Compatibility of aztreonam in four commercial peritoneal dialysis fluids.

The preferable route for treatment of peritoneal dialysis related peritonitis remains the intraperitoneal administration of antibiotics admixed to peritoneal dialysis fluids. It is important to know whether the administered drug is compatible with the PD fluids and its container. In the present study the compatibility of aztreonam with four commercial PDFs at storing temperatures and duration representative for storing conditions in the clinical settings was investigated. Aztreonam concentrations were determined using high-performance liquid chromatography. The antimicrobial activity of aztreonam was evaluated using an E. coli diffusion disk inhibition assay and P. aeruginosa time-kill curves. In Extraneal evaluated at 6 °C, 25 °C and 37 °C aztreonam was stable over the whole study period of 14 days and 24 hours, respectively. In Physioneal and Nutrineal aztreonam was stable at 6 °C for up to 14 days. Antimicrobial activity was retained in all PD fluids over the whole study period. Aztreonam remained stable and was compatible with the PD fluids, particularly with Extraneal or Nutrineal, and no compensatory dose adjustment is needed when stored for up to 14 days at refrigeration temperature before use.

Development and validation of an LC tandem MS assay for the quantification of ß-lactam antibiotics in the sputum of cystic fibrosis patients.

OBJECTIVES: Antibiotic therapy is of vital importance for the control of infectious exacerbations in cystic fibrosis (CF) patients. However, very little is known regarding the fraction of systemically administered antibiotics reaching the lower respiratory tract secretions. We developed and validated a method to measure the concentrations of piperacillin, ceftazidime, meropenem and aztreonam in CF sputum, and present the validation data. METHODS: Ultra-performance LC coupled to tandem MS was used. A single sample can be measured in 2.5 min with multiple reaction monitoring in positive electrospray ionization mode. Deuterated internal standards were used and a concentration range of 0.7-160 mg/L was covered. The method was validated according to the EMA guideline on analytical method validation. RESULTS: The boundaries within which a reliable measurement in CF sputum can be performed were determined. A few constraints are linked to the instability of the antibiotics in sputum. Piperacillin showed limited stability at room temperature and during freeze-thaw cycles. Autosampler instability was observed after 15 h for aztreonam at low concentrations. CONCLUSIONS: The method allows a reliable measurement of the selected antibiotics, if precautions are taken regarding the limited stability of piperacillin at room temperature. Due to freeze-thaw instability, piperacillin should always be analysed on the day of sampling. Quick review of the analytical data and reanalysis are needed as low concentrations of aztreonam are not stable in the autosampler.

In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms.

OBJECTIVES: The combination of aztreonam and avibactam has been proposed for the treatment of infections caused by metallo-ß-lactamase-producing Gram-negative organisms, given the stability of aztreonam against metallo-ß-lactamases plus the broad coverage of avibactam against AmpC ß-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse ß-lactamase profiles. METHODS: The MICs of aztreonam were determined without and with avibactam (1, 2, 4, 8 and 16 mg/L). Using the MIC values, the static time-kill kinetic studies were designed to encompass aztreonam concentrations of 0.25, 0.5, 1, 2 and 4 times the MIC at the respective avibactam concentrations from 0 to 8 mg/L. Aztreonam and avibactam concentrations were determined by LC-MS/MS during the course of the time-kill kinetic studies to evaluate whether avibactam protects aztreonam from degradation. RESULTS: Three of the four isolates had aztreonam MICs ≥128 mg/L in monotherapy. Dramatically increasing susceptibility associated with a decrease in aztreonam MIC was observed with increasing avibactam concentration. Against all isolates, the combinations resulted in greater killing with a much lower dose requirement for aztreonam. The resulting changes in base-10 logarithm of cfu/mL at both the 10 h and 24 h references (versus 0 h) were synergistic. In contrast, a significantly higher concentration of aztreonam in the monotherapy was required to produce the same kill as that in the combination therapy, due to rapid aztreonam degradation in two isolates. CONCLUSIONS: The aztreonam/avibactam combination protects aztreonam from hydrolysis and provides synergy in antimicrobial activity against multiple ß-lactamase-expressing strains with a wide MIC range.

