The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 10 8 -CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored. The bacterial density in lung tissues was examined after 24 h of CLR treatment and in control groups. Pharmacokinetic analysis of CLR in mice demonstrated that the regimen of 150 mg/kg twice a day was representative of human pharmacokinetics and was used to compare the efficacy of CLR against sensitive and resistant S. pneumoniae strains. Immunocompetent CBA/J mice were also infected and treated as described above and evaluated for bacterial density and survival to assess the effect of the presence of leukocytes. All three pharmacodynamic parameters, the duration (percent) of the time that serum CLR concentrations remain above the MIC (%T>MIC), the ratio of the area under the concentrationtime curve from 0 to 24 h (AUC 0-24 ) to the MIC, and the ratio of the maximum concentration of drug in serum to the MIC, were found to be closely correlated to CLR bacterial efficacy (P < 0.001). Furthermore, all parameters had close correlation to bacterial density (r 2 ‫؍‬ 0.72 to 0.82), median survival (r 2 ‫؍‬ 0.93 to 0.94), and total percent survival (r 2 ‫؍‬ 0.91 to 0.92). These in vivo data suggest that the bacterial activity of CLR is closely correlated with all three parameters over a wide range of exposures and, as a consequence of parameter interdependency, AUC 0-24 /MIC is the most reasonable predictor of antibiotic efficacy. In this neutropenic pneumonia model, CLR was less efficacious against S. pneumoniae strains for which MICs were >4 g/ml. However, the presence of leukocytes in the immunocompetent mice resulted in improved bactericidal activity, relative to that in the neutropenic animals, despite an MIC of 4 g/ml.

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Objective. To incorporate Bloom's taxonomy into multiple-choice examination questions in a pharmacotherapeutics course and assess its effectiveness in detecting areas of improvement in learning. Design. Bloom's taxonomy was incorporated into examination questions through a multi-step process: Sample questions representing each learning domain within Bloom's taxonomy (knowledge, comprehension, application, analysis, synthesis, and evaluation) were introduced to students during lecture presentations and discussions. Quiz and examination containing questions categorized according to Bloom's taxonomy were administered to students. During review sessions following each quiz or examination, the categorization of each question was provided to students and feedback from students was gathered. Assessment. The effect of the 5 types of test questions on the correct response fraction and discrimination index was determined after combining synthesis and evaluation. Correct response fractions for knowledge, comprehension, and application questions were significantly higher than those for analysis and synthesis/evaluation questions (p,0.05). However, discrimination index for application and synthesis/ evaluation questions were significantly higher than those for knowledge and comprehension questions (p,0.05). In interviews with students who had requested learning assistance, the majority realized the importance of critical-thinking skills in the learning process. Conclusion. Well-designed multiple-choice questions incorporating different learning domains of Bloom's taxonomy may be a potential method of assessing critical-thinking skills in large classes of students.

The objective of this study was to determine the susceptibility breakpoint of a new carbapenem, ertapenem (MK-0826), against Streptococcus pneumoniae strains based on bacterial density and survival studies in a murine thigh infection model. Sixteen S. pneumoniae isolates for which MICs ranged from 0.015 to 4.0 mg/liter were tested with neutropenic ICR mice. Animals were infected with bacteria at 10 5 to 10 6 CFU per thigh and were treated with ertapenem starting at 2 h postinfection for 4 days. Ertapenem was given subcutaneously at 50 mg/kg of body weight every 6 h, which simulates the human pharmacodynamic profile (in particular, the duration of time that the concentration of free drug remains above the MIC of 2 mg/liter). At 0 and 24 h postinfection, thighs were harvested for bacterial density determination. Survival was assessed during 4 days of therapy and 3 days after the therapy. A protein binding study was conducted with mice by use of the ultrafiltration method. Protein binding in mice was approximately 95%, which is comparable to that in humans. The average change in bacterial density ranged from ؊0.22 to ؊4.4 log CFU per thigh over 24 h compared to 0-h controls. The extent of microbial eradication was dependent on the MIC for the S. pneumoniae isolate. Substantial bactericidal activities (i.e., killing of approximately 2 log CFU per thigh) were consistently observed against isolates for which MICs were <2 mg/liter, which also resulted in nearly 100% survival during the 4 days of drug dosing and 3 days after the therapy. Less-pronounced and highly variable bactericidal activities were detected against isolates for which the MIC was 4 mg/liter. Substantial enhancement in bactericidal activity was observed for CBA/J mice and is attributed to the contribution of the host defenses in the immunocompetent species. Assessment of the effectiveness of ertapenem by bacterial-density reduction over 24 h and by survival over 4 days of therapy in the murine thigh infection model reveals that the drug maintains maximal efficacy against S. pneumoniae isolates for which the MIC of this agent is <2 mg/liter.Ertapenem (MK-0826) is a new, long-acting 1-␤-methyl carbapenem with potent antimicrobial activity against a variety of pathogenic species including pneumococci (4). While this agent apparently has good in vitro activity against Streptococcus pneumoniae, the pharmacodynamic assessment of the susceptibility breakpoint of ertapenem against this important pathogen has not been fully described. The availability of these data will assist not only in optimizing the effectiveness of the prescribed antimicrobial regimen in clinical practice but also in the assessment of appropriate National Committee for Clinical Laboratory Standards (NCCLS) breakpoints for this antimicrobial agent.The purpose of the present study was to determine the susceptibility breakpoint of ertapenem against S. pneumoniae strains based on bacterial density and survival studies using a murine model of pneumococcal thigh infection. MATERIALS AND METHODSA...

Ketolides are a new chemical subclass of 14-member-ring macrolides with a 3-keto functional group, which is semisynthesized by oxidation of the 3-OH group. Through this chemical structure transformation, ketolides achieve a high degree of stability in acidic environments and potent in vitro bactericidal effects against gram-positive cocci, including macrolidesusceptible and -resistant Streptococcus pneumoniae (2). Recently, interest in ketolides has been prompted by the rising incidence of macrolide-resistant S. pneumoniae, which is estimated to be 15 to 20% (5, 13). The mechanism of resistance to macrolides is mainly due to expression of the mef(A) and/or erm(B) genes (12). , abstr. 2161, 2000). However, the in vivo bactericidal effect has not been established in the pneumonia model. Moreover, the pharmacodynamics (PD) of cethromycin in the pneumonia model has not been studied. Before an optimal pneumonia dose regimen for cethromycin can be established, it is of critical importance to determine the optimal PD profile for the maximization of antibiotic efficacy in such a model.The first objective of this study is to investigate the in vivo bactericidal activity of cethromycin against macrolide-susceptible and -resistant S. pneumoniae. The second objective is to describe the pharmacokinetic (PK) and PD profiles of cethromycin against macrolide-susceptible and -resistant S. pneumoniae in a murine pneumonia model. MATERIALS AND METHODSAntibiotics and microorganisms. Laboratory standard powders of cethromycin (Abbott Laboratories, Chicago, Ill.), azithromycin (Pfizer, Groton, Conn.), and clindamycin (Sigma Chemical Co., St. Louis, Mo.) were used for all in vitro and in vivo testing.Eight clinical isolates of S. pneumoniae were utilized for all in vitro and in vivo experiments.Clinical isolates included two macrolide-susceptible isolates, four mef(A) isolates, one mef(A) erm(B) isolate, and one erm(B) isolate (Table 1). All strains were maintained in skim milk medium (Becton Dickinson, Cockeysville, Md.) at