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PubMed1985

Stability of intravenous admixtures of aztreonam and clindamycin phosphate.

The stability of aztreonam and clindamycin phosphate in intravenous admixtures was studied. Each of the following combinations of drugs was added to both 5% dextrose injection and 0.9% sodium chloride injection: aztreonam 20 mg/mL and clindamycin phosphate 6 mg/mL; aztreonam 20 mg/mL and clindamycin phosphate 3 mg/mL; aztreonam 10 mg/mL and clindamycin phosphate 6 mg/mL; and aztreonam 10 mg/mL and clindamycin phosphate 3 mg/mL. One of each of these admixtures was stored at 22-23 degrees C for 48 hours and at 4 degrees C for seven days. At various storage times the admixtures were inspected for visual changes and 1-mL samples were examined microscopically for crystalline and particulate matter, tested for pH, and assayed using high-performance liquid chromatography. No visual changes were observed. The pH of admixtures decreased only slightly during storage. Concentrations of aztreonam and clindamycin phosphate under both storage conditions decreased by less than 10%. Intravenous admixtures of aztreonam and clindamycin phosphate at the concentrations studied are stable for at least 48 hours at 22-23 degrees C and at least seven days at 4 degrees C.

Ampicillin↗

PubMed1993

Pharmacokinetics of aztreonam in healthy elderly and young adult volunteers.

Aztreonam is a monobactam exhibiting an antibacterial spectrum similar to that of the aminoglycosides, with activity against aerobic gram-negative bacilli, and is the only related drug that may be given to patients hypersensitive to beta-lactams. The pharmacokinetics of aztreonam were compared in two groups of healthy volunteers. The young group comprised 10 adults between the ages of 18 and 30 years, and the elderly group included 10 adults older than 65 years of age. The two groups each received two doses (1 and 2 g) aztreonam, separated by 1 week. Although the mean peak serum concentrations of aztreonam for the two groups were similar, there were differences in other pharmacokinetic parameters. For example, for the 2-g dose the mean half-life (1.8 +/- .51 versus 3.1 +/- .9 hour), and area under the curve (AUC) (294.42 +/- 64.08 versus 469.01 +/- 144.02 micrograms x hour/mL per 1.73 m2) were less for the younger group compared with the elderly group. The mean total body clearance of aztreonam was greater for the younger than the elderly group. The results were similar to the pharmacokinetic parameters derived from the 1-g dose. These results mirror the lower creatinine clearances and higher serum creatinine levels found in the elderly group. The data suggest that lower doses of aztreonam given at less frequent intervals may be appropriate in the elderly population.

Adolescent↗

PubMedDate not supplied

Randomized comparison of aztreonam and cefuroxime in gram-negative upper urinary tract infections.

In order to evaluate the efficacy and safety of aztreonam in hospitalized patients with upper urinary tract infections (UTI), a comparative clinical study with cefuroxime was performed. 62/60% (aztreonam/cefuroxime) of the patients had a complicating factor, mostly obstructive uropathy. I.v. bolus injections were used at a dose of 1 g aztreonam or 1.5 g cefuroxime t.i.d., for a mean of 8.2 days (range: five to 14 days) except in patients with bacteraemia, who received a mean of 10.3 days (range: seven to 13 days) of therapy. 89% of the patients treated with aztreonam and 87% of those who received cefuroxime showed clinical cure and the bacteriological cure rate at one week post-therapy was 70% and 73% in the respective groups. The relapse/reinfection rate was high with both drugs; bacteriological cure at one month post-therapy was only 43% after aztreonam and 40% after cefuroxime. This suggests that these infections may need longer treatment times. Superinfections, mostly asymptomatic urinary colonization, occurred in 7% and 3%, respectively, and adverse reactions in 23% and 12%, respectively, of the patients treated with aztreonam or cefuroxime, the majority being mild and reversible and only 3% and 3%, respectively, requiring discontinuation of the therapy. The t 1/2 for aztreonam following a 1 g i.v. bolus was 2.0 h in six patients with creatinine clearance above 80 ml/min and 3.0 h in seven patients with creatinine clearance between 35-75 ml/min.

