Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC 24 )/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving Streptococcus pneumoniae. The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levofloxacin versus gatifloxacin for the treatment of community-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC 24 s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented S. pneumoniae infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classification and Regression Tree analysis. A statistically significant (P ‫؍‬ 0.013) relationship between microbiological response and the free-drug AUC 24 /MIC ratio was detected. At a free-drug AUC 24 /MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC 24 /MIC ratio of >33.7, it was 100% (P < 0.01). These findings may provide a minimum target free-drug AUC 24 /MIC ratio for the treatment of infections involving S. pneumoniae with fluoroquinolone antibiotics and provide a paradigm for the selection of fluoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. Further, when target free-drug AUC 24 /MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and S. pneumoniae.The relationship that exists between drug exposure and the MIC for an infectious organism has been shown to be predictive of microbiological eradication (3,4,5,14). Existing data suggest that, for fluoroquinolones, an area under the concentration-time curve at 24 h (AUC 24 )/MIC ratio of 100 to 125 correlates with optimal clinical and microbiological outcomes in seriously ill patients infected with gram-negative enteric pathogens and Pseudomonas aeruginosa (7,8). However, over the past several years there has been considerable controversy as to whether or not this pharmacodynamic target applies to all patient populations and all organisms.Data from in vitro and animal models of infection have recently emerged and suggest that, for Streptococcus pneumoniae, the optimal free-drug AUC 24 /MIC ratio is much lower than 100 to 125. For instance, an in vitro model of pneumococcal infec...

Tigecycline, a first-in-class expanded-spectrum antimicrobial agent, has demonstrated efficacy in the treatment of complicated intra-abdominal and skin and skin-structure infections. This new antibiotic is available as an intravenous formulation and exhibits linear pharmacokinetics. It is rapidly distributed and has a large volume of distribution, indicating extensive tissue penetration. After a 100-milligram loading dose, followed by 50 milligrams every 12 h, the steady-state maximum concentration in serum after a 1-h infusion is approximately 0.6 microg/mL, the 24-h steady-state area under the concentration-time curve is approximately 5-6 microg.h/mL, and the terminal elimination half-life is approximately 40 h. The major route of elimination of tigecycline is through the feces, primarily as unchanged drug. The pharmacokinetic profile is not affected by severe or end-stage renal disease, nor is it significantly altered by hemodialysis. The pharmacokinetics of tigecycline are also not affected by food, although tolerability is increased if the drug is administered following a meal.

Routine clinical pharmacokinetic (PK) data collected from 59 preterm infants who received phénobarbital were analyzed to estimate population PK parameters. Birth weights ranged from 600 to 3,620 g (mean 1,520 g), and gestational ages ranged from 24 to 42 weeks (mean 31 weeks). Data were analyzed using NONMEM, a computer program designed for population PK analysis. The mean (±CV) clearance of phénobarbital was 0.0047 liter/h/kg (± 19%) and the mean (±CV) volume of distribution (Vd) was 0.96 liter/kg (± 16%). The calculated mean serum half-life was 141 h. Clearance was not affected by gestational age, sex, asphyxia, or duration of therapy. Vd was not affected by gestational age or sex but was increased by 13% in the presence of asphyxia (5-min Apgar score <5, p < 0.05).

Linezolid (Zyvox), belonging to oxazolidinone antibiotics, is commonly used for the treatment of patients infected with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although linezolid has been approved worldwide, the Japanese pharmacokinetic (PK) profile has not been characterized in detail. The objective of this study is to develop a population PK model for linezolid that can be applied to a Japanese population. This population PK model was established based on the 1 Japanese phase III and 4 Caucasian phase II/III studies. A total of 2539 linezolid plasma concentration measurements from 455 patients, aged 18 to 98 years and body weight 30 to 190.5 kg, were used for the analysis. The data were analyzed using nonlinear mixed effects modeling. Body weight (BW), age, ethnicity, and gender were investigated as covariates. The final model was validated by the bootstrap technique. The PK profiles of linezolid were described with a 1-compartment PK model with first-order absorption and first-order elimination. In the final population PK model, BW and age were influential covariates on clearance, and the distribution volume was affected by BW. The present population PK model of linezolid described well the PK profiles in Japanese patients who have lower BW and are relatively older compared with those in the United States/European Union.

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