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...

Purpose The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin’s lymphoma (NHL), and supported understanding of exposure-response relationships for efficacy and safety. Methods Bendamustine was administered as a 60-minute 120 mg/m2 intravenous infusion on Days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. Results Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t1/2 (40 minutes) was considered the pharmacologically relevant (beta elimination) t1/2 since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m2 administration, except bendamustine Cmax was a significant (p-value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. Conclusions The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t1/2 and low concentrations of bendamustine observed by 12 hours after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine Cmax increases.

bTedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (freedrug area under the concentration-time curve over 24 h at steady state [AUC ss(0 -24) ], 7 to 50 g · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC ‫؍‬ 3) against a Staphylococcus aureus strain for which the MIC was <0.5 g/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.T edizolid phosphate is a novel oxazolidinone prodrug antibacterial that is rapidly and extensively converted in vivo by phosphatases to microbiologically active tedizolid. It is intended for oral and intravenous administration in the management of Grampositive infections (1-3), including those caused by methicillinresistant Staphylococcus aureus (MRSA) (4). In two recent phase 3 studies, tedizolid (200 mg once daily for 6 days) demonstrated noninferior efficacy to linezolid (600 mg twice daily for 10 days) in the treatment of acute bacterial skin and skin structure infections (ABSSSI), along with a more favorable hematologic and gastrointestinal tolerability profile than linezolid (1, 2).The pharmacokinetics (PK) of tedizolid, studied extensively using noncompartmental analysis, were similar after administration of two solid forms of the prodrug, tedizolid phosphate and tedizolid phosphate disodium (an alternative prodrug used in tedizolid's early clinical development). The absolute bioavailability of tedizolid is high (Ͼ80%), peak plasma concentrations are achieved within approximately 3 h of oral dosing, and steady-state plasma concentrations are reached within 3 days of initiating once-dail...

Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono-or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/ MIC ratio was also borderline predictive of microbiological response (P ‫؍‬ 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.Evaluating exposure-response relationships by use of clinical trial data is an essential component of optimizing antimicrobial treatment, yet it is often quite challenging. A single dosing regimen is often used, thus limiting the range of observed drug exposure, and it is difficult to collect on an individual-patient basis the three integral pieces of information required to perform such analyses: pharmacokinetic (PK), clinical, and microbiological outcome data. The value of such analyses, however, has become increasingly important in quantifying drug efficacy and in contributing to the establishment of appropriate in vitro MIC susceptibility breakpoints by regulatory and clinical agencies (e.g., the Clinical and Laboratory Standards Institute [CLSI] and the European Committee on Antimicrobial Susceptibility Testing [EUCAST]) (5). Utilizing results from PKpharmacodynamic (PK-PD) analyses may allow a better understanding of the causes of variability in responses among subgroup...

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