Stability of aztreonam in AZACTAM.

The influence of temperature and relative humidity on the stability of aztreonam in AZACTAM was investigated. Changes of the concentration of aztreonam were followed using the HPLC method with UV detection. The first-order rate constants of the reversible reaction of isomerization Z-aztreonam right harpoon over left harpoonE-aztreonam and the parallel reaction Z-aztreonam-->products were determined at RH=76.4% and T=313, 323, 333, 343 and 353 K, and at T=343 K and RH=50.9%, 60.5%, 66.5% and 76.4%. The thermodynamic parameters-energy, enthalpy and entropy of these reactions were calculated.

Pilot study for the development of a new campylobacter selective medium at 37 degrees C using aztreonam.

AIMS: To overcome contamination and temperature inhibition by isolating campylobacter at 37 degrees C. METHODS: The beta lactam antibiotic aztreonam was included in a selective medium because of its inhibitory activity against Gram negative organisms but not against Campylobacter jejuni. Vancomycin and amphotericin were added to inhibit Gram positive bacteria and yeasts. RESULTS: The aztreonam amphotericin vancomycin (AAV) experimental campylobacter selective medium showed growth microaerobically at 37 degrees C of C jejuni, C coli, C lari, C hyointestinalis, C fetus subsp. fetus, and C jejuni subsp. doylei after 24 to 48 hours of incubation. Six campylobacter NCTC strains demonstrated a minimum inhibitory concentration (MIC) > or = 256 mg/litre for vancomycin and aztreonam, whereas C upsaliensis and two "campylobacter-like" strains now reclassified under genus helicobacter--H cinaedi and H fennelliae--had a MIC of 4 mg/litre for vancomycin and aztreonam. In the pilot study (150 samples), AAV medium (37 degrees C) had a higher sensitivity for isolating campylobacters: 14 were isolated on AAV compared with 10 on modified CDA (43 degrees C) over three days, and nine were isolated on AAV medium compared with five on modified CDA (43 degrees C) after 24 hours of incubation. Contamination rates remained low. CONCLUSION: The medium was devised in a pilot study performed between 1990 and 1993; however, this is the first report of AAV medium used as a selective medium capable of growing six campylobacters of pathogenic importance at 37 degrees C. Further studies are indicated.

Spectrophotometric and fluorimetric determination of aztreonam in bulk and dosage forms.

Spectrophotometric and fluorimetric determination of aztreonam were achieved through its reaction with cerium (IV) in acidic medium. The spectrophotometric method involves the quantitation of the amount of ceric equivalent to aztreonam by measuring the absorbance at 317 nm and the corresponding first-derivative value at 284 nm for the blank solution against the reaction solution. Beer's law is obeyed over the concentration ranges of 1.5-4 and 1-4 microg ml(-1), respectively. Meanwhile, in the fluorimetric method, higher sensitivity was achieved by measuring the fluorescence intensity of the formed cerium (III) at lambda(em)=357 nm (lambda(ex)=257 nm) within a concentration range 150-350 ng ml(-1). Study of the reaction conditions and reaction stoichiometry were presented. Interference from L-arginine, which is frequently co-formulated with aztreonam, was tested. The proposed procedures were applied successfully to the determination of aztreonam in pure form and in presence of arginine both in laboratory mixtures and commercial vials. The proposed methods are sensitive, accurate and precise as compared with the official USP 24 HPLC method.

Utilization of colorimetric and atomic absorption spectrometric determination of aztreonam through ion pair complex formation.

Three rapid and sensitive, colorimetric and atomic absorption spectrometric methods were developed for the determination of aztreonam. The proposed methods depend upon the reaction of cobaltthiocyanate (I) or reineckate (II) ions with the drug to form stable ion-pair complexes which extractable with chloroform. The greenish blue and pink color complexes are determined either colorimetrically at lambda(max) 625 and 525 nm for I and II reagents, respectively, or by atomic absorption spectrometry, directly using the organic extracted complex, or indirectly, using the supernatant. The three procedures are applied for the determination of aztreonam in pure and in pharmaceutical dosage forms applying the standard additions technique and the results obtained agreed well with those obtained by the official method.