Adolescent↗

PubMed2001

Pharmacokinetics and pharmacodynamics of aztreonam and tobramycin in hospitalized patients.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) optimization of antibiotic therapy has been shown to improve outcomes in several antibiotic classes. Despite the frequent use of beta-lactams, clinical data in humans remain limited. OBJECTIVE: This study evaluated the relationship between serum pharmacokinetics, pharmacodynamics, pathogen susceptibility, and clinical outcomes in patients receiving aztreonam or tobramycin monotherapy. METHODS: The case-report forms of hospitalized patients who received either aztreonam or tobramycin for a bacterial infection in 3 clinical trials conducted between 1982 and 1984 were reviewed for the present study. A pathogen was identified for all included patients, and susceptibility testing was performed to determine the minimum inhibitory concentration (MIC) for each agent. Pharmacokinetic parameters for each antibiotic were determined using population modeling, and variables potentially related to outcomes were evaluated using tree-based modeling, logistic regression, and nonlinear regression methods. RESULTS: Data from 91 patients were analyzed, 68 treated with aztreonam monotherapy and 23 treated with tobramycin monotherapy. Of the types of infections treated, 39 were intra-abdominal, 42 involved the lower respiratory tract, and 10 involved the skin and skin structures. The pharmacodynamic ratio of the 24-hour area under the curve (AUC24) to the MIC was associated with clinical outcome for both antibiotics: aztreonam and to-bramycin patients with ratios meeting or exceeding the respective 24-hour inverse serum inhibitory titer breakpoints of 184 and 110 were significantly more likely to achieve a successful outcome than were those with ratios not meeting these values (P < 0.01). The probabilities of clinical success in patients at or above and below the AUC24/MIC breakpoints were a respective 85% and 53% for aztreonam and 80% and 47% for tobramycin (both, P < 0.01). When all patients were considered, the likelihood of achieving cure was 5.1 times greater in patients exceeding the target ratios (P < 0.01). CONCLUSION: PK/PD optimization of both aztreonam and tobramycin is associated with improved patient outcomes.

Adult↗

PubMed1996

Selection and characterization of amino acid substitutions at residues 237-240 of TEM-1 beta-lactamase with altered substrate specificity for aztreonam and ceftazidime.

Recently, natural variants of TEM-1 beta-lactamase with amino acid substitutions at residues 237-240 have been identified that have increased hydrolytic activity for extended-spectrum antibiotics such as ceftazidime. To identify the sequence requirements in this region for a given antibiotic, a random library was constructed that contained all possible amino acid combinations for the 3-residue region 237-240 (ABL numbering system) of TEM-1 beta-lactamase. An antibiotic disc diffusion method was used to select mutants with wild-type level activity or greater for the extended-spectrum cephalosporin ceftazidime and the monobactam aztreonam. Mutants that were selected for optimal ceftazidime hydrolysis contained a conserved Ala at position 237, a Ser for Gly substitution at position 238, and a Lys for Glu at position 240. Mutants selected for aztreonam hydrolysis exhibited a Gly for Ala substitution at position 237, a Ser for Gly substitution at position 238, and a Lys/Arg for Glu at position 240. The role of the A237G substitution in differentiating between ceftazidime and aztreonam was further investigated by kinetic analysis of the A237G, E240K, G238S:E240K, and A237G:G238S:E240K enzymes. The A237G single mutant and the G238S:E240K double mutant exhibited increases in catalytic efficiency for both ceftazidime and aztreonam. However, the triple mutant A237G:G238S:E240K, displayed a 12-fold decrease in catalytic efficiency for ceftazidime but a 3-fold increase for aztreonam relative to the G238S:E240K double mutant. Thus, the A237G substitution increases ceftazidime hydrolysis when present alone but antagonizes ceftazidime hydrolysis when it is combined with the G238S:E240K substitutions. In contrast, the A237G substitution acts additively with the G238S:E240K substitutions to increase aztreonam hydrolysis.

Amino Acid Sequence↗

PubMed1995

Compatibility of aztreonam with selected drugs during simulated Y-site administration.

The compatibility of aztreonam injection with selected other drugs during simulated Y-site injection was evaluated. A 5-mL sample of aztreonam 40 mg/mL in 5% dextrose injection was combined with 5 mL of each of 100 other drugs including antineoplastics, anti-infectives, and supportive care drugs in 5% dextrose injection or 0.9% sodium chloride injection. The combinations were stored under fluorescent light at 23 degrees C. The combinations were evaluated initially and at one and four hours after preparation by examination with the unaided eye and with a high-intensity light beam, turbidity measurement, and particle sizing and counting. Most of the test drugs were compatible with aztreonam 40 mg/mL for the observation period. However, aztreonam combinations with 12 drugs exhibited incompatibilities including turbidity, particulate formation, precipitation, and color change. These drugs were acyclovir sodium, amphotericin B, chlorpromazine hydrochloride, daunorubicin hydrochloride, ganciclovir sodium, lorazepam, metronidazole, miconazole, mitomycin, mitoxantrone hydrochloride, prochlorperazine edisylate, and streptozocin. Aztreonam 40 mg/mL in 5% dextrose injection was compatible with most of the drugs tested for up to four hours at 23 degrees C. However, 12 drugs exhibited incompatibility with aztreonam.

