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PubMed1983

High-pressure liquid chromatographic analysis of aztreonam in sera and urine.

Aztreonam (SQ 26,776) is a new synthetic monocyclic beta-lactam antibiotic which is specifically active against aerobic gram-negative bacteria. High-pressure liquid chromatographic (HPLC) systems were developed for the quantitative analysis of aztreonam in human, monkey, rat, mouse, and rabbit sera and urine. The HPLC conditions employed for these analyses were a muBondapak C18 column, a mobile phase made up of 0.005 M tetrabutylammonium hydrogen sulfate at pH 3.0 and acetonitrile or methanol, UV detection at 293 nm, and a flow rate of 2.0 ml/min. For human sera and urine, the mobile phase was 80% 0.005 M tetrabutylammonium hydrogen sulfate-0.005M (NH4)2SO4 and 20% acetonitrile (vol/vol). For the range of sera and urine, HPLC analyses were shown to have excellent detector linearity of aztreonam over a concentration range of 1.0 mg/ml to 0.5 microgram/ml. Correlation coefficients for plots of aztreonam peak area versus its concentration were greater than or equal to 0.990. The detection limit of aztreonam was 1.0 micrograms/ml in sera and 5.0 micrograms/ml in urine. HPLC and microbiological assays of aztreonam in human sera and urine were in good agreement.

Animals↗

PubMed1983

Evaluation of aztreonam in experimental bacterial meningitis and cerebritis.

Aztreonam (SQ 26,776), a new monocyclic beta-lactam agent, was compared with ampicillin, ampicillin plus chloramphenicol, and gentamicin in rabbits with experimental meningitis induced by, respectively, ampicillin-susceptible Haemophilus influenzae, ampicillin-resistant H. influenzae, and Escherichia coli. Aztreonam was also compared with gentamicin in experimentally induced E. coli cerebritis in rats. Doses of the various agents were delivered that produced near-peak concentrations in serum comparable to those attained in humans on standard parenteral regimens. The percent penetration [( concentration in cerebrospinal fluid/concentration in serum] X 100) of aztreonam into purulent rabbit cerebrospinal fluid was 23% (versus 12, 27, and 21%, respectively, for ampicillin, chloramphenicol, and gentamicin). In experimental meningitis in vivo, aztreonam was more rapidly bactericidal than was ampicillin in ampicillin-susceptible H. influenzae meningitis, ampicillin or chloramphenicol in ampicillin-resistant H. influenzae meningitis, or gentamicin in E. coli meningitis. In the therapy of experimental cerebritis, the early stage of brain abscess formation, aztreonam reduced the numbers of E. coli in rat brain as rapidly as did gentamicin. Aztreonam deserves further evaluation in acute gram-negative bacterial infections of the central nervous system in both experimental animals and in humans.

Animals↗

PubMed1984

Disposition of [14C]aztreonam in rats, dogs, and monkeys.

[14C]aztreonam was administered as single 25-mg/kg doses to dogs (intravenously and subcutaneously) and monkeys (intramuscularly and intravenously) and as single 50-mg/kg doses (intramuscularly and intravenously) to rats. In rats and dogs, radioactive moieties were excreted primarily in urine; in monkeys, they were excreted about equally in urine and feces. Unchanged aztreonam accounted for 77 to 86% of the radioactivity excreted in the urine of rats, dogs, and monkeys; SQ 26,992, the metabolite resulting from hydrolysis of the monobactam ring, accounted for 10 to 15%; and minor, unidentified metabolites accounted for the remainder. In rats with cannulated bile ducts, about 15% of an intramuscular dose was excreted in bile in 24 h; the bile contained a greater percentage of metabolites than that found in urine. In dogs, the apparent elimination half-life of aztreonam in serum was 0.7 h after intravenous administration. Aztreonam and SQ 26,992 accounted for most of the radioactivity in the sera of dogs and monkeys. Serum protein binding of aztreonam and its metabolites ranged from 28 to 35% in dogs and from 49 to 59% in monkeys. In the three species studied, aztreonam was most extensively metabolized in monkeys; SQ 26,992 and other minor metabolites from monkey urine were tested and found to be devoid of any significant antimicrobial activity.