High-performance liquid chromatography of alpha-amino acids and aztreonam on reversed phase columns with aqueous Cu2+ as eluent.

Parameters affecting the separation of amino acids on different RP-HPLC columns were studied. Six amino acids were separated on Zorbax TMS, Zorbax CN, Zorbax ODS and Zorbax C8, using 1.8 x 10(-3) M copper sulphate at pH 4.1 as aqueous mobile phase. The best separation was shown by Zorbax TMS followed by Zorbax CN. The column performance was maintained by serial washing after 6 h continuous work with aqueous 10(-4) M disodium edetate, 10(-4) N sulphuric acid, water and gradient elution with aqueous methanol. The separation mechanism was interpreted. The method was applied for separation and quantification of aztreonam and L-arginine in Azactam vials.

Drug degradation during HPLC analysis of aztreonam: effect on pharmacokinetic parameter estimation.

OBJECTIVE: To assess the impact of degradation of aztreonam, a beta-lactam antibiotic, during HPLC analysis on pharmacokinetic parameter estimates. METHODS: The baseline (B) serum concentration-time data from a published pharmacokinetic study of aztreonam were degraded using first-order equations and a degradation rate constant (0.014 h-1) determined from a preliminary degradation study. Samples were mathematically degraded for autosampler run times of 8-13 h (D1) to approximate a normal work day and for autosampler run times of 16-17 h (D2) and compared with B data. It was assumed that B data were nondegraded and that changes in chromatography were the result of degradation of azetreonam and not to any changes in chromatographic conditions. A two-compartment model was used to fit the data and pharmacokinetic parameters were calculated using standard equations. Statistical significance between all pharmacokinetic parameters for B and D1 and B and D2 was determined using the paired, two-tailed Student's t-test. RESULTS: Increased variability was noted for all pharmacokinetic parameters for D1 and D2 compared with B. Statistically significant differences were found for clearance (B < D1, p = 0.0095 and B < D2, p = 0.0194), steady-state volume of distribution (B < D2, p = 0.0392), and area under the serum concentration-time curve (B > D1, p = 0.0497). CONCLUSIONS: Aztreonam degradation resulted in increased variability in pharmacokinetic parameter estimates. Investigators should be cognizant of this and preliminary studies should be performed to characterize degradation for the length of the expected autosampler run.

[Concentration of aztreonam in plasma, urine, and seminal fluid of patients with chronic prostatitis]. / Concentrazioni di aztreonam nel plasma, nell'urina e nel liquido seminale di soggetti affetti da prostatite cronica.

The authors consider the concentration of antibacterial drugs in the seminal fluid as a reliable experimental model for the study of pharmacokinetics in chronic prostatitis (c.p.). The study was conducted on 32 subjects, 20 of whom were affected by c.p. and 12 were normal controls. All subjects were treated with aztreonam at a dosage of 1 g.i.m. The assay was performed 1 hour after the injection, on seminal fluid, urine and serum samples. No difference was observed between normal subjects and patients with c.p. with regard to serum and urinary levels of the drug. There was a trend towards a higher concentration of the drug in the seminal fluid of patients with c.p. when compared to normal subjects, with mean values of 1.8 and 0.9 mcg/ml respectively. This difference was not statistically significant. Furthermore, the drug concentration of the drug in semen was below the sensitivity limits of the assay in 43% of normal subjects and in 10% of patients with c.p. In the latter group of patients the mean values of aztreonam concentration exceeded the minimal inhibitory concentrations for most aetiological agents causing c.p. In conclusion, it is suggested that aztreonam is likely to be effective in acute prostatitis, caused by Gram negative strains and may be indicated in selected cases for the treatment of c.p.

Cavernous tissue antibiotic levels in penile prosthesis surgery.

