Pharmacokinetics and pharmacodynamics of aztreonam and tobramycin in hospitalized patients

Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative microorganisms, including Pseudomonas aeruginosa. We evaluated AZM pharmacokinetics and pharmacokineticpharmacodynamic 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 <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.

mentioning

confidence: 99%

Pharmacokinetics of Aztreonam in Healthy Subjects and Patients with Cystic Fibrosis and Evaluation of Dose-Exposure Relationships Using Monte Carlo Simulation

Vinks

Rossem

Mathôt

et al. 2007

“…These peaks were characterized by MICs at Յ0.06 g/ml, 0.12 to 0.5 g/ml, and Ն8 g/ml. Previous studies with these organisms exhibited elevated nalidixic acid MIC results (Ն32 g/ml) for all isolates having ciprofloxacin, gatifloxacin, or levofloxacin MICs of Ն0.25 g/ml, each possessing a single gyrA target mutation (30), and greater numbers of mutations for Salmonella isolates having MICs in the current resistant range (29).…”

Section: Resultsmentioning

confidence: 90%

“…Based upon current NCCLS susceptibility breakpoints (29), one serovar Typhi strain (85-1416G) was susceptible to gatifloxacin with a MIC of 0.5 g/ml, in contrast to strain G6/9, which had a gatifloxacin MIC of 4 g/ml (intermediate). Sequencing of the QRDR revealed that strain 85-1416G had a single gyrA mutation at Asp873Asn and strain G6/9 had four mutations as follows: gyrA, Ser833Tyr and Asp873Gly; gyrB, none; parC, Thr573Ser and Ser80Ile; and parE, none.…”

Section: Resultsmentioning

confidence: 99%

“…Sequencing of the QRDR revealed that strain 85-1416G had a single gyrA mutation at Asp873Asn and strain G6/9 had four mutations as follows: gyrA, Ser833Tyr and Asp873Gly; gyrB, none; parC, Thr573Ser and Ser80Ile; and parE, none. Both strains had a screening nalidixic acid MIC result of Ն32 g/ml and ciprofloxacin MICs at Ͼ0.12 g/ml (29). These organisms exhibited logarithmic growth prior to initiation of antimicrobial therapy in the model.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Application of an In Vitro Infection Model and Simulation for Reevaluation of Fluoroquinolone Breakpoints for Salmonella enterica Serotype Typhi

Booker

Smith

Forrest

et al. 2005

Self Cite

Salmonella enterica serotype Typhi and nontyphoidal Salmonella remain major causes of morbidity and mortality worldwide. Ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol no longer provide reliable coverage of Salmonella, and fluoroquinoloes have emerged as first-line treatment options. Due to mounting evidence of decreased in vitro susceptibility and diminished clinical response to fluoroquinolone therapy, it has been suggested that the NCCLS breakpoints for the salmonellae be reevaluated. We utilized an in vitro infection model to determine which pharmacokinetic-pharmacodynamic (PK-PD) measure was most closely linked to fluoroquinolone activity against salmonellae and the magnitude that was predictive of efficacy. Monte Carlo simulation was utilized to determine the probability of attaining potential susceptibility breakpoints for three fluoroquinolones. The free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio was the PK-PD measure most predictive of efficacy, and a ratio of 105 corresponded to 90% of maximal activity. Simulation results suggested susceptible breakpoints of 0.12 g/ml for ciprofloxacin and gatifloxacin and 0.25 g/ml for levofloxacin. These proposed breakpoints correspond to the MIC separating the wild-type susceptible organism population from those strains possessing single-step mutations in the quinolone resistance-determining region. These results that integrate PK-PD measures and fluoroquinolone MIC distributions in the genetic context of examined Salmonella isolates clearly demonstrate that the prudent use of a lower susceptibility breakpoint minimizes the probability of clinical failure or delayed response in fluoroquinolonetreated patients.

“…Early and appropriate infection control is a priority in sepsis management of critically ill patients to improve outcome (2,3) and requires optimal use of antibiotics. This goal can be achieved by using the pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics in order to maximize their therapeutic potential and minimize toxicity (4)(5)(6).…”

mentioning

confidence: 99%

Gentamicin in Hemodialyzed Critical Care Patients: Early Dialysis after Administration of a High Dose Should Be Considered

Veinstein

Venisse

Badin

et al. 2013

Gentamicin is a widely used antibiotic in the intensive care unit (ICU). Its dosage is difficult to adapt to hemodialyzed ICU patients. The FDA-approved regimen consists of the administration of 1 to 1.7 mg/kg of gentamicin at the end of each dialysis session. Better pharmacokinetic management could be obtained if gentamicin were administered just before the dialysis session. . Therefore, administration of 6 mg/kg of gentamicin before hemodialysis to critically ill patients achieves a high C max and an acceptable AUC, maximizing pharmacokinetic/pharmacodynamic endpoints.