Animals↗

PubMed1984

Clinical pharmacokinetics of aztreonam in cancer patients.

The pharmacokinetics of aztreonam were studied in 25 adult patients with hematological malignancies. Two groups of nine patients each received aztreonam (1 or 2 g every 8 h) prophylactically, and seven infected patients received a therapeutic regimen of aztreonam (1.5 g every 4 h). The mean peak serum concentration after a 1-g dose of aztreonam (given over 0.5 h on day 1) was 75.5 micrograms/ml; after a 2-g dose it was 177.2 micrograms/ml. The mean peak serum concentration after a 1.5-g dose of aztreonam (given over 2 h on day 1) was 68.5 micrograms/ml. The serum half-life ranged between 1.7 and 2.0 h for all regimens studied. The urinary concentration of the metabolite of aztreonam, SQ 26,992, increased during 1 week of administration of the drug; however, serum levels of the metabolite were barely detectable.

Adolescent↗

PubMed1984

Effects of cirrhosis on kinetics of aztreonam.

Aztreonam was administered as a single, 3-min, 1-g intravenous infusion to 18 subjects, including 6 with biopsy-proven, primary biliary cirrhosis, 6 with biopsy-proven, stable alcoholic cirrhosis, and 6 age- and sex-matched control subjects with normal hepatic functions. Aztreonam was well tolerated by all subjects. Multiple blood samples and timed, cumulative urine samples were taken for assay of aztreonam content and determination of pharmacokinetic profiles. Protein-free filtrates of serum were also assayed for drug levels. Analyses by microbiological and high-pressure liquid chromatographic procedures gave equivalent results. The kinetic data were described by an open, linear, two-compartment model. There were significant differences in elimination half-life (3.2 versus 1.9 h), serum clearance (0.8 versus 1.1 ml/min per kg), and nonrenal clearance (0.2 versus 0.4 ml/min per kg) between the alcoholic cirrhosis group and the normal control group and in elimination half-life (2.2 versus 1.9 h) between the primary biliary cirrhosis group and the normal control group. There was also a difference in nonrenal clearance between the alcoholic cirrhosis and primary biliary cirrhosis groups (0.2 versus 0.5 ml/min per kg). Although the handling of aztreonam differed in the three groups, the magnitude of the difference would warrant a change in aztreonam dosing only for the alcoholic cirrhosis group. In this group, dose adjustment might be required if long-term therapy with high doses of aztreonam is indicated.

Anti-Bacterial Agents↗

PubMed1986

Penetration of aztreonam into cerebrospinal fluid and brain of noninfected rabbits and rabbits with experimental meningitis caused by Pseudomonas aeruginosa.

This study examined the penetration of aztreonam into the cerebrospinal fluid (CSF) and brain in noninfected rabbits and rabbits with experimental meningitis caused by Pseudomonas aeruginosa. Animals received either 600 or 1,200 mg of aztreonam administered intravenously over 6 h. Aztreonam did not readily enter the CSF in the absence of meningitis. In noninfected animals, mean concentrations in the CSF ranged from 1.1 to 3.0 micrograms/ml with the 600-mg dose and from 2.3 to 4.7 micrograms/ml with the 1,200-mg dose. In contrast, mean concentrations of aztreonam in the CSF were significantly higher (P less than 0.01) at each sampling time in rabbits with experimental meningitis caused by P. aeruginosa. They ranged from 10.2 to 14.6 micrograms/ml with the 600-mg dose and from 29 to 40 micrograms/ml with the 1,200-mg dose. Although concentrations in the brain measured at 6 h tended to be higher in infected rabbits, this difference was not statistically significant. Aztreonam therapy produced a substantial decline in CSF bacterium counts over 6 h: mean CSF counts decreased 2.4 log10 CFU/ml in the 600-mg dose group and 3.0 log10 CFU/ml in the 1,200-mg dose group. The results of this study suggest that aztreonam may be useful in the therapy of meningitis caused by P. aeruginosa.

