Pharmacodynamic profiling of modithromycin: assessment in a pneumococcal murine pneumonia model.

The pharmacodynamic profile of modithromycin (EDP-420, EP-013420, S-013420), a novel bicyclolide, was evaluated in a neutropenic pneumococcal murine pneumonia model. Streptococcus pneumoniae median minimum inhibitory concentrations (MICs) for five genotypically diverse isolates ranged from 0.016 µg/mL to 0.125 µg/mL and were unaffected by macrolide or penicillin resistance determinants. The modithromycin dosing regimens (total daily doses of 3.125-1000 mg/kg/day) were derived from the pharmacokinetic profile of the compound in infected mice and were selected to produce a wide range of exposures. Dose-response relationships characterised using the Emax model demonstrated high correlations both with the ratio of the area under the concentration-time curve to MIC (AUC/MIC) and the ratio of the maximum drug concentration to MIC (Cmax/MIC). However, dose fractionation studies suggest that the AUC/MIC is the predominant driver of in vivo efficacy. The free drug AUC/MIC (fAUC/MIC) required for stasis and for 80% of maximum activity ranged from 4 to 53 and 25-99, respectively. The fAUC/MIC needed to achieve a 1 log reduction in bacterial density, which is a conventional measure of the required exposure in man to reliably predict efficacy, ranged from 9 to 69. These data demonstrate the in vitro and in vivo potency of modithromycin against S. pneumoniae irrespective of its phenotypic profile to the macrolides or penicillin.

Pharmacokinetics of dalbavancin in plasma and skin blister fluid.

OBJECTIVES: Dalbavancin is a novel lipoglycopeptide antibiotic in development for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria. The aim of the present study was to assess the penetration of dalbavancin into skin blister fluid. METHODS: Nine healthy subjects (five males; ranging in age from 26 to 57 years) were administered a single 30 min intravenous infusion of dalbavancin at a dose of 1000 mg. Skin blisters were induced by application of cantharidin ointment. Plasma and blister fluid samples were collected over 7 days post-dose, and concentrations of dalbavancin were assessed by a validated LC/MS/MS assay. Pharmacokinetics were determined by non-compartmental methods, and drug penetration was assessed based on the ratio of area under the curve (AUC) in the blister fluid versus plasma for each subject. RESULTS: The mean (SD) peak concentration of dalbavancin in plasma and blister fluid was 285 (31.1) and 67.3 (18.2) mg/L, respectively; the corresponding AUC(Day 7) values were 10 806 (1926) and 6438 (1238) mg . h/L, respectively. The mean (SD) penetration of dalbavancin into blister fluid was 59.6% (6.3%). By Day 7, the mean concentration of dalbavancin in plasma and blister fluid was 46.5 and 30.3 mg/L, respectively. CONCLUSIONS: Dalbavancin concentrations in blister fluid remained well above the MIC90 values for pathogens commonly implicated in cSSSIs such as Staphylococcus aureus, including methicillin-resistant S. aureus (MIC90 = 0.06 mg/L) and beta-haemolytic streptococci (MIC90 = 0.03 mg/L) through Day 7. These pharmacokinetic data support the use of dalbavancin in the treatment of cSSSIs caused by susceptible Gram-positive pathogens.

Resource utilization of adults admitted to a large urban hospital with community-acquired pneumonia caused by Streptococcus pneumoniae.

OBJECTIVE: To determine if penicillin-nonsusceptible Streptococcus pneumoniae, among other variables, was significantly associated with greater hospital costs among patients with community-acquired pneumonia (CAP). DESIGN: Retrospective, cohort study. SETTING: Eight hundred ten-bed, urban, private, teaching hospital. PATIENTS: Adult patients admitted between 1999 and 2003 with CAP caused by S pneumoniae. INTERVENTION: Clinical criteria and costs (inflated to 2004 dollars) were collected from the medical charts and detailed hospital bills for each individual patient. Costs were compared according to classification by penicillin susceptibility. Multivariate linear regression was utilized to determine variables independently associated with increased hospital costs and length of stay. RESULTS: Of 168 patients included, 44 patients (26%) had CAP caused by penicillin-nonsusceptible S pneumoniae. Median total hospital costs were 8,654 dollars (25th to 75th percentile, 5,457 dollars to 16,027 dollars), with no difference between susceptible and nonsusceptible groups. Bed costs accounted for 55.6% of total costs, followed by laboratory (9.9%) and pharmacy (9.8%) costs. Regression analyses determined that ICU admission (p < 0.001), unexplained delays in discharge (p = 0.001), and neoplasm (p < 0.04) were independently predictive of both total hospital costs (adjusted r2 = 0.46) and increasing length of stay (adjusted r2 = 0.30). Hospital mortality, bacteremia, and congestive heart failure were also associated with at least one of the dependent variables. CONCLUSION: In the current era in which more potent antibiotics are empirically utilized to treat CAP, it does not appear that a simple classification of penicillin nonsusceptibility complicates the economic impact of S pneumoniae infection. Focused efforts to reduce length of stay, including minimizing prolonged and unnecessary observation of patients, should have the most profound effect on reducing total costs.

Tissue penetration of telavancin after intravenous administration in healthy subjects.

The pharmacokinetic disposition of telavancin administered 7.5 mg/kg of body weight every 24 h was determined in plasma and skin blister fluid. The mean penetration of telavancin into blister fluid was 40%. This study reveals that adequate concentrations are achieved in both plasma and blister fluid for pathogens frequently implicated in skin and soft tissue infections.

Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: a report from the OPTAMA Program.

