Pharmacokinetics of aztreonam in healthy subjects and patients with cystic fibrosis and evaluation of dose-exposure relationships using monte carlo simulation.

Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative micro-organisms, including Pseudomonas aeruginosa. We evaluated AZM pharmacokinetics and pharmacokinetic-pharmacodynamic relationships in patients with cystic fibrosis (CF) and healthy subjects. Pharmacokinetic data in eight CF patients and healthy subjects that were matched for age, gender, weight, and height were obtained and analyzed by using the nonparametric adaptive grid algorithm. Probabilities of target attainment using percentages of time of unbound concentration above the MIC (fT>MIC) were obtained by using a Monte Carlo simulation. AZM total body clearance was significantly higher in CF patients (100.1 +/- 17.1 versus 76.2 +/- 7.4 ml/min in healthy subjects; P < 0.01). The pharmacokinetic parameter estimates for terminal half-life (1.54 +/- 0.17 h [mean +/- the standard deviation]) and volume of distribution (0.20 +/- 0.02 liters/kg in patients with CF patients were not different from those in healthy subjects. Monte Carlo simulations with a target of a fT>MIC of 50 to 60% at a dose of 1,000 mg every 8 h indicated a clinical breakpoint of 4 mg/liter and 1 to 2 mg/liter for healthy subjects and CF patients, respectively. This study using matched controls showed that AZM total body clearance and not the volume of distribution is higher in CF patients as a result of increased renal clearance. Pharmacokinetic parameter estimates in healthy subjects resulted in a clinical susceptibility breakpoint of < or =4 mg/liter for a dose of 1,000 mg every 8 h. Patients suspected of having high clearance rates, such as CF patients, should be monitored closely, with dosing regimens adjusted accordingly.

Aztreonam: clinical pharmacology.

Monocyclic beta-lactam antibiotics (monobactams) are structurally unique from the traditional bicyclic beta-lactams because of their single ring configuration. Aztreonam, the first of these monobactams, has been studied extensively in order to determine its pharmacologic and pharmacokinetic profile in adults and children with bacterial infections. It has been established, for example, that with intramuscular or intravenous dosing (30 to 50 mg/kg in children and 1 to 2 g in adults), serum concentrations above the minimum inhibitory concentrations of most aerobic Gram-negative bacteria can be maintained for up to 8 hours. Against a less susceptible pathogen such as Pseudomonas aeruginosa, every-6-hour dosing allows for preservation of the bactericidal effect, although longer intervals may be practical in low birth weight infants. The drug is primarily (80%) excreted by renal mechanisms and serum clearance varies with postnatal age. Distribution into body fluids is similar to that of other beta-lactams. For example in the presence of meningeal inflammation, cerebrospinal fluid concentrations are 17 to 33% of serum values. Urinary concentrations are high and prolonged with greater than 80% appearing as the active drug. Preliminary data from cystic fibrosis patients suggest that there are very minor pharmacokinetic differences in this population. The pharmacologic profile indicates that aztreonam may provide an appropriate alternative to traditional therapy for serious Gram-negative aerobic infections in infants and children.

Penetration of aztreonam into cerebrospinal fluid of patients with bacterial meningitis.

The penetration of aztreonam into the cerebrospinal fluid was determined in 16 patients with bacterial meningitis undergoing treatment with other antibiotics. Three aztreonam doses of 30 mg/kg were infused intravenously over 30 to 45 min at 8-h intervals, first between days 2 and 4 and again between days 11 and 20 after onset of the disease. Concentrations of aztreonam in serum and cerebrospinal fluid samples obtained at 60, 90, 120, and 240 min after the third aztreonam dose were measured by high-pressure liquid chromatography. The concentrations of aztreonam in cerebrospinal fluid ranged from 3.5 to 62 micrograms/ml, depending on the sampling time and the time elapsed since the onset of the disease. These concentrations were equal to or higher than the MICs for most of the gram-negative bacilli (including Pseudomonas aeruginosa).

[Clinical evaluation on aztreonam in pediatric field and fundamental study on its penetration into cerebrospinal fluid].

The penetration of aztreonam (AZT), a new synthetic monobactam, into cerebrospinal fluid (CSF) and the clinical studies for bacterial infections were carried out. The following results were obtained. The concentrations of AZT in CSF were less than 0.31 microgram/ml and 0.42 microgram/ml, respectively, at 1 hour after intravenous administration of 34 mg/kg and 71 mg/kg in 2 cases of aseptic meningitis at the acute stage. The concentration of AZT in CSF was 6.9 micrograms/ml at 1 hour after intravenous administration of 100 mg/kg in 1 case of purulent meningitis at the acute stage and was 0.62-0.98 micrograms/ml even at the recovering stage. At each stage, its concentration was more than the minimum inhibitory concentration of E. coli (0.10, less than 0.05 microgram/ml; at inoculum size of 10(8), 10(6) cells/ml). Clinical efficacy of AZT was good in 2 cases of purulent meningitis, excellent in 1 case of septicemia, excellent in 5 cases of urinary tract infection, excellent in 1 case and good in 3 cases out of 4 cases of gastroenteritis, excellent in 4 cases and poor in 2 cases out of 6 cases of pneumonia and bronchitis, excellent in 2 cases and good in 1 case out of 3 cases of tonsillitis. No side effects and no abnormal laboratory findings were observed except 1 case of mild diarrhea out of 21 cases.

[Penetration of aztreonam and ampicillin to cerebrospinal fluid in the concomitant administration to rabbits with Staphylococcus aureus meningitis].

Aztreonam (AZT) and ampicillin (ABPC) were independently administered to 6 and 7 rabbits respectively, with S. aureus meningitis. Additionally, AZT and ABPC were concomitantly given to 6 rabbits with S. aureus meningitis. Concentrations of AZT and ABPC in cerebrospinal fluid (CSF) and serum were determined by HPLC method, and the results in concomitant treatment were compared with those for single treatment of each agent. Results were as follows: Maximum serum concentrations of AZT in concomitant treatment of AZT and ABPC were higher than those in single treatment of AZT. However, there was no significant difference between the 2 treatment groups with regard to maximum CSF concentration, percentage of AUC of CSF to serum, and T1/2 of the CSF and serum concentrations of AZT. ABPC in the concomitant treatment did not influence the CSF concentration of AZT. There was no significant difference in serum concentration of ABPC between concomitant treatment and the single one. However, the values of maximum CSF concentration, percentage of maximum CSF to serum concentration and percentage of AUC of CSF to serum in the concomitant treatment were lower than those in the single treatment of ABPC. With regard to T1/2 of CSF concentration of ABPC, there was no remarkable difference between the 2 treatment groups. The above results suggest that the distribution of ABPC into CSF is suppressed in the concomitant treatment of AZT and ABPC. AZT has no antimicrobial activity against Gram-positive bacteria. The CSF concentration of ABPC is suppressed in the concomitant treatment. Those facts suggest that AZT should be administered for meningitis cases after the identification of causative pathogens.