycin had limited antibacterial activity (MIC90, 8 and 4 mg/l respectively). There were no chloramphenicol-resistant strains. Five beta-lactamase-negative strains were resistant to ampicillin, cefaclor and cefamandole but susceptible to other beta-lactams tested. Different patterns of tolerance were observed: four of five tolerant strains were tolerant to ampicillin and cefamandole, three to cefixime, cefaclor and cefotaxime, one to aztreonam. One tolerant strain was a beta-lactamase producer. Two other strains were tolerant only to co-trimoxazole.

Ampicillin↗

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↗

PubMed1989

Overproduced beta-lactamase and the outer-membrane barrier as resistance factors in Serratia marcescens highly resistant to beta-lactamase-stable beta-lactam antibiotics.

In a clinical isolate of Serratia marcescens different states of low and high resistance to different beta-lactam antibiotics considered to be beta-lactamase-stable, viz. cefotaxime, ceftizoxime, ceftazidime, aztreonam, cefoxitin and imipenem, were found to be connected with the presence of constitutively overproduced, chromosomally encoded beta-lactamase at concentrations in the bacterial periplasm of 0.4 and 0.9 mM, respectively. All the antibiotics were degraded by the beta-lactamase. However, kinetic constants varied widely: k(m) from 92 to 0.012 microM and k(cat) from 3.4 to 2x10(-4)s(-1). The relative contributions to resistance by the functioning of periplasmic beta-lactamase, resynthesis of this enzyme, and limitation of antibiotic penetration by the bacterial outer membrane were analysed by computer simulations according to steady-state and non-steady-state models of interactions in the periplasm. Results for cefotaxime, ceftizomime, ceftazidime, aztreonam and latamoxef revealed overproduced beta-lactamase as the sole cause of the state of low resistance while antibiotic permeability was the same as in non-resistant S. marcescens strains. In contrast, high resistance was due to beta-lactamase action and decreased permeability of antibiotics. For resistance to aztreonam, only, immobilization of the antibiotic as covalent acyl-enzyme by newly synthesized beta-lactamase was essential. For cefoxitin, ampicillin and imipenem the analyses indicated that additional resistance factors may play a role, e.g. induction of beta-lactamase.

Anti-Bacterial Agents↗

PubMed1984

Antagonism by chloramphenicol of broad-spectrum beta-lactam antibiotics against Klebsiella pneumoniae.

Chloramphenicol combined with cefotaxime, moxalactam, cefoperazone, aztreonam, or imipenem was tested in vitro against clinical isolates of Klebsiella pneumoniae. By time-kill cultures (killing curves), chloramphenicol interfered with activity of all five beta-lactams. When chloramphenicol was added before the beta-lactams, the action of cefotaxime, moxalactam, or cefoperazone against all isolates was antagonized at all times tested. The action of aztreonam was antagonized against four of six isolates. With imipenem, antagonism occurred against half of the isolates at some time during 24 h when chloramphenicol was added simultaneously, provided that a sufficient inoculum of K. pneumoniae was employed. Generally, less antagonism resulted when chloramphenicol was added after the cephalosporins. Interference of bactericidal activity of three new cephalosporins by chloramphenicol has potential clinical relevance to the therapy of gram-negative bacillary meningitis. The lesser antagonism of aztreonam and imipenem by chloramphenicol is of uncertain clinical relevance but indicates that this in vitro phenomenon may apply to a wide range of beta-lactam antibiotics.

Anti-Bacterial Agents↗

PubMed1985

In vitro studies of investigational beta-lactams as possible therapy for Pseudomonas aeruginosa endocarditis.

The inadequacy of the present medical therapy of Pseudomonas aeruginosa endocarditis prompted an investigation of the in vitro activities of aztreonam, cefsulodin, and imipenem compared with that of ticarcillin against 37 strains of P. aeruginosa isolated from patients with endocarditis. Inhibitory and bactericidal activities were studied for each beta-lactam alone and in combination with tobramycin. All agents showed excellent inhibitory activity. Imipenem was the most inhibitory beta-lactam yet lacked inhibitory synergy against 95% of the strains and bactericidal synergy against 62%. Tolerance to imipenem was seen in six strains. Aztreonam alone was bactericidal against 46% of the strains (at 16 micrograms/ml) and showed bactericidal synergy in 70%. Cefsulodin alone was even less active but similar to aztreonam synergistically. Ticarcillin and tobramycin inhibited all strains as single agents and showed universal bactericidal synergy in combination. None of the new beta-lactams showed consistent superiority to the presently used agent, ticarcillin.

Anti-Bacterial Agents↗

PubMed1986

Antibacterial activity of Ro 17-2301 and other antimicrobial agents against cefotaxime-resistant aerobic gram-negative bacilli.

The in vitro activity of Ro 17-2301 was determined and compared with those of aztreonam, ceftazidime, amikacin, and piperacillin against 141 cefotaxime-resistant gram-negative bacilli. Ro 17-2301 was bactericidal, and its activity against the majority of these organisms was equal or superior to those of ceftazidime, aztreonam, and piperacillin. An inoculum effect of Ro 17-2301 and aztreonam for many Pseudomonas aeruginosa and Enterobacter spp. isolates was demonstrated.