Animals↗

PubMed1990

Effects of aztreonam on fecal flora and on vitamin K metabolism.

The effects of aztreonam on fecal flora and on descarboxy prothrombin (PIVKA-II) in plasma and gamma-carboxyglutamic acid (Gla) in urine as an index of vitamin K metabolism were studied in seven children (age range, 2 months to 2 years) with urinary tract infections. Daily doses of aztreonam were 60 to 80 mg/kg. Stool specimens were obtained before the treatment, on days 3 to 5 of aztreonam use, and from 3 to 5 days after the cessation of treatment. The counts of enterobacteria decreased (P less than 0.01) and those of streptococci increased (P less than 0.05) during aztreonam treatment. The anaerobic organisms, especially bifidobacteria and bacteroides, showed no marked change. PIVKA-II and Gla were investigated before and during the treatment with aztreonam. PIVKA-II was not detected in seven patients before or during aztreonam use. There were no significant differences in the levels of Gla in urine before or during the treatment.

1-Carboxyglutamic Acid↗

PubMed1991

Comparison of the effects of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo.

A study was performed to investigate the pharmacodynamics of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo. The in vitro concentration-effect relationships were determined in short-term growth experiments. The in vivo dose-effect relationships were determined in an experimental thigh muscle infection in irradiated mice. In this model, E. coli was injected into one thigh muscle and K. pneumoniae was injected into the other. Throughout these experiments aztreonam was administered subcutaneously and tigemonam was administered orally. For analysis of the antibacterial pharmacodynamics, the following parameters were determined: the maximum effect as a parameter for efficacy, the 50% effective concentration (or dose) as a parameter for potency, and the slope of the concentration-effect relationship. To assess the relationship between the concentration of the antibiotic and the antibacterial effect in vivo, the pharmacokinetics of the two drugs in the plasma of mice were determined as well. The maximum in vitro and in vivo effects of aztreonam and tigemonam against both bacteria did not differ substantially. However, both drugs killed E. coli more effectively than K. pneumoniae, indicating that the maximum in vitro effect of these drugs against E. coli was higher than that against K. pneumoniae. The maximum in vivo effect of both drugs against E. coli was similar to that against K. pneumoniae. Furthermore, in vitro aztreonam was about twice as potent as tigemonam, but in vivo the reverse was the case. These findings were explained by pharmacokinetic differences between subcutaneously administered aztreonam and orally administered tigemonam, because concentrations of tigemonam in plasma remained at microbiologically active concentrations longer than those of aztreonam did.

Animals↗

PubMed1992

Pharmacodynamics of once-daily amikacin in various combinations with cefepime, aztreonam, and ceftazidime against Pseudomonas aeruginosa in an in vitro infection model.

The pharmacodynamics of once-daily amikacin administered as monotherapy and in combination with aztreonam, ceftazidime, and cefepime against Pseudomonas aeruginosa ATCC 27853 and clinical isolate 16690 (moderately susceptible to ceftazidime) were investigated with an in vitro model of infection over a 24-h period. Monotherapy with aztreonam, ceftazidime, and cefepime and combinations of aztreonam with cefepime or ceftazidime were also studied. MICs and MBCs were determined for viable organisms at 24 h to test for the development of resistance. Once-daily amikacin demonstrated killing activity over the initial 8 h superior to those of all other drugs administered as monotherapy against both strains tested (P < 0.01). Regrowth by 24 h was greatest for the amikacin regimen (P < 0.01) but was apparent for all monotherapy regimens against both strains. No changes in susceptibilities were observed. All combination therapies containing once-daily amikacin achieved 99.9% reductions in log10 CFU/ml by 2.0 h against both strains, with no regrowth of organisms at 24 h. Aztreonam-cefepime and -ceftazidime combinations required approximately 5 to 6 h to achieve a 99.9% reduction in log10 CFU/ml. Although there was no difference in time to the 99.9% kill between the aztreonam-cefepime and -ceftazidime regimens against either strain, the killing activity of these combinations was significantly less than those of regimens containing once-daily amikacin (P < 0.01). Minor differences in the initial susceptibilities of beta-lactams and the monobactam aztreonam against P. aeruginosa may not be important for therapeutic outcomes when used in combination with single-daily aminoglycoside therapy.

