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.

Simulation of antibiotic pharmacodynamic exposure for the empiric treatment of nosocomial bloodstream infections: a report from the OPTAMA program.

Objective: We developed a model to predict the pharmacodynamic exposure of antibiotics against bacteria commonly implicated in nosocomial bloodstream infections to determine which dosage regimens would provide the greatest likelihood of obtaining a bactericidal effect.

Methods: Pharmacodynamic exposures were simulated for 5000 subjects receiving standard doses of ceftazidime, cefepime, piperacillin/tazobactam, meropenem, imipenem, or ciprofloxacin. Exposures were indexed to the MICs of bacteria weighted by their prevalence in causing nosocomial bloodstream infections, derived from 2002 SENTRY data.

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.

Defining the need for new antimicrobials: clinical and economic implications of resistance in the hospitalised patient.

Resistance among pathogens causing the most common infections encountered in hospitalised patients is increasing. Due to this resistance, the clinical efficacy of current antimicrobial agents is decreasing against many pathogens, including Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Pseudomonas aeruginosa, extended-spectrum beta-lactamases, and AmpC beta-lactamase-producing organisms. Studies assessing the impact of these resistance mechanisms on clinical outcomes have been performed; however, studies determining the economic impact of resistance have been limited.

Pharmacodynamic profile of ertapenem against Klebsiella pneumoniae and Escherichia coli in a murine thigh model.

The pharmacodynamic profile of ertapenem was evaluated in a neutropenic mouse thigh infection model. Extended-spectrum beta-lactamase (ESBL)-positive and ESBL-negative clinical strains of Escherichia coli and Klebsiella pneumoniae were studied. MICs ranged from 0.

Differential efficacy of clarithromycin in lung versus thigh infection models.

Background: Differences in clarithromycin disposition and the resulting changes in bacterial density were studied using mouse lung and thigh infection models.

Methods: Clarithromycin activity was evaluated against seven Streptococcus pneumoniae isolates with efflux-mediated resistance in both murine lung and thigh infection models. Intrapulmonary disposition of clarithromycin was also studied.

Determination of the in vivo pharmacodynamic profile of cefepime against extended-spectrum-beta-lactamase-producing Escherichia coli at various inocula.

Cefepime was evaluated in vivo against two inoculum sizes of four strains of Escherichia coli that produced extended-spectrum beta-lactamases (ESBLs) in a murine neutropenic thigh infection model to characterize the pharmacodynamic activity of cefepime in the presence of ESBL-producing bacteria and to evaluate if differences in lengths of cefepime exposure are required with various inocula. Three strains possessed a single enzyme each: TEM-10, TEM-12, and TEM-26. The fourth strain possessed two TEM-derived ESBLs and a third uncharacterized enzyme.

Efficacy of clarithromycin against Streptococcus pneumoniae expressing mef(A)-mediated resistance.

As a result of macrolide resistance rates of 25% for pneumococci in the US, the clinical use of this class as empirical therapy has been questioned. However, macrolides continue to be used with clinical success. Using an immunocompromised murine pneumonia model, this study evaluated in vivo efficacy of human simulated exposures of clarithromycin for 62 isolates of Streptococcus pneumoniae considered resistant by current methods of breakpoint determinations.

Characterization of the penetration of garenoxacin into the breast milk of lactating women.

The primary objective of this study was to characterize the extent of excretion of garenoxacin, a novel des-F(6)-quinolone antimicrobial, into the breast milk of lactating women. A secondary objective was to determine the time after dose administration that garenoxacin was no longer detected in breast milk so as to define when a mother may resume breastfeeding if it was interrupted for garenoxacin administration. Six healthy, lactating women (age [mean +/- SD]: 32 +/- 6 years; weight: 68.

Impact of pharmacodynamics on dosing of macrolides, azalides, and ketolides.

The study of pharmacodynamics characterizes the relationship between changing drug concentrations over time and antimicrobial and toxicologic effects and thereby offers a targeted approach to the design of dosing regimens for many antimicrobials. Distinct patterns of antimicrobial dynamics have been elucidated from these relationships and pharmacodynamic parameters (peak-MIC, AUC-MIC, T > MIC) have been used to quantify antimicrobial effects in relation to drug exposure. These relationships can be used to predict efficacy of a given dosing regimen.

Bactericidal effect of cethromycin (ABT-773) in an immunocompetent murine pneumococcal pneumonia model.

The efficacy of cethromycin was assessed against isolates of Streptococcus pneumoniae in the presence of neutrophils. Comparison with data from our previous neutropenic model revealed that the presence of neutrophils enhanced the bacteriostatic and bactericidal effect of cethromycin by an average of two- to four-times, respectively.

Pharmacokinetics of meropenem 0.5 and 2 g every 8 hours as a 3-hour infusion.

Study Objective: To assess the pharmacokinetics of meropenem administered as a 3-hour infusion.

Design: Randomized, crossover, open-label study.

Setting: Clinical research center.

Production and resolution of cantharidin-induced inflammatory blisters.

While inflammatory blisters have long been utilized as a means of evaluating antimicrobial disposition to aid in the development of new treatments for skin and skin structure infections, sparse data are available regarding the healing of the blisters once the experiment has been completed. We report the blister induction technique and resolution time in ten volunteers enrolled in a pharmacokinetic study using the cantharidin-induced inflammatory blister technique.

Pharmacokinetic profile of meropenem, administered at 500 milligrams every 8 hours, in plasma and cantharidin-induced skin blister fluid.

The pharmacokinetic disposition of meropenem, administered at 500 mg every 8 h, in plasma and cantharidin-induced blister fluid is described. Peak meropenem concentrations in blister fluid lagged behind peak meropenem concentrations in plasma, while a lower elimination rate from blister fluid was also noted. The mean penetration of meropenem into blister fluid was 67%.

Economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts.

The economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts is described. The pharmacodynamics of novel meropenem dosing regimens were compared with FDA-approved regimens by using Monte Carlo simulation with 5000 subjects. Using the meropenem NCCLS-susceptibility breakpoint of 4 micrograms/mL, the percentage of the dosing interval that drug concentration remained above the minimum inhibitory concentration (%t > MIC) was calculated for each regimen.

Pleconaril, a novel antipicornaviral agent.

Despite the availability of therapy for selected symptoms, no specific antiviral agents are available to treat or prevent infections due to the viruses of the Picornaviridae family--rhinoviruses and enteroviruses. Characterization of the three-dimensional structure of picornaviruses in the 1980s allowed development of compounds targeted at the virus itself. Pleconaril is a novel, orally available, systemically acting molecule whose pharmacokinetics are characterized by a two-compartment open model with first-order absorption and with a safety profile similar to that of placebo.

Extended interval aminoglycoside dosing: from concept to clinic.

Extended-interval aminoglycoside dosing (EIAD), while a relatively recent concept in mainstream clinical practice, actually has its roots in the mid 1970s. Early trial and error approaches of manipulating the dosage regimen to avoid toxicity and improve efficacy have helped to characterize the pharmacodynamic properties of these drugs. The increasing successful use of EIAD and improved understanding of pharmacodynamics has helped this dosing regimen gain acceptance into routine clinical practice.