Executive Summary: Therapeutic Monitoring of Vancomycin for Serious Methicillin- Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review of the American Society of Health- System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154898/1/phar2376.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154898/2/phar2376_am.pd

Steady-State Plasma and Bronchopulmonary Concentrations of Intravenous Levofloxacin and Azithromycin in Healthy Adults

The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (± standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 ± 4.52, 2.50 ± 0.97, and 1.24 ± 0.55 μg/ml; those for 750 mg of levofloxacin were 12.94 ± 1.21, 6.04 ± 0.39, and 1.73 ± 0.78 μg/ml; and those for azithromycin were 1.70 ± 0.74, 1.27 ± 0.47, and 2.86 ± 1.75 μg/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 ± 53.2, 18.3 ± 6.7, and 5.6 ± 3.2 μg/ml; those for 750 mg of levofloxacin were 81.7 ± 37.0, 78.2 ± 55.4, and 13.3 ± 6.5 μg/ml; and those for azithromycin were 650 ± 259, 669 ± 311, and 734 ± 770 μg/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections

Levofloxacin plus Metronidazole Administered Once Daily versus Moxifloxacin Monotherapy against a Mixed Infection of Escherichia coli and Bacteroides fragilis in an In Vitro Pharmacodynamic Model

Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre- and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8- to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B. fragilis infection. A once-daily regimen of levofloxacin plus metronidazole looks promising for the treatment of intra-abdominal infections

The practice of once-daily aminoglycoside dosing in Canada: A national survey

AbstractThe impetus to adopt the use of once-daily aminoglycoside (ODA) therapy has been growing. Controversy however, regarding the exact role of ODA therapy continues to persist. A survey of Canadian hospitals was undertaken to identify perceptions and practice regarding ODA therapy. Information regarding hospital demographics and the institutional practice of dosing and monitoring traditional intermittent aminoglycoside and ODA therapy was obtained. Of 134 hospitals evaluated, 103 (77%) reported using ODA therapy. Primary applications of ODA therapy included urinary tract infection (84%), intra-abdominal infections (79%), pneumonia (78%), sepsis (75%) and bacteremia (69%). Contraindications for ODA therapy included pregnancy (82.7%), renal impairment (71%), dialysis (56%) and ascites (54%). Wide differences in the daily dosage and monitoring of ODA therapy were noted. Clinical judgement (48.9%) was often used to determine whether aminoglycoside serum concentrations were required for ODA therapy. Extension of the dosing interval was the most common (65%) method of adjusting ODA therapy. The use of ODA therapy in Canada appears widespread. Differences in the daily dosing, monitoring and indications for ODA therapy were noted suggesting that the optimal use of ODA therapy may require further refinement.RésuméL'engouement pour le traitement aux aminoglycosides à dos uniquotidienne (ADU) est de plus en plus grand. Cependant, la controverse entourant le rôle exact du traitement ADU persiste toujours. Un sondage a été mené auprès des hôpitaux canadiens pour connaître les habitudes de prescription et d'administration du traitement ADU. Ainsi, les renseignements sur les données démographiques de la population de patients des hôpitaux et sur les habitudes de chaque établissement en matière de posologie et de suivi du traitement intermittent classique au aminoglycosides et du traitement ADU on été recueillis. Des 134 hôpitaux sondés, 103 (77 %) ont dit recourir au traitement ADU. Le traitement ADU était principalement utilisé dans les cas d'infections des voies urinaires (84 %), d'infections intra-abdominales (79 %), de pneumonie (78 %), de septicémie (75 %) et de bactériémie (69 %). Les contreindications au traitement ADU comprenaient la grossesse (83 %), l'insuffisance rénale (71 % ), la dialyse (56 %) et l'ascite (54 %). D'importantes différences dans la posologie quotidienne et le suivi du traitement ADU ont été observées. L'opinion clinique était souvent utilisée (49 %) pour determiner si oui or non les concentrations sériques d'aminoglycosides étaient nécessaires au cours du traitement ADU. Le prolongement de l'intervalle posologique était la méthode d'ajustement du traitement ADU la plus souvent utilisée (65 %). Le recours au traitement ADU au Canada semble donc largement répandu. Les différences en termes de posologie quotidienne, de suivi et d'indication du traitement ADU ont éyé relevées et portent à croire que !'utilisation optimale du traitement ADU pourrait nécessiter d'autres mises au point

Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 μg/ml. In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r(2) values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint—h 3 concentrations of a 6-h dosing interval—between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of ≤8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of ≤16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections