Linezolid was provided for treatment of multidrug-resistant, gram-positive infections through a compassionate-use program. Patients (n=796) received 600 mg of linezolid intravenously or orally every 12 h (828 treatment courses). Bacteremia was present in 46% of infections, endocarditis was present in 10.6%, and line-related infections were present in 31.1%. Other infections included intraabdominal infections (15.1%), complicated skin and skin-structure infections (13.3%), and osteomyelitis (10.7%). Causative pathogens included vancomycin-resistant enterococci (66.3%) and methicillin-resistant staphylococci (22.1%). Clinical intent-to-treat (ITT) outcomes in the evaluable population were as follows: cure, 73.3%; failure, 6.8%; and indeterminate, 19.9%. Microbiological ITT outcomes in evaluable patients were as follows: cure, 82.4%; failure, 14.1%; and indeterminate, 3.5%. At the test of cure assessment, the clinical cure and microbiological success rates were 91.5% and 85.8%, respectively. The most common adverse events possibly related to linezolid use were gastrointestinal disturbances (9.8% of cases), thrombocytopenia (7.4% of cases), decreased hemoglobin/hematocrit levels (4.1% of cases), and cutaneous reactions (4.0% of cases). Linezolid provided high rates of clinical cure and microbiological success in this complicated patient population, with very good overall tolerance.

Higher success rates for linezolid may occur at AUC/MIC values of 80-120 for bacteraemia, LRTI and SSSI. Chance of success in bacteraemia, LRTI and SSSI also appear to be higher when concentrations remain above the MIC for the entire dosing interval.

Conf. Antimicrob. Agents Chemother., abstr. A116, 1997). Absorption of oral linezolid is rapid following administration to humans, with maximum concentrations achieved within 1 to 2 h of dosing. The average absolute bioavailability is 100%, and the drug is 31% bound to plasma protein. The volumes of distribution approximate those of total body water. Nonrenal clearance accounts for ϳ65% of total clearance. Renal clearance is low (40 ml/min), and ϳ30% of the dose is eliminated unchanged in the urine. Linezolid is metabolized by nonenzymatic chemical oxidation into two inactive metabolites and has not been found to either inhibit or induce any of the major cytochrome P450 isoforms. Linezolid is a weak, reversible, nonselective inhibitor of monoamine oxidase. Antimicrob. Agents Chemother., abstr. A51, 1998), a twocompartment nonlinear model was used to describe the pharmacokinetics of linezolid. Forty-eight adult volunteers with S. aureus nasal colonization received either 200, 400, or 600 mg of oral linezolid (16 subjects per dose) every 12 h for either 3 or 5 days. The concentrations of linezolid in plasma were shown to increase nonlinearly with increasing doses. Linezolid clearance was modeled as two parallel processes: a first-order renal clearance and a capacity-limited nonrenal process.The present study was designed to describe the pharmacokinetics of linezolid given i.v. or orally in patients treated under a compassionate-use protocol, including those patients with compromised end organ function and multiple underlying disease states and comorbid conditions.

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.

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...

The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared to that of the immediate-release (IR) product in healthy volunteers. The only significant difference in pharmacokinetic parameters between the two formulations was seen in the rate constant of absorption, which was approximately 50% greater with the IR formulation. The geometric mean plasma ciprofloxacin concentrations were applied to an in vitro pharmacokinetic-pharmacodynamic model exposing three different clinical strains of Escherichia coli (MICs, 0.03, 0.5, and 2.0 mg/liter) to 24 h of simulated concentrations in plasma. A novel mathematical model was derived to describe the time course of bacterial CFU, including capacity-limited replication and first-order rate of bacterial clearance, and to model the effects of ciprofloxacin concentrations on these processes. A "mixture model" was employed which allowed as many as three bacterial subpopulations to describe the total bacterial load at any moment. Comparing the two formulations at equivalent daily doses, the rates and extents of bacterial killing were similar with the IR and XR formulations at MICs of 0.03 and 2.0 mg/liter. At an MIC of 0.5 mg/liter, however, the 1,000-mg/day XR formulation showed a moderate advantage in antibacterial effect: the area under the CFU-time curve was 45% higher for the IR regimen; the nadir log CFU and 24-h log CFU values for the IR regimen were 3.75 and 2.49, respectively; and those for XR were 4.54 and 3.13, respectively. The mathematical model explained the differences in bacterial killing rate for two regimens with identical AUC/MIC ratios.Ciprofloxacin (Cipro), the first broad-spectrum oral fluoroquinolone, was approved by the Food and Drug Administration in 1987. An intravenous formulation was approved in 1991, and an oral suspension formulation followed in 1997. Recently, an extended-release (XR) formulation of ciprofloxacin has been developed by Bayer Healthcare (Cipro XR). Pharmacokinetic studies of XR ciprofloxacin in healthy volunteers have demonstrated a significant difference in peak concentrations in plasma between the XR and immediate-release (IR) formulations: peak concentrations were 40 to 50% higher with the XR formulation, while areas under the concentrationtime curve (AUCs) were comparable to those observed with the IR formulation (H. Stass, J. Nagelschmitz, E. Brandel, et al., Abstr. Am. Fed. Med. Res. Cong., abstr. 24 and 25, 2002).The objectives of this analysis were threefold. The first objective was to characterize the pharmacokinetics of multiple oral doses of ciprofloxacin when given as an IR and an XR formulation in daily doses of either 500 mg or 1,000 mg in healthy male volunteers. The second objective was to apply the geometric mean plasma concentration profiles from the healthy-volunteer study to an in vitro pharmacokinetic-pharmacodynamic (PK-PD) model exposing three different clinical strains of Escherichia coli to 24 h of simulated concentrations in plasma. Finally, the third objective was to devel...

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Tigecycline, a first-in-class expanded glycylcycline antimicrobial agent, has demonstrated efficacy in the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal (cIAI) infections. A population pharmacokinetic (PK) model for tigecycline was developed for patients with cSSSI or cIAI enrolled in two phase 2 clinical trials, and the influence of selected demographic factors and clinical laboratory measures was investigated. Tigecycline was administered as an intravenous loading dose followed by a 0.5-or 1-h infusion every 12 h for up to 14 days. Blood samples were collected the day before or the day of hospital discharge for the determination of serum tigecycline concentrations. Patient covariates were evaluated using stepwise forward (␣ ‫؍‬ 0.05) and backward (␣ ‫؍‬ 0.001) procedures. The predictive performance of the model was assessed separately using pooled data from either two phase 3 studies for patients with cSSSI or two phase 3 studies for patients with cIAI. A two-compartment model with zero-order input and first-order elimination adequately described the steady-state tigecycline concentration-time data. Tigecycline clearance was shown to increase with increasing weight, increasing creatinine clearance, and male gender (P < 0.001). The final model provided a relatively unbiased fit to each data set. Individual predicted values of the area under the concentration-time curve from 0 to 12 h (AUC 0-12 ) were generally unbiased (median prediction error, ؊1.60% to ؊3.78%) and were similarly precise (median absolute prediction error, <4%) when compared across data sets. The population PK model provided the basis to obtain individual estimates of steady-state AUC 0-12 in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.