OBJECTIVE: To compare the probability of achieving specific pharmacodynamic exposures of commonly used intravenous antibiotics for the empirical treatment of nosocomial pneumonia against those pathogens most commonly implicated in the disease. DESIGN: Ten thousand-subject Monte Carlo simulation. SETTING: Research center. SUBJECT: None. INTERVENTIONS: Pharmacodynamic analysis was conducted for the following antimicrobials at standard doses: meropenem, imipenem-cilastatin, ceftazidime, cefepime, piperacillin/tazobactam, and ciprofloxacin. Prevalence of causative pathogens was based on the 2000 SENTRY Antimicrobial Surveillance Study, and minimum inhibitory concentration (MIC) values were obtained using the 2003 US MYSTIC database. The probabilities of each drug and dosing regimen in achieving pharmacodynamic targets were calculated. Bactericidal targets were defined as 40% T>MIC for the carbapenems, 50% T>MIC for other beta-lactams, and an area under the curve (AUC)/MIC ratio of 125 for ciprofloxacin. A sensitivity analysis was performed using two alternate models to determine the impact of varying pathogen prevalence on target attainment. MEASUREMENTS AND MAIN RESULTS: Meropenem and imipenem provided high probabilities of achieving their bactericidal target of 40% T>MIC, with target attainments of 98% for all regimens. At the bactericidal end point of 50% T>MIC, cefepime 2 g every 8 hrs displayed the highest target attainment at 99.9%, followed by cefepime 2 g every 12 hrs, ceftazidime 2 g every 8 hrs, piperacillin/tazobactam 4.5 g every 6 hrs and 3.375 g every 6 hrs, cefepime 1 g every 12 hrs, and ceftazidime 1 g every 8 hrs with target attainments of 95.0%, 92.5%, 92.3%, 91.3%, 90.3%, and 67.9%, respectively. Ciprofloxacin presented the lowest probability of achieving its bactericidal target of an AUC/MIC ratio of 125, with target attainments of 54.7% and 12.0% when given as 400 mg every 8 hrs and 400 mg every 12 hrs, respectively. CONCLUSIONS: Meropenem, imipenem, cefepime, ceftazidime (2 g every 8 hrs), and piperacillin/tazobactam have high probabilities of achieving adequate pharmacodynamic exposures when given for the empirical treatment of nosocomial pneumonia in the absence of methicillin-resistant S. aureus. Ceftazidime 1g every 8 hrs and ciprofloxacin produce low target attainment rates and will not likely result in high clinical success rates when given as monotherapy.

Efficacy of pulsatile amoxicillin and clarithromycin dosing alone and in combination in a murine pneumococcal pneumonia model.

OBJECTIVES: Amoxicillin and clarithromycin have been proven to be effective in the treatment of community-acquired pneumonia. This study investigated the in vivo bactericidal efficacy of a novel, pulsatile dosing strategy for amoxicillin and clarithromycin, when used as monotherapy and combination therapy. METHODS: A neutropenic murine pneumonia model was used to assess the bactericidal activity of amoxicillin and clarithromycin, when the same total daily dose was administered as a traditional regimen (every 8 h and every 12 h, respectively) or as a pulsatile regimen (four doses of antibiotic given every 2 h over the first 6 h of the day) against three isolates of Streptococcus pneumoniae of varying resistance profiles. The three isolates consisted of SP21 (macrolide and penicillin susceptible), SP100 [mef(A) gene], and SP107 [mef(A) + erm(B) genes]. RESULTS: Pulsatile dosing showed similar reductions in bacterial density for amoxicillin and clarithromycin when either drug was given alone compared with traditional dosing regimens against all three bacterial isolates. When amoxicillin and clarithromycin were combined, improved activity was found compared with monotherapy. Overall, when comparing the different combination regimens, the pulsatile regimens provided similar activity compared with the traditional regimens. For one isolate, SP107, pulsatile amoxicillin combination regimens were less effective compared with traditionally dosed amoxicillin combination regimens. CONCLUSIONS: Pulsatile dosing resulted in comparable bactericidal activity against the three isolates tested and may represent an alternative dosing strategy, which may help to alleviate problems with patient adherence to drug therapy.

A sensitive assay of amoxicillin in mouse serum and broncho-alveolar lavage fluid by liquid-liquid extraction and reversed-phase HPLC.

A sensitive and simple high-performance liquid chromatography (HPLC) method was developed and validated for the analysis of amoxicillin in mouse serum and broncho-alveolar lavage (BAL) fluid. One hundred microlitres of sample were needed for the assay. Sample processing was carried out with liquid-liquid extraction. Cefadroxil was used as an internal standard. The chromatographic separation was achieved on a C18 reversed-phase column with a mobile phase consisting of phosphate buffer, 1-octanesulphonic acid sodium salt and acetonitrile. The detection was conducted at 210 nm. The ranges of the standard curves were 0.2-20 and 0.05-5 microg/ml for serum and BAL samples, respectively. The recoveries of amoxicillin from serum and normal saline were 87 and 88%, respectively. The coefficients of variation were 1.78-6.13% for intra-day and 0.82-6.42% for inter-day analyses. The accuracy was within 100+/-6%. This method was successfully applied to analyze amoxicillin in mouse serum and BAL samples from a pharmacokinetic study.

Pharmacokinetic profile of tigecycline in serum and skin blister fluid of healthy subjects after multiple intravenous administrations.

The pharmacokinetics of tigecycline, when given as a 100-mg loading dose followed by 50 mg every 12 h, were determined in serum and blister fluid. The peak tigecycline concentration and half-life in serum were greater than those in blister fluid. Tigecycline penetrates into blister fluid well, with a mean penetration rate of 74%.