Amikacin↗

PubMed1994

Randomized comparison of aztreonam and chloramphenicol in treatment of typhoid fever.

Patients with clinical typhoid fever plus a blood, bone marrow, or bile positive for Salmonella typhi or Salmonella paratyphi were included in an open clinical trial to compare the efficacy of aztreonam (6 g/day [2 g intravenously every 8 h]) given for 10 days with that of chloramphenicol (50 mg/kg of body weight per day [intravenously or orally]) administered for 14 days. A total of 44 patients, 22 in each group, were included in the study, and both groups were comparable in terms of baseline parameters. All patients randomized to receive chloramphenicol completed the 14 days of treatment, while two patients randomized to receive aztreonam developed an intestinal hemorrhage, and a third patient elected to withdraw from the trial. Defervescence occurred more quickly in the subjects receiving chloramphenicol than in those receiving aztreonam (P < 0.05). All patients in the chloramphenicol group were clinically cured during therapy, while four patients (21%) in the group receiving aztreonam were declared clinical treatment failures. None of the 19 patients receiving aztreonam, compared with 7 of 22 (32%) patients receiving chloramphenicol, had a positive blood culture after 24 h of therapy (P < 0.05). Adverse experiences were unusual and mild. In the study, aztreonam was less effective than chloramphenicol with regard to clinical effectiveness and time of defervescence but was more effective in the elimination of the infecting Salmonella organisms from the bloodstream.

Adolescent↗

PubMed1997

Differential distributions in tissues and efficacies of aztreonam and ceftazidime and in vivo bacterial morphological changes following treatment.

The differential tissue distributions of aztreonam and ceftazidime within fibrin clots infected with Pseudomonas aeruginosa, Enterobacter cloacae, and Serratia marcescens, their efficacies, and the in vivo bacterial morphological changes induced by these drugs were evaluated. Rabbits were given intravenously a single dose of 100 mg of either agents/kg of body weight. In the cores of the clots, the peak levels of both drugs were much lower than those observed in the peripheries and in serum. Aztreonam's half-lives within the peripheries and in the cores of the fibrin clots were up to six times higher than observed in serum, while ceftazidime's half-lives in clots were twice that observed in serum. This resulted in a much greater penetration ratio for aztreonam than for ceftazidime. Both drugs controlled the growth of P. aeruginosa in vivo, but E. cloacae and S. marcescens responded better to ceftazidime. Morphological changes were more abundant in the peripheries than in the cores of the clots. In the control group, P. aeruginosa's morphology in the cores was different than that in the peripheries of the clots. Against P. aeruginosa, aztreonam did induce morphological changes in the cores while ceftazidime did not. Electron microscopic studies revealed that morphological changes associated with aztreonam seemed different than those of ceftazidime. Along with elongation of bacteria, more bow tie and herniated bacteria were observed with aztreonam. Though both agents selectively affect PBP 3, as manifested by elongated bacteria, they induce in the peripheries of the clots thickening, breaks, and detachment in bacterial cell walls, alterations which are generally associated with antibiotics affecting PBP 1a and 1b.

Animals↗

PubMed1994

Aztreonam decreases hepatic microsomal cytochrome P450 in cynomolgus monkeys.