A comparison of the delivery of several antibiotics (vancomycin, gentamicin and aztreonam) to the tissue site of prosthesis implantation was studied using cavernous tissue levels for each antibiotic. A total of 32 patients underwent penile prosthesis implantation. Intravenous antibiotics were administered 1 to 2 hours preoperatively, with vancomycin and aztreonam given to patients at the Tulane University Medical Center, and vancomycin and gentamicin given to patients at the New Orleans Veterans Administration Hospital. At operation the urine, serum and cavernous tissue were concurrently sampled and later analyzed for antibiotic concentration. The mean cavernous tissue level for vancomycin was 55.5 +/- 5.5 ng./mg. (standard deviation) for 20 patients, while the mean cavernous tissue levels for aztreonam and gentamicin were 8.9 +/- 2.1 ng./mg. for 10 patients and 4.7 +/- 1.2 ng./mg. for 12 patients, respectively. When the delivery of antibiotic to cavernous tissue was compared (quantitated as ng. antibiotic per mg. tissue per mg. drug administered), a statistically significant value (p less than 0.01) was observed with vancomycin (0.11 ng./mg./mg.) greater than gentamicin (0.06 ng./mg./mg.) or aztreonam (0.01 ng./mg./mg.), and with no significant difference observed between aztreonam or gentamicin. These findings suggest that cavernous tissue levels may be used as a method to determine optimal antibiotic prophylaxis against penile prosthesis infection.

[Determination of moxalactam, aztreonam and imipenem by the perchloric hydroxylamine method]. / Oznaczanie moksalaktamu, aztreonamu i imipenemu metoda hydroksyloaminowo-nadchloranowa.

The reaction of perchloric hydroxylamine was adopted for determination of new beta-lactam antibiotics within monobactam, carbapenem and oxazepam groups. Complexes formed in colour reaction are stable over 2 hours in the case of aztreonam and imipenem, and over 1 hour for moxalactam, statistical analysis proved that both hydroxylamine-perchloric and spectrophotometric methods can be used alternatively.

Aztreonam biliary excretion in bile duct ligated jaundiced rats.

An experimental study was undertaken to assess aztreonam biliary concentrations in bile duct ligated jaundiced rats. The study proved that aztreonam biliary concentrations are sufficient to inhibit Gram-negative bacteria within the first and the second hour after antibiotic administration. The experimental model suggests that clinical conditions such as lithiasis or neoplasms of the biliary tree should not totally inhibit the antibiotic excretion.

Simultaneous derivative spectrophotometric determination of aztreonam and L-arginine in injections.

Mixtures of aztreonam, 2S-[2 alpha,3 beta(Z)]-2-[[[1-(2-amino-4-thiazolyl-2- [(2-methyl-4-oxo-1-sulfo-3-azetidinyl) amino]-2-oxo- ethylidine]amino]oxy]-2-methyl-propanoic acid, and L-arginine are assayed by peak-to-baseline, peak-to-peak, and zero-crossing second-derivative spectrophotometry. Aztreonam is the first of a new class of beta-lactam antibiotics (i.e., the mono-bactam antibiotics, highly effective against aerobic gram-negative bacteria). Beer's law is followed for up to 31 micrograms/mL of aztreonam and L-arginine in the presence of one another. Detection limits at the p = 0.05 level of significance range from 0.11 to 0.37 micrograms/mL. The method was successfully applied to laboratory mixtures and commercial injections containing these substances.

Determination of aztreonam and L-arginine combination in parenteral formulations.

A rapid, sensitive and precise liquid chromatographic method is presented for the determination of aztreonam alone, in the presence of its degradation product, and in a parenteral formulation containing l-arginine. A reverse phase column and 0.2M phosphate buffer (pH 6)-methanol (95 + 5) with mobile phase at a flow rate of 2 mL/min is used. The method is sensitive for the range of 10-50 micrograms/mL with a relative standard deviation of less than 2%. The method has been applied to a parenteral formulation containing aztreonam and l-arginine. L-Arginine is also determined by a nonaqueous titrimetric method.

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.

Hospital routine analysis of penicillins, third-generation cephalosporins and aztreonam by conventional and high-speed high-performance liquid chromatography.

