This is the first prospective clinical trial in which patients with acute bacterial exacerbation of chronic bronchitis have been stratified by degree of underlying illness.Uncomplicated patients were randomised to levofloxacin 750 mg once daily (q.d.) for 3 days or azithromycin q.d. for 5 days. Complicated patients were randomised to levofloxacin 750 mg q.d. for 5 days or amoxicillin 875 mg/clavulanate 125 mg twice daily for 10 days.Regardless of therapy, complicated patients demonstrated lower clinical and microbiological success than uncomplicated patients. Clinical success for clinically evaluable patients was similar for levofloxacin and azithromycin (93.0 versus 90.1%, respectively), and levofloxacin and amoxicillin/clavulanate (79.2 versus 81.7%, respectively). For microbiologically evaluable patients, clinical response to levofloxacin for 3 days was superior to azithromycin for 5 days (96.3 versus 87.4%, respectively), and levofloxacin for 5 days was similar to amoxicillin/ clavulanate for 10 days (81.4 versus 80.9%, respectively). Microbiological eradication was superior for levofloxacin for 3 days compared with azithromycin for 5 days (93.8 versus 82.8%, respectively), and similar for levofloxacin and amoxicillin/clavulanate for 10 days (81.4 versus 79.8%, respectively).In conclusion, levofloxacin 750 mg for 3 days was comparable to azithromycin for 5 days for uncomplicated patients with acute bacterial exacerbation of chronic bronchitis, while 5 days of 750 mg levofloxacin was comparable to 10 days of amoxicillin/clavulanate for complicated acute bacterial exacerbation of chronic bronchitis.
The use of antibiotics, particularly cephalosporins and TMP/SMX, is a significant risk factor for asymptomatic carriage of C. difficile in long-term care facilities. The use of H-2 blockers was also a significant risk factor for carriage; however, this finding has not been reported previously and should be confirmed by independent studies. These medications should be used judiciously in the LTCF population. When diarrheal diseases are encountered in LTCF residents, a high index of suspicion for C. difficile infection should be maintained and the appropriate diagnostic and therapeutic measures taken.
An in-vitro pharmacodynamic system was used to generate time-kill curves to demonstrate the concentration-independent pharmacodynamics of vancomycin against Staphylococcus aureus ATCC 29213. Initial vancomycin concentrations of 5, 10, 20 and 40 mg/L were studied monoexponentially while simulating a 6 h half-life. One parallel experiment was performed in duplicate using an initial peak concentration of 40 mg/L where both a distribution alpha-phase half-life of 0.66 h for 1 h and an elimination beta-phase half-life of 6 h for 11 h were simulated to determine if the transient distribution phase concentrations of vancomycin have any impact on bacterial killing beyond that provided by the elimination phase concentrations. Additionally, two monoexponential experiments with peak concentrations of 40 and 20 mg/L and a half-life of 6 h were repeated in an anaerobic chamber to determine if killing of S. aureus was affected. The time to achieve a 3 log10 kill was calculated from the linear portion of the regression line and averaged (mean +/- S.D.) 9.0 +/- 1.4 h for all aerobic monoexponential experiments and was 8.4 and 8.6 h for the aerobic biexponential experiments (P > 0.05). For the anaerobic studies, the times to reach 3 log10 kill were significantly greater averaging 18.9 +/- 1.7 h. The slopes of the bacterial kill curves were virtually identical for both monoexponential and biexponential aerobic experiments averaging -0.34 +/- 0.04, yet significantly different from the anaerobic bacterial kill curve slopes of -0.16 +/- 0.015 (P < 0.05). Time-kill curve analyses suggest that varying the concentration of vancomycin does not affect the rate or extent of bacterial killing aerobically or anaerobically against S. aureus and more efficient killing was achieved under aerobic conditions. The simulated distribution phase concentrations did not contribute to more effective killing of this strain of S. aureus.