We examined the effect of successive administrations of aztreonam, which is used clinically as an antibiotic, on the mixed function oxidase system in non-human primates. Treatment of cynomolgus monkeys with aztreonam at doses of between 40 and 300 mg/kg for 4 weeks resulted in a significant decrease in the content of hepatic microsomal P450. On the other hand, no significant change was observed in hepatic cytochrome b5 content and NADPH-cytochrome c (P450) reductase activity following treatment with aztreonam. The activity of testosterone 6 beta-hydroxylase, but not 2 beta- and 16 alpha-hydroxylases in hepatic microsomes, was decreased following the treatment of cynomolgus monkeys with aztreonam. The content of P450 CMLc, which is classified into the 3A subfamily, was also decreased by aztreonam treatment although the content of P450 CMLb, which is a 2A enzyme in cynomolgus monkeys, was unchanged. From these results, we concluded that aztreonam decreased P450 CMLc in hepatic microsomes of cynomolgus monkeys.

Animals↗

PubMed1987

Effects of the monobactam antibiotic aztreonam on platelet function and blood coagulation.

The effects of the new monobactam antibiotic aztreonam on platelet function and blood coagulation were evaluated both in vitro and ex vivo. In the in vitro studies carried out on platelets from 6 healthy volunteers, therapeutic concentrations of aztreonam had no effect on platelet function. Aztreonam inhibited platelet aggregation only at concentrations far in excess of those clinically achievable. In the ex vivo studies carried out in 11 patients with aztreonam-sensitive infections, aztreonam, 1 g t.i.d. intravenously, did not produce any effect on platelet function and blood coagulation. We conclude that therapeutic doses of aztreonam appear not to affect haemostasis.

Adenosine Diphosphate↗

PubMed1989

A multicenter comparative trial of aztreonam in the treatment of gram-negative infections in compromised intensive-care patients.

A multicenter comparative trial was conducted in 4 university hospitals to evaluate the efficacy of aztreonam, a new monobactam antibiotic. All patients enrolled in the study were admitted to the intensive-care unit with severe underlying conditions. A total of 167 infections were documented in 157 patients (78 pneumonia, 26 urinary tract infection, 23 peritonitis, and 40 septicemia). The study was performed in 2 phases. In phase 1, 49 patients receiving aztreonam were compared with 26 receiving amikacin. These two drugs were administered as the sole coverage against gram-negative bacilli. In phase 2, 48 patients treated with aztreonam were compared with 34 who received a synergistic combination of amikacin and a broad-spectrum beta-lactam. The results suggest that aztreonam can be used as monotherapy in the treatment of systemic gram-negative infections with an efficacy comparable with that of standard antimicrobial therapy. Aztreonam is probably more effective than amikacin in treating respiratory tract infections and it is at least as effective as a beta-lactam-aminoglycoside combination. An adequate standard dosage of aztreonam could be established as 3-4 g/day in compromised patients, and it should be combined with gram-positive coverage when used empirically.

Adult↗

PubMed1989

Multicenter study of aztreonam in the prophylaxis of colorectal, gynecologic and urologic surgery.

The preliminary results of four multicenter, comparative protocols on the efficacy and safety of aztreonam are discussed. This monobactam antibiotic was used as short-term prophylaxis in patients undergoing colorectal, gynecologic or urologic surgery. When compared with gentamicin in a group of 295 patients undergoing colorectal surgery, aztreonam significantly reduced the incidence of abdominal wound infection (p less than 0.025); it also reduced the incidence of perineal wound and intra-abdominal infections, although these differences were not statistically significant. In patients undergoing abdominal and vaginal hysterectomy, aztreonam was compared with cefotaxime (both combined with clindamycin) in 170 and 142 patients, respectively. No difference in the incidence of infection was found between the two treatment regimens. In the 175 patients undergoing transurethral resection of the prostate, aztreonam was compared with placebo. The prophylactic regimen significantly reduced the number of urinary tract infections (p less than or equal to 0.0001). Its efficacy was particularly evident during the first 10 postoperative days. Side effects experienced by patients taking aztreonam were minor and similar in all three treatment groups studied. Aztreonam (alone or combined with clindamycin) offers a new and efficacious alternative to the standard antibiotic regimens currently used prophylactically in the high-risk postoperative patient.