A high-performance liquid chromatographic procedure for the measurement of fifteen beta-lactam antibiotics in body fluids is described, with special reference to high-speed techniques. The procedure involves a unique sample preparation before analysis for all the following fifteen compounds: benzylpenicillin, ampicillin, cloxacillin, ticarcillin, mezlocillin, azlocillin, piperacillin, cefotaxime and its desacetyl metabolite, cefsulodin, cefoperazone, cefmenoxime, ceftazidime, ceftriaxone and the monobactam aztreonam; thus all biological samples arriving at the laboratory can be treated in batch. Of these fifteen antibiotics, eleven can be chromatographed with the same type of mobile phase, which consists of a mixture of ammonium acetate and acetonitrile in various ratios. Three others need ionpairing chromatography because of their polarity, and ticarcillin requires citric acid. High-speed high-performance liquid chromatography seems to be particularly suitable for the routine analysis of beta-lactam antibiotics because columns equilibrate more rapidly, retention times are much shorter, detection limits are lower and the longer lifetime of columns reduces analysis costs.

Interaction of aztreonam with nafcillin in intravenous admixtures.

An interaction between aztreonam and nafcillin sodium in 0.9% sodium chloride injection or 5% dextrose injection stored in glass or plastic containers is reported. During preliminary experiments, admixtures of aztreonam 10 or 20 mg/mL and nafcillin sodium 10 or 20 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection prepared in glass flasks became cloudy and showed evidence of a fine precipitate. Drug concentrations were measured with a stability-indicating high-performance liquid chromatographic (HPLC) assay. Admixtures of aztreonam 20 mg/mL and nafcillin sodium 20 mg/mL in 5% dextrose injection or 0.9% sodium chloride injection were prepared in polyvinyl chloride bags and stored at room temperature (23-25 degrees C) for 48 hours. The admixtures were assayed at 0, 24, and 48 hours with the same HPLC procedure used during the pretesting experiments. The precipitates were isolated, washed, and centrifuged; the supernatant was analyzed by HPLC assay, and the final residue was analyzed by nuclear magnetic resonance (NMR) spectroscopy. The initial recoveries of drug from the pretesting experiments ranged from 99.2 to 102.4%. Analysis of the precipitates indicated that the precipitate was neither a salt nor a complex formed by the physical interaction of aztreonam and nafcillin sodium, but probably a high-molecular-weight polymer formed by the covalent bonding of subunits of the formulation components. Substantial losses of both drugs from the admixtures were evident after 48 hours of storage. The precipitate was observed sooner in the admixtures containing 0.9% sodium chloride injection than in the admixtures prepared in 5% dextrose injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Stability of clindamycin phosphate with aztreonam, ceftazidime sodium, ceftriaxone sodium, or piperacillin sodium in two intravenous solutions.

In admixtures containing clindamycin and either aztreonam, ceftazidime, ceftriaxone, or piperacillin in either 5% dextrose injection (D5W) or 0.9% sodium chloride injection (NS), the stability of each drug was studied. Each of the following combinations of drugs was added to 100-mL glass bottles of base solution: clindamycin phosphate 0.9 g and aztreonam 2.0 g, clindamycin phosphate 0.9 g and ceftazidime sodium 2.0 g, clindamycin phosphate 1.2 g and ceftriaxone sodium 2.0 g, and clindamycin phosphate 0.9 g and piperacillin sodium 4.0 g. Duplicate samples were prepared. Admixtures containing each single drug were also tested. Samples were visually inspected and tested for pH and drug concentration immediately after mixing and at 1, 4, 8, 12, 24, and 48 hours of storage in room temperature and light. Drug concentrations were determined by high-performance liquid chromatographic assay methods. Ceftriaxone retained greater than 90% of its original concentration for 24 hours in single-drug admixtures in NS, for eight hours with clindamycin in NS, and for one hour with clindamycin in D5W. Ceftazidime retained greater than 90% potency for 24 hours with clindamycin in D5W. In all other test admixtures, all drugs were stable for 48 hours. Under the conditions studied, clindamycin is compatible in the admixtures tested with aztreonam and piperacillin. Admixtures of clindamycin and ceftazidime in D5W should be used within 24 hours at room temperature. Clindamycin and ceftriaxone can be mixed in NS if administered within eight hours, but ceftriaxone is stable for only one hour in combination with clindamycin in D5W.