A previously established in vitro pharmacodynamic system was used to evaluate the antistaphylococcal activities of five fluoroquinolones under both aerobic and anaerobic conditions. Staphylococcus aureus ATCC 29213 was exposed to a 5-g/ml concentration of each of the following fluoroquinolones: ciprofloxacin, ofloxacin, temafloxacin, sparfloxacin, and clinafloxacin. Terminal elimination half-lives of 4, 6, 8, 8, and 13 h were simulated for the respective drugs. Each fluoroquinolone was bactericidal under both aerobic and anaerobic conditions. However, the bactericidal activity of each fluoroquinolone was delayed by anaerobiosis. This difference in fluoroquinolone activity under aerobic and anaerobic conditions could not be attributed to any particular parameter or physiochemical property but was most likely caused by a combination of factors (e.g., variations in hydrophobicity, intracellular pH, antibiotic concentration, and structure-activity relationships). Fluoroquinolone uptake studies were also performed to investigate the possibility of active, energydependent transport mechanisms in S. aureus ATCC 29213. Uptake studies indicated that active efflux does occur in S. aureus ATCC 29213.The antistaphylococcal activity of fluoroquinolones under aerobic conditions has been well established through numerous studies (13,24). However, the antistaphylococcal activity of these antimicrobial agents under anaerobic conditions has not been well studied. As staphylococci are facultative by nature, there is a distinct likelihood that some clinical infections involving these organisms occur in an anaerobic or microaerophilic environment. Hence, there exists a need to evaluate the antistaphylococcal performance of fluoroquinolones under both aerobic and anaerobic conditions. Morrissey and Smith have proposed that fluoroquinolone uptake by Staphylococcus aureus is oxygen dependent (14, 17). Further, Mitsuyama et al. have demonstrated that fluoroquinolone uptake by porin-deficient bacteria is at least partially dependent upon hydrophobicity (16). The purpose of this investigation was to evaluate the antistaphylococcal activities of five fluoroquinolones with various degrees of hydrophobicity under both aerobic and anaerobic conditions.(This report was presented as an abstract at the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim, Calif. [abstract 43].) MATERIALS AND METHODSIn vitro pharmacodynamic system. The pharmacodynamic model used in this investigation represents a modified version of that previously described by Garrison et al. (8) and has been previously described by Zabinski et al. (26). This system consisted of a 1,000-ml glass vessel with inflow and outflow ports, connective silicone tubing (Masterflex L/S thin-wall tubing; Cole-Parmer, Chicago, Ill.), a Masterflex peristaltic pump (Cole-Parmer), a fresh-medium reservoir, a stir-hot plate (Nuovo II; Barnstead/Thermolyne Corp., Dubuque, Iowa), a magnetic stir bar, and a thermometer.A 1-ml volume of a quinolone-containing solution was ...
An in vitro pharmacodynamic system has been successfuly adapted to simulate in vivo antimicrobial pharmacokinetics under anaerobic conditions. This system was used to perform time-kill kinetic studies which were designed to compare the activity of temafloxacin to ciprofloxacin and cefotetan against two strains of Bacteroides fragilis (ATCC 25285 and ATCC 23745 fragilis. Ciprofloxacin was not bactericidal (<3 log10 unit decline in bacterial numbers) to either strain of B.fragilis. Cefotetan was bactericidal (.3 log1o unit decline in bacterial numbers) to each strain but killed at a slower rate than temafloxacin. Times to 3 loglo unit declines of strain ATCC 25285 were 2, 4, and >24 h, whereas those of strain ATCC 23745 were 4, 4, and >24 h for temafloxacin, cefotetan, and ciprofloxacin, respectively. Total logarithmic declines of strain ATCC 25285 were >4.5, >4.5, and 2.9 log1o CFU/ml, whereas those of strain ATCC 23745 were 4.1, >4.5, and 1.2 log1o CFU/ml for each drug, respectively. These and other studies demonstrated that temafloxacin showed potential as an agent that could have been further developed for use in the treatment of anaerobic infections. However, the drug was removed from the market by its manufacturer because of toxicity issues. Although the release of newer fluoroquinolones that possess significant activity against anaerobic bacteria does not appear imminent, the time-kill studies performed in this study demonstrate that further research is warranted in the development of fluoroquinolones which possess significant antianaerobic activity.Bacteroides fragilis is an important human pathogen in intra-abdominal and gynecologic infections. Antimicrobial regimens for infections that involve B. fragilis have generally been limited to certain ,B-lactams, clindamycin, chloramphenicol, or metronidazole. The prevalence of severe adverse reactions to chloramphenicol and the development of significant resistance among B. fragilis strains to clindamycin have driven the search for safe and effective therapeutic alternatives. All of the currently available fluoroquinolones possess excellent activity against aerobic and facultative gram-negative bacteria. Temafloxacin, however, has been shown to have significant in vitro activity against anaerobic bacteria while retaining excellent activity against most members of the Enterobacteriaceae (6,9,17). The in vitro evaluation of the activity of the fluoroquinolones against anaerobic bacteria has been based on standardized MIC testing. MIC testing methods possess some inherent restrictions that limit the researcher's ability to optimally evaluate the activity of a drug in vitro.The purpose of this study was to use an in vitro pharmacodynamic system to evaluate the activity of temafloxacin, ciprofloxacin, and cefotetan against two strains of B. fragilis. Through time-kill curve analysis, this system can exploit the pharmacokinetic and pharmacodynamic differences between drugs and thereby evaluate their relative in vitro efficacies.
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