Abdomen↗

PubMed1989

Comparative in vitro antibacterial activity of aztreonam against clinical isolates of gram-negative bacteria.

The in vitro antibacterial activity of aztreonam was compared with that of cefoperazone, cefotaxime, ceftazidime, gentamicin, latamoxef, and ticarcillin against 140 clinical isolates of gram-negative bacteria. The activity of aztreonam against Enterobacteriaceae is similar to that of cefotaxime and ceftazidime but greater than that of gentamicin, latamoxef, and ticarcillin. The 90% minimum inhibitory concentration (MIC90) of most of these isolates ranges between 0.8 and 1.6 micrograms/ml. The activity of aztreonam against Pseudomonas aeruginosa is similar to that of cefotaxime and cefoperazone, more active than that of latamoxef, and less active than that of ceftazidime. The minimum bactericidal concentration of aztreonam is equal to or twice the MIC for most strains tested. Time-kill studies of selected strains demonstrated rapid killing when they were exposed to 2-4 times the MIC of aztreonam. The selective spectrum of action of aztreonam makes this drug a useful agent in the therapy of a variety of gram-negative infections.

Aztreonam↗

PubMed1989

Comparative study of aztreonam in gram-negative pneumonia versus a therapeutic regimen that includes an aminoglycoside. Spanish Study Group.

Gram-negative pneumonia is a frequent complication in hospitalized patients, particularly in those with diminished defenses. The severity of the infections makes it necessary to start immediately an empirical antimicrobial therapy that usually combines a broad-spectrum beta-lactam antibiotic with an aminoglycoside (AMG), despite the potential toxicity of this regimen. We have compared the efficacy of a new beta-lactam antibiotic, aztreonam, which shows both a specific spectrum of activity against gram-negative bacteria and a very good diffusion into pulmonary tissue, with that of another antibiotic regimen including an AMG. Of a total of 69 patients, 43 were treated with aztreonam and the remaining patients with an AMG. Both groups were comparable with respect to the severity of infection and underlying pathology. Clinical efficacy was similar in the two regimens (81% aztreonam, 62% AMG). However, antimicrobial efficacy was superior in the aztreonam group (88% aztreonam, 65% AMG), although differences disappeared in patients treated with the combination amikacin + cefotaxime or ticarcillin in the AMG group. Colonization/superinfection was also similar in both groups, although the selection of gram-negative bacteria occurred more frequently in the AMG group. Our results suggest that aztreonam, in monotherapy, may be a useful alternative for the treatment of gram-negative pneumonia.

Adult↗

PubMed1999

A pharmacokinetic evaluation of concomitant administration of linezolid and aztreonam.

Linezolid, a new oxazolidinone antimicrobial agent, has a spectrum of activity encompassing a wide variety of Grampositive bacteria. The purpose of this study was to evaluate the pharmacokinetics of linezolid and aztreonam, an antimicrobial agent with selective activity against Gram-negative bacteria, when given alone and in combination. Healthy subjects were randomized to receive single, 30-minute intravenous infusions of (1) linezolid 375 mg, (2) aztreonam 1000 mg, and (3) linezolid 375 mg plus aztreonam 1000 mg in an open-label, crossover manner. The only statistically significant differences observed with combination treatment relative to each drug alone were an increase in the maximum plasma concentration of linezolid (approximately 18%) and an approximate 7% decrease in the apparent elimination rate of aztreonam, neither of which are expected to be clinically significant. In healthy subjects, the combination of linezolid and aztreonam was safe and well tolerated compared with each agent used alone. Pharmacokinetic data demonstrate that coadministration of linezolid and aztreonam does not alter the disposition of either agent under single-dose conditions. Therefore, it is not expected that a dose alteration of either agent will be necessary in a clinical setting.

Acetamides↗