Anti-Infective Agents↗

PubMedDate not supplied

Evaluation of the immunologic cross-reactivity of aztreonam in patients with cystic fibrosis who are allergic to penicillin and/or cephalosporin antibiotics.

The immunogenicity, allergenicity, and cross-reactivity of aztreonam were investigated in 19 patients with cystic fibrosis (CF) who are allergic to beta-lactam antibiotics. Skin tests with benzyl-penicilloyl polylysine (BPO), minor determinant mixture, and the drug responsible for the previous allergic reaction were positive for 26%, 53%, and 79% of the patients, respectively. Serum IgG, but not IgE, antibodies to BPO were detected in nine of 14 patients. Eighteen patients whose skin tests with aztreonam were negative were treated. One developed bronchospasm. The others tolerated aztreonam, with an improvement in clinical score greater than or equal to 1 month after treatment (P less than .001). One patient without previous exposure had positive aztreonam skin tests and was later treated uneventfully after iv desensitization. Treatment with aztreonam did not result in IgG or IgE antibody responses in vitro. However, two patients had anaphylactic reactions on reexposure. In patients with CF, allergy to beta-lactam antibiotics is primarily drug-specific. But despite reduced immunogenicity and cross-reactivity, aztreonam should be administered cautiously to patients with CF who are allergic to other beta-lactam antibiotics because it is potentially allergenic with repeated use.

Adolescent↗

PubMedDate not supplied

Treatment of gram-negative peritonitis with aztreonam in patients undergoing continuous ambulatory peritoneal dialysis.

In a multicenter open study, intraperitoneal aztreonam was used together with vancomycin, cloxacillin, or flucloxacillin for initial empiric treatment of peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). Monotherapy with aztreonam was continued in 34 episodes of gram-negative peritonitis in 28 patients. The microorganisms isolated included Escherichia coli, Acinetobacter species, Pseudomonas species, and Klebsiella species. In three episodes, two organisms were cultured. Microbiologic assessment revealed cure in 27 episodes, cure with relapse in two, cure with superinfection in one, and treatment failure in four (with resistance to aztreonam in three). As assessed by clinical criteria, 27 episodes were cured, five failed to respond, and two responded partially. No adverse reactions to aztreonam were observed. Comparison of these 34 episodes with 35 episodes in historical controls (treated mainly with aminoglycosides and/or trimethoprim-sulfamethoxazole) showed significantly higher rates of cure (84% vs. 51%) and of survival (97% vs. 86%) as well as lower rates of catheter removal (65% vs. 87%) with aztreonam. Thus aztreonam is a safe and efficient agent for the treatment of peritonitis caused by gram-negative organisms in patients undergoing CAPD.

Adult↗

PubMedDate not supplied

Clinical pharmacology of aztreonam in healthy recipients and patients: a review.

Serum and urinary concentrations of aztreonam after 0.5-g, 1-g, and 2-g doses are potentially therapeutic in patients with infections due to susceptible gram-negative organisms. Aztreonam is widely distributed at significant levels in body fluids and tissues. Levels exceeding the minimal inhibitory concentrations for most important gram-negative pathogens are attained in those anatomic locations in which infections are usually found. Aztreonam is eliminated primarily in the urine in unchanged form, although it is also secreted into the bile. The drug is also metabolized to a minor extent to an open-ring compound that is excreted in the urine and feces. No clinically noteworthy interactions have been found between aztreonam and cephradine, clindamycin, gentamicin, metronidazole, nafcillin, probenecid, or furosemide. The elimination of aztreonam may be significantly impaired by renal insufficiency; the dosage must be modified in patients with creatinine clearance rates of less than 30 ml/min. The monobactam can be eliminated efficiently by hemodialysis but to only a minor extent by peritoneal dialysis. Parenterally and orally administered aztreonam can selectively reduce the numbers of aerobic gram-negative bacteria in feces without notably altering the numbers of anaerobic organisms.

Aztreonam↗

PubMedDate not supplied

Safety profile of aztreonam in clinical trials.

