Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease.
The current data demonstrated that the antimicrobial susceptibility of C. trachomatis was influenced by both the serovar type and the duration of exposure to antibiotics in infected cultures.
Conformational study of methylated derivatives of macrolide antibiotics roxithromycin (6-OMe-roxithromycin and 6,11-OMe-roxithromycin) has been achieved by NMR in solution and molecular dynamics (MD) simulations and compared to 6-OMe-erythromycin (clarithromycin). A complete conformational study by NMR has been led by determination of homonuclear coupling constants and NOEs. Heteronuclear 1H-13C coupling constants were also measured to investigate the orientation of the sugar moieties with respect to the erythronolide. MD simulations were performed using the crystallographic coordinates as the starting conformation. For each compound, experimental results were compared to calculated conformations in order to identify eventual conformational equilibrium in solution. It is shown that the effect of the methylation is opposite for roxithromycin compared to erythromycin especially on motional properties as the roxithromycin derivatives gain in mobility while the erythromycin derivatives behaves as a more restrained molecule. The study of macrolide-ribosome interactions has been investigated using transferred NOESY 1H NMR experiments and the conformations weakly bound to bacterial ribosomes were determined. Biological interactions of these compounds with membranar liver protein cytochrome P450 was also discussed with regard to their structural properties.
The in vitro activity of ampicillin, amoxicillin/clavulanate, cefadroxil, cefaclor, cefuroxime (axetil), co-trimoxazole, doxycycline, ciprofloxacin, ofloxacin, erythromycin, and roxithromycin was tested against unselected isolates of S. pneumoniae (70), H. influenzae (93), and M. catarrhalis (46), cultured from clinically significant sputum samples of general practice patients. All isolates of S. pneumoniae were highly susceptible to ampicillin; cefadroxil and cefaclor were markedly less active on a weight basis; resistance was only observed with co-trimoxazole (4.3%), doxycycline (5.7%), and erythromycin (2.9%); however, ciprofloxacin and ofloxacin showed median MICs (MIC50), that were only one dilution below breakpoint. Beta-lactamase was detected in 14.0% of H. influenzae isolates; all isolates were susceptible to amoxicillin/clavulanate, cefaclor, and cefuroxime (axetil), although MICs were generally higher for cefaclor; the highest activity was exhibited by ciprofloxacin and ofloxacin; apart from cefadroxil, erythromycin, and roxithromycin, that showed only marginal activity, resistance was observed with co-trimoxazole (4.3%) and doxycycline (1.1%). All (including 71.7% of beta-lactamase producing) isolates of M. catarrhalis were susceptible to amoxicillin/clavulanate, cefaclor and cefuroxime (axetil), although MICs were markedly lower for amoxicillin/clavulanate; ciprofloxacin and ofloxacin showed the lowest MICs; resistance was only observed with cefadroxil (2.2%). In conclusion, the antimicrobial agents showing the most uniformly high in vitro activity against the 3 common community respiratory pathogens tested in the present study, were amoxicillin/clavulanate and, to a lesser extent, cefuroxime (axetil).
Most macrolides penetrate and persist in peripheral tissues, irrespective of plasma concentrations. For this reason, comparative pharmacodynamics of macrolides might be better based on tissue rather than plasma pharmacokinetics. The present study compares the antimicrobial effects of azithromycin and roxithromycin on Streptococcus pyogenes and Streptococcus pneumoniae using in vitro simulations of steady-state pharmacokinetics in human tonsils expected after a third 500 mg dose of azithromycin administered once a day and after a sixth 150 mg dose of roxithromycin administered twice a day. Clinical isolates of S. pyogenes and S. pneumoniae (MICs 0.12 and 0.47 mg/L of azithromycin, and 0.15 and 0.60 mg/L of roxithromycin, respectively) were used. More pronounced antistreptococcal effects were observed with azithromycin than with roxithromycin. Despite similar rates of initial killing of S. pyogenes and S. pneumoniae, the respective 12 h areas between the control growth curve and the time-kill curve of antibiotic-exposed bacteria (ABBCs) were 22% and 36% greater with azithromycin than roxithromycin. Moreover, with azithromycin, viable bacterial counts reached the theoretically achievable limit of detection (10 cfu/mL) 8-10 h after drug administration, with no regrowth within 48 h. In contrast to azithromycin, S. pyogenes and S. pneumoniae exposed to roxithromycin regrew 26 and 6 h, respectively, after initial reduction of the starting inoculum. Further in vitro simulations of tissue pharmacokinetics might be useful for pharmacodynamic comparisons among other macrolides.
This study performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause.