Levofloxacin versus cefuroxime axetil in the treatment of acute exacerbation of chronic bronchitis: results of a randomized, double-blind study.
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A randomized, double-blind, double-dummy, three-arm parallel design, multicentre study was conducted among adult patients with acute exacerbation of chronic bronchitis (AECB) in order to compare the efficacy and safety of two different doses of levofloxacin with cefuroxime axetil. A total of 832 patients were randomized to receive oral levofloxacin (250 mg od or 500 mg od) or oral cefuroxime axetil (250 mg bd) for 7-10 days. The primary efficacy analysis was based on the clinical response in patients with bacteriologically confirmed AECB, determined 5-14 days after the end of therapy (per-protocol population). Of 839 patients enrolled (at 71 centres in 14 countries), seven were not treated, giving an intention-to-treat (ITT) population of 832. In total, 281 patients received levofloxacin 250 mg, 280 received levofloxacin 500 mg and 271 received cefuroxime axetil. The cure rates in the ITT population were: levofloxacin 250 mg, 70% (196/281); levofloxacin 500 mg, 70% (195/280); cefuroxime axetil, 61% (166/271); those in the per-protocol population were: 78% (121/156), 79% (108/137) and 66% (88/134), respectively. Both doses of levofloxacin were at least as effective as cefuroxime axetil and were active against the main pathogens of clinical relevance (Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis). All three treatment regimens were equally well tolerated. In conclusion, the results show that levofloxacin (250 mg and 500 mg) od is effective and well tolerated in the treatment of AECB in adult patients. (+info)
Anti-pneumococcal activity of gatifloxacin compared with other quinolone and non-quinolone agents.
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An agar dilution MIC method was used to test the activity of gatifloxacin, a new broad-spectrum fluoroquinolone, compared with ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, amoxycillin, cefuroxime, ceftriaxone and clarithromycin against 71 penicillin-susceptible, 81 penicillin-intermediate and 55 penicillin-resistant pneumococci. Quinolone activity was unaffected by penicillin susceptibility, with MIC50/MIC90s (mg/L) of 0.25/0.5 for gatifloxacin; 1/2 for ciprofloxacin; 1/2 for levofloxacin; 0.25/0.5 for sparfloxacin; 0.125/0.25 for trovafloxacin. beta-Lactam and clarithromycin MICs rose with those of penicillin G; MIC50/MIC90 values (mg/L) for penicillin-susceptible, -intermediate and -resistant strains were: 0.03/0.06, 0.25/1, 2/4 for penicillin G; 0.03/0.03, 0.125/1, 2/4 for amoxycillin; 0.03/0.125, 0.5/4, 8/16 for cefuroxime; 0.03/0.03, 0.25/0.5, 2/4 for ceftriaxone; 0.03/0.06, 0.03/>64, 1/>64 for clarithromycin. Time-kill testing of four penicillin-susceptible, four -intermediate and four -resistant strains showed that levofloxacin at the MIC, gatifloxacin and sparfloxacin at 2 x MIC, and trovafloxacin and ciprofloxacin at 4 x MIC, were bactericidal (99.9% killing) for all strains after 12 h and 24 h. By contrast, amoxycillin, cefuroxime and ceftriaxone showed bactericidal activity after 24 h against all strains at 4, 8 and 4 x MIC, respectively. Against ten organisms with clarithromycin MICs of 0.03-4.0 mg/L, clarithromycin was bactericidal against seven strains at 8 x MIC after 24 h. Quinolones showed more rapid killing at lower concentrations and earlier time periods than did beta-lactams and clarithromycin. (+info)
Mutations in the active site of penicillin-binding protein PBP2x from Streptococcus pneumoniae. Role in the specificity for beta-lactam antibiotics.
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Penicillin-binding protein 2x (PBP2x) isolated from clinical beta-lactam-resistant strains of Streptococcus pneumoniae (R-PBP2x) have a reduced affinity for beta-lactam antibiotics. Their transpeptidase domain carries numerous substitutions compared with homologous sequences from beta-lactam-sensitive streptococci (S-PBP2x). Comparison of R-PBP2x sequences suggested that the mutation Gln552 --> Glu is important for resistance development. Mutants selected in the laboratory with cephalosporins frequently contain a mutation Thr550 --> Ala. The high resolution structure of a complex between S-PBP2x* and cefuroxime revealed that Gln552 and Thr550, which belong to strand beta3, are in direct contact with the cephalosporin. We have studied the effect of alterations at positions 552 and 550 in soluble S-PBP2x (S-PBP2x*) expressed in Escherichia coli. Mutation Q552E lowered the acylation efficiency for both penicillin G and cefotaxime when compared with S-PBP2x*. We propose that the introduction of a negative charge in strand beta3 conflicts with the negative charge of the beta-lactam. Mutation T550A lowered the acylation efficiency of the protein for cefotaxime but not for penicillin G. The in vitro data presented here are in agreement with the distinct resistance profiles mediated by these mutations in vivo and underline their role as powerful resistance determinants. (+info)
Clinical effectiveness of levofloxacin in patients with acute purulent exacerbations of chronic bronchitis: the relationship with in-vitro activity.