The clinical safety of aztreonam in the treatment of suspected aerobic gram-negative infections was assessed in 346 patients who received single doses and in 2,388 patients who received multiple doses. Of those administered multiple doses, 163 (6.8%) experienced 172 adverse clinical effects. The most common were local reactions at the injection site, rash, diarrhea, and nausea and/or vomiting. Among aztreonam and control groups, three-fold increases in serum aspartate aminotransferase (SGOT) and serum alanine aminotransferase (SGPT) values occurred at comparably low frequencies; the mean values of SGOT and SGPT were slightly higher in patients administered aztreonam than in those given cefamandole. Treatment with aztreonam was discontinued in 51 (2.1%) of 2,388 patients because of adverse clinical effects or abnormal laboratory test values. Suprainfections (infections due to new pathogens occurring at the original site of infection during treatment with the study drug that were treated with another antibiotic) were reported in 2%-6% of aztreonam-treated patients, a frequency similar to that observed in control groups. Aztreonam is well tolerated and has a safety profile similar to that of other beta-lactam antibiotics.

Alanine Transaminase↗

PubMedDate not supplied

Aztreonam in the treatment of bone and joint infections caused by gram-negative bacilli.

Aztreonam was used successfully in 17 of 17 patients with orthopedic infections due to gram-negative bacilli (11, osteomyelitis; six, septic arthritis). Duration of treatment ranged from 14 to 55 days, and the period of follow-up was four to 18 months. Causative organisms included Pseudomonas aeruginosa, Serratia marcescens, Enterobacter gergoviae, Citrobacter diversus, Proteus mirabilis, and Enterobacter aerogenes. Aztreonam was well tolerated. The only definite reactions attributable to aztreonam were asymptomatic increases in serum aspartate aminotransferase (SGOT) and serum alanine aminotransferase (SGPT) in four patients; none of these reactions interfered with completion of therapy. Adverse reactions that were possibly attributable to aztreonam included rash (two patients), diarrhea (one patient), and leukopenia (one patient). All of these patients were receiving antibiotics active against gram-positive organisms in mixed infections in addition to aztreonam. Aztreonam is a promising new monobactam without significant toxicity. It has good activity against gram-negative aerobic bacteria, including P. aeruginosa, and is effective in the treatment of serious infections due to gram-negative aerobes.

Adolescent↗

PubMed1984

The intrarenal distribution of aztreonam in healthy and diseased kidneys: clinical therapeutic implications.

Using a healthy canine model, we evaluated the influence of renal physiological activity on the stability, intrarenal distribution, and clearance of aztreonam and compared the results with the concentrations of aztreonam that can be achieved in the scarred devitalized renal tissues of patients with end-stage kidney disease. Renal physiological activity significantly modulates the intrarenal distribution of aztreonam. During the production of maximally acid-concentrated urine, urinary aztreonam levels, clearance rates, and inner zone renal tissue concentrations are increased. Aztreonam concentrations in the parenchyma of severely diseased kidneys are significantly reduced in comparison with healthy tissues; nonetheless, the values are similar to concurrent serum drug levels, a result suggesting that treatment may provide adequate coverage for aztreonam-susceptible organisms.

Animals↗

PubMed1986

Pharmacokinetics, in-vitro activity, therapeutic efficacy and clinical safety of aztreonam vs. cefotaxime in the treatment of complicated urinary tract infections.

The minimal inhibitory concentrations (MICs) of aztreonam and cefotaxime were determined against 400 isolates from urological in-patients with complicated and/or hospital acquired urinary tract infections (UTI). Against the Gram-negative rods the activities of both antibiotics were comparable except for higher activity of aztreonam against Pseudomonas aeruginosa. The pharmacokinetic study in nine elderly patients showed a prolonged plasma half life of aztreonam (2.7 h) as compared to younger volunteers (1.6-1.9 h). In a prospective randomized study 39 urological patients with complicated and/or hospital acquired UTI were treated with 1 g aztreonam or cefotaxime iv twice daily for 4 to 15 days. Cure was obtained in 5 out of 18 patients in the aztreonam and 7 out of 20 patients in the cefotaxime group. There were 3 superinfections, 7 relapses and 3 reinfections in the aztreonam group and 1 failure, 1 superinfection, 6 relapses and 5 reinfections in the cefotaxime group. There was no significant difference in therapeutic efficacy between the two antibiotics. Both antibiotics were tolerated well and seem to be equally effective in the treatment of complicated UTI caused by sensitive organisms.

Adult↗

PubMed1987

Determination of aztreonam in faeces of human volunteers: a comparison of reversed-phase high pressure liquid chromatography and bioassay.

Aztreonam was given orally to eight healthy volunteers in two different dosage regimens. To determine the concentration of aztreonam in faecal specimens a method was established using reversed-phase high pressure liquid chromatography (HPLC). Comparison of microbiological and HPLC assays showed a linear relationship between both techniques which, however, was not 1:1. The microbiological assay tended to yield higher aztreonam levels than the HPLC method. The HPLC assay for aztreonam proved to be five-fold less sensitive than the bioassay; however, since in most cases high aztreonam levels were found in the faeces of the test subjects, this was not a disadvantage. The HPLC assay was much easier to perform than the bioassay and yielded easily quantifiable results in a wider concentration range. In the stool specimens of one volunteer no aztreonam could be detected by either method, indicating inactivation and/or degradation of the compound.

Adolescent↗

PubMed1989

A comparison of aztreonam and imipenem induction of class I beta-lactamase in Enterobacter cloacae ATCC 13047.

Aztreonam and imipenem were shown to induce Class I beta-lactamase in Enterobacter cloacae ATCC 13047 to a similar extent. Quantitatively, however, aztreonam was far less efficient as an inducer than imipenem. Optimum induction by aztreonam required a concentration of 200 mg/l, which was 800-fold greater than the concentration of 0.25 mg/l of imipenem which resulted in the optimum induction. The differences in the concentrations of aztreonam and imipenem that gave optimum induction were related to the inherent antibacterial activities of the antibiotics when these were determined under the conditions of broth culture. The beta-lactamase activity of sonicated cell samples following induction was inhibited by the presence of aztreonam but not by imipenem. The inhibition was overcome by first washing the cell samples from induced cultures and then incubating the sonicates for a prolonged period at 4 degrees C. It is proposed that the phenomena of an optimum inducing concentration and the interference with the assay of beta-lactamase by the presence of residual antibiotic demonstrated in this study with aztreonam and imipenem would be of relevance when applied more broadly to studies of beta-lactamase induction. In particular these would have a profound effect on the results of studies which attempt to compare the efficacy of beta-lactams as inducers of Class I beta-lactamase.

Aztreonam↗

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↗

PubMed1987

Efficacy of aztreonam in pulmonary exacerbations of cystic fibrosis.

A noncomparative pilot study was conducted to assess the potential usefulness of aztreonam in pulmonary exacerbations of cystic fibrosis. Of 27 patients initially enrolled 25 received sufficient courses of aztreonam therapy to be evaluable. All patients received 200 mg/kg/day of aztreonam in 4 equally divided doses administered intravenously. Of 57 isolates of Pseudomonas aeruginosa from pretherapy sputum cultures, 48 were susceptible to aztreonam in vitro as were 11 of 18 strains isolated at the conclusion of therapy. With treatment colony counts of P. aeruginosa in sputum were reduced by 3 log10 or more in 15 patients. It was totally (but temporarily) eradicated in 11 of these patients. Clinical scores and white blood cell counts improved significantly (P less than 0.05). Side effects of aztreonam were limited to transient elevations of liver enzymes occurring in 16 patients. Aztreonam merits further evaluation in a randomized, comparative trial with standard antibiotic therapy for cystic fibrosis.

Adolescent↗

PubMed1989

Clinical experience with aztreonam.

Aztreonam, the first of the new class of monobactams, has a narrow and specific range of bactericidal activity; it is highly active against Gram-negative aerobic pathogens but is essentially inactive against Gram-positive or anaerobic bacteria. Several unique features indicate that aztreonam may provide an attractive choice for the treatment of serious Gram-negative infection in adults and children. Clinical study in adults has shown aztreonam to be highly effective against infections of the urinary and lower respiratory tracts, the musculoskeletal system and the female genitourinary tract. It also has proved useful in neutropenic patients, including those with cancer, and for treatment of bacterial peritonitis, gonorrhea, cellulitis and wound infections. Reported clinical and microbiologic cure rates have been comparable to those associated with traditional therapeutic approaches (85 to 100%). In the treatment of children with urinary tract infection as well as other types of infections, aztreonam therapy in a dosage of 30 mg/kg given every 6 to 8 hours was associated with satisfactory clinical and microbiologic cure rates. There appear to be specific clinical situations for which aztreonam may be an appropriate alternative to more toxic therapies, although comparative trials are needed to delineate the exact place of aztreonam in the armamentarium against bacterial infection.

Aztreonam↗