Anti-Bacterial Agents↗

PubMed1987

Effect of broad-spectrum parenteral antibiotics on composition of intestinal microflora of humans.

We compared the effects of four beta-lactam drugs with widely differing antibacterial and pharmacological properties on the composition of the intestinal flora. Cefoxitin, piperacillin, cefoperazone, and aztreonam were given intravenously for 9 days to healthy volunteers. Cefoperazone reduced the numbers of aerobic and anaerobic bacteria to undetectable levels. At the other extreme, cefoxitin had little effect on the normal flora. Aztreonam markedly reduced the numbers of aerobes, whereas piperacillin had a variable effect on both aerobic and anaerobic bacteria. There was extensive overgrowth of enterococci in subjects given cefoxitin or aztreonam, which have little activity against this species, and of yeasts in subjects given cefoperazone or piperacillin. Cefoperazone reached concentrations of 2,727 to 8,840 micrograms/g in the feces, whereas the other agents were generally undetectable. These results show that the new beta-lactam antibiotics produce widely varying effects on the fecal microflora after parenteral administration and that these effects are consistent with the antibacterial and pharmacological properties of the drugs.

Adult↗

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↗

PubMed2004

Role of a mutation at position 167 of CTX-M-19 in ceftazidime hydrolysis.

CTX-M-19 is a recently identified ceftazidime-hydrolyzing extended-spectrum beta-lactamase, which differs from the majority of CTX-M-type beta-lactamases that preferentially hydrolyze cefotaxime but not ceftazidime. To elucidate the mechanism of ceftazidime hydrolysis by CTX-M-19, the beta-lactam MICs of a CTX-M-19 producer, and the kinetic parameters of the enzyme were confirmed. We reconfirmed here that CTX-M-19 is also stable at a high enzyme concentration in the presence of bovine serum albumin (20 micro g/ml). Under this condition, we obtained more accurate kinetic parameters and determined that cefotaxime (k(cat)/K(m), 1.47 x 10(6) s(-1) M(-1)), cefoxitin (k(cat)/K(m), 62.2 s(-1) M(-1)), and aztreonam (k(cat)/K(m), 1.34 x 10(3) s(-1) M(-1)) are good substrates and that imipenem (k(+2)/K, 1.20 x 10(2) s(-1) M(-1)) is a poor substrate. However, CTX-M-18 and CTX-M-19 exhibited too high a K(m) value (2.7 to 5.6 mM) against ceftazidime to obtain their catalytic activity (k(cat)). Comparison of the MICs with the catalytic efficiency (k(cat)/K(m)) of these enzymes showed that some beta-lactams, including cefotaxime, ceftazidime, and aztreonam showed a similar correlation. Using the previously reported crystal structure of the Toho-1 beta-lactamase, which belongs to the CTX-M-type beta-lactamase group, we have suggested characteristic interactions between the enzymes and the beta-lactams ceftazidime, cefotaxime, and aztreonam by molecular modeling. Aminothiazole-bearing beta-lactams require a displacement of the aminothiazole moiety due to a severe steric interaction with the hydroxyl group of Ser167 in CTX-M-19, and the displacement affects the interaction between Ser130 and the acidic group such as carboxylate and sulfonate of beta-lactams.

Aztreonam↗

PubMed1992

Enterobacteriaceae and neonatal necrotising enterocolitis.

A comparative study of bowel colonisation and incidence of necrotising enterocolitis in neonates admitted to an intensive care unit is reported. Neonates of less than 33 weeks gestational age requiring mechanical ventilation for respiratory distress syndrome were randomised during the first week of life to receive either vancomycin and aztreonam or vancomycin and gentamicin for episodes of suspected sepsis after the first week of life. A higher proportion of neonates who received vancomycin and gentamicin had faecal colonisation with enterobacteriaceae at the end of the second, third, and fourth weeks of life. Treatment with vancomycin and aztreonam was associated with a rapid quantitative reduction in faecal colonisation with enterobacteriaceae, whereas there was no quantitative reduction in colonisation with enterobacteriaceae associated with treatment with vancomycin and gentamicin. There were no differences between the two groups in faecal colonisation with anaerobes, Enterococcus sp, Staphylococcus sp, or yeasts. Six (14.6%) of 41 who received vancomycin and gentamicin compared with 0 of 40 who received vancomycin and aztreonam subsequently developed necrotising enterocolitis.

Aztreonam↗

PubMed1984

Interaction of Ro 17-2301 (AMA-1080) with beta-lactamases.

Against a variety of beta-lactamases tested, mostly of chromosomal origin, Ro 17-2301 (AMA-1080) proved to be more stable than the new cephalosporins and thus resembles aztreonam. Against the beta-lactamases from Klebsiella oxytoca and Pseudomonas vulgaris, however, Ro 17-2301 proved to be much more stable than aztreonam. Enzymatic hydrolysis, performed with the K. oxytoca beta-lactamase, yielded a single compound, viz. the microbiologically inactive, ring-opened structure. Ro 17-2301 is a potent and progressive inhibitor of cephalosporinases found, e.g., in Enterobacter cloacae and other gram-negative organisms. The IC50 and Ki values, however, showed that the affinity for these enzymes is lower than that of aztreonam.

Anti-Bacterial Agents↗