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The objective of this randomized, double-blind study was to compare the clinical efficacy of levofloxacin at two different dosages with that of cefuroxime axetil in patients with acute purulent exacerbations of chronic bronchitis and, in particular, to assess the impact of the susceptibility to levofloxacin on the clinical findings. In total, 124 evaluable patients were treated for 7 days with oral levofloxacin 250 mg or 500 mg od, or cefuroxime axetil 250 mg bd. Sputum cultures were monitored pre-treatment, and at 1 and 7 days after the end of treatment. The susceptibility of Streptococcus pneumoniae isolates was tested by agar dilution in Columbia blood agar and by disc diffusion, but all other isolates were tested solely by the disc diffusion method. A greater number of infections were eradicated by levofloxacin than by cefuroxime axetil: infections were eradicated in 68% of patients receiving the 500 mg dosage and in 63% of those taking 250 mg levofloxacin, whereas the eradication rate with the comparator drug was much lower (48%). Against all pre-treatment S. pneumoniae isolates (n = 39), the MICs of levofloxacin were between 0.25 and 2 mg/L (geometric mean 0.95 mg/L), similar to those of the post-treatment strains (n = 32; mean 1.11 mg/L). All except one of the S. pneumoniae isolates were susceptible to penicillin G (MIC < or = 0.06 mg/L), and the remaining isolate was inhibited by 0.5 mg/L of penicillin G, but was fully susceptible to levofloxacin. Some pretreatment strains of Pseudomonas aeruginosa were resistant to levofloxacin, but many more resistant strains were encountered afterwards. All strains of Moraxella catarrhalis and Haemophilus influenzae were highly susceptible to levofloxacin in the disc diffusion tests. All the antimicrobial agents used in the study were well tolerated: only two patients discontinued treatment because of adverse drug effects. The results of this study indicated that, although there were some failures in patients with S. pneumoniae and P. aeruginosa infections, resistance to levofloxacin did not emerge rapidly among strains of S. pneumoniae during therapy with levofloxacin, and that natural resistance among pneumococci, H. influenzae and M. catarrhalis was rare. (+info)
Antimicrobial treatment of an experimental otitis media caused by a beta-lactamase positive isolate of Haemophilus influenzae.
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A gerbil model of otitis media induced by a beta-lactamase producing and non-serotypeable isolate of Haemophilus influenzae was used to assess the in-vivo efficacy of co-amoxiclav and cefuroxime at low (5 mg/kg) and high (20 mg/kg) doses. The MIC of the antibiotics tested against the pathogen was 1 mg/L (1/0.5 mg/L for co-amoxiclav). The organism was inoculated (+/-10(6) cfu) by transbullar challenge directly in the middle ear and antibiotic treatment was commenced 2 h post-inoculation and continued at 8 h intervals for three doses. Only high dose co-amoxiclav significantly reduced the number of culture-positive specimens as compared with untreated animals or with other treatment groups (91.7% as compared with 36.7% for high dose cefuroxime). The results obtained in any treatment group were related to middle ear antibiotic level/MIC. Antibiotic concentrations in the middle ear 90 min after administration were about 10% of serum levels at 15 min, probably related to a slight inflammatory response. Only after high dose co-amoxiclav did the concentration in the middle ear exceed the MIC by a factor of four. In otitis media with effusion, if indicated, antibiotics active in vitro should be administered in high doses and, to avoid side effects, probably in short courses. (+info)
Risk factors for treatment outcome of suspected microbial keratitis. Ofloxacin Study Group.
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BACKGROUND: Primary treatment for suspected microbial keratitis is generally successful. Although risks such as contact lens use are well recognised as causative factors for microbial keratitis, little is known about the risk factors that influence treatment outcome. The present study evaluates the risk factors assessed at diagnosis as prognostic indicators of primary treatment failure. METHODS: Patients were prospectively enrolled in the ofloxacin treatment trial and data concerning symptoms, treatments, past and concurrent eye disease were collected along with the measurement of corneal ulcer size at the slit lamp. All patients were scraped for microbiological investigation, and treated with either ofloxacin (0. 3%) or standard therapy of fortified cefuroxime and gentamicin drops. Treatment success was complete healing of the ulcer with zero dimensions of the epithelial defect within 2 weeks of start of treatment. The important prognostic indicators were selected by comparison among those who failed treatment, had delayed healing, or were culture positive with other patients using univariate and stratified analysis. These were then used in a Poisson model for multiple regression analysis to estimate the relative risk of the main prognostic variables. RESULTS: Of the 118 patients enrolled in the study, 14 were identified as primary treatment failures, 17 had slow healing, and 15 indolent ulcers. There were 49 culture positive patients. The multivariate analysis identified that large culture positive ulcers in patients 60 years or older had 5.5 times the risk of primary treatment failure (p<0.001). Significant predictors of slow healing were previous ocular disease and a positive culture; significant predictors of indolent ulceration were previous ocular disease and steroid use at diagnosis; the main predictor of a culture positive result was ulcer size. CONCLUSIONS: Elderly patients with large ulcers were more likely to be culture positive, fail primary therapy, and require surgical intervention. A positive microbial culture provided prognostic information regardless of the organism isolated. However, this information was of less value for those with small ulcers and for younger patients. (+info)
Treatment of community-acquired pneumonia in outpatients: randomized study of clarithromycin alone versus clarithromycin and cefuroxime.
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OBJECTIVE: To evaluate the efficacy of clarithromycin alone in comparison with the combination of clarithromycin and cefuroxime in the treatment of nonhospitalized patients with community-acquired pneumonia (CAP) in a Mediterranean population. METHODS: CAP was defined as the acute onset of fever (>38 degrees C) with pulmonary opacity on chest roentgenogram. The American Thoracic Society (ATS) criteria (1993) were used to decide on patient hospitalization. Ninety subjects, of whom 53 (59%) were men, with a mean age (+/-SD) of 38+/-15 years, were randomized: 45 received clarithromycin 500 mg b.i.d. orally for 14 days (CL group), and 45 received clarithromycin plus cefuroxime 500 mg b.i.d. orally for 7 days (CLCE group). Patients were monitored with clinical, radiological, and laboratory controls at 3 and 21 days. There were no significant differences between the two groups with regard to demographic, clinical, physical and laboratory data. RESULTS: The mean time to defervescence was 2.4+/-1.4 and 2.4+/-1.5 days, respectively. Chest roentgenogram clearance was complete in all cases, without statistically significant differences in the time to resolution between both arms. Side effects were mild (no significant differences between groups): 5 patients in the CL group and 3 in the CLCE group showed gastrointestinal symptoms. Two patients (2.2%), both in the CLCE group, needed hospital admission during follow-up, but all 90 patients showed an excellent outcome. A causative agent was determined in 25 cases (28%). Legionella pneumophila, Streptococcus pneumoniae, and Mycoplasma pneumoniae were the most frequent pathogens. CONCLUSION: Empirical treatment of outpatient CAP with clarithromycin can be considered adequate in the Mediterranean area, independently of the microbiological etiology. ATS criteria for admitting patients with CAP are appropriate in this population. (+info)
Predicting susceptibility of Streptococcus pneumoniae to ceftriaxone and cefotaxime by cefuroxime and ceftizoxime disk diffusion testing.
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In this study, disk diffusion testing with ceftizoxime and cefuroxime was evaluated for use in predicting the susceptibility of Streptococcus pneumoniae to ceftriaxone and cefotaxime. Of the 194 isolates included in this study, 138 were susceptible, 34 were intermediate, and 22 were resistant to cefotaxime by MIC testing; 138 isolates were susceptible, 35 were intermediate, and 21 were resistant to ceftriaxone by MIC testing. A zone of inhibition around the cefuroxime disk of >/=32 mm correctly categorized 101 of 138 isolates as susceptible to cefotaxime and ceftriaxone. A zone of inhibition around the ceftizoxime disk of >/=26 mm correctly categorized 111 of 138 isolates as susceptible to cefotaxime and 114 of 138 as susceptible to ceftriaxone. We conclude that disk diffusion can separate S. pneumoniae isolates susceptible to ceftriaxone and cefotaxime from those that are not susceptible. Isolates not falling into the susceptible category by disk diffusion require additional testing to determine the MIC. (+info)