Brent M. Booker

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.

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

ABSTRACT 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 μg/ml for ciprofloxacin and gatifloxacin and 0.25 μg/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 fluoroquinolone-treated patients.

Effect of Tenofovir Disoproxil Fumarate on the Pharmacokinetics and Pharmacodynamics of Total, R-, and S-Methadone

Study Objective. To evaluate the potential effect of tenofovir disoproxil fumarate (DF) on the pharmacokinetics of methadone.

Development of a pharmacokinetic and Bayesian optimal sampling model for individualization of oral busulfan in hematopoietic stem cell transplantation.

Therapeutic drug monitoring is used to minimize toxicity and maximize the therapeutic efficacy of busulfan, which shows high intra- and interpatient pharmacokinetic variability and erratic oral absorption. This study was designed to develop a pharmacokinetic model that could accommodate the erratic oral absorption of busulfan and to use this model to develop an optimal sparse pharmacokinetic sampling strategy to improve the precision and efficiency of therapeutic drug monitoring. Twenty-one pharmacokinetic profiles were collected from 12 patients receiving oral busulfan before hematopoietic stem cell transplantation. Each pharmacokinetic profile was defined by 5 to 9 plasma concentrations. Candidate pharmacokinetic models were initially fit to the data by maximum likelihood, with model discrimination by Akaikes Information Criterion. Maximum likelihood results were used to derive Bayesian previous parameter estimates, and D-optimal design was used to determine optimal sparse sampling strategies. Each candidate sampling strategy was tested in each patient by comparing the resultant Css obtained from the sparse strategy to the actual Css derived from each patients full pharmacokinetic dataset. The final model was a 1-compartment model, with oral busulfan absorbed in 1 to 3 phases, and fit the data well. All limited sampling models tested were unbiased in their results, and a 4-sample scheme proved to adequately characterize busulfan pharmacokinetics, and should allow for a reduced sampling frequency for therapeutic drug monitoring.

Pharmacokinetics and Pharmacodynamics of Mesna‐Mediated Plasma Cysteine Depletion

Cellular glutathione (GSH) levels are related to the resistance of tumor cells to platinum and alkylating agents, and depletion of GSH may enhance the activity of these drugs. The pharmacodynamic effects of mesna on depleting plasma cysteine, a GSH precursor, were evaluated in 22 patients as part of a Phase I study. Escalating doses of ifosfamide and mesna were administered; carboplatin was administered to achieve an AUC of 4 mg·min/mL. Plasma samples were collected and assayed by reverse‐phase high‐performance liquid chromatography (HPLC) for total mesna and total cysteine concentrations at 0, 1, 3, 6, 24, 25, 28, and 48 hours. A one‐compartment pharmacokinetic model was fit to the mesna plasma concentrations, using M.A.P. Bayesian estimation (ADAPT II). Pharmacodynamics were evaluated by fitting an inhibitory Emax model to the cysteine concentration data. Both the pharmacokinetic (median R2 = 0.95; range = 0.85–0.98) and pharmacodynamic (median R2 = 0.96; range = 0.74–1.0) models fit the data well. Mean (coefficient of variation [CV%]) mesna pharmacokinetic parameter estimates were as follows: Vss of 15.3 (29) L/m2, CL of 4.6 (29) L/h/m2, and half‐life of 2.2 (37) hours. Mean (CV%) pharmacodynamic parameter estimates were as follows: Emax of 31.7 (19) μg/mL and EC50 of 10.3 (52) μg/mL. Mesna produced a rapid, concentration‐dependent reduction in plasma cysteine concentrations that could be adequately characterized by an inhibitory Emax pharmacodynamic model. The depletion of plasma cysteine was facilitated by ifosfamide, suggesting a pharmacodynamic interaction between these two agents. Further increases in mesna doses beyond those administered in this study would be unlikely to provide additional benefit.

Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with haemophilus influenzae middle ear infection

The pharmacodynamic differences among 3 AZM regimens(R): single dose simulated sustained release (SSR);3DR & 5DR in gerbils with middle ear infections were evaluated.

A novel PD model for gatifloxacin (GF) vs. salmonella typhi (ST) in timed kill curves (KC)

Quinolones are the mainstay of treatment for ST infections but there is growing concern about resistance to older quinolones & poor understanding of quinolone/ST PD. We have developed a new approach to modelling KC data & have applied it to describing the PD of GF vs. ST.

Novel mathematical models for bacterial growth, death & pharmacodynamics

Clinical Pharmacology & Therapeutics (2003) 73, P24–P24; doi: